Inhibitors of the fibroblast growth factor receptor
Described herein are inhibitors of FGFR-4, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions to inhibit the activity of FGFR-4.
1. A compound of Formula Ib or a pharmaceutically acceptable salt thereof:
wherein:
Warhead is a moiety capable of forming a covalent bond with a nucleophile;
Ring A is a 5-8 membered aryl, 5-12 membered heteroaryl, 3-7 membered monocyclic or bicyclic heterocyclyl, or 3-12 membered monocyclic or bicyclic cycloalkyl group;
X is CH;
R 4 is H, C 1-6 alkyl, or 3-12 membered cycloalkyl;
each of R 1 and R 2 is independently halo, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, or optionally substituted 3-7 member heterocyclyl;
R 7 is hydrogen or C 1-6 alkyl, or R 7 together with Ring A forms a 8-12 membered bicyclic heterocyclyl optionally substituted with 1-5 occurrences of R 1 ;
m is 0, 1, 2, 3, 4, or 5; and
n is 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl;
and m is 0, 1, 2, or 3.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 together with Ring A forms an optionally substituted 8-12 membered bicyclic heterocyclyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
m is 1, 2, 3, 4, or 5; and
each R 1 is independently halo, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 4, with two R 2 being halo and two R 2 being alkoxy.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Warhead is selected from
wherein each of R a , R b , and R c is independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted 3-12 membered cycloalkyl, or cyano.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein Warhead is
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
10. A method of treating a cancer mediated by FGFR-4, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the cancer is liver cancer, breast cancer, lung cancer, ovarian cancer, or a sarcoma.
11. A method of treating hepatocellular carcinoma mediated by FGFR-4, the method comprising administering to a subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
12. A compound selected from any one of the following compounds and pharmaceutically acceptable salts thereof:
Compound
Number
Structure
4
9
10
12
17
19
20
21
23
25
26
27
35
37
39
40
41
42
43
45
47
49
51
52
53
54