CPC A61K 47/6803 (2017.08) [A61K 47/6849 (2017.08); A61K 47/6851 (2017.08)] | 23 Claims |
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, 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:
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:
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
or
the immune agonist has the structure of formula iii:
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:
wherein
L5 is selected from —CH2—, —NH—, —C(O)—, —NHC(O)— and —C(O)NH—;
R21 is selected from
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.
|