Pyrimidine FGFR4 inhibitors
Provided herein are compounds of Formula I useful as FGFR4 inhibitors, as well as methods of use of the same.
1. A compound of Formula I:
wherein:
R 3 is selected from the group consisting of: C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, NR 10 R 11 C 1-6 alkyl, R 10 heterocyclylC 1-6 alkyl, R 10 arylC 1-6 alkyl, and R 10 heteroarylC 1-6 alkyl, wherein R 10 and R 11 are each independently selected from the group consisting of: hydrogen and C 1-6 alkyl;
E is selected from the group consisting of:
—NR 13 C(O)CR 14 ═CHR 15 , and
—NR 13 C(O)C≡CR 14 ,
wherein R 13 is selected from the group consisting of: hydrogen and methyl, and R 14 and R 15 are each independently selected from the group consisting of: hydrogen, methyl, fluoro and chloro;
R 12 is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, R 5 R 6 heterocyclyl, —C(O)heterocyclylR 5 R 6 , R 5 R 6 heterocyclylC 1-6 alkyl, NR 5 R 6 , NR 5 R 6 C 1-6 alkyl, —C(O)NR 5 R 6 , and —NR 5 R 6 C 1-6 alkyoxy, wherein R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, —C(O)C 1-6 alkyl and C 1-6 alkylsulfonyl; and
R 1 is phenyl, wherein said phenyl is substituted 2, 3, or 4 times with independently selected halo or C 1-6 alkoxy,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 3 is C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 3 is selected from the group consisting of: methyl, methoxyethyl, 4-pyridylmethyl, 3-pyridylmethyl, 2-pyridylmethyl, benzyl, N,N-dimethylaminopropyl, 3-methylisoxazol-5-yl-methyl, and 4-methylpiperazin-1-yl-propyl, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein E is —NR 13 C(O)CH═CHR 15 or —NR 13 C(O)CF═CH 2 , or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein E is —NHC(O)CH═CH 2 , or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein R 12 is selected from the group consisting of: hydrogen, fluoro, chloro, methyl, methoxy, N,N-dimethylaminoethyl, piperazin-1-yl, 4-ethylpiperazin-1-yl, 4-ethylpiperazin-1-yl-methyl, 1-methylpiperidine-4-yl, 1-ethylpiperidine-4-yl, N,N-dimethylaminomethyl, N,N-dimethylaminopropyl, piperidine-4-yl, morpholino, 3,5-dimethylpiperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, N,N-dimethylaminoethoxy, 4-(2-hydroxyethyl)piperazin-1-yl, hydroxyethoxy, methoxyethoxy, hydroxymethyl, methoxymethyl, 2-methoxypropyl, 2-hydroxypropyl, 2-aminopropyl, 4-methylpiperazin-1-yl-carbonyl, 4-ethylpiperazin-1-yl-carbonyl, 4-[2-propyl]piperazin-1-yl, 4-acetylpiperazin-1-yl, N-methyl-N-hydroxyethyl-amino, N,N-dimethylamido, and 4-(2-aminoethyl)piperazin-1-yl, or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein R 12 is selected from the group consisting of: hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, R 5 R 6 heterocyclyl, R 5 R 6 heterocyclylC 1-6 alkyl, —C(O)NR 5 R 6 , NR 5 R 6 C 1-6 alkyl, NR 5 R 6 C 1-6 alkyoxy, C 1-6 alkoxy, and C 1-6 alkoxyC 1-6 alkyl, wherein R 5 and R 6 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkyl and C 1-6 alkylsulfonyl, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 , wherein R 12 is R 5 R 6 heterocyclyl, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein R 5 R 6 heterocyclyl is R 5 R 6 piperazinyl, or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 , wherein R 12 is 4-ethylpiperazin-1-yl, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein R 1 is 2,6-dichloro-3,5-dimethoxyphenyl, or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein said compound is a compound of Formula 1(a):
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 which is:
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17 , wherein said composition is formulated for oral, intravenous or subcutaneous administration.
19. A method of treating hepatocellular carcinoma in a subject in need thereof comprising administering to said subject a treatment effective amount of a compound or salt of claim 16 .
20. The method of claim 19 , wherein said hepatocellular carcinoma has an altered FGF19 status.
21. The method of claim 20 , wherein said altered FGF19 status comprises increased expression of FGF 19.
22. A method of treating hepatocellular carcinoma in a subject in need thereof, comprising:
detecting an altered FGF19 status in a biological sample containing cells of said hepatocellular carcinoma, and if said hepatocellular carcinoma has said altered FGF19 status,
administering the compound or salt of claim 16 to said subject in a treatment-effective amount.
23. The method of claim 22 , wherein said altered FGF19 status comprises increased expression of FGF19.
24. A method of treating hepatocellular carcinoma in a subject in need thereof comprising administering to said subject a treatment effective amount of the pharmaceutical composition of claim 17 .
25. A method of treating hepatocellular carcinoma in a subject in need thereof, comprising:
detecting an altered FGF19 status in a biological sample containing cells of said hepatocellular carcinoma, and if said hepatocellular carcinoma has said altered FGF19 status,
administering the pharmaceutical composition of claim 17 to said subject in a treatment-effective amount.
26. A pharmaceutical composition comprising the compound or salt of claim 16 and a pharmaceutically acceptable carrier.
27. A method of treating hepatocellular carcinoma in a subject in need thereof comprising administering to said subject a treatment effective amount of the pharmaceutical composition of claim 26 .
28. A method of treating hepatocellular carcinoma in a subject in need thereof, comprising:
detecting an altered FGF19 status in a biological sample containing cells of said hepatocellular carcinoma, and if said hepatocellular carcinoma has said altered FGF19 status,
administering the pharmaceutical composition of claim 26 to said subject in a treatment-effective amount.
29. The compound of claim 1 , wherein R 3 is methyl, E is —NHC(O)CH═CH 2 , and R 1 is 2,6-dichloro-3,5-dimethoxyphenyl, or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 , wherein E is —NHC(O)CH═CH 2 , R 12 is hydrogen, and R 1 is 2,6-dichloro-3,5-dimethoxyphenyl, or a pharmaceutically acceptable salt thereof.