| CPC A61K 47/6889 (2017.08) [A61K 38/07 (2013.01); A61K 47/65 (2017.08); A61K 47/6803 (2017.08); A61K 47/6849 (2017.08); A61K 47/6851 (2017.08); A61K 47/6855 (2017.08); A61K 47/6883 (2017.08); A61K 47/6885 (2017.08); A61P 35/00 (2018.01); A61K 47/549 (2017.08); A61K 47/60 (2017.08)] | 16 Claims |
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1. A conjugate of Formula (I):
 wherein
a1 is 1;
a2 is 3;
a3 is an integer from 0 to 1;
a4 is an integer from 1 to 5;
a5 is an integer from 1 to 3;
d13 is an integer from 1 to about 14;
PBRM is an antibody or antibody fragment that binds to a target antigen;
LP′ is a divalent linker moiety connecting the PBRM to MP, of which the corresponding monovalent moiety LP, when not connected to PBRM, contains a functional group WP, wherein each WP independently is:
 wherein
ring A is optionally substituted C3-8 cycloalkyl or optionally substituted 5- to 12-membered heterocycloalkyl, wherein the cycloalkyl or heterocyloalkyl is monocyclic or bicyclic;
MPP is:
 wherein * denotes attachment to LP′ and ** denotes attachment to LM;
R3 is —C(O)—NR5— or —NR5—C(O)—;
R4 is a bond or —NR5—(CR20R21)—C(O)—;
each R5 independently is hydrogen, C1-6 alkyl, C6-10 aryl, C3-8 cycloalkyl, —COOH, or —COO—C1-6 alkyl;
each R20 and R21 independently is hydrogen, C1-6 alkyl, C6-10 aryl, hydroxylated C6-10 aryl, polyhydroxylated C6-10 aryl, 5- to 12-membered heterocycle, C3-8 cycloalkyl, hydroxylated C3-8 cycloalkyl, polyhydroxylated C3-8 cycloalkyl or a side chain of a natural or unnatural amino acid;
each b1 independently is an integer from 0 to 6;
each f1 independently is an integer from 1 to 6;
g2 is an integer from 1 to 4;
LM is:
 wherein:
 denotes attachment to MP;Y1 denotes attachment to L3 or attachment to MA when L3 is absent;
R2 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, —COOH, or —COO—C1-6 alkyl;
each c6 independently is an integer from 0 to 10;
L3 is —X—C1-10 alkylene—C(O)— or —CH2—(CH2)v—C(O)—NR5—(CH2)v—C(O)—, wherein each v independently is an integer from 1 to 10, from 1 to 6, or from 2 to 4, or v is 2, with X directly connected to LM, wherein X is CH2, O, or NR5;
MAA is a peptide moiety that contains from two to ten amino acids selected from glycine, serine, glutamic acid, aspartic acid, lysine, cysteine and stereoisomers and combinations thereof;
T1 is a hydrophilic group, wherein the hydrophilic is
   or a combination thereof, and the
 between T1 and MA denotes direct or indirect attachment of T1 and MA;
wherein n1 is an integer from 0 to about 6;
each R58 independently is hydrogen or C1-8 alkyl;
R60 is a bond, a C1-6 alkyl linker, or —CHR59—, wherein R59 is H, C1-6 alkyl, C3-8 cycloalkyl, or C6-10 arylalkyl;
R61 is —CH2OR62, —COOR62, —(CH2)n2COOR62, or C3-8 heterocycloalkyl substituted with one or more hydroxyl, wherein the C3-8 heterocycloalkyl comprises one to four heteroatom ring members independently selected from N, O, P, and S;
R62 is H or C1-8 alkyl;
n2 is an integer from 1 to about 5;
n4 is an integer from 1 to about 25;
each R63 independently is hydrogen or C1-8 alkyl;
R64 is a bond or a C1-8 alkyl linker;
R65 is H, C1-8 alkyl, or —(CH2)n2COOR62;
each occurrence of D independently is a therapeutic agent having a molecular weight≤about 5 kDa; and
each occurrence of LD independently comprises a peptide comprising an amino acid selected from alanine, β-alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, leucine, serine, tyrosine, threonine, isoleucine, and tryptophan, connecting D to MA, and LD comprises at least one cleavable bond such that when the bond is broken, D is released.
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