Compounds and compositions for immunotherapy

A compound having the structure of Formula (Ib):

• TM-L-AM (Ib),
• wherein TM is a targeting moiety that comprises an immunoglobulin that specifically binds to a tumor antigen on a tumor cell, wherein the tumor antigen is selected from the group consisting of CD2, CD19, CD20, CD22, CD37, CD38, CD44, CD47, CD52, CD56, CD79, 5T4, AGS-5, AGS-16, Angiopoietin 2, BT-062, BTLA, CAIX, Carcinoembryonic antigen, CTLA4, Cripto, ErbB1, ErbB2, ErbB3, ErbB4, EGFL7, EGFR, EpCAM, EphA2, EphA3, EphB2, FAP, Folate Receptor, Ganglioside GM3, GD2, gp100, gpA33, GPNMB, Her2, ICOS, IGF1R, KIR, LAG-3, Lewis Y, Mesothelin, c-MET, MN Carbonic anhydrase IX, MUC1, MUC16, Nectin-4, NOTCH, OX40, OX40L, PD-1, PD-L1, PSCA, PSMA, RANKL, ROR1, ROR2, SLC44A4, Syndecan-1, TACI, TAG-72, Tenascin, and TIM3;
• L is a linker, -Ta-Ww-Yy-, wherein TM-Ta is
• wherein T forms a bond with a sulfur atom of the immunoglobulin, or T is linked to the immunoglobulin via a disulfide bond;
• a is 0 or 1;
• R1 is —C1-C10 alkylene-, —C3-C8 carbocyclo-, —O—(C1-C8 alkyl)-, -arylene-, —C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, —C1-C10 alkylene-(C3-C8 carbocyclo)-, —(C3-C8 carbocyclo)-C1-C10 alkylene-, —C3-C8 heterocyclo-, —C1-C10 alkylene-(C3-C8 heterocyclo)-, —(C3-C8 heterocyclo)-C1-C10 alkylene-, —(CH2CH2O)r—, or —(CH2CH2O)r—CH2—;
• each W is, independently, an amino acid;
• w is an integer ranging from 2 to 12;
• Y is 2-aminoimidazol-5-methanol, 4-aminobutyric acid amide, 2-aminophenylpropionic acid amide, a branched bis(hydroxymethyl)styrene (BHMS), -glycine-, -glycine-glycine-, or a p-aminobenzyl alcohol (PAB) group that is linked to -Ww- via the nitrogen atom of the PAB unit, and connected directly to -AM via a carbonate, carbamate, or ether group;
• y is 0, 1, or 2;
• and AM is a radical of an activating moiety that is represented by structure of formula (I):
• wherein dashed line represents bond or absence of bond, is the point to be connected to the linker;
• X is S or —NR1, R1 is -W0-W1-W2-W3-W4,
• W0 is a bond, alkyl, alkenyl, alkynyl, alkoxy, or -alkyl-S-alkyl-,
• W1 is a bond, —O—, or —NR2—, wherein R2 is hydrogen, alkyl or alkenyl,
• W2 is a bond, —O—, —C(O)—, —C(S)—, or —S(O)2—,
• W3 is a bond, —NR3—, wherein R3 is hydrogen, alkyl or alkenyl,
• W4 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, or heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH2, nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, —O—R4, —O-alkyl-R4, -alkyl-O—R4, —C(O)—R4, -alkyl-C(O)—R4, -alkyl-C(O)—O—R4, —C(O)—O—R4, —S—R4, —S(O)2—R4, —NH—S(O)2—R4, -alkyl-S—R4, -alkyl-S(O)2—R4, —NHR4, —NR4R4, —NH-alkyl-R4, halogen, —CN, —NO2, and —SH, wherein R4 is independently hydrogen, alkyl, alkenyl, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl;
• Z is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, haloalkyl, heteroaryl, heterocyclyl, each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, —N(R5)2, -alkoxy-alkyl, -alkoxy-alkenyl, —C(O)-alkyl, —C(O)—O-alkyl, —O—C(O)-alkyl, —C(O)—N(R5)2, aryl, heteroaryl, —CO-aryl, and —CO-heteroaryl, wherein each R5 is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl;
• R is hydrogen, alkyl, alkoxy, haloalkyl, halogen, aryl, heteroaryl, heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —NH2, nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, —O—R4, —O-alkyl-R4, -alkyl-O—R4, —C(O)—R4, —C(O)—NH—R4, —C(O)—NR4R4, -alkyl-C(O)—R4, -alkyl-C(O)—O—R4, —C(O)—O—R4, —O—C(O)—R4 , —S—R4, —C(O)—S—R4, —S—C(O)—R4, —S(O)2—R4, —NH—S(O)2—R4, -alkyl-S—R4, - alkyl-S(O)2—R4, —NHR4, —NR4R4, —NH-alkyl-R4, halogen, —CN, and —SH, wherein R4 is independently hydrogen, alkyl, alkenyl, alkoxy, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl;
• n is 0, 1, 2, 3, or 4;
• Y is —NR6R7, —CR6R7R8, or -alkyl-NH2, each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, —NH2, halogen, —N(R5)2, -alkoxy-alkyl, -alkoxy-alkenyl, —C(O)-alkyl, —C(O)—O-alkyl, —C(O)—N(R5)2, aryl, heteroaryl, —CO-aryl, and —CO-heteroaryl,
• wherein R6, R7 and R8 are independently hydrogen, alkyl, alkenyl, alkoxy, alkylamino, dialkylamino, alkylthio, arylthio, -alkyl-hydroxyl, -alkyl-C(O)—O—R9, -alkyl-C(O)—R9, or -alkyl-O—C(O)—R9, wherein each R5 is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl, wherein R9 is hydrogen, alkyl, alkenyl, halogen, or haloalkyl;
• X and Z taken together may optionally form a (5-9)-membered ring;
• or a pharmaceutically acceptable salt thereof.