BR-122023000762-B1 - Conjugated compound, pharmaceutical composition, and synergistic agents.

Abstract

The present invention relates to a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-ligand (a double ligand) containing a 2,3-diaminosuccinyl group. It also relates to the preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-ligand, particularly when the drug possesses amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde, and thiol functional groups for conjugation with the bis-ligand in a specific manner, as well as the therapeutic use of the conjugates.

Inventors

• ROBERT YONGXIN ZHAO
• Huihui GUO
• Wenjun Li
• Shun GAI
• Lu Bai
• Zhixiang GUO
• Junxiang JIA
• Xiaomai ZHOU
• Jun Zheng
• Qianqian Tong
• Hongsheng Xie
• Qingliang YANG
• Yanhong Tong
• MINGJUN CHAO
• Chen Lin
• Zhicang YE
• Binbin Chen
• Yanlei YANG
• Yuanyuan Huang
• Linyao ZHAO
• Hangbo YE
• Xiaotao ZHUO
• Chengyu YANG
• Jun Lei
• Yifang Xu

Assignees

• HANGZHOU DAC BIOTECH CO., LTD

Dates

Publication Date

20260310

Application Date

20181012

Claims (20)

1. 1. Conjugated compound, characterized by the fact that it has the stereoisomeric structure of the 2,3-diaminosuccinyl group represented by Formula (Ia), (Ib), (Ic), (IIIa), (IIIb) and (IIIc) below: in which: It represents a simple connection; It is optionally a simple link or it is absent; is optionally a single or double bond, or may optionally be absent; n is 1 to 30 independently; Q is a cell-binding agent/molecule selected from an antibody; Drug1 is selected from tubulisins, calicheamicins, auristatins, maytamsinoids, CC-1065, daunorubicin and doxorubicin compounds, taxanoids (taxanes), cryptophycins, epothilones, benzodiazepine dimers, calicheamicins and enedine antibiotics, actinomycins, amatoxins, amanitins, azaserines, bleomycins, epirubicins, tamoxifen, idarubicin, dolastatins/auristatins, duocarmycins, geldanamycins, methotrexates, thiotepa, vindesines, vincristines, hemiasterlines, nazumamides, microginines, radiosumins, alterobactins, microsclerodermins, theonelamides, esperamycins, erbulins; X1 and X2 are the same or different, and selected independently from NH; NHNH; N(R1); N(R1)N(R2); O; S; SS, O-NH. ON(R1), CH2-NH. CH2-N(R1), CH=NH. CH=N(R1) 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); or C1-C6 alkyl; C2-C8 alkenyl, heteroalkyl, alkylcycloalkyl or heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl or heteroaryl; Y1, Y2, Z1 and Z2 are the same or different and independently have a functional group that couples to a cell-binding molecule Q, or drug1, in the form of a disulfide, ether, ester, thioether, thioester, peptide, hydrazone, carbamate, carbonate, amine (secondary, tertiary or quaternary), imine, cycloheteroalkane, heteroaromatic, alkyloxime or amide bond; Y1, Y2, Z1 and Z2 independently have 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, SS, O-NH, ON(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) 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 and independently selected from O, NH, S, NHNH, N(R5), N(R3)N(R3'), polyethyleneoxy unit of formula (OCH2CH2)pOR5, or (OCH2CH-(CH3))pOR5, NH(CH2CH2O)pR5, NH(CH2CH(CH3)O)pR5, N[(CH2CH2O)pR5]-[(CH2CH2O)p'R5'], (OCH2CH2)pCOOR5 or CH2CH2(OCH2CH2)pCOOR5, wherein p and p' are independently an integer selected from 0 to about 1000, or a combination thereof; C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, esters, ether or amide; C3C8 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, ethers or amides; or 1-24 amino acids; or R1, R2, R3 and R4 may optionally be composed of one or more linking components of 6-maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), vanilla-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)aminobenzoate (“SIAB”), 4-thiobutyrate (SPDB), 4-thio-2-hydroxysulfonylbutyrate (2-Sulfo-SPDB) or natural or non-natural peptides with 1-8 natural or non-natural amino acids. The natural amino acid is preferably 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: in which is the coupling site; X3, X4, X5, X6, and X7 are independently selected from 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 acids; wherein R5 and R5' are independently H; C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl or heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; C1-C8 esters, ether or amide; or polyethylenexi with the formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 0 to about 5000, or a combination thereof; or R1, R2, R3, R4, Y1, Y2, Z1 and Z2 may independently contain a self-immolating or non-self-immolating component, peptide units, a hydrazone linkage, a disulfide, an ester, an oxime, an amide or a thioether linkage, wherein the self-immolating unit includes, but is not limited to, aromatic compounds electronically similar to para-aminobenzylcarbamoyl (PAB) groups such as 2-aminoimidazol-5-methanol derivatives, heterocyclic analogs of PAB, beta-glucuronide and ortho- or para-aminobenzylacetals; the self-immolating linking component may have one of the following structures: wherein the atom (*) is the attachment point for additional spacer or ligand units that may be released from either 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 cationic salts; the non-self-immolating linker component is a of the following structures: where atom (*) is the attachment point for additional spacers or ligands, cytotoxic agents and/or binding molecules; X1, Y1, U1, R5, R5' are as defined above; r is 0~100; Men are 0~20 independently; or R1, R2, R3 and R4 may independently contain a releasable linker component that includes at least one bond that can be broken under physiological conditions, such as pH labile, acid labile, base labile, oxidation labile, metabolically labile, biochemically labile or enzyme labile, with one of the following structures: -(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-, -(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-, -(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-, -(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)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- phenyl-CO(Aa)t(CR7R8)n-, -(CR5R6)m-furyl-CO(Aa)t(CR7R8)n-, -(CR5R6)m- 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)tpiperazine-CO(Aa)t-(CR7R8)n-, - (CR5R6)tN-methylpiperazin-CO(Aa)t-(CR7R8)n-, -(CR5R)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)t-, -(C R5R6)m-morpholino-(Aa)t-, -(CR5R6)m-piperazino-(Aa)t-, -(CR5R6)mN-methylpiperazino-(Aa)t-, -K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-, -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)t-, -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)thymidazolyl-CO-(CR7R8)n- , -K(CR5R6)tmorpholino-CO(Aa)t(CR7R8)n-, -K(CR5R6)tpiperazino-CO(Aa)t- (CR7R8)n-, -K(CR5R6)tN-methylpiperazin-CO(Aa)t(CR7R8)n-, -K(CR5R)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)t-; wherein m, Aa, men are described above; ether are 0-100 independently; R3, R4, R5, R6, R7 and R8 are chosen independently from H; halide; C1~C8 alkyl; C2~C8 aryl, alkenyl, alkynyl, ether, ester, amine or amide, which optionally substituted with one or more halides, CN, NR1R2, CF3, OR1, Aryl, heterocycle, S(O)Ri, SO2R1, -CO2H, -SO3H, -ORi, -CO2R1, -CONRi, -PO2R1R2, -PO3H