NZ775656B2 - Conjugation linkers containing 2,3-diaminosuccinyl group - Google Patents

Conjugation linkers containing 2,3-diaminosuccinyl group Download PDF

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Publication number
NZ775656B2
NZ775656B2 NZ775656A NZ77565618A NZ775656B2 NZ 775656 B2 NZ775656 B2 NZ 775656B2 NZ 775656 A NZ775656 A NZ 775656A NZ 77565618 A NZ77565618 A NZ 77565618A NZ 775656 B2 NZ775656 B2 NZ 775656B2
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NZ
New Zealand
Prior art keywords
cr5r6
ch2ch2o
cell
xii
och2ch2
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NZ775656A
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NZ775656A (en
Inventor
Lu Bai
Mingjun Chao
Binbin Chen
Shun Gai
Huihui Guo
Zhixiang Guo
Yuanyuan Huang
Junxiang Jia
Jun Lei
Wenjun Li
Original Assignee
Hangzhou Dac Biotech Co Ltd
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Publication date
Application filed by Hangzhou Dac Biotech Co Ltd filed Critical Hangzhou Dac Biotech Co Ltd
Priority claimed from PCT/CN2018/110155 external-priority patent/WO2020073345A1/en
Publication of NZ775656A publication Critical patent/NZ775656A/en
Publication of NZ775656B2 publication Critical patent/NZ775656B2/en

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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Abstract

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

Claims (34)

1. A conjugate compound having stereoisomeric structure of 2,3-diaminosuccinyl group ented by Formula (IIa), (IIb), (IIc), (IVa), (IVb) and (IVc) below: (IIa), (IIb), (IIc), (IVa), (IVb), (IVc), wherein “ ” represents a single bond; “ ” is optionally either a single bond, or absent; “ ” is 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/ molecule that links to R3 and R4 can be any kind presently known, or that become known, of a molecule that binds to, complexes with, or reacts with a moiety of a cell population sought to be therapeutically or otherwise ically modified. The cell-binding agent/molecule is an immunotherapeutic protein, an antibody, a single chain antibody; an antibody fragment that binds to the target cell; a monoclonal dy; a single chain monoclonal antibody; or a onal antibody nt that binds the target cell; a chimeric antibody; a chimeric antibody nt that binds to the target cell; a domain antibody ; a domain antibody fragment that binds to the target cell; adnectins that mimic antibodies; s; a lymphokine; a hormone; a vitamin; a growth factor; a colony stimulating factor; or a nt-transport molecule (a transferrin); a binding peptides having over four aminoacids, or protein, or antibody, or small cell-binding molecule or ligand ed on albumin, polymers, dendrimers, liposomes, rticles, vesicles, or (viral) capsids; Drug1 or/and Drug2 are a xic molecule/agent that is a therapeutic drug /molecule /agent, or an immunotherapeutic n/molecule, or a function molecule for enhancement of binding or stabilization of the cell-binding agent, or a cell-surface receptor binding , or for inhibition of cell proliferation, or for monitoring, detection or study of a cell-binding molecule action. It can also be a pharmaceutically acceptable salt, hydrate, or hydrated salt, or a crystalline structure, or an optical isomer, racemate, diastereomer or enantiomer, of immuno- therapeutic 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 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), (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, H, OC(NH)NH; OC(NR1)NH, NH; NHC(NH)NH; NHC(NR1)NH, C(O)NH, C(NH)NH, C(NR1)NH, OC(O)N(R1), 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, Aralkyl , heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl Y1, Y2, Z1 and Z2 are, the same or different, and ndently a function group that link to a inding molecule Q, or drug1 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 the following structures: C(O)CH, C(O)C, C(O)CH2, ArCH2, C(O), NH, NHNH, N(R1), (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(NH)NH, C(NR1)NH, OC(O)NH, OC(NH)NH; OC(NR1)NH, NHC(O)NH; )NH; 1)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 O, NH, S, NHNH, N(R5), (R3’), polyethyleneoxy unit of formula (OCH2CH2)pOR5, or H- (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 ed 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 ally 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 ), 4-thiopentanoate ("SPP"), 4-(N-maleimidomethyl)cyclohexane-1 carboxylate ), (4-acetyl)aminobenzoate ("SIAB"), 4-thio-butyrate (SPDB), 4-thiohydroxysulfonyl-butyrate (2-Sulfo- SPDB), or natural or unnatural peptides having 1~8 natural or unnatural amino acid unites. The natural aminoacid is preferably selected from aspartic acid, glutamic acid, arginine, histidine, , , threonine, asparagine, glutamine, cysteine, selenocysteine, tyrosine, phenylalanine , glycine, proline, tryptophan, and alanine; or R1, R2, R3, and R4 may ndently contain one or more of the following hydrophilic structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , wherein is the site of linkage; 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 hetero-alkyl, alkylcycloalkyl, or heterocycloalkyl; C3-C8 aryl, yl, heterocyclic , carbocyclic, heteroalkylcycloalkyl, arbonyl, or heteroaryl; C1-C8 esters, ether, or amide; or polyethyleneoxy having formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an r 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 nonself-immolative component, peptidic units, a hydrazone bond, a disulfide, an ester, an oxime, an amide, or a thioether bond; wherein the self-immolative unit includes, aromatic nds that are electronically similar to the para-aminobenzylcarbamoyl (PAB) groups such as 2-aminoimidazolmethanol derivatives, heterocyclic PAB, beta-glucuronide, and ortho or paraaminobenzylacetals the self-immolative linker ent may have one of the following structures: ; ;. X1 Y1*; or wherein the (*) atom is the point of attachment of additional 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’, 5’, 5)(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 ures: (CH2)nCO(OCH2CH2)rOCH3 *(CH2CH2O)r* ; *CH* ; (CH2)nCON(CH2CH2O)rCOCH3 (CH2)n(OCH2CH2)rOCOCH3 *CH* ; *CH* ; O O O (CH2)nCO(OCH2CH2)rOCOCH3 * P N N * S * * ; H * * *CH* m ; O ; OH ; ; HS COOH * * * O ; ; ; ; ; ; m ; COOH R5 R5 O COOH O * * * N* N* * N* * N* m ; m ; * S* ; O ; O ; m ; * * N* * * N* N* * O m O ; m O ; m ;*X1-(CH2)m-Y1* ; *N ; * ; O O N * * *X1 Y1 * N N *N * O ; ; m ; m H ; O R5 R5' R5 R5' S* S* * S ; ; * S ; m ; H O O O O O O N *S N COOH * N * N m * m S* COOH ; * ; O ; O ; COOH O COOH COOH O N HN N O OH O N O OH COOH COOH COOH * NH* m m m * *N * *N * * N* O ; O ; O ; O ; O O O H2)rOCH3 O (OCH2CH2)rOCH3 n m m * N* *N * *N * ; O ; O ; O ; O N(CH2CH2O)rCH3 O N m m H2N *N * *N * H2N * O * ; O ; ; O ; OH OH HN O O OH OH O P m HO OH *NH O * *N * O O ; ; HO ; *N * ; ; O ; HN n HN O S O m O m O OH S *N * *N * O OH O ; O ; ; wherein the (*) atom is the point of attachment of additional releasable linker components, the cytotoxic agents, and/or the binding molecules; 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 ndently contain a releasable linker component which in- cludes at least one bond that can be broken under physiological conditions, such as a pH-labile, abile, base-labile, oxidatively labile, metabolically labile, biochemically labile or enzyme-labile bond having one of the following structures: a releasable linker component has one of the following structurs: -(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- R8)(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-, 6)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-, 6)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)t-N-methylpiperazin-CO(Aa)t-(CR7R8)n-, -(CR5R)m-(Aa)tphenyl-, - (CR5R6)m-(Aa)tfuryl-, 6)m-oxazolyl(Aa)t-, -(CR5R6)m-thiazolyl(Aa)t-, 6)mthienyl- (Aa)t-, -(CR5R6)m-imidazolyl(Aa)t-, -(C R5R6)m-morpholino-(Aa)t-, -(CR5R6)m-piperazino- (Aa)t-, -(CR5R6)m-N-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-, R6)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)mthiazolyl-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-, R)m(Aa)tphenyl, -K- (CR5R6)m-(Aa)tfuryl-, -K(CR5R6)m-oxazolyl(Aa)t-, -K(CR5R6)m-thiazolyl(Aa)t-, -K(CR5R6)mthienyl- (Aa)t-, -K(CR5R6)m-imidazolyl(Aa)t-, R6)m-morpholino(Aa)t-, -K(CR5R6)m-piperazino- (Aa)tG;, -K(CR5R6)mN-methylpiperazino(Aa)t-; wherein m, Aa is an amino acid, (Aa)t comprises the same or different, natural or unnatural amino acids, and wherein m and n are described above; t and r are 0 – 100 independently; R3, R4, R5, R6, R7, and R8 are ndently chosen from H; ; 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, cycle, S(O)R1, SO2R1, -CO 2H, -SO3H, -OR1, , -CONR1, -PO2R1R2, -PO3 H 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 ndently linear alkyl having from 1-18 carbon atoms, or polyethyleneoxy unit having formula (OCH2CH2)p, p = 1~5000, or a peptide containing1~20 units of aminoacids (L or D form), or combination above; in addition, Y1, Y2, R1, R2, R3, R4, Z1 or Z2 are independently composed of one or more following components as shown below: 6-maleimidocaproyl (MC), maleimido propanoyl (MP), O thio-maleido, thio- amino-oxobutanoic acid, thio-amino-oxobutenoic acid, valine-citrulline (val-cit), ala- nine-phenylalanine (ala-phe), lysine-phenylalanine (lys-phe), lysine-alanine (lys-ala), p-ami- nobenzyloxycarbonyl (PAB), 4-thio-pentanoate (SPP), 4-thio-butyrate , 4-(N-maleimidomethyl)cyclo-hex- carboxylate (MCC), maleimidoethyl (ME), 4-thiohydroxysulfonyl-butyrate (2-Sulfo-SPDB), aryl- thiol (PySS), (4-acetyl)aminobenzoate (SIAB), , oxylbenzylthio, aminobenzylthio, benzylthio, diaminobenzylthio, amino-oxylbenzylthio, alkoxy amino (AOA), ethyleneoxy (EO), 4-methyldithio-pentanoic (MPDP), triazole, dithio, alkylsulfonyl, alkylsulfonamide, sulfon-bisamide, Phosphondiamide, O O P N P N OH alkylphosphonamide, inic acid, OH N- methylphosphonamidic acid, N,N’-dimethylphosphon-amidic acid, N,N’-dimethylphosphondiamide, hydrazine, acetimidamide; oxime, acetylacetohydrazide, aminoethyl-amine, aminoethyl-aminoethyl-amine, and L- or D-, natural or unnatural es containing 1-20 amino acids; wherein a connecting bond in the middle of atoms means that it can connect either neighbor carbon atom bonds; wavery line is the site wherein r bond can be connected to; alternatively, Y1, Y2, R1, R2, R3, R4, Z1 or Z2, can be independently absent..
