JP2021066746A - Conjugate of cytotoxic agent with cell binding receptor - Google Patents

Abstract

To provide a conjugate of a potent cytotoxic agent with a cell-surface receptor binding molecule and a synthesis method therefor.SOLUTION: The present invention provides a conjugate consisting of a potent cytotoxic agent with a cell binding receptor, the conjugate having a structure of molecular formula (I), and a pharmaceutical acceptable salt and a solvate thereof. The conjugate is used for treating cancer, autoimmune disease, and infectious disease.SELECTED DRAWING: None

Description

The present invention relates to a conjugate of a potent cytotoxic agent and a cell surface receptor binding molecule and a method for synthesizing the conjugate for targeted therapy, as well as cancer treatment, autoimmune disease and infectivity of the conjugate-containing structure. Regarding use in diseases.

Much of the literature reports that conjugated binding of cell surface receptor-binding molecules and cytotoxic molecules can target and target various pathogenic cells such as cancer cells. The reported cell surface receptor-binding molecules are antibodies (Sela et al, in Immunoconjugates 189-216 (C. Vogel, ed. 1987); Goose et al, in Targeted Drugs 1-22 (E. Goldberg, ed. 1987). ); Diener et al, in Antibodies mediated delivery systems 1-23 (J. RODWELL, ED. 1988); Silverstein, Nat. Immunol. 2004, 5, 1211-7; Faning 79, 1-14; Richard AD, et al., Nature Clinical Practice Oncology 2007, 4, 245-255; Singh R. et Richson HK., Therapeutic Antibodies: -467), Folic acid (Sudimack, J. et al, Adv. Drug Delivery Rev. 2000, 41, 147-162; Reddy, et al, Mol. Pharma. 2009, 6, 1518-25); (PMSA) binding ligand (Low, et al, WO 2009/026177 A1); albumin peptide (Temming, et al, Bioconjugate Chem. 2006, 17, 1385-1394); cobalamine and protein (Gupta, et al, Crit. Re). Therap. Drug Carrier System. 2008, 25, 347-79; Petrus, et al, Agew. Chem. Int. Ed. 2009, 48, 1022-8); Sugar molecule (Darbre, et al, Curr. Chem .. 2008, 8, 1286-93); Bioactive Polymer (Dhar, et al, Proc. Natl. Acad. Sci. 2008, 105, 17356-61); Limmer (Lee, et al, Nat. Biotechnol. 2005, 23, 1517-26; Almutari, et al; Proc. Natl. Acad. Sci. 2009, 106, 685-90); (Liong, et al, ACS Nano, 2008, 19, 1309-12; Medalova, et al, Nat. Med. 2007, 13, 372-7; Javier, et al, Bioconjugate Chem. 2008, 19, 130 Liplips (Medinai, et al, Curr. Har. Des. 2004, 10, 2981-9); Viral conjugations (Frenniken, et al, Viruses Nanotechnology. 2009, 327, 71-93), and the like.

Many types of cytotoxicity have been used to form antibody-drug conjugates, especially with cell conjugates such as antibodies (Wu, et al, Nat. Biotechnol. 2005, 23, 1137-1146. Ricart, et. al, Nat. Clin. Pract. Oncol. 2007, 4, 245-255). These cytotoxins include calikeamycin derivatives (Giles, et al Cancer 2003, 98, 2095-104; Hamann, et al, Bioconjug Chem 2002, 13, 47-58), and Maytancin derivatives (Widdison, et al, J Med). Chem 2006, 49, 4392-408; Ikeda, et al, Clin Cancer Res 2009, 15, 4028-37; Xie, et al, Expert Opin Biol Ther 2006, 6, 281-91), Oristatin , J Biol Chem 2006, 281, 10540-7; Doronina, et al, Bioconjug Chem 2006, 17, 114-24), Taxan Derivatives (Miller, et al, J Med Chem 2004, 47, 458) , Leptomycin derivative (WO 07144709), CC-1065 and its relatives (Suzawa, et al, J Control Release 2002, 79, 229-42; Suzawa, et al, Bioorg Med Chem 2000, 8, 225 2007102069), Adriamycin (Trail, et al, Science 1993, 261, 212-5; Saleh et al, J Clin Oncol 2000, 18, 2282-92), and amesopterin, vincristine, vincristine, daunorubicin, daunorubicin Contains derivatives.

Cell surface receptor-binding molecules, particularly directional antibodies capable of binding to cell surface antigens, allow toxin molecules to be transmitted directly to or near the surface of pathogenic cells. Therefore, the action and effect of the toxin molecule is improved, and the side effects caused by such the toxin molecule are suppressed to the maximum. Currently, several short-chain peptide compounds with biological activity have been isolated from nature. Among them, tube lysine (the structure is shown in the figure below) is included. Tubricin was initially isolated from the culture medium of Myxobacteria in Archangium gephyra by Hofle and Reichenbach (GBF Braunschweig) (F. Sasse et al. J. Antibiot. 2000, 53, 879-88) .. Tubulicin is an anti-mitotic peptide that induces cell apoptosis because it can suppress the polymerization of tubulin during cell division. Tublicin is considered to be a potential leading compound for targeted treatment because of its apparently superior activity over vinblastine, taxol and epothilone (Wipf, et al, Org. Lett. 2004, 6, 6, 4057-60; Peltier, et al, J. Am. Chem. Soc. 2006, 128, 16018-9; Wipf, et al, Org. Lett., 2007, 9, 1605-1607; Wang, et al, Chem. Biol. Drug Des. 2007, 70, 75-86; Pando, et al, Org. Lett. 2009, 11, 5567-9). In terms of structure, tubular lysine is N-terminal N-methylpipecholine acid (Mep), the second amino acid isoleucine (Ile), and the third amino acid, phenylalanine containing specific thiazole (Tuv). And γ-amino acids (tub tyrosine (Tut) or tubu phenylalanine (Tup)) that can be located at two C-terminals. In recent years, some tubular lysines have been synthesized, but at the doses required to achieve a therapeutic effect, a clear toxic effect (> 15% weight loss) has occurred (US patent apple. 2010). / 0048490). We are diligently studying antibody-drug conjugates, such as antibody-drug conjugates that utilize tubular lysine, with the goal of achieving the desired therapeutic effect and avoiding toxic side effects that should not be present. However, tubericin is hardly soluble in buffer solution, and when conjugated with tubericin, a considerable amount of antibody aggregation occurs. In addition, all of the conjugates formed with an antibody by a tubular lysine family having a slightly simple structure, for example, those using phenylalanine (Phe) and tyrosine (Tyr) instead of Tup and Tut, respectively, are blood in the animal. Hydrolysis of Ph and Tyrosine occurs in the middle circulation, resulting in a Mep-Ile-Tub moiety with weak activity (200 times weaker than the activity of tubericin A and D). Here we describe conjugates of cell surface binding ligands with tubelysine derivatives that are water soluble and stable and have lower systemic toxicity, and the application of such conjugates in targeted therapies for cancer and immune disorders. Disclose.

The antibody drug conjugate of the present invention is a conjugate having structural formula (I) and a medicinal salt and solvent compound thereof.

はＬが括弧内構造における原子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０である。 Where T is the target or binding ligand, L is the dissociable linker,

Is a link bond in which L connects to an atom in the structure in parentheses, n is 1 to 20, and m is 1 to 10.

The structures in parentheses are effective anti-thread splitting agents, of which R ¹ , R ² , R ³ and R ⁴ are C _{1 to} C ₈ (1 to 8 carbon atoms) alkyl, heteroalkyl, C. _{2 to} C ₈ (2 to 8 carbon atoms) heterocycle, carbocycle, cycloalkyl, alkylcycloalkyl, heterocyclic alkyl, C3 to _{C8 (3 to 8} carbon atoms) aryl, aralkyl, heteroalkylcycloalkyl , Alkylcarbonyl, or a combination of two R groups (eg, R ¹ R ² _, R ² R ³ _, R ³ R ⁴ , R ⁵ R ⁶ , R ¹² R ¹³⁾ is C _3- C ₇ (3 to 3 carbon atoms). 7) may be a ring-related group such as a carbocyclic group, a cycloalkyl, a heterocyclic group and a heterocycloalkyl), and Y is N or CH, respectively. Further, R ¹ , R ³ and R ⁴ may be H, and R ² may be absent.

R ⁵ , R ⁶ , R ⁸ and R ¹⁰ is an alkyl or heteroalkyl of H or C _{1 to} C ₄ (1 to 4 carbon atoms), respectively.

R ⁷ independently H, R ^14, Alternatively, it can be selected from ^{-R 14} C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ^15. Among them, R ¹⁴ And R ¹⁵ Are C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, cycloalkane, or C _3- C ₈ aryl, condensing ring alkyl, heteroalkylcycloalkyl, respectively. Heteroaralkyl, alkylcarbonyl, where X ¹ is O, S, SS, NH or NR ¹⁴ .

R ⁹ is ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15-, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ). Among them, R ¹⁴ And R ¹⁵ Are C _{1 to C 8} alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl, respectively. Cycloalkyl, heteroaralkyl, alkylcarbonyl.

R ¹¹ is H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² . Among them, ^{X 2} is ^{-O -, - S-, -NH -} , - N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - it is. R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero. Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl. R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units.

R ¹² is _{^{R 14, -OH, -SH, -NH}} 2, = NH, = NNH 2, -NH (R 14), - OR 14, -COR 16, -COOR 14 -, C (O) NH 2, C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (=) O) (OR ¹⁶ ) ₂ or -SO ₂ R ¹⁶ . R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero. Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl. R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units.

R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or aryl Ar. Among them, Ar is an aromatic ring or a complex aromatic ring composed of a one-membered ring or a multi-membered ring, and each aromatic ring or complex aromatic ring contains 4 to 10 carbon atoms, most preferably 4. Contains ~ 6 carbon atoms. A heteroaromatic ring means an aromatic ring in which one or several carbon atoms are substituted with heteroatoms, most preferably one, two or three carbon atoms are O, N, Si, It is substituted with Se, P or S atoms, most preferably with O, S, or N atoms. Aryl Ar means an aromatic ring or a complex aromatic ring in which one or several hydrogen atoms are substituted. These groups that replace the hydrogen atom are R ¹⁷ , F, Cl, Br, I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ¹⁷ . Of these, R ¹⁶ and R ¹⁷ are C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcyclo, respectively. alkyl, heterocycloalkyl, heterocycloalkyl alkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or C ₄ -C ₁₂ glycoside or pharmaceutical acceptable salts.

Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP. (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ (including 4 to 12 carbon atoms) glycoside, or C _1- C ₈ alkyl, carboxyalkyl group, heterocycle. R ¹⁸ is H, C _{1 to} C ₈ alkyl, carboxyalkyl group, heteroalkyl, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, or C _{3 to} C ₈ aryl, alkylcarbonyl. R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, C _{3 to} C ₈ aryl, Alkynecarbonyl or medicinal salt. X is O, S, or NH. Y ¹ and Y ² are N or CH, respectively.

Alternatively, if R ¹¹ is the following group, R ¹² may be H.

X ² is O, S, N-R ⁸ and R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6.

In another example, the structural formula of the linker for linking the antimitotic agent to the cell conjugate is -Ww- (Aa) r-Vv-, of which -W- is an extension. , W is 0 or 1. Each of-(Aa)-is an independent amino acid unit, and r is 0 to 12, respectively. -V- is the interval field and v is 0, 1 or 2. The extension W may independently contain a self-degradable interval, a peptide, a hydrazone bond, a disulfide bond or a thioether bond.

In another embodiment, the cell conjugate T may be of any form of cell conjugate, eg, a peptide or non-peptide structure. In general, T is an antibody, a single chain antibody, an antibody fragment capable of binding to a target cell, a monoclonal antibody, a single chain monoclonal antibody, a monoclonal antibody fragment capable of binding to a target cell, a chimeric antibody, or a chimeric antibody capable of binding to a target cell. Fragments, functional group antibodies, functional group antibody fragments that can bind to target cells, mimic antibody gene process proteins (eg, fibronectin protein conjugate adnectin), designed ankyrin repeat proteins (DARPin, designed ankyrin repeat proteins), lymph Factors, hormones, vitamins, growth factors, colony stimulators, nutrient-transmitting molecules (transferases) or albumins, polymers, branched polymers, liposomes, nanoparticles, sacs or peptides, proteins bound to (virus) capsids, It is an antibody or a small molecule. Most preferably, the cell conjugate T is a monoclonal antibody.

In another aspect of the invention, conjugates having structural formula I-VII, their medicinal salts or solvates, are used to treat cancer, autoimmune or infectious diseases in humans or other animals.

FIG. 1 shows the synthesis of a conjugate of a cytotoxin and a cell junction using a branched chain linker. FIG. 2 shows the synthesis of maleimide linkers and their use in antibody drug conjugates. FIG. 3 shows the synthesis of bromomaleimide and dibromomaleimide linker and its use in antibody drug conjugates. FIG. 4 shows the synthesis of the Val-Cit amino acid linker and its use in antibody drug conjugates. FIG. 5 shows the synthesis of the anti-mitotic agent Tuv component. FIG. 6 shows the synthesis of the anti-mitotic agent Tuv component. FIG. 7 shows the synthesis of the Boc-Tuv fragment and the conjugate anti-mitotic agent used for the conjugate. FIG. 8 shows the synthesis of anti-mitotic agents Tuv, Ile-Tuv and Mep-Ile-Tuv fragments. FIG. 9 shows the synthesis of anti-mitotic agents Ile-Tuv, Mep-Ile-Tuv, Val-Ile-Tuv and Val-Ile-Tuv (O-alky) fragments. FIG. 10 shows the synthesis of an anti-mitotic agent and the conjugate conjugation of one antibody with it. FIG. 11 shows the synthesis of the Phe- (D) Lys amino acid linker. FIG. 12 shows the synthesis of antibody-antimitotic conjugate conjugates. FIG. 13 shows the synthesis of antibody-antimitotic conjugate conjugates. FIG. 14 shows the synthesis of a cell conjugate-antimitotic conjugate. FIG. 15 shows the synthesis of a single cell conjugate-antimitotic conjugate. FIG. 16 shows the synthesis of one antibody-antimitotic conjugate. FIG. 17 shows the synthesis of one antibody-antimitotic conjugate. FIG. 18 shows the synthesis of hydrophilic Tut analogs for synthesizing hydrophilic anti-mitotic agents (prephosphate phosphates). FIG. 19 shows the synthesis of one antibody-anti-mitotic conjugate. FIG. 20 shows the Boc solid phase synthesis of an anti-mitotic agent capable of forming a single conjugated bond. FIG. 21 shows Fmoc-based solid-phase synthesis of an anti-mitotic agent capable of forming a single conjugated bond. FIG. 22 shows the synthesis of one hydrophilic anti-mitotic agent and the other conjugate conjugation with an antibody. FIG. 23 shows the synthesis of Tuv derivatives and the solid phase synthesis of Mep-Ile-Tuv and NMe2-Val-Ile-Tuv fragments. FIG. 24 shows the synthesis of antimitotic agents and the conjugate conjugation of them with antibodies. FIG. 25 shows solid phase synthesis of antimitotic agents and conjugate conjugation of them with antibodies. FIG. 26-1 shows solid phase synthesis of antimitotic agents and conjugate conjugation of them with antibodies. FIG. 26-2 is a continuation of FIG. 26-1. FIG. 27 shows the synthesis of trans-2-arylcyclopropylamine, trans-2-arylpropanecarboxylic acid and trans-2-arylethylepoxycarboxylic acid. FIG. 28 shows the synthesis of vinyl amino acids and alkyl epoxy amino acids. FIG. 29 shows the synthesis of hydrophilic Tut analogs of hydrophilic antimitotic pre-drugs. FIG. 30 shows the synthesis of a hydrophilic anti-mitotic pre-drug that conjugate-conjugates to a cell binder. FIG. 31 shows the synthesis of a hydrophilic anti-mitotic pre-drug that conjugate with an antibody. FIG. 32 shows the synthesis of a hydrophilic anti-mitotic pre-drug that conjugate with an antibody. FIG. 33 shows the toxic effect of anti-CD22 antibody-anti-mitotic agents TZ01-TZ09 conjugates (drug / antibody molar ratio DAR = 3.0-4.3) on Ramos (Burkitt lymphoma cells) during in vitro tests. The duration of action of the conjugate and the cell is 5 days, and the median lethal dose IC ₅₀ is shown in the drawing. FIG. 34 shows the toxic effect of trastuzumab-anti-mitotic agents (TZ03, TZ04 and TZ07) conjugates (drug / antibody molar ratio DAR = 3.5-4.0) on KPL-4 (breast cancer cells). As can be seen from the drawing, in the absence of non-conjugated trastuzumab, the trastuzumab-TZ03 conjugate has the effect of suppressing the growth of cancer cells and its median lethal dose IC ₅₀ is 90 pM. In the presence of unconjugated trastuzumab (including 1 mmol trastuzumab to saturate the antigen binding points), a corresponding median lethal dose IC ₅₀ is greater than 20 nM. Therefore, slayer ratios of the conjugate is greater than _{222 (IC 50 = 20nM / IC} 50 = 0.09nM). FIG. 35 shows BJAB of anti-CD22 antibody-anti-mitotic agent (TZ03, TZ04 and TZ07) conjugates (drug / antibody molar ratio DA = 3.8-4.2) and non-conjugated CD22 antibody and CD20 antibody (rituximab). It has a toxic effect on cells (Burkitt lymphoma cells). As can be seen from the drawings, the conjugate antibody has a stronger inhibitory effect on cancer cell growth than the non-conjugated antibody (median lethal dose IC ₅₀ = 5-19 pM of the conjugate, semi-lethal dose IC of the non-conjugate). ₅₀ > 20 nM). When the antigen binding point was saturated with a non-conjugated antibody CD22 at a concentration of 1 mmol, the efficacy ratio of the huCD22-TZ03 conjugate was greater than 660 (IC ₅₀ = 3.3 nM / IC ₅₀ = 0.005 nM), huCD- The specific efficacy ratio of the TZ07 conjugate is greater than 790 (IC ₅₀ = 15 nM / IC ₅₀ = 0.019 nM).

Definition Alkyl means a chain or cyclic linear or branched aliphatic hydrocarbon having 1 to 8 carbon atoms. Branching refers to having one or more lower alkyl groups in a chain of alkyl groups, for example, binding to methyl, ethyl or propyl. Specific examples of alkyl include methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl, cyclopentyl, cyclohexyl, 2,2-dimethylbutyl, 2, 3-Dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl, 3-methylhexyl, 2,2-dimethylhexyl, 2,. Includes 4-dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl, n-heptyl, isoheptyl, octyl, isooctyl. The alkyls C _{1 to} C ₈ may be unsubstituted or substituted with a substituent (but not limited to one or more of the following substituents), that is, the substituent may be C. alkyl of ₁ -C _8, alkoxy of C 1 -C _8, aryl, acyl, acyloxy, _{Esuteruki, -C (O) NH 2,} -C (O) NHR ', - C (O) N (R') 2 , -NHC (O) R', -S (O) ₂ R', -S (O) R', -OH, halogen (-F, -Cl, -Br, -I), -N ^3, -NH ₂ ^, -NHR', -N (R') ₂ and -CN. Note that the R 'refers to an alkyl or aryl _C 1 -C _8.

The C _3- C ₈ carbocycle refers to a saturated or unsaturated non-aromatic hydrocarbon carbocyclic compound having 3, 4, 5, 6, 7 or 8 carbon atoms. Typical C _3- C ₈ carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohediene group, 1,4-cyclohediene, cycloheptyl, 1,3- Includes, but is not limited to, cyclohepdiene groups, 1,3,5-cycloheptatriene groups, cyclooctyl and cyclooctadiene. The carbon ring of C _3- C ₈ may be unsubstituted or substituted with a substituent (but not limited to one or more of the following substituents). That is, as the substituent, C _{1 to} C ₈ alkyl, C _{1 to} C ₈ alkoxy, aryl, acyl, acyloxy, ester key, -C (O) NH ₂ , -C (O) NHR',- C (O) N (R') ₂ , -NHC (O) R', -S (O) ₂ R', -S (O) R', -OH, Halogen (-F, -Cl, -Br, -I), -N ₃ , -NH ₂ , -NHR', -N (R') ₂ and -CN. Note that the R 'refers to an alkyl or aryl _C 1 -C _8.

