The antibody-drug conjugate of claim 40, wherein the cytotoxin D, D1 and D2 are independently an anti-microtubule agent, DNA minor groove binder, an RNA polymerase II inhibitor, DNA topoisomerase I or II inhibitor, or a DNA alkylating agent, selected from tubulysins, amanitins, auristatins (including its analogs of AFP, MMAF, MMAE, AEB, AEVB, E), calicheamicin, camptothecins (including SN-38, topotecans or exatecans), etoposides, teniposides, daunomycins, doxorubicins (including morpholino-doxorubicins, cyanomorpholino-doxorubicins), duocarmycins (including CC1065 analogs, DC1, DC4, CBI-dimers), dolastatins, enediynes, eribulin, lexitropsins, taxanes, puromycins, maytansinoids, vinca alkaloids, paclitaxels, docetaxels, pyrrolobenzodiazepines (including PBDs, IGN), rhizoxins, dolastatins, echinomycins, combretatstatin, vinca alkaloid, chalicheamicins, maytansine (DM1, DM4, DM21), geldanamycin, vinblastine, methotrexate, hemiasterlin, netropsin, inhibitor of nicotinamide phosphoribosyltransferases (NAMPT), spliceostatin, pladienolide, protein kinase inhibitor, MEK inhibitor, proteinase inhibitor, immunotoxin, cell receptor agonist or their derivatives or analogs above thereof;
- wherein:
- (a) Tubulysin and its analogs having the following formula (IVa):
- or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof,
- wherein is a linkage site that either one or two of them can link to L1 and/or L2 independently;
- when two of “” link to both L1 and L2, R1 and R2, or Z2 and Z3 are dual linkage sites;
- wherein R1, R1′, R2, R3, and R4are independently H, C1˜C8 alkyl;
- C2˜C8 heteroalkyl, or heterocyclic;
- C3˜C8 aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl;
- or R1R2, R1R3, R2R3, R3R4, or R5R6 form a 3-7 membered carbocyclic, cycloalkyl, heterocyclic, heterocycloalkyl, aromatic or heteroaromatic ring system;
- R1 and R2 can be independently absent when they link to L1 or L2 independently or simultaneously, Y1 is N or CH;
- wherein R5, R6, R8, R10 and R11 are independently H, or C1˜C4 alkyl or heteroalkyl;
- wherein R7 is independently H, R14, —R14C(═O)X1R15;
- or —R14X1R15;
- X1 is O, S, S—S, NH, CH2 or NR14;
- wherein R9 is selected from H, OH, ═O, —OR14, —OC(═O)R14, —OC(═O)NHR14, —OC(═O)NR14R15, OP(═O)(OR14)2, —OC(═O)NR14R15, or OR14OP(═O)(OR15)2;
- when R9 links L1 or L2, R9 is, —O—, —OC(═O)NH— or —OC(═O)N(R14)—;
- wherein R11 is independently H, R14, —R14C(═O)R15, —R14C(═O)X2R15, wherein X2 is —O—, —S—, —NH—, or —N(R14)—;
- wherein R12 is —COOH, —COSH, —CONH2, CONHNH2, CONHNHR15, —CONH(R15), —COOR15, —R15COR16, —R15COOR16, —R15C(O)NH2, —R15C(O)NHR16, —COSR15, R15S(═O)2R16, —R15P(═O)(OR17)2, —R15OP(═O)(OR17)2, —COOCH2OP(═O)(OR17)2, —COX2SO2R17, —COOR15X2R16, tetrazole, imidazole, or triazole, where X2 is —O—, —S—, —NH—, —N(R15)—, —O—R15—, —S—R15—, CH2 or —NHR15—;
- when R12 links L1 or L2, R12 is —C(O)O—, —C(O)NH—, —C(═O)NHS(O)2R15— or —C(═O)N(R15)—;
- R13 and R14 are independently C1˜C8 alkyl, heteroalkyl;
- C2-C8 of alkenyl, alkynyl, heteroalkyl, heterocycloalkyl;
- C3-C8 of aryl, Ar-alkyl;
- Z2 and Z3 are independently H, O, S, NH, N(R15), NHNH, —OH, —SH, —NH2, NH, NHNH2, —NH(R15), —OR15, CO, —COX2, —COX2R16, R17, F, Cl, Br, I, SR16, NR16R17, N═NR16, N═R16, NO2, SOR16R17, SO2R16, SO3R16, OSO3R16, PR16R17, POR16R17, PO2R16R17, OP(O)(OR17)2, OCH2OP(O)(OR17)2, OC(O)R17, OC(O)OP(O)(OR17)2, PO(OR16)(OR17), OP(O)(OR17)OP(O)(OR17)2, OC(O)NHR17;
- —O—(C4-C12 glycoside), —N—(C4-C12 glycoside);
- C1˜C8 alkyl, heteroalkyl;
- C2-C8 of alkenyl, alkynyl, heteroalkyl, heterocycloalkyl;
- C3-C8 of aryl, Ar-alkyl, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, or 2-8 carbon atoms of esters, ether, or amide;
