NZ784102B2 - A formulation of a conjugate of a tubulysin analog to a cell-binding molecule - Google Patents

Abstract

formulation of conjugates of tubulysin analogs with a cell-binding molecule having a structure represented by Formula (I), wherein T, L, m, n, -----, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, and R 13 are as defined herein, can be used for targeted treatment of cancer, autoimmune disease, and infectious disease.

Claims (21)

1. A composition comprising: 0.01% ~ 99% by weight of a conjugate of a tubulysin analog to a cell-binding agent of For- mula (I) ; 3.0% ~ 20.0% by weight of one or more polyols selected from sucrose or trehalose; 0.01% ~ 2.0% by weight of one or more surfactants selected from polysorbate; 0.0% ~ 5.0% by weight of one or more preservatives; 0.0% ~ 30% by weight of one or more amino acids; 0.0% ~ 5.0% by weight of one or more antioxidants; 0.0% ~ 0.3% by weight of one or more metal chelating agents; 0.0% ~ 30.0% by weight of one or more buffer salts such that the pH of the composition is between 5 and 7; and 0.0% ~ 30.0% by weight of one or more of isotonic agent; wherein the tubulysin analog conjugate of Formula (I) is illustrated as following: or a pharmaceutically acceptable salt, hydrate, or hydrated salt, isotope, optical isomer, race- mate, diastereomer, or enantiomer thereof; wherein T is a targeting or cell-binding molecule; L is a releasable linker; is a link- age bond that L connects to an atom inside the bracket independently; n is 1~20 and m is 1~10; wherein T is an antibody; a single chain antibody; an antibody fragment that binds to the target cell; a monoclonal antibody; a single chain monoclonal antibody; or a monoclonal antibody fragment that binds the target cell; a chimeric antibody; a chimeric antibody fragment that binds to the target cell; a domain antibody; a domain antibody fragment that binds to the target cell; ad- nectins that mimic antibodies; DARPins; a lymphokine; a hormone; a vitamin; a growth factor; a colony stimulating factor; or a nutrient-transport molecule; a binding peptide, or protein, or anti- body, or small molecule attached on albumin, polymers, dendrimers, liposomes, nanoparticles, vesicles, or capsids; wherein the linker L has the formula: --Ww—(Aa)r--Vv—; wherein: --W-- is a Stretcher unit; w is 0 or 1; each --Aa-- is independently an Amino Acid unit; r is independently an integer ranging from 0 to 12; --V-- is a Spacer unit; and v is 0, 1 or 2, The Stretcher unit W may inde- pendently contain a self-immolative spacer, peptide units, a hydrazone bond, disulfide or thio- lether bonds; The Stretcher unit (--W--), when present, links a targeted binding molecular unit (T) to an amino acid unit (--Aa--), or links V when an Aa is not present; W linked to T has the structures of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 20 21 wherein R and R are independently selected from –C1~C9 alkylene-, -C ~C carbocyclo-, -O-( C ~C alkyl)-, -arylene-, -C ~C alkylene-arylene-,, -C ~C 1 7 1 8 1 9 1 9 alkylene-, -C ~C alkylene-(C ~C carbocyclo)-, -(C ~C carbocyclo)-C ~C alkylene-, -C ~C 1 9 1 8 3 7 1 9 3 8 heterocyclo-, -C1~C10 alkylene-(C3~C8 heterocyclo)-, -(C3~C8 heterocyclo)- C1~C9 alkylene-, - (CH2CH2O)k-, -(CH(CH3)CH2O)k-, and -(CH2CH2O)k-CH2-; k is an integer ranging from 1-20; R’ and R’’ are independently H or CH ; the Spacer unit (--V--), when present, links an Amino Acid unit to the antimitotic agent when an Amino Acid unit is present; alternately, the Spacer unit links the Stretcher unit to anti- mitotic agent when the Amino Acid unit is absent; the Spacer unit also links antimitotic agent to the binding molecule (T) when both the Amino Acid unit and Stretcher unit are absent; spacer units are of two general types: self-immolative and non-self-immolative; a non-self-immolative Spacer unit is one in which part or all of the Spacer unit remains bound to antimitotic agent after cleavage, particularly enzymatic, of an Amino Acid unit from the antimitotic agent-Linker- bind- ing molecule conjugate or the antimitotic agent-Linker Compound; the self-immolative spacer includes beta-glucuronide, and ortho or para-aminobenzylacetals; or one of the following struc- tures: , , , , ; wherein the (*) atom is the point of attachment of ad- ditional spacer or releasable linker units to the tubulysin analog and/or the binding molecule (T); X, Y and Z are independently NH, O, or S; Z is H, NH, O or S independently; v is 0 or 1; Q is 17 17 17 18 17 independently H, OH, C1~C6 alkyl, (OCH2CH2)n F, Cl, Br, I, OR , or SR , NR R , N=NR , 17 17 18 17 18 17 17 17 17 18 17 18 17 18 N=R , NR R , NO2, SOR R , SO2R , SO3R , OSO3R , PR R , POR R , PO2R R , 17 18 17 18 17 18 OPO(OR )(OR ), or OCH PO(OR (OR ) wherein R R are independently H, C ~C of al- 2 , 1 8 kyl; C ~C of alkenyl, alkynyl, heteroalkyl; C ~C of aryl, heterocyclic, carbocyclic, cycloalkyl, 2 8 3 8 heterocycloalkyl, heteroaralkyl, alkylcarbonyl; or pharmaceutical cation salts; the non-self-immolative spacer having structure: (CH ) CO(OCH CH ) OCH (CH ) CON(CH CH O) COCH 2 m 2 2 n 3 2 m 2 2 n 3 *(CH CH O) * 2 2 n *CH* *CH* ; ; ; (CH ) (OCH CH ) OCOCH (CH ) CO(OCH CH ) OCOCH 2 m 2 2 n 3 2 m 2 2 n 3 *CH* *CH* H ; ; ; ; H N HS HO m m m P * * * * * * O O O ; ; ; ; ; ; ; 17 17 COOH COOH COOH N* *N m m m O O ; ; ; ; ; ; * N* * *X Y* N* O O O m m *N m m m ; ; ; ; ; ; ; ; ; ; ; ; R' R'' *X Y* *X Y ; ; ; ; ; R' R'' COOH ; ; ; ; OH OH ; ; ; ; ; ; ; ; N(CH CH O) CH O 2 2 n 3 *N * *N * O O O ; ; ; ; HN HN O P O S m HO m O *N * *N * ; ; ; ; ; ; ; HN HN m m P *N * * *N * O O O ; ; ; , , , , , , , , , , , , , -, , , , , , , , , , , , , , , , ; , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or L- or D-, natural or unnatural peptides containing 1-20 the same or dif- ferent amino acids; wherein the “*” and “ ”atom are the point of attachment of additional spacer or releasa- ble linkers to the tubulysin analog and/or the binding molecules; m is 1~10; n is 1~20; X X X 2, 3, 4, X or X are independently selected from NH; NHNH; N(R ); N(R )N(R ); O; S; C -C of al- 5, 6, 12 12 12’ 1 6 kyl; C2-C6 of heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; CH OR , CH SR , 2 12 2 12 CH NHR , or 1~8 amino acids; wherein R and R are independently H;C -C of alkyl; C -C 2 12 12 12’ 1 8 2 8 of hetero-alkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocy- clic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or 1-8 carbon atoms of esters, ether, or amide; or polyethyleneoxy unit of formula (OCH CH ) or (OCH CH(CH )) , wherein p 2 2 p 2 3 p is an integer from 0 to about 1000, or combination above thereof; or the releasable component L has one of the following structures: -(CR R ) (Aa)r(CR R ) (OCH CH ) -, -(CR R ) (CR R ) (Aa) (OCH CH ) -, -(Aa) - 15 16 m 17 18 n 2 2 t 15 16 m 17 18 n r 2 2 t r (CR R ) (CR R ) (OCH CH ) -, -(CR R ) (CR R ) (OCH CH ) (Aa) -, - 15 16 m 17 18 n 2 2 t 15 16 m 17 18 n 2 2 r t (CR15R16)m(CR17=CR18)(CR19R20)n(Aa) t(OCH2CH2)r-, -(CR15R16)m(NR11CO)(Aa)t(CR19R20)n- (OCH CH ) -, -(CR R ) (Aa) (NR CO)(CR R ) (OCH CH ) -, -(CR R ) (OCO)(Aa) - 2 2 r 15 16 m t 21 19 20 n 2 2 r 15 16 m t (CR R ) (OCH CH ) -, -(CR R ) (OCNR )(Aa) (CR R ) (OCH CH ) -, -(CR R ) - 19 20 n 2 2 r 15 16 m 17 t 19 20 n 2 2 r 15 16 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- (OCH CH ) -, -(CR R ) (CO)(Aa) (CR R ) (OCH CH ) -, -(CR R ) -phenyl-CO(Aa) 2 2 r 15 16 m t 19 20 n- 2 2 r 15 16 m t- (CR17R18)n-, -(CR15R16)m-furyl-CO(Aa)t(CR17R18)n-, -(CR15R6)m-oxazolyl-CO(Aa)t(CR17R18)n-, - (CR15R16)m-thiazolyl-CO(Aa)t(CCR17R18)n-, -(CR15R16)t-thienyl-CO(CR17R18)n-, -(CR15R16)t-imi- dazolyl-CO-(CR R ) -, -(CR R ) -morpholino-CO(Aa) (CR R ) -, -(CR R ) -piperazino- 17 18 n 15 16 t t- 17 18 n 15 16 t CO(Aa) (CR R ) -, -(CR R ) -N-methylpiperazin-CO(Aa) (CR R ) -, -(CR R ) - t 17 18 n 15 16 t t 17 18 n 15 16 m (Aa)tphenyl-, -(CR15R16)m-(Aa)tfuryl-, -(CR15R16)m-oxazolyl(Aa)t-, -(CR15R16)m-thiazolyl(Aa)t-, - (CR15R16)m-thienyl-(Aa)t-, -(CR15R16)m-imidazolyl(Aa)t-, -(CR15R16)m-morpholino-(Aa)t-, - (CR R ) -piperazino-(Aa) -, -(CR