Heterocyclic inhibitors of PTPN11
The present invention relates to compounds which may be useful as inhibitors of PTPN11 for the treatment or prevention of cancer and other PTP-mediated diseases. Disclosed herein are new compounds and compounds based on pyrazolopyrazines and their application as pharmaceuticals for the treatment of disease.
1. A compound of structural Formula I
or a salt or tautomer thereof, wherein:
a is selected from 0 and 1;
b is selected from 0 and 1;
R 1 is selected from 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 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 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 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 , SR 13 , S(O)R 13 , and S(O) 2 R 13 ;
R 2 , R 3 , R 10 , and R 11 are independently selected from hydrogen, C 1-4 alkyl, and C 3-8 cycloalkyl;
R 4 , R 5 , R 8 , and R 9 are independently selected from 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 amino, C 1-4 aminoalkyl, and C 1-4 alkylamino;
R 7 is selected from hydrogen, cyano, amido, halo, and hydroxy, or is selected from 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 more R 17 groups;
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 that can contain 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O) m , and that is optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups;
m is selected from 0, 1, and 2;
any two groups selected from 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, optionally containing a N, O or S heteroatom;
any two groups selected from 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 , R 15 , and R 16 are independently selected from hydrogen, C 1-4 alkyl, and C 3-8 cycloakyl, wherein said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from hydroxy, cyano and halo;
R 17 is selected from amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy; and
each R 18 is independently selected from halo, hydroxy, and cyano.
2. The compound as recited in claim 1 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups 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 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 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 , SR 13 , S(O)R 13 , and S(O) 2 R 13 ; and
R 13 , R 15 , and R 16 are independently selected from hydrogen, C 1-4 alkyl, and C 3-8 cycloakyl, wherein said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from hydroxy, cyano and halo.
3. The compound as recited in claim 2 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups 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 halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl; and
R 17 is selected from amino, halo, and hydroxy.
4. The compound as recited in claim 2 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups 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 halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl;
R 6 is selected from amino, C 1-4 aminoalkyl, and C 1-4 alkylamino; and
R 7 is selected from hydrogen, cyano, amido, halo, and hydroxy, or is selected from 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 more R 17 groups.
5. The compound as recited in claim 1 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups 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 halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl; and
R 4 , R 5 , R 8 , and R 9 are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl, and C 1-4 alkylamino.
6. The compound as recited in claim 5 wherein R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are hydrogen.
7. The compound as recited in claim 6 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 R 17 group, and that is optionally substituted with one or more R 18 groups.
8. The compound as recited in claim 6 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups 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 halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl; and
R 17 is selected from amino, halo, and hydroxy.
9. The compound as recited in claim 6 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups 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 halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl;
R 6 is selected from amino, C 1-4 aminoalkyl, and C 1-4 alkylamino; and
R 7 is selected from hydrogen, cyano, amido, halo, and hydroxy, or is selected from 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 more R 17 groups.
10. 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 can contain 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O) m , and that is optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups.
11. 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 cycloalkyl ring that is optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups.
12. 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 optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups.
13. 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 optionally substituted with one R 17 group.
14. The compound as recited in claim 1 , wherein
R 6 is C 1-4 aminoalkyl; and
R 7 is selected from hydroxy, or is selected from 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 more R 17 groups.
15. The compound as recited in claim 1 , wherein
R 6 is aminomethyl; and
R 7 is selected from hydroxy, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl.
16. The compound as recited in claim 1 , wherein
R 6 is amino; and
R 7 is selected from 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 or more R 17 groups.
17. The compound as recited in claim 1 , wherein
R 6 is amino; and
R 7 is C 1-4 hydroxyalkyl.
18. The compound as recited in claim 1 , wherein
R 1 is selected from C 6-10 aryl and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups 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 halo, hydroxy, alkoxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C 1-4 alkyl.
19. The compound as recited in claim 1 , wherein R 1 is selected from:
and
each R 12 is independently selected from halo, hydroxy, amino, methylamino, dimethylamino, cyano, C 1-4 alkyl, and C 1-4 alkoxy.
20. The compound as recited in claim 19 , wherein R 1 is selected from:
21. The compound as recited in claim 20 , wherein each R 12 is independently selected from halo, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy.
22. The compound as recited in claim 1 , wherein R 1 is selected from pyridyl, piperazinyl, pyrimidinyl, pyrazolyl, and pyridazinyl.
23. The compound as recited in claim 1 , wherein R 1 is phenyl.
24. The compound as recited in claim 1 , wherein the structure is selected from:
25. The compound as recited in claim 24 , wherein
R 6 is selected from amino, C 1-4 aminoalkyl, and C 1-4 alkylamino;
R 7 is selected from hydrogen, cyano, amido, halo, and hydroxy, or is selected from C 1-4 alkyl, and C 1-4 hydroxyalkyl, any of which is optionally substituted with one or more R 17 groups; and
each R 17 is independently selected from amino, halo, and hydroxy.
26. The compound as recited in claim 1 wherein the structure is selected from:
or a salt or tautomer thereof.
27. The compound as recited in claim 1 , wherein the structure is selected from:
or the enantiomer of any one of the above structures,
or a salt or tautomer of any of the above structures,
or a salt or tautomer of the enantiomer of any one of the above structures.
28. The compound as recited in claim 1 , wherein the structure is selected from:
or a salt or tautomer of any of the above structures.
29. The compound as recited in claim 1 , wherein the structure is
30. The compound as recited in claim 1 , wherein the structure is
31. The compound as recited in claim 1 , wherein the structure is
32. The compound as recited in claim 1 , wherein the structure is
33. The compound as recited in claim 1 wherein the structure is selected from:
or a salt or tautomer thereof.
34. The compound as recited in claim 1 wherein the structure is selected from:
or a salt or tautomer thereof.
35. A compound as recited in claim 1 for use as a medicament.
36. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.
37. A method of inhibition of PTPN11 comprising contacting PTPN11 with a compound as recited in claim 1 .