The C _3- C ₈ carbocyclic group refers to a group in which one hydrogen atom in the _{C 3-} C _{8 carbocycle is replaced by a chemical bond.}

The alkenyl group means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond, and has 2 to 8 carbon atoms in the carbon chain. Specific examples of the alkenyl group include vinyl, propenyl, n-butenyl, isobutenyl, 3-methyl-2-butenyl, n-pentenyl, hexenyl, hepsenyl and octenyl.

The alkynyl group means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon triple bond, and has 2 to 8 carbon atoms in the carbon chain. Specific examples of the alkynyl group include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, hexynyl, heptynyl and octynyl.

Heteroalkyl refers to an alkyl having 2 to 8 carbon atoms and having 1 to 4 carbon atoms substituted with O, S or N.

Aryl or aromatic groups are aromatic or heteroaromatic hydrocarbons composed of 3 to 14 carbon atoms (often 6 to 10 carbon atoms) containing one or more rings. Refers to the group. A heteroaromatic hydrocarbon group is one or more carbon atoms (often one, two, three or four carbon atoms) that are O, N, Si, Se, P or S (most preferably). Refers to an aromatic hydrocarbon group substituted with O, S, N). Aryl or aromatic groups also refer to aromatic hydrocarbon groups in which one or more hydrogen atoms have been substituted. These substituents include R ¹³ , F, Cl, Br, I, OR ¹³ , SR ¹³ , NR ¹³ R ¹⁴ , N = NR ¹³ , N = R ¹³ , NR ¹³ R ¹⁴ , NO ₂ , SOR ¹³ R ¹⁴ , SO ₂ R ¹³ , SO ₃ R ¹³ , OSO ₃ R ¹³ , PR ¹³ R ¹⁴ , POR ¹³ R ¹⁴ , PO ₂ R ¹³ R ¹⁴ , OPO ₃ R ¹³ R ¹⁴ or PO ₃ R ¹³ R ¹⁴ . Of these, R ¹³ and R ¹⁴ are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, aralkyl, carbonyl or medicinal salts.

The halogen atom refers to a fluorine, chlorine, bromine, or iodine atom, and a fluorine or chlorine atom is preferable.

The heterocycle refers to an aromatic ring having 2 to 8 carbon atoms, a non-aromatic ring, or a heterocycle in which one to four carbon atoms are replaced by a heteroatom. These heteroatoms are O, N, S, Se and P, preferably O, N and S. For the heterocycles that can be used, see "The Handbook of Chemistry and Physics", 78th Edition, CRC Press, 1997-1998, pp. 225-226. Suitable non-complex aryls include epoxy, ring nitrogen ethyl, ring sulfur ethyl, pyrrolidinyl, pyrazolealkyl group, imidazolidinyl, epoxyethyl, tetrahydrofuran group, dioxolan-group, tetrahydropyranyl, dioxyterocyclohexane group, piperidino, piperazinyl, morpholino. , Pyranyl, imidazoline group, pyrazoline group, pyrazolnthiazolealkyl group, tetrahydrosulfurpyranyl, dithianol, sulfur morpholino, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, dihydropyridyl, ectin group, dihydrogen sulfur pyranyl, nitrogen heterocycloheptyl And, including, but not limited to, these groups and fused rings formed by phenyl.

Heteroaryl refers to an aromatic complex one-membered ring compound, a two-membered ring compound or a multi-membered ring structure containing 5 to 14 (preferably 5 to 10) atoms. For example, pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purine group, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiazolyl, isothiazole, triazole, tetrazolyl, Includes isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl, benzoimidazolyl, isoxazole, pyridyl-N-oxide, and fused rings formed by these groups and phenyl.

Alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic groups are alkylene, cycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, obtained by losing two hydrogen atoms from the corresponding hydrocarbon. Refers to heterocyclic rings and the like.

"Medicinal" or "medicinal" means that the corresponding compound or compound composition is harmful to animals or humans and does not cause allergies or other adverse reactions.

Pharmaceutically acceptable auxiliary materials include all carriers, diluents, auxiliaries or molding agents, such as preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifying agents, suspending agents, solvents. , Dispersive media, coatings, antibacterial agents, antifungal agents, isotonic agents, absorption retarders, etc. In the pharmaceutical field, the method of adding these auxiliary materials to active drug components is a common practice. Unless the auxiliary material is incompatible with the drug active ingredient, it can be said that it is appropriate to use the auxiliary material in the drug ingredient. Active auxiliary materials may be added to the drug component for good results.

In the present invention, the medicinal salt refers to a salt derivative of the compound of the present invention. With appropriate modifications, the compounds according to the present invention can be formed into the corresponding acid salts or alkali salts. Medicinal salts include commonly used non-toxic salts or quaternary ammoniums, which can be prepared with non-toxic inorganic or organic acids corresponding to the compounds according to the invention. For example, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid and the like, and organic acids include acetic acid, propioic acid, succinic acid, tartrate acid, citric acid, methanesulfonic acid, etc. It contains benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, lactic acid and the like, and these acids can be used in pharmaceutically acceptable salts. Other salts include ammonium salts such as tromethamole, meglumin, pyrrole ethanol and metal salts such as sodium, potassium, calcium, zinc and magnesium.

In the present invention, medicinal salts can be produced by conventional academic methods. Generally, these salts are obtained by adding another appropriate equivalent amount of alkali or acid to an aqueous solution or organic solution of a free acid or alkali of the compound according to the present invention or a mixed solution of both. The non-aqueous phase reaction solvent is generally ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For a list of applicable salts, see <Remington's Pharmaceutical Sciences>, 17th Edition. Mack Publishing Company, Easton, PA, 1985, p. 1418.

Conjugated Structure of Drug-Linker-Cell Junction Receptor Molecule As described above, the present invention discloses an antibody drug conjugate represented by structural formula (I), a medicinal salt thereof, and a solvent product.

はＬが括弧内構造における原子と接続するリンク結合、ｎは１〜２０、Ｍは１〜１０である。 Where T is the target or binding ligand, L is the dissociable linker,

Is a link bond in which L connects to an atom in the structure in parentheses, n is 1 to 20, and M is 1 to 10.

The structures in parentheses are effective anti-thread splitting agents, of which R ¹ , R ² , R ³ and R ⁴ are C _{1 to} C ₈ (including 1 to 8 carbon atoms) alkyl and heteroalkyl. , C _{2 to} C ₈ (including 2 to 8 carbon atoms) heterocycle, carbon ring, cycloalkyl, alkylcycloalkyl, heterocyclic alkyl, C _{3 to} C ₈ (including 3 to 8 carbon atoms) aryl, Aralkyl, heteroalkylcycloalkyl, alkylcarbonyl, or a combination of two R groups (eg, R ¹ R ² _, R ² R ³ _, R ³ R ⁴ , R ⁵ R ⁶ , R ¹² R ¹³⁾ is C _3- C. _{It represents 7} (including 3 to 7 carbon atoms) carbocyclic group, cycloalkyl, heterocyclic group and heterocycloalkyl and other ring-related groups, respectively, and Y is N or CH. Further, R ¹ , R ³ and R ⁴ may be H, and R ² may be absent.

R ⁵ , R ⁶ , R ⁸ and R ¹⁰ are independently H or C _{1 to} C ₄ (including 1 to 4 carbon atoms) alkyl or heteroalkyl, respectively.

R ⁷ is independently selected from H, R ¹⁴ , or -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ . Among them, R ¹⁴ And R ¹⁵ Are C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, cycloalkane, or C _3- C ₈ aryl, condensing ring alkyl, heteroalkylcycloalkyl, respectively. Heteroaralkyl, alkylcarbonyl, where X ¹ is O, S, SS, NH or NR ¹⁴ .

R ⁹ is ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15-, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ). Among them, R ¹⁴ And R ¹⁵ Are C _{1 to C 8} alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl, respectively. Cycloalkyl, heteroaralkyl, alkylcarbonyl.

R ¹¹ is H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² . Among them, ^{X 2} is ^{-O -, - S-, -NH -} , - N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - it is. R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero. Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl. R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units.

R ¹² is _{^{R 14, -OH, -SH, -NH}} 2, = NH, = NNH 2, -NH (R 14), - OR 14, - COR 16, -COOR 14 -, C (O) NH 2, C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (=) O) (OR ¹⁶ ) ₂ or -SO ₂ R ¹⁶ . R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero. Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl. R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units.

R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or aryl Ar. Among them, Ar is an aromatic ring or a complex aromatic ring composed of a one-membered ring or a multi-membered ring, and each aromatic ring or complex aromatic ring contains 4 to 10 carbon atoms, most preferably 4. Contains ~ 6 carbon atoms. A complex aromatic ring means an aromatic ring in which one or several carbon atoms are substituted with heteroatoms, most preferably one, two or three carbon atoms are O, N, Si, Substitute with Se, P or S, most preferably with O, S, or N. Aryl Ar means an aromatic ring or a complex aromatic ring in which one or several hydrogen atoms are substituted. These groups that replace the hydrogen atom are R ¹⁷ , F, Cl, Br, I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ¹⁷ . Of these, R ¹⁶ and R ¹⁷ are C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcyclo, respectively. alkyl, heterocycloalkyl, heterocycloalkyl alkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or C ₄ -C ₁₂ glycoside or pharmaceutical acceptable salts.

Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , C (O_) R ¹⁸ , P ( O) (OR ¹⁸ ) OP (O) (OR ¹⁸ ) ₂ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ (including 4 to 12 carbon atoms) glycoside or alkyl , Carboxyalkyl group, heterocycle. R ¹⁸ is H, C _{1 to} C ₈ alkyl, carboxyalkyl group, heteroalkyl, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, or C _{3 to} C ₈ aryl, alkylcarbonyl. R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, C _{3 to} C ₈ aryl, Alkynecarbonyl or medicinal salt. X is O, S, or NH. Y ¹ and Y ² are N or CH, respectively.

Alternatively, if R ¹¹ is the following group, R ¹² may be H.

X ² is O, S, N-R ⁸ and R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6.

The anti-mitotic conjugate of the present invention may contain the structure represented by structural formula (II).

T is the target or binding ligand, L is the dissociable linker, n is 1-20, and M is 1-10.

The structures in parentheses are effective anti-thread splitting agents, of which R ¹ , R ² , R ³ and R ⁴ are C _{1 to} C ₈ alkyls, heteroalkyls, and C _{2 to} C ₈ heterocycles. , Carbocycle, cycloalkyl, alkylcycloalkyl, heterocyclic alkyl, C _{3 to} C ₈ aryl, aralkyl, heteroalkylcycloalkyl, alkylcarbonyl, or two R groups, such as R ¹ R ² _, R ¹ R ³ _, R ² R ³ _, R ³ R ⁴ , R ⁵ R ⁶ , R ¹² R ¹³ are C _3- C ₇ (3 to 7 carbon atoms) carbocyclic groups, cycloalkyls, heterocyclic groups and heterocycloalkyl rings, etc. It may be a related group, where Y is N or CH. Further, R ¹ , R ³ and R ⁴ may be H, and R ² may be absent.

Each R ^{5, R} 6, ^{R 8} and ^{R 10} is alkyl or heteroalkyl H or _C 1 -C _4.

R ⁷ is selected from H, R ¹⁴ , -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ . Among them, R ¹⁴ And R ¹⁵ Are C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, cycloalkyl, or C _3- C ₈ aryl, condensing ring alkyl, heteroalkylcycloalkyl, respectively. Heteroaralkyl, alkylcarbonyl, where X ¹ is O, S, SS, NH or NR ¹⁴ .

R ⁹ is ^{H, -OH -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15-, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ) ₂ . Among them, R ¹⁴ And R ¹⁵ Are C _{1 to C 8} alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl, respectively. Cycloalkyl, heteroaralkyl, alkylcarbonyl.

R ¹¹ is H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² . Of these, X ² is -O-, -S-, -NH-, -N (R ¹⁴ )-, -N (R ¹⁴ ) _2- , -O-R ^14- , -S-R ^14- , -S. (= ^{O) -R 14-} or -NHR ¹⁴ - a. R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero. Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl. R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units.

R ¹² is _{^{R 14, -OH, -SH, -NH}} 2, = NH, = NNH 2, -NH (R 14), - OR 14, - COR 16, -COOR 14 -, - C (O) NH 2 , -C (O) NHR ¹⁴ , -C (O) N (R ¹⁴ ) (R ¹⁶ ), -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ ,- OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (= O) (OR ¹⁶ ) ₂ , or -SO ₂ R ¹⁶ . R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero. Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl. R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units.

R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or aryl Ar. Among them, Ar is an aromatic ring or a complex aromatic ring composed of a one-membered ring or a multi-membered ring, and each aromatic ring or complex aromatic ring contains 4 to 10 carbon atoms, most preferably 4. Contains ~ 6 carbon atoms. A complex aromatic ring means an aromatic ring in which one or several carbon atoms are substituted with heteroatoms, most preferably one, two or three carbon atoms are O, N, Si, Substituted by Se, P or S, most preferably by O, S, or N atoms. Aryl Ar means an aromatic ring or a complex aromatic ring in which one or several hydrogen atoms are substituted. These groups that replace the hydrogen atom are R ¹⁷ , F, Cl, Br, I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ¹⁷ . Of these, R ¹⁶ and R ¹⁷ are H, C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, respectively. alkylcycloalkyl, heterocycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or C ₄ -C ₁₂ glycoside or pharmaceutical acceptable salts.

Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , P ( O) (OR ¹⁸ ) OP (O) (OR ¹⁸ ) ₂ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ (including 4 to 12 carbon atoms) glycoside, or C _1- C ₈ alkyl, carboxyalkyl group, heterocycle. R ¹⁸ is H, C _{1 to} C ₈ alkyl, carboxyalkyl group, heteroalkyl, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, or C _{3 to} C ₈ aryl, alkylcarbonyl. R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, C _{3 to} C ₈ aryl, Alkynecarbonyl or medicinal salt. X is O, S, or NH. Y ¹ and Y ² are N or CH, respectively.

Alternatively, if R ¹¹ is the following group, R ¹² may be H.

X ² is O, S, N-R ⁸ and R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6.

Some specific examples represented by the structural formula (II) are as follows.

Aa refers to a natural or unnatural amino acid, n is 1-20, q is 1-5, X', Y'and Z'are CH, O, S, NH or NR ^22, respectively. R ²² and R ²³ are C _{1 to} C ₈ alkyl, C _{2 to} C ₈ alkenyl, alkynyl, heteroalkyl, C _{3 to} C ₈ aryl, heterocycle, carbocycle, alkylcycloalkyl, heterocycloalkyl, respectively. , Aralkyl, heteroalkylcycloalkyl, heteroaralkyl, or-(OCH ₂ CH ₂ )-where R'and R'' are H or CH ₃ , respectively. Those in parentheses are anti-mitotic agents, those in square brackets are anti-mitotic agents and linking linkers.

The cell conjugate-anti-mitotic agent conjugate according to the present invention may also contain the structure represented by structural formula (III).

Incidentally, T, L, m, Y , R 1, R 2, R 3, R 4, R 5, of ^{R 6, R 8, R 9} , R 10, R 11, R 12, R 13 and n defined It is the same as the structural formula (II).

R ⁷ is ^{R 14, -R 14 C (O} ) X 1 R 15 - or ^-R 14 ^X 1 ^{R 15} - is selected from. R ¹⁴ And R ¹⁵ Alkyl or _heteroalkyl, alkenyl of C 2 -C ₈ each are _C 1 -C _8, alkynyl, heterocyclic, carbocyclic, cycloalkanes, aryl C ₃ -C _8, heterocycloalkyl, heteroaralkyl, heteroalkyl cyclo It is alkyl or carbonylalkyl, where X ¹ is O, S, SS, NH or NR ¹⁴ .

Specific examples of some compounds having structural formula (III) are shown in the drawings below.

The definitions of Ar, n, q, X', Y', Z', R ²² , R ²³ , R'and R'' are the same as those in Compound IIa-IIr.

The cell conjugate-antimitotic conjugate according to the present invention may also contain the structure represented by structural formula (IV).

The definitions of T, L, m, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and n are defined. It is the same as the structural formula (II).

R ⁹ is -O-, -OR ¹⁴ , -OC (O) R ¹⁴ , -OC (O) NHR ¹⁴ , -OC (O) R ¹⁴ SSR ¹⁵ , or -OP (O) (OR ¹⁴ ) O- Among them, R ¹⁴ and R ¹⁵ are C _{1 to} C ₈ alkyl or heteroalkyl, C _{3 to} C ₈ aryl, heteroaryl, heterocyclic group, carbocyclic group, cycloalkyl, alkylcycloalkyl, heterocyclic alkyl, respectively. , Heteroalkylcycloalkyl, heteroaralkyl, carboxylicalkyl or drug salts. Also, R ⁹ may be absent.

Specific examples of some compounds having structural formula (IV) are shown in the drawings below.

The definitions of Ar, Aa, n, q, X', Y', R ²² , R ²³ , R'and R'' are the same as those in Compound IIa-IIr.

The cell conjugate-anti-mitotic agent conjugate according to the present invention may also contain the structure represented by the structural formula (V).

The definitions of T, L, m, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ and n are defined. It is the same as the structural formula (II).

R ¹¹ is R ¹⁴ , −R ¹⁴ C (= O) R ¹⁷ −, −R ¹⁴ X ² R ¹⁷ −, −R ¹⁴ X ² R ¹⁷ −, −R ¹⁴ C (= O) X ² −. Of these, R17 is H, OH, C _1- C ₈ alkyl, C _2- C ₈ alkenyl, alkynyl, heteroalkyl, C _3- C ₈ aryl, arylene, heterocyclic group, carbocyclic group, heterocycloalkyl. or one or a two amino acid units, ^{X 2} is ^{-O -, - S -, -} NH -, - NR 14 -, - oR 14 -, - SR 14 -, S (= O) R 14 - or - NHR ¹⁴ , where R ¹⁴ is C _1- C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, C _3- C ₈ aryl, heterocyclic group, cycloalkyl, alkylcycloalkyl, heterocycloalkyl , Heteroalkylcycloalkyl, heteroaralkyl or carbonylalkyl.

Specific examples of some compounds having the structural formula (V) are shown in the figure below.

The definitions of Ar, Aa, n, q, X', R ²² , R ²³ , R'and R'' are the same as those in Compound IIa-IIr.

The cell conjugate-antimitotic conjugate according to the present invention may also contain the structure represented by the structural formula (VI).

The definitions of T, L, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , R ¹³ and n are defined in Structural Formula (II). Is the same as.

R ¹² is ^{R 14, -O-, -S-, -NH-} , = N-, = NNH-, -N (R 14) -, -OR 14 -, C (O) O-, C (O) ^{NH-, C (O) NR 14} -, - SR 14, -S (O) R 14, -NHR 14 -, - CH 2 OP (= O) (OR 15) -, - P (= O) (OR ¹⁵ ) −, −OP (= O) (OR ¹⁵ ) O−, or −SO ₂ R ¹⁴ . R ¹⁴ and R ¹⁵ are C _1- C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, or C _3- C ₈ aryl, heterocyclic, carbocyclic, cycloalkyl, alkyl, respectively. Cycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl or alkylcarbonyl.

Specific examples of some compounds having a structural formula (VI) are as follows.

The definitions of Ar, Aa, n, q, X', R ²² , R ²³ , R'and R'' are the same as those in Compound IIa-IIr.

The cell conjugate-antimitotic conjugate according to the present invention may also contain the structure represented by the structural formula (VII).

The definitions of T, L, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹¹ , R ¹² , and n are structural formulas (II). ) Is the same.

