Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof

1. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is —N— and X 2 is —C(R 9 )—, or X 1 is —C(R 9 )— and X 2 is —N—;

R 9 is —H, halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 20 R 21 or —NR 20 R 21 ;

R 20 and R 21 are each independently —H or (C 1 -C 6 )alkyl;

R 1 is halo, —CN, —C(O)NR 10 R 11 , —C(O)(C 1 -C 6 )alkyl, —OR 12 or —NR 10 R 11 ;

R 10 and R 11 are each independently —H or (C 1 -C 6 )alkyl;

R 12 is —H or (C 1 -C 6 )alkyl;

R 2 is —NR 13 R 14 ;

R 13 and R 14 are each independently —H or (C 1 -C 6 )alkyl, or taken together with the N to which they are attached, form a (C 3 -C 7 )heterocyclyl optionally substituted with one or more R 30 ;

R 30 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 3 is —H, halo, cyano or (C 1 -C 6 )alkyl;

R 4 is —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or —C(O)(C 1 -C 6 )alkyl;

R 5 is —H; and

R 6 is —H, halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy or (C 3 -C 7 )cycloalkoxy; or

R 5 and R 6 , taken together with their intervening atoms, form a (C 6 )aryl or (C 5 -C 6 )heteroaryl optionally substituted with one or more R 40 , or (C 5 -C 8 )carbocyclyl or (C 5 -C 8 )heterocyclyl optionally substituted with one or more R 50 ;

R 40 , for each occurrence, is optionally and independently halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 50 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 7 is halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 17 R 18 or —NR 17 R 18 ;

R 17 and R 18 are each independently —H or (C 1 -C 6 )alkyl;

R 8 , for each occurrence, is independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

m is 0 or 1, provided that if R 9 is halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy, m is 0; and

n is 0, 1 or 2.

2. The compound of claim 1 , wherein X 1 is —N— and X 2 is —C(R 9 )—.

3. The compound of claim 1 , wherein X 1 is —C(R 9 )— and X 2 is —N—.

4. The compound of claim 1 , wherein R 9 is —H.

5. The compound of claim 1 , wherein R 20 and R 21 are each —H.

6. The compound of claim 1 , wherein R 1 is halo or —CN.

7. The compound of claim 6 , wherein R 1 is chloro, bromo or —CN.

8. The compound of claim 7 , wherein R 1 is chloro.

9. The compound of claim 1 , wherein R 13 and R 14 are each independently selected from (C 1 -C 6 )alkyl.

10. The compound of claim 1 , wherein R 13 and R 14 , taken together with the N to which they are attached, form a (C 3 -C 7 )heterocyclyl optionally substituted with one or more R 30 .

11. The compound of claim 10 , wherein R 13 and R 14 , taken together with the N to which they are attached, form a (C 3 -C 7 )heterocyclyl substituted with one oxo and optionally substituted with one or more R 30 .

12. The compound of claim 1 , wherein R 13 and R 14 , taken together with the N to which they are attached, form a piperidinone, pyrrolidinone or imidazolidinone optionally substituted with one or more R 30 .

13. The compound of claim 1 , wherein R 30 , for each occurrence, is optionally and independently, halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy.

14. The compound of claim 1 , wherein R 2 is —N(CH 3 ) 2 , 1-piperidinyl-2-one, 1-pyrrolidinyl-2-one, 1-imidazolidinyl-2-one, 1-pyrrolidinyl or 1-piperidinyl.

15. The compound of claim 1 , wherein R 3 is halo, cyano or (C 1 -C 6 )alkyl.

16. The compound of claim 15 , wherein R 3 is chloro or methyl.

17. The compound of claim 1 , wherein R 3 is —H, halo or (C 1 -C 6 )alkyl.

18. The compound of claim 17 , wherein R 3 is —H, chloro or methyl.

19. The compound of claim 1 , wherein R 4 is —H, —CH 3 , 2-hydroxyethyl or —C(O)CH 3 .

20. The compound of claim 19 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , wherein R 5 is —H, and R 6 is halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy or (C 3 -C 7 )cycloalkoxy.

22. The compound of claim 21 , wherein R 6 is (C 1 -C 6 )alkoxy or (C 3 -C 7 )cycloalkoxy.

23. The compound of claim 22 , wherein R 6 is methoxy, ethoxy or isopropyloxy.

24. The compound of claim 23 , wherein R 6 is methoxy.

25. The compound of claim 1 , wherein R 5 and R 6 , taken together with their intervening atoms, form a (C 6 )aryl or (C 5 -C 6 )heteroaryl optionally substituted with one or more R 40 , or (C 5 -C 8 )carbocyclyl or (C 5 -C 8 )heterocyclyl optionally substituted with one or more R 50 .

26. The compound of claim 25 , wherein R 5 and R 6 , taken together with their intervening atoms, form a (C 6 )aryl.

27. The compound of claim 1 , wherein R 7 is halo, cyano, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy.

28. The compound of claim 1 , wherein R 17 and R 18 are each —H.

29. The compound of claim 1 , wherein R 9 is —H, and m is 1.

30. The compound of claim 1 , wherein m is 0.

31. The compound of claim 1 , wherein R 8 , for each occurrence, is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy.

32. The compound of claim 1 , wherein n is 0.

33. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

35. The compound of claim 33 , wherein R 4 is —CH 3 .

36. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

37. The compound of claim 36 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

39. The compound of claim 38 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Z is —N(R 60 )— or —C(R 60 ) 2 —;

R 30 , for each occurrence, is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 60 , for each occurrence, is independently hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy; and

p is 0, 1, 2, 3, 4 or 5.

