Nitrobenzyl derivatives of anti-cancer agents

A method of treating cancer overexpressing AKR1C3 reductase comprising administering to a patient in need thereof a therapeutically effective amount of a compound, wherein the compound is formula (I):

• or a pharmaceutically acceptable salt, or a solvate thereof, wherein
• X10 consists of O;
• A is C6-C10 aryl, 5-15 membered heteroaryl, or —N═CR1R2;
• each R1 and R2 independently is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR13R14, or —NR13COR14;
• each X, Y, and Z independently is hydrogen, CN, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR13R14, or —NR13COR14;
• each R independently is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR13R14, or —NR13COR14;
• each R13 and R14 independently is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether;
• wherein L1 and D are defined as follows:
• (1) L1 is selected from the group consisting of:
• R40 and R41 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-15 membered heterocycle, or 5-15 membered heteroaryl;
• R42 is C2-C3 alkylene or heteroalkylene optionally substituted with 1-3 C1-C6 alkyl groups;
• V(−) is any anion;
• D is a moiety such that D-OH is an anti-cancer drug wherein OH is an aliphatic or a phenolic hydroxy group or is an OH moiety attached to a phosphorous atom;
• or
• (2) L1 is:
• R40 is defined as above, R43 is hydrogen or together with D forms a heterocycle ring, and the phenylene moiety is optionally substituted, and
• D is a moiety such that D-NR43H is an anti-cancer drug;
• or
• (3) L1 is a bond, —O—C(R40R41)2—, —O—C(R40R41)—NR40R41(+)-C(R40R41)—, or
• wherein R40, R41 and V are defined as above, and
• D is an anti-cancer drug containing a tertiary or a secondary nitrogen atom, wherein the tertiary or the secondary nitrogen atom is bonded to L1;
• and
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, or ether groups are optionally substituted.