R ¹³ is a C _1- C ₁₀ alkyl, heteroalkyl, alkyl acid, alkyl amide, alkyl amine or aryl. Among them, aryl is an aromatic ring or a complex aromatic ring composed of a one-membered ring or a multi-membered ring, and each aromatic ring or complex aromatic ring contains 4 to 10 carbon atoms, most preferably 4. Contains ~ 6 carbon atoms. A complex aromatic ring means an aromatic ring in which one or several carbon atoms are substituted with heteroatoms, preferably one, two or three carbon atoms are O, N, Si, Se. , P or S, most preferably O, S or N. Aryl Ar means an aromatic ring or a complex aromatic ring in which one or several hydrogen atoms are substituted. These groups that replace the hydrogen atom are R ¹⁷ , F, Cl, Br, I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ¹⁷ . Of these, R ¹⁶ and R ¹⁷ are H, C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, respectively. , alkyl cycloalkyl, heterocycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or C ₄ -C ₁₂ glycoside or a pharmaceutically acceptable salt.

Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , P ( O) (OR ¹⁸ ) OP (O) (OR ¹⁸ ) ₂ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ (including 4 to 12 carbon atoms) glycoside, or C alkyl of ₁ -C _8, carboxyalkyl group, a heterocycle. R ¹⁸ is H, C _{1 to} C ₈ alkyl, carboxyalkyl group, heteroalkyl, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, or C _{3 to} C ₈ aryl, alkylcarbonyl. R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative, C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, C _{3 to} C ₈ aryl, Alkynecarbonyl or a medicinal salt. X is O, S, or NH. Y ¹ and Y ² are N or CH, respectively.

Alternatively, if R ¹¹ is the following group, R ¹² may be H.

X ² is O, S, an ^{N-R 8, R 8} is _H, alkyl or heteroalkyl C 1 -C _4.

Specific examples of some compounds having the structural formula (VII) are shown in the figure below.

The definitions of Ar, Aa, n, q, X', R ²² , R ²³ , R'and R'' are the same as those in Compound IIa-IIr, where R ²⁴ is H or CH ₃ .

Examples are not limited to these. See FIGS. 1-32 for the synthesis of the antimitotic agents of the present invention and the conjugates formed by them and the cell conjugates of the present invention.

As a specific conjugated junction according to the present invention, the dissociable linker (L) is a chemical chain having C, N, O, S, Si or P atoms. In the conjugate, one end of the chemical chain is covalently connected to the cell conjugate (T) and the other end is covalently connected to the antimitotic agent. The linkers may have different lengths, for example a length consisting of 2 to 100 atoms. All atoms on the linker can be connected by a variety of suitable chemical methods. For example, alkene, alkerene, acetylene, ether, polyalkylene oxide, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, aminourea, dihydrazine carboxylic, alkoxyamine, urea ethane, amino acid, acyloxyamine or hydroxamic acid. There is a joining method of forming. The atoms on these dissociable linkers may be saturated or unsaturated, and may be radicals or those formed by cyclizing with each other to form a divalent ring structure, for example, cycloparaffin, cycloether, cycloamine, arylene or hetero. There are Aliren and so on.

A dissociable linker refers to one containing at least one chemical bond that is dissociated under physiological conditions. For example, it refers to a chemical bond that is sensitive to pH, unstable to acid, unstable to alkali, easily oxidized, easily metabolized, unstable to bio, or easily decomposed by an enzyme. It should be noted that such physiological conditions for chemical bond rupture can be realized not only in biological or metabolic processes but also in ordinary chemical processes such as hydrolysis or substitution reaction. Since the pH of the nucleus is lower than that of cell solute, a chemical bond that can be hydrolyzed under acidic conditions is a good choice. For the same reason, the exchange reaction of mercapto and disulfide bond is also feasible because the intracellular glutathione concentration reaches the millimolar level.

The structure of the dissociable linker L of the present invention is represented by -Ww- (Aa) r-Vv-. However, W- is an extension, w is 0 or 1, -Aa- is an amino acid unit, r is an integer of 0 to 12, -V- is a spacer, and v is 1 or 2.

If the dilator -W- is present, it serves to connect the cell junction (T) with the amino acid unit -Aa- or spacer-V- (in the absence of -Aa-). The extension W may contain one self-degradable spacer, polypeptide unit, hydrazone bond, disulfide bond or thioether bond. It is clear that the cell conjugate (T) has a group capable of binding to the corresponding functional group in the extended form. Connectable functional groups originally present in the cell junction or generated by chemical methods include mercapto, amino, hydroxy, carbonyl, anomeric hydroxyl groups of sugars, and carboxyl, preferably mercapto, carboxyl and amino. Not limited to these. Mercapto may be the result of reducing disulfide bonds within a cell conjugate (eg, antibody) molecule. The mercapto may also be produced by reacting 2-iminothiolane (Traut reagent) or thiolactone with amino at lysine on the cell junction. Alternatively, another mercapto production method is used in which the cell conjugate is modified with a disulfide bond-containing linker or thioester to produce mercapto by reduction or hydrolysis.

Specific examples of some Ws connected to T are shown in the figure below.

^Here, R ^{20, R 21} are, -C ₁ -C ₉ alkylene -, _- C 1 -C ₇ carbocyclyl _{-, - O - (- (} C 1 ~C 8 alkyl) -, - arylene -, - _{C 1} ~ C ₉ alkylene-allylen-, -allylene, -C ₁ ~ C ₉ alkylene, -C ₁ ~ C ₉ alkylene- (C ₁ ~ C ₈ carbocyclyl)-,-(C ₃ ~ C ₈ carbocyclyl) -C ₁ ~ C ₉ alkylene-,-C _{3 to} C ₈ heterocyclic groups-,-C _{1 to} C ₁₀ alkylene- (C _{3 to} C ₈ heterocyclic groups)-,-(C _{3 to} C ₈ heterocyclic groups) -C ₁ -C ₉ alkylene _{-, - (CH 2 CH 2} O) k -, - (CH (CH 3) CH 2 O) k - and _{- (CH 2 CH 2 O)} k -CH 2 - is selected from, k is Integers 1-20, R'and R'', are H or CH ₃ , respectively.

The covalent bond between W and T can be realized by various chemical reactions.

For example, the formation of amide bonds:

Among them, the extended unit contains one active reactive group E, which can form an amide bond with a primary or secondary amine on the cell conjugate. Available active reaction sites E are hydroxysuccinimide esters (such as NHS and S-NHS), 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters (including S-tetrafluorophenyl esters), acid anhydrides, Contains, but is not limited to, acid chlorides, sulfonamide acid chlorides, isocyanates and isothiocyanates, and the like.

Specific examples of connecting with a sulfo ether or a disulfide bond are as follows.

Among them, the extended unit contains one mercapto that can participate in the reaction and can form a thioether or disulfide bond with the cell conjugate T. To form a disulfide bond, the mercapto on the cell junction T is formed by reducing the intramolecular double bond in the cell junction T or modifying the cell junction T by another chemical process. It may be something.

The extension may have one active group capable of reacting with an aldehyde or ketone group. With appropriate chemical modifications, such aldehyde or ketone groups can be introduced at appropriate positions in the cell conjugate T. For example, in the sugar of cell conjugate T, an aldehyde or ketone group can be formed by oxidation of an oxidizing agent such as sodium periodate. Further, for example, a ketone group can be introduced by reacting an amine group at the N-terminal amino acid of an antibody (or protein or polypeptide) with pyridoxal 5-phosphate (PLP). These aldehyde or ketone groups (-C = O) are active reactive groups in extensions such as, for example, hydrazine, oxime, primary or secondary amines, hydrazine, thiosemicarbazones, hydrazine carboxylate or aryl hydrazine. Can react with. This connects the two.

Specific examples of connections by hydrazone, oxime or imine are as follows.

Among them, ^{the definitions of R 20} and R ²¹ are as described above, and R ²⁵ is an organic substitution of an amino acid.

The dilator (which may contain one spacer V and / or amino acid) is conjugated to the cell junction T and then conjugated to connect this cell conjugate-expansion fragment with an antimitotic agent. The treatment can be carried out in a buffered aqueous solution. The (not connected toxin molecule R ¹⁶⁾ some of the specific example in which a conjugated bonding in two stages as methods are as follows.

のような構造を有する抗有糸分裂剤又は他の薬剤を少なくとも一つ含有する。 Among them, E is hydroxysuccinimide ester (NHS, S-NHS, etc.), 4-nitrophenyl ester, pentafluorophenyl ester, tetrafluorophenyl ester (including S-tetrafluorophenyl ester), acid anhydride, acid chloride. , Such as, but not limited to, sulfonamide acid chlorides, isocyanates and isothiocyanates. R'and R'' are H or CH ₃ , ^{respectively, the definitions of R 20} , R ¹⁶ and Ar are the same as above, R ²⁶ is H, F or NO ₂ , and J is F, Cl, Br. , I, tosylate (TSO), or mesylate (MSO). In addition, in the said structure

It contains at least one anti-mitotic agent or other agent having the structure as described above.

The dilator was first connected to an anti-mitotic agent and then with an aqueous solution of pH 3-10 (preferably 5-8.5) (which could contain up to 50% organic solvent) with the cell conjugate T. Conjugation may be performed. Some specific examples of performing conjugated bonding in two steps like this method are as follows.

のような構造を有する抗有糸分裂剤又は他の薬剤を少なくとも一つ含有する。 Among them, E is hydroxysuccinimide ester (NHS, S-NHS, etc.), 4-nitrophenyl ester, pentafluorophenyl ester, tetrafluorophenyl ester (including S-tetrafluorophenyl ester), acid anhydride, acid chloride. , Such as, but not limited to, sulfonamide acid chlorides, isocyanates and isothiocyanates. R'and R'' are H or CH ₃ , ^{respectively, the definitions of R 20} , R ¹⁶ and Ar are the same as above, R ²⁶ is H, F or NO ₂ , and J is F, Cl, Br. , I, tosylate _(T S O), or mesylate _(M S O). In addition, in the said structure

It contains at least one anti-mitotic agent or other agent having the structure as described above.

If an amino acid unit (--Aa--) is present, it connects the extension with the spacer. In the absence of spacers, it is continuous with dilators and antimitotic agents. In the absence of both dilators and spacers, it directly connects the cell conjugate T with the antimitotic agent. -(Aa) r- is a natural or unnatural amino acid such as dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit. It may be, and r is an integer from 0 to 12. Here, the amino acid collectively refers to an aminoalkylcarboxylic acid. Among them, the alkyl may be, for example, an alkyl substituted with a group such as alkyl, acyl, hydroxyalkyl, mercaptoalkyl, aminoalkyl or carboxyalkyl. The structure of natural and unnatural amino acids and polypeptides is described in detail in the authors, GC Barrett and DT Elmore, "Amino Acid and Peptides" (Cambridge University Press, 2004). The amino acid also refers to a beta amino acid, a gamma amino acid, and a long-chain amino acid having methyl, benzyl, hydroxymethyl, thiomethyl, carboxyl, carboxymethyl, guanidinopropyl or the like in the molecule. The most preferred amino acids are arginine, asparagine, aspartic acid, citrulline, cysteine, glycine, glutamic acid, leucine, lysine, glutamine, serine, ornithine, phenylalanine ammonia acid, threonine, tyrosine, and valine.

The amino acid unit of the present invention can release an antimitotic agent by degradation by one or more enzymes, such as a proteolytic enzyme present in a tumor. In the description of the embodiment, it is first protonated in vivo and then becomes a protonated anti-mitotic agent.

If a spacer (-V-) is present, it connects the amino acid unit with the antimitotic agent. In the absence of amino acid units, it connects the dilator with the antimitotic agent. In the absence of both amino acid units and dilators, the spacer connects the antimitotic agent to the cell conjugate T. Spacers can contain several functional groups, which provide water solubility, biological transmission, proper renal clearance, ingestion, absorption, biodistribution, and bioavailability of the conjugate. Can be improved. Spacers are roughly classified into two types, self-destructive type and non-self-destructive type. Non-self-destructive is a spacer in which one amino acid unit is cleaved from an anti-mitotic agent-linker-cell junction or anti-mitotic agent-linker, and in particular after enzymatic degradation, some or all spacers. Is still connected to the anti-mitotic agent.

Some specific examples of self-destructing spacers are as follows.

Of these, the atoms marked with (*) are spacers, dissociable linkers, antimitotic agents or T access points of cell conjugates. X, Y and Z ³ are NH, O or S, respectively; Z ² is H, NH, O or S. v is 0 or 1; Q is an H, OH, C _{1 to} C ₆ alkyl group, (OCH ₂ CH ₂ ) n, F, Cl, Br, I, OR ¹⁷ , or SR ¹⁷ , NR ¹⁷ R ¹⁸ , N = NR ¹⁷ , N = R ¹⁷ , NR ¹⁷ R ¹⁸ , NO ₂ , SOR ¹⁷ R ¹⁸ , SO ₂ R ¹⁷ , SO ₃ R ¹⁷ , OSO ₃ R ¹⁷ , PR ¹⁷ R ¹⁸ , POR 17R ¹⁸ , PO ₂ R ¹⁷ R ¹⁸ , OPO (OR ¹⁷ ) (OR ¹⁸ ), OCH ₂ PO (OR ¹⁷ (OR ¹⁸ )) or glycoside, where R ¹⁷ and R ¹⁸ are H, C _1- C ₈ alkyl, C. _2- C _8- alkylene group, alkynyl, heteroalkyl, C _3- C _8- aryl group, heterocyclic group, carbocyclic group, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl, or pharmaceutically acceptable cation It is salt.

Some specific examples of non-self-destructive spacers are as follows.

Of these, the atoms marked with (*) are spacers, dissociable linkers, antimitotic agents or access points for cell junctions. As described above, Q is 1 to 10 and n is 1 to 20.

The cell conjugate T may be any known molecule on the target cell that is capable of binding, complexing and reacting with fragments used for treatment or denaturation. By interacting with specific target cells, cell conjugates serve to transmit antimitotic agents to such target cells.

Cell conjugates are high molecular weight proteins, such as whole antibodies (polyclonal or monoclonal); single-stranded antibodies; antibody fragments, such as Fab, Fab', F (ab') 2, Fv [Parham, J. Immunol. 131. , 2895-2902 (1983)], Fragments produced by Fab expression libraries, anti-idiotype antibodies (anti-Ids), CDR's, cancer cell epitopes, viral epitopes or any that may specifically bind to microbial epitopes. Fragments of said above; interferons (types I, II, III); polypeptides; phosphokines such as IL-2, IL-3, IL-4, IL-6, GM-CSF, or IFN-γ; hormones, For example, steroid hormones such as insulin, thyroid stimulating hormone-releasing hormone (TRH), melanin cell stimulating hormone (MSH), androgen, estrogen, or melanin cell stimulating hormone (MSH); growth factors and colony stimulating factors, such as epithelial growth factors. (EFG), granulocyte macrophage colony stimulator (GM-CSF); transforming growth factor (TGF), eg, TGFα, TGFβ; insulin and insulin-like growth factors (IGF-I, IGF-II) G-CSF, M -CSF and GM-CSF [Burges, Immunology Today, 5,155-158 (1984)], etc .; Vaccine Proliferation Factor (VGF); Fibroblast Proliferation Factor (FGF); Small Molecular Weight Proteins, Polypeptides, Peptides and Peptides Hormones such as bombesin, gastrin and gustrin-releasing peptides; platelet-derived growth factors; interleukins and cytokines such as interleukin-2 (IL-2), interleukin-6 (IL-6), leukemia inhibitors, granulocytes Macrophage colony stimulating factor (GM-CSF) and vitamins such as folic acid; apoproteins and glycoproteins such as transferase [O'Keefe et al, J. Bio. Chem. 260, 923-927 (1985)]; sugar Binding or lipoproteins such as lectin; cellular nutrient transfer molecules; and small molecule inhibitors such as prostate-specific membrane antigen (PSMA) inhibitors, small molecule tyrosine kinase inhibitors (TKIs), non-peptides, or Other cell-binding molecules or substances, such as bioactive proteins Limmer (Dhar, et al, Proc. Nat. Acad. Sci. 2008, 105, 17356-61), Dendrimer (Lee, et al, Nat. Biotechnol. 2005, 23, 1517-26; Almutari, et al; Pro. Natl. Acad. Sci. 2009, 106, 685-90), nanoparticles (Ling, et al, ACS Nano, 2008, 19, 1309-12; Medalova, et al, Nat. Med. 2007, 13, 372-7 Javier, et al, Bioparticle Chem. 2008, 19, 1309-12), liposomes (Medinai, et al, Curr. Har. Des. 2004, 10, 2981-9), virus cap (Flenniken, et al). 2009, 327, 71-93), but not limited to these. In general, with a suitable monoclonal antibody, the monoclonal antibody is the most preferred cell conjugate.

A specific polypeptide, protein, drug molecule or other functional molecule is previously attached to the cell conjugate by modifying it with a bifunctional group-containing cross-linking agent prior to conjugate binding with the antimitotic agent. You can stay. These bifunctional group-containing cross-linking agents are amine-non-selective functional cross-linking agent (succinimide (NHS) -dinitrogen ring propylene (SDA), succinimidyl ester-azido), amine-sulfhydryl cross-linking agent (NHS ester-mamareimide). , NHS ester-pyridinedimercapto, NHS ester-haloacetyl), mercapto-sugar crosslinker (maleimide-hydrazide, pyridinedimercapto-hydrazide), hydroxy-mercapto crosslinker (isocyanide-maleimide), amine-DNA crosslinker (NHS ester) / Solarene) and amine-carboxycrosslinkers (carbodiimide) and the like.

In the method of modification with a succinimide (NHS) -dinitrogen ring propylene (SDA) cross-linking agent, the NHS ester in the cross-linking agent first reacts with an amine group on the cell conjugate skeleton (in a buffer solution of pH 6-9). A stable amide bond can be formed and then exposed to a long wave with a wavelength of 330-370 nm to activate the SDA and produce a carbene-reactive intermediate. The connection is complete after the intermediate reacts with the amine group on the specific polypeptide, protein or other functional molecule. The order of these two steps can be changed as follows. First, the amine on the functional molecule and the NHS ester on the cross-linking agent are reacted, and then exposed to light (330 to 370 nm) to carry out a chemical reaction with the cell conjugate. Succinimide (NHS) -dinitrocycle propylene (SDA) crosslinkers are also dissociable (along with SDAD crosslinkers with intramolecular disulfide bonds).

In the method of modifying NHS with an ester-azide crosslinker, the NHS ester in the crosslinker first reacts with an amine group on the cell conjugate skeleton (in a buffer solution of pH 6-9) to form a stable amide bond. The Huisgen azide-alkyne ring addition reaction then reacts the specific polypeptide, protein or other functional molecule alkynyl with the azide of another terminal of the cross-linking agent to form a 1,2,3-triazole linker. be able to. Also, the NHS ester of this cross-linking agent forms a stable amide bond with the amine on the functional molecule (in a buffered solution at pH 6-9), after which the alkynyl on the conjugate is azide at another terminal of the cross-linking agent. It is also possible to form a 1,2,3-triazole linker by carrying out a Huisgen azide-alkyne ring addition reaction.

In the method of modification with an amine-mercapto crosslinker, the NHS ester in the crosslinker first reacts with the amine group on the cell conjugate skeleton (in a buffer solution of pH 6-9) to form a stable amide bond, followed by a stable amide bond. Under conditions of pH 4.5-8.5, the mercapto of a particular polypeptide, protein or other functional molecule is reacted with maleimide, pyridyldithiol or haloacetyl, another terminal of the cross-linking agent, to form a thioether or disulfide bond. Can be formed. The order of this cross-linking reaction can be changed as appropriate. For example, an amino group in a functional molecule can be first reacted with a cross-linking agent to form an amide bond and then reacted with a mercapto on a cell conjugate. Also, for example, under the conditions of pH 4.5-7, the mercapto on the functional molecule first reacts with a cross-linking agent to form a thioether or disulfide bond, and then under the conditions of pH 6-9, the cell conjugate. It can be reacted with the above amino group to form an amide bond.

In the method of modification with a mercapto-sugar crosslinker, under conditions of pH 4.5-8, the mercapto in the cell conjugate reacts with the maleimide or pyridine dimercapto in the crosslinker to form a thioether or disulfide bond, which is then functional. Carbonyls (aldehydes or ketones) in sex molecules can further react with hydrazides to form hydrazone bonds. Alternatively, under conditions of pH 4.5-8, mercapto in the functional molecule reacts with a cross-linking agent to form a thioether or disulfide bond, which is then sugar, oxidized sugar or carbonyl (aldehyde or carbonyl) in the cell conjugate. It can react with a ketone) to form a hydrazone bond.

