Pyrimidine fgfr4 inhibitors

A method of treating intrahepatic 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 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 intrahepatic cholangiocarcinoma has an altered FGFR4 status.

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, 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 NR5R6C1-6alkoxy, 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 altered FGFR4 status.