Inhibitors of the fibroblast growth factor receptor
View Patent ↗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 I, or a pharmaceutically acceptable salt thereof:
wherein:
denotes a double bond;
Warhead is a moiety capable of forming a covalent bond with a nucleophile;
Ring A is phenyl;
W is C;
X is N;
Z is CH;
Y is CH;
each of R 1 -R 3 is, independently, halo, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, 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 0-5;
n is 0-5; and
p is 0-2.
2. The compound of claim 1 , wherein R 7 is hydrogen or C 1-6 alkyl.
3. The compound of claim 1 , wherein R 7 together with Ring A form an optionally substituted 8-12 membered bicyclic heterocyclyl.
4. The compound of claim 1 , wherein m is at least 1 and R 1 is selected from the group consisting of halo, optionally substituted C 1-6 alkyl, and optionally substituted C 1-6 alkoxy.
5. The compound of claim 1 , wherein n is 4, with two R 2 being halo and two R 2 being alkoxy.
6. The compound of claim 1 , wherein the warhead moiety is selected from the group consisting of
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.
7. The compound of claim 1 , wherein the warhead moiety is
8. The compound of claim 1 , wherein the compound is a compound of Formula I(a), or a pharmaceutically acceptable salt thereof:
wherein X is N.
9. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt thereof.
10. A compound selected from any one of the compounds depicted in the table below, or a pharmaceutically acceptable salt thereof:
Compound
Structure
2
3
5
6
7
8
11
13
14
15
16
18
24
28
33
34
36
38
44
48
11. The compound of claim 1 , wherein the warhead moiety is
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.
12. The compound of claim 8 , wherein the warhead moiety is
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.
13. The compound of claim 8 , wherein the warhead moiety is
14. The compound of claim 8 , wherein m is at least 1 and R 1 is selected from the group consisting of halo, optionally substituted C 1-6 alkyl, and optionally substituted C 1-6 alkoxy.
15. The compound of claim 12 , wherein m is at least 1 and R 1 is selected from the group consisting of halo, optionally substituted C 1-6 alkyl, and optionally substituted C 1-6 alkoxy.
16. The compound of claim 13 , wherein m is at least 1 and R 1 is selected from the group consisting of halo, optionally substituted C 1-6 alkyl, and optionally substituted C 1-6 alkoxy.
17. The compound of claim 8 , wherein n is 4, with two R 2 being halo and two R 2 being alkoxy.
18. The compound of claim 12 , wherein n is 4, with two R 2 being halo and two R 2 being alkoxy.
19. The compound of claim 8 , wherein R 7 is hydrogen.
20. The compound of claim 12 , wherein R 7 is hydrogen.