TH2101008043A - Conjugate formulation of tubulysin analogues with cell-binding molecules - Google Patents

Abstract

DEPCT65 The formulas of conjugates of tubulysin analogues containing cell-binding molecules having the structure represented by formula (I), where T, L, m, n,, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are as given herein, and can be used for targeted therapy of cancer, autoimmune diseases, and infectious diseases.

Claims (21)

1. DEPCT65 1. A pre-lyophilized liquid composition or in a lyophilized solid formulated or reconstituted formulation from a lyophilized solid, having the following composition: a conjugate of a tubulysin analogue with a cell-binding agent of formula (I) may consist of 0.01%~99% by weight as a plurality of gradients in the formula, 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 chelating agents, 0.0%~30.0% of one or more buffer salts, or More than for adjusting the pH of the formulation to pH4.5 to 8.5 and 0.0%~30.0% of one or more isotonic agents for adjusting the osmotic pressure to between approximately 250 and 350mOsm after reconstitution for administration to the patient, wherein a tubulysin analog conjugate of formula (I) is illustrated as follows: (chemical formula) (I) or a pharmaceutically acceptable salt, hydrate or hydrated salt thereof, or a polymorphic crystal structure of these compounds or their isotopes, optical isomers, racemates, diastereomers or enantiomers, wherein T is a targeting molecule or cell-binding molecule, L is a releasable linker, is a linkage bond in which L is independently connected to the atoms inside the parentheses, n is 1~20 and m is 1~10, wherein T is an antibody, a single-chain antibody, an antibody fragment that binds to target cells, a monoclonal antibody, a single-chain monoclonal antibody, or a monoclonal fragment. Antibodies that bind to target cells Chimeric antibodies Chimeric fragments Antibodies that bind to target cells Target domain Antibody domain fragments of antibodies that bind to target cells Adnectin mimics antibody DARPin Lymphokine Hormone Vitamin Growth factor Colony stimulating factor or nutrient transport molecule (transferrin) Binding peptide or protein Or antibodies or small molecules anchored to albumins, polymers, dendrimers, liposomes, nanoparticles, vesicles, (viral) capsids Where the linker L has the formula: Ww(Aa)rVv Where: W is the extensor unit W is 0 or 1 Aa Each independent is an amino acid unit R is an independent integer in the range 0 to 12 V is the spacer unit And v is 0, 1 or 2 extensor units W Independent may have a self-denying spacer Peptide unit Hydrazone bond Disulfide bond Or thiol ether bond The extensor unit (w) When present, it links the units of the binding molecule that are Targeted (T) to amino acid (Aa) units or linked to V when Aa is not present. The independent W-linked units may contain self-destructing spacers, peptide units, hydrazone bonds, disulfide bonds or thiol ether bonds. The T-linked W has the structure: (chemical formula) (chemical formula), where R20 and R21 are independently selected from C1~C9 alkylenes, C1~C7 carbocyclo, O(C1~C8 alkyl), arylene, C1~C9 alkylene arylene, arylene, C1~C9 alkylene, C1~C9 alkylene(C1~C8 carbocyclo),(C3~C7 carbocyclo)C1~C9 alkylene, C3~C8 heterocycle, C1~C10 Alkylenes (C3~C8 heterocycles), (C3~C8 heterocycles) C1~C9 alkylenes, (CH2CH2O)k, (CH(CH3)CH2O)k and (CH2CH2O)kCH2k are integers in the range from 120. R’ and R” are independent H or CH, the spacer unit (V) when present links the amino acid unit to the antimitotic substance. When the amino acid unit is alternatively present, the spacer unit links the extensor unit to the antimitotic substance. When the amino acid unit is absent, the spacer unit also links the antimitotic substance to the binding molecule. (T) When neither the amino acid unit nor the extensor unit are present, the spacer linker may contain functional groups that enhance the water solubility, biotransport, preferential renal elimination, absorption, bioavailability, biodistribution and/or bioavailability of the conjugate are described here. Essentially, spacer units are of two general types: denatured and nondenatured. A nondenatured spacer unit is one in which a part Or all of the spacer units remain bound to the antimitotic agent after specific cleavage by the enzyme of the amino acid unit from the conjugate of the antimitotic agent. The linker molecules used to bind or the antimitotic agent compounds. Self-destructing linker units include aromatic compounds electronically similar to para-aminobenzylcarbamoyl (PAB) groups, 2-aminoimidazole derivatives, 5-methanol, heterocyclic PAB analogues, beta-glucuronides and ortho- or para-aminobenzyl acetals, or one of the following structures: (chemical formula), (chemical formula)wherein (*) atoms are the binding sites of the spacer unit or the releasable linker unit, the antimitotic agent and/or the binding molecule (T)X, Y and Z3 independently are NH, O or SZ2 independently are H, NH, O or S, v is 0 or 1Q independently is H,OH,C1~C6 alkyl,(OCH2CH2)nF,Cl,Br,I,OR17 or SR17,NR17R18, N=NR17,N=R17,NR17R18,NO2,SOR17R18,SO2R17,SO3R17,OSO3R17,PR17R18,POR17R18, PO2R17R18,OPO(OR17)(OR18)orOCH2PO(OR17(OR18)where R17,R18 independently is H, C1~C8 of alkyl C2~C8 of alkynyl,alkenyl,heteroalkyl C3~C8 of aryl,heterocyclic. ,carbocyclic,cycloalkyl,heterocycloalkyl,heteroaralkyl,alkylcarbonyl or pharmaceutical cationic salts,non-self-limiting spacer linkers with the structure: (chemical formula) 6maleimidocaproyl(MC),(chemical formula) maleimidopropanoyl(MP),(chemical formula)valenecitrulline(valcit), (chemical formula)alaminephenylalanine(alaphe) (chemical formula) lysinephenylalanine(lysphe),(chemical formula)p-aminobenzyloxycarbonyl(PAB),(chemical formula)4-thiopentanoate(SPP),(chemical formula) 4-thiobutyrate(SPDB),(chemical formula)4(N-maleimidomethyl)cyclo Hexane1Carboxylate(MCC),(Chemical formula)maleimidoethyl(ME),(Chemical formula)4Thio2Hydroxysulfonylbutyrate(2SulfoSPDB),(Chemical formula)arylthiol(PySS),(Chemical formula)(4Acetyl)amimobenzoate(SIAB),(Chemical formula),oxylbenzylthio,(Chemical formula)aminobenzylthio,(Chemical formula)dioxylbenzyl Thio,(chemical formula)diaminobenzylthio,(chemical formula)aminooxybenzylthio,(chemical formula)alkoxyamino(AOA),(chemical formula)ethyleneoxy(EO),(chemical formula)4methyl4dithiopentanoic(MPOP),(chemical formula)triazole,(chemical formula)dithio,(chemical formula)alkylsulfonyl,(chemical formula)alkylsulfonamide,(chemical formula)sulfonbisamide,(chemical formula)phosphondiamide,(chemical formula)alkylphosphonamide,(chemical formula)phosphineic acid,(chemical formula)N-methylphosphonamidic acid,(chemical formula)N,N'dimethyl acid Phosphonamidic, (chemical formula) N,N'dimethylphosphonic acid, (chemical formula) hydrazine, (chemical formula) acetimidamide, (chemical formula) oxime, (chemical formula) acetyl acetohydrazide, (chemical formula) aminoethylamine, (chemical formula) aminoethylamoethylamine, (chemical formula), (chemical formula), (chemical formula), or naturally occurring or non-native peptides of type L or D with 120 identical or different amino acids, where “*” and “(symbol)” atoms are the attachment sites of a spacer or releasable linker, antimitotic agents and/or binding moleculesm is 1~10n is 1~20X2,X3,X4,X5 or X6 are selected independently fromNHNHNHN(R12)N(R12)N(R12,)OSC1C6 of alkyl C2C6. Heteroalkyl, alkylcycloalkyl, heterocycloalkyl C3C8 aryl, Aralkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroarylCH2OR12, CH2SR12, CH2NHR12 or 1~8 amino acids in which R12 and R12, independently, are HC1C8 of alkyl C2C8 of heteroalkyl, alkylcycloalkyl, hetero cycloalkyl C3C8 of aryl, Aralkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl or 18 carbon atoms. of esters, ethers or amides or polyethylene oxy units having the formulas (OCH2CH2)p or (OCH2CH(CH3))p, where p is an integer from 0 to approximately 1000, or combinations thereof. The dissociable components of the L-linkage in which at least one bond in L is present can be destroyed under physiological conditions: pH-intolerant, acid-intolerant, base-intolerant, oxidatively intolerant, metabolically intolerant, biochemically intolerant or enzymatically intolerant bonds, which have one In the following structures: (CR15R16),m(Aa)r(CR17R18)n(OCH2CH2)t,(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t,(Aa)r (CR15R16)m(CR17R18)n(OCH2CH2)t,(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t,(CR15R16)m (CR17=CR18)(CR19R20)n(Aa)t(OCH2CH2)r,(CR15R16)m(NR11CO)(Aa)t(CR19R20)n(OCH2CH2)r, (CR15R16)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r,(CR15R16)m(OCO)(Aa)t (CR19R20)n(OCH2CH2)r,(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r,(CR15R16)m (CO)(Aa)t(CR19R20)n(OCH2CH2)r,(CR15R16)m(NR21CO)(Aa)t(CR19R20)n(OCH2CH2)r, (CR15R16)m(OCO)(Aa)t(CR19R20)n(OCH2CH2)r,(CR15R16)m(OCNR17)(Aa)t(CR19R20)n (OCH2CH2)r,(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r,(CR15R16)mphenylCO(Aa)t (CR17R18)n,(CR15R16)mfurylCO(Aa)t(CR17R18)n,(CR15R6)moxazolylCO(Aa)t(CR17R18)n, (CR15R16)mthiazolylCO(Aa)t(CCR17R18)n,(CR15R16)tthienylCO(CR17R18)n,,(CR15R16)timidazolylCO(CR17R18)n,(CR15R16)tmorpholinoCO(Aa)t(CR17R18)n,(CR15R16)t