- or peptides containing 1-8 amino acids (NH(Aa)1˜8, or CO(Aa)1˜8 (which are respectively N-terminal or C-terminal 1-8 the same or different amino acids)), or polyethyleneoxy unit of formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 0 to about 1000, or combination of above groups thereof, X2 is O, S, S—S, NH, CH2, OH, SH, NH2, CHR15 or NR15;
- R15, R16 and R17 are independently H, C1˜C8 alkyl, heteroalkyl;
- C2-C8 of alkenyl, alkynyl, heteroalkyl, heterocycloalkyl;
- C3-C8 of aryl, Ar-alkyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, alkylcarbonyl, or Na+, K+, Cs+, Li+, Ca2+, Mg+, Zn2+, N+(R1)(R2)(R3)(R4), HN+(C2H5OH)3 salt;
- Y1 and Y2 are independently N or CH;
- q is 0 or 1;
- when q=0, Y3 does not exist, Y4, Y5, Y6 and Y7 are independently CH, N, NH, O, S, or N (R1), thus Y2, Y4, Y5, Y6 and Y7form a heteroaromatic ring of furan, pyrrole thiophene, thiazole, oxazole and imidazole, pyrazole, triazole, tetrazole, thiadiazole;
- when q=1, Y3, Y4, Y5, Y6 and Y7 are independently CH or N, thus Y2, Y3, Y4, Y5, Y6 and Y7 form aromatic ring of benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, pentazine;
- (a) the tubulysin analogs of Formula (IVa) specifically having the structures shown below:
- wherein R20 is H;
- C1-C8 of linear or branched alkyl or heteroalkyl;
- C2-C8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl;
- C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
- carbonate (—C(O)OR17), carbamate (—C(O)NR17R18);
- or 1-8 carbon atoms of carboxylate, ester, ether, or amide;
- or 1˜8 amino acids;
- or polyethyleneoxy unit of formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 0 to about 1000;
- or R20 is absent and the oxygen forms a ketone, or combination above thereof, Z3 and Z3 are independently H, OH, NH2, O, NH, COOH, COO, C(O), C(O), C(O)NH, C(O)NH2, R18, OCH2OP(O)(OR18)2, OC(O)OP(O)(OR18)2, OPO(OR18)2, NHPO(OR18)2, OP(O)(OR18)OP(O)(OR18)2, OC(O)R18, OC(O)NHR18, OSO2(OR18), O—(C4-C12-glycoside), of linear or branched alkyl or heteroalkyl;
- C2-C8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl;
- C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
- carbonate (—C(O)OR17), carbamate (—C(O)NR17R18);
- R17 and R18 are independently H, linear or branched alkyl or heteroalkyl;
- C2-C8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl;
- C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
- carbonate (—C(O)OR17), carbamate (—C(O)NR17R18);
- R19 is H, OH, NH2, OSO2(OR18), XCH2OP(O)(OR18)2, XPO(OR18)2, XC(O)OP(O)(OR18)2, XC(O)R18, XC(O)NHR18, C1˜C8alkyl or carboylate;
- C2˜C8alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl;
- C3˜C8 aryl or alkylcarbonyl;
- or pharmaceutical salts;
- X is O, S, NH, NHNH, or CH2;
- R7 is defined the same above;
- wherein the linkage sites, “” in formula IV-01-IV-94 are omitted here but they are followed the same positions indicated in Formula (IV) of claim 42;
- (b). the calicheamicins and their related enediyne antibiotics having the following formula:
- wherein the calicheamicin, geldanamycin, maytansinoid, eribulin, and spliceostatin, have the following formula respectively:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof,
- wherein is the site linked to L1 or L2;
- (c). the geldanamycin having the following formula:
- wherein X is O, NH, CH2, is the link site linked to L1 or L2;
- (d). the Maytansines or their derivatives maytansinoids having the following formula:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof;
- wherein is the site inked to L1 or L2;
- (e). the camptothecin (CPTs) and its derivatives having the following formula:
- or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts;
- or the polymorphic crystalline structures of these compounds;
- or the optical isomers, racemates, diastereomers or enantiomers;
- wherein R1, R2 and R4 are independently selected from H, F, Cl, Br, CN, NO2, C1˜C8 alkyl;
- O—C1˜C8alkyl;
- NH—C1˜C8 alkyl;
- C2-C8 of heteroalkyl, alkylcycloalkyl, heterocycloalkyl;