or PiOiR-RR.; K is NRi, -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 with C3-C8) or peptides containing 1-20 amino acids; or R1, R2, R3 and R4 are independently linear alkyl with 1-18 carbon atoms or polyethyleneoxy unit with the formula (OCH2CH2)p, p = 1~5000, or a peptide containing 1~20 amino acid units (L or D form) or a combination of the above; furthermore, Y1, Y2, R1, R2, R3, R4, Z1 or Z2 may independently be composed of one or more of the following components as shown below: 6-maleimidocaproyl (MC), maleimido propanoyl (MP), tiomaleido, thio-amino-oxobutanoic acid, thio-amino-oxobutenoic acid, Vanilla-citrulline (val-cit), alanine-phenylalanine (ala-phe), isin-phenylalanine (lys-phe), lysine-alanine (lys-ala), p-aminobenzyloxycarbonyl(PAB), 4-thiopentanoate (SPP), 4-thiobutyrate (SPDB), 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (MCC), maleimidoethyl (ME), 4-thio-2-hydroxysulfonyl-butyrate (2-Sulfo-SPDB), aryl-thiol (PySS), (4-acetyl)aminobenzoate(SIAB), ,oxylbenzylthio, aminobenzylthio, dioxylbenzylthio, diaminobenzylthio, amino-oxylbenzylthio, alkoxyamino (AOA), ethyleneoxy (EO), 4-methyl-4-dithio-pentanoic acid (MPDP), triazole, ditio, alkylsulfonyl, alkylsulfonamide, sulfon-bisamide, Phosphondiamide, alkylphosphonamide, phosphinic acid, N-methylphosphonamidic acid, N,N'-dimethylphosphonamidic acid, N,N'-dimethylphosphondiamide, hydrazine, acetimidamide; next, acetylacetohydrazide, aminoethylamine, aminoethyl-aminoethylamine and natural or non-natural L- or D-peptides containing 1-20 amino acids; wherein a connecting link in the middle of the atoms means that it can connect bonds of neighboring carbon atoms; the wavy line is the site to which another bond can be connected; alternatively, Y1, Y2, R1, R2, R3, R4, Z1 or Z2 may be absent independently, but Y1, Y2, R1, R2, R3, R4, Z1 and Z2 cannot be absent at the same time.
2. 2. Conjugated compound according to claim 1, characterized in that it is further represented by Formula (I01), (I-02), (I-03), (I-04), (I-05), (I-06), (I-07), (I-08), (I-09), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20), (I-21), (I-22), (I-23), (III-01), (III-02), (III-03), (III-04), (III-05), (III-06), (III-07), (III-08), (III-09), (III-10), (III-11), (III-12), (III-13), (III-14), (III-15), (III-16), (III-17), (III-18), (III-19) and (III-20) below: in which Q, Xi, X2, Yi, Y2, Ri, R2, R3, R4, R5, Ry, Zi, Z, and Drug1 are defined as in claim 1.
3. 3. Conjugated compounds according to claim 2, characterized in that they are made from a readily reactive stereoisomeric compound represented by Formula (Va), (Vb), (Vc), (VIIa), (VIIb) and (VIIc) below, respectively, wherein two or more cell-binding molecule function groups can react simultaneously or sequentially to the Lvi and/or Lv2 of the compounds: in which: It is optionally a single bond, a double bond, or a triple bond, or it may optionally be absent; provided that, when represents a triple bond, Lvi and Lv2 are missing; , Farmacot, n, XI, X2, Y1, Y2, R1, R2, R3, R4, R5, R5', Z1 and Z2 are as defined in claim 1; Lv1 and Lv2 represent the same or different leaving group that can be reacted with a thiol, amine, carboxylic acid, selenol, phenol or hydroxyl group in a cell-binding molecule. Lv1 and Lv2 are independently selected from OH; F; Cl; Br; I; nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; mono-fluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, anhydrides that have self-formed or been formed with another anhydride, acetic anhydride, formic anhydride; or an intermediate molecule generated with a condensation reagent for peptide coupling reactions or for Mitsunobu reactions, which are selected from EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide), DCC (Dicyclohexylcarbodiimide), N,N'-diisopropylcarbodiimide (DIC), N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (CMC or CME-CDI), 1,1'-carbonyldiimidazole (CDI), TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), hexafluorophosphate (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diethyl cyanophosphonate (DEPC), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium hexafluorophosphate 3-oxide (HATU), 1-[(dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazol[4,5-b]pyridinium hexafluorophosphate 3-oxide (HDMA), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), hexafluorophosphate fluoro-N,N,N',N'-bis(tetramethylene)formamidinium (BTFFH), N,N,N',N'-tetramethyl-S-(1-oxide-2-pyridyl)thiuronium hexafluorophosphate,O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate(TPTU), tetrafluoroborate S-(1-oxide-2-pyridyl)-N,N,N',N'-tetramethylthiuronium, O-[(ethoxycarbonyl)-cyanomethylenamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), (1-cyano-2-ethoxy-2-oxoethylideneamino-oxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), hexafluorophosphate O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium (HBPyU), N-benzyl-N'-cyclohexyl-carbodiimide (with or without polymer linkage), dipyrrolidino(N-succinimidyl-oxy)carbenium hexafluorophosphate (HSPyU), chlorodipyrrolidinecarbenium hexafluorophosphate (PyClU), 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate (CIB), (benzotriazol-1-yloxy)dipiperidinecarbenium hexafluorophosphate (HBPipU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), propylphosphonic anhydride (PPACA, T3P®), 2-morpholinoethyl isocyanide (MEI), N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), 2-bromo-1-ethyl-pyridinium tetrafluoroborate (BEP), O-[(ethoxycarbonyl)cyano- tetrafluoroborate methyleneamino]-N,N,N',N'-tetra-methyluronium (TOTU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (MMTM, DMTMM), N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)- N,N,N',N'-tetramethyluronium borate (TDBTU), 1,1'-(azodicarbonyl)-dipiperidine (ADD), di-(4-chlorobenzyl)azodicarboxylate (DCAD), di-tert-butyl azodicarboxylate (DBAD), diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD). Furthermore, Lv1 and Lv2 may be an anhydride, formed by the acid itself or formed with other C1~C8 acid anhydrides; or Lv1 and Lv2 may be independently selected from a halide (fluoride, chloride, bromide and iodide), methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), trifluoromethylsulfonate, nitrophenoxyl, N-succinimidyl (NHS), phenoxyl; dinitrophenoxyl; pentafluorophenoxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluorophenoxyl, monofluorophenoxyl, pentachlorophenoxyl, 1H-imidazol-1-yl, chlorophenoxyl, dichlorophenoxyl, trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazolyl)oxyl, 2-ethyl-5-phenylisoxazolium-3'-sulfonyl, phenyloxadiazol-sulfonyl (-sulfone-ODA), 2-ethyl-5-phenylisoxazolium-yl, phenyloxadiazol-yl (ODA), oxadiazol-yl, unsaturated carbon (a double or triple bond between carbon-carbon, carbon-nitrogen, carbon-sulfur, carbon-phosphorus, sulfur-nitrogen, phosphorus-nitrogen, oxygen-nitrogen or carbon-oxygen), or one of the following structures: disulfide; haloacetyl; acyl halide (halide) acid; N-hydroxysuccinimide ester; maleimida; Monosubstituted maleimide; dissubstituted maleimide; monosubstituted succinimide; disubstituted succinimide; aldehyde-CHO; ethenesulfonyl; acrylic (acryloyl); 2-(tosyloxy)acetyl; 2-(mesyloxy)acetyl; 2-(nitrophenoxy)acetyl; 2-(dinitrophenoxy)acetyl; 2-(fluorophenoxy)-acetyl; 2-(difluorophenoxy)-acetyl; 2-(((trifluoromethyl)-sulfonyl)oxy)acetyl; ketone or aldehyde, 2-(pentafluorophenoxy)acetyl; methylsulfonaphenyloxadiazole (ODA); , acid anhydride, alkyloxyamino; azido, alkynyl or hydrazide, wherein X1' is F, Cl, Br, I or Lv3; X2' is O, NH, N(R1) or CH2; R3 is independently H, an aromatic, heteroaromatic or aromatic group in which one or more H atoms are independently substituted by -R1, -halogen, -OR1, -SR1, -NR1R2, -NO2, -S(O)R1, -S(O)2R1 or -COOR1; Lv3 is a leaving group selected from F, Cl, Br, I, nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3′-sulfonate; R1 and R2 are defined above.