PiperazinoCO(Aa)t(C17R18)n,(CR15R16)tNmethylpiperazinCO(Aa)t(CR17R18)n, (CR15R16)m(Aa)tphenyl,(CR15R16)m,(Aa)tfuryl,(CR15R16)moxazolyl(Aa)t,(CR15R16)m thiazolyl(Aa)t,(CR15R16)m thienyl(Aa)t,(CR15R16)m imidazolyl(Aa)t,(CR15R16)m Morpholino(Aa)t,(CR15R16)m,Piperazino(Aa)t,(CR15R16)mNmethylpiperazino(Aa)t, K(CR15R16)m(Aa)r(CR17R18)n(OCH2CH2)t,K(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t,K(Aa)r (CR15R16)m(CR17R18)n(OCH2CH2)t,K(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t,K(CR15R16)m (CR17=CR18)(CR19R20)n(Aa)t(OCH2CH2)r,K(CR15R16)m(NR11CO)(Aa)t(CR19R20)n(OCH2CH2)r, K(CR5R6)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r,K(CR15R16)m(OCO)(Aa)t(CR19R20)n (OCH2CH2)r,K(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r,K(CR15R16)m(CO)(Aa)t (CR19R20)n(OCH2CH2)r,K(CR15R16)m(NR21CO)(Aa)t(CR19R20)n(OCH2CH2)r,K(CR15R16)m (OCO)(Aa)t(CR19R20)n(OCH2CH2)r,K(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r, K(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r,K(CR15R16)mphenylCO(Aa)t(CR17R18)n, K(CR15R16)mfurylCO(Aa)t(CR17R18)n,K(CR15R16)moxazolylCO(Aa)t(CR17R18)n, K(CR15R16)mthiazolylCO(Aa)t(CR17R18)n,K(CR15R16)tthienylCO(CR17R18)n, K(CR15R16)timidateCO(CR17R18)n,K(CR5R6)tmorpholinoCO(Aa)t(CR17R18)n, K(CR15R16)tpiperazinCO(Aa)t(CR17R18)n,K(CR15R16)tNmethylpiperazin CO(Aa)t(CR17R18)n,K(CR15R16)m(Aa)tphenyl,K(CR15R16)m(Aa)tfuryl,K(CR15R16)moxazolyl(Aa)t,K(CR15R16)mthiazolyl(Aa)t,K(CR15R16)mthienyl(Aa)t,K(CR15R16)mimidazolyl(Aa)t,K(CR15R16)mmorpholino(Aa)t,K(CR15R16)mpiperazino(Aa)tG,K(CR5R6)mN methylpiperazino(Aa)twherem,Aa,n,R13,R14andR15aredescribedabovetandrherein. It is 0100 independently R16, R17, R18, R19 and R20 independently are selected from H halides C1~C8 of alkyl or heteroalkyl, C2~C8 of aryl, alkenyl, alkynyl, ether, ester, amine or Amide, C3~C8 of aryl which can be optionally replaced by one or more halides, CN, NR12R12', CF3, OR12, aryl, heterocycle, S(O)R12, SO2R12, CO2H, SO3H, OR12, CO2R12, CONR12, PO2R12R13, PO3H or P(O)R12R12'R13K is NR12, SS, C(=O), C(=O)NH, C(=O)O, C=NHO, C=NNH, C(=O)NHNH, O, S, Se, B, Het(heterocyclic or hetero aromatic ring having C3C12) or peptide having the same or different 120 amino acids. Inside the parentheses of formula (I) is the analogue of tubulysin where R1, R2, R3 and R4 are as follows. Free is linear or branched C1C8 of alkyl, alkyl alcohol.C2C8 of heteroalkyl, alkylcycloalkyl, heterocycloalkyl, alkyl ether, alkyl carboxylate, alkyl amine, alkyl ester, alkyl amide.C3C8 of aryl, Aralkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkyl carbonyl or of two R groups: R1R2, R3R4, R5R6 or R12R13 together forming aromatic or heteroaromatic carbocyclic, cycloalkyl, heterocyclic, heterocyclic alkyl ring system with 3~7 members.Y is N or C.In addition, R1, R2, R3 and R4 can be free. where R5, R6, R8 and R10 are chosen independently from H and C1C4 linear or branched alkyl or heteroalkyl C2C4 where R7 is chosen from H, R14 or R14C(=O)X1R15R14X1R15X1 is chosen from O, S, SS, NH or NR14 where R9 is H, O, OR14, OC(=O)R14, OC(=O)NHR14, OC(=O)NR14R15, OC(=O) R14SSR15, OP(=O)(OR14) or OR14OP(=O)(OR15) where R11 is H, R14, R14C(=O)R16, R14C(=O)X2R16, R14X2R16, R14C(=O)X2 where X2 is O,S,NH,NHS(O2),NHS(O),N(R14),OR14,SR14,S(=O)R14orNHR14 where R12 isH,R14,O,S,N,=N,=NNH,OH,SH,NH2,=NH,=NNH2, NH(R14),OR14,C(O)O,C(O)OR16,COR16,COOR14,C(O)NH,C(O)NH2,C(O)NHR14, SR14,S(=O)R14,P(=O)(OR16)2,OP(=O)(OR16)2,CH2OP(=O)(OR16)2,SO2R16 where R13 is C1C10linear or branched alkyl,alkyl acid,alkyl amide,alkyl A heteroalkyl amine or C2C10 or C3C10 of ArAr refers to an aromatic or heteroaromatic group consisting of one or more rings comprising four to ten carbon atoms, preferably four to six carbon atoms. The term heteroaromatic group refers to an aromatic group in which one or more carbon atoms are replaced by a heteroatom, preferably one, two or three carbon atoms, replaced by O, N, Si, Se, P or S, preferably O, S, N. The term aryl or Ar also refers to an aromatic group in which one or more H atoms can be substituted by a heteroatom. Independent by R17,F,Cl,Br,I,OR16,SR16,NR16R17,N=NR16,N=R16,NR16R17,NO2,SOR16R17, SO2R16,SO3R16,OSO3R16,PR16R17,POR16R17,PO2R16R17,OP(O)(OR17)2,OCH2OP(O)(OR17)2, OC(O)OP(O)(OR17)2,PO(OR16)(OR17),OP(O)(OR17)OP(O)(OR17)2,OC(O)R17 or OC(O)NHR17 where R14 and R15 independently are linear or branched alkyl C2C8. of alkenyl, alkynyl, heteroalkyl, heterocyclic, carbocyclic C3C8 aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkyl cycloalkyl, alkylcarbonyl wherein R14 is bivalent it is R14 further connected to an additional functional group of one to four amino acid units or (CH2CH2O)r,r is an integer in the range 0 to 12 or C4C12 of glycosides or C1C8 of carboxylic acids wherein R16 is H,OH,R14 or one to four amino acid units. wherein R17 is H, C1C8 linear or branched alkyl C2C8 of alkenyl, alkynyl, heteroalkyl, heterocyclic C3C8 of aryl, carbocyclic, cycloalkyl, alkyl cycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkyl carbonyl or C4C12 of glycosides or pharmaceutical salts, wherein a suitable buffering agent in the formulation includes the sodium salt, potassium salt, ammonium salt or trihydroxyethyl amino salt of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or tris phthalic acid, tromethamine hydrochloride, sulfate or phosphate buffer. In addition, cationic components of amino acids may be used as buffering agents. Such amino acid components include: Arginine, glycine, glycylglycine and histidine Arginine buffers including arginine acetate, arginine chloride, arginine phosphate, arginine sulfate, arginine succinate Histidine buffers including histidine chloride Arginine chloride, histidine acetate Arginine acetate, histidine phosphate Arginine phosphate, histidine sulfate Arginine sulfate, histidine succinate Arginine succinate Buffer formulations having a pH of 4.5 to pH 8.5, preferably from about 4.5 to about 6.5, more preferably from about 5.0 to about 6.2 The concentration of the organic acid salts in the buffer is from about 10 mM to about 500 mM. Wherein 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 their metal salts, Wherein the surfactant selected in the formulation is selected from polysorbates (polysorbate 20, polysorbate 40, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85. Poloxamers (including poloxamer 188, poly(ethylene oxide), poly(propylene oxide), poloxamer 407 or polyethylene polypropylene glycol and the like), triton sodium dodecyl sulfate (SDS), sodium laurel sulfate, sodium octyl glycoside, lauryl, myristyl, linoleyl or stearyl sulfo-betaine, lauryl, myristyl, linoleyl or stearyl sarcosine, linoleyl, myristyl or cetyl betaine, lauromidopropyl, cocamidopropyl, linoleamido propyl, myristamidopropyl, palmidopropyl or isostearamidopropyl betaine, myristamidopropyl, palmidopropyl or isostearamidopropyl dimethylamine, sodium Methyl cocoyl or disodium methyl oleyl taurate, dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine and cocoamfoglycinate, isostearyyl ethyl imidolyl ethosulfate, polyethyl glycol, polypropyl glycol and copolymers of ethylene and propylene glycol, wherein the optional “preservative” in the formulation is selected from octadecyl dimethyl benzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (mixture of alkyl benzyldimethyl ammonium chlorides wherein the alkyl groups are long-chain compounds) and benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl parabens such as Methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol, wherein the appropriate free amino acids as bulking agents or tonicity agents or osmotic pressure adjusters in the formulation are selected from one or more of the following: arginine, cystine, glycine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glycineglutamic acid or aspartic acid; wherein the antioxidants in the formulation can optionally be selected from methionine, glutathione, cysteine, cystine or ascorbic acid; wherein the formulation optionally contains a metal chelating agent selected from EDTA, EGTA; wherein the final formulation is adjusted to the desired pH with a selected buffering agent. derived from HCl, H2SO4, acetic acid, H3PO4, citric acid, NaOH, KOH, NH4OH, ethanolamine, diethanolamine or triethanolamine, sodium phosphate, potassium phosphate, trisodium citrate, tromethamine wherein the isotonic agent is selected from mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate or NaCl to maintain the osmotic pressure at about 250 to 350mOsm of the solution used. The final infusion formula is 2. A conjugate of a tubulysin analogue with a cell-binding agent having formula (I) according to claim 1 having the specific formula (II): (chemical formula)(II), or a pharmaceutically acceptable salt, hydrate or hydrated salt thereof, or a polymorphic crystal structure of any of these compounds or an isotope, optical isomer, racemate, diastereomer or enantiomer thereof, wherein T, L, n, m, Y, R1, R2, R3, R4, R5, R6, R8, R10, R13, R14, R15, R16 and R17 are determined, as in formula (I), wherein R7 is chosen from H, R14 or R14C(=O)X1R15R14X1R15X1 is chosen from O, S, SS, NH or NR14. where R9 is H,OH,OR14,OC(=O)R14,OC(=O)NHR14,OC(=O)NR14R15,OC(=O) R14SSR15,OP(=O)(OR14)2orOR14OP(=O)(OR15) where R11 is H,R14,R14C(=O)R16,R14C(=O)X2R16,R14X2R16,R14C(=O)X2 where X2 is O,S,NH,NHS(O2),N(R14),OR14,SR14,S(=O)R14 or NHR14 where R12 is H,R14,O,S,N,=N,=NNH,OH,SH,NH2,=NH,=NNH2, NH(R14),OR14,C(O)O,C(O)OR16,COR16,COOR14,C(O)NH,C(O)NH2,C(O)NHR14, SR14, S(=O)R14,P(=O)(OR16)2,OP(=O)(OR16)2,CH2OP(=O)(OR16)2,SO2R16 3. A conjugate of the tubulysin analogue according to claim 1 having formula (III): (chemical formula)(III), or a pharmaceutically acceptable salt, hydrate or hydrated salt thereof, or a polymorphic crystal structure of any of these compounds, or an isotope, optical isomer, racemate, diastereomer or enantiomer thereof, wherein T, L, m, Y, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13 and n are defined, as in formulas (I) and (II), wherein R7 is chosen independently of R14 or R14C(=O)X1R15 or R14X1R15, wherein R14 and R15 independently are linear or branched alkyl, heteroalkyl C1~C8. Alkenyl, alkynyl C3~C8 aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkylheteroalkylcycloalkyl, alkylcarbonylX1 is selected from O,S,SS,NH or NR14. 