Azithromycin derivatives containing a phosphonium ion as anticancer agents

A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:

• wherein
• either Z1 is
• and Z2 is R4b;
• or Z2 is
• and Z1 is R2b;
• Z3 is independently selected from H, C(O)—C1-C6-alkyl or Z3 has the structure:
• Z4 is independently selected from H, C(O)—C1-C6-alkyl or Z4 has the structure:
• -L1- is independently absent or is selected from —C(O)—, —C(O)O—, —S(O)2—, —S(O)—, —C(O)NR5, and —S(O)2NR5—;
• -L3- is independently at each occurrence either absent or selected from:
• —O—, —S—, —NR6—, —C(O)—, —OC(O)—, —C(O)O—, —S(O)2—, —S(O)—, —NR5C(O)—, —C(O)NR5, —NR5S(O)2—, —S(O)2NR5—, —OC(O)NR5—, —NR5C(O)O—, NR5C(O)NR5, —CR7═CR7— and —C≡C—;
• -L2- and -L4- are each independently at each occurrence —C1-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R8 groups;
• provided that any -L2- or -L4- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is —C2-C4-alkylene-;
• -L5- is independently absent or is selected from:
• —C(O)— and —C(O)NR5—;
• n is an integer selected from 0, 1, 2, 3, 4 and 5;
• wherein L1, L2, L3, L4, L5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;
• R1a, R1b and R1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered heteroaryl, C3 to C8-cycloalkyl, C1-C8-alkyl and 4- to 8-membered heterocycloalkyl;
• wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered heteroaryl is optionally substituted with from 1 to 5 independently selected R1d groups;
• and wherein said C3 to C8-cycloalkyl, C1-C8-alkyl and 4- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R1e groups;
• provided that R1a, R1b and R1c are not each unsubstituted phenyl;
• wherein R1a and R1b are optionally connected to each other via a bond or a group selected from —O—, NR6a, and C1-C3-alkylene;
• R1d is independently at each occurrence selected from:
• C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or 10-membered heteroaryl, phenyl, OR9, SR10, NR10R11, C(O)OR10, C(O)NR10R10, halo, cyano, nitro, C(O)R10, S(O)2OR10, S(O)R10, S(O)2R10, S(O)2NR10R10, OC(O)NR10R10 and NR10C(O)OR10;
• R1e is independently at each occurrence selected from:
• oxo, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or 10-membered heteroaryl, phenyl, OR9, SR10, NR10R11, C(O)OR10, C(O)NR10R10, halo, cyano, nitro, C(O)R10, S(O)2OR10, S(O)R10, S(O)2R10, S(O)2NR10R10, OC(O)NR10R10 and NR10C(O)OR10;
• R2a, R2b and R2c are each independently selected from H and C1-C6-alkyl;
• R3a is independently selected from:
• H, C1-C6-alkyl and C(O)—C1-C6-alkyl;
• R3b and R3c are each independently selected from:
• H and C(O)—C1-C6-alkyl;
• R4a and R4b are each independently selected from:
• H, C1-C6-alkyl and C(O)—C1-C6-alkyl;
• or R4a and R4b taken together form C(O);
• R5 and R6a are each independently at each occurrence selected from H and C1-C6-alkyl;
• R6 and R11 are each independently at each occurrence selected from:
• H, C1-C6-alkyl, C(O)C1-C6-alkyl and S(O)2—C1-C6-alkyl;
• R7 is independently at each occurrence selected from H, C1-C4-alkyl and halo;
• R8 is independently at each occurrence selected from:
• C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, OR9, SR10, NR10R11, C(O)OR10, C(O)NR10R10, halo, cyano, nitro, C(O)R10, S(O)2OR10, S(O)R10, S(O)2R10, S(O)2NR10R10, OC(O)NR10R10 and NR10C(O)OR10;
• R9 is independently at each occurrence selected from:
• H, C1-C6-alkyl and C1-C6-haloalkyl;
• R10 is independently at each occurrence selected from:
• H and C1-C6-alkyl;
• and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, ORa, NRaRb, SRa, C(O)ORa, C(O)NRaRa, halo, cyano, nitro, C(O)Ra, S(O)2ORa, S(O)2Ra, S(O)Ra and S(O)2NRaRa;
• wherein Ra is independently at each occurrence selected from:
• H and C1-C6-alkyl;
• and Rb is independently at each occurrence selected from:
• H, C1-C6-alkyl, C(O)C1-C6-alkyl and S(O)2—C1-C6-alkyl.