Pyrrole derivatives as PLK1 inhibitors

A method for the treatment of a disease state or condition characterised by the presence of a mutated form of KRAS, which method comprises administering a therapeutically effective amount of a compound to a patient who has been screened and has been determined as suffering from a disease or condition which would be susceptible to treatment with a compound having activity against KRAS, wherein the compound is a compound of formula (3):

• or a pharmaceutically acceptable salt or tautomer thereof, wherein:
• Z is selected from a pyrrole, pyrazole or isoxazole ring;
• ring X is a benzene or pyridine ring;
• ring Y is a benzene, pyridine, thiophene or furan ring;
• Ar1 is a benzene, pyridine, thiophene or furan ring optionally substituted with one or more substituent R5;
• m is 0, 1 or 2;
• n is 0, 1 or 2;
• R1 is CF3;
• Hyd1 and Hyd2 are the same or different and are C1-4 hydrocarbon groups;
• R2 is selected from hydrogen and a C1-4 hydrocarbon group;
• R3 is selected from hydrogen and a C1-4 hydrocarbon group;
• R4 is selected from:
• fluorine;
• chlorine;
• bromine;
• hydroxyl;
• cyano;
• carboxyl;
• C(O)O(Hyd1);
• amino;
• -(Hyd2)NH;
• (Hyd2)2N;
• and
• a C1-5 hydrocarbon group where 0, 1 or 2 of the carbons in the hydrocarbon group are replaced with a heteroatom selected from N, O and S, the hydrocarbon group being optionally substituted with one or more fluorine atoms;
• R5 is selected from halogen;
• O—Ar2;
• cyano, hydroxy;
• amino;
• Hyd1-SO2— and a non-aromatic C1-8 hydrocarbon group where 0, 1 or 2 but not all of the carbons in the hydrocarbon group are optionally replaced with a heteroatom selected from N, O and S and where the hydrocarbon group is optionally substituted with one or more fluorine atoms:
• Ar2 is a phenyl, pyridyl or pyridone group optionally substituted with 1 or 2 substituents selected from halogen;
• cyano and a C1-4 hydrocarbon group optionally substituted with one or more fluorine atoms;
• R6 is a group Q1-Ra—Rb;
• Q1 is absent or is a C1-3 saturated hydrocarbon linker;
• Ra is selected from O;
• C(O);
• C(O)O;
• CONRc;
• N(Rc)CONRc, NRc;
• and SO2NRc;
• Rb is selected from:
• hydrogen;
• a C1-8 non-aromatic hydrocarbon group where 0, 1 or 2 of the carbon atoms in the hydrocarbon group are replaced with a heteroatom selected from N and O, the C1-8 non-aromatic hydrocarbon group being optionally substituted with one or more substituents selected from fluorine and a group Cyc1;
• and
• a group Cyc1;
• Cyc1 is a non-aromatic 4-7 membered carbocyclic or heterocyclic ring group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and being optionally substituted with one or more substituents selected from hydroxyl;
• amino;
• (Hyd2)NH;
• (Hyd2)2N;
• and a C1-5 hydrocarbon group where 0, 1 or 2 of the carbons in the hydrocarbon group are replaced with a heteroatom selected from N, O and S, the hydrocarbon group being optionally substituted with one or more fluorine atoms or by a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatom ring members selected from N and O;
• Rc is selected from hydrogen and a C1-4 non-aromatic hydrocarbon group;
• R7 is selected from R4;
• with the proviso that when n is 2 and both occurrences of R7 are —OCH3, R6 is not —NH2 or —NHCH3;
• and
• provided that the compound is other than:
• (i) a compound wherein R6 is hydroxy, methoxymethyl or unsubstituted or fluoro-substituted C1-8 alkoxy;
• (ii) a compound wherein the ring Z is an isoxazole ring and Ar1 is an unsubstituted 4-pyridyl group attached to the isoxazole 3-position;
• and R2 and R3 are both absent or
• (iii) a compound wherein Z is an isoxazole ring and R4 is an azetidin-4-yloxy group
• with the proviso that said treatment excludes prophylaxis and prevention of recurrence.

