US 11,717,576 B2
Antibody-immune agonist conjugate and applications thereof
Paul H. Song, Suzhou (CN); Gang Qin, Suzhou (CN); and Chong Liu, Suzhou (CN)
Assigned to GENEQUANTUM HEALTHCARE (SUZHOU) CO., LTD., Suzhou (CN)
Filed by GENEQUANTUM HEALTHCARE (SUZHOU) CO., LTD., Suzhou (CN)
Filed on Mar. 8, 2022, as Appl. No. 17/689,198.
Claims priority of application No. PCT/CN2021/079609 (WO), filed on Mar. 8, 2021.
Prior Publication US 2022/0378930 A1, Dec. 1, 2022
Int. Cl. A61K 47/68 (2017.01)
CPC A61K 47/6803 (2017.08) [A61K 47/6849 (2017.08); A61K 47/6851 (2017.08)] 23 Claims
OG exemplary drawing
 
1. A compound with the formula (I):

OG Complex Work Unit Chemistry
wherein n is an integer of 3 to 10;
Lm2 is

OG Complex Work Unit Chemistry
or a mixture thereof;
x is selected from hydrogen, OH, NH2, an amino acid fragment comprising 1-10 amino acids, and a nucleotide fragment comprising 1-10 nucleotides;
Lk is a combination of L1-L2-L3;
L1 and L3 are each independently selected from:
—CH2—, —NH—, —C(O)—, —NHC(O)—, —C(O)NH—; and combination of a C1-4 alkylene with one of the following groups: —CH2—, —NH—, —C(O)—, —NHC(O)—, or —C(O)NH—;
L2 is absent or is a C7-34 alkylene, and wherein one or more (—CH2—) 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: —(CH2)kC(O)—, —(CH2)kC(O)—Val-Cit-PABC-, —(CH2)kC(O)-Val-Cit-PABC-(NH—CR1R2—C(O))d—, —(CH2)k1C(O)—NH—(C2H4—O)j—(CH2)k2C(O)-Lys-, —(CH2)kC(O)—NH—(C2H4—O)j—, —(CH2)kC(O)—(NH—CR1R2—C(O))d—NH—(C2H4—O)j—, and —(CH2)kC(O)—(NH—CR1R2—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;
R1 and R2 are each independently selected from: hydrogen, —OH, —NH2, —C1-6 alkyl, —O—C1-6 alkyl, —NH—C1-6 alkyl, —C1-6 alkyl-NH2, —N(C1-6 alkyl)-C1-6 alkyl, —C1-6 alkyl-O—C1-6 alkyl, —C1-6 alkyl-NH—C1-6 alkyl, —C(O)—C1-6 alkyl, —NHC(O)—C1-6 alkyl, —C(O)—NH2, —C(O)NH—C1-6 alkyl, —C(O)N(C1-6 alkyl)-C1-6 alkyl, —S(═O)2—C1-6 alkyl, —NHS(═O)2—C1-6 alkyl, —S(═O)2O—C1-6 alkyl, —S(═O)2NH—C1-6 alkyl and —S(═O)2N(C1-6 alkyl)-C1-6 alkyl; and
PL is a payload which is an immune agonist;
wherein the immune agonist has the structure of formula i:

OG Complex Work Unit Chemistry
wherein
each R9 is independently selected from hydrogen, halogen, C1-7 alkyl-OC(O)—C1-7 alkyl, C1-7 alkyl-OC(O)—C2-7 alkenyl and 5-7 membered heterocycle;
R10 and R11 are each independently selected from hydrogen and C1-7 alkyl;
R12 is selected from C1-7 alkyl and C1-7 alkoxy-C1-7 alkyl;
R13 is selected from C1-7 alkyl, which is optionally substituted by a substituent selected from —OH and —NH2; and
u is 1, 2, 3 or 4; or
the immune agonist has the structure of formula ii:

OG Complex Work Unit Chemistry
wherein
L4 is selected from —CH2—, —NH—, —O— and —C(O)—;
R14 is selected from C1-7 alkyl, C1-7 alkoxy and C1-7 alkyl-OC(O)—C1-7 alkyl;
R15 and R16 are each independently selected from hydrogen and C1-7 alkyl;
R17 is selected from —NH2, —OH, C1-7 alkyl, C1-7 alkoxy and —NH—C1-7 alkyl; and
R18 is selected from —CH2-aryl, and —CH2-heteroaryl, wherein the aryl and the heteroaryl are each independently optionally substituted by a substituent selected from —C(O)OH and

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or
the immune agonist has the structure of formula iii:

OG Complex Work Unit Chemistry
wherein
R19 is selected from —OH, —NH2, C1-7 alkyl, C1-7 alkoxy and —NH—C1-7 alkyl; and
R20 is selected from —CH2-aryl, wherein the aryl is optionally substituted by two substituents selected from —OH, C1-7 alkoxy and —C1-7 alkyl-piperidinyl; or
the immune agonist has the structure of formula iv:

OG Complex Work Unit Chemistry
wherein
L5 is selected from —CH2—, —NH—, —C(O)—, —NHC(O)— and —C(O)NH—;
R21 is selected from

OG Complex Work Unit Chemistry
wherein B is a heteroaryl ring;
R22 is selected from hydrogen and C1-7 alkyl;
R23 and R24 are each independently selected from hydrogen and C1-7 alkyl;
L6 is selected from —CH2— and —C(O)—;
R25 is selected from —N(C1-7 alkyl)(C1-7 alkyl);
R26, R27 and R28 are each independently selected from hydrogen and C1-7 alkyl; and
v is 1, 2 or 3.