In the method of modification with a hydroxyl group-mercapto crosslinker, under conditions of pH 6-8, the mercapto on the cell conjugate first reacts with the maleimide or pyridine dimercapto in the crosslinker to form a thioether or disulfide bond, followed by pH 8-8. Under the condition of 9, the hydroxyl group in the functional molecule and the isocyanate in the cross-linking agent can be reacted to produce a carbamate ester. In addition, mercapto in a functional molecule first reacts with a cross-linking agent under conditions of pH 6 to 8 to form a thioether or disulfide bond, and then reacts with a hydroxyl group on a cell conjugate under conditions of pH 8 to 9. The reaction can be carried out to produce a carbamic acid ester.

Another aspect of the invention is the production of antibodies. Among them, in vivo, in vitro generation processes or combinations of processes are included. Methods for preparing anti-receptor peptide polyclonal antibodies are well known. For example, there is US Patent No. 4,493,795 (Nestor et al.). A typical method for preparing monoclonal antibodies is to fuse mouse spleen cells and myeloma cells isolated from specific antigen-immunized mice (Kohler, G; Milstein, C.1975. Nature 256: 495). -497). See Antibodies-A Laboratory Manual, Halloween and Line, eds., Cold spring harbor laboratory press, NY (1988) for a detailed operating process. The method is incorporated in the literature for reference in this application. In particular, special monoclonal antibodies can be obtained by immunizing mice, rats, hamsters, or other mammals with the antigen of interest. Among them, the target antigens include intact cells, antigens isolated from cells, all viruses, all weakened viruses and viral proteins. Spleen cells and myeloma cells are fused using PEG6000. The hybridomas obtained after fusion are screened using the sensitivity to HAT. Monoclonal antibodies produced by hybridoma cells suppress the immune response or receptor activity with specific target cell receptors. This is useful in the practice of the present invention.

The monoclonal hybridoma cells obtained after fusion can secrete antibodies against specific antigens. Currently, the monoclonal antibody used in the invention enriches the antibody by culturing monoclonal hybridoma cells in a nutrient-rich medium. Culture conditions need to ensure that the hybridoma cells have sufficient time to secrete the resulting antibody into the culture medium. After collecting the supernatant of the antibody-containing medium, the antibody is purified by a well-known technique. Isolation methods include protein A affinity chromatography, anion exchange chromatography, cation exchange chromatography, hydrophobic interaction chromatography, and molecular sieve chromatography (particularly affinity chromatography and molecular sieve chromatograph using antigen-crosslinked protein A). Chromatography is commonly used), including centrifugation, precipitation or other standard purification methods.

Medium and artificial synthetic media required for hybridoma culture can be obtained via technical synthesis or commercial routes. Among them, typical artificial synthetic media are DMEM (Vilcol 8: 396 (1959) such as Dulbecco), 4.5 mg / L glucose, 20 mM glutamine, 20% FBS and antifoaming agent (for example, polyoxyethylene poly). Oxypropylene copolymer) is added.

In addition to cell fusion techniques, the following methods can also construct cell lines for producing antibodies. For example, a method of directly transfecting tumor immunogenic DNA into B lymphocytes, or a method of introducing a carcinogenic viral gene (eg, EBV or KSHV also known as HHV-4) into B lymphocytes. (See US Pat. No. 4,341,761; 4399121; 4427783; 4444887; 4451572; 4466917; 4472500; 4491632; 4493890 for details). Monoclonal antibodies can be prepared with anti-receptor polypeptides or terminal carboxyl group-containing polypeptides (see, for details, Niman et al., Proc. Natl. Acad. Sci. USA, 80: 4949-4953 (1983); Geysen et al. Proc. Natl. Acad. Sci. USA, 82: 178-182 (1985); see Lei et al. Biochemistry 34 (20): 6675-6688 (1995)). Generally, an anti-receptor polypeptide or polypeptide analog can be used alone or as a cross-linked immunogenic carrier as an immunogen for preparing an anti-receptor polypeptide for a monoclonal antibody.

In the present invention, there are other commonly used production methods for the antibody of the binding molecule. Of these, the method of producing a fully human antibody has attracted particular attention. Phage display technology provides fully human antibodies that specifically bind to known antigens from a fully human antibody library by affinity selection. The literature provides detailed information on the phage display technology itself, vector construction, and library screening. For details, see Dente et al. Gene. 148 (1): 7-13 (1994); Little et al. Biotechnol Adv. 12 (3): 539-55 (1994); Clackson et al. Nature 352: 264-628 (1991); Huse et al. See Science 246: 1275-1281 (1989).

Monoclonal antibodies obtained by other species (eg, mice) using hybridoma technology need to be denatured for humanization. The denatured antibody can significantly reduce the immune side effects of the heterologous antibody against the human body. Of these, well-known methods for antibody humanization are complementarity determining region transplantation and remodeling. For more information, US Pat. Nos. 5,859,205 and 6797492; Liu et al., Immunol Rev. 222: 9-27 (2008); Almagro et al., Front Bioscii. 1; 13: 1619-33 (2008); Lazar et al. Mol Immunol.44 (8). ): 1986-98 (2007); Li et al., Proc. Natl. Acad. Sci. USA. 103 (10): 3557-62 (2006). The document is incorporated herein by reference. Fully human antibodies can be prepared by subjecting antigen immunization to transgenic mice, rabbits, monkeys and other mammals that carry large amounts of human immunoglobulin light and heavy chains. Examples of mice include Xenomouse (Abgenix, Inc.), HuMab-Mouse (Medarex / BMS), and VelociMouse (Regeneron). For more information, see U.S. Patent Nos. 6596541, 6207418, 6150584, 6111166, 6075181, 5922545, 5661016, 5545806, 5436149 and 5569825. In the process of human treatment, the reactivity produced in the human body by a chimeric antibody constructed by integrating a mouse antibody variable region gene and a human antibody constant region gene is much lower than that of a mouse antibody (Kipriyanov, etc.). , Mol Biotechnol. 26: 39-60 (2004); Houdebine, Curr Opin Biotechnol. 13: 625-9 (2002)). The document is incorporated herein by reference. Furthermore, antibody affinity and specificity can be improved by inducing specific mutagenesis at the site of the antibody variable region (Brannigan et al., Nat Rev Mol Cell Biol. 3: 964-70 (2002); Adams et al. , J Immunol Methods. 231: 249-60 (1999)). The cytotoxic effect can be enhanced by effectively promoting affinity with immune effector cells by partially replacing the constant region of the antibody.

Immune-specific antibodies against malignant cell antigens can be obtained through commercial routes or some commonly used technical methods, such as chemical synthesis or recombinant expression techniques. The coding genes for such antibodies are also obtained by several commercial routes, publications, or conventional cloning sequencing methods, such as the GenBank database or other similar databases.

In addition to antibodies, polypeptides or proteins also, as binding molecules, interact with the corresponding receptors or epitopes on the surface of the target cell by binding, blocking, aggression or other means. As long as these peptides or proteins can specifically bind to an epitope or its corresponding receptor, they need not belong to the immunoglobulin family. These polypeptides are also isolated by techniques similar to phage display antibodies (Szardenings, J Recept Signal Transduct Res. 2003; 23 (4): 307-49). Peptide fragments obtained from a random peptide library are similar to antibodies and antibody fragment applications. A polypeptide or protein molecule maintains its antigen binding specificity by connecting to several macromolecules or media via binding molecules. These macromolecules include albumin, polymers, liposomes, nanoparticles or dendrimers.

Antibodies for conjugating anti-tocilizumab in the treatment of cancer, autoimmune and infectious diseases include 3F8 (anti-GD2 antibody), avagobomab (anti-CA-125 antibody), and absiximab (anti-CD41 antibody (anti-CD41 antibody). Integrin α-IIB)), adalimumab (anti-TNF-α antibody), adalimumab (anti-EpCAM antibody, CD326), aferimomab (anti-TNF-α); aftuzumab (anti-CD20 antibody), alacizumab pegol ) (Anti-VEGFR2 antibody), ALD518 (anti-IL6 antibody), alemtuzumab (also known as Campath, MabCampath, campus, anti-CD52 antibody), altumomab (anti-CEA antibody), anatumomab (anti-tag-72) Antibodies), Anrukinzumab (also known as IMA-638, anti-IL-13 antibody), apolizumab (anti-HLA-DR antibody), alcitumomab (anti-CEA antibody), azelina tocilizumab (anti-L-selectin) CD62L) antibody, Atlizumab (also known as tocilizumab, Actemra, RoACTEMRA's anti-IL-6 receptor antibody), Atorolimumab (anti-akagesal factor antibody), bapineozumab (anti-β-amyloid antibody), baciliximab (anti-β-amyloid antibody) Bacilizumab, antiCD25 (IL-2 receptor α chain) antibody, Bavi infliximab (anti-phosphatidylserine antibody), bavituximab (also known as LymphoScan, anti-CD22 antibody), Bailey adalimumab (also known as BENLYSTA, LymphoStat-B, anti) BAFF antibody), Benralizumab (anti-CD125 antibody), vertilimumab (anti-CCL11 (eosinophilia-forming factor-1) antibody), besilesomab (also known as Scintimun, anti-CEA-related antigen antibody), bevasizumab (also known as Avastin, anti) VEGF-antibody), bicilomab (also known as FibriScint, anti-fibriIIβ chain antibody), vivatuzumab (anti-CD44 v6 antibody), blinatumomab (also known as BiTE, anti-CD19 antibody), Brentuximab (CAC10, anti-CD30 TNFRSF8 antibody) , Briakinumab (anti-IL-12, IL-2) 3 antibodies), canaquinumab (also known as Ilaris, anti-IL-1 antibody), cantuzumab (also known as C242, anti-CanAg antibody), capromab, katsumakisomab (also known as removeab, anti-EpCAM, anti-CD3 antibody), CC49 (Anti-TAG -72 antibody), Cedelizumab (anti-CD4 antibody), race trussutzumab (antibody α also known as CIMZIA anti-TNF-), setuximab (also known as Elvitax, IMC-C225, anti-EGFR antibody), citatsuzumab (anti-EGFR antibody) Anti-EpCAM antibody), Cixutumumab (anti-IGF-1 antibody), keriximab (anti-CD4 antibody), Clivatuzumab (anti-MUC1 antibody), Conatumumab (anti-TRAIL-R2 antibody), CR6261 (Anti-type A influenza hemagglutinin antibody), Dacetuzumab (anti-CD40 antibody), dacrizumab (also known as dacrizumab, anti-CD25 (IL-2α chain receptor) antibody), Daratumumab (anti-CD38 (anti-CD38) ADP ribose hydrolase cyclization antibody), denosumab (also known as prolia, anti-RANKL antibody), against detumomab antibody (anti-B-lymphoma cell antibody), dollimomab, dollixizumab, ecromeximab (anti-GD3 ganglioside antibody) , Ecrizumab antibody (also known as Solidis, anti-C5 antibody), Aval monoclonal antibody (anti-endotoxin antibody), Edrecolomab (also known as Panorex, MAb17-1A, anti-EpCAM antibody), Efarizumab (also known as Raptiva), anti LFA-1 (CD11a) antibody), Eve ancient monoclonal antibody (also known as Mycograb, anti-Hsp90 antibody), Elotuzumab (anti-SLAMF7 antibody), Islamic Limone (anti-IL-6 antibody), Emmo monoclonal antibody (anti-Hsp90 antibody) ICAM-1 (CD54) antibody), Epitumomab (anti-epicialin antibody), Eplatzumab antibody (anti-CD22 antibody), Erlizumab (anti-ITGB2 (CD18) antibody), Ertumaxomab (also known as Rexomun, anti-HER2 /) neu's CD3 antibody), etarasizumab antibody (also known as) : Abegrin, anti-integrin α _v β ₃ ), exhibivirumab antibody (anti-hepatitis B surface antigen antibody (HBs antibody)), fanolesomab antibody (also known as NeutroSpec, anti-CD15 antibody), faralimomab antibody (anti-interferon) Felvizumab (antibody), Farletuzumab (anti-folic acid receptor 1 antibody), Felvizumab (antibody), Fezakinumab (anti-IL-22 antibody), Figitumumab (anti-antibody) IGF-1 receptor antibody), Fontolizumab (anti-IFN-γ antibody), Foravirumab (anti-mad dog disease virus glycoprotein antibody), Fresolimumab (anti-TGF-β antibody), Galiximab (Galiximab) ) (Anti-CD80 antibody), Gantenerumab (anti-amyloid antibody-β), Gavilimomab (anti-CD147 (basigin) antibody), gemtuzumab (anti-CD33 antibody), Girentuximab (anti-carbonide dehydration enzyme 9) Antibodies), Glembatumumab (also known as CR011, anti-GPNMB antibody), Golimumab (also known as SIMPONI, anti-TNF-α antibody), Gomiliximab (anti-CD23 (IgE receptor) antibody), Ibalizumab (anti-antibodies) CD4 antibody), Ibritumomab Ibri (anti-CD20 antibody), Igovomab antibody (also known as Indimacis-125, anti-CA-125 antibody), imciromab (also known as Myoscint, anti-myocardial myosin antibody), infliximab (Also known as Remicade, anti-TNF-α antibody), Intetumumab (anti-CD51 antibody), Inolimomab antibody (anti-CD25 (IL-2 receptor α chain) antibody), Inotumumab (anti-CD22 antibody) ), Ipirimumab (anti-CD152 antibody), Iratumumab (anti-CD30 (TNFRSF8) antibody), Keliximab (anti-CD4 antibody), label Tuzumab (also known as CEA-dide, anti-CEA antibody), Lebrikizumab (anti-IL-13 antibody), Lemalesomab (anti-NCA-90 (granulocyte antigen) antibody), Lerdelimumab (anti-TGFβ-2 antibody) Lexatumumab antibody (anti-TRAIL-R2 antibody), Libivirumab antibody (anti-hepatitis B surface antigen-antibody), lintrastuzumab (anti-CD33 antibody) antibody, Lucatumumab (anti-CD40 antibody), Lumiliximab (Lumiliximab) ( Anti-CD23 (IgE receptor) antibody), mapatumumab (anti-TRAIL-R1 antibody), Maslimomab antibody (anti-T cell receptor antibody), Matsuzumab antibody (anti-EGFR antibody), mepolizumab (also known as Bosatria, Anti-IL-5 antibody), Metelimumab (anti-TGFβ-1 antibody), Milatuzumab (anti-CD74 antibody), Minretumomab (anti-TAG-72 antibody), Mitumomab antibody (also known as BEC- 2. Anti-ganglioside antibody-GD3), Morolimumab (anti-Akagesaru factor antibody), Motavizumab (also known as NUMAX, antibody against respiratory follicles virus), Muromonab-CD3 (also known as OKT3 ORTHOCLONE, Anti-CD3 antibody), Nacolomab antibody (anti-C242 antibody), Naptumomab antibody (anti-5T4 antibody), Natalizumab (also known as Tysabri, anti-integrin α4 antibody), Nebacumab antibody (anti-endotoxin antibody), Necitumumab (anti-EGFR antibody), Nerelimomab (anti-TNF-α antibody), Nimotuzumab (also known as Theracim, Theraloc, anti-EGFR antibody), Nofetumomab, okrelimomab (anti-CD20 antibody), odurizumab (anti-CD20 antibody) Afolimomab, anti-LFA-1 (CD11a)), ofatumumab (also known as Arzerra, anti-CD20 antibody), Oralatumab (anti-PDGF-R α antibody), omalizuma Omalizumuba (also known as Zolea, anti-IgE Fc region of antibody), Oportuzumab (anti-EpCAM antibody), Oregovomab antibody (also known as OvaRex, CA-125 anti-antibody), Otelixizumab ) (Anti-CD3 antibody), Pagibaximab antibody (anti-LTA antibody), paribizumab (also known as Synagis, Abbosynagis, antibody against respiratory follicles virus), Panitumumab (also known as Vectibix, ABX-EGF, anti-EGFR) Antibodies), Panobabacumab (antibodies against pyogenic bacteria), Pascolizumab (anti-IL-4 antibody), Pemtumomab (also known as Theragyn, anti-MUC1 antibody), Pertuzumab (also known as OMNITARG, 2C4, anti) HER2 / neu antibody), pecnatarizumab (anti-C5 antibody), Pintumomab (anti-adenocarcinoma antigen antibody), Priliximab (anti-CD4 antibody), pritumumab (anti-vimentin antibody), PRO140 ( Anti-CCR5 antibody), racotumomab (also known as 1E10, anti- (NN-glycolylneuraminic acid (NeuGc, NGNA) --ganglioside GM3) antibody), rafivirumab (anti-mad dog disease virus glycoprotein antibody), ramsylumab (Ramucirumab) (anti-VEGFR2 antibody), ranibizumab (also known as Lucentis, anti-VEGF-A antibody), Raxisbacumab (anti-carcinogen toxin, defense antigen antibody), Regavirumab (anti-CMV glycoprotein B antibody), Reslizumab (anti-IL-5 antibody), rilotumumab (anti-HGF antibody), rituximab (also known as MabThera, Rituxanmab, anti-CD20 antibody), Robatumumab (anti-IGF-1 receptor antibody), Rontarizumab (Rontalizumab) (anti-IFN-α antibody), revelizumab (also known as LeukArrest, anti-CD11, CD18 antibody), Ruprizumab (also known as Antova, anti-C) D154 (CD40L) antibody), Satsumomab (anti-TAG-72 antibody), Sevirumab (anti-CMV antibody), cibrotuzumab (anti-FAP antibody), cifalimumab (anti-IFN-α antibody), siltuximab (anti-IFN-α antibody) Siltuximab) (anti-IL-6 antibody), cyprizumab (anti-CD2 antibody), (smart) MI95 (anti-CD33 antibody), solanezumab (anti-β-amyloid antibody), sonepcizumab (anti-sphingosin-1-line) Acid antibody), sontuzumab (anti-epicialin antibody), Stamulumab (anti-myostatin antibody), sulesomab (sulesomab (also known as LeukoScan, (anti-NCA-90 (granulocyte antigen) antibody))), Takatsuzumab ( Tacatuzumab) (anti-α-fetoprotein antibody), tadocizumab (anti-integrin αIIbβ3 antibody), tarizumab (anti-IgE antibody), tanezumab (anti-NGF antibody), tapritumomab (taplitumab) Tefibazumab (also known as Aulexis, anti-clamping factor A antibody), terimomab, tenatumomab (anti-tenacin C antibody), teneriximab (anti-CD40 antibody), teplizumab (anti-CD40 antibody), teplizumab (anti-CD40 antibody) , TGN1412 (anti-CD28 antibody), ticilimumab (also known as trimerimumab (anti-CTLA-4 antibody), Tigatuzumab (anti-TRAIL-R2 antibody), TNX-650 (anti-IL-13 antibody), tosirizumab (also known as anti-IL-13 antibody) Atlizumab, Actemra, RoActemra, (anti-IL-6 receptor antibody), tralizumab (anti-CD154 (CD40L) antibody), toshitumomab (anti-CD20 antibody), trussutzumab (herceptin (anti-HER2 / neu antibody), tremelimmumab (tremelimumab) ) (Anti-CTLA-4 antibody), Tucotuzumab celmoleukin (anti-EpCAM antibody), tuvirumab (tuvirumab) ( Anti-hepatitis antibody), Urtoxazumab (antibody against Escherichia coli), Ustekinumab (also known as Stellara, anti-IL-12, IL-23 antibody), Vapaliximab (anti-AOC3 (VAP-1) antibody) ), Vedrizumab (anti-integrin α4β7 antibody), Bertzzumab (anti-CD20 antibody), Vepalimomab (anti-AOC3 (VAP-1) antibody), visilizumab (also known as Nuvion, anti-CD3 antibody), Vitaxin (anti-angiogenic integran avb3 antibody), boroxiximab (anti-integrin α5β1), botumumab (also known as HumaSPECT, CTAA16.88 antibody against tumor antigen), saltumumab (also known as HuMax-EGFr ), Zanolimumab (also known as HuMax-CD4, anti-CD4 antibody), ziralimumab (anti-CD147 (basic immunoglobulin) antibody), zolimomab (anti-CD5 antibody), etanelcept (Enbrel R), Alefacept (AmeviveR), Avatacept (Orencia R), Rilonacept (Arcalyst), 14F7 [anti-IRP-2 (iron regulatory protein 2) antibody], Nat. Cancer Inst to 14G2a (anti) for the treatment of melanoma and solid tumors Ganglioside GD2 antibody), J591 (anti-PSMA antibody, Weil Cornell Medical College), 225.28S [anti-HMW-MAA (high molecular weight melanoma-related antigen) antibody, Sorin Radiofarmaci SRL (Milan, Italy) melanoma In the treatment of], COL-1 (from Nat.Cancer Inst, anti-CEACAM3 antibody for the treatment of colon and gastric cancer, CGM1,), CYT-356 (OncoltadR, treatment of prostate cancer), HNK20 (from OraVax company) ImmuRAIT (for the treatment of non-Hodikin lymphoma from IMMUNOMEDICS treatment), Lym-1 (anti-HLA-DR10 antibody, Peregrine Pharm for the treatment of tumors), MAK -195F (antibodies, toxins Anti-TNF antibody (tumor necrosis factor, TNFA, tumor necrosis factor-α, TNFSF2) from Abbott / Knoll for the treatment of yocks, MEDI-500 [also known as: T10B9, anti-CD3 antibody, TRαβ (T cell receptor α /) β), Composite Material for Treatment of Transplant vs. Host Disease from Medimune], RING SCAN [Anti-TAG72 (72 Tumor Necrosis Factor Antibodies) for the Treatment of Breast Cancer, Colon Cancer and Colon Rectal Cancer from Neoprobe ], Avicidin (anti-EPCAM antibody (epithelial cell adhesion molecule), anti-TACSTD1 antibody (tumor-related calcium signaling 1), anti-GA733-2 (gastrointestinal tumor-related protein 2), anti-EGP-2 antibody (epithelial glycoprotein 2) CD326 from NeoRx for the treatment of anti-KSA antibody, KS1 / 4 antigen, M4S, tumor antigen 17-1A, colon cancer, ovarian cancer, prostate cancer, and non-Hodgkin lymphoma; LYMPHOCIDE (IMMUNOMEDICS, NJ), Smart ID10 (Protein Dessing Labs), Oncolym (Techniclone, California), Allomune (BioTransplant, CA), Anti-VEGF antibody (Genetech, CA); CEAcide (IMMUNOMEDICS, NJ), IMC-1C11 (Imclon, NJ) ) And Setuximab (an antibody company, New Jersey), but not limited to these.