4. A conjugate of the tubulysin analogues according to claim 1 having formula (IV): (chemical formula)(IV), or a pharmaceutically acceptable salt, hydrate or hydrated salt thereof, or a polymorphic crystal structure of any of these compounds, or an isotope, optical isomer, racemate, diastereomer or enantiomer thereof, wherein T, L, m, R1, R2, R3, R4, R5, R6, R7, R8, R10, R11, R12, R13 and n are determined. As in formula (II), where R9 independently is H,O,OR14,OC(=O)R14,OC(=O)NHR14, OC(=O)NR14R15,OC(=O)R14SSR15,OP(=O)(OR14)Owhere R14,R15 independently is H, C1~C8 of alkyl,heteroalkylC3~C8 of aryl,heteroarl,heterocyclic,carbocyclic,cycloalkyl,alkylcycloalkyl,heterocycloalkyl,heteroalkylcycloalkyl,heteroalkylcycloalkyl,heteroalkyl,alkylcarbonyl or pharmaceutical salt. 5. A conjugate of the tubulysin analogue according to claim 1 having formula (V) (chemical formula) (V), or a pharmaceutically acceptable salt, hydrate or hydrated salt thereof, or a polymorphic crystal structure of any of these compounds, or an isotope, optical isomer, racemate, diastereomer or enantiomer thereof, wherein T, L, m, Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13 and n are designated, as in formula (II), wherein R11 is R14, R14C(=O)R17, R14C(=O)X2R17, R14X2R17, R14C(=O)X2wherein R17 Independently, H, OH, C1~C8 of alkyl C2~C8 of alkenyl, alkynyl, heteroalkyl C3~C8 of aryl, arylene, heterocyclic, carbocyclic, heterocycloalkyl or amino acid or two amino acid units X2 are O, S, NH, NHS(O2), NHS(O), N(R14), OR14, SR14, S(=O) R14 or NHR14 R14 is H, C1~C8 of alkyl, heteroalkyl C2~C8 of alkenyl, alkynyl C3~C8 of aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl. 6. A conjugate of the tubulysin analogue of claim 1 having the formula (VI): (chemical formula)(VI), or a pharmaceutically acceptable salt, hydrate or hydrated salt thereof, or a polymorphic crystal structure of any of these compounds, or an isotope, optical isomer, racemate, diastereomer or enantiomer thereof. where T,L,m,Y,R1,R2,R3,R4,R5,R6,R7,R8,R9,R11,R13 and n are defined as in formula(II) where R12 independently is R14,O,S,NH,=N,=NNH,N(R14),OR14,C(O)O, C(O)NH,C(O)NR14,SR14,S(=O)R14,NHR14,CH2OP(=O)(OR15),P(=O)(OR15), OP(=O)(OR15)O,SO2 R14,R14,R15 independently is C1~C8 of alkyl,heteroalkyl C2~C8 of alkenyl,alkenyl C3~C8 of aryl,heterocyclic,carbocyclic,cycloalkyl,alkyl Cycloalkyl,heterocycloalkyl,heteroaralkyl,heteroalkylcycloalkyl,alkyl carbonyl 7. A conjugate of the tubulysin analogue according to claim 1 having formula (VII): (chemical formula)(VII), or a pharmaceutically acceptable salt, hydrate or hydrated salt thereof, or a polymorphic crystal structure of any of these compounds or an isotope, optical isomer, racemate, diastereomer or enantiomer thereof, wherein T, L, n, m, Y, R1, R1', R2, R3, R4, R5, R6, R8, R10, R11 and R12 are designated as in formula (II), wherein R13 is C1~C10 of an alkyl, heteroalkyl, alkyl acid, alkyl amide, alkyl amine or ArAr referring to an aromatic group or heteroaromatic group consisting of one or more rings comprising four to ten carbon atoms, preferably carbon atoms. The term heteroaromatic group refers to one or more carbon atoms on an aromatic group, preferably one, two or three carbon atoms replaced by O, N, Si, Se, P or S, preferably O, S, N. The term aryl or Ar also refers to aromatic groups in which one or more H atoms are independently replaced by R18, F, Cl, Br, I, OR16, SR16, NR16R18, N=NR16, N=R16, NR16R18, NO2, SOR16R18, SO2R16, SO3R16, OSO3R16, PR16R18, POR16R18, PO2R16R18, OPO3R16R18 or PO3R16R18 where R16, R18 independently. is H,C1~C8 of alkyl C2~C8 of alkenyl, alkynyl, heteroalkyl C3~C8 of aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl or C4~C12 glycoside or pharmaceutical salt. 8. The tubulysin analogue in parentheses with formula (I) according to claim 1 having the structure represented by the following formulas II01~II73,III01~III71,IV01~IV71,V01~V71,VI01. ~VI16 and VII01~VII82 below: (Chemical formula)II01, (Chemical formula)II02, (Chemical formula)II03, (Chemical formula)II04, (Chemical formula)II05, (Chemical formula)II06, (Chemical formula)II07, (Chemical formula)II08, (Chemical formula)II09, (Chemical formula)II10, (Chemical formula)II11, (Chemical formula)II12, (Chemical formula)II13, (Chemical formula)II14, (Chemical formula)II15, (Chemical formula)II16, (Chemical formula)II17, (Chemical formula)II18, (Chemical formula)II19, (Chemical formula)II20, (Chemical formula)II21, (Chemical formula)II22, (Chemical formula)II23, (Chemical formula)II24, (Chemical formula)II25, (Chemical formula)II26, (Chemical formula)II27, (Chemical formula)II28, (Chemical formula)II29, (Chemical formula)II30, (Chemical formula)II31, (Chemical formula)II32, (Chemical formula)II33, (Chemical formula)II34, (Chemical formula)II35, (Chemical formula)II36, (Chemical formula)II37, (Chemical formula)II38, (Chemical formula)II39, (Chemical formula)II40, (Chemical formula)II41, (Chemical formula)II42, (Chemical formula)II43, (Chemical formula)II44, (Chemical formula)II45, (Chemical formula)II46, (Chemical formula)II47, (Chemical formula)II48, (Chemical formula)II49, (Chemical formula)II50, (Chemical formula)II51, (Chemical formula)II52, (Chemical formula)II53, (Chemical formula)II54, (Chemical formula)II55, (Chemical formula)II56, (Chemical formula)II57, (Chemical formula)II58, (Chemical formula)II59, (Chemical formula)II60, (Chemical formula)II61, (Chemical formula)II62, (Chemical formula)II63, (Chemical formula)II64, (Chemical formula)II65, (Chemical formula)II66, (Chemical formula)II67, (Chemical formula)II68, (Chemical formula)II69, (Chemical formula)II70, (Chemical formula)II71, (Chemical formula)II72, (Chemical formula)II73, (Chemical formula)III01, (Chemical formula)III02, (Chemical formula)III03, (Chemical formula)III04, (Chemical formula)III05, (Chemical formula)III06, (Chemical formula)III07, (Chemical formula)III08, (Chemical formula)III09, (Chemical formula)III10, (Chemical formula)III11, (Chemical formula)III12, (Chemical formula)III13, (Chemical formula)III14, (Chemical formula)III15, (Chemical formula)III16, (Chemical formula)III17, (Chemical formula)III18, (Chemical formula)III19, (Chemical formula)III20, (Chemical formula)III21, (Chemical formula)III22, (Chemical formula)III23, (Chemical formula)III24, (Chemical formula)III25, (Chemical formula)III26, (Chemical formula)III27, (Chemical formula)III28, (Chemical formula)III29, (Chemical formula)III30, (Chemical formula)III31, (Chemical formula)III32, (Chemical formula)III33, (Chemical formula)III34, (Chemical formula)III35, (Chemical formula)III36, (Chemical formula)III37, (Chemical formula)III38, (Chemical formula)III39, (Chemical formula)III40, (Chemical formula)III41, (Chemical formula)III42, (Chemical formula)III43, (Chemical formula)III44, (Chemical formula)III45, (Chemical formula)III46, (Chemical formula)III47, (Chemical formula)III48, (Chemical formula)III49, (Chemical formula)III50, (Chemical formula)III51, (Chemical formula)III52, (Chemical formula)III53, (Chemical formula)III54, (Chemical formula)III55, (Chemical formula)III56, (Chemical formula)III57, (Chemical formula)III58, (Chemical formula)III59, (Chemical formula)III60, (Chemical formula)III61, (Chemical formula)III62, (Chemical formula)III63, (Chemical formula)III64, (Chemical formula)III65, (Chemical formula)III66, (Chemical formula)III67, (Chemical formula)III68, (Chemical formula)III69, (Chemical formula)III70, (Chemical formula)III71, (Chemical formula)IV01, (Chemical formula)IV02, (Chemical formula)IV03, (Chemical formula)IV04, (Chemical formula)IV05, (Chemical formula)IV06, (Chemical formula)IV07, (Chemical formula)IV08, (Chemical formula)IV09, (Chemical formula)IV10, (Chemical formula)IV11, (Chemical formula)IV12, (Chemical formula)IV13, (Chemical formula)IV14, (Chemical formula)IV15, (Chemical formula)IV16, (Chemical formula)IV17, (Chemical formula)IV18, (Chemical formula)IV19, (Chemical formula)IV20, (Chemical formula)IV21, (Chemical formula)IV22, (Chemical formula)IV23, (Chemical formula)IV24, (Chemical formula)IV25, (Chemical formula)IV26, (Chemical formula)IV27, (Chemical formula)IV28, (Chemical formula)IV29, (Chemical formula)IV30, (Chemical