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1. (WO2019007447) MULTIFUNCTIONAL CONJUGATES
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CLAIMS

1. A compound of formula Q-T-L wherein Q is a bisphosphonate moiety, T is linker and L is an anti-osteolytic or osteoinductive phytochemical.

2. A compound according to any one of the preceding claims wherein the anti-osteolytic or osteoinductive phytochemical is a phenolic phytochemical.

3. A compound according to any one of the preceding claims wherein the anti-osteolytic or osteoinductive phytochemical is a selected from the group consisting of vitamin E derivatives, reserveratrols, retinols, flavonoids, terpenes, germacrane sesquiterpenes, matairesinol, xanthine derivatives, hallucinogens, isoflavones, lignans, flavones, flavanols, flavanones, catechins, epigallocatechin gallate (EGCG), stilbenes, cannabinoids, curcuminoids, caryophyllene type sesquiterpene lactone, zerumbone, andrographolide, natural diterpenoid lactone, carotenoids, quercetin, lycopene, phenolics, resveratrol, phloridzin, pectin (suitably derived from tomato, grapes, apples, and citrus fruits), vitamin D, genistein, curcumin (suitably from turmeric), capsaicin, (red pepper), eugenol, (suitably from cloves), gingerol, (suitably from ginger), anethol (suitably from cumin, anise, or fennel), ursolic acid (basil and rosemary), diallyl sulfide, S-allylmercaptocysteine, ajoene (suitably from garlic), ellagic acid (suitably from pomegranate), daidzein, medicarpin (suitably from legumes) and equol.

4. A compound according to any one of the preceding claims wherein the anti-osteolytic and/or osteoinductive phytochemical is a vitamin E derivatives.

5. A compound according to claim 1 wherein the anti-osteolytic and/or osteoinductive phytochemical is selected from α-, β-, γ-, or δ-tocopherol, α-, β-, γ- or δ-tocotrienol, eupafolin, carnosol, scutellarein, genkwanin, kaempferol, acacetin, rosmarinic acid, rosmanol, cirsimaritin, luteolin and 7-epi-rosmanol matairesinol, epigallocatechin gallate (EGCG), zerumbone, andrographolide, quercetin, lycopene, resveratrol, phloridzin, vitamin D, genistein, curcumin (suitably from turmeric), capsaicin, (red pepper), eugenol, (suitably from cloves), gingerol, (suitably from ginger), anethol (suitably from cumin, anise, or fennel), ursolic acid (basil and rosemary), diallyl sulfide, S-allylmercaptocysteine, ajoene (suitably from garlic), ellagic acid (suitably from pomegranate), daidzein, medicarpin (suitably from legumes) and equol.

6. A compound according to any one of the preceding claims wherein the anti-osteolytic and/or osteoinductive phytochemical is selected from α-, β-, γ-, or δ-tocopherol and α, β-, γ-or δ-tocotrienol.

7. A compound of formula (I), or a salt or solvate thereof:


wherein,

A, E, J and G are independently selected from hydrogen and C-|.6 alkyl;

Z is selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, and Ci_6 alkyl, wherein said aryl, heteroaryl and C^e alkyl may optionally be substituted by one or more Rz groups;

Rz is selected from hydrogen, hydroxyl, halogen, COOH, CN, C1-6 haloalkyl, d-6 haloalkoxy, C3.6cycloalkyl, C1-6 alkyl and O-C^ alkyl;

X1 is a (CR'R")n group and X2 is a (CR'R")m group, wherein R' and R" are independently selected from hydrogen and C1-6 alkyl and m and n are numbers independently selected from 0 to 5;

M is selected from N(R), S, O and C(0)0; wherein R is selected from hydrogen and C^ alkyl;

R1, R2 and R3 are independently selected from hydrogen and C1-6 alkyl;

R4 is a Ci-6 alkyl group;

R5 is selected from:


8. A compound of formula (I) according to claim 7 wherein A, E, J and G are independently selected from hydrogen, methyl and ethyl.

9. A compound of formula (I) according to any one of claims 7 and 8 wherein A, E, J and G are all hydrogen or all ethyl.

10. A compound of formula (I) according to any one of claims 7 to 9 wherein X1 is (CH2)n and n is a number selected from 2 and 3.

11. A compound of formula (I) according to any one of claims 7 to 10 wherein M is O and n is 3.

12. A compound of formula (I) according to any one of claims 7 to 11 wherein M is C(0)0 and n is 2.

13. A compound of formula (I) according to any one of claims 7 to 12 wherein Z is hydrogen.

14. A compound of formula (I) according to any one of claims 7 to 13 wherein m is 0.

15. A compound of formula (I) according to any one of claims 7 to 14 wherein R1, R2, and R3 are independently selected from hydrogen or methyl.

