Pyrrolo[2,3-d]pyrimidine compounds as inhibitors of protein kinases
The present invention relates to certain pyrrolopyrimidine derivatives, pharmaceutical compositions containing them, and methods of using them, including methods for the treatment of proliferation disorders and other diseases related to the dysregulation of kinase (such as, but not limited to, EGFR (including HER), Alk, PDGFR, BLK, BMX/ETK, BTK, FLT3(D835Y), ITK, JAK1, JAK2, JAK3, TEC and TXK) and/or the respective pathways.
1. A compound of Formula (VII):
wherein
R 1 and R 2 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 8 is selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;
R 10 is C 1-6 alkyl; and
R 13 is hydrogen or C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.
3. The compound of claim 1 , wherein R 8 is halo.
4. The compound of claim 3 , wherein R 8 is fluoro.
5. The compound of claim 1 , wherein R 10 is methyl, ethyl, or isopropyl.
6. The compound of claim 5 , wherein R 10 is methyl.
7. The compound of claim 1 , wherein R 13 is hydrogen.
8. A compound of Formula (III):
wherein
R 1 and R 2 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 3 is selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, cyano, and nitro;
n is a number from zero to 4;
R 4 is selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, and NR 22 R 23 ;
wherein the alkyl or cycloalkyl is unsubstituted or substituted with hydroxyl or amino; and
wherein each R 22 and R 23 is independently selected from hydrogen and C 1-6 alkyl, or R 22 and R 23 taken with the nitrogen to which they are attached are joined to form a 3 to 10 membered ring;
R 5 is selected from hydrogen and C 1-6 alkyl;
R 6 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;
R 7 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;
R 8 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;
R 9 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;
R 10 is selected from hydrogen and C 1-6 alkyl;
R 11 is selected from hydrogen and C 1-6 alkyl;
R 12 is selected from hydrogen and C 1-6 alkyl; and
R 13 is selected from hydrogen, C 1-6 alkyl, and C 6-20 aryl, wherein each alkyl or aryl is unsubstituted or substituted with hydroxyl, C 1-6 alkoxy, or halo;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein R 11 and R 12 are each hydrogen.
10. The compound of claim 8 , wherein R 1 and R 2 are each hydrogen.
11. The compound of claim 8 , wherein n is zero.
12. The compound of claim 8 , wherein R 10 is methyl.
13. The compound of claim 8 , wherein R 13 is hydrogen.
14. The compound of claim 8 , wherein R 9 is hydrogen or halo.
15. The compound of claim 14 , wherein R 9 is fluoro.
16. The compound of claim 8 , wherein R 6 and R 7 are hydrogen.
17. The compound of claim 8 , wherein R 8 is hydrogen or halo.
18. The compound of claim 8 , wherein R 6 , R 7 , and R 8 are hydrogen and R 9 is fluoro.
19. The compound of claim 8 , wherein R 4 and R 5 are each hydrogen.
20. A pharmaceutical composition comprising: (a) at least one compound of claim 8 or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier or excipient.
21. The pharmaceutical composition of claim 20 , wherein the pharmaceutically acceptable salt is an HCl salt, a maleate salt, an HBr salt, a hydroxybutanedioic acid salt, or a fumaric acid salt.
22. A compound of Formula (VI):
wherein
R 1 and R 2 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 8 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;
Q is CR 9 or N;
R 9 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;
R 10 is selected from hydrogen and C 1-6 alkyl; and
R 13 is selected from hydrogen, C 1-6 alkyl, and C 6-20 aryl, wherein each alkyl or aryl is unsubstituted or substituted with hydroxyl, C 1-6 alkoxy, or halo;
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 22 , wherein R 1 and R 2 are each hydrogen.
24. The compound of claim 22 , wherein Q is CR 9 .
25. The compound of claim 24 , wherein R 9 is hydrogen or halo.
26. The compound of claim 22 , wherein R 8 is hydrogen or halo.
27. The compound of claim 22 , wherein one of R 8 and R 9 is hydrogen and the other is fluoro.
28. The compound of claim 22 , wherein R 10 is methyl.
29. The compound of claim 22 , wherein R 13 is hydrogen.
30. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.