Polyethylene glycol-conjugated glucocorticoid prodrugs and compositions and methods thereof

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

n is an integer from 3 to 500;

m is an integer from 1 to 5;

w is an integer from 1 to 5;

A is absent, C 1 -C 6 alkylene, or C 6 -C 10 arylene;

B is absent, NR 4 , O, or C(O);

D is absent, NR 4 , O, C(O), or CR 5 R 5 ;

E is absent, C 1 -C 6 alkylene, or a linker comprising a branched structure capable of connecting to two or more R 2 groups, said linker optionally comprising one, two, or more heteroatoms independently selected from the group consisting of O, S, and N;

G is absent, NR 4 , or O;

P is absent or C(O);

Q is absent, C 6 -C 10 arylene, or C 1 -C 6 alkylene;

T is absent, C 1 -C 6 alkylene, C 6 -C 10 arylene, or C(O);

X is absent, O, S, or NR 4 ;

Y is absent, C(O), C 6 -C 10 arylene, or C 1 -C 6 alkylene;

Z is absent, NR 4 , O, C 1 -C 6 alkylene, or a linker comprising a branched structure capable of connecting to one or more dexamethasone moieties, said linker optionally comprising one or more heteroatoms independently selected from the group consisting of O, S, and N;

R 1 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, each group except H optionally substituted by one to five substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, oxo (═O), —NR a R b , —NO 2 , —CN, —OR 3 , and —SR 3 ; or alternatively, R 1 is —CH 2 -A-B-D-E-(R 2 ) m ;

R 3 at each occurrence is independently H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

R 4 at each occurrence is independently H or C 1 -C 4 alkyl;

R 5 at each occurrence is independently H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

R a and R b are each independently H or C 1 -C 4 alkyl; and

wherein when any of groups A, B, D, E, G, P, Q, T, X, Y, and Z is absent, its two available adjacent groups are single-bonded to each other directly;

provided, however, that if the compound of formula (I) is a compound of formula:

then n is greater than 30.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is a linker comprising a branched structure capable of covalently bonding to two or more R 2 groups, said linker optionally comprising one or more heteroatoms independently selected from the group consisting of O, S, and N.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a linker comprising a branched structure capable of covalently bonding to two or more dexamethasone moieties, said linker optionally comprising one or more heteroatoms independently selected from the group consisting of O, S, and N.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E and Z are each independently selected from the group consisting of absent, C 1 -C 4 alkylene, an amino acid-based linker, a citric acid-based linker, a glycerol-based linker, a tris(2-aminoethyl)amine-based linker, a pentaerythritol-based linker, and a pentetic acid-based linker, respectively having a formula as follows:

wherein i and j are each independently 0 or an integer select from 1 to 5.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

w is 1;

Z is absent or C 1 -C 4 alkylene;

E is selected from the group consisting of:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1; w is 1; and A, B, D, E, and Z are all absent, and the compound is a compound of formula (II):

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 ; Y is C(O); X is NH; and T, Q, P, and G are all absent, and the compound is a compound of formula:

8. The compound of claim 5 , wherein A is C(O); B and D are absent; E is the amino acid based linker; m is 2; w is 1; Z and Y are absent, and X is NH, and the compound is a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

i=0 or an integer from 1 to 5;

j=0 or an integer from 1 to 5;

G=absent, NR 4 , or O;

P=absent or C(O);

Q=absent, C 6 -C 10 arylene, or C 1 -C 6 alkylene;

T=absent, C 1 -C 6 alkylene, C 6 -C 10 arylene, or C(O);

X=absent, O, S, or NR 4 ;

Y=absent or C 1 -C 6 alkylene;

R 1 =H or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, 5-10 membered heterocyclyl, each group except H optionally substituted by one to three substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, oxo (═O), —NR a R b , —NO 2 , —CN, —OR 3 , and SR 3 ;

R 3 at each occurrence is independently H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

R 4 at each occurrence is independently H or C 1 -C 4 alkyl;

R a and R b are each independently H or C 1 -C 4 alkyl; and

wherein when any of groups G, P, Q, T, X, and Y is absent, its two available adjacent groups are single-bonded to each other directly.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein i is 0; j is 2; E is a glutamic acid based linker having a formula:

10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein i is 0, j is 2, X is NH; and Q is methylene, P is C(O), G is NH, and the compound is a compound of formula:

11. The compound of claim 5 , wherein A is methylene, B is NH, m is 1, w is 2, E is a citric acid based linker, Z is NH, and the compound is a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

i=0 or an integer from 1 to 5;

j=0 or an integer from 1 to 5;

G=absent, NR 4 , or O;

P=absent or C(O);

Q=absent, C 6 -C 10 arylene, or C 1 -C 6 alkylene;

T=absent, C 1 -C 6 alkylene, C 6 -C 10 arylene, or C(O);

X=absent, O, S, or NR 4 ;

Y=absent or C 1 -C 6 alkylene;

R 1 =H or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, 5-10 membered heterocyclyl, each group except H optionally substituted by one to three substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, oxo (═O), —NR a R b , —NO 2 , —CN, —OR 3 , and —SR 3 ;

R 3 at each occurrence is independently H, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;

R 4 at each occurrence is independently H or C 1 -C 4 alkyl;

R a and R b are each independently H or C 1 -C 4 alkyl; and

wherein when any of groups G, P, Q, T, X, and Y is absent, its two available adjacent groups are single-bonded to each other directly.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein G, P, Q, T, X, and Y are all absent, and the compound is a compound of formula:

13. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein m is 3, w is 1, A is methylene, B is NH, D is C(O) and E is a pentaerythritol-based linker, and the compound is a compound of formula (V):

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein Y is C(O); X is NH; and G, P, Q, and T are all absent, and the compound is a compound of formula:

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure of any one of formulas (VI)-(XI):

wherein R is selected from the group consisting of:

wherein k at each occurrence is independently an integer selected from 1 to 10.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein E is a glutamic acid based linker having a formula:

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 40 to 50.