Other antibodies for binding to the antigen include aminopeptidase N (CD13), annexin A1, B7-H3 (CD276, various cancers), CA125, CA15-3 (carcinoma), CA19-9 (carcinoma). , L6 (carcinoma), Lewis Y (carcinoma), Lewis X (carcinoma), α-fetoprotein (carcinoma), CA242, placenta alkaline phosphatase (carcinoma), prostate-specific antigen (carcinoma) Prostate), prostatic acid phosphatase (prostatic), epithelial growth factor (carcinoma), CD2 (hodgkin's disease, NHL lymphoma, multiple myeloma), ε CD3 (T cell lymphoma, lung cancer, breast cancer, gastric cancer, ovarian cancer, Autoimmune disease, malignant ascites), CD19 (B-cell malignant tumor), CD20 (NHL), CD22 (leukemia, lymphoma, multiple myeloma, systemic erythematosus), CD30, CD33, CD38 (multiple myeloma), CD40 (Lymphoma, multiple myeloma, leukemia), CD51 (metastatic melanoma, sarcoma), CD52, CD56 (small cell lung cancer, ovarian cancer, merkel cell cancer, and humoral tumor, multiple myeloma), CD66e (carcinoma) ), CD70 (metastatic renal cell carcinoma and non-hodgkin lymphoma), CD74 (multiple myeloma), CD80 (carcinoma), CD98 (carcinoma), mutin (carcinoma), CD221 (solid tumor), CD227 (breast cancer) , Ovarian cancer), CD262 (non-small cell lung cancer and other cancers), CD309 (ovarian cancer), CD326 (solid tumor), CEACAM3 (carcinoma, gastric cancer), CEACAM5 (carcinoma fetal antigen, CEA, CD66e) ( Breast cancer, colorectal cancer and lung cancer), DLL4 (Δ-like-4), EGFR (epithelial growth factor receptor, various carcinomas), CTLA4 (carcinoma), CXCR4 (CD184, hem tumor, solid tumor), endoglin (CD105, solid tumor), EPCAM (epithelial cell adhesion molecule, bladder, head, neck, colon carcinoma, NHL prostate carcinoma, and ovarian carcinoma), ERBB2 (epithelial growth factor receptor 2; lung carcinoma, breast cancer, prostate carcinoma) , FCGR1 (autoimmune disease), FOLR (folic acid receptor, ovarian cancer), GD2 ganglioside (carcinoma), G-28 (cell surface antigen glycolipid, carcinoma), idiotype GD3 (carcinoma), heat shock protein (carcinoma) ), HER1 (lung cancer, gastric cancer), HER2 (breast cancer, lung cancer and ovarian cancer), HLA-DR10 (NHL), HLA-DRB (NHL, B-cell leukemia), human chorionic gonadotropin (carcinoma), IGF1R (carcinoma) Carcinoma Long factor-1 receptor, solid tumor, hematological cancer), IL-2 receptor (interleukin-2 receptor, T-cell leukemia and lymphoma), IL-6R (interleukin 6 receptor, multiple myeloma, RA) , Castleman's disease, IL6-dependent tumor), Integrin (αVβ3, α5β1, α6β4, αllβ3, α5β5, αVβ5 various cancers), MAGE-1 (cancer), MAGE-2 (cancer), MAGE-3 (Cancer), MAGE-4 (Cancer), Antitransferase receptor (Cancer), P97 (Black tumor), MS4A1 (Transmembrane domain 4 subfamily A member, Non-Hodgkin B cell lymphoma, Leukemia) , MUC1 or MUC1-KLH (breast cancer, ovarian cancer, cervical cancer, bronchial and gastrointestinal cancer), MUC16 (CA125) (ovarian cancer), CEA (colon), gp100 (melanoma), MART1 (melanoma), MPG ( Black tumor), MS4A1 (transmembrane domain 4 subfamily A, small cell lung cancer, NHL), nuclear body, neurocancer gene product (cancer), P21 (cancer), anti (N-hydroxyacetylneuramine) Acid, breast cancer, melanoma cancer), PLAP-like testicular alkaline phosphatase (ovarian cancer, testicular cancer), PSMA (prostatic cancer), PSA (prostatic), RObO4, TAG72 (tumor-related glycoprotein 72, leukemia (AML), gastric cancer, Colon rectal cancer, ovarian cancer), transmembrane protein of T cells (cancer), Thailand (CD202b), TNFRSF10B (tumor necrosis factor receptor superfamily member 10B, cancer), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B, Multiple myeloma, NHL, other cancers, RA and SLE), TPBG (nutrient membrane glycoprotein, renal cell carcinoma), TRAIL-R1 (TNF-related apoptosis ligand receptor 1, lymphoma, NHL, colorectal cancer, lung cancer) , VCAM-1 (CD106, melanoma), VEGF, VEGF-A, VEGF-2 (CD309) (various cancers), but not limited to these. Other tumor-related antigens identified by the antibody have been disclosed (Gerber et al., mAbs 1: 3, 247-253 (2009); Novellino et al., Cancer immunol immunother. 54 (3), 187 -207 (2005) Franke. Etc., cancer biother radiopharm. 2000, 15, 459 --76). Many other antigens include other different clusters (CD4, CD5, CD6, CD7, CD8, CD9, CD10, CD11a, CD11b, CD11c, CD12w, CD14, CD15, CD16, CDw17, CD18, CD21, CD23, CD24. , CD25, CD26, CD27, CD28, CD29, CD31, CD32, CD34, CD35, CD36, CD37, CD41, CD42, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD53, CD54 , CD59, CD61, CD62E, CD62L, CD62P, CD63, CD68, CD69, CD71, CD72, CD79, CD79a, CD79b, CD81, CD82, CD83, CD86, CD87, CD88, CD89, CD90, CD91, CD95, CD , CD103, CD105, CD106, CD109, CD117, CD120, CD127, CD133, CD134, CD135, CD138, CD141, CD142, CD143, CD144, CD147, CD151, CD152, CD154, CD156, CD158, CD163, CD166, CD168 , CDw186, CD195, CD202 (a, b), CD209, CD235a, CD271, CD303, CD304), Apo2, ASLG659, BMPR1B (bone-forming protein receptor), CRIPTO, annexin A1, nuclear body, endoglin (CD105) , RObO4, Aminopeptidase N, Δ-like 4 (DLL4), VEGFR-2 (CD309), CXCR4 9CD184), Tie2, B7-H3, WT1, MUC1, LMP2, HPV E6 E7, EGFRvIII, HER-2 / neu, Idiotype, MAGE A3, P53 non-variant, NY-ESO-1, GD2, CEA, MelanA / MAR T1, Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34, member 2, type II sodium-dependent phosphate transporter 3b), ras variant, gp100, p53 variant, proteinase 3 (PR1), bcr- abl, malformation-derived growth factor), EphA receptor, EphB receptor, EGFr, EGFRvIII, ETBR (endoserine), HER2 / neu, HER3, HLA-DOB (MHC II molecule IA antigen), integrin, IRTA2, MPF (MPF, MSLN, SMR, giant nucleus growth factor, mesocellin), cripto, Sema 5b (FLJ10372, KIAA1445, Mm42015, SEMA5B, 5EMAG, semaphorin 5 bHlog, sdema domain, 7 platelet repeat sequence, cytoplasmic domain), PSCA, STEAP1 6 transmembrane epidermal antigens), and STEAP2 (HGNC8639, IPCA-1, PCANP1, STAMP1, STEAP2, STMP, prostate) tyrosinase, survivin, hTERT, sarcoma translocation cleavage point, EphA2, PAP, ML-IAP, AFP, EpCAM, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, ALK, androgen receptor, cyclin B1, polysialic acid, MYCN, RhoC, TRP-2, GD3, fucose GM1, mesothelin, PSCA, MAGE A1, sLe (a), CYP1B1 , PLAC1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, carbonate dehydration enzyme IX, PAX5, OY-TES1, sperm protein 17, LCK, HMWMAA, AKAP-4, There are SSX2, XAGE1, B7H3, receptor, tie 2, page 4 (Page 4), VEGFR2, MAD-CT-1, FAP, PDGFR-β, MAD-CT-2, Fos protein related antigen 1.

The conjugate of the antimitotic molecule-binding molecule in the present invention can be applied to cancer treatment by different combinations and methods. These cancers include adrenocortical cancer, anal cancer, bladder cancer, and brain tumors (adults, brain stem glioma, children, cerebral stellate cell tumors, brain stellate cell tumors, garment tumors, medullary tumors, and tent primordial nerve epidermoid. And pine fruit tumor, visual tract and hypothalamic glioma), breast cancer, cartinoid tumor, gastrointestinal, cancer of unknown primary origin, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct Cancer, Ewing Family Tumor (PNET), Extracranial Malignant Embryonic Cell Tumor, Eye Cancer, Intraocular Black Tumor, Biliary Sac Cancer, Gastric Cancer (Stomach), Embryonic Cell Tumor, Extragonadal, Pregnant Nutrition Membrane Tumor, Head and Neck Cancer, Pharyngeal cancer, pancreatic islet cell cancer, kidney cancer (renal cell cancer), laryngeal cancer, leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cells), lips and oral cavity Cancer, liver cancer, lung cancer (non-small cells, small cells, lymphoma (AIDS-related, central nervous system, skin T cells, Hodgkin's disease, non-Hojikin's disease, malignant mesoderma, melanoma, Mercel cell cancer, primary unknown) Metastatic flat neck cancer, multiple myeloma and other plasma cell tumors, mycobacterial sarcoma, myelodystrophy syndrome, myelodystrophy syndrome, nasopharyngeal cancer, neuroblastoma, oral cancer, pharyngeal cancer, osteosarcoma, Ovarian cancer (epithelial, germ cell tumor, low malignant potential tumor), pancreatic cancer (exocrine gland, pancreatic islet cell cancer), sinus and nasal cavity cancer, parathyroid cancer, penis cancer, brown cell tumor cancer, pituitary cancer, plasma cells Tumors, prostate cancer, horizontal print myoma, rectal cancer, renal cell carcinoma (renal cancer), renal pelvis and urinary tract (transitional cells), salivary adenocarcinoma, cesarly syndrome, skin cancer, skin cancer (skin-like T-cell lymphoma, capsicum sarcoma) , Black bowel cancer), small bowel cancer, soft tissue sarcoma, gastric cancer, testis cancer, thoracic adenoma (malignant), thyroid cancer, urinary tract cancer, uterine cancer (sarcoma), abnormal cancer in children, vaginal cancer, genital cancer, Wilms tumor Including, but not limited to.

By different combinations and methods, the conjugate of the antimitotic molecule-binding molecule in the present invention can be applied to the prevention and treatment of autoimmune diseases. Autoimmune diseases include autoimmune gastric acid deficiency chronic active hepatitis, acute diffuse encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia, muscular atrophic lateral sclerosis, Tonic spondylitis, anti-globulous basal membrane / tubular basal nephritis, antiphospholipid syndrome, antisynthase syndrome, arthritis, atopic allergy, atopic dermatitis, autoimmune poor regeneration anemia, autoimmune cardiomyopathy , Autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune internal ear disease, autoimmune lymphocyte proliferation syndrome, autoimmune peripheral nervous system disease, autoimmune pancreatitis, multiple autoimmune endocrine disorders I, II , Type III, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune vasculitis, Barlow's disease / Barlow concentric sclerosis, Bechet's disease, Berger's disease, Bickerstaff's encephalitis, Blau syndrome, blisters Syndrome, Castleman's disease, Shagas' disease, Chronic fatigue immune dysfunction syndrome, Chronic inflammatory demyelinating polyneuropathy, Chronic recurrent polyfocal myelitis, Chronic Lime's disease, Chronic obstructive pulmonary disease, Allergies Granulomatous vasculitis, scarring scoliosis, Celiac disease, Cogan syndrome, cold agglutinosis, complement component C2 deficiency, head arteritis, crest syndrome, Crohn's disease (idiopathic inflammatory bowel disease), Cushing syndrome, cutaneous leukocyte crushing vasculitis, malignant atrophic scaly disease, painful steatosis, herpes dermatitis, dermatomyitis, type 1 diabetes, diffuse cutaneous sclerosis, myocardial infarction, discoid erythema. , Eczema, endometriosis, attachment inflammation-related arthritis, eosinophilia myelitis, acquired epidermal vesicular disease, nodular erythema, idiopathic mixed cryoglobulinemia, Evans syndrome, progressive ossifying fibrosis Abnormalities, fibromyalgia, fibromyitis, fibrotic alveolar cystitis, gastrointestinal inflammation, gastrointestinal cystitis, giant cell arteritis, nephrocyte nephritis, Good Pasture syndrome, Basedou disease, Gillan Valley syndrome, Hashimoto encephalopathy , Hashimoto thyroiditis, hemolytic anemia, allergic purpura, gestational herpes, purulent sweat adenitis, Hughes syndrome (antiphospholipid antibody syndrome), hypogamma globulinemia, idiopathic inflammatory demyelinating disease, idiopathic lung Fibrosis, idiopathic thrombocytopenic purpura (autoimmune thrombocytopenic purpura), IgA nephropathy (Berger's disease), inclusion myopathy, inflammatory demyelinating polyneuropathy, interstitial cystitis, hypersensitivity Genticular syndrome, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, mucocutaneous lymph node syndrome, Lambert-Eaton muscle asthenia syndrome, leukocyte-destroying vasculitis, squamous lichen, sclerosing moss Tumor, Linear IgA disease (LAD), Lou Gehrig's disease (muscle atrophic lateral sclerosis), scab-like hepatitis, erythema scab, Blau syndrome, Meniere's disease, microscopic polyangiitis, Miller-Fisher's syndrome, mixed Cohesive tissue disease, strong skin disease, Musha-Jacob's disease, McCull Wells syndrome, multiple myeloma, multiple sclerosis, severe myasthenia, myitis, narcolepsy, optic neuromyelitis (Devik's disease), neuromuscular, eye Scarring nephelosis, Opsocronus myocronus syndrome, eau de thyroiditis, recurrent rheumatism, panda syndrome (child autoimmune neuropsychiatric disorder with comorbid streptococcal infection), tumor cerebral degeneration, paroxysmal nocturnal hemochromatosis, progression Sexual hemi-facial atrophy;, Pakistan-Georgia syndrome, squamous inflammation, vesicles, vulgaris vulgaris, malignant anemia, perivenous cerebral spinal inflammation, POEMS syndrome, nodular polyarteritis, rheumatic polymyopathy, multiple Syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, necrotizing pyoderma, pure erythropoiesis anemia, Rasmussen encephalitis, Reynaud's disease, recurrent Polychondritis, Reiter syndrome, lower limb immobility syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler syndrome, embolitis, scleroderma, Schegren syndrome, spondylosis , Adhesive blood syndrome, Still's disease, Stiffman's syndrome, Subacute bacterial endocarditis, Suzak's syndrome, Acute febrile neutrophil dermatosis, Sidenum butoh disease, Sympathetic ophthalmitis, Hyperan arteritis, Temporal Arteritis (giant cell arteritis), Trosa-Hunt syndrome, transverse myelitis, ulcerative colitis (idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthropathies, vasculitis, leukoplakia, Wegener's granulomatosis, Wilson's Syndrome, Brooke Westcott-Aldrich Syndrome, but not limited to.

In another specific embodiment, as binding molecules for conjugates for the treatment or prevention of autoimmune disorders, anti-erastin antibodies; Abys anti-epithelial cell antibodies; anti-basal membrane type IV collagen protein antibodies. , Anti-nuclear antibody, anti-double-stranded DNA antibody, anti-single-stranded DNA antibody, anti-cardiolipin antibody IgM, IgG; anti-celiac antibody; anti-phospholipid antibody IgK, IgG; anti-SM antibody; Body antibody, T-cell antibody, thyroglobulin antibody, anti-strong skin disease-70 antibody (anti-SCL-70); anti-Jo antibody (anti-Jo), anti-U1RNP antibody (Anti-U.sub.1RNP); anti-La / SSB antibody; anti-SSA antibody; anti-SSB antibody; wall cell antibody; anti-histon antibody; anti-RNP antibody; C-ANCA; P-ANCA; anti-centromea antibody; anti-fibrin antibody, anti-GBM antibody, anti-ganglioside antibody; anti-desmosome Includes glycoprotein 3-core antibody (anti-Desmogene 3), anti-P62 antibody, anti-SP100 antibody, anti-mitichomic M2 antibody, rheumatoid factor antibody, anti-MCV antibody; anti-topoisomerase antibody; anti-neutrophil cytoplasmic (cANCA) antibody. Not limited to these.

In some preferred embodiments, the binding molecule used for the conjugated conjugate in the present invention is capable of binding to a receptor or receptor complex expressed by activated lymphocytes associated with an autoimmune disease. The receptor or receptor complex is, for example, a member of the immunoglobulin gene superfamily (eg, CD2, CD3, CD4, CD8, CD19, CD22, CD28, CD79, CD90, CD152 / CTLA-4, PD-1 or ICOS), TNF Receptor Superfamily (eg CD27, CD40, CD95 / Fas, CD134 / OX40, CD137 / 4-1BB, INF-R1, TNFR-2, RANK, TACI, BCMA, Osteoprotein, Apo2 / Apo2 -R1, TRAIL-R2, TRAIL-R3, TRAIL-R4 and 30 APO-3), integrin protein, cytokine receptor, chemokine receptor, major tissue compatible protein, lectin (type C, type S or type I), Alternatively, a complement-regulating protein may be mentioned.

