Exatecan derivatives, linker-payloads, and conjugates and thereof
The present disclosure relates to the biopharmaceutical field, in particular, Exatecan derivatives, linker-payloads, and conjugates and thereof antibody-drug conjugates, and the corresponding preparing process and use thereof.
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (i):
wherein,
a is 0 or 1;
the carbon atoms marked with p1* and p2* each is asymmetric center, and the asymmetric center is S configured, R configured or racemic;
L 1 is selected from C 1-6 alkylene, which is unsubstituted or substituted with one substituent selected from halogen, —OH and —NH 2 ;
M is —CH 2 —, —NH— or —O—;
L 2 is C 1-3 alkylene;
R 1 is Cl; and
R 2 is F.
2. The compound of claim 1 , which is selected from:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein L 1 is selected from C 1-6 linear alkylene, C 1-6 branched alkylene, C 3-6 cyclic alkylene and C 3-4 cyclic alkyl-C 1-2 linear alkylene group, which are each independently unsubstituted or substituted with one substituent selected from halogen, —OH and —NH 2 .
4. The compound of claim 1 , wherein L 1 is selected from C 1-4 linear alkylene, C 1-4 branched alkylene, C 3-4 cyclic alkylene and cyclopropyl-methylene, which are each independently unsubstituted or substituted with one substituent selected from halogen, —OH and —NH 2 .
5. The compound of claim 1 , wherein L 1 is selected from —CH 2 —, —C 2 H 4 —,
which are each independently unsubstituted or substituted with at least one substituent selected from halogen, —OH and —NH 2 .
6. The compound of claim 1 , wherein L 1 is selected from —CH 2 —,
wherein “#” marks the position attached to carbonyl.
7. The compound of claim 1 , wherein L 1 is selected from —CH 2 —,
wherein “#” marks the position attached to carbonyl.
8. The compound of claim 1 , wherein L 1 is selected from —CH 2 —,
wherein “#” marks the position attached to carbonyl.
9. The compound of claim 1 , wherein the halogen is selected from F, Cl and Br.
10. The compound of claim 1 , wherein M is —CH 2 —, —NH— or —O—; and L 2 is —C 2 H 4 —; or M is —CH 2 —, and L 2 is —CH 2 —.
11. The compound of claim 1 , wherein the carbon atom marked with p1* is S configured or racemic; and/or the carbon atom marked with p2* is S configured or racemic.
12. The compound of claim 1 , wherein
a is 0, R 1 is Cl, R 2 is F, and L 1 is selected from —CH 2 —,
13. The compound of claim 1 , wherein the carbon atom marked with p1* is S configured; and/or the carbon atom marked with p2* is S configured.
14. A method of inhibiting the proliferation of a tumor and/or cancel cell, comprising contacting the tumor and/or cancer cell with the compound of claim 1 .
15. The method of claim 14 , wherein the compound of claim 1 is delivered to the tumor and/or cancer cell using an ADC (antibody-drug conjugate) comprising the compound of claim 1 .
16. A method of inhibiting the proliferation of a tumor and/or cancer cell, comprising contacting the tumor and/or cancer cell with the compound of claim 2 .
17. The method of claim 16 , wherein the compound of claim 2 is delivered to the tumor and/or cancer cell using an ADC (antibody-drug conjugate) comprising the compound of claim 2 .