2. The conjugate compound according to Claim 1 is further represented by Formula (II-01), (II-02), (II-03), (II-04), (II-05), (II-06), (II-07), (II-08), (II-09), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15), (II-16), (II-17), (II-18), (IV-01), (IV-02), (IV-03), (IV-04), ), (IV-06), (IV-07), (IV-08), (IV-09), (IV-10), (IV-11), (IV-12), (IV-13), (IV-14), (IV-15), (IV-16), (IV- 17), (IV-18), (IV-19), and (IV-20) below: (II-01), (II-03), (II-04), (II-05), (II-06), (II-07), (II-08), (II-10), (II-11), (II-12), (II-13), (II-14) (II-15), (II-17), (II-18), (IV-01), O O N N Drug1 S R3 Z1 Q O H H S O H O N Drug2 N R2 N O R4 Z2 H n O (IV-02), (IV-03), (IV-04), (IV-05), (IV-07), (IV-08), (IV-09), (IV-10), (IV-11), (IV-12), O R1 O O S Y1 N N Drug1 S H H R3 Z1 Q O O H O Drug2 S S Y2 N N R4 Z2 O R2 O H n (IV-14), (IV-15), (IV-16), (IV-18), (IV-19), (IV-20), wherein “ ”, “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, Drug1 and Drug2 are defined the same above in Claim 1; in addition, one of Drug1 and Drug2 can be independently absent but may not be absent at the same time.
3. The conjugates compounds ing to Clai m 2 are made from readily –reactive stereoisomeric compound presented by Formula (VIa), (VIb), (VIc), (VIIIa), (VIIIb) and (VIIIc) below accordingly, wherein two or more function groups of cell-binding molecule can simultaneously or sequentailly react to Lv1 and/or Lv2 of the compounds: (VIa), (VIb), (VIc), (VIIIa), (VIIIb), wherein: “ ” is optionally either a single bond, or a double bond, or a triple bond, or can optionally be absent; It provided that when represents a triple bond, Lv1 and Lv2 are absent; “ ”, “ ”, Drug1, Drug2, n, X1, X2, Y1, Y2, R1, R2, R3, R4, R5 , R5’, Z1, and Z2 are defined the same as in Claim 1; Lv1 and Lv2 represent the same or different g group that can be reacted with a thiol, amine, carboxylic acid, selenol, phenol or hydroxyl group on a cell-binding molecule. Lv1 and Lv2 are independently selected from OH; F; Cl; Br; I; henol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol ; pentachlorophenol; triflate; ole;dichlorophenol;tetrachlorophenol;1-hydroxybenzotriazole ; tosylate; mesylate; 2-ethylphenylisoxazolium-3'-sulfonate,anhydrides formed its self, or formed with the other anhydride, acetyl anhydride, formyl 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 (Dicyclohexyl-carbodiimide), N,N '-Diisopropylcarbodiimide (DIC), N-Cyclohexyl-N'-(2-morpholino-ethyl)carbodiimide metho-p-toluenesulfonate (CMC,or CME-CDI), 1,1'-Carbonyldiimi-dazole (CDI), TBTU (O-(Benzotriazolyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), N,N,N ',N'-Tetramethyl-O-(1H-benzotriazolyl)-uronium hexafluorophosphate (HBTU), (Benzotriazolyloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), (Benzotriazolyloxy)tripyrrolidinophosphonium uorophosphate (PyBOP), l hosphonate (DEPC), Chloro-N,N,N',N'-tetramethylformamidiniumhexafluorophosphate , 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid uorophos-phate (HATU), methylami-no)(morpholino)methylene ]-1H-[1,2,3]triazolo[4,5-b]pyridineium 3-oxide hexafluoro-phosphate (HDMA), 2- Chloro-1,3-dimethyl-imidazolidinium hexafluorophosphate (CIP), Chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), Fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH), N,N,N',N'-Tetramethyl-S-(1-oxidopyridyl)thiuronium hexafluoropho sphate, O-(2-Oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetra- fluoroborate (TPTU), S-(1-Oxidopyridyl)-N,N,N ',N'-tetramethylthiuronium tetrafluorobo- rate, O-[(Ethoxycarbonyl)-cyanomethylenamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), (1-Cyanoethoxyoxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), O-(Benzotriazolyl)-N,N,N',N'-bis(tetramethylene )uronium hexafluorophosphate (HBPyU), N-Benzyl-N'-cyclohexyl-carbodiimide (with, or without polymer-bound), Dipyrrolidino(N-succinimidyl-oxy)carbenium hexafluorophosphate (HSPyU), Chlorodipyrrolidinocarbeni um hexafluorophosphate (PyClU), 2-Chloro- 1,3-dimethylimidazolidinium tetrafluoroborate(CIB), (Benzotriazolyloxy)dipiperidino-carbenium hexafluorophosphate (HBPipU), O-(6-Chlorobenzotriazolyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), Bromotris(dimethylamino)-phosphonium hexafluorophosphate (BroP), Propylphosphonic anh ydride (PPACA, T3P®), 2-Morpholinoethyl isocyanide (MEI), N,N,N ',N'-Tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), 2-Bromoethyl-pyridinium tetrafluoroborate (BEP), O-[(Ethoxycarbonyl)cyanomethylenamino ]-N,N,N',N'-tetra-methyluronium tetrafluoroborate (TOTU), 4-(4,6-Dimethoxy-1 ,3,5-triazinyl)-4 -methylmorpholiniumchloride (MMTM, DMTMM), N,N,N ',N'- Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), O-(3,4-Dihydrooxo- 1,2,3-benzotriazinyl)-N,N,N',N'-tetramethyluronium tetrafluoro-borate ),1,1 '- (Azodicarbonyl)-dipiperidine (ADD), Di-(4-c enzyl)azodicarboxyl ate (DCAD), Di-tertbutyl azodicarboxylate (DBAD),Diisopropyl azod icarboxylate (DIAD), Diethyl azodicarboxylate (DEAD). In addition, Lv1 and Lv2 can be an ide, formed by acid lves or formed with other C1~C8 acid anhydrides; or Lv1 and Lv2 can be independently selected from, a halide (fluoride, chloride, bromide, and iodide), esulfonyl ), toluenesulfonyl (tosyl), trifluoromethyl-sulfonyl (triflate ), oromethylsulfonate, nitrophenoxyl, inimidyloxyl (NHS), phenoxyl; dinitrophenoxyl ; pentafluorophenoxyl, luorophenoxyl, trifluorophenoxyl, difluorophenoxyl, monofluorophenoxyl, pentachlorophenoxyl, dazoleyl, chlorophenoxyl, dichlorophenoxyl , trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazol-yl)oxyl, 2-ethylphenylisox- m-3'-sulfonyl, phenyloxadiazole-sulfonyl one-ODA), 2-ethylphenylisoxazolium-yl , phenyloxadiazol-yl (ODA), oxadiazol-yl, unsaturated carbon (a double or a triple bond n carbon-carbon, carbon-nitrogen, carbon-sulfur, carbon-phosphorus, sulfur-nitrogen, phosphorus-nitrogen, oxygen-nitrogen, or carbon-oxygen), or one of the following structure: disulfide; haloacetyl; acyl halide (acid halide N-hydroxysuccinimide ester; maleimide; monosubstituted maleimide; disubstituted maleimide; monosubstituted succinimide; disubstituted imide; -CHO aldehyde ethenesulfonyl; acryl (acryloyl); 2-(tosyloxy)acetyl; 2-(mesyloxy)acetyl; 2-(nitrophenoxy)acetyl; 2-(dini- trophenoxy)acetyl; 2-(fluorophenoxy)-acetyl; 2-(difluorophenoxy)-acetyl; 2-(((trifluoro- methyl)-sulfonyl)oxy)acetyl; ketone, or aldehyde, 2-(pentafluorophenoxy)acetyl; , me- thylsulfonephenyloxadiazole (ODA); , acid anhydride, alkyloxyamino; azido, alkynyl, or hydrazide , wherein X1’ is F, Cl, Br, I or Lv3; X 2’ is O, NH, N(R1), or CH2; R3 is independently H, aromatic, aromatic, or aromatic group wherein one or several H atoms are replaced ndently 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; lphenylisoxazolium-3'-sulfonate,R1 and R2 are defined above.
4. The nd according to Claim 3 having a structure further represented by Formula (VI-01), (VI-02), (VI-03), (VI-04), (VI-05), ), (VI-07), (VI-08), (VI-09), (VI-10), (VI- 11), ), (VI-13), (VI-14), (VI-15), (VI-16), (VI-17), (VI-18), (VIII-01), (VIII-02), (VIII- 03), (VIII-04), (VIII-05), (VIII-06), (VIII-07), (VIII-08), (VIII-09), (VIII-10), 11), (VIII- 12), (VIII-13), (VIII-14), (VIII-15), (VIII-16), (VIII-17), (VIII-18), (VIII-19), and (VIII-20) below: (VI-01), (VI-02), O O O Drug1 Y1 N N N H H H O O Drug2 R2 N Y2 N R4 N O H O (VI-04), (VI-05), (VI-06), (VI-07), (VI-08), (VI-09), (VI-10), (VI-11), (VI-12), (VI-13), (VI-14) (VI-16), (VI-17), (VI-18), (VIII-01), (VIII-02), N R1 O O H N Drug1 N Z1 OH H H R3 O O H O Drug2 HN R2 N O R4 Z2 O 03), (VIII-04), (VIII-06), (VIII-07), (VIII-08), (VIII-09), (VIII-10), (VIII-12), (VIII-13), (VIII-14), (VIII-15), (VIII-16), R1 O O X1 N Drug1 H N N H H R3 Z1 H O Drug2 X1' Z2 HN R2 N O R4 H (VIII-17), R1 O O X1 N H N N Drug1 H Z1 H R3 H O N Drug2 HN R2 N O R4 Z2 H (VIII-18), (VIII-20), wherein “ ”, “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, Drug1 and Drug2 are defined the same above;X1 and X1’ are independently H, F, Cl, Br, I, OTs, OMs, OTf, N3, CHO, -C=CH, , ArC(=O)R1, C(=O)NHNH2, -O-NH2, nitrophenol; oxy-succinimide (NHS); phenol; ophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; mono-fluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; lphenylisoxazolium-3'-sulfonate, anhydrides formed its self, or formed with the other anhydride, e.g. acetyl anhydride, formyl anhydride ; O-NHS (O-N-hydrosuccinimide), O-imidazole, O-triazole, O-tetrazole, O-Ar, O-ArNO2, O-Ar(NO2)2, , 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-trichloro-phenol , O-dichlorophenol, O-chlorophenol, O-pyridine, O-nitropyridine, O-dinitropyridine, O-C1- C8 alkyl, O-triflate, O-benzotriazole, S-Ar, 2, S-Ar(NO2)2, S-ArF4, S-ArF3, S-ArF5, SArF2 , S-ArF, S-ArCl4, S-ArCl3, 5, S-ArCl2, S-ArCl, S-ArSO3H, S-ArOPO3H2, S- Ar(NO2)COOH, S-Ar(NO2)2COOH, S-pyridine, S-S-pyridine, S-nitropyridine, S-dinitropyridine , S-C1-C8 alkyl, S-S-C1-C8 alkyl, S-triflate, S-benzotriazole, wherein Ar is C3-C8 aromatic ring; or an intermediate molecule ted with a sation reagent for peptide coupling reactions, or for Mitsunobu ons.
