Conjugates comprising cleavable beta-glucuronide-containing linkers
The specification relates to conjugates comprising a linker of Formula (IA): and pharmaceutically acceptable salts thereof. The specification also relates the use of the conjugates for the treatment of diseases such as cancer, and intermediates useful for the synthesis of the conjugates.
1. A conjugate of Formula (I)
Ab-(G A -J A -D R ) k (I)
or a pharmaceutically acceptable salt thereof, wherein
Ab is an antibody or antigen-binding fragment thereof,
k is an integer from 1 to 10,
each G A is independently a conjugation group conjugated to the antibody or antigen-binding fragment thereof,
each D R is independently a drug comprising a nitrogen atom N R ,
each J A is independently a group of Formula (IA)
E is (CH 2 ) n1 , wherein n1 is 0, 1, 2 or 3,
Q is
R 1 is C 1-4 alkyl,
X is (CH 2 ) n2 , wherein n2 is 0, 1, 2 or 3,
Y is (CH 2 ) n3 , wherein n3 is 0, 1, 2, 3 or 4,
Z is (CH 2 ) n4 , wherein n4 is 1, 2, 3, 4 or 5,
m is an integer from 5 to 17,
p is 1 or 0,
(G A ) indicates the point of attachment to G A , and
(N R ) indicates the point of attachment to the nitrogen atom N R .
2. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein Q is
3. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein m is 9, 10, 11, 12 or 13.
4. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 1 is CH 3 .
5. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein n1 is 1.
6. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein n2 is 1.
7. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein n3 is 2.
8. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein n4 is 2.
9. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein p is 1.
10. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein each J A is a group of Formula (IB)
11. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 10 , wherein G A is
wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.
12. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 10 , wherein G A is
wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.
13. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein G A is selected from
wherein R K is H or CH 3 , R L is C 1-6 alkyl, and indicates the point of attachment to the antibody or antigen-binding fragment thereof.
14. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 13 , wherein G A is
15. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 13 , wherein G A is
16. The conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein k is an integer from 2 to 8.
17. A pharmaceutical composition comprising the conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , and a pharmaceutically acceptable excipient.
18. A method of treating cancer in a patient comprising administering to the patient the conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 .
19. A compound of Formula (II)
G B -J B -D R (II),
or a salt thereof, wherein G B is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof,
D R is a drug comprising a nitrogen atom N R ,
J B is a group of Formula (IIA)
E is (CH 2 ) n1 , wherein n1 is 0, 1, 2 or 3,
Q is
R 1 is C 1-4 alkyl,
X is (CH 2 ) n2 , wherein n2 is 0, 1, 2 or 3,
Y is (CH 2 ) n3 , wherein n3 is 0, 1, 2, 3 or 4,
Z is (CH 2 ) n4 , wherein n4 is 1, 2, 3, 4 or 5,
m is an integer from 5 to 17,
p is 1 or 0,
(G B ) indicates the point of attachment to G B , and (N R ) indicates the point of attachment to the nitrogen atom N R .
20. The compound of Formula (II), or a salt thereof, as claimed in claim 19 , wherein G B is selected from
wherein X 1 is CH or N,
h is 0 or 1,
Hal is Cl, Br or I,
R K is H or CH 3 , and
R L is C 1-6 alkyl.
21. The compound of Formula (II), or a salt thereof, as claimed in claim 20 , wherein G B is
22. The compound of Formula (II), or a salt thereof, as claimed in claim 20 , wherein G B is
23. A compound of Formula (V)
or a salt thereof, wherein
E is (CH 2 ) n1 , wherein n1 is 0, 1, 2 or 3,
Q is
R 1 is C 1-4 alkyl,
X is (CH 2 ) n2 , wherein n2 is 0, 1, 2 or 3,
Y is (CH 2 ) n3 , wherein n3 is 0, 1, 2, 3 or 4,
m is an integer from 5 to 17,
p is 1 or 0,
R P1 is a carboxylic acid protecting group, each R P2 is independently an alcohol protecting group and R P3 is an amine protecting group.
24. A compound of Formula (VII)
or a salt thereof, wherein G B is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof,
E is (CH 2 ) n1 , wherein n1 is 0, 1, 2 or 3,
Q is
R 1 is C 1-4 alkyl,
X is (CH 2 ) n2 , wherein n2 is 0, 1, 2 or 3,
Y is (CH 2 ) n3 , wherein n3 is 0, 1, 2, 3 or 4,
Z is (CH 2 ) n4 , wherein n4 is 1, 2, 3, 4 or 5,
m is an integer from 5 to 17, and
p is 1 or 0.
25. A compound of Formula (VIII)
or a salt thereof, wherein
E is (CH 2 ) n1 , wherein n1 is 0, 1, 2 or 3,
Y is (CH 2 ) n3 , wherein n3 is 0, 1, 2, 3 or 4,
p is 1 or 0,
R P1 is a carboxylic acid protecting group, each R P2 is independently an alcohol protecting group and R P3 is an amine protecting group.
26. A compound of Formula (IX)
G B -J B -D R (IX),
or a salt thereof, wherein G B is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof,
D R is a drug comprising a nitrogen atom N R ,
J B is a group of Formula (IXA)
wherein
E is (CH 2 ) n1 , wherein n1 is 0, 1, 2 or 3,
Y is (CH 2 ) n3 , wherein n3 is 0, 1, 2, 3 or 4,
Z is (CH 2 ) n4 , wherein n4 is 1, 2, 3, 4 or 5,
p is 1 or 0,
(G B ) indicates the point of attachment to G B , and (N R ) indicates the point of attachment to the nitrogen atom N R , R Q1 is H or R P1 , R Q2 is H or R P2 and R Q3 is H or R P3 , wherein R P1 is a carboxylic acid protecting group, each R P2 is independently an alcohol protecting group and R P3 is an amine protecting group.