R ) -N-methylpiperazino-(Aa) 15 16 m t 15 16 m t- -K(CR R ) (Aa)r(CR R ) (OCH CH ) -, -K(CR R ) (CR R ) (Aa) (OCH CH ) - , 15 16 m 17 18 n 2 2 t 15 16 m 17 18 n r 2 2 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- (CR R ) (OCH CH ) -, -K(CR R ) (Aa) (NR CO)(CR R ) (OCH CH ) -, -K(CR R ) - 19 20 n 2 2 r 5 6 m t 21 19 20 n 2 2 r 15 16 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- (OCH CH ) -, -K(CR R ) (OCO)(Aa) (CR R ) (OCH CH ) -, -K(CR R ) (OCNR )(Aa) - 2 2 r 15 16 m- t 19 20 n 2 2 r 15 16 m- 17 t (CR R ) (OCH CH ) -, -K-(CR R ) (CO)(Aa) (CR R ) (OCH CH ) -, -K(CR R ) -phe- 19 20 n 2 2 r 15 16 m t 19 20 n 2 2 r 15 16 m nyl-CO(Aa)t(CR17R18)n-, -K-(CR15R16)m-furyl-CO(Aa)t(CR17R18)n-, -K(CR15R16)m-oxazolyl- CO(Aa)t(CR17R18)n-, -K(CR15R16)m-thiazolyl-CO(Aa)t-(CR17R18)n-, -K(CR15R16)t-thienyl- CO(CR R ) -, -K(CR R ) imidazolyl-CO-(CR R ) -, -K(CR R ) morpholino-CO(Aa) - 17 18 n 15 16 t 17 18 n 5 6 t t (CR17R18)n-, -K(CR15R16)t-piperazino-CO(Aa)t-(CR17R18)n-, -K(CR15R16)t-N-methylpiperazin- CO(Aa)t(CR17R18)n-, -K(CR15R16)m-(Aa)tphenyl, -K-(CR15R16)m-(Aa)tfuryl-, -K(CR15R16)m- oxazolyl-(Aa) -, -K(CR R ) -thiazolyl(Aa) -, -K(CR R ) -thienyl-(Aa) -, -K(CR R ) -imi- t 15 16 m t 15 16 m t 15 16 m dazolyl(Aa) -, -K(CR R ) -morpholino(Aa) -, -K(CR R ) piperazino(Aa) G, -K(CR R ) -N- t 15 16 m t 15 16 m t 5 6 m methyl-piperazino(Aa)t-; wherein m, Aa, m, n, R13, R14, and R15 are described above; t and r here are 0 – 100 independently; R , R , R R , and R are independently chosen from H; halide; 16 17 18, 19 20 C ~C of alkyl or heteroalkkyl, C ~C of aryl, alkenyl, alkynyl, ether, ester, amine or amide, 1 8 2 8 C3~C8 of aryl, which optionally substituted by one or more halide, CN, NR12R12’, CF3, OR12, Aryl, heterocycle, S(O)R , SO R -CO H, -SO H, -OR , -CO R , -CONR , -PO R R , - 12 2 12, 2 3 12 2 12 12 2 12 13 PO H or P(O)R R R ; K is NR , -SS-, -C(=O)-, -C(=O)NH-, -C(=O)O-, -C=NH-O-, -C=N- 3 12 12’ 13 12 NH-, -C(=O)NH-NH-, O, S, Se, B, heterocyclic or heteroaromatic ring having C3-C12; or pep- tides containing the same or different 1- 20 amino acids; 1 2 3 4 inside the bracket of the Formula (I) is a tubulysin analog wherein R , R R and R are in- dependently linear or branched C1-C8 of alkyl, alkyl alcohol; C2-C8 of heteroalkyl, alkylcyclo- alkyl, heterocycloalkyl, alkyl ether, alkyl carboxylate, alkyl amine, alkyl ester, alkyl amide; C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl; or 1 2 3 4 5 6 12 13 two R’s: R R , R R , R R , or R R together form a 3~7 membered carbocyclic, cycloalkyl, het- erocyclic, heterocycloalkyl, aromatic or heteroaromatic ring system; Y is N or C; In addition, R , 2 3 4 R , R , and R can be independently absent; 5 6 8 10 wherein R R , R and R are independently selected from H and linear or branched C - C4 of alkyl or C2-C4 of heteroalkyl; 7 14 14 1 15 14 1 15 1 wherein R is selected from H, R , or -R C(=O)X R ; -R X R ; X is selected from O, S, S-S, NH, or NR ; 9 14 14 14 14 15 wherein R is H, -O-, -OR , -OC(=O)R -, -OC(=O)NHR -, -OC(=O)NR R -, -OC(=O) 14 15 14 14 15 R SSR -, OP(=O)(OR )-, or OR OP(=O)(OR ); 11 14 14 16 14 2 16 14 2 16 14 2 wherein R is H, R , -R C(=O)R , -R C(=O)X R , -R X R , -R C(=O)X , wherein 2 14 14 14 14 14 X is -O-, -S-, -NH-, -NHS(O ), -NHS(O), -N(R )-, -O-R -, -S-R -, -S(=O)-R -, or -NHR -; 12 14 wherein R is H, R , -O-, -S-, -N-, =N-, =NNH-, -OH, -SH, -NH2, =NH, =NNH2, - 14 14 16 16 14 14 NH(R ), -OR , -C(O)O-, -C(O)OR -,-COR , -COOR -, C(O)NH-, C(O)NH2, C(O)NHR , - 14 14 16 16 16 16 SR , -S(=O)R , -P(=O)(OR ) , -OP(=O)(OR ) , -CH OP(=O)(OR ) , -SO R ; 2 2 2 wherein R is linear or branched C -C of alkyl, alkyl acid, alkyl amide, alkyl amine; or C2-C10 of heteroalkyl; or C3-C10 of Ar; Ar refers to an aromatic or hetero aromatic group, composed of one or several rings, comprising four to ten carbon atoms; The term of hetero aro- matic group refers to an aromatic group that has one or several carbon atoms replaced by hetero atoms; The term aryl or Ar also refers to an aromatic group, wherein one or several H atoms can 17 16 16 16 17 16 16 16 17 be replaced independently by R , F, Cl, Br, I, OR , SR , NR R , N=NR , N= R , NR R , 16 17 16 16 16 16 17 16 17 16 17 17 NO SOR R , SO R , SO R OSO R , PR R , POR R , PO R R , OP(O)(OR ) , 2 3 3 2 2 17 17 16 17 17 17 OCH OP(O)(OR ) , OC(O)OP(O)(OR ) , PO(OR )(OR ), OP(O)(OR )OP(O)(OR ) , 2 2 2 2 17 17 OC(O)R or OC(O)NHR ; 14 15 wherein R and R are independently H; linear or branched C -C of alkyl; C -C of 1 8 2 8 alkenyl, alkynyl, heteroalkyl, heterocyclic, carbocyclic; C -C of aryl, cycloalkyl, alkylcycloal- kyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl; 14 14 Wherein when R is bivalent, it is a R that is further connected to an additional func- tional group of one to four amino acid units, or (CH CH O) r is an integer ranging from 0 to 12, 2 2 r, or C -C glycosides, or C -C of carboxylic acid; 4 12 o f 1 8 16 14 wherein R is H, OH, R or one to four amino acid units; wherein R is H, linear or branched C -C of alkyl; C -C of alkenyl, alkynyl, het- 1 8 2 8 eroalkyl, heterocyclic; C -C of aryl, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl or C -C glycosides, or pharmaceutical 4 12 o f salts; wherein a suitable buffering agent in the formulations includes, sodium, potassium, ammo- nium, or trihydroxyethylamino salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tar- taric acid, succinic acid, acetic acid or phthalic acid; Tris, tromethamine hydrochloride, sulfate or phosphate buffer; In addition, amino acid cationic components can also be used as buffering agent; Such amino acid component includes arginine, glycine, glycylglycine, and histidine; The arginine buffers include arginine acetate, arginine chloride, arginine phosphate, arginine sulfate, arginine succinate; Histidine buffers include histidine chloride-arginine chloride, histidine acetate- arginine acetate, histidine phosphate-arginine phosphate, histidine sulfate-arginine sulfate, histi- dine succinate-arginine succinate; the formulations of the buffers have a pH of 4.5 to pH 8.5; 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 its metallic salts; wherein a surfactant optionally in the formulations is selected from polysorbate (polysorb- ate 20, polysorbate 40, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85; polox- amer, poloxamer 188, poly(ethylene oxide)-poly(propylene oxide), poloxamer 407 or polyeth- ylene-polypropylene glycol; Triton; sodium dodecyl sulfate; 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-, lino- leamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamido-propyl-betaine; myristam- idopropyl-, palmidopropyl-, or isostearamido-propyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine and coco ampho glycinate; isostearyl ethylimidonium ethosulfate; polyethyl glycol, poly- propyl glycol, and copolymers of ethylene and propylene glycol; wherein a "preservative" optionally in the formulations is selected from octadecyldime- thylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, and benzetho- nium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl parabens, catechol, resorcinol, cyclo- hexanol, 3-pentanol, and m-cresol; wherein a suitable free amino acid as a bulky material, or tonicity agent, or osmotic pres- sure adjustment in the formulation, is selected from one or more of arginine, cystine, glycine, ly- sine, histidine, ornithine, isoleucine, leucine, alanine, glycine glutamic acid or aspartic acid; wherein an antioxidant in the formulations can optionally selected from methionine, gluta- thione, cysteine, cystine or ascorbic acid; wherein the formulations can optionally comprise metal chelating agent selected from EDTA, EGTA; wherein the buffer adjusting agent selected from HCl, H SO , acetic acid, H PO , citric 2 4 3 4 acid, NaOH, KOH, NH OH, ethanolamine, diethanolamine or triethanol amine, sodium phos- phate, potassium phosphate, trisodium citrate, tromethamine; wherein an isotonic agent is selected from mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate, or NaCl.