4. 4. Compound according to claim 3, characterized in that it has a structure additionally represented by the Formula (V01), (V-02), (V-03), (V-04), (V-05), (V-06), (V-07), (V-08), (V-09), (V-10), (V-11), (V-12), (V-13), (V-14), (V-15), (V-16), (V-17), (V-18), (V-19), (V-20), (V-21), (V-22), (V-23), (VII-01), (VII-02), (VII-03), (VII-04), (VII-05), (VII-06), (VII-07), (VII-08), (VII-09), (VII-10), (VII-11), (VII-12), (VII-13), (VII-14), (VII-15), (VII-16), (VII-17), (VII-18), (VII-19) and (VII-20) below: in which , Q, Xi, X2, Yb Y2, Rb R2, R3, R4, R5, R5', Zi, Z2, and the Drug are as defined above; X1 and X1' are independently H, F, Cl, Br, I, OTs, OMs, OTf, N3, CHO, -C=CH, -C=C- , ArC(=O)Ri, C(=O)NHNH2, -O-NH2, nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; mono-fluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; i-hydroxybenzo-triazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, anhydrides that have self-formed or formed with another anhydride, for example, acetic anhydride or formic anhydride; O-NHS (ON-hydrosuccinimide), O-imidazole, O-triazole, O-tetrazol, O-Ar, O-ArNO2, O-Ar(NO2)2, O-ArF4, O-ArF3, O-ArF5, O-ArF2, O-ArF, O-ArCl4, O-ArCl3, O-ArCl5, O-ArCl2, O-ArCl, O-ArSO3H, O-ArOPO3H2, O- Ar(NO2)COOH, S-Ar(NO2)2COOH, O-pyridine, O-nitrophenol, O-dinitrophenol, O-pentafluorophenol, O-tetrafluorophenol, O-trifluorophenol, O-difluorophenol, O- fluorophenol, O-pentachlorophenol, O-tetrachlorophenol, O-trichlorophenol, O- dichlorophenol, O-chlorophenol, O-pyridine, O-nitropyridine, O-dinitropyridine, O-Ci-C8 alkyl, O-triflate, O-benzotriazole, S-Ar, S-ArNO2, S-Ar(NO2)2, S-ArF4, S-ArF3, S-ArF5, S-ArF2, S-ArF, S-ArCl4, S-ArCl3, S-ArCl5, S-ArCl2, S-ArCl, S-ArSO3H, S-ArOPO3H2, S-Ar(NO2)COOH, S-Ar(NO2)2COOH, S-pyridine, SS-pyridine, S-nitropyridine, S-dinitropyridine, S-Ci-C8 alkyl, SS-Ci-C8 alkyl, S-triflate, S-benzotriazole, where Ar is C3-C8 aromatic ring; or an intermediate molecule generated with a condensation reagent for peptide coupling reactions or for Mitsunobu reactions.
5. 5. Conjugate according to claim 1, characterized in that Y1, Y2, Z1 and Z2 can bind to thiol pairs of a cell-binding agent/molecule by reducing the interchain disulfide bonds of the cell-binding agent with dithiothreitol (DTT), dithioerythriol (DTE), L-glutathione (GSH), tris(2-carboxyethyl)phosphine (TCEP), 2-mercaptoethylamine (β-MEA) and/or beta-mercaptoethanol (β-ME, 2-ME).
6. 6. Conjugated compounds according to claim 1, characterized in that the drug is selected from: (1) . a chemotherapeutic agent selected from the group consisting of: a) . an alkylating agent: selected from the group consisting of nitrogen mustards: chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, manomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, fenesterin, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1065 and adozelesin, carzelesin, bizelesin or their synthetic analogues; duocarmycin and its synthetic analogues, KW-2189, CBI-TMI or CBI dimers; Benzodiazepine dimers or pyrrolobenzodiazepine (PBD) dimers, tomaimycin dimers, indolinobenzodiazepine dimers, imidazobenzothiadiazepine dimers or oxazolidinobenzodiazepine dimers; Nitrosoureas: comprising carmustine, lomustine, chlorozotocine, fotemustine, nimustine, ranimustine; Alkyl sulfonates; Triazenes or dacarbazine; Platinum-containing compounds: comprising carboplatin, cisplatin and oxaliplatin; Aziridines, benzodopa, carboquone, meturedopa or uredopa; Ethyleneimines and methylamylamines; b) A plant alkaloid: selected from the group consisting of vinca alkaloids; Taxoids: comprising paclitaxel, docetaxol and their analogues, Maitansinoids, cryptophycins; epothilones, eleuthrobin, discodermolide, bryostatins, dolostatins, auristatins, tubulisins, cephalostatins; pancratistatin; erbulins, a sarcodictin; spongistatin; c) a DNA topoisomerase inhibitor: selected from the Epipodophilin groups: comprising 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novanthrone, retinoic acids (or retinols), teniposide, topotecan, 9-nitrocamptothecin or RFS 2000; and mitomycins and their analogues; d) an antimetabolite: selected from the group consisting of {[Anti-folate: (DHFR inhibitors: comprising methotrexate, trimetrexate, denopterin, pteropterin, aminopterin (4-aminopteroic acid) or folic acid analogues); IMP dehydrogenase inhibitors; Ribonucleotide reductase inhibitors: (comprising hydroxyurea, deferoxamine)]; [Pyrimidine analogues: uracil analogues; cytosine analogues; purine analogues; folic acid replacement, frolinic acid}; and Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors); e) . a hormonal therapy: selected from the group consisting of {Receptor antagonists: [Anti-estrogens; LHRH agonists; Anti-androgens]; Retinoids/Deltoids: [Vitamin D3 analogs; photodynamic therapies; cytokines]};f) . a kinase inhibitor, selected from the group consisting of BIBW 2992, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, Pazopanib, vandetanib, E7080, mubritinib, ponatinib (AP24534), bafetinib (INNO- 406), bosutinib (SKI-606), cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, ispinesib; g). Poly(ADP-ribose) polymerase (PARP) inhibitors selected from the group consisting of olaparib, niraparib, iniparib, talazoparib, veliparib, CEP 9722 (Cephalon’s), E7016 (Eisai’s), BGB-290 (BeiGene’s) or 3-aminobenzamide.h) . An antibiotic, selected from the group consisting of an antibiotic of enedine, aclacinomycins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophiline; cromomycins, dactinomycin, daunorubicin, detorrubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and desoxyxorubicin, epirubicin, eribulin, esorubicin, idarubicin, marcelomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamicin, rodorrubicin, streptonigrin, streptozocin, tubercidine, ubenimex, zinostatin, zorrubicin; i) a polyketide, bulatacin and bulatacinone; gemcitabine, epoxomycins and carfilzomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, alovectin-7, Xegeva, Provenge, Yervoy, isoprenylation inhibitors and lovastatin, dopaminergic neurotoxins and 1-methyl-4-phenylpyridinium ion, cell cycle inhibitors, actinomycins, amanitins, bleomycins, anthracyclines, MDR inhibitors or verapamil, Ca2+ATPase inhibitors or thapsigargine, histone deacetylase inhibitors; thapsigargine, celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A.; Antiadrenal drugs, selected from the group consisting of aminoglutethimide, mitotane, trilostane; aceglathone; aldophosphamide glycoside; aminolevulinic acid; ansacrine; arabinoside, bestrabucil; bisanthrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine (DFMO), elfomitine; elliptinium acetate, etoglucid; galcium nitrate; gacytosine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; pSK®; razoxane; rhizoxine; sizofirane; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes; urethane, siRNA, antisense drugs;(2) . an anti-autoimmune disease agent: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids, DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate, prednisone, sirolimus, tacrolimus.