formula)IV31, (Chemical formula)IV32, (Chemical formula)IV33, (Chemical formula)IV34, (Chemical formula)IV35, (Chemical formula)IV36, (Chemical formula)IV37, (Chemical formula)IV38, (Chemical formula)IV39, (Chemical formula)IV40, (Chemical formula)IV41, (Chemical formula)IV42, (Chemical formula)IV43, (Chemical formula)IV44, (Chemical formula)IV45, (Chemical formula)IV46, (Chemical formula)IV47, (Chemical formula)IV48, (Chemical formula)IV49, (Chemical formula)IV50, (Chemical formula)IV51, (Chemical formula)IV52, (Chemical formula)IV53, (Chemical formula)IV54, (Chemical formula)IV55, (Chemical formula)IV56, (Chemical formula)IV57, (Chemical formula)IV58, (Chemical formula)IV59, (Chemical formula)IV60, (Chemical formula)IV61, (Chemical formula)IV62, (Chemical formula)IV63, (Chemical formula)IV64, (Chemical formula)IV65, (Chemical formula)IV66, (Chemical formula)IV67, (Chemical formula)IV68, (Chemical formula)IV69, (Chemical formula)IV70, (Chemical formula)IV71, (Chemical formula)V01, (Chemical formula)V02, (Chemical formula)V03, (Chemical formula)V04, (Chemical formula)V05, (Chemical formula)V06, (Chemical formula)V07, (Chemical formula)V08, (Chemical formula)V09, (Chemical formula)V10, (Chemical formula)V11, (Chemical formula)V12, (Chemical formula)V13, (Chemical formula)V14, (Chemical formula)V15, (Chemical formula)V16, (Chemical formula)V17, (Chemical formula)V18, (Chemical formula)V19, (Chemical formula)V20, (Chemical formula)V21, (Chemical formula)V22, (Chemical formula)V23, (chemical formula)V24, (chemical formula)V25, (chemical formula)V26, (chemical formula)V27, (chemical formula)V28, (chemical formula)V29, (chemical formula)V30, (chemical formula)V31, (chemical formula)V32, (chemical formula)V33, (chemical formula)V34, (chemical formula)V35, (chemical formula)V36, (chemical formula)V37, (chemical formula)V38, (chemical formula)V39, (chemical formula)V40, (chemical formula)V41, (chemical formula)V42, (chemical formula)V43, (chemical formula)V44, (chemical formula)V45, (chemical formula)V46, (chemical formula)V47, (chemical formula)V48, (chemical formula)V49, (chemical formula)V50, (chemical formula)V51, (chemical formula)V52, (chemical formula)V53, (Chemical formula)V54, (Chemical formula)V55, (Chemical formula)V56, (Chemical formula)V57, (Chemical formula)V58, (Chemical formula)V59, (Chemical formula)V60, (Chemical formula)V61, (Chemical formula)V62, (Chemical formula)V63, (Chemical formula)V64, (Chemical formula)V65, (Chemical formula)V66, (Chemical formula)V67, (Chemical formula)V68, (Chemical formula)V69, (Chemical formula)V70, (Chemical formula)V71, (Chemical formula)VI01, (Chemical formula)VI02, (Chemical formula)VI03, (Chemical formula)VI04, (Chemical formula)VI05, (Chemical formula)VI06, (Chemical formula)VI07, (Chemical formula)VI08, (Chemical formula)VI09, (Chemical formula)VI10, (Chemical formula)VI11, (Chemical formula)VI12, (Chemical formula)VI13, (Chemical formula)VI14, (Chemical formula)VI15, (Chemical formula)VI16, (Chemical formula)VII01, (Chemical formula)VII02, (Chemical formula)VII03, (Chemical formula)VII04, (Chemical formula)VII05, (Chemical formula)VII06, (Chemical formula)VII07, (Chemical formula)VII08, (Chemical formula)VII09, (Chemical formula)VII10, (Chemical formula)VII11, (Chemical formula)VII12, (Chemical formula)VII13, (Chemical formula)VII14, (Chemical formula)VII15, (Chemical formula)VII16, (Chemical formula)VII17, (Chemical formula)VII18, (Chemical formula)VII19, (Chemical formula)VII20, (Chemical formula)VII21, (Chemical formula)VII22, (Chemical formula)VII23, (Chemical formula)VII24, (Chemical formula)VII25, (Chemical formula)VII26, (Chemical formula)VII27, (Chemical formula)VII28, (Chemical formula)VII29, (Chemical formula)VII30, (Chemical formula)VII31, (Chemical formula)VII32, (Chemical formula)VII33, (Chemical formula)VII34, (Chemical formula)VII35, (Chemical formula)VII36, (Chemical formula)VII37, (Chemical formula)VII38, (Chemical formula)VII39, (Chemical formula)VII40, (Chemical formula)VII41, (Chemical formula)VII42, (Chemical formula)VII43, (Chemical formula)VII44, (Chemical formula)VII45, (Chemical formula)VII46, (Chemical formula)VII47, (Chemical formula)VII48, (Chemical formula)VII49, (Chemical formula)VII50, (Chemical formula)VII51, (Chemical formula)VII52, (Chemical formula)VII53, (Chemical formula)VII54, (Chemical formula)VII55, (Chemical formula)VII56, (Chemical formula)VII57, (Chemical formula)VII58, (Chemical formula)VII59, (Chemical formula)VII60, (Chemical formula)VII61, (Chemical formula)VII62, (Chemical formula)VII63, (Chemical formula)VII64, (Chemical formula)VII65, (Chemical formula)VII66, (Chemical formula)VII67, (Chemical formula)VII68, (Chemical formula)VII69, (Chemical formula)VII70, (Chemical formula)VII71, (Chemical formula)VII72, (Chemical formula)VII73, (Chemical formula)VII74, (Chemical formula)VII75, (Chemical formula)VII76, (Chemical formula)VII77, (chemical formula)VII78, (chemical formula)VII79, (chemical formula)VII80, (chemical formula)VII81, (chemical formula)VII82, or pharmaceutically acceptable salts, hydrates or hydrated salts thereof, or any polymorphic crystal structures of these compounds or any isotopes, optical isomers, racemates, diastereomers or enantiomers thereof, wherein R20 is a linear or branched alkyl, heteroalkyl or acyl HC1C8 (C(O)R17)C2C8 alkenyl, alkynyl, alkylcycloalkyl, linear or branched heterocycloalkyl C3C8 linear or branched aryl, Aralkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroarylcarbonate. (C(O)OR17), carbamate (C(O)NR17R18) or 18 carbon atoms of a carboxylate, ester, ether or amide or 1~8 amino acids or polyethylene oxy units with the formula (OCH2CH2)p or (OCH2CH(CH3))p where p is an integer from 0 to approximately 1000 or R20 is absent and oxygen forms a ketone or a combination of the above where R21 is H,C1C8. The linear or branched alkyl groups X,X1,X2 and X3 are independent of each other, namely O,S,NH,NHNH, NHR17,CH2 or none of them are P1, namely H,R17,P(O)(OH)2,P(O)(X1R17)2,CH2P(O)(OH)2,S(O2)(X1R17), C6H12O5(glycoside),(CH2CH2O)PR17 where p is chosen from 0100 and R17 is already defined. The above also X1P1 can exist (together as H), where Z3 and Z3 independently are H, OH, NH2, OR17, NHR17, COOH, COOR17, C(O) R17, C(O) NHR17, C(O) NHNHR17, C(O) NH2, R18, OCH2 OP(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(C4C12 glycosides), C1C8 of linear or branched alkyl or heteroalkyl C2C8. Of alkenyl, alkynyl, alkylcycloalkyl, linear or branched heterocycloalkyl C3C8 linear or branched aryl, Aralkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroarylcarbonate(C(O)OR17), carbamate(C(O)NR17R18)R17andR18 independently are H,C1C8alkyl or heteroalkyl linear or branched C2C8 of alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl. Linear or branched C3C8 Linear or branched aryl,Ar alkyl,heterocyclic,carbocyclic,cycloalkyl,heteroalkylcycloalkyl,alkylcarbonyl,heteroalkyl carbonate(C(O)OR17),carbamate(C(O)NR17R18)R19isH,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 carboxylateC2~C8alkenyl,alkynyl,alkylcycloalkyl,heterocycloalkylC3~C8 Aryl or alkyl carbonyl or pharmaceutical salt X is O,S,NH,NHNH,NHR17 or CH2 R7 is designated in the same way as above, where "(symbol)" is the position linked to the L linker. 9. A conjugate of the tubulysin analogue of claim 1 having the following structure: (chemical formula) (chemical formula)C481, (chemical formula)C495, (chemical formula)C528, (chemical formula)C629, (chemical formula)C633, (chemical formula)C641, (chemical formula)C645, (chemical formula)C649, (chemical formula)C654, (chemical formula)C659, (chemical formula)C663, (chemical formula)C673, (chemical formula)C709, (chemical formula)C712, (chemical formula)C166a, (chemical formula)C719, wherein the mAb is a cell-binding agent, preferably an antibody, n is 1~20, p is 0~100. 10. The conjugate of the tubulysin analogue of claim 9 is made up of the following structures: (chemical formula) 130 (chemical formula) 132 (chemical formula) 166 (chemical formula) 168 (chemical formula) 170 (chemical formula) 172 (chemical formula) 174 (chemical formula) 176 (chemical formula) 185 (chemical formula) 195 (chemical formula) 197 (chemical formula) 199 (chemical formula) 201 (chemical formula) 214 (chemical formula) 216 (chemical formula) 266,R'=HEt267,R'=Me2268,R'=HiPr (chemical formula) 275,R'=HEt276,R'=Me2277,R'=HiPr (chemical formula) 286 (chemical formula) 288 (chemical formula) 296 (chemical formula). 