Releasable GLP-1 conjugates

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

the aliphatic moiety is a polyethylene glycol having an average molecular weight from about 500 Da to about 40,000 Da;

D is a residue of a GLP-1 polypeptide or an analog thereof;

Z 1 is selected from O, S, and N(R N );

Z 3 is selected from O and N(R N ), or Z 3 is absent;

A is O or N, wherein when A is O then R 3 is absent;

R N is selected from H and optionally substituted C 1-6 alkyl;

R 3 is selected from H and C 1-6 alkyl, or

R 3 and R 1 , together with A and the carbon atom to which R 1 is attached, form an optionally substituted 4 to 7 membered aliphatic heterocyclic ring; or

R 3 and R 2 , together with A, the carbon atom to which R 1 is attached, and the carbon atom to which R 2 is attached, form an optionally substituted 4 to 8 membered aliphatic heterocyclic ring;

M A is a self-immolative group having any one of formulae (a)-(i):

wherein x denotes a point of attachment to Z 1 and y denotes a point of attachment to Z 3 ;

R 1 and R 2 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl and optionally substituted 5- to 14-membered heteroaryl;

or R 1 and R 2 are joined together with the carbon atoms to which they are attached to form an optionally substituted C 3-7 cycloalkyl ring, an optionally substituted 4 to 7 membered aliphatic heterocyclic ring, an optionally substituted C 6-10 aryl or an optionally substituted 5-to 14-membered heteroaryl;

or R 1 and R 2 are joined together to form a ribose ring system;

R 7 and R 8 are independently selected from H and C 1-6 alkyl; and

E is a cleavable moiety.

2. The compound of claim 1 , wherein the polyethylene glycol is linear.

3. The compound of claim 1 , wherein the polyethylene glycol is branched.

4. The compound of claim 1 , wherein the polyethylene glycol has an average molecular weight from about 1,000 Da to about 30,000 Da.

5. The compound of claim 1 , wherein the polyethylene glycol has an average molecular weight from about 1,000 Da to about 20,000 Da.

6. The compound of claim 1 , wherein the polyethylene glycol has an average molecular weight from about 5,000 Da to about 20,000 Da.

7. The compound of claim 1 , wherein the polyethylene glycol has the following structural formula:

8. The compound of claim 7 , wherein n is an integer from 1 to 1,000.

9. The compound of claim 8 , wherein n is selected from 10, 20, 50, 100, 200, 250, 300, 500, 600, and 1000.

10. The compound of claim 1 , wherein:

Z 1 is O;

Z 2 is O; and

Z 3 is NH.

11. The compound of claim 1 , wherein R 1 and R 2 together form a ribose ring system of formula:

wherein either a denotes a point of attachment to O and b denotes a point of attachment to A, a denotes a point of attachment to A and b denotes a point of attachment to O, and wherein W is selected from the group consisting of H, an acyl group and a protecting group.

12. The compound of claim 11 , wherein:

Z 1 is O;

Z 2 is O; and

Z 3 is NH.

13. The compound of claim 11 , wherein the nucleobase is selected from the group consisting of adenine, cytosine, guanine, thymine, uracil, and other natural and non-natural nucleobases.

14. The compound of claim 1 , wherein A is O or NH.

15. The compound of claim 1 , wherein E is cleavable by an enzyme selected from the group consisting of an esterase, a specific or an unspecific peptidase, a reductase, an oxidase, a glycosidase, a hydrolase, a glycosyl transferase, and a transaminase, or E is non-enzymatically cleavable at acidic or physiological pH.

16. The compound of claim 1 , wherein the compound of Formula (I) has any one of the following formulae:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein the GLP-1 polypeptide or an analog thereof is selected from liraglutide, dulaglutide, taspoglutide, albiglutide, semaglutide, teduglutide, glepaglutide, and elsiglutide.

18. The compound of claim 1 , wherein the GLP-1 polypeptide analog is liraglutide.

19. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A method of treating a disease or condition selected from diabetes and obesity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.