(3) . Anti-infectious disease agents comprising:a) . aminoglycosides: amikacin, astromycin, gentamicin, hygromycin B, kanamycin, netilmicin, spectinomycin, streptomycin, tobramycin, verdamycin;b) . amphenicols; azidanphenicol, chloramphenicol, florfenicol, thiamphenicol;c) . ansamycins: geldanamycin, herbimycin;d) . carbapenems: biapenem, doripenem, ertapenem, imipenem/cilastatin, meropenem, panipenem;e) . cefens: carbacefen (loracarbef), cefacetrile, cefaclor, cefradine, cefadroxil, cephalonium, cephaloridine, cephalothin or cephalothin, cephalexin, cephaloglycin, cefamandole, cefapirin, cefatrizin, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil, cefroxadine, ceftezol, cefuroxime, cefixime, cefdinir, cefditoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicicide, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cephalexin, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefsulodin, ceftazidime, cefteram, ceftibuten, ceftiolene, ceftizoxime, ceftobiprol, ceftriaxone, cefuroxime, cefuzonam, cefamycin (cefoxitin, cefotetan, cefmetazole), oxacefem (flomoxef, latamoxef); f) . glycopeptides: bleomycin, vancomycin (oritavancin, telavancin), teicoplanin (dalbavancin), ramoplanin; g) . glycylcyclines: tigecycline; h) . β-Lactamase inhibitors: penam (sulbactam, tazobactam), clavam (clavulanic acid); i) . lincosamides: clindamycin, lincomycin; j) . lipopeptides: daptomycin, A54145, calcium-dependent antibiotics (CDA); k) . macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide (telithromycin, cethromycin), midecamycin, myocamycin, oleandomycin, rifamycins (rifampicin, rifampin, rifabutin, rifapentine), roquitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus (FK506), troleandomycin, telithromycin;1). monobactams: aztreonam, tigemonam;m) . oxazolidinones: linezolid;n) . penicillins: amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam (pivmecillinam), mezlocillin, methicillin, nafcillin, oxacillin, penamecillin, penicillin, feneticillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin;o). polypeptides: bacitracin, colistin, polymyxin B;p) . - moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin;q) . streptogramins: pristinamycin, quinupristin/dalfopristin;r) . sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (co-trimoxazole);s) . steroidal antibacterials: selected from fusidic acid;t) . tetracyclines: doxycycline, chlortetracycline, clomocycline, demeclocycline, limecycline, meclocycline, methacycline, minocycline, oxytetracycline, penimepicilline, rolitetracycline, tetracycline, glycylcyclines (including tigecycline);u) . other antibiotics: selected from the group consisting of anonacin, arsphenamine, bactoprenol inhibitors (Bacitracin), DADAL/AR inhibitors (cycloserine), dictyostatin, discodermolide, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitors (fosfomycin), nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin (rifampin), tazobactam, tinidazole, uvaricin;(4) . antiviral drugs comprising:a) . Entry/fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41 (enfuvirtide), PRO 140, CD4 (ibalizumab); b) Integrase inhibitors: raltegravir, elvitegravir, globoidnan A; c) Maturation inhibitors: bevirimat, vivecon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleoside and nucleotides: abacavir, acyclovir, adefovir, andoxovir, apricitabine, brivudine, cidofovir, clevudine, dexelvucitabine, didanosine (ddI), elvucitabine, emtricitabine (FTC), entecavir, famciclovir, fluorouracil (5-FU), 3’-fluoro-substituted 2’,3’-dideoxynucleoside analogs and 3’-fluoro-2’,3’-dideoxyguanosine (FLG), fomivirsen, ganciclovir, idoxuridine, lamivudine (3TC), l-nucleosides, penciclovir, racivir, ribavirin, estampidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluridine, valacyclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT);f) . non-nucleoside inhibitors: amantadine, atazanavir, capravirin, diarylpyrimidines, delavirdine, docosanol, emivirine, favirenz, foscarnet (phosphonoformic acid), imiquimod, interferon alfa, loviride, lodenosine, methiazone, nevirapine, NOV-205, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod (R-848), tromantadine;g) . protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir (VX-950), tipranavir;h) . Other types of antiviral drugs: abzima, arbidol, calanolide, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate (EGCG), foscarnet, griffitsine, taribavirin (viramidine), hydroxyurea, KP-1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, seliciclib.
7. 7. Conjugated compounds according to any one of claims 1, 2, or 6, characterized in that the cell-binding agent/molecule is capable of targeting a tumor cell, a virus-infected cell, a microorganism-infected cell, a parasite-infected cell, an autoimmune disease cell, an activated tumor cell, a myeloid cell, an activated T cell, an affected B cell, or a melanocyte, or any cell expressing any of the following antigens or receptors: CD2, CD2R, CD3, CD3gd, CD3e, CD4, CD5, CD6, CD7, CD8, CD8a, CD8b, CD9, CD10, CD11a, CD11b, CD11c, CD12, CD12w, CD13, CD14, CD15, CD15s, CD15u, CD16, CD16a, CD16b, CD17, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD42a, CD42b, CD42c, CD42d, CD43, CD44, CD44R, CD45, CD45RA, CD45RB, CD45RO, CD46, CD47, CD47R, CD48, CD49a, CD49b, CD49c, CD49e, CD49f, CD50, CD51, CD52, CD53, CD54, CD55,CD56, CD57, CD58, CD59, CD60, CD60a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD63, CD64, CD65, CD65s, CD66, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD74, CD75, CD75s, CD76, CD77, CD78, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CDw84, CD85, CD86, CD87, CD88, CD89, CD90, CD91, CD92, CDw92, CD93, CD94, CD95, CD96, CD97, CD98, CD99, CD99R, CD100, CD101, CD102, CD103, CD104, CD105, CD106, CD107, CD107a, CD107b, CD108, CD109, CD110, CD111, CD112, CD113, CDw113, CD114, CD115, CD116, CD117, CD118, CD119, CDw119, CD120a, CD120b, CD121a, CD121b, CDw121b, CD122, CD123, CDw123, CD124, CD125, CDw125, CD126, CD127, CD128, CDw128, CD129, CD130, CD131, CDw131, CD132, CD133, CD134, CD135, CD136, CDw136, CD137, CDw137, CD138, CD139, CD140a, CD140b, CD141, CD142, CD143, CD144, CD145, CDw145, CD146, CD147, CD148, CD149, CD150, CD151, CD152, CD153, CD154, CD155, CD156a, CD156b, CDw156c, CD157, CD158a, CD158b, CD159a, CD159b, CD159c, CD160, CD161, CD162, CD162R, CD163, CD164, CD165, CD166, CD167, CD167a, CD168, CD169, CD170, CD171, CD172a, CD172b, CD172g, CD173, CD174, CD175, CD175s, CD176, CD177, CD178, CD179, CD180, CD181, CD182, CD183, CD184, CD185, CD186, CDw186, CD187, CD188, CD189, CD190, Cd191, CD192, CD193, CD194, CD195, CD196, CD197, CD198, CDw198, CD199, CDw199, CD200, CD200a, CD200b, CD201, CD202, CD202b, CD203, CD203c, CD204, CD205, CD206, CD207, CD208, CD209, CD210, CDw210, CD211, CD212, CD213a1, CD213a2, CD214, CD215, CD216, CDw217, CDw218a, CDw218b, CD219, CD220, CD221, CD222, CD223, CD224, CD225, CD226, CD227, CD228, CD229, CD230, CD231, CD232, CD233, CD234, CD235a, CD235ab, CD235b, CD236, CD236R, CD237, CD238, CD239, CD240, CD240CE, CD240D, CD241, CD242, CD243, CD244, CD245, CD246, CD247, CD248, CD249, CD250, CD251, CD252, CD253, CD254, CD256, CD257, CD258, CD259, CD260, CD261, CD262, CD263, CD264, CD265, CD266, CD267, CD268, CD269, CD270, CD271, CD272, CD273, CD274, CD275, CD276 (B7-H3), CD277, CD278, CD279, CD280, CD281, CD282, CD283, CD284, CD285, CD286, CD287, CD288, CD289, CD290, CD291, CD292, CDw293, CD294, CD295, CD296, CD297, CD298, CD299, CD300a, CD300c, CD300e, CD301, CD302, CD303, CD304, CD305, CD306, CD307, CD308, CD309, CD310, CD311, CD312, CD314, CD315, CD316, CD317, CD318, CD319, CD320, CD321, CD322, CD323, CD324, CDw325, CD326, CDw327, CDw328, CDw329, CD330, CD331, CD332, CD333, CD334, CD335, CD336, CD337, CDw338, CD339, 4-1BB, 5AC, 5T4 (Trophoblast glycoprotein, TPBG, 5T4, Wnt-activated inhibitory factor 1 or WAIF1), adenocarcinoma antigen, AGS-5, AGS-22M6, activin receptor-like kinase 1 (AFP, AKAP-4, ALK, alpha integrin, alpha v beta6, aminopeptidase N, beta amyloid, androgen receptor, angiopoietin 2, angiopoietin 3, annexin A1, anthrax toxin protective antigen, anti-transferrin receptor, AOC3 (VAP-1), B7-H3, Bacillus anthracis anthrax, BAFF (B-cell activating factor), B-lymphoma cell, bcr-abl, Bombesin, BORIS, C5, C242, CA125 antigen (antigen of carbohydrate 125, MUC16), CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg, Canis lupus familiaris IL31, carbonic anhydrase IX, cardiac myosin, CCL11 (C-C motif chemokine 11), CCR4 (C-C type chemokine receptor, CD194), CCR5, CD3E (epsilon), CEA (carcinoembryonic antigen), CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD (Factor D), Ch4D5, cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), Clustering Factor A, cMet, CRIPTO, FCSF1R (Colony-stimulating factor 1 receptor, CD115), CSF2 (colony-stimulating factor 2, granulocyte-macrophage colony-stimulating factor) (GM-CSF), CTLA4 (cytotoxic T-cell-associated protein 4), CTAA16.88 tumor antigen, CXCR4, (CD184), C-X-C chemokine receptor type 4, ADP-cyclic ribose hydrolase, Cyclin B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL3 (delta-type ligand 3), DLL4 (delta-type ligand 4), DPP4 (dipeptidyl peptidase 4), DR5 (death receptor 5), E. coli Shiga-1 toxin, E. coli Shiga-2 toxin, ED-B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRvIII, Endoglin (CD105), endothelin B receptor, endotoxin, EpCAM (molecule (epithelial cell adhesion), EphA2, Episialin, ERBB2 (Epidermal growth factor receptor 2), ERBB3, ERG (TMPRSS2 ETS fusion gene), Escherichia coli, ETV6-AML, FAP (Fibroblast activating protein alpha), FCGR1, alpha-fetoprotein, fibrin II, beta chain, fibronectin-B extra domain, FOLR (folate receptor), folate receptor alpha, folate hydrolase, Fos-related antigen, respiratory syncytial virus F protein, Frizzled receptor, Fucosyl GM1, ganglioside GD2, G-28 (cell surface antigen glycolipid), GD3 idiotype, GloboH, glypican 3, N-glycolylneuramic acid, GM3, GMCSF receptor α chain, growth differentiation factor 8, GP100, GPNMB (transmembrane glycoprotein) NMB), GUCY2C (Guanylate cyclase 2C, guanylyl cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase-C receptor, heat-stable enterotoxin receptor (hSTAR)), heat shock proteins, hemagglutinin, hepatitis B antigen, hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2/neu, HER3 (ERBB-3), IgG4, HGF/SF (hepatocyte growth factor/dispersing factor), HHGFR, HIV-1, histone complex, HLA-DR (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, human chorionic gonadotropin, HNGF, human dispersing factor receptor kinase, HPV E6/E7, Hsp90, hTERT, ICAM-1 (adhesion molecule). intercellular 1), idiotype, IGF1R, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-17A, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-27 or IL-28), IL31RA, ILGF2 (insulin-like growth factor 2), integrins (α4, αnbβ3, avβ3, O4β7, a5β1, a6β4, a7β7, allβ3, a5β5, avβ5), interferon-gamma-induced protein, ITGA2, ITGB2, KIR2D, LCK, Le, Legumain, Lewis-Y antigen, LFA-1 (lymphocyte function-associated antigen 1, CD11a), LHRH, LINGO-1, lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MART1, MCP-1, MIF (macrophage migration inhibitory factor or glycosylation inhibitory factor (GIF)), MS4A1 (member 1 of the A subfamily of 4 transmembrane domains), MSLN (mesothelin), MUC1 (Mucin 1, cell surface-associated cell (MUC1) or epithelial mucin). polymorphic (PEM)), MUC1-KLH, MUC16 (CA125), MCP1 (monocytic chemotactic protein 1), MelanA/MART1, ML-IAP, MPG, MS4A1 (transmembrane 4-domain subfamily A), MYCN, myelin-associated glycoprotein, myostatin, NA17, NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME), NGF, neural apoptosis-regulated proteinase 1, NOGO-A, Notch receptor, Nucleolin, Neu oncogene product, NY-BR-1, NY-ESO-1, OX-40, OxLDL (oxidized low-density lipoprotein), OY-TES1, P21, non-mutant p53, P97, Page4, PAP, anti-(N-glycolylneuraminic acid) paratopic, PAX3, PAX5, PCSK9, PDCD1 (PD-1, programmed cell death protein 1, CD279), PDGF-Ra (platelet-derived growth factor receptor alpha), PDGFR-β, PDL-1, PLAC1, PLAP-type testicular alkaline phosphatase, platelet-derived growth factor receptor beta, sodium phosphate cotransporter, PMEL 17, polysialic acid, proteinase 3 (PR1), prostate carcinoma, PS (phosphatidylserine), prostate carcinoma cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI), CD240), Rhesus factor, RANKL, RANTES receptors (CCR1, CCR3, CCR5), RhoC, mutant Ras, RGS5, ROBO4, respiratory syncytial virus, RON, sarcoma translocation breakpoints, SART3, Sclerostin, SLAMF7 (member of the SLAM 7 family), Selectin P, SDC1 (Syndecan 1), sLe (a), Somatomedin C, SIP (Sphingosine-1-phosphate), Somatostatin, sperm protein 17, SSX2, STEAP1 (prostate epithelial transmembrane antigen 6), STEAP2, STn, TAG-72 (tumor-associated glycoprotein 72), Survivin, T-cell receptor, T-cell transmembrane protein, TEM1 (tumor endothelial marker 1), TENB2, Tenascin C (TN-C), TGF-α, TGF-β (transforming growth factor beta), TGF-β1, TGF-β2 (transforming growth factor beta 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF-α, TNFRSF8, TNFRSF10B (member of the 10B family of the tumor necrosis factor receptor superfamily), TNFRSF13B (member of the 13B member of the tumor necrosis factor receptor superfamily), TPBG (trophoblast glycoprotein), TRAIL-R1 (tumor necrosis apoptosis-inducing ligand receptor 1), TRAILR2 (death receptor 5 (DR5)), tumor-associated calcium signal transducer 2, tumor-specific glycosylation of MUC1, TWEAK receptor, TYRP1 (glycoprotein 75), TROP-2, TRP-2, tyrosinase, (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2 or vimentin, WT1, XAGE 1 or cells expressing any insulin-like growth factor receptor or any epidermal growth factor receptor.