5. The conjugate compound ing to Claim 1 are made from a readlly-reactive com- pound represented by Formula (IX-01), (IX-02), (IX-03), (IX-04), ), (IX-06), ), (IX-08), (IX-09), (IX-10), (IX-11), (IX-12), (IX-13), (IX-14), ), (IX-16), (IX-17), (IX- 18), (IX-19), (IX-20), (IX-21), (IX-22), (IX-23), (X-01), (X-02), (X-03), (X-04), (X-05), (X- 06), (X-07), (X-08), (X-09), (X-10), (X-11), , (X-13), (X-14), (X-15), (X-16), (X-17), (X-18), (X-19), and (X-20) below accordingly, wherein two or more function groups of a cytotoxic molecule can simultaneously or requentially react to Lv1’ and /or Lv2’ of the compounds (IX-01), (IX-02), (IX-03), (IX-04), (IX-05), (IX-06), (IX-08), (IX-09), (IX-10), (IX-11), (IX-13), (IX-14), (IX-15), (IX-16), (IX-17) (IX-18), (IX-19), (IX-20), (IX-21), (IX-22), (X-01), (X-02), (X-03), (X-04), (X-06), (X-07), (X-08), (X-09), (X-10), (X-11), (X-12), (X-13), (X-15), (X-16), (X-17), (X-18), (X-20), wherein “ ”, “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, Lv1, Lv2, Lv1’, and Lv2’ are d the same above. In addition, one of Drug1 and Drug2 can be independently absent but may not be absent at the same time.
6. The conjugate compounds according to Clai m 1 are made from a readily-reactive compound represented by Formula (XI-01) , (XI-02) , (XI-03) , (XI-04) , (XI-05) , (XI-06) , (XI- 07) , (XI-08) , (XI-09) , ) , (XI-11) , (XI-12) , ) , (XI-14) , (XI-15) , (XI-16) , (XI- 17) , (XI-18) , (XII-01) , (XII-02) , (XII-03) , (XII-04) , (XII-05) , (XII-06) , (XII-07) , (XII- 08) , (XII-09) , (XII-10) , (XII-11) , (XII-12) , (XII-13) , (XII-14) , (XII-15) , (XII-16) , (XII- 17) , (XII-18) , (XII-19) , (XII-20) , (XII-21) , (XII-22) , (XII-23) , and (XII-24) below accordingly , wherein a cytotoxic molcecule and a inding molecule can react the compound independently , or simultaneously, or sequentially: (XI-02), O O O Lv1 R1 X1 Y1 N N R3 N H H H O O Lv2 Y2 N X1' N R4 N R2 O H O (XI-03), (XI-04), (XI-05), (XI-06) (XI-07), (XI-08), (XI-09), (XI-10), (XI-12), (XI-13), (XI-14), (XI-15), (XI-17), (XI-18), (XII-01), (XII-02), (XII-04), (XII-05), (XII-06), (XII-07), (XII-08), (XII-09), (XII-10), (XII-12), (XII-13), (XII-14), (XII-15), (XII-16), (XII-17), (XII-18), (XII-19), (XII-21), (XII-22), (XII-23), (XII-24), wherein “ ”, “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, Lv1, Lv2, Lv1’, Lv2’, X1 and X1’ are defined the same above.
7. The ate according to Claim 1, wherein Y1, Y2, Z1 and Z2 may link to pairs of thiols of a cell-binding agent/molecule through reducation from the inter chain disulfide bonds of the cell-binding agent with dithiothreitol (DTT) , dithioerythritol (DTE) , L-glutathione (GSH) , tris (2-carboxyethyl) phosphine (TCEP) , aptoethylamine (ß-MEA) , or/and beta mercaptoeth-anol (ß-ME, 2-ME) .
8. The conjugates compound according to Claim 1, wherein the Drug1 or Drug2 is selected from: (1). A chemotherapeutic agent selected from the group consisting of: a). an alkylating agent: selected from the group consisting of en mustards: chlorambucil , chlornaphazine, hosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine , mechlorethamine oxide hloride, mannomustine, mitobronitol, melphalan, mitolactol , pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1065 and adozelesin, carzelesin or bizelesin; duocarmycin, KW-2189, CBI-TMI, or CBI ; benzodiazepine dimers or pyrrolobenzodiazepine (PBD) dimers, tomaymycin dimers, indolinobenzodiazepine dimers, imidazobenzothiadiazepine dimers, or oxazolidinobenzodiazepine dimers; Nitrosoureas: comprising tine, lomustine, chlorozotocin, fotemustine, nimustine, ranimustine; ulphonates: comprising busulfan, treosulfan, improsulfan and piposulfan); Triazenes or dacarbazine; Platinum containing nds: comprising latin, cisplatin, and oxaliplatin; aziridines, benzodopa, carboquone, meturedopa, or uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide , triethylenethiophosphoramide and trimethylolomelamine]; b). A plant alkaloid: selected from the group consisting of Vinca ids: comprising vincristine , vinblastine, vindesine, vinorelbine, and navelbin; Taxoids: comprising paclitaxel, and docetaxol, Maytansinoids comprising DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine and ansamitocins, cryptophycins (including the group consisting of cryptophycin 1 and cryptophycin 8); epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins; pancratistatin; erbulins, a sarcodictyin; spongistatin, optionally wherein the cryptophycins are cryptophycin-l or cryptophycin-8; c). A DNA Topoisomerase tor: ed from the groups of Epipodophyllins: comprising 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate , ecan, mitoxantrone, rone, ic acids (or retinols), teniposide, topotecan, 9-nitrocamptothecin or RFS 2000; and mitomycins; d). An antimetabolite: selected from the group consisting of Anti-folate optionally comprising DHFR inhibitors: comprising methotrexate, trimetrexate, denopterin, pteropterin, aminopterin ; IMP dehydrogenase Inhibitors optionally comprising mycophenolic acid, tiazofurin, ribavirin , EICAR); Ribonucleotide reductase Inhibitors optionally comprising hydroxyurea, deferoxamine; Uracil analogs selected from ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, rouracil, floxuridine, ratitrexed ; Cytosine analogs selected from cytarabine, cytosine arabinoside, fludarabine; Purine analogs ed from azathioprine, fludarabine, mercaptopurine, thiamiprine, thioguanine; folic acid replenisher, frolinic acid; and Inhibitors of namide phosphoribosyltransferase e). A al therapy: selected from the group consisting of Anti-estrogen sing megestrol, fene, tamoxifen; LHRH agonistscomprising goscrclin, leuprolide e; Antiandrogens comprising bicalutamide, flutamide, calusterone, dromostanolone nate, epitiostanol , goserelin, leuprolide, mepitiostane, nilutamide, testolactone, trilostane and other androgens inhibitors; Retinoids/DeltoidsVitamin D3 analogs optionally comprising CB 1093, EB 1089 KH 1060, cholecalciferol, ergocalciferol; Photodynamic ies optionally comprising verteporfin, phthalocyanine, ensitizer Pc4, demethoxyhypocrellin A; Cytokines optionally comprising Interferon-alpha, Interferon-gamma, tumor necrosis factor , human proteins containing a TNF domain); 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, bafetinib, bosutinib, ntinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, Trastuzumab, Ranibizumab, Panitumumab, ispinesib; g). A poly (ADP-ribose) polymerase (PARP) tors selected from the group consisting of olaparib, niraparib, iniparib, parib, veliparib, CEP 9722, E7016, BGB-290, or 3-aminobenzamide. h). An antibiotic, selected from the group consisting of an enediyne antibiotic, aclacinomycins , actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomycin, daunorubicin, bicin, 6-diazooxo-L-norleucine , doxorubicin, lino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and oxorubicin, epirubicin, eribulin, esorubicin, icin, marcellomycin, nitomycins, mycophenodlic acid, mycin, olivomycins, peplomycin, potfiromycin, puromycin , quelamycin, bicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; optionally, wherein the enediyne antibiotic is selected from the group consisting of calicheamicin, calicheamicin ?1, d1, a1 or ß1; cin, including dynemicin A and ynemicin ; esperamicin, kedarcidin, C-1027, maduropeptin, or neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), i). A polyketide, bullatacin and bullatacinone; gemcitabine, epoxomicins andcarfilzomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, 2, STA- 9090, Stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, Isoprenylation tors and Lovastatin , Dopaminergic neurotoxins and1-methylphenylpyridinium ion, Cell cycle inhibitors optionally selected from sporine, Actinomycins optionally comprising Actinomycin D or dactinomycin, amanitins, Bleomycins optionally comprising bleomycin A2, cin B2, or peplomycin, Anthracyclines optionally comprising daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, bicin, zorubicin, mtoxantrone, MDR inhibitors or verapamil, Ca2+ATPase inhibitors or thapsigargin, Histone deacetylase inhibitors optionally comprising Vorinostat, Romidepsin, Panobinostat, Valproic acid, nostat, Belinostat, PCI-24781, Entinostat , SB939, Resminostat, Givinostat, AR-42, CUDC-101, aphane or Trichostatin A; Thapsigargin, Celecoxib, glitazones, epigallocatechin gallate, Disulfiram, Salinosporamide A.; Anti-adrenals, selected from the group consisting of aminoglutethimide, mitotane, trilostane; aceglatone; aldophosphamide ide; aminolevulinic acid; amsacrine; arabinoside, bestrabucil ; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine , elfomithine; elliptinium acetate, etoglucid; gallium nitrate; sine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin ; podophyllinic acid; lhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; ermanium; onic acid; quone; 2, 2',2''-trichlorotriethylamine; trichothecenes; urethane, siRNA, antisense drug optionally wherein the trichothecese include the group consisting of (including the group consisting of T-2 toxin, verrucarin A, roridin A and anguidine); (2). An anti-autoimmune disease agent: cyclosporine, cyclosporine A, aminocaproic acid, oprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate , prednisone, sirolimus, tacrolimus, optionally wherein the corticosteroids include the group consisting of amcinonide, betamethasone, budesonide, ortisone, olide, fluticasone propionate, fluocortolone danazol, dexamethasone, Triamcinolone ide, beclometasone dipropionate; (3). An nfectious e agents comprising: a). lycosides: amikacin, astromicin, gentamicin, netilmicin, sisomicin, isepamicin, hygromycin B, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin), neomycin (framycetin, paromomycin, ribostamycin, netilmicin, spectinomycin, streptomycin, tobramycin , verdamicin; b). Amphenicols: azidamfenicol, chloramphenicol, florfenicol, henicol; c). Ansamycins: geldanamycin, herbimycin; d). Carbapenems: biapenem, doripenem, ertapenem, imipenem/cilastatin, meropenem, panipenem; e). Cephems: carbacephem, cefacetrile, cefaclor, cefradine, cefadroxil, cefalonium, cefaloridine , cefalotin or cefalothin, cefalexin, cefaloglycin, cefamandole, cefapirin, cefatrizine, flur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil, cefroxadine, ole, cefuroxime, cefixime, cefdinir, cefditoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam , cefozopran, cephalexin, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, nome, cefsulodin, idime, cefteram, ceftibuten, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, cephamycin, oxacephem; f). Glycopeptides: cin, vancomycin, teicoplanin, ramoplanin; g). Glycylcyclines: tigecycline; h). ß-Lactamase tors: penam, clavam; i). amides: clindamycin, lincomycin; j). Lipopeptides: daptomycin, A54145, calcium-dependent otics (CDA); k). Macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide, midecamycin, ycin, oleandomycin, rifamycins, rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus, troleandomycin, telithromycin ; optionally wherein the ketolide is telithromycin or cethromycin and optionally wherein the rifamycin is rifampicin, rifampin, tin or rifapentine; l). Monobactams: aztreonam, tigemonam; m). Oxazolidinones: linezolid; n). Penicillins: amoxicillin, llin, pivampicillin, hetacillin, bacampicillin, metampicillin , talampicillin, azidocillin, azlocillin, penicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, clometocillin, ne penicillin, carbenicillin (carindacillin ), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam (pivmecillinam), mezlocillin, meticillin, nafcillin, oxacillin, penamecillin, penicillin, pheneticillin, phenoxymethylpenicillin , piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin; o). Polypeptides: bacitracin, colistin, polymyxin B; p). Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, loxacin, danofloxacin, difloxacin , enoxacin, enrofloxacin, floxin, garenoxacin, gatifloxacin, oxacin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, marbofloxacin, 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 imoxazole); s). Steroid antibacterials: selected from fusidic acid; t). Tetracyclines: doxycycline, chlortetracycline, clomocycline, demeclocycline, cline , meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline , tetracycline, glycylcyclines, ally wherein the glycyclcycline is tigecycline; u). Other antibiotics: selected from the group consisting of annonacin, arsphenamine, bactoprenol inhibitors, DADAL/AR inhibitors, dictyostatin, discodermolide, eleutherobin, lone , ethambutol, etoposide, faropenem, fusidic acid, furazolidone, zid, laulimalide, metronidazole , mupirocin, mycolactone, NAM synthesis inhibitors, nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin, ctam tinidazole, uvaricin , optionally wherein the DADAL/AR inhibitor is erine and optionally wherein the NAM synthesis inhibitor is fosfomycin; (4). Anti-viral drugs comprising: a). Entry/fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41, PRO 140, CD4; b). Integrase inhibitors: raltegravir, elvitegravir, globoidnan A; c). Maturation inhibitors: bevirimat, vivecon; d). Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e). Nucleosides & nucleotides: abacavir, vir, adefovir, amdoxovir, apricitabine, brivudine , cidofovir, clevudine, dexelvucitabine, didanosine, elvucitabine, emtricitabine, entecavir, lovir, fluorouracil, 3’-fluoro-substituted 2’, 3’-dideoxynucleoside analogues selected from the group consisting of 3’-fluoro-2’,3’-dideoxythymidine and 3’-fluoro-2’,3’-dideoxyguanosine , fomivirsen, ganciclovir, idoxuridine, lamivudine, l-nucleosides ), penciclovir, r, ribavirin, stampidine, ine , taribavirin, telbivudine, tenofovir, trifluridine valaciclovir, valganciclovir , zalcitabine, zidovudine (AZT), optionally wherein the eoside is ß-l-thymidine and ß-l-2’-deoxycytidine; f). cleosides: dine, ateviridine, capravirine, diarylpyrimidines, delavirdine, docosanol, emivirine, efavirenz, foscarnet, imiquimod, interferon alfa, de, lodenosine, methisazone , nevirapine, NOV-205, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod, tromantadine, allly wherein the diarypyrimidine is etravirine or rilpivirine; g). Protease inhibitors: amprenavir, atazanavir, boceprevir, vir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir, tipranavir; h). Other types of anti-virus drugs: abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate, net, griffithsin, taribavirin, hydroxyurea, KP- 1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, seliciclib. (5). A radioisotope that can be selected from the group consisting of the radionuclides 3H, 11C, 14C, 18F, 32P, 35S, 64Cu, 68Ga, 86Y, 99Tc, 111In, 123I, 124I, 125I, 131I, 133Xe, 177Lu, 211At, or 213Bi. (6). A chromophore molecule, which is capable of absorbing UV light, florescent light, IR light, near IR light, visual light; A class or subclass of xanthophores, ophores, iridophores, leucophores, phores, cyanophores, fluorophore molecules which are fluorescent chemical compounds ting light upon light, visual ransduction molecules, photophore molecules, luminescence molecules, luciferin compounds; Non-protein organic fluorophores, selected from: Xanthene derivatives selected from fluorescein, rhodamine, Oregon green, eosin, and Texas red; Cyanine derivatives selected from e, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine; ine derivatives and ring-substituted squaraines selected from Seta, SeTau, and Square dyes; alene derivatives selected from dansyl and prodan tives); Oxadiazole derivatives selected from pyridyloxazole, nitrobenzoxadiazole and benzoxadiazole; Anthracene derivatives selected from anthraquinones, including DRAQ5, DRAQ7 and CyTRAK Orange; the Pyrene derivatives cascade blue; Oxazine derivatives selected from Nile red, Nile blue, cresyl violet, oxazine 170. Acridine derivatives (comprising proflavin, acridine orange, acridine yellow). Arylmethine derivatives (comprising auramine, l violet, malachite green). Tetrapyrrole derivatives (comprising porphin, phthalocyanine, bilirubin); Fluorophore compounds selected from the group comprising CF dye, DRAQ and CyTRAK probes, BODIPY, Alexa Fluor, DyLight Fluor, Atto and Tracy, FluoProbes, Abberior Dyes, DY and MegaStokes Dyes, Sulfo Cy dyes , HiLyte Fluor, Seta, SeTau and Square Dyes, Quasar and Cal Fluor dyes, SureLight Dyes (optionally selected from APC, RPEPerCP and Phycobilisomes), APC, APCXL, RPE, BPE, Allophycocyanin (APC), Aminocoumarin, APCCy7 conjugates, -FL, Cascade Blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, Fluorescein , FluorX, ycoumarin, ine Rhodamine B, Lucifer , Methoxycoumarin , NBD, Pacific Blue, Pacific Orange, PE-Cy5 conjugates, PE-Cy7 conjugates, PerCP, R-Phycoerythrin (PE), Red 613, SetaAzide, SetaDBCO, SetaNHS, SetaNHS, 80-NHS, SetaNHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-670, SeTau NHS, SeTauMaleimide, 405-NHS, 425-NHS, SeTauNHS, Texas Red, TRITC, TruRed, X-Rhodamine, 7-AAD (7-aminoactinomycin D, CG-selective), ne Orange , Chromomycin A3, CyTRAK Orange (red excitation dark), DAPI, DRAQ5, DRAQ7, Ethidium Bromide, Hoechst33258, Hoechst33342, LDS 