Phosphonium-ion tethered tetracycline drugs for treatment of cancer

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

• wherein
• RW is H or OH;
• RX is H;
• RY is H, C1-C6-alkyl or C1-C6-haloalkyl;
• RZ is H, NRZ1RZ2, C1-C6-haloalkyl, or halo, wherein RZ1 and RZ2 are both independently selected from H or C1-C6-alkyl;
• -L1- is absent or is —CR2aR2b;
• -L2- is absent or is independently selected from —O—, —S—, —NR3a—, —C(O)NR3b—, —C(O)—, —OC(O)—, —NR3bC(O)—, NR5S(O)2—, —OC(O)NR3b—, —NR3bC(O)O— and —NR3bC(O)NR3c;
• -L3- and L5- are each independently at each occurrence selected from —C1-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 10 independently selected R4 groups;
• provided that any -L3- or -L5- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is —C2-C4-alkylene-;
• -L4- is independently at each occurrence either absent or is selected from:
• —O—, —S—, —NR3a—, —C(O)—, —OC(O)—, —C(O)O—, —SO2—, —S(O)—, —NR3bC(O)—, —C(O)NR3b, NR3bS(O)2—, —S(O)2NR3b—, —OC(O)NR3b—, —NR3bC(O)O—, NR3bC(O)NR3c, —CR5a═CR5b— and —C≡C—;
• n is an integer selected from 0, 1, 2, 3, 4 and 5;
• wherein L1, L2, L3 L4 and L5 together form a linker and L1, L2, L3 L4 and L5 are selected such that length of the linker 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 R1c 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, OR6, SR7, NR7R8, C(O)OR7, C(O)NR7R7, halo, cyano, nitro, C(O)R7, S(O)2OR7, S(O)R7, S(O)2R7 and S(O)2NR7R7;
• 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, OR6, SR7, NR7R8, C(O)OR7, C(O)NR7R7, halo, cyano, nitro, C(O)R7, S(O)2OR7, S(O)R7, S(O)2R7, S(O)2NR7R7, OC(O)NR7R7 and NR7C(O)OR6;
• R2a and R2b are each independently selected from H and C1-C4-alkyl;
• R3a, is independently at each occurrence selected from H, C1-C6-alkyl, —C(O)H, —C(O)—C1-C6-alkyl and —S(O)2—C1-C6-alkyl
• R3b and R3c are each independently at each occurrence selected from H and C1-C6-alkyl;
• R4 is independently at each occurrence selected from:
• C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, C1-C6-haloalkyl, OR6, SR7, NR7R8, C(O)OR7, C(O)NR7R7, halo, cyano, nitro, C(O)R7, S(O)2OR7, S(O)R7, S(O)2R7 and S(O)2NR7R7;
• R5a and R5b are independently at each occurrence selected from H, C1-C4-alkyl and halo;
• R6 is independently at each occurrence selected from:
• H, C1-C6-alkyl and C1-C6-haloalkyl;
• R7 and R6a are independently at each occurrence selected from:
• H and C1-C6-alkyl;
• R8 is independently at each occurrence selected from:
• H, C1-C6-alkyl, C(O)C1-C6-alkyl and S(O)2—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 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.