Inhibitors of the fibroblast growth factor receptor
Described herein are inhibitors of FGFR, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions to inhibit the activity of tyrosine kinases.
1. A method of treating a cancer selected from breast cancer, lung cancer, and liver cancer in a subject, the method comprising administering an effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, wherein:
Ring A is a 3-8 membered aryl, heteroaryl, heterocyclic or alicyclic group;
X is CH or N;
Y is CH or N—R 4 where R 4 is H or C 1-6 alkyl;
L is —[C(R 5 )(R 6 )] q —, where each of R 5 and R 6 is, independently, H or C 1-6 alkyl, wherein q is 0-4;
each of R 1 and R 3 is, independently, halo, cyano, optionally substituted C 1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heterocyclyl;
two R 2 are halo and two R 2 are C 1-6 alkoxy;
m is 0-3; n is 4; p is 0-2; and
Warhead is selected from the group consisting of
wherein X is halo, or triflate; and each of R a , R b , and R c is, independently, H, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 cycloalkyl, to thereby treat the cancer.
2. The method of claim 1 , wherein X is N and Y is CH.
3. The method of claim 1 , wherein Ring A is aryl.
4. The method of claim 1 , wherein Ring A is heteroaryl.
5. The method of claim 1 , wherein Ring A is heterocyclic.
6. The method of claim 1 , wherein Ring A is alicyclic.
7. The method of claim 1 , wherein Ring A is phenyl.
8. The method of claim 1 , wherein two R 2 are chloro and two R 2 are methoxy.
9. The method of claim 1 , wherein R 1 is methyl.
10. The method of claim 1 , wherein q is 0.
11. The method of claim 1 , wherein Warhead is
12. The method of claim 1 , wherein the compound is selected from the group consisting of:
13. The method of claim 1 , wherein the compound is present in a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
14. The method of claim 1 , wherein the cancer is liver cancer.
15. The method of claim 14 , wherein the liver cancer is hepatocellular carcinoma.
16. The method of claim 1 , further comprising administering a second therapeutic agent.
17. A method of inhibiting fibroblast growth factor receptor 4 (FGFR-4) the method comprising contacting FGFR4 with a compound of Formula I or pharmaceutically acceptable salt thereof, wherein:
Ring A is a 3-8 membered aryl, heteroaryl, heterocyclic or alicyclic group;
X is CH or N;
Y is CH or N—R 4 where R 4 is H or C 1-6 alkyl;
L is —[C(R 5 )(R 6 )] q —, where each of R 5 and R 6 is, independently, H or C 1-6 alkyl, wherein q is 0-4;
each of R 1 and R 3 is, independently, halo, cyano, optionally substituted C 1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heterocyclyl;
two R 2 are halo and two R 2 are C 1-6 alkoxy;
m is 0-3; n is 4; p is 0-2; and
Warhead is selected from the group consisting of
wherein X is halo, or triflate; and each of R a , R b , and R c is, independently, H, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 cycloalkyl.
18. The method of claim 17 , wherein X is N and Y is CH.
19. The method of claim 17 , wherein Ring A is aryl.
20. The method of claim 17 , wherein Ring A is heteroaryl.
21. The method of claim 17 , wherein Ring A is heterocyclic.
22. The method of claim 17 , wherein Ring A is alicyclic.
23. The method of claim 17 , wherein Ring A is phenyl.
24. The method of claim 17 , wherein two R 2 are chloro and two R 2 are methoxy.
25. The method of claim 17 , wherein R 1 is methyl.
26. The method of claim 17 , wherein q is 0.
27. The method of claim 17 , wherein Warhead is
28. The method of claim 17 , wherein the compound is selected from the group consisting of:
29. A method of treating liver cancer in a subject, the method comprising administering an effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, wherein:
Ring A is a 3-8 membered aryl, heteroaryl, heterocyclic or alicyclic group;
X is CH or N;
Y is CH or N—R 4 where R 4 is H or C 1-6 alkyl;
L is —[C(R 5 )(R 6 )] q —, where each of R 5 and R 6 is, independently, H or C 1-6 alkyl, wherein q is 0-4;
each of R 1 and R 3 is, independently, halo, cyano, optionally substituted C 1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 heterocyclyl;
two R 2 are halo and two R 2 are C 1-6 alkoxy;
m is 0-3; n is 4; p is 0-2; and
Warhead is selected from the group consisting of
wherein X is halo, or triflate; and each of R a , R b , and R c is, independently, H, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 cycloalkyl, to thereby treat the liver cancer.
30. The method of claim 29 , wherein Ring A is aryl.
31. The method of claim 29 , wherein Ring A is heteroaryl.
32. The method of claim 29 , wherein Ring A is heterocyclic.
33. The method of claim 29 , wherein Ring A is alicyclic.
34. The method of claim 29 , wherein Ring A is phenyl.
35. The method of claim 29 , wherein two R 2 are chloro and two R 2 are methoxy.
36. The method of claim 29 , wherein R 1 is methyl.
37. The method of claim 29 , wherein the liver cancer is hepatocellular carcinoma.
38. The method of claim 29 , further comprising administering a second therapeutic agent.
39. The method of claim 29 , wherein X is N and Y is CH.
40. The method of claim 29 , wherein q is 0.
41. The method of claim 29 , wherein Warhead is