Phosphoramidate derivatives of nucleoside compounds for use in the treatment of cancer

A method of treatment of leukaemia comprising administering to a patient in need of such treatment an effective dose of a compound of formula I:

• wherein:
• each of X and Z is independently selected from H, OH, F, Cl, Br, I, C1-6alkyl and NR5R6, where each of R5 and R6 is independently selected from H and C1-6alkyl;
• Y is selected from H, OH, F, Cl, Br, I, C1-6alkyl, C2-8alkynyl, and NR5R6, where each of R5 and R6 is independently selected from H and C1-6 alkyl;
• each of T and T′ is independently selected from H, F and OH, with the proviso that only one of T and T′ can be OH;
• Q is selected from O, S and CR7R8, where R7 and R8 are independently selected from H and C1-6 alkyl,
• Ar is selected from C6-30aryl and C6-30heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, SO3H, SH, SR′, wherein R′ is independently selected from the same group as R1;
• carboxyl, C1-6 esters, C1-6aldehyde, cyano, C1-6alkylamino, C1-6dialkylamino, thiol, chloro, bromo, fluoro, iodo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkoxy-C5-10aryl, C5-7cycloalkyl, C5-11cycloalkyl-C1-6alkyl, C5-7cycloalkenyl, C5-7cycloalkynyl, C5-11arylC1-6alkyl, C1-6alkylC5-11aryl, C5-11aryl, C1-6 fluoroalkyl and C2-6fluoroalkenyl;
• each of R1 and R2 is independently selected from H, and the group consisting of C1-20alkyl, C2-20alkenyl, C1-20alkoxy, C1-20alkoxyC1-20alkyl, C1-20alkoxyC6-30aryl, C2-20alkynyl, C3-20cycloalkylC6-30aryl, C6-30aryloxy and C5-20heterocyclyl, any of which is optionally substituted with optional substituents;
• each of R3 and R4 is independently selected from H, and the group consisting of C1-20alkyl, C2-20alkenyl, C1-20alkoxy, C1-20alkoxyC1-20alkyl, C1-20alkoxyC6-30aryl, C2-20alkynyl, C3-20cycloalkylC6-30aryl, C6-30aryloxy and C5-20heterocyclyl, any of which is optionally substituted with optional substituents;
• the optional substituents on R1, R2, R3, and R4 being one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, amido, SO3, H, SH, SR′, wherein R′ is independently selected from the same group as R1;
• carboxy, C1-6esters, C1-6aldehyde, cyano, C1-6alkylamino, C1-6dialkylamino, thiol, chloro, bromo, fluoro, iodo C5-7cyclo alkyl, C5-7cycloalkenyl, C5-7cycloalkynyl, C5-11aryl, C5-11arylC1-6alkyl, and C5-20heterocyclyl;
• and pharmaceutically acceptable salts thereof.

A process for the preparation of a compound of formula I,

• the process comprising the process comprising reacting a compound of formula III:
• with a compound of formula IV:
• wherein
• each of X and Z is independently selected from H, OH, F, Cl, Br, I, C1-6alkyl and NR5R6, where each of R5 and R6 is independently selected from H and C1-6alkyl;
• Y is selected from OH, F, Cl, Br, I, C1-6alkyl, C2-8alkynyl, and NR5R6, where each of R5 and R6 is independently selected from H and C1-6 alkyl;
• each of T and T′ is independently selected from H, F and OH, with the proviso that only one of T and T′ can be OH;
• Q is selected from O, S and CR7R8, where R7 and R8 are independently selected from H and C1-6alkyl,
• Ar is selected from C6-30aryl and C6-30heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, SO3H, SH, SR′, wherein R′ is independently selected from the same group as R1;
• carboxyl, C1-6esters, C1-6aldehyde, cyano, C1-6alkylamino, C1-6dialkylamino, thiol, chloro, bromo, fluoro, iodo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy-C1-6alkyl, C1-6alkoxy-C5-10aryl, C5-7cycloalkyl, C5-11cycloalkyl-C1-6alkyl, C5-7cycloalkenyl, C5-7cycloalkynyl, C5-11arylC1-6alkyl, C1-6alkylC5-11aryl, C5-11aryl, C1-6fluoroalkyl and C2-6fluoroalkenyl;
• each of R1 and R2 is independently selected from H, and the group consisting of C1-20alkyl, C2-20alkenyl, C1-20alkoxy, C1-20alkoxyC1-20alkyl, C1-20alkoxyC6-30aryl, C2-20alkynyl, C3-20cycloalkylC6-30aryl, C6-30aryloxy and C5-20heterocyclyl, any of which is optionally substituted with optional substituents;
• each of R3 and R4 is independently selected from H, and the group consisting of C1-20alkyl, C2-20alkenyl, C1-20alkoxy, C1-20alkoxyC1-20alkyl, C1-20alkoxyC6-30aryl, C2-20alkynyl, C3-20cycloalkylC6-30aryl, C6-30aryloxy and C5-20heterocyclyl, any of which is optionally substituted with optional substituents;
• the optional substituents on R1, R2, R3, and R4 being one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, amido, SO3, H, SH, SR′, wherein R′ is independently selected from the same group as R1;
• carboxy, C1-6esters, C1-6aldehyde, cyano, C1-6alkylamino, C1-6dialkylamino, thiol, chloro, bromo, fluoro, iodo, C5-7cycloalkyl, C5-7cycloalkenyl, C5-7cycloalkynyl, C5-11aryl, C5-11arylC1-6alkyl, and C5-20heterocyclyl.