A method for the treatment of a subject suffering from a cancer in a patient who has been screened and has been determined as suffering from a cancer which is characterised by elevated levels of PLK1 kinase;

• which method comprises administering to the subject a therapeutically effective amount of a compound of formula (3):
• or a pharmaceutically acceptable salt or tautomer thereof, wherein:
• Z is selected from a pyrrole, pyrazole or isoxazole ring;
• ring X is a benzene or pyridine ring;
• ring Y is a benzene, pyridine, thiophene or furan ring;
• Ar1 is a benzene, pyridine, thiophene or furan ring optionally substituted with one or more substituent R5;
• m is 0, 1 or 2;
• n is 0, 1 or 2;
• R1 is CF3;
• Hyd1 and Hyd2 are the same or different and are C1-4 hydrocarbon groups;
• R2 is selected from hydrogen and a C1-4 hydrocarbon group;
• R3 is selected from hydrogen and a C1-4 hydrocarbon group;
• R4 is selected from:
• fluorine;
• chlorine;
• bromine;
• hydroxyl;
• cyano;
• carboxyl;
• C(O)O(Hyd1);
• amino;
• -(Hyd2)NH;
• (Hyd2)2N;
• and
• a C1-5 hydrocarbon group where 0, 1 or 2 of the carbons in the hydrocarbon group are replaced with a heteroatom selected from N, O and S, the hydrocarbon group being optionally substituted with one or more fluorine atoms;
• R5 is selected from halogen;
• O—Ar2;
• cyano, hydroxy;
• amino;
• Hyd1-SO2— and a non-aromatic C1-8 hydrocarbon group where 0, 1 or 2 but not all of the carbons in the hydrocarbon group are optionally replaced with a heteroatom selected from N, O and S and where the hydrocarbon group is optionally substituted with one or more fluorine atoms;
• Ar2 is a phenyl, pyridyl or pyridone group optionally substituted with 1 or 2 substituents selected from halogen;
• cyano and a C1-4 hydrocarbon group optionally substituted with one or more fluorine atoms;
• R6 is a group Q1-Ra—Rb;
• Q1 is absent or is a C1-3 saturated hydrocarbon linker;
• Ra is selected from O;
• C(O);
• C(O)O;
• CONRc;
• N(Rc)CO;
• N(Rc)CONRc, NRc;
• and SO2NRc;
• Rb is selected from:
• hydrogen;
• a C1-8 non-aromatic hydrocarbon group where 0, 1 or 2 of the carbon atoms in the hydrocarbon group are replaced with a heteroatom selected from N and O, the C1-8 non-aromatic hydrocarbon group being optionally substituted with one or more substituents selected from fluorine and a group Cyc1;
• and
• a group Cyc1;
• Cyc1 is a non-aromatic 4-7 membered carbocyclic or heterocyclic ring group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and being optionally substituted with one or more substituents selected from hydroxyl;
• amino;
• (Hyd2)NH;
• (Hyd2)2N;
• and a C1-5 hydrocarbon group where 0, 1 or 2 of the carbons in the hydrocarbon group are replaced with a heteroatom selected from N, O and S, the hydrocarbon group being optionally substituted with one or more fluorine atoms or by a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatom ring members selected from N and O;
• Rc is selected from hydrogen and a C1-4 non-aromatic hydrocarbon group;
• R7 is selected from R4;
• with the proviso that when n is 2 and both occurrences of R7 are —OCH3, R6 is not —NH2 or —NHCH3;
• and
• provided that the compound is other than:
• (i) a compound wherein R6 is hydroxy, methoxymethyl or unsubstituted or fluoro-substituted C1-8 alkoxy;
• (ii) a compound wherein the ring Z is an isoxazole ring and Ar1 is an unsubstituted 4-pyridyl group attached to the isoxazole 3-position, and R2 and R3 are both absent or
• (iii) a compound wherein Z is an isoxazole ring and R4 is an azetidin-4-yloxy group wherein the cancer is selected from:
• (a) leukemias, colon cancer, pancreatic cancer and lung cancer, or
• (b) brain cancers,
• (c) gliomas and glioblastomas, or
• (d) lymphomas,
• with the proviso that said treatment excludes prophylaxis and prevention of recurrence.