2. The composition of claim 1, wherein the conjugate of the tubulysin analog with a cell- binding agent of formula (I) according to Claim 1 is of Formula (II): or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or their isotopes, optical isomers, racemates, diastere- omers or enantiomers thereof; 1 2 3 4 5 6 8 10 13 14 15 16 17 Wherein T ,L, n, m, Y, R , R , R , R , R , R , R , R , R R , R , R and R are de- fined the same as in the Formula (I); 7 14 14 1 15 14 1 15 1 Wherein R is selected from H, R or -R C(=O)X R ; -R X R X is selected from O, S, S-S, NH, or NR 9 14 14 14 14 15 Wherein R is H, -OH, -OR , -OC(=O)R , -OC(=O)NHR , -OC(=O)NR R , -OC(=O) 14 15 14 14 15 R SSR , OP(=O)(OR ) , or OR OP(=O)(OR ); 11 14 14 16 14 2 16 14 2 16 14 2 Wherein R is H, R , -R C(=O)R , -R C(=O)X R , -R X R , -R C(=O)X , 2 14 14 14 14 14 wherein X is -O-, -S-, -NH-, -NHS(O2), -N(R )-, -O-R -, -S-R -, -S(=O)-R -, or -NHR -; 12 14 Wherein R is H, R , -O-, -S-, -N-, =N-, =NNH-, -OH, -SH, -NH2, =NH, =NNH2, - 14 14 16 16 14 14 NH(R ), -OR , -C(O)O-, -C(O)OR -,-COR , -COOR -, C(O)NH-, C(O)NH , C(O)NHR , - 14 14 16 16 16 16 SR , -S(=O)R , -P(=O)(OR ) 2, -OP(=O)(OR )2, -CH OP(=O)(OR )2, -SO R .

3. The composition of claim 1, wherein the conjugate of the tubulysin analog according to claim 1 is of Formula (III): (III) or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or their isotopes, optical isomers, racemates, diastere- omers or enantiomers thereof; 1 2 3 4 5 6 8 9 10 11 12 13 wherein T, L, m, Y, R , R R R , R R R R R R R R and n are defined the , , , , , , , , , same as in Formula (I) and (II); 7 14 14 1 15 14 1 15 wherein R is independently selected from -R - or -R C(=O)X R - or -R X R - 14 15 wherein R and R are independently linear or branched C ~C of alkyl, heteroalkyl; C ~C of 1 8 2 8 alkenyl, alkynyl; C3~C8 of aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, het- eroaralkyl heteroalkylcycloalkyl, alkylcarbonyl; X is selected from O, S, S-S, NH, or NR .

4. The composition of claim 1, wherein the conjugate of the tubulysin analog according to Claim 1 is of Formula (IV): or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or their isotopes, optical isomers, racemates, diastere- omers or enantiomers thereof; 1 2 3 4 5 6 7 8 10 11 12 13 wherein T, L, m, R , R R R , R R R R R R R R and n are defined the same , , , , , , , , , as in Formula (II); 9 14 14 14 Wherein R is independently H, -O-, -OR -, -OC(=O)R -, -OC(=O)NHR -, - 14 15 14 15 14 14 15 OC(=O)NR R -, -OC(=O)R SSR -, -OP(=O)(OR )O-, wherein R R are independently H, C ~C of alkyl, heteroalkyl; C ~C of aryl, heteroaryl, heterocyclic, carbocyclic, cycloalkyl, al- 1 8 3 8 kylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl or pharma- ceutical salts.

