EGFR modulators and uses thereof

1. A method of treating a proliferation disorder comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof,

wherein

X 1 is O, NH, S, CH 2 , or CF 2 ;

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 are independently selected from hydrogen and C 1-6 alkyl or R 22 and R 23 may be 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 alkoxy, 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 alkoxy, 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 alkoxy, 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 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 11 is selected from hydrogen and C 1-6 alkyl;

R 12 is selected from hydrogen and C 1-6 alkyl;

R 13 is selected from hydrogen, C 1-6 alkyl, C 1-6 acyl, SO 2 —C 1-6 alkyl, C 3-7 cycloalkyl, and C 6-20 aryl;

wherein each alkyl or aryl is unsubstituted or substituted with hydroxyl, C 1-6 alkoxy, or halo; and

—NR 18 R 19 is

wherein R 10 is selected from hydrogen and C 1-6 alkyl;

R 15 is unsubstituted methyl, or is C 2-4 alkyl unsubstituted or substituted with hydroxy, methoxy, or halo; and

m is 1 or 2;

or R 19 and R 9 taken together form a 5- or 6-membered heteroaryl ring optionally substituted with C 1-6 alkyl that is unsubstituted or substituted with amino, hydroxyl, or halo; and R 18 is hydrogen or C 1-6 alkyl, or is absent to satisfy valency of the heteroaryl ring;

provided that neither of R 6 or R 7 is methoxy when —NR 18 R 19 is

2. The method of claim 1 , wherein the proliferation disorder is selected from the group consisting of sarcoma, epidermoid cancer, fibrosarcoma, cervical cancer, gastric carcinoma, skin cancer, leukemia, lymphoma, lung cancer, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, liver cancer, head and neck cancers, and pancreatic cancer.

3. The method of claim 1 , further comprising administering an effective amount of a second therapeutic agent for treating a proliferation disorder in a subject.

4. The method of claim 1 , wherein the compound is a compound of Formula (Ia) or (Ib):

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 are independently selected from hydrogen and C 1-6 alkyl or R 22 and R 23 may be 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 2-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 7 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxy, 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 alkoxy, 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 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 10 is selected from hydrogen and C 1-6 alkyl;

a is one or two;

Ring A is an aromatic ring;

R 20 and R 21 are independently selected from hydrogen and C 1-6 alkyl; wherein alkyl is unsubstituted or substituted with amino, hydroxyl, or halo; wherein R 21 may not present to satisfy valency;

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, C 1-6 acyl, SO 2 —C 1-6 alkyl, C 3-7 cycloalkyl, 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.

5. The method of claim 1 , wherein the compound is a compound of Formula (II):

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 are independently selected from hydrogen and C 1-6 alkyl or R 22 and R 23 may be 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 2-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 7 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxy, 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 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

Q is CR 9 or N;

where R 9 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, 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.

6. The method of claim 1 , wherein X 1 is O or NH.

7. The method of claim 1 , wherein R 11 is hydrogen.

8. The method of claim 1 , wherein R 12 is hydrogen.

9. The method of claim 1 , wherein R 1 and R 2 are each hydrogen.

10. The method of claim 1 , wherein n is zero.

11. The method of claim 1 , wherein —NR 18 R 19 is

12. The method of claim 1 , wherein R 10 is methyl.

13. The method of claim 1 , wherein R 13 is hydrogen.

14. The method of claim 1 , wherein R 13 is C 1-6 alkyl substituted with hydroxyl or halo.

15. The method of claim 1 , wherein R 6 is hydrogen.

16. The method of claim 1 , wherein R 7 is hydrogen or methoxy.

17. The method of claim 1 , wherein R 8 is hydrogen.

18. The method of claim 1 , wherein Q is N.

19. The method of claim 1 , wherein Q is CR 9 .

20. The method of claim 19 , wherein R 9 is hydrogen or fluoro.

21. The method of claim 1 , wherein R 19 and R 9 together form a 5- or 6-membered heteroaryl ring optionally substituted with C 1-6 alkyl that is unsubstituted or substituted with amino.

22. The method of claim 1 , wherein the compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

23. The method of claim 1 , wherein the compound is 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 alkoxy, 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.

24. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25. The method of claim 24 , wherein the compound is N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide hydrochloride salt or maleate salt.

26. The method of claim 1 , wherein the compound inhibits a mutated EGFR in the subject.

27. The method of claim 26 , wherein the mutated EGFR comprises a T790M mutation.

28. The method of claim 27 , wherein the mutated EGFR comprises T790M/L858R mutations.

29. The method of claim 27 , wherein the mutated EGFR comprises delE746-A750 mutation.

30. The method of claim 1 , wherein the proliferation disorder is selected from the group consisting of fibrosarcoma, cervical cancer, gastric carcinoma, lymphoma, lung cancer, non-small cell lung cancer, and liver cancer.

31. The method of claim 1 , wherein the compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

32. The method of claim 1 , wherein the compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.