- C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
- or 2-8 carbon atoms of esters, ether, amide, carbonate, urea, or carbamate;
- R3 is H, OH, NH2, C1˜C8 alkyl;
- O—C1˜C8 alkyl;
- NH—C1˜C8 alkyl;
- C2-C8 of heteroalkyl, alkylcycloalkyl, heterocycloalkyl;
- or 2-8 carbon atoms of esters, ether, amide, carbonate, urea, or carbamate;
- or R1R2, R2R3 and R3R4 independently form a 5-7 membered carbocyclic, heterocyclic, heterocycloalkyl, aromatic or heteroaromatic ring system;
- is the site in the molecule that can be linked to L1 or L2;
- the camptothecin (CPTs) and its derivatives of the formula (Cpt-I) have the following formula:
- or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts;
- or the polymorphic crystalline structures of these compounds;
- or the optical isomers, racemates, diastereomers or enantiomers;
- P1 is H, OH, NH2, COOH, C(O)NH2, OCH2OP(O)(OR18)2, OC(O)OP(O)(OR18)2, OPO(OR18)2, NHPO(OR18)2, OC(O)R18, OP(O)(OR18)OP(O)(OR18)2, OC(O)NHR18, OC(O)N(C2H4)2NCH3, OSO2(OR18), O—(C4-C12-glycoside), OC(O)N(C2H4)2CH2N(C2H4)2CH3, O—(C1-C8 of linear or branched alkyl), C1-C8 of linear or branched alkyl or heteroalkyl;
- C2-C8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl;
- C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
- carbonate (—C(O)OR17), carbamate (—C(O)NR17R18);
- R17 and R18 are independently H, linear or branched alkyl or heteroalkyl;
- C2-C8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl;
- C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
- carbonate (—C(O)OR17), carbamate (—C(O)NR17R18);
- R1 and R2 are independently selected from H;
- O—C1˜C8 alkyl;
- C2-C8 of heteroalkyl, alkylcycloalkyl, heterocycloalkyl;
- C3-C8 of aryl, Ar-alkyl;
- wherein the linkage sites, “” in the above CPTs structures (Icp-01-Icp-24) are omitted here but they are defined the same positions as indicated in formula (Cpt-I);
- (f). the Combretastatin and its derivatives having the following formula:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof;
- wherein is the site linked to L1 or L2;
- (g). the Taxane and its derivatives having the following formula:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof;
- wherein is the site linked to L1 or L2;
- Ar and Ar′ are independently aryl or heteroaryl;
- (h). the anthracycline and its derivatives having the following formula:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof;
- wherein is the site linked to L1 or L2;
- (i). the Vinca alkaloid and its derivatives having the following formula:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein is the site linked to L1 or L2;
- (j). the dolastatin, auristatin and their derivatives having the following formula:
- (Ih-01), (Ih-02), (Ih-03), (Ih-04), (Ih-05), (Ih-06), (Ih-07), (Ih-08), (Ih-09), (Ih-10), and (Ih-11):
- or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts;
- or the polymorphic crystalline structures of these compounds;
- or the optical isomers, racemates, diastereomers or enantiomers;
- wherein R1, R2, R3, R4 and R5 are independently H;
- C1-C8 linear or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amine, 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 1000;
- two Rs:
- R1R2, R2R3, R1R3 or R3R4 together can form 3˜8 member cyclic ring of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl group;
- 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(R2), C(O)NHNHC(O) and C(O)NR1 when linked to the connecting site “” (that links to L1 and/or L2 independently);
- or OH, NH2, NHNH2, NHR5, SH, C(O)OH, C(O)NH2, OC(O)NH2, OC(O)OH, NHC(O)NH2, NHC(O)SH, OC(O)NH(R1), N(R1)C(O)NH(R2), C(O)NHNHC(O)OH and C(O)NHR1 when not linked to the connecting site “”;
- 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)pCH2CH2NH—SO3H, NH(CH2CH2O)pCH2CH2NHSO3H, R1—NHSO3H, 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, wherein Aa is 1-8 the same or different amino acids;
