Antibody-immune agonist conjugate and applications thereof

1. A compound with the formula (I):

wherein n is an integer of 3 to 10;

Lm2 is

or a mixture thereof;

x is selected from hydrogen, OH, NH 2 , an amino acid fragment comprising 1-10 amino acids, and a nucleotide fragment comprising 1-10 nucleotides;

Lk is a combination of L 1 -L 2 -L 3 ;

L 1 and L 3 are each independently selected from:

—CH 2 —, —NH—, —C(O)—, —NHC(O)—, —C(O)NH—; and combination of a C 1-4 alkylene with one of the following groups: —CH 2 —, —NH—, —C(O)—, —NHC(O)—, or —C(O)NH—;

L 2 is absent or is a C 7-34 alkylene, and wherein one or more (—CH 2 —) structures in the alkylene is optionally replaced by —O—;

Y and W are each independently absent, PABC or selected from a spacer comprising 1-10 amino acids;

B2 is selected from the following group or their combination: —(CH 2 ) k C(O)—, —(CH 2 ) k C(O)—Val-Cit-PABC-, —(CH 2 ) k C(O)-Val-Cit-PABC-(NH—CR 1 R 2 —C(O)) d —, —(CH 2 ) k1 C(O)—NH—(C 2 H 4 —O) j —(CH 2 ) k2 C(O)-Lys-, —(CH 2 ) k C(O)—NH—(C 2 H 4 —O) j —, —(CH 2 ) k C(O)—(NH—CR 1 R 2 —C(O)) d —NH—(C 2 H 4 —O) j —, and —(CH 2 ) k C(O)—(NH—CR 1 R 2 —C(O)) d ;

a and b are each independently 0 or 1;

each k, k1 and k2 are independently an integer of 0 to 10;

d is an integer of 1 to 10;

j is an integer of 1 to 10;

R 1 and R 2 are each independently selected from: hydrogen, —OH, —NH 2 , —C 1-6 alkyl, —O—C 1-6 alkyl, —NH—C 1-6 alkyl, —C 1-6 alkyl-NH 2 , —N(C 1-6 alkyl)-C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-NH—C 1-6 alkyl, —C(O)—C 1-6 alkyl, —NHC(O)—C 1-6 alkyl, —C(O)—NH 2 , —C(O)NH—C 1-6 alkyl, —C(O)N(C 1-6 alkyl)-C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, —NHS(═O) 2 —C 1-6 alkyl, —S(═O) 2 O—C 1-6 alkyl, —S(═O) 2 NH—C 1-6 alkyl and —S(═O) 2 N(C 1-6 alkyl)-C 1-6 alkyl; and

PL is a payload which is an immune agonist;

wherein the immune agonist has the structure of formula i:

wherein

each R 9 is independently selected from hydrogen, halogen, C 1-7 alkyl-OC(O)—C 1-7 alkyl, C 1-7 alkyl-OC(O)—C 2-7 alkenyl and 5-7 membered heterocycle;

R 10 and R 11 are each independently selected from hydrogen and C 1-7 alkyl;

R 12 is selected from C 1-7 alkyl and C 1-7 alkoxy-C 1-7 alkyl;

R 13 is selected from C 1-7 alkyl, which is optionally substituted by a substituent selected from —OH and —NH 2 ; and

u is 1, 2, 3 or 4; or

the immune agonist has the structure of formula ii:

wherein

L 4 is selected from —CH 2 —, —NH—, —O— and —C(O)—;

R 14 is selected from C 1-7 alkyl, C 1-7 alkoxy and C 1-7 alkyl-OC(O)—C 1-7 alkyl;

R 15 and R 16 are each independently selected from hydrogen and C 1-7 alkyl;

R 17 is selected from —NH 2 , —OH, C 1-7 alkyl, C 1-7 alkoxy and —NH—C 1-7 alkyl; and

R 18 is selected from —CH 2 -aryl, and —CH 2 -heteroaryl, wherein the aryl and the heteroaryl are each independently optionally substituted by a substituent selected from —C(O)OH and

or

the immune agonist has the structure of formula iii:

wherein

R 19 is selected from —OH, —NH 2 , C 1-7 alkyl, C 1-7 alkoxy and —NH—C 1-7 alkyl; and

R 20 is selected from —CH 2 -aryl, wherein the aryl is optionally substituted by two substituents selected from —OH, C 1-7 alkoxy and —C 1-7 alkyl-piperidinyl; or

the immune agonist has the structure of formula iv:

wherein

L 5 is selected from —CH 2 —, —NH—, —C(O)—, —NHC(O)— and —C(O)NH—;

R 21 is selected from

wherein B is a heteroaryl ring;

R 22 is selected from hydrogen and C 1-7 alkyl;

R 23 and R 24 are each independently selected from hydrogen and C 1-7 alkyl;

L 6 is selected from —CH 2 — and —C(O)—;

R 25 is selected from —N(C 1-7 alkyl)(C 1-7 alkyl);

R 26 , R 27 and R 28 are each independently selected from hydrogen and C 1-7 alkyl; and

v is 1, 2 or 3.

2. The compound of claim 1 , wherein Lk is L 1 -L 2 -L 3 , L 1 is —NH—, L 3 is —C(O)—, L 2 is —(C 2 H 4 —O) i —C 2 H 4 —, and i is an integer of 2 to 10.

3. The compound of claim 1 , wherein B2 is —(CH 2 ) k C(O)—NH—(C 2 H 4 —O) j —.

4. The compound of claim 3 , wherein k is 1 or 2.

5. The compound of claim 1 , wherein Y and W are independently selected from leucine (Leu), glutamine (Gln), and PABC.

6. The compound of claim 1 , wherein a and b are 0.

7. The compound of claim 1 , wherein R 1 and R 2 are each independently hydrogen or C 1-6 alkyl.

8. The compound of claim 1 , wherein x is NH 2 .

9. The compound of claim 1 , wherein the immune agonist is selected from imidazoquinolines.

10. The compound of claim 1 , wherein the immune agonist is selected from compound i-1 to i-5:

11. The compound of claim 1 , wherein the immune agonist is selected from compound ii-1:

12. The compound of claim 1 , wherein the immune agonist is compound iv-1:

13. The compound of claim 1 , which is selected from the following structures:

14. The compound of claim 1 , wherein Y and W are each independently selected from a spacer comprising 1-6 amino acids.

15. The compound of claim 14 , wherein Y and W are each independently selected from a spacer comprising 1-4 amino acids.

16. The compound of claim 1 , wherein each k, k1 and k2 are independently an integer of 0, 1 or 2.

17. The compound of claim 16 , wherein each k, k1 and k2 are independently an integer of 1 or 2.

18. The compound of claim 1 , wherein d is an integer of 1 or 2.

19. The compound of claim 1 , wherein j is an integer of 1, 3, or 4.

20. The compound of claim 2 , wherein i is an integer of 4.

21. The compound of claim 7 , wherein R 1 and R 2 are each independently both hydrogen or both C 1-6 alkyl.

22. The compound of claim 21 , wherein R 1 and R 2 are both methyl.

23. The compound of claim 13 , which is: