A conjugation linker containing 2,3-diaminosuccinyl group

A conjugate compound having a stereoisomeric structure of 2,3-diaminosuccinyl group represented by Formula (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IVa), (IVb) or (IVc) below

• wherein
• “” represents a single bond;
• “” is optionally either a single bond, or absent;
• “-----” optionally either a single bond, or a double bond, or can optionally be absent;
• n is 1 to 30 independently;
• Q is a cell-binding agent that links to R3 and R4, of a molecule that binds to, complexes with, or reacts with a moiety of a cell population sought to be therapeutically or otherwise biologically modified;
• the cell-binding agent is an immunotherapeutic protein, an antibody, a single chain antibody;
• an antibody fragment that binds to the target cell;
• a monoclonal antibody;
• a single chain monoclonal antibody;
• or a monoclonal antibody fragment that binds the target cell;
• a chimeric antibody;
• a chimeric antibody fragment that binds to the target cell;
• a domain antibody;
• a domain antibody fragment that binds to the target cell;
• adnectins that mimic antibodies;
• DARPins;
• a lymphokine;
• a hormone;
• a vitamin;
• a growth factor;
• a colony stimulating factor;
• or a nutrient-transport molecule (a transferrin);
• a binding peptide having over four aminoacids, or protein, or antibody, or small cell-binding molecule or ligand attached on albumin, polymers, dendrimers, liposomes, nanoparticles, vesicles, or (viral) capsids;
• Drug1 and Drug2 are each a cytotoxic agent that is a therapeutic drug, or an immunotherapeutic molecule, or a function molecule for enhancement of binding or stabilization of the cell-binding agent, or a cell-surface receptor binding ligand, or for inhibition of cell proliferation, or for monitoring, detection or study of a cell-binding molecule action, an analog, or prodrug, or a pharmaceutically acceptable salt, hydrate, or hydrated salt, or a crystalline structure, or an optical isomer, racemate, diastereomer or enantiomer, of immunotherapeutic compound, a chemotherapeutic compound, an antibody (probody) or an antibody (probody) fragment, or siRNA or DNA molecule, or a cell surface binding ligand;
• X1 and X2 are the same or different, and independently selected from the group consisting of NH;
• NHNH;
• N(R1);
• N(R1)N(R2);
• O;
• S;
• S—S, O—NH, O—N(R1), CH2—NH, CH2—N(R1), CH═NH, CH═N(R1), S(O), S(O2), P(O)(OH), S(O)NH, S(O2)NH, P(O)(OH)NH, NHS(O)NH, NHS(O2)NH, NHP(O)(OH)NH, N(R1)S(O)N(R2), N(R1)S(O2)N(R2), N(R1)P(O)(OH)N(R2), OS(O)NH, OS(O2)NH, OP(O)(OH)NH, C(O), C(NH), C(NR1), C(O)NH, C(NH)NH, C(NR1)NH, OC(O)NH, OC(NH)NH;
• OC(NR1)NH, NHC(O)NH;
• NHC(NH)NH;
• NHC(NR1)NH, C(O)NH, C(NH)NH, C(NR1)NH, OC(O)N(R1), OC(NH)N(R1), OC(NR1)N(R1), NHC(O)N(R1), NHC(NH)N(R1), NHC(NR1)N(R1), N(R1)C(O)N(R1), N(R1)C(NH)N(R1), N(R1)C(NR1)N(R1);
• C1-C6 alkyl;
• C2-C8 alkenyl, heteroalkyl, alkylcycloalkyl, or heterocycloalkyl;
• and C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl;
• Y1, Y2, Z1 and Z2 are, the same or different, and independently a function group that link to a cell-binding molecule Q, or Drug, or Drug2, in a form of a disulfide, ether, ester, thioether, thioester, peptide, hydrazone, carbamate, carbonate, amine (secondary, tertiary, or quarter), imine, cycloheteroalkyane, heteroaromatic, alkyloxime or amide bond;
• Y1, Y2, Z1 and Z2 independently have one of the following structures:
• C(O)CH, C(O)C, C(O)CH2, ArCH2, C(O), NH, NHNH, N(R1), N(R1)N(R2), O, S, S—S, O—NH, O—N(R1), CH2—NH. CH2—N(R1), CH═NH. CH═N(R1), S(O), S(O2), P(O)(OH), S(O)NH, S(O2)NH, P(O)(OH)NH, NHS(O)NH, NHS(O2)NH, NHP(O)(OH)NH, N(R1)S(O)N(R2), N(R1)S(O2)N(R2), N(R1)P(O)(OH)N(R2), OS(O)NH, OS(O2)NH, OP(O)(OH)NH, C(O), C(NH), C(NR1), C(O)NH, C(NH)NH, C(NR1)NH, OC(O)NH, OC(NH)NH;
• OC(NR1)NH, NHC(O)NH;
• NHC(NH)NH;
• NHC(NR1)NH, C(O)NH, C(NR1)NH, OC(O)N(R1), OC(NH)N(R1), OC(NR1)N(R1), NHC(O)N(R1), NHC(NH)N(R1), NHC(NR1)N(R1), N(R1)C(O)N(R1), N(R1)C(NH)N(R1), N(R1)C(NR1)N(R1);
• or C1-C8 alkyl, C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl;
• C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
• R1, R2, R3, and R4 are, the same or different, independently selected from the group consisting of O, NH, S, NHNH, N(R5), N(R3)N(R3′), polyethyleneoxy unit of formula (OCH2CH2)pOR5, or (OCH2CH—(CH3))pOR5, or NH(CH2CH2O)pR5, or NH(CH2CH(CH3)O)pR5, or N[(CH2CH2O)pR5]—[(CH2CH2O)p′R5′], or (OCH2CH2)pCOOR5, or CH2CH2(OCH2CH2)pCOOR5, wherein p and p′ are independently an integer selected from 0 to about 1000, or combination thereof;
• C1-C8 alkyl;
• C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, esters, ether, or amide;
• C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl;
• or 1-24 amino acids;
• wherein R5 and R5′ are independently H;
• C1-C8 alkyl;
• C2-C8 heteroalkyl, alkylcycloalkyl, or heterocycloalkyl;
• C3-C8 aryl, Ar-alkyl, heterocyclic;
• C2-C8 carbon atoms of esters, ether, or amide;
• or 1-24 amino acids;
• or R1, R2, R3, and R4 may optionally be composed of one or more linker components of 6-maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), valine-citrulline (“val-cit” or “vc”), alanine-phenylalanine (“ala-phe” or “af”), p-aminobenzyloxycarbonyl (“PAB”), 4-thiopentanoate (“SPP”), 4-(N-maleimidomethyl)cyclohexane-1 carboxylate (“MCC”), (4-acetyl)amino-benzoate (“SIAB”), 4-thio-butyrate (SPDB), 4-thio-2-hydroxysulfonyl-butyrate (2-Sulfo-SPDB), or natural or unnatural peptides having 1-8 natural or unnatural amino acid unites;
• the natural aminoacid being selected from aspartic acid, glutamic acid, arginine, histidine, lysine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, tyrosine, phenylalanine, glycine, proline, tryptophan, and alanine;
• or R1, R2, R3, and R4 may independently contain one or more of the following hydrophilic structures:
• wherein is the site of linkage;
• X3, X4, X5, X6, and X7, are independently NH;
• NHNH;
• N(R5);
• N(R5)N(R5);
• O;
• S;
• C1-C6 alkyl;
• C2-C6 heteroalkyl, alkylcycloalkyl, or heterocycloalkyl;
• C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
• or 1-8 amino acid;
• wherein R5 and R5′ are independently H;
• C1-C8 alkyl;
• C2-C8 hetero-alkyl, alkylcycloalkyl, or heterocycloalkyl;
• C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl;
• C1—C ester, ether, or amide;
• or polyethyleneoxy having formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 0 to about 5000, or combination above thereof;
• or R1, R2, R3, R4, Y1, Y2, Z1, and Z2 are independently contain a self-immolative or a non-self-immolative component, peptidic units, a hydrazone bond, a disulfide, an ester, an oxime, an amide, or a thioether bond;
• the self-immolative unit includes, aromatic compounds that are electronically similar to the para-aminobenzylcarbamoyl (PAB) groups such as 2-aminoimidazol-5-methanol derivatives, heterocyclic PAB analogs, beta-glucuronide, and ortho or para-aminobenzylacetals;
• the self-immolative linker component has one of the following structures:
• wherein the (*) atom is the point of attachment of additional spacer or releasable linker units, or the cytotoxic agent, and/or the binding molecule (CBA);
• X1, Y1, Z2 and Z3 are independently NH, O, or S;
• Z1 is independently H, NHR5, OR1, SR5, COX1R5, wherein X1 and R5 are defined above;
• v is 0 or 1;
• U1 is independently H, OH, C1-C6 alkyl, (OCH2CH2)n, F, Cl, Br, I, OR5, SR5, NR5R5′, N═NR5, N═R5, NR5R5′, NO2, SOR5R5′, SO2R5, SO3R5, OSO3R5, PR5R5′, POR5R5′, PO2R5R5′, OPO(OR5)(OR5′), or OCH2PO(OR5(OR5′), wherein R5 and R5′ are independently selected from H, C1-C8 alkyl;
• C2-C8 alkenyl, alkynyl, heteroalkyl, or amino acid;
• C3-C8 aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, alkylcarbonyl, or glycoside;
• or pharmaceutical cation salts;
• the non-self-immolative linker component is one of the following structures:
• wherein the (*) atom is a point of attachment of additional spacer or releasable linkers, the cytotoxic agent, and/or the binding molecule;
• X1, Y1, U1, R5, R5′ are defined as above;
• r is 0-100;
• m and n are 0-20 independently;
• or R1, R2, R3, and R4 may independently contain a releasable linker component which includes at least one bond that can be broken under physiological conditions, and is a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labile or enzyme-labile bond having one of the following structures:
