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

1. A compound of formula I:

wherein:

each of X and Z is independently selected from H, OH, F, Cl, Br, I, C 1-6 alkyl and NR 5 R 6 , where each of R 5 and R 6 is independently selected from H and C 1-6 alkyl;

Y is selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 2-8 alkynyl, and NR 5 R 6 , where each of R 5 and R 6 is independently selected from H and C 1-6 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 CR 7 R 8 , where R 7 and R 8 are independently selected from H and C 1-6 alkyl,

Ar is selected from C 6-30 aryl and C 6-30 heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, SO 3 H, SH, SR′, wherein R′ is independently selected from the same group as R 1 ; carboxyl, C 1-6 esters, C 1-6 aldehyde, cyano, C 1-6 alkylamino, C 1-6 dialkylamino, thiol, chloro, bromo, fluoro, iodo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 5-10 aryl, C 5-7 cycloalkyl, C 5-11 cycloalkyl-C 1-6 alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkynyl, C 5-11 arylC 1-6 alkyl, C 1-6 alkylC 5-11 aryl, C 5-11 aryl, C 1-6 fluoroalkyl and C 2-6 fluoroalkenyl;

each of R 1 and R 2 is independently selected from H, and the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkylC 6-30 aryl, C 6-30 aryloxy and C 5-20 heterocyclyl, any of which is optionally substituted with optional substituents;

each of R 3 and R 4 is independently selected from H, and the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkylC 6-30 aryl, C 6-30 aryloxy and C 5-20 heterocyclyl, any of which is optionally substituted with optional substituents;

the optional substituents on R 1 , R 2 , R 3 , and R 4 being one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, amido, SO 3 , H, SH, SR′, wherein R′ is independently selected from the same group as R 1 ; carboxy, C 1-6 esters, C 1-6 aldehyde, cyano, C 1-6 alkylamino, C 1-6 dialkylamino, thiol, chloro, bromo, fluoro, iodo, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkynyl, C 5-11 aryl, C 5-11 arylC 1-6 alkyl, and C 5-20 heterocyclyl;

and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 wherein each of X and Z is independently selected from H, OH, F, Cl and NH 2 and Y is selected from OH, F, Cl, NH 2 and C 2-8 alkynyl.

3. The compound according to claim 2 wherein X is NH 2 , Y is Cl and Z is H.

4. The compound according to claim 2 wherein X is Cl, Y is NH 2 and Z is H.

5. The compound according to claim 2 wherein X is NH 2 , Y is F and Z is H.

6. The compound according to claim 1 wherein one or both of T and T′ is F.

7. The compound according to claim 2 wherein X is NH 2 , Y is C 2-8 alkynyl, Z is H, T is H and T′ is OH.

8. The compound according to claim 1 wherein T and T′ are each H.

9. The compound according to claim 1 wherein Q is O.

10. The compound according to claim 1 wherein R 4 is H.

11. The compound according to claim 1 wherein R 1 and R 2 are selected such that the moiety —N—CR 1 R 2 —COO— corresponds to that of a natural amino acid.

12. The compound according to claim 1 wherein each of R 1 and R 2 is independently selected from Me and H.

13. The compound according to claim 12 wherein one of R 1 and R 2 is Me and one of R 1 and R 2 is H such that the C atom bearing R 1 and R 2 has chirality L as in natural alanine.

14. The compound according to claim 1 wherein Ar is unsubstituted.

15. The compound according to claim 1 wherein Ar is substituted with one, two, three, four, five or more substituents.

16. The compound according to claim 1 wherein Ar is selected from the group consisting of phenyl, pyridyl, naphthyl and quinolyl, each of which may be substituted or unsubstituted.

17. The compound according to claim 1 comprising the diastereoisomer R p , the diastereoisomer S p or a mixture of the diastereoisomers R p and S p .

18. A compound selected from the group consisting of:

and

19. The compound:

20. A pharmaceutical composition comprising the compound according to claim 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient.

21. A method of treatment of leukaemia, comprising administering to a patient in need of such treatment an effective dose of a compound according to claim 1 .