751, Mithramycin, iumIodide (PI), SYTOX Blue, SYTOX Green, SYTOX Orange, Thiazole Orange, TO-PRO: Cyanine r , TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOSeta-1, YOYO-1; A fluorophore compound : comprising DCFH (2'7'Dichorodihydro-fluorescein, oxidized form), DHR (Dihydrorhodamine 123, oxidized form, light catalyzes oxidation), Fluo-3 (AM ester. pH > 6), Fluo-4 (AM ester. pH 7.2), Indo-1 (AM ester, low/high calcium (Ca2+)), SNARF(pH 6/9), Allophycocyanin (APC), AmCyan1 (tetramer, Clontech), AsRed2 (tetramer), Azami Green (monomer), Azurite , B-phycoerythrin (BPE), Cerulean, CyPet, DsRed r, DsRed2 ("RFP"), EBFP, EBFP2, ECFP, EGFP (weak dimer), Emerald (weak dimer), EYFP (weak dimer), GFP (S65A mutation), GFP (S65C mutation), GFP (S65L mutation), GFP (S65T mutation), GFP (Y66F mutation), GFP (Y66H mutation), GFP (Y66W mutation), GFPuv, HcRed1, J-Red, Katusha, Kusabira Orange (monomer, MBL), mCFP, mCherry, mCitrine, Midoriishi Cyan (dimer, MBL), mKate (TagFP635, monomer), mKeima-Red (monomer), mKO, mOrange, mPlum, mRaspberry, mRFP1 (monomer), mStrawberry, mTFP1, mTurquoise2, P3 (phycobilisome complex ), Peridinin Chlorophyll (PerCP), R-phycoerythrin (RPE), T-Sapphire, TagCFP (dimer), TagGFP (dimer), TagRFP (dimer), TagYFP (dimer), tdTomato m dimer), Topaz, TurboFP602 (dimer), TurboFP635 (dimer), TurboGFP (dimer), TurboRFP (dimer), TurboYFP (dimer ), Venus, Wild Type GFP, YPet, ZsGreen1 (tetramer), ZsYellow1 (tetramer). (7). cell-binding s or receptor agonists selected fromSomatostatin and its analogs selected from the group consisting of octreotide and lanreotide; Aromatic sulfonamides; Pituitary adenylate cyclase activating es (PACAP; optionally PAC1; tive intestinal peptides (VIP/PACAP; optionally ed from VPAC1 and VPAC2; Melanocyte-stimulating hormones (a-MSH); Cholecystokinins (CCK) /gastrin receptor agonists; Bombesins (selected from the group consisting of Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2)/gastrin-releasing peptide (GRP); Neurotensin or ligands optionally seled from NTR1, NTR2 and NTR3; Substance P (NK1 receptor) ligands; Neuropeptide Y (Y1–Y6); Homing Peptides include RGD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), the c and multimeric cyclic RGD es (optionally selected from cR GDfV, TAASGVRSMH and LTLRWVGLMS (Chondroitin sulfate proteoglycan NG2 receptor ligand s) and F3 peptides; Cell Penetrating Peptides; Peptide Hormones, selected from the group consisting of luteinizing hormone-releasing hormone (LHRH) agonists and nists, and gonadotropin-releasing hormone (GnRH) agonist, acts by ing follicle stimulating hormone (FSH) and luteinising hormone (LH), as well as testosterone tion, selected from the group consisting of buserelin is-Trp-Ser-Tyr- D-Ser(OtBu)-Leu-Arg-Pro-NHEt), Gonadorelin (Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly- NH2), Goserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2), Histrelin (Pyr- His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), leuprolide (Pyr-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NHEt ), Nafarelin (Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2), Nafarelin, Deslorelin, Abarelix (Ac-D-2Nal-DchloroPhe-D(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro- DAla-NH2), Cetrorelix (Ac-D-2Nal-DchloroPhe-D(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu- o-D-Ala-NH2), lix (Ac-D-2Nal-DchloroPhe-D(3-pyridyl)Ala-SeraminoPhe roorotyl)-DaminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2), and Ganirelix (Ac-D-2Nal-DchloroPhe-D(3-pyridyl)Ala-Ser-Tyr-D-(N9, N10-diethyl)-homoArg- Leu-(N9, N10-diethyl)-homoArg-Pro-D-Ala-NH2); Pattern Recognition Receptor (PRRs), selected from the group consisting of Toll-like receptors’ (TLRs) ligands, C-type lectins and Nodlike Receptors’ (NLRs) ligands; Calcitonin or agonists; integrin receptors’ and their receptor subtypes’ (selected from the group consisting ofaVß1, aVß3, aVß5, aVß6, a6ß4, a7ß1, aLß2, aIIbß3) ts (selected from the group consisting of GRGDSPK, cyclo(RGDfV) (L1) and its tives optionally selected from cyclo(-N(Me)R-GDfV), cyclo(R-Sar-DfV), cyclo(RGN (Me)D-fV), cyclo(RGD-N(Me)f-V), and cyclo(RGDf-N(Me)V-); dy (a derivative of VHH (camelid Ig)); Domain antibodies (dAb, a derivative of VH or VL domain); Bispecific T cell Engager (BiTE, a bispecific diabody); Dual ty ReTargeting (DART, a bispecific diabody ); Tetravalent tandem antibodies b, a dimerized ific diabody); Anticalin (a derivative of Lipocalins); Adnectins (10th FN3 (Fibronectin)); Designed Ankyrin Repeat Proteins (DARPins); Avimers; EGF receptors and VEGF receptors’ agonists. (8). The pharmaceutically acceptable salts, acids, hydrate or hydrated salt; or a crystalline structure; or an optical isomer, racemate, diastereomer or enantiomer of any of the above drugs.
9. The conjugate compound according to claim 1, wherein the Drug1 or Drug2 is a chro- mophore molecule, is used for detecting, monitoring, or studying the interactions and/or functions of the cell binding le, and/or the interactions of the conjugate with a targeted cell.
10. The conjugate compound according to claim 1, wherein the Drug1 or Drug2 is a polyalkylene s optionally selected from poly(ethylene glycol) (PEGs), poly(propylene glycol), or a copolymer of ethylene oxide or propylene oxide], is used for extending the halflife of the cell-binding molecule when it is administered to a non-human mammal.
11. The conjugate compound according to claim 1, wherein the Drug1 or Drug2 is a cell-binding ligand, a cell receptor agonist, or a ce ll receptor binding molecule, is used for as a targeting conductor/director to deliver the conjugate compound to ant cells, or for modulating or co-stimulating a desired immune response, or for ng signaling pathways.
12. The conjugate compound of any one of claim 1 or Claim 2, wherein the Drug1 or Drug2 is ed from the group consisting of tubulysins, eamicins, auristatins, maytansinoids , CC-1065 analogs, daunorubicin and bicin compounds, taxanoids (taxanes), cryptophycins, epothilones, benzodiazepine dimers optionally selected from pyrrolobenzodiazepine dimers (PBD), tomaymycin dimers, anthramycin dimers, indolinobenzodiazepine dimers , obenzothiadiazepine dimers, or oxazolidinobenzodiazepine dimers, eamicins and the enediyne antibiotics, mycins, amatoxins, amanitins, azaserines, bleomycins, epirubicins, tamoxifen, icin, dolastatins/auristatins optionally selected from monomethyl auristatin E, MMAE , MMAF, auristatin PYE, auristatin TP, Auristatins 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP), duocarmycins, amycins, methotrexates, thiotepa, ines, vincristines, hemiasterlins, nazumamides, microginins, radiosumins, alterobactins, microsclerodermins , theonellamides, esperamicins, erbulins, inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), siRNA, miRNA, piRNA, nucleolytic enzymes, and/or pharmaceutically acceptable salts, acids, or/and hydrate or hydrated salt; or a crystalline structure; or an l isomer, racemate, diastereomer or enantiomer of any of the above drugs thereof.
13. The ate compound according to claim 1, 2, 8, 9, 10, 11 or 12, wherein the cell binding agent/molecule is selected from the group consisting of an antibody, a protein, y, nanobody, a n (optionally folate), peptides, a polymeric micelle, a liposome, a lipoprotein-based drug carrier, a nano-particle drug carrier, a dendrimer, and a molecule or a particle said above coating with cell-binding ligands, or a combination of said above thereof.
14. The conjugate compounds according to any one of claims 1, 2, 8, 9, 10, 11 , 12, or 13 wherein the cell binding agent/molecule is selected from an antibody, an antibody-like n, a full-length antibody (optionally, selected from a polyclonal antibody, monoclonal antibody, antibody dimer, or antibody multimer), or multispecific dy (optionally ed from, bispecific antibody, trispecific antibody, or tetraspecific antibody); a single chain dy , 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 ic antibody nt that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, a resurfaced dy, a resurfaced single chain antibody, or a resurfaced antibody fragment that binds to the target cell, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment that binds to the target cell, anti-idiotypic (anti-Id) dies, CDR's, diabody, triabody , tetrabody, miniantibody, a y, a probody fragment, small immune proteins (SIP), a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrienttransport molecule, large molecular weight proteins, nanoparticles or polymers modified with antibodies or large molecular weight proteins.
