A method of treating a subject having, or at risk of having triple negative breast cancer or a brain metastasis arising from triple negative breast cancer, said method comprising administering to the subject a therapeutically effective amount of a compound which is a compound of the formula (1):
- or a salt, tautomer or N-oxide thereof;
- wherein:
- one of Y and Z is R3 and the other is Ar2;
- Q1 is a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached;
- and wherein a carbon atom of the C1-8 alkylene group may optionally be replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group provided that the total number of carbon atoms in an alkylene group containing such a replacement does not exceed 8;
- Q2 is a bond or a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached;
- R1 is selected from hydrogen, NRxRy and a group Cy1;
- Rx and Ry are the same or different and each is selected from hydrogen, C1-4 hydrocarbyl or hydroxy-C1-4 hydrocarbyl;
- or NRxRy forms a 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S and oxidised forms thereof, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms in line between the amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino and hydroxy substituents when present and the nitrogen atom of the NRxRy group;
- Cy1 is a C-linked 3 to 7 membered monocyclic non-aromatic carbocyclic or heterocyclic group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and oxidised forms of S, and being optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy;
- R2 and R4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;
- R3 is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;
- Ar1 is a monocyclic 5 or 6-membered aryl or heteroaryl ring containing 0, 1 or 2 heteroatom ring members selected from O, N and S, the aryl or heteroaryl being optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from halogen, cyano and a group Ra—Rb;
- Ra is a bond, O, CO, X3C(X4), C(X4)X3, X3C(X4)X3, S, SO, SO2, NRc, SO2NRc or NRcSO2;
- Rb is:
- hydrogen;
- a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6;
- or
- an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy;
- oxo;
- halogen;
- cyano;
- carboxy;
- amino;
- mono- or di-C1-4 alkylamino;
- and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6;
- wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2, NRc, X3C(X4), C(X4)X3 or X3C(X4)X3;
- R6 is selected from the substituents R5 except that R6 does not consist of or contain a carbocyclic or heterocyclic group;
- X3 is O, S or NRc;
- and
- X4 is ═O, ═S or ═NRc;
- and
- Rc is hydrogen or C1-4 hydrocarbyl;
- Ar2 is a bicyclic 8 to 11-membered heteroaryl group containing 1, 2, 3 or 4 heteroatom ring members selected from O, N and S and being optionally substituted with 1, 2 or 3 substituents R7 selected from oxo, fluorine;
- chlorine;
- bromine;
- C1-4 hydrocarbyl optionally substituted with one or more fluorine atoms;
- C1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms;
- hydroxy;
- cyano;
- N(Rc)2;
- Rc—C(O)—;
- Rc—C(O)N(Rc)—;
- (Rc)2NC(O)—;
- Rc—SO2NRc—;
- Rc—NHC(O)NH—;
- (Rc)2NSO2-;
- and five and six-membered monocyclic groups containing from 0 to 3 heteroatom ring members selected from O, N and S, the five and six-membered monocyclic groups being unsubstituted or substituted with one or more substituents R8 selected from C1-4 hydrocarbyl, C1-4 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, mono-C1-4 hydrocarbylamino and di-C1-4hydrocarbylamino and wherein the hydrocarbyl moieties when present are optionally substituted with fluorine, C1-2 alkoxy, hydroxy, amino, mono-di-C1-2alkylamino or di-C1-4alkylamino;
- and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.