Releasable GLP-1 conjugates

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

the aliphatic moiety is selected from a polymer, R P , and a group selected from:

polymer-L-(CH 2 ) m — and polymer-L-(CH 2 —CH 2 —O) p —(CH 2 ) m —;

R P is selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-3 alkyl-O—(CH 2 —CH 2 —O) p —(CH 2 ) m —, and optionally substituted C 3-7 cycloalkyl;

L is a linking group;

m and p are each independently an integer from 1 to 10;

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 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 Ware 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. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

the aliphatic moiety is selected from a polymer, R P , and a group selected from:

polymer-L-(CH 2 ) m — and polymer-L-(CH 2 —CH 2 —O) p —(CH 2 ) m —;

R P is selected from optionally substituted C 1-6 alkyl, optionally substituted C 1-3 alkyl-O—(CH 2 —CH 2 —O) p —(CH 2 ) m —, and optionally substituted C 3-7 cycloalkyl;

L is a linking group;

m and p are each independently an integer from 1 to 10;

D is a residue of a biologically active drug;

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;

Z 4 is selected from O and S;

A is selected from O and N(R N );

R N is selected from H and optionally substituted C 1-4 alkyl;

M A is a diradical selected from:

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

and

b) a stable diradical selected from any one of formulae (j)-(l):

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

R 2 is 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;

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

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

R 7 and R 8 are independently selected from H, C 1-6 alkyl, amino, (C 1-6 alkyl)amino, di-(C 1-6 alkyl)amino, acylamino, and a protected amino group; and

E is a cleavable moiety.

3. The compound of claim 1 , wherein the aliphatic moiety is a polymer selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(α-hydroxy acid), poly(vinyl alcohol), polyoxazoline, and copolymers thereof.

4. The compound of claim 1 , wherein the polymer is a polyethylene glycol.

5. 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.

6. 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.

7. The compound of claim 1 , wherein E is non-enzymatically cleavable at acidic or physiological pH.

8. The compound of claim 1 , wherein A is NR N or NR 3 , and E is a cleavable moiety of formula:

wherein:

R 9 is selected from H, an optionally substituted C 6-10 aryl, and an optionally substituted C 1-6 alkyl;

R 10 and R 11 are each independently selected from H, CN, NO 2 , COR 12 , SOR 12 or SO 2 R 12 , an optionally substituted C 1-6 alkyl, an optionally substituted C 6-10 aryl, and an optionally substituted 5- to 14-membered heteroaryl; or

R 10 and R 11 together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloalkyl ring which is fused with one or more optionally substituted C 6-10 aryl rings;

R 12 is selected from an optionally substituted C 1-6 alkyl and an optionally substituted C 6-10 aryl.

9. The compound of claim 1 , wherein E is a cleavable moiety of any one of the following formulae (E-1) to (E-12) and (E-37) to (E-42):

wherein any one of the phenyl rings in the formulae (E-1) to (E-12), (E-37) or (E-39) to (E-41) is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkoxy, OH, NO 2 , CN, halogen and acyl.

10. The compound of claim 1 , wherein E is a group of any one of the following formulae (E-13) to (E-36):

wherein R is C 1-6 alkyl.

11. The compound of claim 1 , wherein D is a residue of a GLP-1 polypeptide or a residue of a GLP-1 polypeptide analog.

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

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

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 2 , wherein the compound of Formula (II) has any one of the following formulae:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 wherein the compound of Formula (I) is selected from any one of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein liraglutide is the residue of liraglutide.

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

17. 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.

18. A method of making a compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof, the method comprising:

(i) reacting a compound of formula:

wherein LG is a leaving group, with the GLP-1 polypeptide or an analog thereof of formula HZ 3 -D.

19. The method of claim 18 , wherein the compound of formula:

is obtained by the method comprising:

(i) deprotecting a compound of formula:

wherein PG 1 is a protecting group, to obtain a compound of formula:

 and

(ii) reacting the compound obtained in step (i) with a compound comprising a leaving group.

20. The compound of claim 2 , wherein 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.

21. The compound of claim 2 , wherein R 1 and R 2 are joined together to form a ribose ring system.

22. The compound of claim 2 , wherein the biologically active drug is a GLP-1 polypeptide or an analog thereof.

23. The compound of claim 20 , wherein the biologically active drug is a GLP-1 polypeptide or an analog thereof.