5. The composition of claim 1, wherein the conjugate of the tubulysin analog according to Claim 1 is of Formula (V): or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or their isotopes, optical isomers, racemates, diastere- omers or enantiomers thereof; 1 2 3 4 5 6 7 8 9 10 12 13 wherein T, L, m, Y, R , R R R R R R R R R R R and n are defined the , , , , , , , , , , same as in Formula (II); 11 14 14 17 14 2 17 14 2 17 14 2 Wherein R is -R -, -R C(=O)R -, -R C(=O)X R -, -R X R -, - R C(=O)X -, wherein R is independently H, OH, C1~C8 of alkyl; C2~C8 of alkenyl, alkynyl, heteroalkyl; C ~C of aryl, arylene, heterocyclic, carbocyclic, heterocycloalkyl; or an amino acid, or two 2 14 14 14 amino acid units; X is -O-, -S-, -NH-, -NHS(O )-, -NHS(O)-, -N(R )-, -O-R -, -S-R -, -S(=O)- 14 14 14 R -, or -NHR -; R 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. The composition of claim 1, wherein the conjugate of the tubulysin analog according to Claim 1 is of Formula (VI): or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or their isotopes, optical isomers, racemates, diastere- omers or enantiomers thereof; 1 2 3 4 5 6 7 8 9 11 13 wherein T, L, m, Y, R , R , R , R , R , R , R , R , R , R , R and n are defined the same as in Formula (II); 12 14 14 14 wherein R is independently R , -O-, -S-, -NH-, =N-, =NNH-, -N(R )-, -OR -,C(O)O-, 14 14 14 14 15 15 C(O)NH-, C(O)NR -, -SR -, -S(=O)R -, -NHR -, -CH2OP(=O)(OR )- , -P(=O)(OR )-, - 15 14 14 15 OP(=O)(OR )O-, -SO R , R R are independently C ~C of alkyl, heteroalkyl; C ~C of 2 , 1 8 2 8 alkenyl, alkynyl; C ~C of aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocy- cloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl.

7. The composition of claim 1, wherein the conjugate of the tubulysin analog according to Claim 1 is of Formula (VII): (VII) or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or their isotopes, optical isomers, racemates, diastere- omers or enantiomers thereof, 1 1’ 2 3 4 5 6 8 10 11 12 wherein T, L, n, m, Y, R , R , R , R , R , R , R , R , R , R , and R are defined the same as in Formula (II); wherein R is C ~C of alkyl, heteroalkyl, alkyl acid, alkyl amide, alkyl amine, or Ar; Ar refers to a aromatic or hetero aromatic group, composed of one or several rings, comprising four to ten carbon; The term of hetero aromatic group refers one or several carbon on aromatic group; The term aryl or Ar also refers to a aromatic group, wherein one or several H atoms are replaced 18 16 16 16 18 16 16 16 18 independently by R , F, Cl, Br, I, OR , SR , NR R , N=NR , N=R NR R NO , , 2, 16 18 16 16 16 16 18 16 18 16 18 16 18 SOR R , SO2R , SO3R , OSO3R , PR R , POR R , PO2R R , OPO3R R , or 16 18 16 18 PO3R R wherein R , R are independently H, C1~C8 of alkyl; C2~C8 of alkenyl, alkynyl, het- eroalkyl; C ~C of aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl; or C ~ C glycosides; or pharmaceutical salts.

8. The composition of claim 1, wherein the tubulysin analog inside the bracket of Formula (I) according to Claim 1 is of a structure represented by the following Formula II-01 ~II-73, III- 01 ~III-71, IV-01 ~IV-71, V-01 ~V-71, VI-01 ~VI-16, and VII-01 ~VII-82, below: II-01, II-02, II-03, II-04, II-05, II-06, II-07, II-08, II-09, II-10, II-11, II-12, II-13, II-14, II-15, II-16, II-17, II-18, II-19, II-20, II-21, II-22, II-23, II-24, II-25, II-26, II-27, II-28, II-29, II-30, II-31, II-32, II-33, II-34, II-35, II-36, II-37, II-38, II-39, II-40, II-41, II-42, II-43, II-44, II-45, II-46, II-47, II-48, II-49, II-50, II-51, II-52, II-53, II-54, II-55, II-56, II-57, II-58, II-59, II-60, II-61, II-62, II-63, II-64, II-65, II-66, II-67, II-68, II-69, II-70, II-71, II-72, II-73, III-01, III-02, III-03, III-04, III-05, III-06, III-07, III-08, III-09, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17, III-18, III-19, III-20, III-21, III-22, III-23, III-24, III-25, III-26, III-27, III-28, III-29, III-30, III-31, III-32, III-33, III-34, III-35, III-36, III-37, III-38, III-39, III-40, III-41, III-42, III-43, III-44, III-45, III-46, III-47, III-48, III-49, III-50, III-51, III-52, III-53, III-54, III-55, III-56, III-57, III-58, III-59, III-60, III-61, III-62, III-63, III-64, III-65, III-66, III-67, III-68, III-69, III-70, III-71, IV-01, IV-02, IV-03, IV-04, IV-05, IV-06, IV-07, IV-08, IV-09, IV-10, IV-11, IV-12, IV-13, IV-14, IV-15, IV-16, IV-17, IV-18, IV-19, IV-20, IV-21, IV-22, IV-23, IV-24, IV-25, IV-26, IV-27, IV-28, IV-29, IV-30, IV-31, IV-32, IV-33, IV-34, IV-35, IV-36, IV-37, IV-38, IV-39, IV-40, IV-41, IV-42, IV-43, IV-44, IV-45, IV-46, IV-47, IV-48, IV-49, IV-50, IV-51, IV-52, IV-53, IV-54, IV-55, IV-56, IV-57, IV-58, IV-59, IV-60, IV-61, IV-62, IV-63, IV-64, IV-65, IV-66, IV-67, IV-68, IV-69, IV-70, IV-71, V-01, V-02, V-03, V-04, V-05, V-06, V-07, V-08, V-09, V-10, V-11, V-12, V-13, V-14, V-15, V-16, V-17, V-18, V-19, V-20, V-21, V-22, V-23, V-24, V-25, V-26, V-27, V-28, V-29, V-30, V-31, V-32, V-33, V-34, V-35, V-36, V-37, V-38, V-39, V-40, V-41, V-42, V-43, V-44, V-45, V-46, V-47, V-48, V-49, V-50, V-51, V-52, V-53, V-54, V-55, V-56, V-57, V-58, V-59, V-60, V-61, V-62, V-63, V-64, V-65, V-66, V-67, V-68, V-69, V-70, V-71, VI-01, VI-02, VI-03, VI-04, VI-05, VI-06, VI-07, VI-08, VI-09, VI-10, VI-11, VI-12, VI-13, VI-14, VI-15, VI-16, VII-01, VII-02, VII-03, VII-04, VII-05, VII-06, VII-07, VII-08, VII-09, VII-10, VII-11, VII-12, VII-13, VII-14, VII-15, VII-16, VII-17, VII-18, VII-19, VII-20, VII-21, VII-22, VII-23, VII-24, VII-25, VII-26, VII-27, VII-28, VII-29, VII-30, VII-31, VII-32, VII-33, VII-34, VII-35, VII-36, VII-37, VII-38, VII-39, II-40, VII-41, VII-42, VII-43, VII-44, VII-45, VII-46, VII-47, VII-48, VII-49, VII-50, VII-51, VII-52, VII-53, VII-54, VII-55, VII-56, VII-57, VII-58, VII-59, VII-60, VII-61, VII-62, VII-63, VII-64, VII-65, VII-66, VII-67, VII-68, VII-69, VII-70, VII-71, VII-72, VII-73, VII-74, VII-75, VII-76, VII-77, VII-78, VII-79, VII-80, VII-81, VII-82, or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or their isotopes, optical isomers, racemates, diastere- omers or enantiomers thereof; 20 17 wherein R is H; C -C of linear or branched alkyl, heteroalkyl, or acyl (-C(O)R ); C -C 1 8 2 8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcar- 17 17 18 bonyl, heteroaryl; carbonate (-C(O)OR ), carbamate (-C(O)NR R ); or 1-8 carbon atoms of carboxylate, esters, 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 R is absent and the oxygen forms a ketone, or combination above thereof; wherein R is H, C -C of linear 1 2 3 17 or branched alkyl; X, X , X , and X , are independently O, S, NH, NHNH, NHR , CH2 or ab- 1 17 1 17 2 1 17 sent; P is H, R , P(O)(OH)2, P(O)(X R )2, CH2P(O)(OH)2, S(O )(X R ), C6H12O5 , 17 17 1 1 (CH2CH2O)pR , wherein p is selected from 0 -100,and R is defined above; in addition X P can be absent (together is H); 3 3’ 17 17 wherein Z and Z are independently H, OH, NH , OR , NHR , COOH, 17 17 17 17 18 COOR , C(O)R , C(O)NHR , C(O)NHNHR , C(O)NH 2, R , 18 18 18 18 OCH OP(O)(OR ) , OC(O)OP(O)(OR ) , OPO(OR ) , NHPO(OR ) , 2 2 2 2 2 18 18 18 18 18 OP(O)(OR )OP(O)(OR ) , OC(O)R , OC(O)NHR , OSO (OR ), O-(C -C glycoside), C - 2 2 4 12- C8 of linear or branched alkyl or heteroalkyl; C2-C8 of linear or branched alkenyl, alkynyl, alkyl- cycloalkyl, heterocycloalkyl; C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocy- clic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; carbonate (-C(O)OR ), carba- 17 18 17 18 mate (-C(O)NR R ); R and R are independently H, C -C linear or branched alkyl or het- eroalkyl; C2-C8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, 17 17 18 19 alkylcarbonyl, heteroaryl; carbonate (-C(O)OR ), carbamate (-C(O)NR R ); R is H, OH, 18 18 18 18 18 NH , OSO (OR ), XCH OP(O)(OR ) , XPO(OR ) XC(O)OP(O)(OR ) , XC(O)R , 2 2 2 2 2, 2 XC(O)NHR C ~C alkyl or carboxylate; C ~C alkenyl, alkynyl, alkylcycloalkyl, heterocyclo- , 1 8 2 8 alkyl; C ~C aryl or alkylcarbonyl; or pharmaceutical salts; X is O, S, NH, NHNH, NHR , or CH2; R is defined the same above ; wherein “ ” is the site that linked to a linker L.