8. 8. Conjugated compounds according to claim 7, characterized in that the tumor cell is selected from the group consisting of lymphoma cells, myeloma cells, kidney cells, breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cell carcinoma cells, small cell lung cancer cells, non-small cell lung cancer cells, testicular cancer cells, malignant cells or any cells that grow and divide at an accelerated and unregulated rate to cause cancer.
9. 9. Conjugated compound according to claim 1, characterized in that the drug is a chromophore molecule, selected from the group consisting of the structures of Ac01, Ac02, Ac03, Ac04, Ac05, Ac06, and Ac07, Ac08, Ac09, Ac010, and Ac11 as follows: in which Q, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2 and are as defined above; R12 and R12' are independently OH, NH2, NHR1, NHNH2, NHNHCOOH, O-Ri-COOH, NH-Ri-COOH, NH-(Aa)nCOOH, O(CH2CH2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2,NH(CH2CH2O)pCH2CH2NH2, O(CH2CH2O)pCH2CH2COOH,NH(CH2CH2O)pCH2CH2COOH, O(CH2CH2O)pCH2CH2NHSO3H,NH(CH2CH2O)pCH2CH2NHSO3H, Ri-NHSO3H, NH-Ri-NHSO3H,O(CH2CH2O)pCH2CH2NHPO3H2, NH(CH2CH2O)pCH2CH2NHPO3H2, Ri- NHPO3H2, Ri-OPO3H2, O(CH2CH2O)pCH2CH2OPO3H2, NH(CH2CH2O)pCH2CH2NHPO3H2, ORi-NHPO3H2, NH-Ri-NHPO3H2, NH-Ar-COOH, NH-Ar-NH2, where p=0-5000, Aa is an amino acid, (Aa)n comprises the same or different natural or non-natural amino acids, n=i-30.
10. 10. Conjugated compound according to claim i, characterized in that the drug i is a tubulisin analog, selected from the structures of T0i, T02, T03, T04, T05, T06, T07, T08, T09 and T10 as follows: in which , Q, Xi, X2, R1, R2, R3, R4, R5, R5', Aa, « Zi,Z2, pen are as defined above; Y1 and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NHNHC(O) and C(O)NR1; mAb is antibody, preferably monoclonal antibody; R12 is OH, NH2, NHR1, NHNH2, NHNHCOOH, O-R1-COOH, NH-R1-COOH, NH- (Aa)nCOOH, O(CH2CH2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2,NH(CH2CH2O)pCH2CH2NH2, NR1R1', NHOH, NHOR1,O(CH2CH2O)pCH2CH2COOH, NH(CH2CH2O)pCH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O)pCH2CH2NHSO3H,NH(CH2CH2O)pCH2CH2NHSO3H, R1-NHSO3H, NH-R1-NHSO3H,O(CH2CH2O)pCH2CH2NHPO3H2, NH(CH2CH2O)pCH2CH2NHPO3H2, OR1, R1-NHPO3H2, R1-OPO3H2, O(CH2CH2O)pCH2CH2OPO3H2, OR1-NHPO3H2, NH-R1-NHPO3H2, NH(CH2CH2NH)pCH2CH2NH2,NH(CH2CH2S)pCH2CH2NH2, NH(CH2CH2NH)pCH2CH2OH,NH(CH2CH2S)pCH2CH2OH, NH-R1-NH2 orNH(CH2CH2O)pCH2CH2NHPO3H2; R1, R1', R2, R3, R4 and R5 are independently H, linear or branched C1-C8 alkyl, amide or amines; C2-C8 aryl, alkenyl, alkynyl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, heterocycloalkyl or acyloxylamines; or peptides containing 1-8 amino acids, or polyethyleneoxy unit with the formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 1 to about 5000; The two Rs: RR, RR, RRRR may form a 3-8 membered cyclic ring of the alkyl, aryl, heteroaryl, heteroalkyl or alkylcycloalkyl group; X3 is H, CH3, CH2CH3, C3H7 or X1'R1', wherein X1' is NH, N(CH3), NHNH, O or S; R1' is H or linear or branched C1-C8 alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl or acyloxylamines; R3' is H or linear or branched C1-C6 alkyl; Z3 is H, COOR1, NH2, NHR1, OR1, CONHR1, NHCOR1, OCOR1, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, R1, O-glucoside (glucoside, galactoside, mannoside, glucuronoside/glucuronide, alloside, fructoside, etc.), NH-glucoside, S-glucoside or CH2-glucoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
11. 11. Conjugated compound according to claim 1, characterized in that the drug is a calicheamicin analogue, selected from the CO1 and CO2 structures as follows: in which , Q, Xi X2, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2 and n are as defined above; preferably X1,
12. 12. Conjugated compound according to claim i, characterized in that the drug i is a maytansinoid analogue, selected from the following structures My01, My02, My03, My04, My05 and My06: in which , Q, Xi, X2, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2 and n are as defined above; preferably X1,
13. 13. Conjugated compound according to claim i, characterized in that the drug i is a taxane analog, selected from the structures of Tx01, Tx02 and Tx03 as follows: in which , Q, Xi, X2, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2 and n are as defined above; preferably X1,
14. 14. Conjugated compound according to claim i, characterized in that the drug i is an analog of CC-1065 and/or an analog of duocarmycin, selected from the CC0i, CC02, CC03, CC04, CC05 and CC06 structures as follows: in which Q, Xi, X2, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2 and n are as defined above; preferably X1, X2, Y1 and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(Ri), N(Ri)C(O)N(Ri), CH, C(O)NHNHC(O) and C(O)NR1; Q is preferably a monoclonal antibody; Z3 is H, PO(OM1)(OM2), SO3M1, CH2PO(OM1)(OM2), CH3N(CH2CH2)2NC(O)-, O(CH2CH2)2NC(O)-, R1 or glycoside.
15. 15. Conjugated compound according to claim 1, characterized in that the drug is an analogue of daunorubicin or doxorubicin, selected from the structures of Da01, Da02, Da03, Da04, Da05, Da06, Da07 and Da08 as follows: in which , Q, preferably X1, Ri2 is OH, NH2, NHRi, NHNH2, NHNHCOOH, O-Ri-COOH, NH-Ri-COOH, NH(Aa)nCOOH, O(CH2CH2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2, NH(CH2CH2O)pCH2CH2NH2, NRiRi', NHOH, NHORi, O(CH2CH2O)pCH2CH2COOH, NH(CH2CH2O)pCH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O)pCH2CH2NH-SO3H,NH(CH2CH2O)pCH2CH2NH-SO3H, R1-NHSO3H, NH-R1-NHSO3H,O(CH2CH2O)pCH2-CH2NHPO3H2, NH(CH2CH2O)pCH2-CH2NHPO3H2, OR1, R1-NHPO3H2, R1-OPO3H2, O(CH2CH2O)pCH2CH2OPO3H2, OR1-NHPO3H2, NH-R1-NHPO3H2,NH(CH2CH2S)pCH2CH2NH2,NH(CH2CH2S)pCH2-CH2OH, NH(CH2CH2O)pCH2CH2NHPO3H2.
16. 16. Conjugated compound according to claim 1, characterized in that Drug 1 is an analog of auristatin or dolastatin, selected from the structures of Au01, Au02, Au03, Au04, Au05, Au06, Au07, Au08, Au09, Au10, Au11, Au12, Au13, Au14 and Au15. in which , Q, Xi, X2, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2, Aa, (Aa)n, pen are as defined above; preferably X1, Ri2 is OH, NH2, NHRi, NHNH2, NHNHCOOH, O-Ri-COOH, NH-Ri-COOH, NH-(Aa)nCOOH, O(CH2CH2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2, NH(CH2CH2O)pCH2CH2NH2, NRiRi', NHOH, NHORi, O(CH2CH2O)pCH2CH2COOH, NH(CH2CH2O)pCH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O)pCH2CH2NH-SO3H,NH(CH2CH2O)pCH2CH2NHSO3H, Ri-NHSO3H, NH-Ri-NHSO3H,O(CH2CH2O)pCH2-CH2NHPO3H2, NH(CH2CH2O)pCH2CH2NHPO3H2, ORi, Ri-NHPO3H2, Ri-OPO3H2, O(CH2CH2O)pCH2CH2OPO3H2, ORi-NHPO3H2, NH-Ri-NHPO3H2, NH(CH2CH2NH)pCH2-CH2NH2,NH(CH2CH2S)pCH2CH2NH2, NH(CH2CH2NH)pCH2CH2OH,NH(CH2CH2S)pCH2-CH2OH, NH-Ri-NH2, orNH(CH2CH2O)pCH2CH2NHPO3H2; R1, R2, R3, R4 and R5 are independently H; linear or branched C1-C8 alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amines, heterocycloalkyl, or acyloxylamines; or peptides containing i-8 amino acids or polyethylenexi units with the formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer number of approximately 5000. The two Rs: RiR2, R2R3, RiR3 or R3R4 may form a cyclic ring of 3-8 members of the alkyl, aryl, heteroaryl, heteroalkyl or alkylcycloalkyl group; X3 is H, CH3 or Xi'Ri', wherein Xi' is NH, N(CH3), NHNH, O or S, and Ri' is H or linear or branched C1-C8 alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxylamines; R3' is H or linear or branched C1-C6 alkyl; Z3' is H, COORi, NH2, NHRi, OR1, CONHR1, NHCOR1, OCOR1, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, R1, or O-glycoside (glycoside, galactoside, mannoside, glucuronoside/glucuronide, alloside, fructoside, etc.), NH-glycoside, S-glycoside or CH2-glycoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