In another specific embodiment, a useful conjugate having immunospecificity against a viral or bacterial antigen is a humanized or human monoclonal antibody. The term "viral antigen" used in the text refers to any viral peptide, polypeptide protein (eg, HIVgp120, HIV nef, RSVF glycoprotein, influenza virus neurominidase, influenza virus blood cell aggregation) that can elicit an immune response. It includes, but is not limited to, elementary, HTLVtax, simple herpesvirus glycoproteins (eg, gB, gC, gD and gE), and hepatitis B surface antigens. The term "bacterial antigen" used in the text refers to any microbial peptide, polypeptide, protein, carbohydrate, polysaccharide, lipid molecule (eg, bacteria, fungus, pathogenic protozoa, yeast) that can elicit an immune response. Contains, but is not limited to, polypeptides (eg, LPS and capsular polysaccharide 5/8, etc.). Type I antibodies useful in the treatment of viral or bacterial infections include parivismab (human antirespiratory spore virus monoclonal antibody used in the treatment of RVS infection), PRO542 (CD4 fusion antibody used in the treatment of HIV infection), Ostavir ( Human antibodies used in the treatment of hepatitis B virus), PROTVIR (human antibody IgG.sub.1 antibody used in the treatment of cytomegalovirus), antilipopolysaccharide (anti-LPS) antibody, but not limited to these.

The binding molecule-antimitotic conjugate of the present invention has been used in the treatment of infectious diseases. These infectious diseases include asinetobacter infection, actinomycete, African sleep disease (African tripanosoma), AIDS (acquired immunodeficiency syndrome), amoeba disease, anaplasma, charcoal, bacterial tuberculosis infection, hemolytic secret Argentine hemorrhagic fever. , Roundworm disease, Aspergillosis, Astrovirus infection, Babesia disease, Seleus infection, Bacterial pneumonia, Bacterial vaginal inflammation, Bacteroides infection, Valantedium disease, Bailey nematode roundworm infection, BK virus infection, Black sand hair, Blastosishominis infection, Blast Mrs., Bolivian hemorrhagic fever, Borrelia infection, Botulinum poisoning (and infant botulinum disease), Brazilian hemorrhagic fever, Brucella disease, Bohuoerde tuberculosis infection, Bruli ulcer, infectious calicivirus (norovirus, sapovirus) , Campylobacter infection, Candida infection (Candida disease, scab), Cat scratch disease, Honeycombitis, Shagas disease (American tripanosoma disease), Soft scrotum, varicella, Cloth progenitor, Pneumonia Cloth progenitor infection, Disturbance, Colored fungal disease, Liver sucking insect Diseases, Crostridium difficile infection, Coccidioidesosis, Colorado tick fever, cold (acute viral nasopharyngitis, acute rhinitis), Kreuzfeld-Jakob disease, Crimea-Congo hemorrhagic fever, cryptococcus, cryptospolidium, skin larvae migration, cyclospora Infectious disease, cyst disease, cytomegalovirus infection, dengue fever, dinuclear amoeba disease, diphtheria, cleft cleft streak disease, medina worm disease, Ebola hemorrhagic fever, cyst disease, aerrichia disease, worm (worm worm infection), enterococcal infection , Enterovirus infection, rash typhoid, infectious erythema (fifth disease), acute rash in children, hypertrophic worm disease, unilateral worm disease, lethal familial insomnia, filariasis, food poisoning caused by Welsh bacteria, non-parasitic amoeba Infectious disease, fuzobacterium infection, gas necrosis (Crostridium muscle necrosis), geotricum disease, Gerstmann-Stroisler-Shineker syndrome, rumble whiplash, nasal ulcer, jaw-mouthworm disease, gonorrhea, inguinal granulomas (Donovan disease) , Group A streptococcal infection, Group B streptococcal infection, influenza infection, limb mouth disease (HFMD), Hantavirus lung syndrome, Helicobacter pylori infection, hemolytic urinary toxicosis syndrome, nephropathy hemorrhagic fever, type A Hepatitis, hepatitis B, hepatitis C, hepatitis D, hepatitis E, simple herpes, histoplasmosis, worm infection, human vulcan virus infection, human errichia evance, human granulocyte anaplasmosis, human meta Pneumovirus infection, human monocytic A. Liquia disease, human papilloma virus infection, human parainfluenza virus infection, small streak disease, influenza, isosporosis, Kawasaki disease, mononuclear (sphere) disease, Kim bacterium infection, Cooloo, Lassa fever, Regenerosis (local military personnel), Resionerosis (Pontiac fever), Lieschmania, Hansen's disease, Leptospyrosis, Listeria, Lime's disease (Limeborelia), Lymphophilaria (elephant skin disease), Lymphocytic Choroidal meningitis, malaria, Marburg hemorrhagic fever, measles, rhinorrhea (Whitmore disease), meningitis, meningitis fungal disease, metagonimosis, microspore disease, infectious soft tumor, epidemic parotid inflammation , Rash typhoid (climate rash typhoid), mycoplasma pneumonia, myoma, fly disease, neonatal conjunctivitis (neonatal ophthalmitis), Kreuzfeld-Jakob disease (vCJD, nvCJD), nocardiosis, oncoselka disease (blind filariasis), vice Coccidiosis (South American Blast Mrs.), Pulmonary infectious disease, Pastorella disease, Atamajirami (Atamajirami), Body shirami disease (Body shirami), Kejirami disease (Kejirami, Crabice), Infectious pelvic disease, Pertussis (Wooping disease) , Pneumococcal infection, Carini pneumonia, pneumonia, polio, prebotera infection, PAME, progressive multifocal leukoencephalopathy, parrot disease, Q fever, mad dog disease, rat bite fever, respiratory follicles virus infection, rhinovirus infection, Rikecchia infection, Rikecchia, Rift Valley fever, Rocky mountain erythema fever, Rotavirus infection, wind rash, salmonerosis, SARS (severe acute respiratory syndrome), scab, sedation, sepsis, diarrhea (red diarrhea), herpes zoster ( Herpes zoster), natural pox, sporotricum, staphylococcal food poisoning, staphylococcal infection, nematodes, syphilis, stellate disease, tetanus (opening disorder), tinea pedis (Barber's itch), tinea pedis, black scab Eruption, tinea pedis, tinea pedis, flu, toxocarosis (eye larvae migrating disease), toxocarosis (visceral larvae migrating disease), toxoplasmosis, curly worm, trichomoniasis, cryptobiosis (whistle worm infection), pulmonary tuberculosis Includes illness, rabbit disease, urea-degrading urea mycoplasma infection, Venezuelan encephalitis, Venezuelan hemorrhagic fever, viral pneumonia, Westnile fever, gray root granulitis, pseudotuberculous infection, ersinia, yellow fever, zygomyosis , Not limited to these.

The binding molecule described in the preamble of the present specification, preferably an antibody, can be used for the following anti-pathogenic strains. Antipathogenic strains include Acinetobacta baumani, Israeli actinomycetes, Actinomyces odontolyticus and actinomyces odontolyticus and varicella-zoster pyonipropionic acid, tripanosoma bluesei, HIV (human immunodeficiency virus), diarrhea amoeba, anaplasma genus. , Charcoal bacterium, Methylshemoriticum (Arcanobacterium haemolyticum), Funin virus, Roundworm, Aspergillus, Astrovirus family, Babesia genus, Seleus bacterium genus, Multiple bacteria, Bacteroides genus, Colon pouch fiber worm, Bailey roundworm nematode , BK virus, Piedraia hortae, Blastcystis hominis, dermatitis blast fungus, Macpo virus, borrelia, botulinum, savia, brucella, usually barkholderia sepacia and other barkholderia Species, Mycobacterium urserans, Calicivirus family, Campylobacter, usually Candida albicans and other Candida species, Bartonella henselae, Group A varicella and staphylococcus, Cruztripanosoma, Varicella zoster Bacteria, Varicella-zoster virus (VZV), Chlamydia trachomatis, Chlamydia pneumoniae, Cholera, Fonsecae pedrosoy, Liver worm disease, Crostridium dificile, Coxigiodes imitis, Coccidioides posadashi, Colorado tick virus Virus, Kreuzfeld-Jakob's disease-Prion, Crimea-Congo hemorrhagic fever virus, Cryptocox neoformans, Cryptosporidium, cat worm, coparasite, cyclospora, varicella-zoster, cytomegalovirus, dengue virus (DEN) -1, DEN-2, DEN-3 and DEN-4)-Flavivirus, vulnerable dual-core amoeba, corinebacterium diphtheria, varicella-zoster, varicella-zoster, eboravirus, echinocox, Erikia, worm, enterococcus, enterovirus, rash varicella-zoster, parvovirus B19, human herpesvirus 6, human herpesvirus 7, hypertrophic insect, hepatic and giant hepatic worm, FFI prion, filaria head superior, Welsh Fungus, virus Virus, Welsh virus, other genus Clostridium, Geotricum candidium, GSS prion, rumble whipworm (Giardia lamblia), Burkeholderia nasal bacillus, jaw-mouth-jaw nematode, stinging-jaw worm, gonococcus, granulomatosis, suppuration Streptococcus agaractier, influenza, intestinal virus, most coxsackie type A virus, intestinal virus type 71, sinnomble virus, helicobacter pyrori, Escherichia coli O157: H7, Bunyavirus family, hepatitis A virus, type B Hepatitis virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, simple herpesvirus type 1, simple herpesvirus type 2, histoprasma capslatum, duodenal worm, American worm, influenza bacterium, boca human virus, Erikia Ewingi (Ehrlichia ewingii), Anaplasma fagosite film, human metapneumovirus, Ehrlichia chafensis, human papillomavirus, human parainfluenza virus, dwarf worm, reduced streak, Epstein bar virus, orthomixovirus family, isospora・ Beri (Isospora belli), Kingella kingae, pneumonia rod, Klebsiella ozena, Klebsiella rhinoscleromotis, Couruprion, Lassa fever virus, Legionella pneumophila, , Leishmania, Hansen and Mycobacterium lepromatosis, Leptospira, Listeria, Borrelia disease and other Borrelia species, Bancroft filamentous worm and Murray filamentous worm, Lymphocytic choroiditis virus (LCMV) ), Plasmodium genus, Marburg virus, measles virus, Burkholderia pseudomallei, meningitis, Yokokawa sucker, microspore phylum, infectious soft tumor virus (MCV), mumps virus, Rikecchia tifi, mycoplasma pneumoniae, various bacteria (actinomysetoma) and fungi (fungal myoma), dipteran of parasitic fly larvae, chlamydia trachomatis and gonococci, vCJD prion, nocardia asteroides and other nocardia Seeds, times Rickettsia, Brazilian Blast Mrs., Pulmonary Sucker and Other Pulmonary Suckers, Rickettsia, Rickettsia, Rickettsia, Phthirus pubis, Pertussis, Pest, Pneumococcus, Pneumocystis cyst, Polyovirus, Prebotera , Negrelia amoeba, JC virus, parrot disease chlamydia, cocciella burnetti, mad dog disease virus, bead chain Escherichia coli and rat bite fever spirochete, respiratory RS virus, Siberian nasal bump, rhinovirus, rickettsia genus, rickettsia tick, rocky mountain erythema Fever rickettsia, rickettsia rickettsia, rotavirus, ruin virus, salmonella, atypical pneumonia coronavirus, tinea mite, venom worm, tinea, varicella virus, tinea pedis and tinea, spirochetes shenky, staphylococcus, Rickettsia, Rickettsia, Rickettsia, Rickettsia, Rickettsia, Rickettsia, Rickettsia, Trichophyton tonsulans, Trichophyton tonsulans, Trichophyton, Epidermophyton, Floccorum, Trichophyton and Trichophyton, Trichophyton Bacteria, Holtea Welnecki, Trichophyton, Maracetia, Canine roundworm and Cat roundworm, Toxoplasma, Spirochaetes, Vaginal tricomonas, Whipworm, Tuberculosis, Tula hot Frances bacterium, Ureaplasma ureariticam, Venezuelan encephalitis virus, Cholera Bacteria, guanaritovirus, western Nile virus, ringworm, pseudotuberculosis, enteritis ersinia, yellow fever virus, rickettsiae (Mucorosis) and insect mesh mold (Entomovtra disease), tinea bacillus, Campylobacter fetal (Vibrio) Aeromonas bacterium, Edward Sierra. Talda, Pest, Shiga rickettsiae, rickettsiae, rickettsiae, rickettsiae, treponema pertenue, treponema karateneum, fensembrugdolferi, borrelia burgdolferi, leptspiral hemorrhagic jaundice, pneumocystis Karini, bovine abortion, porcine abortion, fever, Maltese fever, mycoplasma, rash rickettsia, rickettsia, rickettsiae, chlamydia, pathogenic fungi (Aspergillus fumigatus, Candida albicans, Histoplus macaps ratum); Protozoa (red diarrhea amoeba, Vaginal tricomonas, human tricomonas, tripanosoma gambience, rhodesia tripanosoma, donovan rickettsia, rickettsia tropical, rickettsia Brazil, pneumocystiscarini pneumonia, vivax mala Lear protozoa, Plasmodium falciparum, malignant malaria); or helminths (Schistosoma japonicum, Schistosoma mansson, Schistosoma haematobium and hookworm), but not limited to these.

Other antibodies are used as binding ligands of the present invention in the treatment of the following viral diseases. These pathogenic virus antigens include Poxylidae, herpesvirus, adenovirus, papovavirus, enterovirus, small RNAvirus, parvovirus, leovirus, retrovirus family, influenza virus, parainfluenza virus. , Epidemic parotid adenitis, measles, respiratory symptom virus, wind rash, arbovirus, rabdovirus, arenavirus family, non-A / non-B hepatitis virus, rhinovirus, coronavirus, rotavirus, tumor virus [eg , HBV (hepatocellular carcinoma), HPV (cervical cancer, anal cancer), Kaposi sarcoma-related herpesvirus (Kaposi sarcoma), EB virus (nasopharyngeal cancer, Berkit lymphoma, primary central nervous system lymphoma), MCPyV (Merkel) Cellular cancer), SV40 (Simian virus 40), HCV (hepatocellular carcinoma), HTLV-I (adult T-cell leukemia / lymphoma)]; Immune diseases caused by the virus: [eg, human immunodeficiency virus (AIDS)], CNS virus: [For example, JCV (progressive multifocal leukoencephalopathy), MeV (subacute sclerosing panencephalitis), LCV (lymphocytic choriomyelitis), arbovirus encephalitis, orthomyxovirus virus family (probably) (Drowsiness encephalitis), RV (mad dog disease), bullous stomatitis, herpesvirus meningitis, Ramsey-Hunt syndrome type II; poliovirus (acute gray-white myelitis, post-porio syndrome), HTLV-I (tropical spastic paralysis) )]; Cytomegalovirus (CMV retinitis, HSV (herpes keratitis)); Cardiovascular virus [eg CBV (carditis, myocarditis)]; Respiratory system / acute nasopharyngitis / viral pneumonia: [EB virus (EBV infection / infectious mononuclear cell disease), cytomegalovirus, SARS coronavirus (severe acute respiratory syndrome), orthomixovirus virus family: influenza virus A / B / C (influenza / bird influenza) ), Paramyxovirus: Human parainfluenza virus (parainfluenza), RSV (human respiratory vesicle virus), hMPV]; Digestive virus [MuV (epidemic parotitis), cytomegalovirus (CMV esophagitis) ); Adenovirus (Adenovirus infection); Rotavirus, Norovirus, Astrovirus, Coronavirus, HBV (Hepatitis B virus), CBV, HAV (Hepatitis A virus), HCV (Hepatitis C Wi) Ruth), HDV (hepatitis D virus), HEV (hepatitis E virus), HGV (hepatitis G virus)]; including urogenital system viruses [eg, BK virus, MuV (mumps)] However, it is not limited to these.

According to a further goal, the present invention also includes combining the conjugated drug component with another available drug carrier to provide a therapeutic drug for cancer and autoimmune diseases. In the present invention, methods for treating cancer and autoimmune diseases include in vitro, in vivo or ex vivo therapies. Examples of applications of in vitro therapy include treating cultured in vitro cells with a drug to kill all cells except cells that do not express the target antigen, or kill cells that express an undesired antigen. As an example of the treatment method of Exvivo therapy, there is an example in which hematopoietic stem cells are treated in vitro to kill the affected area or malignant cells and then return them to the patient's body. For example, in the clinical case, cancer and autoimmune diseases are treated by eliminating tumor cells in the bone marrow or lymphocytes by exobibo therapy and then returning them to the body of the former patient, or T in the bone marrow before transplantation. Prevents the immunoantagonism of the implant by removing cells and other lymphocytes. The implementation method is as follows. After acquiring bone marrow cells from a patient or another individual, the cells are cultured at 37 ° C. in a serum-containing medium containing the conjugate drug of the present invention. The drug concentration range is 1 pM to 0.1 mM, and the culture time is about 30 minutes to about 48 hours. The specific concentration and time of the drug will be determined by an experienced clinician. After completion of the culture, the bone marrow cells are washed with a serum-containing medium and then injected into the human body by intravenous injection. If the patient requires other treatment (eg, ablation radiation therapy or systemic chemotherapy) prior to bone marrow cell acquisition or reinjection therapy, the treated bone marrow cells are stored in a standard liquid nitrogen medical device. can do.

For clinical application in vivo, the conjugated drug of the present invention is provided in the form of a solution or in the form of a lyophilized solid that can be injected after being dissolved in sterile water. Examples of suitable conjugated drug administration methods are as follows. The weekly intravenous infusion of the conjugated drug will continue for 8 weeks. A single dose can be dissolved in 50-500 mL saline and human serum albumin can be added to the saline (eg 0.5 ml-1 ml 100 mg / ml concentrated human serum albumin). The drug dose is approximately 50 μg to 20 mg / kg body weight per week and is intravenous injection (each injection is 10 μg to 200 mg / kg body weight). After 8 weeks of treatment, the patient will be eligible for a new round of treatment. Detailed treatment methods, including routes of administration, excipients, diluents, dosages, and duration of treatment, will be determined by an experienced clinician.

Examples of treating the disease by selectively killing the cell population by in vivo or ex vivo methods include any type of cancer, autoimmune disease, transplant rejection, and (including viruses, bacteria or parasites). There is an infection.

The amount of conjugated drug required for the ideal biological effect depends on multiple factors. These factors include the nature characteristics of the compound, efficacy and bioavailability of the conjugate drug, disease type, patient race, patient pathology, route of administration, and these factors work together on the dosing schedule. And the route of administration will be decided.

In summary, the conjugated drug of the present invention may be for parenteral administration dissolved in physiological buffer in a volume ratio of 0.1-10% by weight. Typical doses are 1 μg to 0.1 g / kg body weight per day. The recommended drug dose range is 0.01 mg to 20 mg / kg body weight per day, or an equivalent dose for children. The recommended drug dose depends on the following variables: For example, the type of disease or disorder in the selected mode of administration, the overall health of the individual patient, the relative biological activity of the conjugate drug, the dosage form of the compound, the mode of administration (intravenous, intramuscular,, Or others), pharmacokinetic properties, as well as dosing rate (single or continuous infusion) and dosing schedule (frequency of dosing within a given time).

The conjugate drug of the present invention can be administered in unit doses. Here, the "unit dose" means a single dose administered to one patient. The unit dose of the drug can be used in simple and convenient packaging, and the unit dose of the drug can be the conjugated drug itself, or the pharmacy described below, to maintain physically and chemically stable activity. It is a physically acceptable mixture. Typical daily doses range from 0.01 to 100 mg per kilogram of body weight. Generally, the unit dose ranges from 1 to 3000 mg per day. The recommended unit dose is 4 times daily, 1 mg to 500 mg; or 10 mg to 500 mg once daily. The conjugate drug of the present invention can be prepared by adding one or more pharmaceutically acceptable excipients to a pharmaceutical preparation. Unit doses of the drug are as tablets, simple capsules or soft capsules for oral administration; as powders, nasal drops, or aerosols for intranasal administration; or for skin administration, eg ointments, It can be administered as a cream, lotion, gel or spray or skin patch. The drug can be conveniently administered in unit dosage form and can be prepared by any known method of pharmacy. For example, refer to the method described in "Remington: The Science and Practice of Pharmacy, 21th ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005".