9. The composition of claim 1, wherein the conjugate of tubulysin analog according to claims 1 having the following structures: C-481, C-495, C-528, C-629, C-633, C-641, C-645, C-649, C-654, C-659, C-663, C-673, C-709, C-166a, C-719, wherein mAb is a cell-binding agent; n is 1 ~20; p is 0~100.

10. A tubulysin analog linker compound having one of the following structures:

11. The composition according to any one of claims 1, 2, 3, 4, 5, 6, 7, or 9, wherein the cell- binding agent is an Ig-based protein scaffold molecule selected from Nanobody, Domain antibodies, Bispecific cell Engager, bispecific antibody, trispecific antibody, Dual Affinity Re- Targeting; Tetravalent tandem antibodies; biparatopic antibody; a non-Ig-based protein scaffold molecule selected from Anticalin, Adnectins, Designed Ankyrin Repeat Proteins, DARPin C9, DARPin Ec4 and DARPin E69_LZ3_E01, Avimers; a small molecule itself or a small molecule coated on a protein, a nano particle, a polymer, a micelle or a lipid having the following structure LB01~LB54: LB01, LB02, LB03, LB04, LB05, LB06, LB07, LB08, LB09, LB10, LB11, LB12, LB13, LB14, LB15, R19 is 5’deoxyadenosyl, Me, OH, CN; LB16, R is 5’deoxyadenosyl, Me, OH, CN; LB17, LB18, LB19, LB20, LB21, LB22, LB23, LB24, LB25, LB26, LB27, LB28, LB29, LB30, LB31, LB32, LB33, LB34, LB35, LB36, LB37, LB38, LB39, wherein Y , is N, CH, C(Cl), C(CH ), or C(COOR ); R is H, C -C Alkyl, C -C Ar; 1 1 1 6 3 8 LB40, LB41, LB42, LB43, LB44, LB45, LB46, LB47, LB48, LB49, LB50, LB51, LB52, LB53, LB54, wherein “ ” is the site to link the linker L of the present patent; X4,and Y1 are inde- pendently 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(R ), N(R )C(O)N(R ), CH C(O)NHNHC(O) and C(O)NR ; X is H, CH , 1 1 1 2, 1 1 2 OH, O, C(O), C(O)NH, C(O)N(R1), R1, NHR1, NR1, C(O)R1 or C(O)O; X5 is H, CH3, F, or Cl; 1 1’ 2 3 1 1’ 2 3 M1 and M2 are independently H, Na, K, Ca, Mg, NH4, N(R R R R ); R , R , R and R are de- fined in Formula (I) of Claim 1.

12. The composition according to any one of claims 1, 2, 3, 4, 5, 6, 7, or 9, wherein the cell binding agent is capable of targeting against a tumor cell, a virus infected cell, a microorganism infected cell, a parasite infected cell, an autoimmune disease cell, an activated tumor cells, a myeloid cell, an activated T-cell, an affecting B cell, or a melanocyte, or any cells expressing any one of the following antigens or receptors: CD2, CD2R, CD3, CD3gd, CD3e, CD4, CD5, CD6, CD7, CD8, CD8a, CD8b, CD9, CD10, CD11a, CD11b, CD11c, CD12, CD12w, CD13, CD14, CD15, CD15s, CD15u, CD16, CD16a, CD16b, CD17, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD42a, CD42b, CD42c, CD42d, CD43, CD44, CD44R, CD45, CD45RA, CD45RB, CD45RO, CD46, CD47, CD47R, CD48, CD49a, CD49b, CD49c, CD49e, CD49f, CD50, CD51, CD52, CD53, CD54, CD55,CD56, CD57, CD58, CD59, CD60, CD60a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD63, CD64, CD65, CD65s, CD66, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD74, CD75, CD75s, CD76, CD77, CD78, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CDw84, CD85, CD86, CD87, CD88, CD89, CD90, CD91, CD92, CDw92, CD93, CD94, CD95, CD96, CD97, CD98, CD99, CD99R, CD100, CD101, CD102, CD103, CD104, CD105, CD106, CD107, CD107a, CD107b, CD108, CD109, CD110, CD111, CD112, CD113, CDw113, CD114, CD115, CD116, CD117, CD118, CD119, CDw119, CD120a, CD120b, CD121a, CD121b, CDw121b, CD122, CD123, CDw123, CD124, CD125, CDw125, CD126, CD127, CD128, CDw128, CD129, CD130, CD131, CDw131, CD132, CD133, CD134, CD135, CD136, CDw136, CD137, CDw137, CD138, CD139, CD140a, CD140b, CD141, CD142, CD143, CD144, CD145, CDw145, CD146, CD147, CD148, CD149, CD150, CD151, CD152, CD153, CD154, CD155, CD156a, CD156b, CDw156c, CD157, CD158a, 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), 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, CR, CR1, CRGF, CXCR5, LY64, TDGF1, 4-1BB, APO2, ASLG659, BMPR1B, 4-1BB, 5AC, 5T4, Ade- nocarcinoma antigen, AGS-5, AGS-22M6, Activin receptor-like kinase 1, AFP, AKAP-4, ALK, Alpha integrin, Alpha v beta6, Amino-peptidase N, Amyloid beta, Androgen receptor, Angio- poietin 2, Angiopoietin 3, Annexin A1, Anthrax toxin protective antigen, Anti-transferrin recep- tor, AOC3, B7-H3, Bacillus anthracis anthrax, BAFF, BCMA, B-lymphoma cell, bcr-abl, Bombesin, BORIS, C5, C242 antigen, CA125, CA-IX, CALLA, CanAg, Canis lupus familiaris IL31, Carbonic anhydrase IX, Cardiac myosin, CCL11, CCR4, CCR5, CD3E, CEA, CEA- CAM3, CEACAM5, CFD, Ch4D5, Cholecystokinin 2, CLDN18, CLDN18.1, CLDN18.2, Clumping factor A, cMet, FCSF1R, CSF2, CSP4, CTLA4, CTAA16.88 tumor antigen, CXCR4, C-X-C chemokine receptor type 4, cyclic ADP ribose hydrolase, Cyclin B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL3, DLL4, DPP4, DR5, E. coli shiga toxin type-1, E. coli shiga toxin type-2, ED-B, EGFL7, EGFR, EGFRII, EGFRvIII, Endoglin, Endothelin B receptor, Endotoxin, EpCAM, EphA2, Episialin, ERBB2, ERBB3, ERG, Escherichia coli, ETV6-AML, FAP, fibroblast surface antigen, FCGR1, alpha-Fetopro- tein, Fibrin II, beta chain, Fibronectin extra domain-B, FOLR, Folate receptor alpha, Folate hy- drolase, Fos-related antigen 1F protein of respiratory syncytial virus, Frizzled receptor, Fucosyl GM1, GD2 ganglioside, G-28, GD3 idiotype, GloboH, Glypican 3, N-glycolylneuraminic acid, GM3, GMCSF receptor a-chain, Growth differentiation factor, GP100, GPNMB, GUCY2C, Heat shock proteins, Hemagglutinin, Hepatitis B surface antigen, Hepatitis B virus, HER1, HER2, HER2/neu, HER3, IgG4, HGF/SF, HHGFR, HIV-1, Histone complex, HLA-DR, HLA- DR10, HLA-DRB , HMWMAA, Human chorionic gonadotropin, HNGF, Human scatter factor receptor kinase, HPV E6/E7, Hsp90, hTERT, ICAM-1, Idiotype, IGF1R, IGHE, IFN- ?, Influ- enza hemagglutinin, IgE, IgE Fc region, IGHE, interleukins, IL31RA, ILGF2, Integrins, Inter- feron gamma-induced protein, ITGA2, ITGB2, KIR2D, Kappa Ig, LCK, Le, Legumain, Lewis- Y antigen, LFA-1, LHRH, LINGO-1, Lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MART1, MCP- 1, MIF, MS4A1, MSLN, MUC1, MUC1-KLH, MUC16, MCP1, MelanA/MART1, ML-IAP, MPG, MS4A1, MYCN, Myelin-associated glycoprotein, Myostatin, NA17, NARP-1, NCA-90, Nectin-4, NGF, Neural apoptosis-regulated proteinase 1, NOGO-A, Notch receptor, Nucleolin, Neu oncogene product, NY-BR-1, NY-ESO-1, OX-40, OxLDL, OY-TES1, P21, p53 nonmu- tant, P97, Page4, PAP, Paratope of anti-(N-glycolylneuraminic acid), PAX3, PAX5, PCSK9, PDCD1, PDGF-Ra, PDGFR-ß, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, Platelet-derived growth factor receptor beta, Phosphate-sodium co-transporter, PMEL 17, Pol- ysialic acid, Proteinase3, Prostatic carcinoma, PS, Prostatic carcinoma cells, Pseudomonas aeru- ginosa, PSMA, PSA, PSCA, Rabies virus glycoprotein, RHD, Rhesus factor, RANKL, RhoC, Ras mutant, RGS5, ROBO4, Respiratory syncytial virus, RON, ROR1, Sarcoma translocation breakpoints, SART3, Sclerostin, SLAMF7, Selectin P, SDC1, sLe(a), Somatomedin C, SIP, So- matostatin, Sperm protein 17, SSX2, STEAP1, STEAP2, STn, TAG-72, Survivin, T-cell recep- tor, T cell transmembrane protein, TEM1, TENB2, Tenascin C, TGF-a, TGF-ß, TGF-ß1, TGF- ß2, Tie, Tie2, TIM-1, Tn, TNF, TNF-a, TNFRSF8, TNFRSF10B, TNFRSF-13B, TPBG, TRAIL-R1, TRAILR2, tumor-associated calcium signal transducer 2, tumor specific glycosyla- tion of MUC1, TWEAK receptor, TYRP1, TRP-1, TRP-2, Tyrosinase, VCAM-1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VEGFR2, or vimentin, WT1, XAGE 1, or cells expressing any insulin growth factor receptors, or any epidermal growth factor receptors.