15. The conjugate compounds according to any one of claims 1, 2, 8, 9, 10, 11, 12, 13 or 14 wherein the cell binding agent/molecule is e of targeting against a tumor cell, a virus infected cell, a microorganism infected cell, a te infected cell, an autoimmune disease cell, an activated tumor cells, a d cell, an activated T-cell, an ing B cell, or a melanocyte, or any cells expressing any one 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, , CD159a, , 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, , 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, , 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, Adenocarcinomaantigen, AGS-5, AGS- 22M6, Activin receptor-like kinase 1, AFP, AKAP-4, ALK, Alpha intergrin, Alpha v beta6, Amino-peptidase N, Amyloid beta, Androgen receptor, oietin 2, Angiopoietin 3, Annexin A1, Anthrax protective antigen, Anti-transferrin receptor, AOC3, B7-H3, us anthracisanthrax, BAFF (B-cell activating factor), B-lymphoma cell, bcr-abl, Bombesin, BORIS , C5, C242 antigen, CA125 (carbohydrate antigen 125, , CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg, Canis lupus familiaris IL31, Carbonic anhydrase IX, Cardiac myosin, CCL11(C-C motif ine 11), CCR4 (C-C chemokine or type 4, CD194), CCR5, CD3E (epsilon), CEA (Carcinoembryonic antigen), CEACAM3, CEACAM5, CFD (Factor D), Ch4D5, Cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), Clumping factor A,CRIPTO, FCSF1R (Colony stimulating factor 1 receptor, CD115), CSF2 (colony stimulating factor 2, Granulocyte-macrophage colony-stimulating factor (GM-CSF)), CTLA4 (cytotoxic T-lymphocyte associated n 4), CTAA16.88 tumor antigen, CXCR4 (CD184),C- X-C chemokine receptor type 4, cyclic ADP ribose hydrolase, Cyclin B1, , Cytomegalovirus , Cytomegalovirus glycoprotein B, tran, DLL3 (delta-like-ligand 3), DLL4 (delta-like-ligand 4), DPP4 (Dipeptidyl-peptidase 4), DR5 (Death receptor 5), E. coli shiga toxintype-1, E. coli shiga toxintype-2, ED-B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRvIII, Endoglin (CD105), Endothelin B receptor, Endotoxin, EpCAM (epithelial cell adhesion le), EphA2, Episialin, ERBB2 (Epidermal Growth Factor Receptor 2), ERBB3, ERG (TMPRSS2 ETS fusion gene), Escherichia coli, ETV6-AML, FAP (Fibroblast activation proteinalpha), FCGR1, alpha-Fetoprotein, Fibrin II, beta chain, Fibronectin extra domain-B, FOLR (folate receptor), Folate receptor alpha, Folate hydrolase, Fosrelated antigen 1, F protein of respiratory syncytial virus, Frizzled receptor, Fucosyl GM1,GD2 ganglioside, G-28, GD3 idiotype, GloboH, an 3, N-glycolylneuraminic acid, GM3, GMCSF receptor a-chain, Growth differentiation factor 8, GP100, GPNMB membrane glycoprotein NMB), GUCY2C (Guanylate cyclase 2C, guanylyl cyclase C(GC-C), inal Guanylate cyclase, Guanylate cyclase-C receptor, Heat-stable toxin receptor (hSTAR)), Heat shock proteins, Hemagglutinin, Hepatitis B surface antigen, Hepatitis B virus, HER1 (human epidermal growth factor or 1), HER2, HER2/neu, HER3, IgG4, HGF/SF (Hepatocyte growth factor/scatter factor), HHGFR, HIV-1, Histone complex, HLA-DR, HLA-DR10, HLA-DRB , , Human chorionic gonadotropin, HNGF, Human scatter factor receptor kinase, HPV E6/E7, Hsp90, hTERT, ICAM-1 (Intercellular Adhesion le 1), Idiotype , IGF1R (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN-?, Influeza hemagglutinin , IgE, IgE Fc region, IGHE, interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-6R, IL- 7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, , 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, Interferon 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, MS4A1 (membrane-spanning 4-domains subfamily A member 1), MSLN (mesothelin), ucin 1) orpolymorphic epithelial mucin (PEM)), MUC1-KLH, MUC16 (CA125), MCP1(monocyte chemotactic protein 1), MelanA/MART1, ML-IAP, MPG, MS4A1 (membrane-spanning 4-domains subfamily A), MYCN, Myelin-associated glycoprotein, Myostatin, NA17, NARP-1, NCA-90 (granulocyte antigen), Nectin-4, NGF, Neural apoptosis-regulated proteinase 1, , Notch receptor, Nucleolin, Neu oncogene product, NY-BR-1, NYESO-1 , OX-40, OxLDL (Oxidized low-density lipoprotein), 1,P21, p53 nonmutant, P97, Page4, PAP, Paratope of N-glycolylneuraminic acid), PAX3, PAX5, PCSK9, PDCD1 (Programmed cell death protein 1,CD279), PDGF-Ra (Alpha-type platelet-derived growth factor receptor), PDGFR-ß, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, Platelet-derived growth factor receptor beta, Phosphate-sodium co-transporter, PMEL 17, Polysialic acid, nase3 (PR1), Prostatic carc inoma, PS (Phosphatidylse rine), Prostatic carcinoma cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, Rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI), , Rhesus factor, RANKL, RANTES receptors (CCR1, CCR3, CCR5), RhoC, Ras mutant,RGS5, ROBO4, Respiratory syncytial virus, RON, Sarcoma translocation breakpoints,SART3, stin, SLAMF7 (SLAM family member 7), Selectin P, SDC1 can 1), sLe(a), Somatomedin C, SIP (Sphingosinephosphate), statin, Sperm protein 17, SSX2, STEAP1 ransmembrane lial antigen of the prostate 1), 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-a, TGF-ß (Transforming growth factor beta), TGF-ß1, TGF-ß2 (Transforming growth factor-beta 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF-a, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAILR1 (Tumor necrosis apoprosis Inducing ligand or 1), TRAILR2, tumor-associated calcium signal transducer 2, tumor specific glycosylation ofMUC1, TWEAK receptor, TYRP1, TROP-2, TRP-2, Tyrosinase, VCAM-1 ), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2, or vimentin, WT1, XAGE 1, or cells expressing any insulin growth factor receptors, or any epidermal growth factor receptors.
16. The conjugate of claim 15, wherein the tumor cell is selected from the group consisting of ma cells, myeloma cells, renal cells, breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, none cell lung cancer cells, testicular cancer cells, malignant cells, or any cells that grow and divide at an unregulated, quickened pace to cause cancers.
17. The conjugate compound of claim 1, wherein the Drug1 or Drug2 is a tubulysin analog selected from structures of T11, T12, T13, T14, T15, T16 T017, T18, T19, T20, T21, T22 and T23 as following: O R5 H O O X3 O Y1 R1 R3 Z1 R3 R4 N N X1 R1 N N N X2 O N R2 N R4 Z2 R2 R5 S H R12 O n O R5' R5 O O Z1 R3 Z3 N R1 Y1 H X1 R3 R4 N O O X3 O Q N N N Z2 N R2 O S N R4 H R12 O R2 R5' R1 O n R5 O O Z1 R3 Z3 N R1 H X1 Y1 R3 R4 N O O X3 O Q N X2 N N Z2 N R2 O R4 R2 S N R12 R5' O H O n wherein “ ”, Q, X1, X2, R1, R2, R3, R4, R5, R5’, Aa, (Aa)n, Z1, Z2, p, and n are defined the same 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, S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NHNHC(O) and C(O)NR1; mAb is dy, preferably monoclonal dy; 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, CH2NH)pCH2CH2NH2, NH(CH2CH2S)pCH2CH2NH2, NH(CH2CH2NH)pCH2CH2OH, CH2S)pCH2CH2OH, NH-R1-NH2, or NH(CH2CH2O)pCH2CH2NHPO3H2; R1, R1’, R2, R3, R4 and R5 are independently H, C1-C8 lineal or branched alkyl, amide, or amines; C2-C8 aryl, alkenyl, alkynyl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, heterocycloalkyl, or acyloxylamines; or peptides containing 1-8 aminoacids, or polyethyleneoxy unit having a (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 1 to about 5000; The two Rs: R1R2, R2R3, R1R3 or R3R4 can form 3~8 member cyclic ring of 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 C1-C8 lineal or branched alkyl, aryl, heteroaryl, heteroalkyl , alkylcycloalkyl, or acyloxylamines; R3’ is H or C1-C6 lineal or branched alkyl; Z3 is H, COOR1, NH2, NHR1, OR1, CONHR1,NHCOR1, OCOR1, OP(O)(OM1)(OM2), (O)(OM1)(OM2), OSO3M1, R1, O-glycoside (glucoside, galactoside, mannoside, glu- curonoside/ glucuronide, alloside, side, etc.), NH-glycoside, S-glycoside or CH2-glycoside ; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
18. The conjugate compound of claim 1, wherein the Drug1 or Drug2 is a Maytansinoid analog is selected from structures of the following My07, and My08: O R1 Y1 R1 O R5 O O R3 Cl O N X1 N Z1 MeO N O X2 R2 N Z2 N O O R5' H3CO n My07, My08, wherein “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, and n are d the same above; Preferabably X1, X2, Y1 and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, H, 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.
19. The conjugate compound of claim 1, wherein the Drug1 or Drug2 is a CC-1065 and/or duocarmycin is selected from structure of CC07 as following: CC07, wherein “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, and n are defined the same above; preferabably X1, X2, Y1 and Y2 are ndently 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; Q is preferably monoclonal antibody; Z3 is H, PO(OM1)(OM2), SO3M1, CH2PO(OM1)(OM2), CH3N(CH2CH2)2NC(O)-, O(CH2CH2)2NC(O)-, R1, or glycoside.
20. The conjugate nd of claim 1, wherein the Drug1 or Drug2 is a Daunorubicin or Doxorubicin, is selected from ures of Da09, Da10, and Da11 as following: Da09, Da10, O OH O N R1 H X1 N Z1 OH Q O X2 R4 O OH H3CO O R2 OH N Z2 O R5' n H2N Da11, wherein “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, Aa, (Aa)n, p, and n are defined the same above; Preferabably 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(R1), N(R1)C(O)N(R1), CH, C(O)NHNHC(O) and C(O)NR1; R12 is OH, NH2, NHR1, NHNH2, NHNHCOOH, O-R1-COOH, COOH, NH(Aa)nCOOH, O(CH2CH2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2, NH(CH2CH2O)pCH2CH2NH2, NR1R1’, NHOH, NHOR1, O(CH2CH2O)pCH2CH2COOH, NH(CH2CH2O)pCH2CH2COOH, COOH, 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(CH2CH2NH)pCH2-CH2NH2, NH(CH2CH2S)pCH2CH2NH2, NH(CH2CH2NH)pCH2CH2OH, CH2S)pCH2-CH2OH, NH-R1-NH2, or NH(CH2CH2O)pCH2CH2NHPO3H2.