The drug dosage form containing the compound of the present invention contains a pharmaceutical composition and is preferably administered orally or extraintestally. For example, orally administered drug dosage forms such as tablets, powders, capsules and tablets (sugar-coated tablets) can contain one or more of the following ingredients or other compounds with similar properties. For example, binders such as microcrystalline cellulose or tragacant rubber; diluents such as starch or lactose; dispersants such as starch, cellulose derivatives; lubricants such as magnesium stearate; flow promoters such as colloidal silica Body; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint and methyl salicylate. Capsules are obtained in the form of hard or soft, with a mixture of gelatin, optionally mixed with a plasticizer, as well as starch capsules. In addition, the physical form of the unit of administration can be added to a variety of different materials, such as sugar coating, shellac or enteric solvent. Other oral dosage forms such as syrups or elixirs can include sweeteners, preservatives, pigments, colorants and seasonings. In addition, the active compound can be prepared in a fast-dissolving dosage form, a sustained release form or a sustained release dosage form by another treatment and formulation, preferably the dosage form is a sustained release dosage form. A preferred tablet formulation is a mixture containing lactose, cornstarch, magnesium silicate, sodium croscarmellose, povidone, magnesium stearate, talc and the like.

Liquid formulations for extraintestinal administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The liquid agent may contain a binder, a buffer, a preservative, a chelating agent, a sweetening agent, a flavoring agent, a coloring agent and the like. Non-aqueous solvents include vegetable oils such as ethanol, propylene glycol, polyethylene glycol, olive oil, and organic lipids such as ethyl oleate. Aqueous solvents include a mixture of water, ethanol, buffer and salt. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyethylene glycol / polyglycerin copolymers can be used as release control excipients for active agents. Excipients for intravenous injection can include liquid and nutritional supplements, electrolyte supplements and excipients based on Ringer's dextrose, and similar materials. Other possible extraintestinal delivery systems for the activators of the invention include ethylene-vinyl acetate copolymer particles, implantable osmotic pumps, and liposomes.

Other possible modes of administration include inhalants, which include dry powders, aerosols and drops. The inhalant may include, for example, polyoxyethylene-9-lauryl ether, glycocholate, deoxycholate or an oily solution, which is colloidally administered intranasally by nasal drops. The troche agent may include tablets, tablets such as candy and the like, and flavors such as sucrose, gum arabic and other accessories such as glycocholates. Suppositories suitable for unit dosage forms may include salicylic acid added to a solid carrier such as cocoa butter. The skin topical preparation is preferably a plaster, emulsion, lotion, patch, gel, spray, aerosol or oil preparation. Vaseline, lanolin, polyethylene glycol, alcohol, and mixtures thereof can be used as drug carriers. The skin dosage form can be dissolved or dispersed in patches, emulsions, buffers, polymers or adhesives.

In particular, the conjugated drugs of the invention are other known drugs, such as chemotherapeutic agents, radiotherapeutic agents, immunotherapeutic agents, autoimmune disease therapeutic agents, anti-infective agents, or other antibody drugs, or unknown drugs. Can be used in combination with to achieve a synergistic effect. Synergistic or radiation therapy can be administered or administered before or after the conjugate drug of the invention, for 1 hour, 12 hours, 1 day, 1 week, 1 month before or after the conjugate drug of the invention. It can be administered later, but may be several months.

In other embodiments, synergistic drugs include, but are not limited to:

1) Chemotherapeutic agent: Alkylating agent: a). For example, [Nitrogen mustard: (chlorambusyl, cyclophosphamide, ifofamide, mechloretamine, merphalan, trophosphamide); nitrosourea compound: (carmustin, romustine); (Busulfane, Treosulfan); Triasen (dacarbazine); Platinum-containing compounds: (Carboplatin, cisplatin, oxaliplatin)]; b) Plant alkaloids: For example [vincaalkaloids: (vincristine, vinblastine, bindesin, vinorelbine); taxoid compounds : (Pacrytaxel, docetaxel)]; c). DNA topoisomerase inhibitors: eg, [epipodophylline: (9-aminocamptothecin, camptothecin, chrysnator, etopocid, phosphate etopocid, irinotecan, teniposide, topotecan); mitomycin: (mitomycin). C)]; d). Metabolic antagonists: eg {[anti-folic acid: dihydrofolate reductase inhibitors: (methotrexate, trimetrexate); IMP dehydrogenase inhibitors (mycophenolic acid, thiazofurin, rivavirin, EICAR); ribonucleotides Reductase inhibitors (hydroxycarbamide, deferroxamine)]; pyrimidine analogs: uracil analogs (5-fluorouracil, doxiflulysine, larcitrexed (tomudex)); citocin analogs: (citarabin, citarabin, fludalabine); purine analogs: (azathiopurine) , Mercaptopurine, thioguanine)]}; e) Hormones: For example, {Receptor antagonists: [Anti-estrogen: (Megestrol, Laroxyphen, Tamoxyphen); LHRH agonists: (Gocerelin, Leuprolide acetate); Anti-androgen: (Vincristine) , Flutamide)]; Retinoid / Triangular Muscle: [Vintimate D3 analogs (CB1093, EB1089 KH1060, Cholecalciferol, Vitamin D2), Photodynamic therapies: (Vinorelbine, PC4, Demethoxyhypoclerin); (Interferon-α, Interferon-γ, Tumor necrosis factor (TNF), human protein-containing TNF domain)]}; f) Kinase inhibitors: eg bibw 2992 (anti-EGFR / Erb2), imatinib, gefitinib, pegaptanib, sorafenib, Dasatinib, snichinib , Erlotinib, nilotinib, lapatinib, axitinib, pazopanib. Bandetanib, e7080 (anti-VEGFR2), mubritinib, ponatinib, bafetinib (ap24534), HQP1351, bafetinib (INNO-406), bostinib (SKI-606), snitinib, cabozantinib, volitinib, bismodegib , Bebasizumab, sorafenib, trastuzumab, cetuximab, ranibizumab, panitummab, ispinesib; g) Other categories: eg gemcitabine, epoxomicin (eg lenalidemid), bortezomib, salidamide 9090, Stimuvax, Arovectin-7, Zygeba, Provenge, Elvoy, Isoprene inhibitors (eg, robastatin), dopaminergic neurotoxins (eg, 1-methyl-4-phenylpyridine ion), cell cycle inhibitors (eg, su) Taurosporin), dactinomycin (eg, dactinomycin D, cosmegen), bleomycin (eg, bleomycin bleomycin A2, B2, pepromycin), anthracyclin (eg, daunomycin, doxorubicin (adriamycin), idarubicin, epirubicin, pyrarubicin, sorbicin) , Mitoxanthron, MDR inhibitor (eg bellapamil), Ca ²⁺ ATP inhibitor (tapsigargin), histone deacetylase inhibitor (bortezomib, lomidepsin, panobinostat, valproic acid, mosetinostat (MGCD0103), verinostat, PCI-24781 , Entinostat, SB939, Resminostat, Gibinostat, AR-42, Sulforaphan, Tricostatin A); Tapsigargin, Cetuximab, Glytazone, Epigalocatecingalate, Disulfiram, Salinosporamide A.

2) Anti-autoimmune disease drugs: cyclosporine, cyclosporin A, azathioprine, aminocaproic acid, bromocryptin, chlorambusyl, chloroquin, cyclophosphamide, corticoid (eg, hormonal agents, betamethasone, budesonide, flunisolide, fluticazone propionate, hydrocortisone, dexamethasone) , Fluocortodanazole, triamcinolone acetonide, betamethasone dipropionate), dehydroisoandrosterone, etanelcept, hydroxychloroquine, infliximab, meroxycam, methotrexate, mofetil mycophenolate, sirolimus, tacrolimus, prednisone, but not limited to these.

3). Anti-infective agents: aminoglycoside: amikacin, astromycin, gentamicin (netylmycin, cisomycin, isepamicin), hyglomycin, kanamycin (amikacin, albecacin, aminodeoxykanamycin, dibecasin, tobramycin), neomycin (neomycin B, paromomycin, tobramycin) Mycin), netylmycin, spectinomycin, streptomycin, tobramycin, verdamicin; b). Amfenicol: Azidum phenicol, chloramphenicol, fluorophenicol, thianphenicol; c). Ansamycin: geldanamycin, Herbimycin; d) Kanamycin: Viapenem, Dripenem, Eltapenem, Amikacin / Silastatin, Melopenem, Panipenem; e). Phosphorus, cephalexin, cephalogricin, cephamandol, cephapyrin, cephatridin, cefazaflu, cefazedon, cefazoline, cefbuperazone, cefcapene, cefdaloxime, cefepim, cefminox, cefoxidin, cefprodil, cefminox, cefoxidin, cefprodil, cephalosporin Cefepim, cefetameth, cefmenoxym, cefodidim, cefonicid, cefoperazone, cefolanide, cefotaxim, cefotiam, cefosoplan, cephalexin, cefpymizole, cefpyramid, cefpyrom, cefpodoxime, cefpyrom, cefpodoxime, cefprodil Xon, cefloxim, cefazolinefuran, cefamicin (cefoxitin, cefotetan, cefmethazole), oxacephem (flomoxef, ratamoxef); f). Glycopeptides: neomycin, vancomycin (oritavancin, teravancin), teicopranin (dalvavancin), lamoplanin, cubicin; g). Glycyrrhiclin: eg, tigecycline; h). β-lactamase inhibitors: penum (sulbactam, tazobactam), clavam (clavamic acid); i). lincosamide: clindamycin, Lincomycin; j). Rifampicin: daptomycin, A54145, calcium-dependent antibiotic (CDA); k). Macrolides: azithromycin, cesromycin, clarisromycin, girisromycin, erythromycin, fururisromycin, josamicin, ketride ( Telithromycin, Esselomycin), Midekamycin, Myocamycin, Oleandomycin, Rifampicin (Rifampicin, Rifampin, Rifabtin, Rifapentin), Lokitamycin, Loxythromycin, Spectinomycin, Spiramycin, Tachlorimus (FK506), Trolley Andomycin, telithromycin; l). Single-ring β-lactam antibiotics: azthreonum, tigemonum; M) oxazolidinone: linezolide; N) penicillin: amoxicillin, ampicillin (pivanpicillin, hetacillin, bacampicillin, methanepicillin, tarampicin) , Azlocillin, Penicillin, Benzatin Penicillin, Phenoxybenzatin Penicillin, Chrometocillin, Procaine Penicillin, Carbenicillin (Carindacillin), Chloxacillin, Dicloxacillin, Sepharosporin, Flucloxacillin, Mecilinum (Pibmesylinum) Sodium, pheneticillin, penicillin, pheneticillin, penicillin, piperacillin, propycylin, sulbenicin, temocillin, ticarcillin; o). Clinafloxacin, danofloxacin, difloxacin, enoxacin, enlofloxacin, ophroxacin, galenoxacin, gachifloxacin, gemifloxacin, grepafloxacin, Kanotrovafloxacin, levofloxacin, romefloxacin, malvofloxacin, moxyfloxacin , Nadifloxacin, Norfloxacin, Orbifloxacin, Ophroxacin, Pefloxacin, Trovafloxacin, Grepafloxacin, Citafloxacin, Sparfloxacin, Temafloxacin, Tosfloxacin, Trovafloxacin; q). / Dalhopristin; r) Sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethoxazole, sulfanilamide, sulfasalazine, sulfafurazole, trimethoprim, trimethoprim-sulfamethoxazole (cotrimoxazole); s). Antibacterial agents for steroids : For example, fusidic acid; t). Tetracycline: Doxycycline, Chlortetracycline, Chromocyclin, Demecrocycline, Limecycline, Mecrocycline, Metacycline, Minocycrine, Oxytetracycline, Penimepicycline, Loritetracycline, Tetracycline, Glycyll Cyclone (eg, trimethoprim) ;; u). Other types of antibiotics: annonacin, arsphenamine, bactoprenol inhibitor (basitrasin), DADAL / AR inhibitor (cycloserine), dicthiostatin, discodermo Ride, eleutellobin, epotilone, etabutol, etopocid, faropenem, fusidic acid, frazolidone, isoniazide, laurimalide, metronidazole, mupyrosine, mycolactone, NAM synthesis inhibitors (eg, phosphorycin), nitrofurantin, paclitaxel, platensimycin, pyrazinamide, Includes, but is not limited to, quinupristin / dalhopristin, rifampin (rifampicin), tazobactamtinidazole, ubaricin.

4). Antiviral agents: a). Invasion / fusion inhibitors: apravirock, maraviroc, bicliviroc, g p41 (enfvirtide), PRO140, CD4 (ibarizumab); b). Integrase inhibitors: raltegravir, elbitegrabir, globoidnan A; c). Maturation inhibitors: Babylimat, Vivicon; d). Neuraminidase inhibitors: Osertamivir, Zanamivir, Peramivir; e). Nucleoside and nucleotides: abacavir, acyclovir, adefobil, amdoxovir, apricitabine, bribdin, sidophobyl, clebudin Busitabin, didanosine (DDI), elbusitabin, emtricitabin (FTC), entecavir, famucyclovir, fluorouracil (5-FU), 3'-fluorosubstituted 2', 3'-deoxynucleoside analogs (eg, 3'-fluoro) -2', 3'-dideoxytimidin (FLT) and 3'-fluoro-2', 3'-dideoxyguanosine (FLG), homivirsen, gancyclovir, idoxuridine, ramibdin (3TC), L-nucleoside (eg β) -L-thymidine, β-L-2'-deoxycitidine), pencyclovir, racivir, ribavirin, stampidin, stubzin set (d4T), taribavirin (viramidin), tervibdin, tenohovir, trifluidine, balaccyclovir, balgancyclovir, zarcitabin ( ddC), didobudin (AZT); f). Non-nucleosides: amantadine, atevirinin, couplerabilin, diallylpyrimidine (etrabilin, lylpivirin), delavirdin, docosanol, emivirin, efavirents, foscarnet (phosphorylgirate), imikimod , Rodenosin, Methisazone, Nevilapin, NOV-205, Peginterferon α, Podophilotoxin, Rifampicin, Remantadin, Resikimod (R-848), Tromantadin; g). Protease inhibitors: Amprenavir, Atazanavir, Boseprevir, Darnavir, Hosamprenavir, Inzinavir, Lopinavir, Nerphinavir, Preconalil, Litonavir, Sakinavir, Terraprevir (VX-950), Tipranavir; H) Other types of antivirals: Abzyme, Albidol, Caranolide A, Seragenin, Cyanovirin-N, DAPY, maraviroc epi Galocatechin (EGCG), foscarnet, glyphiscin, taribavirin (viramidin), hydroxycarbamide, KP-1461, pleconaril, portmanteau inhibitor, ribavirin, seliciclib.

5). Other immunotherapeutic agents: eg imikimod, interferon (eg α, β), granulocyte colony stimulators, cytokines, interleukins (IL-1 to IL-35), antibodies (eg trastuzumab, pertuzumab, etc. Bebasizumab, cetuximab, panitumumab, infliximab, adalimumab, baciliximab, dacrizumab, omalizumab), protein binding agents (eg, abraxane), antibody binding agents are calikeamycin derivatives, maytancin derivatives (DM1 and DM4), CC-1065 and duocal Mycin sulcus binding agent, effective paclitaxel derivative, doxorubicin, aristatin thread division inhibitor (eg, trastuzumab-DM1, Inozumab monoclonal antibody, brentuximab bedotin, grenbatum mabbedotin, lorbotzumab mertancin, AN-152) LMB2, TP-38, VB4-845, trastuzumab-doxorubicin, AVE9633, SAR3419, CAT-8015 (anti-CD22), IMGN388, IMGN529, IMGN853, trastuzumab-doxorubicin, SGN-75 (anti-CD70), anti-CD22 -Selected from MCC-DM1).

The present invention is also a further object of the present invention with respect to methods for preparing antibody drug conjugates. The conjugate of the present invention can be prepared by various methods known in the art. For example, in the present invention, the conjugate of the antimitotic agent is synthesized by the following method, or the following. It can be transformed as follows. For experts in the field, these improved methods are readily available from the well-known and highly explicit scientific literature. In particular, these methods are detailed in the book "Comprehensive Organic Transformations" (R.C. Larock, 1999, Wiley-VCH Publishing, 2nd Edition).

During the reactions described herein, it may be necessary to protect reactive functional groups that may be involved in the reaction, such as hydroxy, amino, imino, mercapto groups and carboxyl groups, in order to avoid side reactions. .. For conventional protection of functional groups, see "Greene's Protective Groups in Organic Synthesis" (2006, Wiley-Interscience Publishing, 4th Edition), authored by P.G. Wuts and T.W. Greene. Some reactions can be carried out in a solution containing a suitable acid or base. Any conventional acid, base and solvent can be used herein and is not limited as long as the acid, base and solvent do not particularly adversely affect the reaction. Also, these reactions can be carried out over a wide temperature range. However, in general, it is usually relatively easy to operate when the reaction temperature is between -80 ° C and 150 ° C (room temperature to 100 ° C is better). The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the solvent. In general, a reaction time of 3 to 20 hours is more appropriate for an ideal reaction.

After the reaction is complete, the manipulation process can be performed by conventional means. For example, the reaction product may be recovered by distilling off the solvent from the reaction system. Alternatively, if necessary, after distilling off the solvent, the residue may be poured into water and extracted with an organic solvent that is immiscible with water. After distilling off the extraction solvent, the reaction product is finally obtained. Obtainable. In addition to where higher purity is required, various purifications can be further performed by common methods such as recrystallization, precipitation methods or various chromatographies. In general, column chromatography and preparative thin layer chromatography are more commonly used. The synthesis of the antimitotic agents of the present invention and their conjugates is shown in Figure 1-28.

In the following examples, the cell conjugate-mitotic inhibitor conjugate will be described more specifically. Of course, the present invention is not limited to the following examples.

Example Mass spectrometric data was from the Bruker Esquire 3000 system and nuclear magnetic data was from the Bruker AVANCE 300 spectrometer. The chemical displacement accuracy was accurate to one millionth, and tetramethylsilane was internally standardized. The UV spectral data was derived from the Hitachi U1200 spectrophotometer. The high performance liquid chromatography data was from an Agilent 1100 HPLC system with a fraction collector and a tunable wavelength probe. For thin plate chromatography, Analtech GF silica gel and TLC thin layer chromatography plate were used. Amino acids and their derivatives, as well as preloaded resins, were purchased from Merck Chemicals International, Synthetech, Peptides International, Chembridge International or Sigma-Aldrich. Some cross-linking agents, such as NHS ester / maleimide (AMAS, BMPS, GMBS, MBS, SMCC, EMCS or Sulfo-EMCS, SMPB, SMPH, LC-SMCC, Sulfo-KMUS, SM (PEG) 4, SM (PEG) ) 6, SM (PEG) 8, SM (PEG) 12, SM (PEG) 24), NHS ester / pyridine dimercapto (SPDP, LC-SPDP or Sulfo-LC-SPDP, SMPT, Sulfo-LC-SMPT); NHS ester / acetyl halide (SIA, SBAP, SIAB or Sulfo-SIAB), NHS ester / diazilin (SDA or Sulfo-SDA, LC-SDA or Sulfo-LC-SDA, SDAD or Sulfo-SDAD), maleimide / hydrazide ( BMPH, EMCH, MPBH, KMUH), pyridinedimercapto / hydrazide (PDPH), and isocyanate / maleimide (PMPI) were purchased from Thermo Fisher Scientific. SPDBs and SPPs were prepared according to the literature (Cumber, A. et al, Bioconjugate Chem., 1992, 3, 397-401). The human anti-CD22 antibody was purchased from Santa Cruz Biotechnology. The trastuzumab monoclonal antibody was purchased from Genentech. All other chemical reagents and anhydrous solvents were purchased from Sigma-Aldrich International.