13. The composition according to claim 12, wherein the tumor cell is selected from the group consisting of lymphoma cells, myeloma cells, renal cells, breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, none small-cell lung cancer cells, testicular cancer cells, malignant cells, or any cells that grow and divide at an unregulated, quickened pace to cause cancers.

14. A pharmaceutical composition comprising a therapeutically effective amount of the conju- gate compounds of any one of claim 1, 2, 3, 4, 5, 6, 7, or 9, and a pharmaceutically acceptable salt, carrier, diluent, or excipient therefore, or a combination of the conjugates thereof. 15. The composition according to any one of claims 1 to 7, wherein the composition com- prises: 1%-95% by weight of the composition of the conjugate of formula (I), (II), (III), (IV), (V), (VI) or (VII); 0.0%-15.0% of a polyol; 0.0%-0.5% of one or more surfactants; 0.0% -10% of one or more amino acids; 0.0% ~5% of preservative; and 0.0% ~10% of buffuer salt; or wherein the composition comprises: 1%-95% by weight of the composition of the conjugate of formula (I), (II), (III), (IV), (V), (VI) or (VII); 0.0%-15.0% of a polyol; 0.0%-0.5% of one or more surfactants; 0.0% -10% of one or more amino acids, 0.0% ~5% of preservative; and 0.0% ~10% of buffuer salt; and 0.0% -30.0% of one or more of isotonic agent; 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 metallic salts; wherein the surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 65, pol- ysorbate 80, polysorbate 81, or polysorbate 85, poloxamer, poly(ethylene oxide)-poly(propylene oxide), polyethylene-polypropylene, Triton; sodium dodecyl sulfate, sodium laurel sulfate; so- dium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostear- amidopropyl-betaine; myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethyla- mine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; dodecyl betaine, dodecyl dime- thylamine oxide, cocamidopropyl betaine and coco ampho glycinate; or isostearyl ethylimido- nium ethosulfate; polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol; wherein the preservative is selected from benzyl alcohol, octadecyldimethylbenzyl ammo- nium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, alkyl parabens, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; wherein the amino acid is selected from arginine, cystine, glycine, lysine, histidine, orni- thine, 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 phthalic acid; Tris or tromethamine hydrochloride, phosphate or sulfate; arginine, glycine, glycylglycine, or histidine with anionic acetate, chloride, phosphate, sulfate, or succin- ate salts; wherein the isotonic agent is selected from mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate, or sodium chloride.

15. The composition according to any one of claims 1 to 13, wherein the composition com- prises: 10% ~ 85% by weight of the a conjugate of formula (I), (II), (III), (IV), (V), (VI) or (VII); 0.0% ~ 10.0% of a polyol selected from sucrose or trehalose; 0.1% ~0.25% of surfactants selected from polysorbate 20 or polysorbate 80; 0.0% ~ 8.0% of one or more amino acids selected from arginine, histidine, ornithine, gly- cine or alanine; 0.0% ~5% of preservative selected from benzyl alcohol; and 1% ~10% of buffuer salt selected from sodium citrate or citric acid monohydrate.

16. The composition according to any one of Claims 1 to 15, wherein the compositision is held in a vial, bottle, pre-filled syringe, or pre-filled auto-injector syringe, in a form of a liquid or ly- ophilized solid.

17. The composition according to any one of Claims 1 to 15, wherein the conjugate of formula (I) has in vitro, in vivo or ex vivo cell killing activity.

18. Use of the composition according to any one of claims 1to 17 in the manufacture of a me- dicament for the treatment and/or prevention of a cancer, or an autoimmune disease, or an infec- tious disease.

19. The use according to claim 18, wherein the medicament is formulated to be administered in combination with one or more of a chemotherapeutic agent, a radiation therapy, an immunother- apy agent, an autoimmune disorder agent, an anti-infectious agents or the other conjugates for synergistically treatment or prevention of a cancer, or an autoimmune disease, or an infectious disease.