334 (chemical formula) 481 (chemical formula) 495 (chemical formula) 528 (chemical formula) 541 (chemical formula) 628 (chemical formula) 629 (chemical formula) 632 (chemical formula) 633 (chemical formula) 641 (chemical formula) 644 (chemical formula) 645 (chemical formula) 648 (chemical formula) 649 (chemical formula) 653 (chemical formula) 654 (chemical formula) 658 (chemical formula) 659 (chemical formula) 662 (chemical formula) 663 (chemical formula) 673 (chemical formula) 709 (chemical formula) 712 (chemical formula) 166a (chemical formula) 719 11. The cell-binding agent according to claims 1, 2, 3, 4, 5, 6, 7 or 9, any one of which may be a protein scaffold molecule based on Ig selected from a nanobody (a derivative of VHH (camel Ig)), a domain antibody (dAb, a derivative of the VH or VL domain), a cell-engaging bispecific (BiTE, bispecific diabody), a bispecific antibody, a trispecific antibody, a dual affinity targeting (DART, bispecific diabody), a tetravalent tandem antibody (TandAb, a dimerized bispecific diabody), a bipartite antibody, a non-Ig protein scaffold molecule selected from anticalin (a derivative of lipocalin), adenectin (FN310 (fibronectin)), a protein containing a designed ancrine repeat unit. (DARPin)(ancrine repeating protein derivative(AR)),DARPinC9,DARPinEc4 and DARPinE69_LZ3_E01,Avimer(low density lipoprotein receptor A domain (LDL)) small molecules themselves or small molecules coated on proteins, nanoparticles, polymers, micelles or lipids with the following LB01~LB54 structures: (chemical formula)LB01(folate derivative), (chemical formula)LB02(PMSA ligand derivative), (chemical formula)LB03(PMSA ligand derivative), (chemical formula)LB04(PMSA ligand), (chemical formula)LB05(somatostatin), (chemical formula)LB06(somatostatin), (chemical formula)LB07(octreotide, somatosstatin analog) (chemical formula)LB08(lanreotide, somatosstatin analog), (chemical formula)LB09(vapreotide(Sanvar), somatose Tatin analog), (chemical formula) LB10(CAIX ligand), (chemical formula) LB11(CAIX ligand), (chemical formula) LB12(gastrin-releasing peptide receptor(GRPr),MBA), (chemical formula) LB13(luteinizing hormone-releasing hormone(LHRH)and(GnRH)ligand), (chemical formula) LB14(luteinizing hormone-releasing hormone(LHRH)and(GnRH)ligand), (chemical formula) LB15(GnRH antagonist,abarylix), (chemical formula) R19 is 5'deoxyadenosyl,Me, OH,CNLB16(cobalamin,vitamin B12 analog), (chemical formula) R19 is 5'deoxyadenosyl,Me,OH,CNLB17(cobalamin,vitamin B12 analog), (chemical formula) LB18(for alpha v beta 3 integrin receptor, cyclic RGD pentapeptide), (chemical formula) LB19(heterobivalent peptide ligand conjugate for VEGF receptor), (chemical formula) LB20(neuromedin B), LB21(bombecin conjugate for G protein-coupled receptor), (chemical formula) LB22(TLR2 conjugate for TLR2 receptor. Toll-like), (chemical formula)LB23(androgen receptor), (chemical formula)LB24(silengitide/cyclo(RGDfV) derivative for alpha v integrin receptor) (chemical formula)LB25(rifabutin analog), (chemical formula)LB26(rifabutin analog), (chemical formula)LB27(rifabutin analog), (chemical formula)LB28(fludrocortisone), (chemical formula)LB29(dexamethasone), (chemical formula)LB30(fluticasone propionate), (chemical formula)LB31(beclomethasone dipropionate), (chemical formula)LB32(triamcinolone acetonide), (chemical formula)LB33(prednisone), (chemical formula)LB34(pradnisolone), (chemical formula)LB35(methylprednisolone), (Chemical formula)LB36(Betamethasone), (Chemical formula)LB37(Irinotecan analog), (Chemical formula)LB38(Crizotinib analog), (Chemical formula)LB39(Bortezomib analog)whereY5,is N,CH,C(CI),C(CH3)orC(COOR1)R1isH,C1C6alkyl,C3C8Ar (Chemical formula)LB40(carfizomib analog), (Chemical formula)LB41(carfizomib analog), (Chemical formula)LB42(leuprolide analog), (Chemical formula)LB43(triptorelin analog), (Chemical formula)LB44(clindamycin), (Chemical formula)LB45(liraglutide analog), (Chemical formula)LB46(semaglutide analog), (Chemical formula)LB47(retapamulin analog), (Chemical formula)LB48(indibulin analog), (Chemical formula)LB49(vinblastine analog), (Chemical formula)LB50(lixisenatide analog), (Chemical formula)LB51(osimertinib analog), (Chemical formula)LB52(nucleoside analog), (Chemical formula)LB53(erlotinib analog), (Chemical formula)LB54(lapatinib analog) where “(symbol)” is the position of the linker L of this patent X4 and Y1 independently, namely 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(R,) C(O)N(R1), CH2, C(O)NHNHC(O) and C(O)NR1 X1 is H, CH2, OH, O, C(O), C(O)NH, C(O)N(R1), R1, NHR1, NR1, C(O)R1 or C(O) OX5 is H, CH3, F or Cl M1 and M2 independently, namely H, Na, K, Ca, Mg, NH4, N(R1R1'R2R3) R1, R1', R2 and R3 are determined in formula (I) according to claim 1. 12. A conjugate of a tubulysin analogue containing any of claims 1, 2, 3, 4, 5, 6, 7 or 9, wherein the binding agent can be targeted against tumor cells, virus-infected cells, microbial-infected cells, parasite-infected cells, autoimmune disease cells, activated tumor cells, myeloid cells, activated T cells, affected B cells. or any melanocyte or cell expressing any of the following antigens or receptors: CD2,CD2R,CD3,CD3gd,CD3e,CD4,CD5,CD6,CD7,CD8,CD8a,CD8b,CD9,CD10, CD11a,CD11b,CD11c,CD12,CD12w,CD13,CD14,CD15,CD15s,CD15u,CD16,CD16a, CD16b,CD17,CDW17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27, CD28,CD29,CD30,CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40, CD41,CD42,CD42a,CD42b,CD42c,CD42d,CD43,CD44,CD44R,CD45,CD45RA, CD45RB,CD45RO,CD46,CD47,CD47R,CD48,CD49a,CD49b,CD49c,CD49e,CD49f, CD50,CD51,CD52,CD53,CD54,CD55,CD56,CD57,CD58,CD59,CD60,CD60a,CD60b, CD60c,CD61,CD62E,CD62L,CD62P,CD63,CD64,CD65,CD65s,CD66,CD66a,CD66b, CD66c,CD66d,CD66e,CD66f,CD67,CD68,CD69,CD70,CD71,CD72,CD73,CD74,CD74, CD75,CD75s,CD76,CD77,CD78,CD79,CD79a,CD79b,CD80,CD81,CD82,CD83,CD84, CDw84,CD85,CD86,CD87,CD88,CD89,CD90,CD91,CD92,CDw92,CD93,CD94,CD95, CD96,CD97,CD98,CD99,CD99R,CD100,CD101,CD102,CD103,CD104,CD105,CD106, CD107,CD107a,CD107b,CD108,CD109,CD110,CD111,CD112,CD113,CDw113,CD114, CD115,CD116,CD117,CD118,CD119,CDw119,CD120a,CD120b,CD121a,CD121b, CDw121b,CD122,CD123,CDw123,CD124,CD125,CDw125,CD126,CD127,CD128, CDW128,CD129,CD130,CD131,CDw131,CD132,CD133,CD134,CD135,CD136,CDw136, CD137,CDW137,CD138,CD139,CD140a,CD140b,CD141,CD142,CD143,CD144,CD145, CDw145,CD146,CD147,CD148,CD149,CD150,CD151,CD152,CD153,CD154,CD155, CD156a,CD156b,CDw156c,CD157,CD158a,CD158b,CD159a,CD159b,CD159c,CD160, CD161,CD162,CD162R,CD163,CD164,CD165,CD166,CD167,CD167a,CD168,CD169, CD170,CD171,CD172a,CD172b,CD172g,CD173,CD174,CD175,CD175s,CD176,CD177, CD178,CD179,CD180,CD181,CD182,CD183,CD184,CD185,CD186,CDw186,CD187, CD188,CD189,CD190,Cd191,CD192,CD193,CD194,CD195,CD196,CD197,CD198, CDw198,CD199,CDw199,CD200,CD200a,CD200b,CD201,CD202,CD202b,CD203, CD203c,CD204,CD205,CD206,CD207,CD208,CD209,CD210,CDw210,CD212,CD213a1, CD213a2,CDw217,CDw218a,CDw218b,CD220,CD221,CD222,CD223,CD224,CD225, CD226,CD227,CD228,CD229,CD230,CD231,CD232,CD233,CD234,CD235a,CD235ab, CD235b,CD236,CD236R,CD238,CD239,CD240,CD240CE,CD240D,CD241,CD242, CD243,CD244,CD245,CD246,CD247,CD248,CD249,CD252,CD253,CD254,CD256, CD257,CD258,CD261,CD262,CD263,CD265,CD266,CD267,CD268,CD269,CD271, CD273,CD274,CD275,CD276(B7H3),CD277,CD278,CD279,CD280,CD281,CD282, CD283,CD284,CD289,CD292,CDw293,CD294,CD295,CD296,CD297,CD298,CD299, CD300a,CD300c,CD300e,CD301,CD302,CD303,CD304,CD305,CD306,CD309,CD312, CD314,CD315,CD316,CD317,CD318,CD319,CD320,CD321,CD322,CD324,CDw325, CD326,CDw327,CDw328,CDw329,CD331,CD332,CD333,CD334,CD335,CD336,CD337, CDw338,CD339,CD340,CD341,CD342,CD343,CD344,CD345,CD346,CD347,CD348, CD349,CD350,CD351,CD352,CD353,CD354,CD355,CD356,CD357,CD358,CD359, CD360,CD361,CD362,CD363,CD364,CD365,CD366,CD367,CD368,CD369,CD370, CD371,CD372,CD373,CD374,CD375,CD376,CD377,CD378,CD379,CD381,CD382, CD383,CD384,CD385,CD386,CD387,CD388,CD389,CRIPTO,CRIPTO,CR,CR1,CRGF, CRIPTO,CXCR5,LY64,TDGF1,41BB,APO2,ASLG659,BMPR1B,41BB,5AC,5T4(Trophoblastic glycoprotein,TPBG,5T4,Activated Wnt inhibitory factor 1 or WAIF1),Adenocarcinoma antigen,AGS5,AGS22M6,Activin receptor like kinase 1,AFP,AKAP4,ALK,Alpha integrin,Alpha v beta 6,Aminopeptidase N,Amyloid beta,Androgen receptor,Angiopoietin 2,Angiopoietin 3,Annexin A1,Anthrax Toxin protective antigen, antitransferrin receptor, AOC3(VAP1), B7H3, Bacillus anthracis anthrax, BAFF(B cell activating factor), BCMA, B lymphoma cell, bcrabl, bombasin, BORIS, C5, C242 antigen, CA125(Carbohydrate antigen 125, MUC16), CAIX(or CAIX, carbonic anhydrase 9), CALLA, CanAg, Canis lupus familialis IL31, carbonic anhydrase IX, cardiac myosin, CCL11(CC motif chemokine 11), CCR4 (CC chemokine receptor type 4), CCR5, CD3E(epsilon), CEA(carcino embryonic antigen),CEACAM3,CEACAM5(carcinoembryonic antigen),CFD(factor D), Ch4D5,cholecystokinin2(CCK2R),CLDN18(cladin18),CLDN18.1(cladin18.1), CLDN18.2(cladin18.2),Clumping factor A,cMet,CRIPTO,FCSF1R(colony stimulating factor 1 receptor),CSF2(colony stimulating factor 2,granulocyte macrophage colony stimulating factor(GMCSF)),CSP4,CTLA4(toxic T lymphocyte-associated protein 4),CTAA16.88tumor antigen,CXCR4,CXC chemokine receptor type 4,cyclic ADP Ribose hydrolase, cyclin B1, CYP1B1, cytomegalovirus, cytomegalovirus glycoprotein B, dabigatran, DLL3(delta-like ligand 3), DLL4(delta-like ligand 4), DPP4(dipeptidyl peptidase 4), DR5(dereceptor 5), E.coli shiga toxin type 1, E.coli shiga toxin type 2, EDB, EGFL7(EGF7-like domain protein), EGFR, EGFRII, EGFRvIII, endoglin, endothelin B receptor, endotoxin, EpCAM(epithelial cell adhesion molecule), EphA2, episialin, ERBB2(epidermal growth factor receptor 2), ERBB3, ERG(TMPRSS2ETS fusion gene), Escherichiacoli, ETV6AML, FAP(fibroblast activation protein alpha), fibroblast surface antigen, FCGR1, alpha fetoprotein, fibrin II, beta chain, fibronectin extradomain B, FOLR(folate receptor), folate receptor alpha, folate hydrolase, Fos1F related antigen of respirator syncytial virus protein, Frizzle receptor, fucosyl GM1, GD2 ganglioside, G28(glyvolipid of cell surface antigen), GD3 