# US 9,434,697 B2 · Pyrimidine FGFR4 inhibitors

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- Number: US 9,434,697 B2
- Document ID: US9434697B2
- Status: Granted
- Kind: B2
- Application number: 15/000,659
- Filed: 2016-01-19
- Published: 2016-05-12
- Granted: 2016-09-06
- Earliest claimed: 2013-10-18
- Assignees: Eisai R&D Management Co., Ltd.
- Applicants: Eisai R&D Management Co., Ltd.
- Inventors: Dominic Reynolds; Ming-Hong Hao; John Wang; Sudeep Prajapati; Takashi Satoh; Anand Selvaraj
- Web page: https://patentgrep.com/patent/US9434697B2

## CPC

- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/48: Two nitrogen atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

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

## Claims

### Claim 1

A compound of Formula I:
wherein:
R3 is selected from the group consisting of: C1-6alkyl, C1-6alkoxyC1-6alkyl, NR10R11C1-6alkyl, R10heterocyclylC1-6alkyl, R10arylC1-6alkyl, and R10heteroarylC1-6alkyl, wherein R10 and R11 are each independently selected from the group consisting of: hydrogen and C1-6alkyl;
E is selected from the group consisting of:
—NR13C(O)CR14═CHR15, and
—NR13C(O)C≡CR14,
wherein R13 is selected from the group consisting of: hydrogen and methyl, and R14 and R15 are each independently selected from the group consisting of: hydrogen, methyl, fluoro and chloro;
R12 is selected from the group consisting of: hydrogen, halo, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, C1-6alkoxyC1-6alkyl, R5R6heterocyclyl, —C(O)heterocyclylR5R6, R5R6heterocyclylC1-6alkyl, NR5R6, NR5R6C1-6alkyl, —C(O)NR5R6, and —NR5R6C1-6alkyoxy, wherein R5 and R6 are each independently selected from the group consisting of hydrogen, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, —C(O)C1-6alkyl and C1-6alkylsulfonyl; and
R1 is phenyl, wherein said phenyl is substituted 2, 3, or 4 times with independently selected halo or C1-6alkoxy,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R3 is C1-6alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R3 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.

### Claim 4 (depends on 1)

The compound of claim 1, wherein E is —NR13C(O)CH═CHR15 or —NR13C(O)CF═CH2, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein E is —NHC(O)CH═CH2, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R12 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.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R12 is selected from the group consisting of: hydrogen, C1-6alkyl, hydroxyC1-6alkyl, R5R6heterocyclyl, R5R6heterocyclylC1-6alkyl, —C(O)NR5R6, NR5R6C1-6alkyl, NR5R6C1-6alkyoxy, C1-6alkoxy, and C1-6alkoxyC1-6alkyl, wherein R5 and R6 are each independently selected from the group consisting of: hydrogen, C1-6alkyl, hydroxyC1-6alkyl, —C(O)C1-6alkyl and C1-6alkylsulfonyl, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R12 is R5R6heterocyclyl, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R5R6heterocyclyl is R5R6piperazinyl, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R12 is 4-ethylpiperazin-1-yl, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R1 is 2,6-dichloro-3,5-dimethoxyphenyl, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, wherein said compound is a compound of Formula 1(a):
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1, wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1, wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The compound of claim 1, wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound of claim 1 which is:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein said composition is formulated for oral, intravenous or subcutaneous administration.

### Claim 19 (depends on 16)

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.

### Claim 20 (depends on 19)

The method of claim 19, wherein said hepatocellular carcinoma has an altered FGF19 status.

### Claim 21 (depends on 20)

The method of claim 20, wherein said altered FGF19 status comprises increased expression of FGF 19.

### Claim 22 (depends on 16)

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.

### Claim 23 (depends on 22)

The method of claim 22, wherein said altered FGF19 status comprises increased expression of FGF19.

### Claim 24 (depends on 17)

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.

### Claim 25 (depends on 17)

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.

### Claim 26 (depends on 16)

A pharmaceutical composition comprising the compound or salt of claim 16 and a pharmaceutically acceptable carrier.

### Claim 27 (depends on 26)

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.

### Claim 28 (depends on 26)

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.

### Claim 29 (depends on 1)

The compound of claim 1, wherein R3 is methyl, E is —NHC(O)CH═CH2, and R1 is 2,6-dichloro-3,5-dimethoxyphenyl, or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 1)

The compound of claim 1, wherein E is —NHC(O)CH═CH2, R12 is hydrogen, and R1 is 2,6-dichloro-3,5-dimethoxyphenyl, or a pharmaceutically acceptable salt thereof.