21. The conjugate compound of claim 1, wherein the Drug1 or Drug2 is an Auristatin or dolastatin, is selected from structures of Au16, Au17, Au18, Au19, Au20, Au21, Au22, Au23, Au24, Au25, Au26, and Au27 as following: Au16, Au17, Au18, Au19, Au20, Au21, Au22, Au23, Au24, Au25, Au26, Au27, wherein “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, Aa, (Aa)n, p and n are d the same above; Preferabably X1 X2, Y1 and Y2 are ndently 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; 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, , NHOH, NHOR1, O(CH2CH2O)pCH2CH2COOH, NH(CH2CH2O)pCH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O)pCH2CH2NH-SO3H, NH(CH2CH2O)pCH2CH2NHSO3H, O3H, NH-R1- NHSO3H, O(CH2CH2O)pCH2-CH2NHPO3H2, NH(CH2CH2O)pCH2CH2NHPO3H2, OR1, R1- NHPO3H2, R1-OPO3H2, O(CH2CH2O)pCH2CH2OPO3H2, OR1-NHPO3H2, NH-R1-NHPO3H2, NH(CH2CH2NH)pCH2-CH2NH2, NH(CH2CH2S)pCH2CH2NH2, NH(CH2CH2NH)pCH2CH2OH, NH(CH2CH2S)pCH2-CH2OH, NH-R1-NH2, or NH(CH2CH2O)pCH2CH2NHPO3H2; R1, R2, R3, R4 and R5 are independently H; C1-C8 lineal or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amines, heterocycloalkyl , or acyloxylamines; or peptides containing 1-8 aminoacids, or polyethyleneoxy unit having formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 1 to about 5000. The two Rs: R1R2, R2R3, R1R3 or R3R4 can form 3~8 member cyclic ring of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl group; X3 is H, CH3 or X1’R1’, wherein X1’ is NH, N(CH3), NHNH, O, or S, and R1’ is H or C1-C8 lineal or branched alkyl, aryl, heteroaryl, heteroalkyl , alkylcycloalkyl, acyloxylamines; R3’ is H or C1-C6 lineal or branched alkyl; Z3’ is H, COOR1, NH2, NHR1, OR1, CONHR1,NHCOR1, OCOR1, OM1)(OM2), (O)(OM1)(OM2), OSO3M1, R1, or O-glycoside (optionally selected from glucoside, galactoside, mannoside, glucuronoside/ glucuronide, alloside, and fructoside), coside, S-glycoside or CH2-glycoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
22. The conjugate compound of claim 1, n the Drug1 or Drug2 is a dimer of benzodiazepine and is selected from structures of PB27, PB28, PB29, PB30, PB31 and PB32: PB27, PB28, PB29, PB30, PB31, PB32, wherein “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, and n are defined the same above; preferabably 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, S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NHNHC(O) and C(O)NR1; R1, R2, R3, R1’, R2’, and R3’ are independently H; F; Cl; =O; =S; OH; SH; C1-C8 lineal or branched alkyl, aryl, alkenyl, heteroaryl, heteroalkyl, alkylcycloalkyl , ester (COOR5 or –OC(O)R5), ether (OR5), amide (CONR5), carbamate (OCONR5), amines (NHR5, ), heterocycloalkyl, or acyloxylamines (-C(O)NHOH, -ONHC(O)R5); or peptides containing 1-20 natural or unnatural aminoacids, or polyethyleneoxy unit of formula (OCH2CH2)p or H(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 3~8 member cyclic ring of 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 C1-C8 lineal or branched alkyl, aryl, heteroaryl, heteroalkyl , ycloalkyl, ylamines; Z3 is H, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, or O-glycoside (optionally selected from glucoside, galactoside , mannoside, glucuronoside/ glucuronide, alloside, and side), NH-glycoside, S- glycoside or CH2-glycoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
23. The conjugate compound of claim 1, wherein the Drug1 or Drug2 is an amanitin, is selected from structures of Am05, Am06, Am07, Am08 and Am09 below: Am05, Am06, Am07, Am08, Am09, wherein “ ”, X1, X2, Q, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, and n are defined the same above; abably X1, X2, Y1 and Y2 are independently O, N, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, , NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NH-NHC(O), C(O)NR1 or absent; R7, R8, and R9 are independently H, OH, OR1, NH2, NHR1, C1-C6 alkyl, or absent; Y2 is O, O2, NR1, NH, or absent; R10 is CH2, O, NH, NR1, NHC(O), NHC(O)-NH, NHC(O)O, OC(O)O, C(O), OC(O), OC(O)(NR1), (NR1)C(O)(NR1), C(O)R1 or absent; R11 is OH, NH2, NHR1, NHNH2, NHNHCOOH, O-R1-COOH, NH-R1- COOH, NH-(Aa)nCOOH, H2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2, NH(CH2CH2O)pCH2CH2NH2, , 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, or NH(CH2CH2O)pCH2CH2NHPO3H2, wherein Aa is 1-8 aminoacids; n and m1 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 oside (glucoside , galactoside, mannoside, glucuronoside/ glucuronide, alloside, side, etc.), NH-glycoside , S-glycoside or CH2-glycoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3.
24. The conjugate compound of claim 1, wherein the Drug1 or Drug2 is a camptothecin and its derivative, is selected from structures of CP01, CP02, CP03, CP04, CP05, and CP06 below: CP01, O R5 N O O R1 X1 N Y1 R4 N O X2 Z3 R2 N O Z2 n R5' CP02, CP03, CP04, O R5 N O O R1 X1 N Z1 Y1 R4 Q N O X2 Z3 R2 N O Z2 n R5' CP05, CP06, wherein “ ”, Q, X1, X2, Y1, Y2, R1, R2, R3, R4, R5, R5’, Z1, Z2, and n are defined the same above; preferabably 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, CH2, C(O)NHNHC(O), C(O)NR1 or absent; Z3 is H, OH, COOR1, NH2, NHR1, OR1, CH3, CONHR1,NHCOR1, OCOR1, OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, R1, or O-glycoside (glucoside, 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.
25. The conjugate nd of claim 1, wherein the Drug1 or Drug2 is an in and its derivative, is selected from structures of Eb01, and Eb02 below: Eb01, Eb02, wherein “ ”, Q, X1, X2, Y1, R1, R2, R3, R4, R5, R5’, Z1, Z2, and n are defined the same above; preferabably 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, (R1), N(R1)C(O)N(R1), CH, CH2, C(O)NHNHC(O), C(O)NR1 or absent.
26. The conjugate compound of claim 1, n the Drug1 or Drug2 is an inhibitor of nicotinamide phosphoribosyltransferases, is selected from structures of NP01, NP02, NP03, NP04, NP05, NP06, NP07, NP08, and NP09 below: NP01, NP02, NP03, NP04, NP05, NP06, NP07, NP08, NP09, wherein “ ”, Q, X1, X2, Y1, R1, R2, R3, R4, R5, R5’, Z1, Z2, and n are defined the same above; X5 is F, Cl, Br, I, OH, OR1, R1, OPO3H2, OSO3H, NHR1, OCOR1, NHCOR1; Preferabably 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, NH, NHC(O)S, (R1), N(R1)C(O)N(R1), CH, CH2, C(O)NHNHC(O), C(O)NR1 or absent.
27. The compound according to Claim 3, having the formula of A-02, A-03, A-04, B-01, B-02, B-03, B-04, B-05, B-06, B-07, B-08, B-09, B-10, B-11, B-12, B-13, B-14, B-15, B-16, C-01, C-02, C-03, C-04, C-05, C-06, C-07, C-08, C-09, C-10, C-11, C-12, D-01, D-02, D-03, D-04, D-05, D-06, Pg-04, 97, 98, 116, 125, 129, 133, 135, 157a, 157b, 157c, 157d, 157e, 157f, 162, 163, 235a, 235b, 235c, 236a, 236b, 236c, 238a, 238b, 238c, 255, 256, 258a, 258b, 258c, 260, 262, 267, 271, 272, 274, 276, 278, 282, 284, 286, 287, 306, 309, 314, 318, and 325, as illustrated below: A-02, A-03, A-04, B-04, H O O O N O N OAc O H O H N O N O N N N O H 3 HN O H O H O O O S HN N H N N N O O H 3 O O O NH2 B-09 B-15, Pg-04, 0 0 OMO/b/NH N/UVCI H 0 OACN 0 0 COOH \\\¢ 0 135 CH 0 5 O H 0 NH = O 157a,m=0 HN n’\ HN N 151,, O O OaE?OdEH/N I 157b m=3 \ /N 0HO =4 I," N “ IN N O s Wm WM: GaNj-1/-\ 12329:;= 21 O 3 _ \‘\ HO 9 \‘ COOH 0 157f,m=12 0 H 0 0 N H 0 OAcN 0 WOW NH2 419 419 O O NOH %NH O—‘K/h dVN NHZ O E E: m2 O E O /;\| O\ O COZH E r?wo?x—O NH2 O O 236a,m1=2, m2=6; 236b, m1=2, m2=(8; 236c,m1=4, m2=]2. 2383,m1=2, m2=6; 238b, m1=2Hm2=8; 2380,m1=4, m2=12. \\\\\ E O ”N N?w/LN’U‘M MNH O H O 0 “N ‘NH ’ H W N 0 321% / NHAH 0 151 NHZ ,0 \ H OHH N II”: 0% )\/N O H m 0 \\\\\ H O 1‘1de H O H O 0 H M MAN 0 420 420 O H O O H O N O N HN N N N O HO H O O H m H O N H O O O N N N N H H N O m H Cl 272 O O H O HN HN O N N O N O O O H m HO H O H N N O O O N N N O N H O H m H Cl O 423 423 O O O H O N HN N NH H N O O O HO N O H m N O O H O NH O O N HO H O HO O O m N NH N O O O N OCH3 H3CO N O O
28. The conjugates of Claim 1, having the a of Aa-02, Aa-03, Aa-04, Ba-01, Ba-02, Ba-03, Ba-04, Ba-05, Ba-06, Ba-07, Ba-08, Ba-09, Ba-10, Ba-11, Ba-12, Ba-13, Ba-14, Ba-15, Ba-16, Ca-02, Ca-03, Ca-04, Ca-05, Ca-06, Ca-07, Ca-08, Ca-09, Ca-10, Ca-11, Ca-12, Da-01, Da-02, Da-03, Da-04, Da-05 or Da-06, 99, 117, 126, 130, 136, 158a, 158b, 158c, 158d, 158e, 158f, 164, 237a, 237b, 237c, 239a, 239b, 239c, 257, 259, 261, 263, 268, 273, 275, 277, 279, 283, 285, 288, 307, 310, 315, 319, and 326, as shown in the following structures: {M“NEW413% OHJWMW 0\ 0 0 0 COZH 0\/\0/\/0\/\O//\,\0\I/\O/\/0\/\O/\/0\/\OH Aa-03 0 0 H SWjNJLNH NWMMIV 0 H HjL N NM 0 /\ w 0 0 0\ 0 ,0 COZH S O O O N 1&1 QN 0 0 0 MNE/‘LONJZLN NgLN Q/L?k?phH H 0 Aa-04 0/=\' 0\0 /0 0 C02H “ 0 0 j“ (:0 H2 2 EM? H HNMO??/LWO H 0 EC 5 o MNHN1 _Ww?§:rz1: 9/ n NMO?N/‘WO/T‘NWCOZ“ 425 425 426 426 éiINJK/VH HN S HN H_Lk/\N O mAb N N N 0 n O O O H 0 N 0 33-12 0 HNLHWOVETV wNVONOH ”9% 0 M N N / 0 0 “?l 2N - s \\‘ I Mij/{J/Ngf0 4» mAb Ba-13 H0 NO ?wzg n Mil/9 \ WI/(ZONIJLE/l? """II 33-14 MN4%?Mfg l\/\NO;O/ 1mg MN” 0%?/ngé:?NM1H)z/\:O8??W?HOZC ll” "IA" 427 427 O NHBoc H O O N O N O 3 N N O H H NHBoc S CO2tBu O O mAb O HN N O O H S O N HO N N O CO2tBu O H 3 O H N O O O O N OH OMe MeO N Ca-02 n O O 429 429 \\“ N H YL ”’4 / )V/\ ngH0 H 0 H O0 mAb O Ots O ””0 NWO?N SS 0 Da-Ol , 0 0 v H 0 HN mm?m 0 0 Ni} \‘ §% 15‘ \\\ ‘ S HO N 0 0 NW0? 4” H0 H / mAb / O H 00 N 0‘ O \S ’4 N N OH ” S ’5’ H N% ?g N 0 HN HOT< 0 EAR/bag» 0 2 156151 H N O 0 Da-OZ a 0 O HN {“1151 1;JI/\ \\\“ H \ S HO O O NWO?/ /”’ H0 00 "W” 0 H N O\ ”’I/ O ‘S I N N 0 )V/\ NW/LN N s HO \(r)1/\H 0 N 0 Da-O3 430 430 O O H O O HN OH N N O H O H NH H H N N N S HO O O N N O H 3 O O mAb O H O H O N O S N OH N N N S O O HN HO O H H N H 3 O N O O HO N O O H Da-04 n O O O O OH H H O HN N N O NH N N H N H N O HO O O H 3 S O N O mAb O H O H O N N S O S N OH N N O N O 3 O H H O HN O O H N O H2N N O HN OH O H O Da-05 n 158a, m=0; 158b, m=3; 158C, m=4; O 158d, m=6; 158e, m=8; 158f, m=12. 432 432 433 433 434 434 [1 Pg TQ’ ___L______ 0 mAb VQNHOW ’ N 0W ll OCH3 H3COI:Ln/N 0g 0 vmwwWW0 0“ H *NH 0 435 435 n m1, and n are defined the same as in Claim 1; mAb is an antibody; A cross bond means that it can connect either one of two atoms.