22. 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, C 1-6 alkyl and NR 5 R 6 , where each of R 5 and R 6 is independently selected from H and C 1-6 alkyl;

Y is selected from H, OH, F, Cl, Br, I, C 1-6 alkyl, C 2-8 alkynyl, and NR 5 R 6 , where each of R 5 and R 6 is independently selected from H and C 1-6 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 CR 7 R 8 , where R 7 and R 8 are independently selected from H and C 1-6 alkyl,

Ar is selected from C 6-30 aryl and C 6-30 heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, SO 3 H, SH, SR′, wherein R′ is independently selected from the same group as R 1 ; carboxyl, C 1-6 esters, C 1-6 aldehyde, cyano, C 1-6 alkylamino, C 1-6 dialkylamino, thiol, chloro, bromo, fluoro, iodo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 5-10 aryl, C 5-7 cycloalkyl, C 5-11 cycloalkyl-C 1-6 alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkynyl, C 5-11 arylC 1-6 alkyl, C 1-6 alkylC 5-11 aryl, C 5-11 aryl, C 1-6 fluoroalkyl and C 2-6 fluoroalkenyl;

each of R 1 and R 2 is independently selected from H, and the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkylC 6-30 aryl, C 6-30 aryloxy and C 5-20 heterocyclyl, any of which is optionally substituted with optional substituents;

each of R 3 and R 4 is independently selected from H, and the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkylC 6-30 aryl, C 6-30 aryloxy and C 5-20 heterocyclyl, any of which is optionally substituted with optional substituents;

the optional substituents on R 1 , R 2 , R 3 , and R 4 being one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, amido, SO 3 , H, SH, SR′, wherein R′ is independently selected from the same group as R 1 ; carboxy, C 1-6 esters, C 1-6 aldehyde, cyano, C 1-6 alkylamino, C 1-6 dialkylamino, thiol, chloro, bromo, fluoro, iodo C 5-7 cyclo alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkynyl, C 5-11 aryl, C 5-11 arylC 1-6 alkyl, and C 5-20 heterocyclyl;

and pharmaceutically acceptable salts thereof.

23. A method of preparing a pharmaceutical composition comprising the step of combining an effective dose of a compound according to claim 1 with a pharmaceutically acceptable excipient, carrier or diluent.

24. 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, C 1-6 alkyl and NR 5 R 6 , where each of R 5 and R 6 is independently selected from H and C 1-6 alkyl;

Y is selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 2-8 alkynyl, and NR 5 R 6 , where each of R 5 and R 6 is independently selected from H and C 1-6 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 CR 7 R 8 , where R 7 and R 8 are independently selected from H and C 1-6 alkyl,

Ar is selected from C 6-30 aryl and C 6-30 heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, SO 3 H, SH, SR′, wherein R′ is independently selected from the same group as R 1 ; carboxyl, C 1-6 esters, C 1-6 aldehyde, cyano, C 1-6 alkylamino, C 1-6 dialkylamino, thiol, chloro, bromo, fluoro, iodo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 5-10 aryl, C 5-7 cycloalkyl, C 5-11 cycloalkyl-C 1-6 alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkynyl, C 5-11 arylC 1-6 alkyl, C 1-6 alkylC 5-11 aryl, C 5-11 aryl, C 1-6 fluoroalkyl and C 2-6 fluoroalkenyl;

each of R 1 and R 2 is independently selected from H, and the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkylC 6-30 aryl, C 6-30 aryloxy and C 5-20 heterocyclyl, any of which is optionally substituted with optional substituents;

each of R 3 and R 4 is independently selected from H, and the group consisting of C 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkylC 6-30 aryl, C 6-30 aryloxy and C 5-20 heterocyclyl, any of which is optionally substituted with optional substituents;

the optional substituents on R 1 , R 2 , R 3 , and R 4 being one or more substituents independently selected from the group consisting of hydroxy, acyl, acyloxy, nitro, amino, amido, SO 3 , H, SH, SR′, wherein R′ is independently selected from the same group as R 1 ; carboxy, C 1-6 esters, C 1-6 aldehyde, cyano, C 1-6 alkylamino, C 1-6 dialkylamino, thiol, chloro, bromo, fluoro, iodo, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkynyl, C 5-11 aryl, C 5-11 arylC 1-6 alkyl, and C 5-20 heterocyclyl.