17. 17. Conjugated compound according to claim 1, characterized in that the drug is a dimer of benzodiazepine analogs, selected from the structures of PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08, PB09, PB10, PB11, PB12, PB13, PB14, PB15, PB16, PB17, PB18, PB19, PB20, PB21, PB22, PB23, PB24, PB25 and PB26: in which , Q, Xi, X2, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2 and n are as defined above; preferably X1, Ri, R2, R3, Ri', R2' and R3' are independently H; F; Cl; =O; =S; OH; SH; linear or branched C1-C8 alkyl, aryl, alkenyl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester (COOR5 or -OC(O)R5), ether (OR5), amide (CONR5), carbamate (OCONR5), amines (NHR5, NR5R5'), heterocycloalkyl or acyloxylamines (-C(O)NHOH, -ONHC(O)R5); or peptides containing 1-20 natural or non-natural amino acids or polyethylenexi unit of the formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 1 to about 5000. The two Rs: R1R2, R2R3, R1R3, R1'R2', R2'R3' or R1'R3' can independently form a cyclic ring of 3-8 members of the alkyl, aryl, heteroaryl, heteroalkyl or alkylcycloalkyl group; X3 and Y3 are independently N, NH, CH2, or CR5, wherein R5, R6, R12, and R12' are independently H, OH, NH2, NH(CH3), NHNH2, COOH, SH, OZ3, SZ3, F, Cl, or linear or branched C1-C8 alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxylamines; Z3 is H, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, or O-glucoside (glucoside, galactoside, mannoside, glucuronoside/glucuronide, alloside, fructoside, etc.), NH-glucoside, S-glucoside, or CH2-glucoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
18. 18. Conjugated compound according to claim 1, characterized in that Drug 1 is an amanitin analogue, selected from the Am01, Am02, Am03 and Am04 structures below: in which X, X2, Q, Y1, Y2, R1, R2, R3, R4, R5, R5', Z1, Z2 and n are as defined above; preferably X1, X2, Y1 and Y2 are independently O, N, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NH-NHC(O), C(O)NRi or are absent; R7, R8 and R9 are independently H, OH, ORi, NH2, NHRi, C1-C6 alkyl or are absent; Y2 is O, O2, NRi, NH or is absent; Ri0 is CH2, O, NH, NRi, NHC(O), NHC(O)-NH, NHC(O)O, OC(O)O, C(O), OC(O), OC(O)(NRi), (NRi)C(O)(NRi), C(O)Ri or is absent; Rii is OH, NH2, NHRi, NHNH2, NHNHCOOH, O-Ri-COOH, NH-Ri-COOH, NH-(Aa)nCOOH, O(CH2CH2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2,NH(CH2CH2O)pCH2CH2NH2, NRiRi', O(CH2CH2O)pCH2CH2COOH, NH(CH2CH2O)pCH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2,O(CH2CH2O)pCH2CH2NHSO3H, NH(CH2CH2O)pCH2CH2NHSO3H, Ri-NHSO3H, NH-Ri-NHSO3H, O(CH2CH2O)pCH2CH2NHPO3H2,NH(CH2CH2O)pCH2CH2NHPO3H2, ORi, Ri-NHPO3H2, Ri-OPO3H2, O(CH2CH2O)pCH2CH2OPO3H2, ORi-NHPO3H2, NH-Ri-NHPO3H2 or NH(CH2CH2O)pCH2CH2NHPO3H2, wherein Aa is i-8 amino acids; ne mi are independently 1-30; p is 1-5000; Z3 is H, OH, COOR1, NH2, NHR1, OR1, CONHR1, NHCOR1, OCOR1, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, R1 or O-glycoside (glycoside, galactoside, mannoside, glucuronoside/glucuronide, alloside, fructoside etc.), NH-glycoside, S-glycoside or CH2-glycoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
19. 19. Conjugated compound according to claim 1 or 8, characterized in that Drug 1 is a polyalkylene glycol analog, selected from the Pg01, Pg02, and Pg03 structures, in which Q, XI, X2, Y1, Y2, R1, R2, R3, R4, R5, R5', Z1, Z2 and are as defined above; preferably, Y1 and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NH-NHC(O) and C(O)NR1; p is 1-5000; R1 and R3 are as defined for R1 above and, preferably, R1 and R3 are H, OH, OCH3, CH3 or OC2H5 independently.
20. 20. Conjugated compound according to claim 1, characterized in that Drug 1 is a cell-binding ligand or cell receptor agonist and its analogs, selected from the structures of: LB01 (folate conjugate), LB02 (PMSA ligand conjugate), LB03 (PMSA ligand conjugate), LB04 (PMSA ligand conjugate), LB05 (somatostatin conjugate), LB06 (somatostatin conjugate), LB07 (octreotide, a somatostatin conjugate), LB08 (lanreotide, a somatostatin analog conjugate), LB09 (vapreotide (Sanvar), a somatostatin analog conjugate), LB10 (CAIX ligand conjugate), LB11 (CAIX ligand conjugate), LB12 (gastrin-releasing peptide receptor). (GRPr), MBA conjugate), LB13 (luteinizing hormone-releasing hormone (LH-RH) ligand and GnRH conjugate), LB14 (luteinizing hormone-releasing hormone (LH-RH) ligand and GnRH conjugate), LB15 (GnRH antagonist, Abarelix conjugate), LB16 (cobalamin, vitamin B12 analog conjugate), LB17 (cobalamin, vitamin B12 analog conjugate), LB18 (for αvβ3 integrin receptor, RGD cyclic pentapeptide conjugate), LB19 (heterobivalent peptide ligand conjugate for VEGF receptor), LB20 (Neuromedin B conjugate), LB21 (bombesin conjugate for a G protein-coupled receptor), LB22 (TLR2 conjugate for a receptor Toll type), LB23 (for an androgen receptor), LB24 (Cilengitide/cyclo(-RGDfV-) conjugate for an αv integrin receptor, LB23 (fludrocortisone conjugate), LB25 (rifabutin analog conjugate), LB26 (rifabutin analog conjugate), LB27 (rifabutin analog conjugate), rifabutin), LB28 (fludrocortisone conjugate), LB29 (dexamethasone conjugate), LB30 (fluticasone propionate conjugate), LB31 (beclomethasone dipropionate conjugate), LB32 (triamcinolone acetonide conjugate), LB33 (prednisone conjugate), LB34 (prednisolone conjugate), LB35 (methylprednisolone conjugate), LB36 (methylprednisolone conjugate), betamethasone), LB37 (irinotecan analogue conjugate), LB38 (crizotinib analogue conjugate), LB39 (bortezomib analogue conjugate), LB40 (carfilzomib analogue conjugate), LB41 (carfilzomib analogue conjugate), LB42 (leuprolide analogue conjugate), LB43 (triptorelin analogue conjugate), LB44 (clindamycin conjugate), LB45 (liraglutide analogue conjugate), LB46 (semaglutide analogue conjugate), LB47 (retapamulin analogue conjugate), LB48 (indibulin analogue conjugate), LB49 (vinblastine analogue conjugate), LB50 (lixisenatide analogue conjugate), LB51 (osimertinib analogue conjugate), LB52 (an analogue conjugate of neucleoside), LB53 (erlotinib analogue conjugate) and LB54 (lapatinib analogue conjugate) as shown in the following structures: where Y5 is N, CH, C(Cl), C(CH3) or C(COOR1); R1 is H, C1-C6, C3-C8 Ar alkyl; in which , Xi, X2, Q, Yi, Y2, Ri, R2, R3, R4, R5, R5', Zi, Z2 and n are as defined above; preferably X1, X3 is CH2, O, NH, NHC(O), NHC(O)NH, C(O), OC(O), OC(O)(NR3), Ri, NHRi, NRi, C(O)Ri or is absent; X4 is H, CH2, OH, O, C(O), C(O)NH, C(O)N(Ri), Ri, NHRi, NRi, C(O)Ri or C(O)O; X5 is H, CH3, F or Cl; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3; R6 is 5'-deoxyadenosyl, Me, OH or CN;