- p is 1-5000;
- R1, R2, R3, R4, R5, R5′, Z1, Z2, and n are defined the same above;
- (k). the Hemiasterlin and its derivatives having the following formula:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein is the site linked to L1 or L2;
- wherein R1, R2, R3, R4 and R5 are independently H;
- C1-C8 linear or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amine, 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;
- or R2R3 can form 3˜8 member cyclic ring of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl group;
- (l). the Eribulin and its derivatives having the following formula:
- or derivatives with one or more isotopes, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof;
- wherein is the site linked to L1 or L2;
- (m). the Inhibitor of nicotinamide phosphoribosyltransferases (NAMPT) and their derivatives having the following formula:
- NP01, NP02, NP03, NP04, NP05, NP06, NP07, NP08, and NP09:
- or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts;
- or the polymorphic crystalline structures of these compounds;
- or the optical isomers, racemates, diastereomers or enantiomers;
- wherein “” is the same above;
- X5 is F, Cl, Br, I, OH, OR1, R1, OPO3H2, OSO3H, NHR1, OCOR1, NHCOR1;
- (n). the benzodiazepine dimer and its derivatives having the following formula:
- PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08, PB09, PB10, PB11, PB12, PB13, PB14, PB15, PB16, PB17, PB18, PB19, PB20:
- or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts;
- or the polymorphic crystalline structures of these compounds;
- or the optical isomers, racemates, diastereomers or enantiomers;
- wherein X1, X2, Y1, Y2, Z1, Z2, and n are defined the same 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)NHNHC(O) and C(O)NR1;
- R1, R2, R3, R1′, R2′, and R3′ are independently H;
- F;
- Cl;
- ═O;
- ═S;
- ═CH2;
- ═CH—R1, OH;
- SH;
- C1-C8 linear or branched 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 unnatural aminoacids, or polyethyleneoxy unit of formula (OCH2CH2)p or (OCH2CH(CH3))p, wherein p is an integer from 1 to about 5000;
- 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, or one of X3 and Y3 can be absent;
- wherein R1, and R2 are C1-C8 linear or branched alkyl, heteroalkyl;
- C3-C8aryl, heteroaryl, alkylcycloalkyl, acyloxyl, alkylaryl, alkylaryloxyl, alkylarylamino, alkylarylthiol;
- or 1-6 the same or different sequence of amino acid/peptides (Aa)r, r=1-6;
- wherein R4, R5, R5′,R6, R12 and R12′ are independently H, OH, NH2, NH(CH3), NHNH2, COOH, SH, OZ3, SZ3, F, Cl, or C1-C8 linear or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxylamines;
- Z3 is H, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, or O-glycoside (glucoside, galactoside, mannoside, glucuronoside/glucuronide, alloside, fructoside, etc.), NH-glycoside, S-glycoside or CH2-glycoside;
- Mi and M2 are independently H, Na, K, Ca, Mg, NH4, NR1R2R3;
- X6 is CH, N, P(O)NH, P(O)NR1, CHC(O)NH, C3-C8aryl, heteroaryl, alkylcycloalkyl, acyloxyl, alkylaryl, alkylaryloxyl, alkylarylamino, or an Aa (amino acid);
- “” is defined the same above;
- (o). the CC-1065 analog or doucarmycin analogs and their derivatives having the following formula:
- CC01, CC02, CC03, CC04, CC05, CC06 and CC07:
- or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts;
- or the polymorphic crystalline structures of these compounds;
- or the optical isomers, racemates, diastereomers or enantiomers;
- wherein 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(R2), C(O)NHNHC(O) and C(O)NR1 when linked to the connecting site “”;
- or OH, NH2, NHNH2, NHR1, SH, C(O)OH, C(O)NH2, OC(O)NH2, OC(O)OH, NHC(O)NH2, NHC(O)SH, OC(O)NH(R1), N(R1)C(O)NH(R2), C(O)NHNHC(O)OH and C(O)NHR1 when not linked to the connecting site “”;
