Pyrimidine FGFR4 inhibitors

Patent metadata

Field	Value
Publication number	US-9434697-B2
Application number	US-201615000659-A
Country	US
Kind code	B2
Filing date	Jan 19, 2016
Priority date	Oct 18, 2013
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

Abstract

Provided herein are compounds of Formula I useful as FGFR4 inhibitors, as well as methods of use of the same.

First claim

We claim:

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 cell

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Reynolds Dominic
• Hao Ming-Hong
• Wang John
• Prajapati Sudeep
• Satoh Takashi
• Selvaraj Anand

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D239/48 Primary

  Two nitrogen atoms · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title