Description

FIELD OF THE INVENTION [001] The present invention relates to a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-ligand (double ligand) containing a 2,3-aminosuccinyl group. It also relates to the preparation of a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-ligand, particularly when the drug has functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-ligand in a specific manner, as well as the therapeutic use of the conjugates. FUNDAMENTALS OF THE INVENTION [002] An antibody-drug conjugate (ADC), which is a synergistic combination of an antibody (mAb) conjugated to small chemotherapeutic molecules via a conditionally stable ligand for preferential accumulation of small molecule drugs within the tumor via receptor-mediated endocytosis and thus sparing healthy tissue, has given rise to a class of highly effective antineoplastic drugs with a large and rapidly growing clinical development pipeline. The three components of ADCs (mAb, ligand, and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each while enhancing the functionality of the ADC as a whole has been a key consideration in ADC design and development. It is believed that ligand technology to achieve release at the desired site, efficient drug loading, optimal stoichiometry, and macromolecule homogeneity are of vital importance for achieving good pharmacokinetics, efficacy, and tolerability (Lambert, J. and Chari, R., J. Med. Chem. 2014, 57, 6949-64; Ponte, J. et al., Bioconj. Chem., 2016, 27(7), 158898; Dovgan, I., et al. Sci. Rep. 2016, 6, 30835; Ross, P. L. and Wolfe, J. L. J. Pharm. Sci. 105(2), 391-7; Chen, T. et al. J. Pharm. Biomed. Anal., 2016, 117, 304-10; Zhao, R. Y. et al, 2011, J. Med. Chem. 54, 3606-23). [003] Previous investigations into antibody-drug conjugate (ADC) stability have focused on drug release by ligand deconjugation when ADC stability is affected by relatively stable loadings such as maytansines (Piwko C, et al, Clin Drug Investig. 2015, 35(8), 487-93; Lambert, J. and Chari, R., J. Med. Chem. 2014, 57, 6949-64). However, a commercially available antibody-drug conjugate, called T-DM1, failed in a clinical trial as a first-line treatment for patients with locally advanced or metastatic unresectable HER2-positive breast cancer and as a second-line treatment for advanced HER2-positive gastric cancer due to little benefit for patients when compared to toxicity contralateral to efficacy (Ellis, P. A., et al, J. Clin. Oncol. 2015, 33, (suppl; abstract 507 of 2015 ASCO Annual Meeting); Shen, K. et al, Sci Rep. 2016; 6: 23262; de Goeij, B. E. and Lambert, J. M. Curr Opin Immunol 2016, 40, 14-23; Barrios, C. H. et al, J Clin Oncol 2016, 34, (suppl; abstract 593 of 2016 ASCO Annual Meeting). [004] To address off-target toxicity issues, research and development in ADC chemistry and design is now expanding the scopes of ligand cargo compartments and conjugate chemistry beyond single potent cargoes, and especially to address the ligand cargo activity of ADCs toward target/target diseases (Lambert, JM Ther Deliv 2016, 7, 279-82; Zhao, RY et al, 2011, J. Med. Chem. 54, 3606-23). Currently, many drug developers and academic institutions are highly focused on establishing new, reliable, specific conjugation ligands and methods for site-specific ADC conjugation, which appear to have longer circulating half-lives, greater efficacy, potentially decreased off-target toxicity, and a narrow range of in vivo pharmacokinetic (PK) properties of ADCs, as well as better batch-to-batch consistency in ADC production (Hamblett, KJ et al., Clin. Cancer Res. 2004, 10, 7063-70; Adem, Y. T. et al, Bioconjugate Chem. 2014, 25, 656-664; Boylan, N. J. Bioconjugate Chem. 2013, 24, 1008-1016; Strop, P., et al 2013 Chem. Biol. 20, 161-67; Wakankar, A. mAbs, 2011, 3, 161-172). These specific conjugation methods reported so far include the incorporation of manipulated cysteines (Junutula, J. R. et al. Nat. Biotechnol. 2008, 26, 925-32; Junutula, J. R., et al. 2010 Clin. Cancer Res. 16, 4769; US patents 8,309,300; 7,855,275; 7,521,541; 7,723,485, WO2008/141044), selenocysteines (Hofer, T., et al. Biochemistry 2009, 48, 12047-57; Li, X., et al. Methods 2014, 65, 133-8; US patent 8,916,159 granted to the US National Cancer Institute), cysteine containing reagent labels. perfluoroaromatics (Zhang, C. et al. Nat. Chem. 2015, 8, 1-9), thiolfucose (Okeley, N. M., et al 2013 Bioconjugate Chem. 24, 1650), unnatural amino acids (Axup, J. Y., et al, Proc. Nat. Acad. Sci. USA. 2012, 109, 16101-6; 1052-67; and US Patent 8,778 631 and US Patent Application 20100184135, WO2010/081110 granted to Sutro Biopharma; WO2006/069246, 2007/059312, US Patents 7,332,571, 7,696,312, and 7,638,299 granted to Ambrx; WO2007/130453, US Patents 7,632,492 and 7,829,659 granted to Allozyne), conjugation to reduced intermolecular dis