idiotype, GloboH, glypican 3, N glycolyl neuraminic acid, GM3, GMCSF alpha chain receptor, growth differentiation factor, GP100, GPNMB(trans Membrane glycoprotein NMB),GUCY2C(guanylate cyclase 2C,guanylyl cyclase C(GCC), intestinal guanylate cyclase,guanylate cyclase C receptor,heat-stable enterotoxin receptor(hSTAR)),heat shock protein,haemagglutinin,hepatitis B virus surface antigen,hepatitis B virus,HER1(human epidermal growth factor receptor 1),HER2, HER2/neu,HER3(ERBB3),IgG4,HGF/SF(hepatocyte growth factor/scatter factor), HHGFR,HIV1,histone complex,HLADR(human leukocyte antigen),HLADR10, HLADRB,HMWMAA,human cholinergic gonadotropin,HNGF,scatter factor Human kinase receptor, HPVE6/E7, Hsp90, hTERT, ICAM1(cell adhesion molecule 1), idiotype, IGF1R(IGF1, insulin-like growth factor 1 receptor), IGHE, IFN gamma, influenza hemagglutinin, IgE, IgE Fc region, IGHE, interleukin(including IL1, IL2,IL3,IL4,IL5,IL6,IL6R,IL7,IL8,IL9,IL10,IL11,IL12,IL13,IL15,IL17, IL17A,IL18,IL19,IL20,IL21,IL22,IL23,IL27 or IL28), IL31RA, ILGF2(insulin Like growth factor 2), integrin (alpha 4, alpha IIb beta 3, alpha V beta 3, alpha 4 beta 7, alpha 5 beta 1, alpha 6 beta 4, alpha 7 beta 7, alpha 11 beta 3, alpha 5 beta 5, alpha v beta 5), interferon gamma-inducing protein, ITGA2, ITGB2, KIR2D, kappa Ig, LCK, Le, legumin, Lewis Y antigen, LFA1 (lymphocyte antigen-associated 1, CD11a), LHRH, LINGO1, lipoteichoic acid, LIV1A, LMP2, LTA, MADCT1, MADCT 2, MAGE1, MAGE2, MAGE3, MAGEA1, MAGEA3, MAGE4, MART1, MCP1, MIF (macrophage migration inhibitory factor or glycosylation inhibitory factor (GIF)),MS4A1(membrane spanning 4-domain superfamily A member 1),MSLN(mesothelin), MUC1(cell surface-associated mucin 1(MUC1) or polymorphic epithelial mucin(PEM)), MUC1KLH,MUC16(CA125),MCP1(monocyte chemotactic protein 1),MelanA/MART1, MLIAP,MPG,MS4A1(membrane spanning 4-domain superfamily A),MYCN,glycoprotein Associated with myelin, myostatin, NA17, NARP1, NCA90(granulocyte antigen), nectin4(ASG22ME), NGF, neural cell apoptosis-regulated protease1, NOGOA, Notch receptor, nucleolin, neuro oncogene product, NYBR1, NYESO1, OX 40, OxLDL(oxidized low density lipoprotein), OYTES1, P21, p53 nonmutant, P97, PAGE4, PAP, paratope of anti(N-glycolyl neuraminic acid), PAX3, PAX5, PCSK9, PDCD1(PD1, programmed cell death protein1), PDGFRalpha(platelet-derived growth factor receptor alpha), PDGFRbeta, PDL1, PLAC1, PLAPliketicular alkaline phosphatase ,Platelet-derived growth factor receptor beta,Sodium phosphate cotransporter,PMEL17,Polysialic acid,Protease 3(PR1),Prostate carcinoma,PS(Phosphatidyl serine),Prostate carcinoma cells,Pseudomonas aeruginosa,PSMA,PSA,PSCA,Rabies virus glycoprotein,RHD(Rh polypeptide 1(RhPI)),Rhesus factor,RANKL,RhoC,Ras mutant,RGS5,ROBO4,Restorative syncytial virus,RON,ROR1,Sarcoma translocation point,SART3,Sclerostin,SLAMF7(SLAM family member 7),Selectin P,SDC1(Syndecan 1),sLe(a),Somatomedin C,SIP(Sphingosine 1 phosphate), somatostatin, sperm protein 17, SSX2, STEAP1(transmembrane epithelial antigen six of the prostate gland 1), STEAP2, STn, TAG72(tumor-associated glycoprotein 72), survivin, T cell receptor, T cell transmembrane protein, TEM1(tumor endothelial marker 1), TENB2, tenassin C(TNC), TGF alpha, TGF beta(transforming growth factor beta), TGF beta1, TGF beta2(transforming growth factor beta2), Tie (CD202b), Tie2, TIM1(CDX014), Tn, TNF, TNF alpha, TNFRSF8, TNFRSF10B(tumor necrosis factor receptor superfamily member 10B), TNFRSF13B(tumor necrosis factor receptor superfamily member 13B), TPBG(tophoblast glycoprotein), TRAILR1(tumor necrosis-inducing receptor ligand 1), TRAILR2(dereceptor 5 (DR5)), tumor-associated calcium transmitter 2, tumor-specific glycosylation of MUC1, TWEAK receptor, TYRP1(glycoprotein 75), TRP1(Trop1), TRP2 (Trop2), tyrosinase, VCAM1, VEGF, VEGFA, VEGF2, VEGFR1, VEGFR2 or vimentin, WT1, XAGE1 or cells expressing any insulin growth factor receptor or any epidermal growth factor receptor. 13. The tumor cells of claim 12 are selected from a group consisting of lymphoma cells, myeloma cells, renal cell tissue cells, breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cell carcinoma cells, small cell lung cancer cells, non-small cell lung cancer cells, testicular cancer cells, malignant cells, or any cell that grows and divides at an accelerated and uncontrolled rate causing cancer. 14. A pharmaceutical composition comprising a therapeutically effective amount of the conjugated compounds of any one of claims 1, 2, 3, 4, 5, 6, 7 or 9 and a pharmaceutically acceptable salt, carrier, diluent or excipient thereof or a combination thereof for the treatment and prevention of cancer or autoimmune or infectious diseases. 15. The pharmaceutical composition of claim 1, more specifically: the conjugate having the formulae (I), (II), (III), (IV), (V), (VI) or (VII) may consist of 1%95% by weight as a plurality of gradients in the formulae, 0.0%15.0% of polyols, 0.0%0.5% of one or more surfactants, 0.0%10% of one or more amino acids, 0.0%~5% of preservatives and 0.0%~10% of buffer salt for pH adjustment4.58.5 conjugate with formula(I),(II),(III),(IV), (V),(VI)or(VII)may consist of1%95% by weight as most of the gradient in the formula, 0.0% 15. 0% of polyol, 0.0%, 0.5% of one or more surfactants, 0.0%, 10% of one or more amino acids, 0.0% ~ 5% of preservatives and 0.0% ~ 10% of salts, buffer for pH adjustment to 4.58.5 and 0.0%30.0% of one or more isotonic agents for the measurement of osmotic pressure between approximately 250 and 350mOsm after reconstitution, for administration to patients. wherein 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 metal salts), wherein the surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 65, polysorbate 80, polysorbate 81 or polysorbate 85, poloxamer, poly(ethylene oxide). Poly(propylene oxide), polyethylene polypropylene, tritium 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, myristamido propyl, palmidopropyl or isostearamidopropyl betaine (lauroamidopropyl) myris tamidopropyl, palmidopropyl or isostearamidopropyl dimethylamine sodium methyl Cocoyl or disodium methyl oleyl torate, dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine and cocoamfoglycinate or isostearyl ethyl imidonium ethosulfate, polyethyl glycol, polypropyl glycol and copolymers of ethylene and propylene glycol, wherein the preservative is selected from benzyl alcohol, octadecyl dimethyl benzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol or m-cresol. Wherein the amino acids are selected from arginine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid or aspartic acid Wherein the buffer salt is selected from sodium, potassium, ammonium or trihydroxyethyl amino salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or trisodium phthalate or tromethamine hydrochloride, phosphate or sulfate of arginine, glycine, glycylglycine or histidine with anionic salts of acetate, chloride, phosphate, sulfate or succinate Wherein the tonicity agent is selected from mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate or sodium chloride 16. The pharmaceutical composition of claim 1, furthermore, is as follows: the conjugate having formula (I),(II),(III),(IV),(V),(VI) or (VII) may comprise 10%~85% by weight as a plurality of gradients in the formulation, 0.0%~10.0% of a polyol selected from sucrose or trehalose, 0.1%~0.25% of a surfactant selected from polysorbate 20 or polysorbate 80, 0.0%~8.0% of one or more amino acids selected from arginine, histidine, ornithine, glycine or alanine, 0.0%~5% of a preservative selected from benzyl alcohol and 1%~10% of a buffer salt selected from sodium citrate or citric acid monohydrate for pH adjustment to 5.0~6.5. 17. The pharmaceutical composition of claims 1, 15 or 16, contained in a vial, bottle, pre-filled syringe or automatic injection syringe containing the pre-filled syringe in a lyophilized liquid or solid form. 18. Any conjugate of claims 1, 2, 3, 4, 5, 6, 7, 9, 15, or 16, which has in vitro, in vivo, or ex vivo cell-killing activity. 19. The pharmaceutical composition of claims 1, 2, 3, 4, 5, 6, 7, 9, 15 or 16, administered together with an adjuvant selected from a chemotherapeutic agent, radiation therapy, immunotherapy, autoimmune agent, anti-infective agent or other conjugate for the synergistic treatment or prevention of cancer or autoimmune or infectious diseases. 