Inhibitors of the fibroblast growth factor receptor
View Patent ↗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