• —(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)r, —(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t—, - (Aa)r (CR5R6)m(CR7R8)n(OCH2CH2)r, —(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t, —(CR5R6)m—(CR7═CR8)(CR9R10)n(Aa)t(OCH2CH2)r, —(CR5R6)m(NR11CO)(Aa)t(CR9R10)n-(OCH2CH2)r, —(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r, —(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r, —(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r, —(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r, —(CR5R6)m(NR11CO)(Aa)t(CR9R10)r(OCH2CH2)r, —(CR5R6)m—(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r, —(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r, —(CR5R6)m(CO)(Aa)t(CR9R10)n—(OCH2CH2)r, —(CR5R6)m-phenyl-CO(Aa)t(CR7R8)n—, —(CR5R6)m-furyl-CO(Aa)t(CR7R8)n—, —(CR5R6)n-oxazolyl-CO(Aa)t(CR7R8)n—, —(CR5R6)m-thiazolyl-CO(Aa)t(CCR7R8)n—, —(CR5R6)t-thienyl-CO(CR7R8)n—, —(CR5R6)t-imidazolyl-CO—(CR7R8)n—, —(CR5R6)t-morpholino-CO(Aa)t-(CR7R8)n—, —(CR5R6)tpiperazino-CO(Aa)t(CR7R8)n—, —(CR5R6)r—N-methylpiperazin-CO(Aa)t-(CR7R8)n—, —(CR5R6)m-(Aa)tphenyl-, —(CR5R6)m-(Aa)tfuryl-, —(CR5R6)m-oxazolyl(Aa)t-, —(CR5R6)m-thiazolyl(Aa)t-, —(CR5R6)m-thienyl-(Aa)t-, —(CR5R6)m-imidazolyl(Aa)r, —(CR5R6)m-morpholino-(Aa)r, —(CR5R6)m-piperazino-(Aa)r, —(CR5R6)m—N-methylpiperazino-(Aa)r, —K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)r, —K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t—, —K(Aa)r (CR5R6)m(CR7R8)n(OCH2CH2)t, —K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)r, —K(CR5R6)m—(CR7═CR8)(CR9R10)n(Aa)t(OCH2CH2)r, —K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r, —K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r, —K(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r, —K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r, —K(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r, —K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r, —K(CR5R6)m—(OCO)(Aa)t(CR9R10)n(OCH2CH2)r, —K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r, —K—(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r, —K(CR5R6)m-phenyl-CO(Aa)t(CR7R8)n—, —K—(CR5R6)m-furyl-CO(Aa)t-(CR7R8)n—, —K(CR5R6)m-oxazolyl-CO(Aa)t(CR7R8)n—, —K(CR5R6)m-thiazolyl-CO(Aa)t-(CR7R8)n—, —K(CR5R6)t-thienyl-CO(CR7R8)n—, —K(CR5R6)timidazolyl-CO—(CR7R8)n—, —K(CR5R6)tmorpholino-CO(Aa)t(CR7R8)n—, —K(CR5R6)tpiperazino-CO(Aa)t(CR7R8)n—, —K(CR5R6)t—N-methylpiperazinCO(Aa)t(CR7R8)n—, —K(CR5R6)m(Aa)tphenyl, —K—(CR5R6)m-(Aa)tfuryl-, —K(CR5R6)m-oxazolyl(Aa)t-, —K(CR5R6)m-thiazolyl(Aa)t-, —K(CR5R6)m-thienyl-(Aa)t-, —K(CR5R6)m-imidazolyl(Aa)t-, —K(CR5R6)m-morpholino(Aa)t-, —K(CR5R6)m-piperazino-(Aa)tG, —K(CR5R6)mN-methylpiperazino(Aa)r;
• wherein Aa, m, and n are described above;
• t and r are 0-100 independently;
• R3, R4, R5, R6, R7, and R8 are independently chosen from H;
• halide;
• C1-C8 alkyl;
• C2-C8 aryl, alkenyl, alkynyl, ether, ester, amine or amide, which optionally substituted by one or more halide, CN, NR1R2, CF3, OR1, Aryl, heterocycle, S(O)R1, SO2R1, —CO2H, —SO3H, —OR1, —CO2R1, —CONR1, —PO2R1R2, —PO3H or P(O)R1R2R3;
• K is NR1, —SS—, —C(═O)—, —C(═O)NH—, —C(═O)O—, —C═NH—O—, —C═N—NH—, —C(═O)NH—NH—, O, S, Se, B, Het (heterocyclic or heteroaromatic ring having C3-C8), or peptides containing 1-20 amino acids;
• or R1, R2, R3, and R4, are independently linear alkyl having from 1-18 carbon atoms, or polyethyleneoxy unit having formula (OCH2CH2)p, p=1-5000, or a peptide containing 1-20 units of aminoacids (L or D form), or combination above;
• or Y1, Y2, R1, R2, R3, R4, Z1 or Z2 may independently be composed of one or more following components:
• and L- or D-, natural or unnatural peptides containing 1-20 amino acids;
• wherein a connecting bond in the middle of atoms means that it can connect either neighbor carbon atom bonds;
• wavy line is the site wherein another bond can be connected to;
• or Y1, Y2, R1, R2, R3, R4, Z1 or Z2 can be independently absent, provided that Y1, Y2, R1, R2, R3, R4, Z1 and Z2 may not be absent at the same time.