Substituted heterocyclic inhibitors of PTPN11

1. A compound of structural Formula I

or a salt or tautomer thereof, wherein:

a is 0 or 1;

b is 0 or 1;

R 1a is selected from the group consisting of halo, C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from the group consisting of N, C(O), 0, and S; said aryl or heteroaryl of R 1a is unsubstituted or substituted with 1 to 5 R 12 groups independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 dihydroxyalkyl, hydroxyC 1-4 alkoxy, dihydroxyC 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 13 , NR 15 C(O)OR 13 , NR 13 C(O)NR 15 R 16 , NR 15 S(O)R 13 , NR 15 S(O) 2 R 13 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 13 , C(O)OR 13 , OR 13 , SR 13 , S(O)R 13 , and S(O) 2 R 13 ;

R 1b is selected from the group consisting of cyano, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 19 , —NH—OR 19 , —O—NR 19 R 20 , —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 ) n OH, —C(O)NH(CH 2 ) n R 21 , —C(O)R 21 , —NH 2 , —OH, —S(O) 2 NR 19 R 20 , C 3 -C 8 cycloalkyl, aryl, heterocyclyl having 1-5 heteroatom ring vertices selected from the group consisting of N, O, S and P, and heteroaryl having 1-5 heteroatom ring vertices selected from the group consisting of N, O, S and P; wherein the subscript n is an integer of from 0 to 6; and wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl are each unsubstituted or substituted with 1 to 3 members independently selected from the group consisting of C 1-4 alkyl, —OH, —NH 2 , —OR 21 , halogen, cyano and oxo;

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 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 and R 7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring that can contain 1 to 3 heteroatoms or groups independently selected from the group consisting of N, C(O), O, and S(O) m , and that is unsubstituted or substituted with one R 17 group, and that is unsubstituted or substituted with one or more R 18 groups;

m is 0, 1, or 2;

any two groups of R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 11 can form a 5- to 6-membered ring, optionally containing a N, O or S heteroatom;

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

R 13 , R 15 , and R 16 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 cycloakyl, and 3- to 6-membered heterocyclyl, wherein said alkyl, cycloalkyl, and 3- to 6-membered heterocyclyl are each unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano and halo;

each R 17 and R 18 is independently selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;

each R 19 and R 20 is independently selected from the group consisting of H, 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 H, —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 as recited in claim 1 , wherein

R 1b is selected from the group consisting of cyano, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl, —CF 2 OH, —CHFOH, and C 3 -C 8 cycloalkyl.

3. The compound as recited in claim 1 , wherein

R 1a is phenyl or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from the group consisting of N, C(O), O, and S; and

the phenyl or heteroaryl of R 1a is unsubstituted or substituted with 1 to 5 R 12 groups independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

4. The compound as recited in claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are each hydrogen.

5. The compound as recited in claim 1 , wherein R 6 and R 7 together with the carbon atom to which they are both attached forms a 3- to 7-membered saturated or unsaturated ring that contains 1 to 3 heteroatoms or groups independently selected from the group consisting of N, C(O), O, and S(O) m , and that is unsubstituted or substituted with one R 17 group, and that is unsubstituted or substituted with one or more R 18 groups.

6. The compound as recited in claim 1 , wherein R 6 and R 7 together with the carbon atom to which they are both attached form a 3- to 6-membered heterocycloalkyl ring that is unsubstituted or substituted with one R 17 group, and that is unsubstituted or substituted with one or more R 18 groups.

7. The compound as recited in claim 1 , wherein each R 17 is amino; and each R 18 is methyl.

8. The compound as recited in claim 1 , wherein R 1a is selected from the group consisting of:

and

each R 12 is independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

9. The compound as recited in claim 8 , wherein each R 12 is independently selected from the group consisting of halo, amino, methylamino, and ethylamino.

10. The compound as recited in claim 1 , wherein R 1a is phenyl or pyridyl, each of which is substituted with 2 R 12 .

11. The compound as recited in claim 1 , wherein R 1b is C 1-6 hydroxyalkyl.

12. The compound as recited in claim 11 , wherein R 1b is —CH 2 OH.

13. The compound as recited in claim 1 , having a structure selected from the group consisting of:

or a salt or tautomer thereof.

14. A pharmaceutical composition comprising a compound as recited in claim 1 , together with a pharmaceutically acceptable carrier.

15. A method of treatment of a PTPN11-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 , to a patient in need thereof.

16. The method as recited in claim 15 , wherein the disease is cancer.

17. The method as recited in claim 16 , wherein the cancer is selected from the group consisting of breast cancer, colon cancer, leukemia, and melanoma.

18. The compound as recited in claim 1 , represented by the formula:

or a pharmaceutically acceptable salt thereof.

19. The compound as recited in claim 1 , represented by the formula:

or a pharmaceutically acceptable salt thereof.

20. The compound as recited in claim 1 , represented by the formula:

or a pharmaceutically acceptable salt thereof.

21. The method as recited in claim 15 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.