29. A pharmaceutical composition comprising a therapeutically ive amount of the conjugate compounds of any one of claim 1, 2, 8, 9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 , and a pharmaceutically acceptable salt, carrier, t, or excipient therefore, or a combination of the conjugates thereof, for the treatment or prevention of a cancer, or an autoimmune disease, or an infectious disease.
30. The pharmaceutical ition according to Claim 29 either in in the liquid formula or in the formulated lyophilized solid, comprising by weight of: 0.01%-99% of one or more conjugates of any one of claim 1, 2, 8, 9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, 0.0%-20.0% of one or more polyols; 0.0%-2.0% of one or more surfactants; 0.0% -5.0% of one or more preservatives; 0.0% -30% of one or more amino acids; 0.0% -5.0% of one or more antioxidants; 0.0% -0.3% of one or more metal ing agents; 0.0% -30.0% of one or more buffer salts for adjusting pH of the ation to pH 4.5 to 8.5; and 0.0% - 30.0% of one or more of ic agent for adjusting osmotic pressure bewteen about 250 to 350 mOsm when reconstituted for administration to a patient; n the polyol is selected from fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, glucose, sucrose, trehalose, sorbose, melezitose, raffinose, mannitol , xylitol, erythritol, maltitol, lactitol, erythritol, threitol, sorbitol, glycerol, or L-gluconate and its metallic salts); wherein the surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 65, polysorbate 80, polysorbate 81, or rbate 85, poloxamer, poly(ethylene oxide)-poly(pro- pylene oxide), polyethylene-polypropylene, Triton; sodium dodecyl sulfate (SDS), sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl- , myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl- , cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine ; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; dodecyl e, dodecyl dimethylamine oxide, cocamidopropyl e and coco ampho glycinate; or isostearyl ethylimidonium ethosulfate; polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol; wherein the vative is selected from benzyl alcohol, octadecyldimethylbenzyl ammonium chloride, hexamethonium de, benzalkonium chloride, benzethonium chloride, phenol, butyl and benzyl alcohol, alkyl parabens, methyl or propyl paraben, ol, resorcinol , cyclohexanol, 3-pentanol, or m-cresol; wherein the amino acid is selected from arginine, cystine, glycine, lysine, histidine, ornithine , cine, leucine, alanine, glycine glutamic acid or aspartic acid; wherein the antioxidant is selected from ascorbic acid, glutathione, cystine or and methionine wherein the chelating agent is selected from EDTA or EGTA; wherein the buffer salt is selected from sodium, potassium, ammonium, or trihydroxyethylamino salts of citric acid, ic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid; Tris or tromethamine hydrochloride, phosphate or sulfate; arginine, glycine, glycylglycine, or histidine with anionic acetate, chloride, phosphate, sulfate, or succinate salts; wherein the tonicity agent is selected from ol, ol, sodium acetate, potassium chloride, sodium phosphate, potassium ate, trisodium citrate, or sodium chloride.
31. The ceutical ition ing to Claim 29 or 30, is held in a vial, , pre-filled syringe, or pre-filled auto-injector syringe, in a form of a liquid or lyophilized solid.
32. The conjugate of Claim 1, 2, 8, 9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, or in the form of the pharmaceutical composition of Claim 29 or 30, having in vitro, in vivo or ex vivo cell killing activity.
33. A pharmaceutical composition according to Claim 29 or 30 , formulated for con- current administration with a chemotherapeutic agent, a radiation y, an immunotherapy agent, an autoimmune disorder agent, an anti-infectious agents or the other conjugates for synergistically treatment or prevention of a cancer, or an autoimmune disease, or an infectious disease.
34. The synergistic agents according to claim 33 are selected from one or several of the following drugs: Abatacept, abemaciclib, Abiraterone acetate, Abraxane, Aducanumab, Acetaminophen/hydrocodone, Acalabrutinib, aducanumab, umab, ADXS31-142, ADXS-HER2, afatinib ate, aldesleukin, alectinib, alemtuzumab, allitinib, Alitretinoin, ado-trastuzumab emtansine, Amphetamine/ dextroamphetamine, anastrozole, apatinib, Aripiprazole , anthracyclines, razole, Atazanavir, Atezolizumab, Atorvastatin, Avelumab, AVXS-101, Axicabtagene ciloleucel, axitinib, belinostat, BCG Live, Bevacizumab, bexarotene , umomab, Bortezomib, bosutinib, brentuximab vedotin, brigatinib, Brolucizumab, Budesonide, Budesonide/ formoterol, Buprenorphine, BYL719 (alpha-specific PI3K inhibitor), Cabazitaxel, Cabozantinib, capmatinib, tabine, carfilzomib, chimeric antigen receptorengineered T (CAR-T) cells, Celecoxib, ceritinib, Cetuximab, anib, ide, porin , Cinacalcet, crizotinib, Cobimetinib, Cosentyx, crizotinib, Tisagenlecleucel, Dabigatran, dabrafenib, dacarbazine, umab, dacomotinib, ycin, Daratumumab, Darbepoetin alfa, Darunavir, nib, denileukin diftitox, Denosumab, te, Dexlansoprazole , Dexmethylphenidate, Dexamethasone, DigniCap Cooling System, L-3,4-dihydroxyphenyl-alanine , Dinutuximab, dornase alfa, Doxycycline, Duloxetine, Duvelisib, durvalumab, elotuzumab, emicizumab, Emtricibine/Rilpivirine/Tenofovir, disoproxil fumarate, Emtricitbine /tenofovir/efavirenz, Enoxaparin, ensartinib, Enzalutamide, epitinib, Epoetin alfa, erlotinib , Esomeprazole, Eszopiclone, cept, Everolimus, exemestane, everolimus, exenatide ER, Ezetimibe, Ezetimibe/simvastatin, famitinib, Fenofibrate, Filgotinib, Filgrastim, fingolimod , flumatinib, Fluticasone nate, Fluticasone/salmeterol, fruquintinib, fulvestrant, gazyva, gefitinib, Glatiramer, Goserelin acetate, GSK2857916 ADC), nib, Icotinib , Imatinib, Ibritumomab an, ibrutinib, icotinib, isib, ifosfamide, Infliximab, mod, ImmuCyst, Immuno BCG, iniparib, Insulin aspart, Insulin detemir, Insulin glargine, Insulin lispro, Interferon alfa, Interferon alfa-1b, Interferon alfa-2a, Interferon alfa- 2b, Interferon beta, Interferon beta 1a, Interferon beta 1b, Interferon gamma-1a, lapatinib, Ipilimumab , Ipratropium bromide/ salbutamol, ib, Kanuma, Lanadelumab, Lanreotide acetate , lenalidomide, lenaliomide, lenvatinib mesylate, letrozole, Levothyroxine, yroxine, Lidocaine, Linezolid, Liraglutide, Lisdexamfetamine, LN-144 (tumor-infiltrating lymphocyte ), lorlatinib, lucitanib/delitinib, Memantine, Methoxy polyethylene glycol-epoetin beta, Methylphenidate, Metoprolol, Mekinist, tabine/Rilpivirine/ Tenofovir, Modafinil, Mometasone , Mycidac-C, mycophenolic acid, Necitumumab, nib, Nilotinib, niraparib, Nivolumab, ofatumumab, obinutuzumab, ocrelizumab, olaparib, Olmesartan, Olmesartan/ hydrochlorothiazide , Omalizumab, Omega-3 fatty acid ethyl esters, Oncorine, Oseltamivir, Osimertinib , Oxycodone, Ozanimod, palbociclib, zumab, panitumumab, panobinostat, pazopanib , pembrolizumab, PD-1 antibody, PD-L1 antibody, Pemetrexed, pertuzumab, Pirfenidone, Pneumococcal conjugate vaccine, pomalidomide, alin, ProscaVax, Propranolol , puquitinib, pyrotinib, Quetiapine, Rabeprazole, radium 223 chloride, Raloxifene, ravir, ramucirumab, Ranibizumab, regorafenib, ribociclib, Risankizumab, Rituximab, Rivaroxaban, psin, Rosuvastatin, ruxolitinib ate, Salbutamol, savolitinib, semaglutide , Sevelamer, Sildenafil, siltuximab, simotinib, sipatinib/cipatinib, Siponimod, Sipuleucel-T , Sitagliptin, Sitagliptin/metformin, Solifenacin, zumab, Sonidegib, Sorafenib, sulfatinib, Sunitinib, imus, tacrimus, Tadalafil, tamoxifen, Tafinlar, Talimogene laherparepvec , talazoparib, Telaprevir, talazoparib, Temozolomide, temsirolimus, Tenecteplase, Tenofovir/emtricitabine, tenofovir disoproxil fumarate, Testosterone gel, tezacaftor/ivacaftor, Thalidomide, theliatinib, TICE BCG, Tiotropium bromide, Tisagenlecleucel, Tocilizumab, toremifene, trametinib, Trastuzumab, tedin (ecteinascidin 743), trametinib, tremelimumab, Trifluridine/tipiracil, Tretinoin, Upadacitinib, Uro-BCG, Ustekinumab, ocogene rvovec, Valsartan, veliparib, vandetanib, vemurafenib, venetoclax, vismodegib , volitinib, vorinostat, ziv-aflibercept, Zostavax, and their pharmaceutically acceptable salts, carriers, diluents, or excipients thereof, or a combination above thereof. WO 73345
NZ775656A 2018-10-12 Conjugation linkers containing 2,3-diaminosuccinyl group NZ775656B2 (en)

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