- Z3 is H, PO(OM1)(OM2), SO3M1, CH2PO(OM1)(OM2), CH3N(CH2CH2)2NC(O)—, O(CH2CH2)2NC(O)—, R1, or glycoside;
- wherein R1, R2, R3, M1, M2, and n are defined the same above;
- (p). the amatoxin and its derivatives having the following formula:
- Am01, Am02, and Am03:
- or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts;
- or the polymorphic crystalline structures of these compounds;
- or the optical isomers, racemates, diastereomers or enantiomers;
- wherein X1, and Y1 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), CH2, CHNH, CH2O, C(O)NHNHC(O) and C(O)NR1;
- 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)rCOOH, O(CH2CH2O)pCH2CH2OH, O(CH2CH2O)pCH2CH2NH2, NH(CH2CH2O)pCH2CH2NH2, NR1R2, O(CH2CH2O)pCH2CH2—COOH, NH(CH2CH2O)pCH2CH2COOH, NH—Ar—COOH, NH—Ar—NH2, O(CH2CH2O)pCH2CH2—NHSO3H, NH(CH2CH2O)pCH2CH2NHSO3H, R1—NHSO3H, NH—R1—NHSO3H, O(CH2CH2O)p—CH2CH2NHPO3H2, NH(CH2CH2O)pCH2CH2NHPO3H2, OR1, R1—NHPO3H2, R1—OPO3H2, O(CH2CH2O)pCH2CH2OPO3H2, OR1—NHPO3H2, NH—R1—NHPO3H2, or NH(CH2CH2O)pCH2—CH2NHPO3H2, wherein (Aa)r is 1-8 aminoacids;
- n and m1 are independently 1-20;
- p is 1-5000;
- R1, R2 and Ar, are the same defined;
- “” is defined the same above;
- (q). the spliceostatin, pladienolide and their derivatives having the following formula:
- or an isotope of a chemical element, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein is the link site linked to L1 or L2;
- (r). the Protein kinase inhibitors and their derivatives having the following formula:
- PK01˜PK40:
- or an isotope of a chemical element, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein Z5 and Z5′ are independently selected from O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R2), C(O)NHNHC(O) and C(O)NR1, wherein is the link site linked to L1 or L2;
- (s). the MEK inhibitor and its derivatives having the following formula:
- or an isotope of a chemical element, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein Z5 is selected from O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R2), C(O)NHNHC(O) and C(O)NR1;
- wherein is the site linked to L1 or L2;
- (t). the proteinase inhibitor and its derivatives having the following formula:
- or an isotope of a chemical element, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein is the link site linked to L1 or L2;
- (u). the immunotoxins that can be used as payloads for the conjugation are selected from Diphtheria toxin (DT), Cholera toxin (CT), Trichosanthin (TCS), Dianthin, Pseudomonas exotoxin A (ETA′), Erythrogenic toxins, Diphtheria toxin, AB toxins, Type III exotoxins, proaerolysin and topsalysin, the immunotoxins are constructed to the antibody via a bioengineering of protein fusions, or via through an amino acid of the immunotoxin having free amino, thiol or carboxyl acid group;
- (v). the cell-binding molecule/ligand or a cell receptor agonist and their derivatives having the following formula:
- or an isotope of a chemical element, or a pharmaceutically acceptable salt, hydrates, or hydrated salt;
- or a polymorphic crystalline structure;
- or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein is the link site linked to L1 or L2;
- wherein X4,and Y1 are independently O, NH, NHNH, NR1, 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), CH2, C(O)NHNHC(O) and C(O)NR1;
- (w). the one, two or more DNA, RNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA), and PIWI interacting RNAs (piRNA) can be as a chemotherapeutic/function compound conjugated to BCMA antibody having the following formula:
- wherein “” is the site to link the side chain linker;
- is single or double strands of DNA, RNA, mRNA, siRNA, miRNA, or piRNA;
- X1, and Y are independently O, NH, NHNH, NR1, 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), CH2, C(O)NHNHC(O) and C(O)NR1.