20. The use according to claim 18 or claim 19, wherein the medicament is formulated to be ad- ministered in combination with one or more of : (1) A chemotherapeutic agent selected from the group consisting of: a) an alkylating agent: selected from the group consisting of nitrogen mustards: chlorambu- cil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechloretham- ine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1065 and adozelesin, carzelesin, bizelesin or their synthetic analogues; duocarmycin and its synthetic analogues, KW-2189, CBI-TMI, or CBI dimers; benzodiazepine dimers or pyrrolo- benzodiazepine dimers, tomaymycin dimers, indolinobenzodiazepine dimers, imidazobenzothi- adiazepine dimers, or oxazolidinobenzodiazepine dimers; Nitrosoureas; carmustine, lomustine, chlorozotocin, fotemustine, nimustine, ranimustine; Alkylsulphonates; busulfan, treosulfan, im- prosulfan and piposulfan; Triazenes or dacarbazine; Platinum containing compounds; car- boplatin, cisplatin, and oxaliplatin; aziridines, benzodopa, carboquone, meturedopa, or uredopa; ethylenimines methylamelamines; b) A plant alkaloid: selected from the group consisting of Vinca alkaloids; Taxoids, May- tansinoids comprising DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine, ansamitocins and their analogs, cryptophycins; epothilones, eleutherobin, discodermolide, bryostatins, dolo- statins, auristatins, tubulysins, cephalostatins; pancratistatin; a sarcodictyin; spongistatin; c) A DNA Topoisomerase Inhibitor: selected from the groups of Epipodophyllins: compris- ing 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phos- phate, irinotecan, mitoxantrone, novantrone, retinoic acids, retinols, teniposide, topotecan, 9- nitrocamptothecin or RFS 2000; and mitomycins and their analogs; d) An antimetabolite: selected from the group consisting of: Anti-folate: DHFR inhibitors; methotrexate, trimetrexate, denopterin, pteropterin, aminopterin or folic acid analogues; IMP dehydrogenase Inhibitors; Ribonucleotide reductase Inhibitors; Pyrimidine analogs; Uracil ana- logs; Cytosine analogs; Purine analogs; folic acid replenisher, frolinic acid; e) A hormonal therapy: selected from the group consisting of: Receptor antagonists; Anti- estrogen; LHRH agonists; Anti-androgens; Retinoids/Deltoids: Vitamin D3 analogs; Photody- namic therapies; Cytokines; f) A kinase inhibitor, selected from the group consisting of BIBW 2992, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib; vandetanib, E7080, mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, Trastuzumab, Ranibizumab, Panitumumab, ispinesib; g) A poly (ADP-ribose) polymerase inhibitors selected from the group consisting of olaparib, niraparib, iniparib, talazoparib, veliparib, CEP 9722, E7016, BGB-290, or 3-amino- benzamide; h) An antibiotic, selected from the group consisting of an enediyne antibiotic selected from the group consisting of calicheamicin, calicheamicin ?1, d1, a1 or ß1; dynemicin; esperamicin, kedarcidin, C-1027, maduropeptin, or neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores; aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomy- cin, daunorubicin, detorubicin, 6-diazooxo-L-norleucine, doxorubicin, morpholino-doxorubi- cin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, eribulin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; i) A polyketide , bullatacin and bullatacinone; gemcitabine, epoxomicins andcarfilzomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA- 9090, Stimuvax, allovectin-7, Xegeva, Isoprenylation inhibitors and Lovastatin, Dopaminergic neurotoxins and1-methylphenylpyridinium ion, Cell cycle, Actinomycins, amanitins, Bleo- mycins, Anthracyclines, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubi- cin, mtoxantrone, MDR inhibitors or verapamil, Ca ATPase inhibitors or thapsigargin, His- tone deacetylase inhibitors, Vorinostat, Romidepsin, Panobinostat, Valproic acid, Mocetinostat, Belinostat, PCI-24781, Entinostat, SB939, Resminostat, Givinostat, AR-42, CUDC-101, sul- foraphane, Trichostatin A; Thapsigargin, Celecoxib, glitazones, epigallocatechin gallate, Disul- firam, Salinosporamide A.; Anti-adrenals, selected from the group consisting of aminoglute- thimide, mitotane, trilostane; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; arabinoside, bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; dia- ziquone; eflornithine, elfomithine; elliptinium acetate, etoglucid; gallium nitrate; gacytosine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitra- crine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2',2''-trichloro- triethylamine; trichothecenes; urethane, siRNA, antisense drugs; (2) An anti-autoimmune disease agent: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids, DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, myco- phenylate, prednisone, sirolimus, tacrolimus; (3) An anti-infectious disease agents comprising: a) Aminoglycosides: amikacin, astromicin, gentamicin, hygromycin B, kanamycin, neomy- cin, netilmicin, spectinomycin, streptomycin, tobramycin, verdamicin; b) Amphenicols: azidamfenicol, chloramphenicol, florfenicol, thiamphenicol; c) Ansamycins: geldanamycin, herbimycin; d) Carbapenems: biapenem, doripenem, ertapenem, imipenem/cilastatin, meropenem, panipenem; e) Cephems: carbacephem, cefacetrile, cefaclor, cefradine, cefadroxil, cefalonium, cefalo- ridine, cefalotin or cefalothin, cefalexin, cefaloglycin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil, cefroxadine, ceftezole, cefuroxime, cefixime, cefdinir, cefditoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefo- tiam, cefozopran, cephalexin, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefsulodin, ceftazidime, cefteram, ceftibuten, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, cephamycin, oxacephem; f) Glycopeptides: bleomycin, vancomycin, teicoplanin, ramoplanin; g) Glycylcyclines: tigecycline; h) ß-Lactamase inhibitors: penam, clavam; i) Lincosamides: clindamycin, lincomycin; j) Lipopeptides: daptomycin, A54145, calcium-dependent antibiotics; k) Macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide, midecamycin, miocamycin, oleandomycin, rifamycins, rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus, troleandomycin, telithro- mycin; l) Monobactams: aztreonam, tigemonam; m) Oxazolidinones: linezolid; n) Penicillins: amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicil- lin, talampicillin, azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, ben- zathine phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin, cloxa- cillin, dicloxacillin, epicillin, flucloxacillin, mecillinam, mezlocillin, meticillin, nafcillin, oxacillin, penamecillin, penicillin, pheneticillin, phenoxymethylpenicillin, piperacillin, propicil- lin, sulbenicillin, temocillin, ticarcillin; o) Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, di- floxacin, enoxacin, enrofloxacin, floxin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, spar- floxacin, temafloxacin, tosufloxacin, trovafloxacin; q) Streptogramins: pristinamycin, quinupristin/dalfopristin; r) Sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasal- azine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole; s) Steroid antibacterials: selected from fusidic acid; t) Tetracyclines: doxycycline, chlortetracycline, clomocycline, demeclocycline, lymecy- cline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracy- cline, tetracycline, glycylcyclines; u) Other antibiotics: selected from the group consisting of annonacin, arsphenamine, bacto- prenol inhibitors, DADAL/AR inhibitors, dictyostatin, discodermolide, eleutherobin, epothi- lone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, met- ronidazole, mupirocin, mycolactone, NAM synthesis inhibitors, nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin, tazobactam tinidazole, uvari- (4) Anti-viral drugs comprising: a) Entry/fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41, PRO 140, CD4; b) Integrase inhibitors: raltegravir, elvitegravir, globoidnan A; c) Maturation inhibitors: bevirimat, vivecon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleosides & nucleotides: abacavir, aciclovir, adefovir, amdoxovir, apricitabine, brivu- dine, cidofovir, clevudine, dexelvucitabine, didanosine, elvucitabine, emtricitabine, entecavir, famciclovir, fluorouracil, 3’-fluoro-substituted 2’, 3’-dideoxynucleoside analogues selected from the group consisting of3’-fluoro-2’,3’-dideoxythymidine and 3’-fluoro-2’,3’-dideoxygua- nosine, fomivirsen, ganciclovir, idoxuridine, lamivudine, l-nucleosides, penciclovir, racivir, rib- avirin, stampidine, stavudine, taribavirin, telbivudine, tenofovir, trifluridine valaciclovir, val- ganciclovir, zalcitabine, zidovudine; f) Non-nucleosides: amantadine, ateviridine, capravirine, diarylpyrimidines, delavirdine, docosanol, emivirine, efavirenz, foscarnet, imiquimod, interferon alfa, loviride, lodenosine, methisazone, nevirapine, NOV-205, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod, tromantadine; g) Protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir, tipranavir; h) Other types of anti-virus drugs: abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate, foscarnet, griffithsin, taribavirin, hydroxyurea, KP- 1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, seliciclib. 3 11 14 18 (5) A radioisotope for radiotherapy selected from the group consisting of H, C, C, F, 32 35 64 68 86 99 111 123 124 125 131 133 177 211 213 P, S, Cu, Ga, Y, Tc, In, I, I, I, I, Xe, Lu, At, or Bi; (6) Another cell-binding molecule-drug conjugate having a cytotoxic agent of a tubulysin analog, maytansinoid analog, taxanoid analog, CC-1065 analog, daunorubicin and doxorubicin compound, amatoxin analog, benzodiazepine dimer, calicheamicins and the enediyne antibiotic compound, actinomycin, azaserine, bleomycins, epirubicin, tamoxifen, idarubicin, dolastatins, auristatins, duocarmycins, geldanamycins, methotrexates, thiotepa, vindesines, vincristines, hemiasterlins, nazumamides, microginins, radiosumins, topoisomerase I inhibitors, alterobactins, microsclerodermins, theonellamides, esperamicins, and PNU-159682; (7) Other immunotheraphy drugs: selected from imiquimod, interferons, granulocyte colony- stimulating factors, cytokines, Interleukins, antibodies, Protein-bound drugs, an antibody conju- gated with drugs selected from Trastuzumab-DM1, Trastuzumab deruxtecan, Inotuzumab ozo- gamicin, Brentuximab vedotin, Sacituzumab govitecan, Glembatumumab vedotin, lorvotuzumab mertansine, AN-152 LMB2, TP-38, VB4-845, Cantuzumab mertansine, AVE9633, SAR3419, CAT-8015, IMGN388, Mirvetuximab soravtansine, Enfortumab vedotin, milatuzumab-doxorubi- cin, SGN-75, anti-Her3-exetecan, anti-Trop2-exetecan, nnti-CD79b-MMAE, anti-Her2-MMAE, anti-trop2-MMAE, anti-Her2-MMAF, anti-trop2-MMAF, anti-CD22-calicheamicin derivative, anti-CD22-MMAE, anti-Her2-auristatin derivatives, anti-Muc1- auristatin derivatives, anti- cMet- auristatin derivatives, or anti-Claudin18.2-auristatin derivatives; (8) The pharmaceutically acceptable salts, acids or derivatives of any of the above drugs.

