Pyrimidine FGFR4 inhibitors
AssigneeEisai R&D Management Co., Ltd.
InventorsDominic Reynolds, Ming-Hong Hao, John Wang, Sudeep Prajapati, Takashi Satoh, Anand Selvaraj
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Abstract
Provided herein are compounds of Formula I useful as FGFR4 inhibitors, as well as methods of use of the same.
Claims12
A method of treating cholangiocarcinoma in a subject in need thereof comprising administering to said subject a treatment effective amount of 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 R10and R11are 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 NR5R6C1-6aloxy, 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,
- wherein said cholangiocarcinoma has an expression or overexpression of FGFR4.
A method of treating cholangiocarcinoma in a subject in need thereof, comprising:
- administering an effective amount of a compound having the formula:
- or a pharmaceutically acceptable salt thereof to a patient in which expression or overexpression of FGFR4 has been detected in a biological sample from said patient, said biological sample containing cells of said cholangiocarcinoma.
A method of treating hepatocellular carcinoma in a subject in need thereof comprising administering to said subject a treatment effective amount of a compound of Formula I:
- wherein:
- R3 is selected from the group consisting of:
- C1-6alkyl, C1-6alkoxyC1-6alkyl, NR10R11C1-6alkyl, R10heterocyclC1-6alkyl, 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 NR5R6C1-6alkoxy, 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,
- wherein said hepatocellular carcinoma has an increased expression of FGFR4.
A method of treating hepatocellular carcinoma in a subject in need thereof, comprising:
- administering an effective amount of a compound having the formula:
- or a pharmaceutically acceptable salt thereof to a patient in which increased expression of FGFR4 has been detected in a biological sample from said patient, said biological sample containing cells of said hepatocellular carcinoma.
Dependencies are inferred from the claim text.