Bortezomib conjugates and methods using same

1. A compound of formula (I):

wherein in formula (I):

each occurrence of R 1 is independently selected from the group consisting of hydrogen and alkyl;

R 2 is selected from the group consisting of hydrogen and —OR 13 ;

R 3 is selected from the group consisting of hydrogen and alkyl;

R 4 is selected from the group consisting of hydrogen, alkyl, aryl, and alkylaryl wherein the alkyl group is optionally substituted with hydroxyl group;

L 1 is selected from the group consisting of alkyl, and alkyl-Z 4 C(O)NR 10 ;

L 2 is aryl or an alkyl chain of C 1 -C 6 alkyl, wherein any carbon atom in the alkyl chain is optionally substituted with one to two substituents selected from the group consisting of alkyl, cycloalkyl, and carbonyl;

L 3 is aryl or an alkyl chain of C 1 -C 6 alkyl, wherein any carbon atom in the alkyl chain is optionally substituted with one to two substituents selected from the group consisting of alkyl, cycloalkyl, and carbonyl; or

Y is selected from the group consisting of —PO(OR 8 )(OR 9 ), —PO(R 9 )(OR 8 ), and —CO 2 R 8 ;

Z 1 is selected from the group consisting of CH 2 and NR 6 ;

A is C(═O);

Z 2 is selected from the group consisting of CH 2 , NR 11 , S, and O;

Z 3 is N;

Z 4 is selected from the group consisting of CH 2 and O;

Z 5 is selected from the group consisting of

each occurrence of R 5 is independently selected from the group consisting of alkyl, aryl, F, Cl, Br, and I;

X 1 is selected from the group consisting of CR 15 and N;

X 2 is selected from the group consisting of CR 1′ and N;

R 6 is selected from the group consisting of hydrogen and alkyl;

R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen and alkyl;

R 11 and R 13 are each independently selected from the group consisting of hydrogen and alkyl;

R 15 and R 16 are each independently selected from the group consisting of hydrogen, alkyl, aryl, F, Cl, Br, and I;

n is an integer from 0 to 10; and

z is an integer from 0 to 2;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II):

wherein in formula (II):

each occurrence of R 1 is independently selected from the group consisting of hydrogen and alkyl;

R 2 is selected from the group consisting of hydrogen and —OR 13 ;

Y is selected from the group consisting of —PO(OR 8 )(OR 9 ), —PO(R 9 )(OR 8 ), and —CO 2 R 8 ;

A is C(═O);

Z 2 is selected from the group consisting of CH 2 , NR 11 , S, and O;

L 1 is selected from the group consisting of alkyl, and alkyl-Z 4 C(O)NR 10 ;

Z 4 is selected from the group consisting of CH 2 and O;

R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen and alkyl;

R 11 and R 13 are each independently selected from the group consisting of hydrogen and alkyl;

m is 1, or 2 or 3;

p is 1, or 2, or 3; and

n is an integer from 0 to 10; or

a pharmaceutically acceptable salt thereof.

3. A compound of formula (III):

wherein in formula (III):

each occurrence of R 1 is independently selected from the group consisting of hydrogen and alkyl;

R 2 is selected from the group consisting of hydrogen and —OR 13 ;

Y is selected from the group consisting of —PO(OR 8 )(OR 9 ), —PO(R 9 )(OR 8 ), and —CO 2 R 8 ;

Z 1 is selected from the group consisting of CH 2 and NR 6 ;

A is C(═O);

Z 2 is selected from the group consisting of CH 2 , NR 11 , S, and O;

Z 4 is selected from the group consisting of CH 2 and O;

R 6 is selected from the group consisting of hydrogen and alkyl;

R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen and alkyl;

R 11 and R 13 are each independently selected from the group consisting of hydrogen and alkyl; and

m is an integer from 1 to 5;

n is an integer from 0 to 10;

p is an integer from 1 to 5; and

x is an integer from 0 to 10; or

a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein Y is —PO 3 (R 1 ) 2 .

5. The compound of claim 1 , wherein L 1 is alkyl.

6. The compound of claim 1 , wherein L 2 is selected from the group consisting of phenyl and an alkyl chain of C 1 -C 6 alkyl, wherein one carbon atom in the alkyl chain is optionally substituted with two alkyl groups, a carbonyl group, or a cycloalkyl group.

7. The compound of claim 1 , wherein L 3 is selected from the group consisting of phenyl and an alkyl chain of C 1 -C 6 alkyl, wherein one carbon atom in the alkyl chain is optionally substituted with two alkyl groups, a carbonyl group, or a cycloalkyl group.

