Polymer-des-ethyl sunitinib conjugates

1. A compound of Formula I-C, multi-arm:

wherein:

Xr is a releasable linkage-containing spacer moiety;

POLY is a poly(ethylene oxide);

R, when taken with Q, is a residue of polyol, polythiol, or polyamine bearing from 3 to about 50 hydroxyl, thiol or amino groups, respectively;

each Q is a linker selected from O, S, and NH; and

q is a positive integer from 3 to about 50;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Xr comprises a thioether, carbamate, ester, carbonate, urea, or enzyme-cleavable peptidic linkage.

3. The compound of claim 1 , wherein Xr is according to Formula III:

˜[X 1 ] a -Lr-[X 2 ] b ˜   (Formula III)

wherein:

a is zero or one;

b is zero or one;

X 1 , when present, is a first spacer;

Lr is a releasable linkage; and

X 2 , when present, is a second spacer.

4. A compound of claim 1 , wherein Xr comprises a structure selected from the group consisting of ˜C(O)O—,

wherein AASC 1 is a first amino acid side chain; AASC 2 is a second amino acid side chain; and AASC 1 and AASC 2 are selected such that the compound includes an enzymatically cleavable linkage.

5. The compound of claim 1 , wherein each POLY has a molecular weight of less than 2000 Daltons.

6. The compound of claim 1 , wherein each POLY has from about 1 to about 30 monomers.

7. The compound of claim 1 , wherein each POLY has from about 1 to about 10 monomers.

8. The compound of claim 1 , wherein each POLY has a molecular weight of from 2000 Daltons to about 150,000 Daltons.

9. The compound of claim 1 , wherein each POLY includes an alkoxy or hydroxy end-capping moiety.

10. The compound of claim 1 , wherein Q is oxygen and wherein R, when taken with Q, has a structure selected from:

wherein m is a positive integer from 0-40.

11. The compound of claim 1 , wherein q is 3.

12. The compound of claim 1 , wherein q is 4.

13. The compound of claim 1 , wherein q is 5.

14. The compound of claim 1 , wherein q is 6.

15. The compound of claim 1 , wherein q is 7.

16. The compound of claim 1 , wherein q is 9.

17. The compound of claim 1 , wherein q is 10.

18. A compound of claim 1 , wherein the compound is selected from the group consisting of

(Z)-1-(ethyl(2-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)ethyl)carbamoyloxy)ethyl 2-(2-(4armPEG 20,000)acetamido)propanoate (Compound 14);

(Z)-1-(ethyl(2-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)ethyl)carbamoyloxy)ethyl 2-(2-(4armPEG 20,000)acetamido)acetate (Compound 15); and

(Z)-1-(ethyl(2-(5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)ethyl)carbamoyloxy)ethyl 2-((4armPEG 20,000)carbonylamino)-4-methylpentanoate (Compound 16).

19. A composition comprising:

(i) a compound of claim 1 ; and

(ii) a pharmaceutically acceptable excipient.

20. A dosage form comprising the composition of claim 19 .

21. A method of treating a subject having a condition that is mediated by abnormal protein kinase activity, the method comprising administering to the subject, a therapeutically effective amount of a compound of claim 1 .