16. A compound of formula (I) according to any "one of claims 7 to 15, wherein R1, R2 and R3 are methyl.

17. A compound of formula (I) according to any one of claims 7 to 15, wherein R is methyl, R2 is hydrogen and R3 is methyl.

18. A compound of formula (I) according to any one of claims 7 to 15, wherein R1 is hydrogen, R2 is methyl and R3 is methyl.

19. A compound of formula (I) according to any one of claims 7 to 15, wherein R1 is hydrogen, R2 is hydrogen and R3 is methyl.

20. A compound of formula (I) according to any one of claims 7 to 19 wherein R4 is methyl.

21. A compound of formula (I) according to any one of claims 7 to 20 wherein R5 is


22. A compound of formula (I) according to any one of claims 7 to 20 wherein R5 is


23. A compound of formula (la), or a pharmaceutically acceptable salt or solvate thereof:


(la)

wherein,

A is selected from hydrogen and Ci_3 alkyl;

Z is selected from hydrogen or hydroxyl;

X is selected from (CH)n and n is a number between 1 and 5;

M is selected from O and C(0)0; and

R1, R2 and R3 are independently selected from hydrogen and C -3 alkyl.

24. A compound of formula (la) according to claim 23 wherein A is selected from hydrogen or ethyl.

25. A compound of formula (la) according to any one of claims 23 and 24 wherein Z is H, n is 2 and M is C(0)0.

26. A compound of formula (la) according to any one of claims 23 and 24 wherein Z is OH, n is 3 and M is O.

27. A compound of formula (la) according to any one of claims 23 to 26 wherein R1, R2, and R3 are independently selected from hydrogen or methyl.

28. A compound of formula (la) according to any one of claims 23 to 27 wherein R1, R2 and R3 are methyl.

29. A compound of formula (la) according to any one of claims 23 to 27 wherein R1 is methyl, R2 is hydrogen and R3 is methyl.

30. A compound of formula (la) according to any one of claims 23 to 27, wherein R1 is hydrogen, R2 is methyl and R3 is methyl.

31. A compound of formula (la) according to any one of claims 23 to 27, wherein R1 is hydrogen, R2 is hydrogen and R3 is. methyl.

32. A compound of formula (lb), or a pharmaceutically acceptable salt or solvate thereof:


(lb)

wherein,

A is selected from hydrogen and Ci_3 alkyl;

Z is selected from hydrogen and hydroxyl;

X is selected from (CH)n and n is a number between 1 and 5;

M is selected from O and C(0)0; and

R1, R2 and R3 are independently selected from hydrogen and Ci-3 alkyl.

33. A compound of formula (lb) according to claim 32 wherein A is selected from hydrogen or ethyl.

34. A compound of formula (lb) according to any one of claims 32 and 33 wherein Z is H, n is 2 and M is C(0)0.

35. A compound of formula (lb) according to any one of claims 32 and 34 wherein Z is OH, n is 3 and M is O.

36. A compound of formula (lb) according to any one of claims 32 to 35 wherein R1, R2, and R3 are independently selected from hydrogen or methyl.

37. A compound of formula (lb) according to any one of claims 32 to 36 wherein R1, R2 and R3 are methyl.

38. A compound of formula (lb) according to any one of claims 32 to 36 wherein R1 is methyl, R2 is hydrogen and R3 is methyl.

39. A compound of formula (lb) according to any one of claims 32 to 36, wherein R is hydrogen, R2 is methyl and R3 is methyl.

40. A compound of formula (lb) according to any one of claims 32 to 36, wherein R1 is hydrogen, R2 is hydrogen and R3 is methyl.

41. A compound selected from:


69

or pharmaceutically acceptable salts or solvates thereof. 42. A compound according to claim 36 selected from:


or pharmaceutically acceptable salts or solvates thereof.

43. A compound according to any one of claims 41 and 42 selected from:

or pharmaceutically acceptable salts or solvates thereof.

44. A pharmaceutical composition comprising a compound according to claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

45. A compound as defined in any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

46. A compound as defined in any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a proliferative disorder.

47. A compound as defined in any one of claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of bone cancer.

48. A method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to claims 1 to 43, or a pharmaceutically acceptable salt or solvate thereof.

49. The method of claim 48, wherein the proliferative condition is bone cancer.

50. A combination comprising a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 43, with one or more additional therapeutic agents.