20. The synergistic agent of claim 19 is selected from one or more of the following: (1). A chemotherapeutic agent selected from the group consisting of: a). An alkylating agent: selected from the group consisting of nitrogen mustards: chlorambucil, chlornafaxine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melplanin, mitolactol, pipobran, novembin, fenasterine, prednimustine, thiotepa, trophosphamide, uracil mustard CC1065 and adozelen, carzelen, biselen or their synthetic analogs, duocarmycin and their synthetic analogs. ,KW2189,CBITMI or CBI Benzodiazepine dimer or pyrrobenzodiazepine (PBD) dimer, tomamycin dimer, indolinobenzodiazepine dimer, imidazo benzothiadiazepine dimer or oxazolidone Benzodiazepine dimer Nitrosoureas: comprising carmustine, lomustine, chlorozotocin, fotimustine, nimustine, ranimustine Alkyl sulfonates: comprising bullosulfan, triosulfan, imposulfan and pipesulfan) Triazine or dacarbazine Platinum-containing compounds: comprising carboplatin, cisplatin and oxaliplatin Aziridine, benzodopa, carbocuone, methuredopa or uredopaethylenimine and methylamelamine including altertamine, triethylenemelamine, triethyl phosphoramide, triethylenethiophosphoramide and trimethylolomelamamine] b). Plant alkaloids: selected from the group consisting of vinca alkaloids: comprising vincristine, vinblastine, vindicinine, vinorelbine and navelbintaxoids: comprising paclitaxel, docetaxel and their analogues, maytansinoids comprising DM1,DM2,DM3,DM4,DM5,DM6,DM7, maytansine, ansamitosin and their analogues, cryptophysin (including the group consisting of cryptophysin 1 and Cryptophysin 8) epothilone, eleuthromycin, discodermolide, bryostatin, dolostatin, orlistatin, tubulisin, cephalosstatin pancratitisstatin sarcodic thyinspongistatin c). DNA topoisomerases inhibitors: selected from the group of epipodophilins: comprising 9-aminocamptothecin, camptothecin, chrysnatale, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novontrone, retinoic acid (or retinol), teniposide, topotecan, 9-nitrocamptothecin or RFS2000 and mitomycin and their analogues d). Anti-metabolic agents: selected from the group comprising {[antifolate:(substances DHFR inhibitors: consisting of methotrexate, trimetexate, denopterin, pteropterin, aminopterin (4-aminopteroic acid) or folic acid analogs) IMP dehydrogenase inhibitors: ( consisting of mycophenolic acid, thiazofurin, ribavirin, EICAR) Ribonucleotide reductase inhibitors: ( consisting of hydroxyurea, defferosamine)] [Pyrimidine analogs: Uracil analogs: ( consisting of ancetabine, azacitidine, 6-azauridine, capecitabine (Zeloda), carmopher, cytarabine, dideoxyuridine, doxyfluridine, inocitabine, 5-fluorouracil, floxuridine, ratitrexade (Tomudex)) Analogs of Cytosine: (including cytarabine, cytosine arabinoside, fludarabine) Purine analogues: (including azathiophrine, fludarabine, mercaptopurine, thiaminprene, thioguanine) Folic acid supplement, folinic acid} e). Hormone therapy: selected from a group consisting of {receptor antagonists: [anti-estrogen agents: (including megestrol, raloxifene, tamoxifen) LHRH agonists: (including goxyrelin, leuprolide acetate) Antiandrogen agents: (including Consisting of bicalutamide, flutamide, calisterone, dromostanolone propionate, epitiostanol, goxyrelin, leuprolide, mepitiostane, nilutamide, testolactone, trilostane and other androgen inhibitors)] Retinoids/deltoids:[Vitamin D3 analogues: (containing CB1093, EB1089KH1060, cholecalciferol, ergocalciferol) Photodynamic therapy: (containing verteporfin, phthalocyanine, photosensitivity Pc4, Demethoxyhypocrellin A) Cytokines: (including interferon alpha, interferon gamma, Tumor necrosis factor (TNF), Human TNF domain protein)]} f).A Kinase inhibitors selected from the group consisting of BIBW2992 (anti-EGFR/Erb2), Imatinib, Gefitinib, Pgabtanib, Sorafenib, Dasatinib, Sunitinib, Erlotinib, Nilotinib, Lapatinib, Axitinib, Pazopanib, Vanditanib, E7080 (anti-VEGFR2), Mubritinib, Ponatinib (AP24534), Bafitinib (INNO406), Bosutinib (SKI606), Cabozantinib. , vismodekib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, ispinesib g). Poly(ADP ribose) polymerase (PARP) inhibitors selected from the group that includes olaparib, niraparib, iniparib, talazoparib, viliparib, CEP9722(Cephalon's), E7016(Eisai's), BGB290(BeiGene's) or 3-aminobenzamide h). Antibiotics selected from the group that includes indiene antibiotics(indiene Selected from the group consisting of calikimicin, calikimicin gamma 1, delta 1, alpha 1 or beta 1 dyneimicin including dyneimicin A and deoxydyneimicin esperamicin, kedaracidin, C1027, maduropeptin or neocarcinostatin chromophores and related chromoprotein indium antibiotic chromophores), alacinomycin, actinomycin, anthramycin, azazerine, bleomycin, cactinomycin, carabicin, carminomycin, carcinophilin chromomycin, dactinomycin, daunorubicin, detorubicin, 6 diazo5 oxo-L-norleucine, doxorubicin, morpholino doxorubicin, cyanomorpholino doxorubicin, 2 pyrrololinodoxorubicin and deoxy Doxorubicin, Epirubicin, Eribulin, Isorubicin, Idarubicin, Marcellomycin, Nitomycin, Mycophenolic Acid, Nocalamycin, Olivomycin, Peplomycin, Potfiromycin, Puromycin, Culamycin, Rhodorubicin, Streptonicrin, Streptozocin, Tubercidin, Ubenimex, Sinostatin, Sorubicin i). Polyketides (acetogenin), tullatacin and bullatacinone gemcitabine, epoxomicin and carfilzomib, bortezomib, thalidomide, lenalidomide, pomalidomide, toxidostat, cybristat, PLX4032, STA9090, stimuvax, allovectin 7, CGVA, Provengie, Yervoy, isoprenylation inhibitors and lovastatin, dopaminergic neurotoxins and 1-methyl-4-phenyl pyridinium ion, cell cycle inhibitors (selected from staurosporine), actinomycin (including actinomycin D, dactinomycin), amanitin, bleomycin (including bleomycin A2, bleomycin B2, peplomycin), anthracyclines (including Daunorubicin, Doxorubicin (Adriamycin), Idarubicin, Epirubicin, Pyrarubicin, Sorubicin, Mitoxantrone, MDR Inhibitors or Verapamil, Ca2+ATPase Inhibitors or Tapsigargin, Histone Deacetylase Inhibitors (including Vorinostat, Romidepsin, Panobinostat, Valproic Acid, Mositinostat (MGCD0103), Bilinostat, PCI24781, Entinostat, SB939, Resminostat, Givinostat, AR42, CUDC101, Sulforaphane, Tricostatin A), Tapsigargin, Celecoxib, Glytazone, Epigallocatechin Gallate, Disulfiram, Salino Sporamide A antiadrenal selected from the group consisting of aminoglutethimide, mitotane, trilostane azeglatone aldophosphamide glycoside aminolevulinic acid amsacrine arabinoside bestrabic acid bisanthrene edatracene defofamine demochlorinated diazecuone eflornithine (DFMO), elfomitine elliptinium acetate, etoglucid gallium nitrate gas cytosine, hydroxyurea ibandronate, lentinan lonidamine mitoguanine mitoxantrone mopidamol nitracrine pentostatin phenamate pyararubicin podophyllinic acid 2 ethyl hydrazide procarbazine PSKRegistered Trademark razoxan risoxin xizofiran Spirogermanium, tenosonic acid, triacecuone, 2,2’,2”trichlorotriethylamine, trichlorthecenes (including the group consisting of T2 toxin, verrucarin A, rhoridin A and anguidine), urethane, siRNA, antisense drugs. (2). Autoimmune agents: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids (including those containing amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, flucortolone danazol, dexamethasone, triamcinolone acetonide, beclomethasone dipropionate), DHEA, etanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate, prednisone, xylolimus, tacrolimus. (3) Anti-infective agents comprising: a). Aminoglycosides: amikacin, astromycin, gentamicin (netilmicin, sisomicin, izepamicin), hygromycin B, kanamycin (amikacin, arbekacin, bekanamycin, dibigacin, tobramycin), neomycin (framycinetin, paromomycin, ribostamcin), netilmicin, spectinomycin, streptomycin, tobramycin, verdamicin b). Amphenicols: azidamphenicol, chloramphenicol, florphenicol, thiamphenicol c). Ansamycins: geldanamycin, herbimycin d). Carbapenems: biapenem, doripenem, ertapenem, imipenem/cilasatin, meropenem, panipenem e).Cefem: Carbacefem (Loracarebev), Cefacetrile, Cefaclor, Cefadroxil, Cephalonium, Cefaloridine, Cefalotin or Cefalotin, Cefalexin, Cefaloglycin, Cefamandole, Cefapirin, Cefatrizine, Cefazafler, Cefoxidine, Cefazolin, Cebupirazone, Cefacapine, Cefadaloxime, Cefepime, Ceminox, Cefoxitin, Ceprozil, Cefrosadine, Ceftizole, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefepime, Cefetamate, Cefodisime, Cefonizid, Cefopyrazine, Cefotaxime, Cefotazime, Cefosopran, cephalexin, cefpimazole, cefpiramide, cefiroze, cefpodoxime, cefprozil, cefquinome, cefsullodin, ceftazidime, ceftirame, ceftioline, ceftizoxime, ceftioline, ceftazidime, ceftazidime, ceftiozone, ceftazidime, cefzonam, cefamycins (cefoxitin, cefotitan, ceftazole), oxocefem (flomocef, latamocef) f). Glycopeptides: bleomycin, vancomycin (orithavancin, telavancin), teicoplanin (dalbavancin), ramoplanin g). Glykylcyclines: tigecycline h). Beta-lactamase inhibitors: penam (sulbactam, tazobactam), clavam (clavulanic acid) i). Lincosamides: clindamycin, lincomycin j). Lipopeptides: daptomycin, A54145, calcium-dependent antibiotic (CDA) k). Macrolides: azithromycin, zythromycin, clarithromycin, kiritomycin, erythromycin, flurithromycin, josamycin, ketolides (telithromycin, zythromycin), midicamycin, myokamycin, oleandomycin, rifamycins (rifampicin, rifampin, rifabutin, rifapentine), rokitamine, roxithromycin, spectinomycin, spiramycin, tacrolimus (FK506), troleandomycin, telithromycin l). Monobactams: aztreonum, tigemonum m). Oxazolidinone: linezolid n). Penicillin: amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, azidocillin, azolcillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, clomiphenetocillin, procaine benzyl penicillin, carbenicillin (carindacillin), clozacillin, diclozacillin, epicillin, flucloxacillin, mecillinum (pibmecillinum), mezlocillin, methicillin, nafcillin, oxacillin ,penamecillin,penicillin,pheneticillin,phenoxymethylpenicillin,piperacillin,propicillin,sulfenicillin,timocillin,ticarcillin o).Polypeptide:bacitracin,colistin,polymyxin B p). Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxin, garinofloxacin, gatifloxacin, gemifloxacin, grapafloxacin, canotrovafloxacin, levofloxacin, lomifloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pifloxacin, trovafloxacin, grapafloxacin, citafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin q). Streptogramin: pristinamycin, quinupristin/dalfopistin r). Sulfonamides: mafenide, prontocil, sulfacetamide, sulfamethizole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim sulfamethoxazole (cotrimoxazole) s). Steroid antibacterial agents: selected from fusidic acid t). Tetracyclines: doxycycline, chlortetracycline, clomocycline, demeclocycline, limecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, glycylicylene (including tigecycline) u). Other antibiotic: Selected from the group that includes annonasin, arsphenamine, bactoprenol inhibitor (bacitracin), DADAL/AR inhibitor (cycloserine), dictyostatin, discodermolide, eleuthromycin, epothylone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, lolimalide, metronidazole, mupirocin, mycolactone, NAM inhibitor (fosfomycin), nitrofurantoin, paclitaxel, platensis, pyrazinamide, quinupristin/dalfopistin, rifampin (rifampin), tazobactamtinidazole, uvaricin. (4). Antiviral drugs comprising: a). Target cell entry/integration inhibitors: aplaviroc, maraviroc, vicriviroc, gp41(enfuvertide), PRO140, CD4(ibalizumab) b). Integrase inhibitors: raltegravir, elvitegravir, globoidan A c). Maturation inhibitors: bevirimat, vivicon d). Neuraminidase inhibitors: oseltamivir, zanamivir, piramivir: e). Nucleosides & nucleotides: abacavir, aciclovir, adefovir, amdoxovir, apricitabine, brivudine, cidofovir, cleuvudine, dieselvucitabine, didanosine (ddI), elvucitabine, emtricitabine(FTC), entecavir, famciclovir, fluorouracil(5FU), 3'fluorosubstituted at position 2', 3'dideoxynucleoside analogues(including groups consisting of 3'fluoro2',3'dideoxythymidine(FLT) and 3'fluoro2',3'dideoxy guanosine(FLG), fomivirsen, ganciclovir, idouridine, lamivudine(3TC), 1 nucleoside (including the group consisting of beta1 thymidine and beta12' deoxycytidine), penciclovir, racevir, ribavirin, stampidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluridine valaciclovir, valganciclovir, salcitabine (ddC), zidovudine (AZT) f). Non-nucleosides: amantadine, ateviridine, capravirine, diarylpyrimidine (etravirine, rilpivirine), delaverdine, docosanol, emivirine, efavirenz, foscarnate (aminobutyric acid). phosphonoformic), imiquimod, interferon alfa, loviride, lodenosine, methixazone, nevirapine, NOV205, pec interferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod(R848), tromantadine g). Protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir(VX950), tipranavir h). Other antiviral drugs: absimetrium, arbidol, calanolide a, seraginine, cyanovirin n, diarylpyrimidine, epigallocatechin gallate (EGCG), foscarnate, griffitsin, taribavirin (viramidine), hydroxyurea, KP1461, miltifosine, pleconaril, portmanteau inhibitor, ribavirin, seleciclib (5). Radioactive isotopes for radiation therapy that can be selected from the group consisting of (radionuclides) 3H, 11C, 14C, 18F, 32P, 35S, 64Cu, 68Ga, 86Y, 99Tc, 111In, 123I, 124I, 125I, 131l, 133Xe, 177Lu, 211At or 213Bi (6). Conjugates of another drug-binding molecule containing a cytotoxic compound. Tubulisin analogues, maytansinoit analogues, taxanoid (taxane) analogues, CC1065 analogues, daunorubicin and doxorubicin compounds, amatoxin analogues, benzodiazepine dimers (dimers of (pyrrobenzodiazepines(PBD), tomemycin, anthramycin, indolinobenzodiazepines, imidazobenzothiazepines or oxazolidinobenzodiazepines)), calycheamicin and enadiine compoundsantibiotics and Indiene, actinomycin, azazerine, bleomycin, epirubicin, tamoxifen, idarubicin, dolastatin, orlistatin (monomethyl orlistatin E, MMAE, MMAF, orlistatin PYE, orlistatin TP, orlistatin 2AQ, 6AQ, EB(AEB) and EFP(AEFP)), duocarmycin, geldanamycin, methotrexate, thiotepa, vindesine, vincristine, hemiacetal, nazumamide, microgenin, radiosumin, topoisomerase I inhibitors, alterobactin, microscleroderma, theonelamide, esperamicin, PNU159682 and their analogues and derivatives thereof (7). Other immunotherapeutic agents: selected from imiquimod, interferon (alpha or beta), granulocyte colony stimulating factor, cytokines, interleuin (IL1~IL35), antibodies (trastuzumab, pertuzumab, bevacizumab, cetuximab, panitumumab, ifliximab, adalimumab, basilizumab, daclizumab, omalizumab, PD1 or PDL1), drugs that bind to proteins. (abracell), antibody conjugated with selected drug from trastuzumab DM1, trastuzumab deructecan(DS8201a), inotuzumab ozogamicin, brentuximab vedotin, sacituzumab govitecan, glembatuumab vedotin, lorvotuzumab mertansine, AN152LMB2, TP38, VB4845, cantuzumab mertansine, AVE9633, SAR3419, CAT8015, IMGN388, mirvetuzimab soraftansin(IMGN853), enfortumab vedotin, milatuzumab doxorubicin, SGN75(anti-CD70), anti-Her3 ectecan, anti-Trop2 ectecan, anti-CD79b MMAE, anti-Her2MMAE, anti-trop2MMAE, anti-Her2MMAF, anti-trop2 MMAF, anti-CD22 calikiemicin derivative, anti-CD22MMAE, anti-Her2 auristatin derivative, anti-Muc1 auristatin derivative, anti-cMet auristatin derivative or anticladin18.2 auristatin derivative (8). Any pharmaceutically acceptable salt, acid or derivative of any of the above drugs. 21. The adjuvant of claim 20 is selected from one or more of the following drugs: abatacept, abiraterone acetate, abraxen, acetaminophen/hydrocodone, acalabrutinib, aducanumab, adalimumab, ADXS31142, ADXSHER2, afatinib dimaleate, aldesleukin, alectinib, alemtuzumab, alitretinoin, alpilizib, ado trastuzumab emtansine, amphetamine/dextroamphetamine, analotinib, anastrozole, apalutamide, aripiprazole, anthracycline, aripiprazole, atazanavir, atezolizumab. ,atorvastatin,avilumab,azicabtagene siloleucel,azitinib,belinostat,BCGlife,bevacizumab,bexarotene,blinatumomab,bortezomib,bosutinib,brentuximab vedotin,brigatinib,budesonide,budesonide/formoterol,buprenorphine,cabazitaxel,cabozantinib,camrelizumab,capmatinib,capecitabine,carfilzomib,chimeric antigen receptor engineered T(CART)cells,celecoxib,ceritinib,cetuximab,kaidamide,cicloporine ,sinacalcet,crizotinib,cobimetinib,cocentix,crizotinib,CTL019,dabigatran,dabrafenib,dacarbazine,daclizumab,dacomitinib,dacomotinib,daptomycin,daratumumab,darbepoetin alfa,darolutamide,darunavir,dasatinib,denileukindivtitox,denozumab,depakote,dexlansoprazole,dexmethylphenidate,dexamethasone,cooling system Dignicap, dinutuximab, doxycycline, duloxetine, duvelisib, durvalumab, elotuzumab, emtricitabine/rilpivirine/tenofovir, disoproxil fumarate, emtricitabine/tenofovir/ efavirenz, enfortumab vedotin ejfv, enoxaparin, ensartinib, entrectinib, enzalutamide, epoetin alfa, erlotinib, erdafitinib, esomeprazole, eszopiclone, etanesafe, everolimus, ecemestane, everolimus, exenatide ER, ezetimibe, ezetimibe/ Simvastatin, famtrastuzumab deructecane, fenofibrate, filgastrin, fingolimod, flumatinib, fluticasone propionate, fluticasone/salmeterol, fulvestrant, gaziva, gefitinib, glatiramer, goserelin acetate, icotinib, imatinib, ibritumomab tiuxitan, ibrutinib, idelalisib, ifosfamide, infliximab, imiquimod, imuzist, immunoBCG, iniparib, insulin aspart, insulin detemir, insulin glargine, insulin lispro, interferon alpha, interferon alpha 1b, interferon alpha 2a, Interferon alpha2b, Interferon beta, Interferon beta1a, Interferon beta1b, Interferon gamma1a, Lapatinib, Ipilimumab, Ipratropium bromide/Salbutamol, Ixazomib, Kanuma, Lanreotide acetate, Lenalidomide, Lenaliomide, Lenvatinib mesylate, Letrozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Liraglutide, Lisdexamfetamine, LN144, Lorlatinib, Memantine, Methylphenidate, Metoprolol, Mekinist, Mericitabine/Rilpivirine/Tenofovir, Modafinil, Mometasone, Mizidac C, Nesitumumab, Neratinib, Nilotinib, Niraparib, Nivolumab, Ofatumumab, Obintuzumab, Olaparib, Olmesartan, Olmesartan/Hydrochlorothiazide, Omalizumab, Omega-3 Fatty Acid Ethyl Ester, Oncorine, Osseltamivir, Osimertinib, Oxycodone, Palbociclib, Palivizumab, Panitumumab, Panobinostat, Pasopanib, Pembrolizumab, Pexidartinib Hydro Chloride, PD1 Antibody, PDL1 Antibody, Pemetrexed, Pertuzumab, Pneumococcal Conjugate vaccine,polatuzumab velodin,pomalidomide,pregabalin,proscavax,propanolol,quetiapine,rabeprazole,radium223chloride,raloxifene,raltegravir,ramucirumab,ranibizumab,rerugolix,regorafenib,rituximab,rivaroxaban,romidepsin,rosuvastatin,ruxolitinib phosphate,salbutamol,savolitinib,semaglutide,selinexer,sevelamer,sildenafil,siltuximab,cypuleucel T,cytagliptin,cytagliptin/metformin, Solifenacin, Solanezumab, Sonidegib, Sorafenib, Sunitinib, Tacrolimus, Tacrimus, Tadalsfil, Tamoxifen, Tafinlar, Talimogenelaherparepec, Talazoparib, Telaprevir, Talasopa Ribe, Timozolamide, Temsirolimus, Tenofovir/Emtricitabine, Tenofovir Disoproxil Fumarate, Testosterone Gel, Thalidomide, TICEBCG, Thiotropium Bromide, Tisagenleucel, Toremifene, Trametinib, Trastuzumab, Trastuzumab/Hyaluronidase Oil, Trabectidin (ecteinascidin 743), trametinib, twimelimumab, trifluridine/tipiracil, twitonoin, tisselizumab, uroBCG, ussekinumab, valsartan, veriparib, vanditanib, vemurafenib, venetoclax, vorinostat, zanubrutinib, cifaflex, sostavax and analogues, derivatives, pharmaceutically acceptable salts, carriers, diluents or excipients thereof or combinations thereof.