41. The compound of claim 40 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

42. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

43. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

44. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

46. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1 , represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

48. A compound of any of the following structural formulas:

or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition, comprising a therapeutically effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is —N— and X 2 is —C(R 9 )—, or X 1 is —C(R 9 )— and X 2 is —N—;

R 9 is —H, halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 20 R 21 or —NR 20 R 21 ;

R 20 and R 21 are each independently —H or (C 1 -C 6 )alkyl;

R 1 is halo, —CN, —C(O)NR 10 R 11 , —C(O)(C 1 -C 6 )alkyl, —OR 12 or —NR 10 R 11 ;

R 10 and R 11 are each independently —H or (C 1 -C 6 )alkyl;

R 12 is —H or (C 1 -C 6 )alkyl;

R 2 is —NR 13 R 14 ;

R 13 and R 14 are each independently —H or (C 1 -C 6 )alkyl, or taken together with the N to which they are attached, form a (C 3 -C 7 )heterocyclyl optionally substituted with one or more R 30 ;

R 30 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 3 is —H, halo, cyano or (C 1 -C 6 )alkyl;

R 4 is —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or —C(O)(C 1 -C 6 )alkyl;

R 5 is —H; and

R 6 is —H, halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy or (C 3 -C 7 )cycloalkoxy; or

R 5 and R 6 , taken together with their intervening atoms, form a (C 6 )aryl or (C 5 -C 6 )heteroaryl optionally substituted with one or more R 40 , or (C 5 -C 8 )carbocyclyl or (C 5 -C 8 )heterocyclyl optionally substituted with one or more R 50 ;

R 40 , for each occurrence, is optionally and independently halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 50 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 7 is halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 17 R 18 or —NR 17 R 18 ;

R 17 and R 18 are each independently —H or (C 1 -C 6 )alkyl;

R 8 , for each occurrence, is independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

m is 0 or 1, provided that if R 9 is halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy, m is 0; and

n is 0, 1 or 2, and

one or more pharmaceutically acceptable carriers.

50. A pharmaceutical combination, comprising a therapeutically effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is —N— and X 2 is —C(R 9 )—, or X 1 is —C(R 9 )— and X 2 is —N—;

R 9 is —H, halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 20 R 21 or —NR 20 R 21 ;

R 20 and R 21 are each independently —H or (C 1 -C 6 )alkyl;

R 1 is halo, —CN, —C(O)NR 10 R 11 , —C(O)(C 1 -C 6 )alkyl, —OR 12 or —NR 10 R 11 ;

R 10 and RH are each independently —H or (C 1 -C 6 )alkyl;

R 12 is —H or (C 1 -C 6 )alkyl;

R 2 is —NR 13 R 14 ;

R 13 and R 14 are each independently —H or (C 1 -C 6 )alkyl, or taken together with the N to which they are attached, form a (C 3 -C 7 )heterocyclyl optionally substituted with one or more R 30 ;

R 30 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 3 is —H, halo, cyano or (C 1 -C 6 )alkyl;

R 4 is —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or —C(O)(C 1 -C 6 )alkyl;

R 5 is —H; and

R 6 is —H, halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy or (C 3 -C 7 )cycloalkoxy; or

R 5 and R 6 , taken together with their intervening atoms, form a (C 6 )aryl or (C 5 -C 6 )heteroaryl optionally substituted with one or more R 40 , or (C 5 -C 8 )carbocyclyl or (C 5 -C 8 )heterocyclyl optionally substituted with one or more R 50 ;

R 40 , for each occurrence, is optionally and independently halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 50 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 7 is halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 17 R 18 or —NR 17 R 18 ;

R 17 and R 18 are each independently —H or (C 1 -C 6 )alkyl;

R 8 , for each occurrence, is independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

m is 0 or 1, provided that if R 9 is halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy, m is 0; and

n is 0, 1 or 2, and

a therapeutically effective amount of one or more other therapeutic agents.

51. A method of improving intestinal barrier function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is —N— and X 2 is —C(R 9 )—, or X 1 is —C(R 9 )— and X 2 is —N—;

R 9 is —H, halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 20 R 21 or —NR 20 R 21 ;

R 20 and R 21 are each independently —H or (C 1 -C 6 )alkyl;

R 1 is halo, —CN, —C(O)NR 10 R 11 , —C(O)(C 1 -C 6 )alkyl, —OR 12 or —NR 10 R 11 ;

R 10 and R 11 are each independently —H or (C 1 -C 6 )alkyl;

R 12 is —H or (C 1 -C 6 )alkyl;

R 2 is —NR 13 R 14 ;

R 13 and R 14 are each independently —H or (C 1 -C 6 )alkyl, or taken together with the N to which they are attached, form a (C 3 -C 7 )heterocyclyl optionally substituted with one or more R 30 ;

R 30 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 3 is —H, halo, cyano or (C 1 -C 6 )alkyl;

R 4 is —H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or —C(O)(C 1 -C 6 )alkyl;

R 5 is —H; and

R 6 is —H, halo, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy or (C 3 -C 7 )cycloalkoxy; or

R 5 and R 6 , taken together with their intervening atoms, form a (C 6 )aryl or (C 5 -C 6 )heteroaryl optionally substituted with one or more R 40 , or (C 5 -C 8 )carbocyclyl or (C 5 -C 8 )heterocyclyl optionally substituted with one or more R 50 ;

R 40 , for each occurrence, is optionally and independently halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 50 , for each occurrence, is optionally and independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

R 7 is halo, hydroxy, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, —C(O)NR 17 R 18 or —NR 17 R 18 ;

R 17 and R 18 are each independently —H or (C 1 -C 6 )alkyl;

R 8 , for each occurrence, is independently halo, oxo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy;

m is 0 or 1, provided that if R 9 is halo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )haloalkoxy, m is 0; and

n is 0, 1 or 2, and

a therapeutically effective amount of one or more other therapeutic agents.