21. The use according to claim 20, wherein the medicament is formulated to be administered in combination with one or more of Abatacept, Abiraterone acetate, Abraxane, Acetaminophen/hy- drocodone, Acalabrutinib, aducanumab, Adalimumab, ADXS31-142, ADXS-HER2, afatinib di- maleate, aldesleukin, alectinib, alemtuzumab, Alitretinoin, alpelisib, ado-trastuzumab emtansine, Amphetamine/ dextroamphetamine, analotinib, anastrozole, apalutamide, Aripiprazole, anthracy- clines, Aripiprazole, Atazanavir, Atezolizumab, Atorvastatin, Avelumab, Axicabtagene ciloleucel, axitinib, belinostat, BCG Live, Bevacizumab, bexarotene, blinatumomab, Bortezomib, bosutinib, brentuximab vedotin, brigatinib, Budesonide, Budesonide/formoterol, Buprenorphine, Cabazitaxel, Cabozantinib, camrelizumab, capmatinib, Capecitabine, carfilzomib, chimeric anti- gen receptor-engineered T cells, Celecoxib, ceritinib, Cetuximab, Chidamide, Ciclosporin, Ci- nacalcet, crizotinib, Cobimetinib, Secukinumab, crizotinib, CTL019, Dabigatran, dabrafenib, dacarbazine, daclizumab, dacomitinib, dacomotinib, daptomycin, Daratumumab, Darbepoetin alfa, darolutamide, Darunavir, dasatinib, denileukin diftitox, Denosumab, Depakote, Dexlansopra- zole, Dexmethylphenidate, Dexamethasone, Dinutuximab, Doxycycline, Duloxetine, Duvelisib, durvalumab, elotuzumab, Emtricitabine/ Rilpivirine/Tenofovir, disoproxil fumarate, Emtricit- bine/ tenofovir/efavirenz, enfortumab vedotin-ejfv, Enoxaparin, ensartinib, entrectinib, Enzalu- tamide, Epoetin alfa, erlotinib, erdafitinib, Esomeprazole, Eszopiclone, Etanercept, Everolimus, exemestane, everolimus, exenatide ER, Ezetimibe, Ezetimibe/simvastatin, fam-trastuzumab deruxtecan, Fenofibrate, Filgrastim, fingolimod, flumatinib, Fluticasone propionate, Fluticasone/salmeterol, fulvestrant, gazyva, gefitinib, Glatiramer, Goserelin acetate, Icotinib, Imatinib, Ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, Infliximab, imiquimod, Im- muCyst, Immuno BCG, iniparib, Insulin aspart, Insulin detemir, Insulin glargine, Insulin lispro, Interferon alfa, Interferon alfa-1b, Interferon alfa-2a, Interferon alfa-2b, Interferon beta, Interferon beta 1a, Interferon beta 1b, Interferon gamma-1a, lapatinib, Ipilimumab, Ipratropium bromide/sal- butamol, Ixazomib, Kanuma, Lanreotide acetate, lenalidomide, lenaliomide, lenvatinib mesylate, letrozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Liraglutide, Lisdexamfetamine, LN-144, lorlatinib, Memantine, Methylphenidate, Metoprolol, Mekinist, mericitabine/Rilpivirine/ Tenofovir, Modafinil, Mometasone, Mycidac-C, Necitumumab, neratinib, Nilotinib, niraparib, Nivolumab, ofatumumab, obinutuzumab, olaparib, Olmesartan, Olmesartan/ hydrochlorothiazide, Omalizumab, Omega-3 fatty acid ethyl esters, Oncorine, Oseltamivir, Osimertinib, Oxycodone, palbociclib, Palivizumab, panitumumab, panobinostat, pazopanib, pembrolizumab, pexidartinib hydrochloride, PD-1 antibody, PD-L1 antibody, Pemetrexed, pertuzumab, Pneumococcal conju- gate vaccine, polatuzumab vedotin, pomalidomide, Pregabalin, ProscaVax, Propranolol, Quetiap- ine, Rabeprazole, radium 223 chloride, Raloxifene, Raltegravir, ramucirumab, Ranibizumab, relugolix, regorafenib, Rituximab, Rivaroxaban, romidepsin, Rosuvastatin, ruxolitinib phosphate, Salbutamol, savolitinib, semaglutide, selinexor, Sevelamer, Sildenafil, siltuximab, Sipuleucel-T, Sitagliptin, Sitagliptin/metformin, Solifenacin, solanezumab, Sonidegib, Sorafenib, Sunitinib, tac- rolimus, tacrimus, Tadalafil, tamoxifen, Tafinlar, Talimogene laherparepvec, talazoparib, Telaprevir, talazoparib, Temozolomide, temsirolimus, Tenofovir/emtricitabine, tenofovir disoproxil fumarate, Testosterone gel, Thalidomide, TICE BCG, Tiotropium bromide, Tisagen- lecleucel, toremifene, trametinib, Trastuzumab, trastuzumab/hyaluronidase-oysk, Trabectedin, tra- metinib, tremelimumab, Trifluridine/tipiracil, Tretinoin, tislelizumab, Uro-BCG, Ustekinumab, Valsartan, veliparib, vandetanib, vemurafenib, venetoclax, vorinostat, zanubrutinib, ziv-afliber- cept, Zostavax, pharmaceutically acceptable salts, carriers, diluents, or excipients thereof, or a combination above thereof. OEt OEt , (NH4)2S NH2 Br )—C=N MeOH, i .t.^ EtO'^VN||' OEt ^ EtO ^J)-C02Et S 3 AMS S EtOH, reflux 2NHC1 Tf20, NaN3 C02Et H2N OH cat. CuS04, K2CQ3 acetone, reflux OH 4 H20, MeOH x'"'* Tf20, NaN3 OH cat. CuSQ4, K2C03> H20, MeOH EDA, ClTi(0'Pr)3 C02Et then 4, THE, -78 °C o Ti(OEt)4> ^ THE, reflux >r^ n NaBH4, Ti(OEt)4 4 N HCl/dioxane fr C02Et THE, -45 °C EtOH O' HC1H2N COOEt 6,'Bu02CC1 6, (COCl)2 NMM, THE COOEt DM I H DIPEA 14 TESC1 Imidazole, DCM OTES O OTES KHMDS, CH3I, THE