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 compound of Formula I, or a 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 wherein R 4 is H or C 1-6 alkyl;
L is —[C(R 5 )(R 6 )] q —, wherein each of R 5 and R 6 is, independently, H or C 1-6 alkyl; and q is 0-4;
each of R 1 -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;
m is 0-3;
n is 0-4; and
p is 0-2.
2 . The compound of claim 1 , wherein Ring A is aryl.
3 . The compound of claim 1 , wherein Ring A is phenyl substituted with 0-3 R 1 .
4 . The compound of claim 1 , wherein X is N.
5 . The compound of claim 1 , wherein Y is CH.
6 . The compound of claim 1 , wherein Y is N—R 4 wherein R 4 is H or C 1-6 alkyl; and R 3 is oxo or alkyl urea.
7 . The compound of claim 1 , wherein L is a bond.
8 . The compound of claim 1 , wherein the warhead moiety is
wherein 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.
9 . The compound of claim 8 , wherein the warhead moiety is
10 . The compound of claim 1 , wherein each R 1 is, independently, halo, cyano, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 heterocyclyl.
11 . The compound of claim 10 , wherein R 1 is, independently, chloro, fluoro, methyl, methoxy, CF 3 , or morpholinyl.
12 . The compound of claim 1 , wherein R 2 is alkoxy or halo.
13 . The compound of claim 12 , wherein R 2 is methoxy or chloro.
14 . The compound of claim 1 , wherein L is a bond and the warhead moiety is
15 . The compound of claim 1 , wherein the compound has the following formula:
16 . The compound of claim 15 , wherein R 2 is halo or methoxy, and n is 4.
17 . The compound of claim 1 , wherein the compound is selected from:
18 . A pharmaceutical composition comprising a compound of claim 1 or claim 17 , and a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt thereof.
19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound inhibits FGFR-4 activity more potently, when measured in a biochemical assay, than it inhibits FGFR-1 activity.
20 . A method of modulating FGFR-4 in a subject in need thereof, the method comprising administering to said subject a compound of claim 1 or 17 , or a pharmaceutical composition of claim 18 , or a pharmaceutically acceptable salt thereof.
21 . A method of treating a disorder associated with FGFR-4 in a subject in need thereof, the method comprising administering to said subject a compound of claim 1 or 17 , or a pharmaceutically acceptable salt thereof.
22 . The method of claim 21 , wherein the disorder is cancer.
23 . The method of claim 22 , wherein the cancer is selected from the group consisting of liver cancer, breast cancer, lung cancer, ovarian cancer, or a sarcoma.
24 . The method of claim 22 , wherein the cancer is hepatocellular carcinoma.
25 . The method of claim 21 , wherein the disorder is hyperlipidemia.
26 . A method for treating a condition characterized by amplified FGF-19 in a subject, the method comprising administering to said subject a therapeutically effective amount of a compound of claim 1 or 17 , or a pharmaceutically acceptable salt thereof.