8. The compound of claim 1 , wherein Z 2 is O.

9. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or

a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. A composition for controlled local delivery of a therapeutic agent to bone, comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein in formula (I):

each occurrence of R 1 is independently selected from the group consisting of hydrogen and alkyl;

R 2 is selected from the group consisting of hydrogen and —OR 13 ;

R 3 is selected from the group consisting of hydrogen and alkyl;

R 4 is selected from the group consisting of hydrogen, alkyl, aryl, and alkylaryl wherein the alkyl, group is optionally substituted with hydroxyl group;

L 1 is selected from the group consisting of alkyl, and alkyl-Z 4 C(O)NR 10 ;

L 2 is aryl or an alkyl chain of C 1 -C 6 alkyl, wherein any carbon atom in the alkyl chain is optionally substituted with one to two substituents selected from the group consisting of alkyl, cycloalkyl, and carbonyl;

L 3 is aryl or an alkyl chain of C 1 -C 6 alkyl, wherein any carbon atom in the alkyl chain is optionally substituted with one to two substituents selected from the group consisting of alkyl, cycloalkyl, and carbonyl; or

Y is selected from the group consisting of —PO(OR 8 )(OR 9 ), —PO(R 9 )(OR 8 ), and —CO 2 R 8 ;

Z 1 is selected from the group consisting of CH 2 and NR 6 ;

A is C(═O);

Z 2 is selected from the group consisting of CH 2 , NR 11 , S, and O;

Z 3 is N;

Z 4 is selected from the group consisting of CH 2 and O;

Z 5 is selected from the group consisting of

each occurrence of R 5 is independently selected from the group consisting of alkyl, aryl, F, Cl, Br, and I;

X 1 is selected from the group consisting of CR 15 and N;

X 2 is selected from the group consisting of CR 16 and N;

R 6 is selected from the group consisting of hydrogen and alkyl;

R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen and alkyl;

R 11 and R 13 are each independently selected from the group consisting of hydrogen and alkyl;

R 15 and R 16 are each independently selected from the group consisting of hydrogen, alkyl, aryl, F, Cl, Br, and I;

n is an integer from 0 to 10; and

z is an integer from 0 to 2;

or a pharmaceutically acceptable salt thereof.

12. The composition of claim 11 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. The composition of claim 12 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

14. The composition of claim 11 , wherein the composition further comprises at least one pharmaceutically acceptable carrier.

15. The composition of claim 11 , wherein the therapeutic agent is controllably released from the compound at a site in need of bone formation.

16. A method of promoting bone formation at a site in need of bone formation in a subject or reducing bone resorption in a subject in need of less bone resorption, or both, the method comprising administering a therapeutically effective amount of a composition comprising at least one compound according to claim 1 .

17. A method of treating a disease selected from the group consisting of multiple myeloma and bone cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising at least one compound according to claim 1 .

18. The method of claim 16 , wherein the compound is selected from the group consisting of:

or

a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The method of claim 16 , wherein the composition further comprises at least one pharmaceutically acceptable carrier.

21. The method of claim 16 for prevention or treatment of the symptoms of a disease, wherein the subject has a disease or disorder selected from the group consisting of multiple myeloma, osteoporosis, osteonecrosis, osteoarthritis, rheumatoid arthritis, Paget's disease, bone fracture healing, prosthesis loosening, bone cancer, a myeloproliferative disease, radiotherapy-induced osteoporosis, leukemia, and cancers metastasized to bone.

22. The method of claim 16 , wherein the therapeutic agent is controllably released from the compound at the site in need of bone formation.

23. A method of killing cancer cells of bone, bone marrow and bone surrounding tissues in a subject, the method comprising administering a therapeutically effective amount of a composition comprising at least one compound according to claim 1 .

24. The method of claim 23 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25. The method of claim 23 , wherein the subject has multiple myeloma.

26. A method of promoting bone formation at a site in need of bone formation in a subject or reducing bone resorption in a subject in need of less bone resorption, or both, the method comprising administering a therapeutically effective amount of a composition comprising at least one compound according to claim 3 .

27. A method of treating a disease selected from the group consisting of multiple myeloma and bone cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a composition comprising at least one compound according to claim 3 .

28. The method of claim 17 for prevention or treatment of the symptoms of a disease, wherein the subject has a disease or disorder selected from the group consisting of multiple myeloma, osteoporosis, osteonecrosis, osteoarthritis, rheumatoid arthritis, Paget's disease, bone fracture healing, prosthesis loosening, bone cancer, a myeloproliferative disease, radiotherapy-induced osteoporosis, leukemia, and cancers metastasized to bone.

29. The method of claim 27 for prevention or treatment of the symptoms of a disease, wherein the subject has a disease or disorder selected from the group consisting of multiple myeloma, osteoporosis, osteonecrosis, osteoarthritis, rheumatoid arthritis, Paget's disease, bone fracture healing, prosthesis loosening, bone cancer, a myeloproliferative disease, radiotherapy-induced osteoporosis, leukemia, and cancers metastasized to bone.

30. The method of claim 17 , wherein the therapeutic agent is controllably released from the compound at the site in need of bone formation.

31. The method of claim 27 , wherein the therapeutic agent is controllably released from the compound at the site in need of bone formation.

32. A method of killing cancer cells of bone, bone marrow and bone surrounding tissues in a subject, the method comprising administering a therapeutically effective amount of a composition comprising at least one compound according to claim 3 .

33. The method of claim 26 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

34. The method of claim 27 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

35. The method of claim 29 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

36. The method of claim 31 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.