Example 1 Methyl bis (2-hydroxyethyl) amino-4-oxobutanoate (3)

Didimethyl succinate (20.0 g, 136.9 mmol) and dihydroxyethylamine (7.20 g, 68.7 mmol) were dissolved in a mixed solution of toluene anhydride (500 ml) and pyridine (50 ml) and ^{refluxed at 150 o} C for 28 hours. The mixture was concentrated and then _{purified on a SiO 2} column (EtOAc / DCM = 5% -25% to EtOAc) to give the title compound (12.5 g, 83%). ESI MS m / z + ion peak: C ₉ H ₁₇ NaNO ₅ (M + Na), calculated value: 242.2, experimental value: 242.4.

Example 2 Methyl bis (2- (methylsulfonyloxy) ethyl) amino-4-oxobutanoate (4)

Methyl bis (2-hydroxyethyl) amino-4-oxobutanoate (12.0 g, 49.56 mmol) was dissolved in anhydrous pyridine (350 ml) and methanesulfonyl chloride (20.0 g, 175.4 mmol) was added. After overnight reaction, the solution is concentrated, then diluted with EtOAc (350 ml _{), washed with chilled 1M NaH 2} PO ₄ solution (2 x 300 ml), dried with DDL ₄ , filtered and spin dried and then crude. A product (18.8 g, 101%) was obtained. The crude product was used in the next reaction step without purification. ESI MS m / z + ion peak: C ₁₁ H ₂₁ NaNO ₉ S ₂ (M + Na), calculated value: 398.2, experimental value: 398.4.

Example 3 Methyl bis (2- (thioacetyl) ethyl) amino-4-oxobutanoate (5)

Methyl bis (2- (methylsulfonyloxy) ethyl) amino-4-oxobutanoate (new, 90% purity, 8.5 g, about 20 mmol) is dissolved in DMA (350 ml) and triethylamine (30 ml, 215 mmol). ) And thioacetic acid (10 ml, 134 mmol) were added sequentially ^{at 0 o C.} Stir overnight at room temperature to concentrate, dilute with EtOAc (350 ml), then in order with LVDS ₃ saturated solution (300 ml), NaCl saturated solution (300 ml) and 1 M NaH ₂ PO ₄ solution (300 ml). It was washed. The organic phase is then _{dried over Na 2} SO ₄ , filtered and spin dried _{, then purified on a SiO 2} column (EtOAc / Hexanes (10% -25% EtOAc)) to give the title compound (5.1 g, 76%). Obtained. ESI MS m / z + ion peak: C ₁₃ H ₂₁ NaNO ₅ S ₂ (M + Na), calculated value: 358.1, experimental value: 358.2.

Example 4 4- (bis (2-pyridin-2-yl-disulfanyl)) amino-4-oxobutanoic acid (6)

Methyl bis (2- (thioacetyl) ethyl) amino) -4-oxobutanoate (5.0 g, 14.9 mmol) is dissolved in THF (150 ml) to add an aqueous solution (100 ml) of NaOH (5.0 g, 125 mmol). added. After stirring at room temperature for 35 minutes, it was neutralized to pH 7 with _{H 3} PO _4. Then, a solution of 1,2-dipyridine disulfide in ether (Aldrithiol-2, 26.0 g, 118 mmol) in THF (100 ml) was added, and the mixture was stirred for 4 hours. After concentration _{, purification was performed on a SiO 2} column (MeOH / DCM / HOAc (1: 20 / 1%)) to give the title compound (5.8 g, 85.6%). ESI MS m / z + ion peak: C ₁₈ H ₂₁ NaN ₃ O ₃ S ₄ (M + Na), calculated value: 478.0, experimental value: 478.2.

Example 5 2,5-dioxopyrrolidine-1-yl-4-bis (2- (pyridin-2-yl-disulfanyl) ethyl) amino-4-oxobutanoic acid ester (7)

4- (Bis (2-pyridin-2-yl-disulfanyl) ethyl) amino) -4-oxobutanoic acid (5.2 g, 11.5 mmol) was dissolved in DMA (100 ml) and NHS (1.6 g, 13.9 mmol) was dissolved. ) And EDC (5.0 g, 26.1 mmol) were added. Stir overnight, spin dry _{and purify on a SiO 2} column (EtOAc / DCM = 5% -15% to EtOAc) to give the title compound (5.8 g, 85.6%). ESI MS m / z + ion peak: C ₂₂ H ₂₄ NaN ₄ O ₅ S ₄ (M + Na), calculated value: 575.1, experimental value: 575.2.

Example 6 Endooxo-3,6-epoxy-Δ-tetrahydrophthalimide (12)

After adding furan (10.0 ml, 137.4 mmol) to a solution of maleimide (10.0 g, 103.0 mmol) in toluene (200 ml), the mixed solution was placed in a 1 L autoclave ^{and heated to 100 o} C, and the reaction was carried out for 8 hours. It was. After cooling to room temperature, the solid in the autoclave was washed with methanol, concentrated, and recrystallized in a mixed solution of ethyl acetate and normal hexane to give the title compound (16.7 g, 99%). ^{1 1} H NMR (CDCl ₃ ): 11.12 (s, 1H) (NH), 6.68-6.64 (m, 2H), 5.18-5.13 (m, 2H), 2.97-2.92 (m, 2H). MS m / z + ion peak: C ₈ H ₇ NaNO ₃ (M + Na), calculated value: 188.04, experimental value: 188.04.

Example 7 4-((2-((3aR, 4R, 7S, 7aS) -1,3-dioxo 3a, 4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-3H) -yl) ethyl) ) (2-((4R, 7S, 7aS) -1,3-dioxo-3a, 4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-2 (3H) -yl) ethyl) amino) -4-oxobutanoic acid methyl ester (13)

Methyl 4- (bis (2- (methylsulfonyl) oxy) ethyl) amino) -4-oxobutanoate (4, new system, 90% purity, 8.5 g, ~ 20 mmol) was dissolved in DMA (350 mL) and 3, 6-endooxo-Δ-tetrahydrophthalimide (10.2 g, 61.8 mmol), sodium carbonate (8.0 g, 75.5 mmol) and sodium iodide (0.3 g, 2.0 mmol) were added in that order. The reaction mixture was stirred at room temperature overnight. After concentrating the reaction solution, ethyl acetate (350 mL) was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution (300 mL), saturated brine (300 mL) and 1 M NaH ₂ PO ₄ (300 mL). The organic phase was dried over anhydrous sodium sulfate and filtered to concentrate the filtrate. The obtained product was separated by silica gel column chromatography (10% to 30% ethyl acetate / normal hexane), purified, and the target compound was obtained (7.9 g, 77%). ESI MS m / z +: C ₂₅ H ₂₇ NaN ₃ O ₉ (M + Na), calculated value: 536.2, experimental value: 536.4.

Example 8 4- (bis (2- (2,5-dioxo-2,5-dihydro-1H-pyrrolidin) ethylamine-4-oxobutanoic acid (14))

Compound 13 (3.0 g, 5.8 mmol) and tin trimethyl hydroxide (4.8 g, 26.4 mmol) were dissolved in 1,2-dichloroethane (150 mL) and refluxed at 80 ° C. for 8 hours. After cooling to room temperature, the reaction was filtered through silica gel and washed with dichloromethane / methanol to remove the remaining tin trimethyl hydroxide. The filtrate was combined, concentrated under reduced pressure, N, N-dimethylacetamide and toluene were added, refluxed at 120 ° C., and the mixture was stirred overnight. Separation was performed by silica gel column chromatography (5% to 10% methanol / dichloromethane) to obtain the target compound (1.62 g, 76%). ESI MS m / z + C ₁₆ H ₁₇ NaN ₃ O ₉ (M + Na), calculated value: 386.1, experimental value: 386.2.

Example 9 2,5-dioxopyrrolidine-1-yl-4- (bis (2- (2,5-dioxy-dihydro-1H-pyrrolidin) ethylamine-4-oxobutanoic acid)

Compound 14 (16.0 g, 4.4 mmol) was dissolved in DMA (100 mL) and NHS (0.76 g, 6.61 mmol) and EDC (1.70 g, 8.90 mmol) were added. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated and separated by silica gel column chromatography (5% to 15% ethyl acetate / dichloromethane) to obtain the target compound (1.72 g, 85.0%). ESI MS m / z + C ₂₀ H ₂₀ NaN ₄ O ₉ (M + Na), calculated value: 483.1, experimental value: 483.2.

Example 10 5-(3', 6'-endooxo- △ -tetrahydrophthalimide) t-butylpentanoate

T-Butyl 5-hydroxyvalerate (10.0 g, 57.4 mmol) was dissolved in pyridine (60 mL) and methanesulfonyl chloride (8.0 mL, 103.3 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours. The reaction is concentrated, diluted with ethyl acetate _{, washed with a cooled 1M NaH 2} PO ₄ (pH 6) solution, dried over anhydrous magnesium sulfate, filtered, and the mother liquor is concentrated under reduced pressure to give mesylate. It was. The resulting mesylate was added to a solution of compound 12 (9.90 g, 60.0 mmol) and Na ₂ CO ₃ (8.5 g, 80.1 mmol) in DMF (80 mL). The mixed reaction was stirred at room temperature overnight. After concentrating the reaction solution, add ethyl acetate _{, wash with saturated brine and 1M NaH 2} PO ₄ (pH 6) solution, dry with anhydrous magnesium sulfate, filter, concentrate the mother liquor, and then perform silica gel column chromatography. (Ethyl acetate / dichloromethane = 1: 12) to obtain the target compound (14.01 g, 76%). ESI MS m / z + C ₁₇ H ₂₃ NaNO ₅ (M + Na), calculated value: 344.16, experimental value: 344.16.

Example 11 5-maleimidepentanoic acid (21b)

After dissolving compound 17 (5.0 g, 15.57 mmol) in 1,4-dioxane (40 mL), concentrated hydrochloric acid (10 mL) was added at 4 ° C., and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness to give 5- (3 '6'-endooxo- △ -tetrahydrophthalimide) valeric acid (4.08 g, 99%). The compound was dissolved in N, N-dimethylacetamide / toluene (1: 1, 40 mL) and subjected to a reflux reaction for 6 hours. The reaction mixture was concentrated and recrystallized from ethanol / ether / normal hexane to give the target compound (2.76 g, 90%). ESI MS m / z + C ₉ H ₁₂ NO ₄ (M + H), calculated value: 198.07, experimental value: 198.07.

Example 12 5- (maleimide) succinimidylpentanoate (23b) (DMPS linker)

After dissolving 5-maleimidopentanoic acid 21b (2.0 g, 10.1 mL) in dichloromethane (20 mL), add NHS (1.50 g, 13.0 mmol) and EDC (7.0 g, 36.4 mmol) to prepare the reaction mixture. Stirred overnight at room temperature. The reaction mixture was concentrated to dryness and then separated by silica gel column chromatography (ethyl acetate / dichloromethane = 10: 10) to obtain the target compound 23b (2.43 g, 82%). ESI MS m / z + C ₁₃ H ₁₄ NaN ₂ O ₆ (M + Na): Calculated value: 317.09, Experimental value: 317.09.

Example 13 5- (3', 6'-endooxo- △ -tetrahydrophthalimide) t-butyl pentanoylhydrazine formic acid (25a-a)

After dissolving 5- (3 '6'-endooxo- △ -tetrahydrophthalimide) valeric acid (1.0 g, 3.77 mmol) in DMF (30 mL), t-butyl carbamate (0.60 g, 4.53 mmol) and EDC ( 2.0 g, 10.4 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and then purified by silica gel column chromatography (ethyl acetate / dichloromethane = 10: 10) to obtain the target compound (1.18 g, 83%). ESI MS m / z + C ₁₈ H ₂₅ NaN ₃ O ₆ (M + Na): Calculated value: 402.17; Experimental value: 402.18.

Example 14 5- (maleimide) valeric acid hydrazide (25a-b)

Compound 25a-a (1.18 g, 3.11 mmol) was dissolved in N, N-dimethylformamide / toluene (1: 1, 20 mL), and a reflux reaction was carried out for 6 hours. The reaction mixture was concentrated, 1,4-dioxane (20 mL) was added, HCl (5 mL, 36%) was added at 4 ° C., and the mixture was stirred for 30 minutes. The reaction mixture was concentrated to dryness and then recrystallized from ethanol / ether / normal hexane to obtain the target compound (577 mg, 88%). ESI MS m / z + C ₉ H ₁₄ N ₃ O ₃ (M + H): Calculated value: 212.10; Experimental value: 212.10.

Example 15 3'-bromo-maleimide compounds 39, 40, and 3', 4'-dibromo-maleimide compounds 43, 44

After dissolving compound 37 or 38 (~ 6 g) in DMF (60 mL), bromomaleic anhydride (1 eq) or 2,3-dibromo-maleic anhydride (1 eq) is added and the reaction is carried out. The mixture was stirred overnight. The reaction mixture was concentrated to dryness to obtain pure trans acid. Acetic acid (~ 50 mL) and acetic anhydride (2-4 g) were added to the trans acid, and the reaction mixture was refluxed at 120 ° C. for 6 to 12 hours. The reaction mixture was concentrated and then separated by silica gel column chromatography (ethyl acetate / dichloromethane = 10: 10 to 1: 1) to obtain 3'-bromo-maleimide compounds 39 and 40. By the same production method, 3', 4'-dibromo-maleimide compounds 43 and 44 were obtained (61% to 87%).

ESI MS m/z+ C₉H₁₁BrNO₄ (M+H)：計算値：275.98；実験値：275.98。 5- (3-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) valeric acid

ESI MS m / z + C ₉ H ₁₁ BrNO ₄ (M + H): Calculated value: 275.98; Experimental value: 275.98.

ESI MS m/z+ C₁₃H₁₉BrNO₇ (M+H)：計算値：380.03；実験値：380.03。 3-(2-(2-(2-(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethoxy) ethoxy) propioic acid.

ESI MS m / z + C ₁₃ H ₁₉ BrNO ₇ (M + H): Calculated value: 380.03; Experimental value: 380.03.

ESI MS m/z+ C₉H₁₀Br₂NO₄ (M+H)：計算値：353.89；実験値：353.89。 5- (3,4-dibromo-- 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) valeric acid

ESI MS m / z + C ₉ H ₁₀ Br ₂ NO ₄ (M + H): Calculated value: 353.89; Experimental value: 353.89.

ESI MS m/z+ C₁₃H₁₈Br₂NO₇ (M+H)：計算値：457.94；実験値：457.94。 3-(2-(2-(2-(3,4-dibromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethoxy) ethoxy) propioic acid

ESI MS m / z + C ₁₃ H ₁₈ Br ₂ NO ₇ (M + H): Calculated value: 457.94; Experimental value: 457.94.

Example 16 3'-bromo-maleimide N-hydroxysuccinimide ether compounds 41, 42, and 3', 4'-dibromo-maleimide N-hydroxysuccinimide ether compounds 45, 46

After dissolving 3'-bromo-maleimide compounds 39, 40 (1 eq) or 3', 4'-dibromo-maleimide 43, 44 in DMA (~ 0.15 ml), NHS (1.1 eq) and EDC (2 ~ 4 eq) was added and the reaction mixture was stirred overnight. After concentrating the reaction solution, it was separated by silica gel column chromatography (ethyl acetate / dichloromethane = 1: 20 to 1: 5), and 3'-bromo-maleimide N-hydroxysuccinimide ether compounds 41, 42, and 3', N-Hydroxysuccinimide ether compounds 45,46 of 4'-dibromo-maleimide were obtained (70% -93%).

ESI MS m/z+ C₁₃H₁₃BrN₂NaO₇ (M+Na)：計算値：395.00；実験値：395.00。 2,5-Dioxopyrrolidine-1-yl 5- (3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) pentanoate

ESI MS m / z + C ₁₃ H ₁₃ BrN _{2 NaO 7} (M + Na): Calculated value: 395.00; Experimental value: 395.00.

ESI MS m/z+ C₁₃H₁₂Br₂N₂NaO₆ (M+Na)：計算値：472.91；実験値：472.91。 2,5-Dioxopyrrolidine-1-yl 5- (3,4-dibromo-- 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) pentanoate)

ESI MS m / z + C ₁₃ H ₁₂ Br ₂ N ₂ NaO ₆ (M + Na): Calculated value: 472.91; Experimental value: 472.91.

ESI MS m/z+ C₁₇H₂₁BrN₂NaO₉ (M+Na)：計算値：499.04；実験値：499.04。 2,5-Dioxopyrrolidine-1-yl 3-(2-(2-(2-(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethoxy) ethoxy) ) Ethoxy) propioic acid ester

ESI MS m / z + C ₁₇ H ₂₁ BrN _{2 NaO 9} (M + Na): Calculated value: 499.04; Experimental value: 499.04.

ESI MS m/z+ C₁₇H₂₀Br₂N₂NaO₉ (M+Na)：計算値：576.95；実験値：576.95。 2,5-Dioxopyrrolidine-1-yl-3- (2-(2-(2-(3,4-dibromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)) Ethoxy) ethoxy) ethoxy) propioic acid ester

ESI MS m / z + C ₁₇ H ₂₀ Br ₂ N ₂ NaO ₉ (M + Na): Calculated value: 576.95; Experimental value: 576.95.

Example 17 4- (2-pyridyl disulfide) -4-methyl pentanoate

After dissolving 4-mercapto-4-methylpentanoate (Goff, D. et al., Bioconjugate Chem. 1990, 1, 381-386) (4.67 g, 31.5 mmol) in methanol (15 mL), 2,2, --A methanol solution (80 mL) of disulfide dipyridine (30.0 g, 136.2 mmol) and 100 mM sodium phosphate buffer (pH 7.5, 70 mL) were added, and the reaction solution was stirred for 6 hours. The reaction mixture was concentrated and extracted with ethyl acetate / normal hexane (1: 1), then the aqueous layer was adjusted to pH 3 with 1 M HCl and then extracted with ethyl acetate (3 x 100 mL). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered and concentrated. Separation by silica gel column chromatography (MeOH / dichloromethane / acetic acid = 1: 15: 0.01) gave the desired compound (7.05 g, 87%). ESI MS m / z + C ₁₁ H ₁₆ NO ₂ S ₂ (M + H): Calculated value: 258.05; Experimental value: 258.05.

Example 18 4- (2-Pyridine disulfide) -4-methylpentanoate succinimide ester (243) (SMDP linker)

4- (2-Pyridine disulfide) -4-methylvaleric acid (2.0 g, 7.78 mmol) was dissolved in dichloromethane (20 mL), followed by NHS (1.10 g, 9.56 mmol) and EDC (4.0 g, 20.8 mmol). Was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated and separated by silica gel column chromatography (ethyl acetate / dichloromethane = 10: 10) to obtain the target compound (2.48 g, 90%). ESI MS m / z + C ₁₅ H ₁₈ NaN ₂ O ₄ S ₂ (M + Na): Calculated value: 377.07; Experimental value: 377.08.

Example 19 (3aR, 4R, 6S, 6aR) -6-((R) -2,2-dimethyl-1,3-dioxolane) -2,2-dimethyltetrahydrofuran [3,4-d] [1,3] Dioxolane-4-ol (62)

After dissolving compound D-gulonic acid lactone (20.01 g, 112.37 mmol) and anhydrous copper sulfate (25.0 g, 157.22 mmol) in dry acetone (450 mL), concentrated sulfuric acid (1.6 mL) was added and the reaction was mixed. The solution was stirred at room temperature for 24 hours. The reaction solution is adjusted to pH 7 with calcium hydroxide, the suspension is filtered, the mother liquor is concentrated to obtain a pale yellow syrup-like diacetone, which does not need to be purified and can be used as it is in the next reaction step. It was possible. The above obtained diacetone is dissolved in THF (300 mL), cooled to -78 ° C, and then a 1 M DIBAL-H toluene solution (180 mL, 180 mM) is slowly added dropwise to bring the reaction mixture to -78 ° C. Was stirred for 1 hour. After erasing the reaction solution with water (50 mL), the mixture was filtered, the organic layer was separated, dried over anhydrous sodium sulfate, and filtered and concentrated. Separation by silica gel column chromatography (normal hexane / ethyl acetate = 5: 1) gave the desired compound in the form of a colorless, morphological syrup (25.27 mmol, total yield of two steps 83%). ESI MS m / z + C ₁₂ H ₂₀ NaN ₂ O ₆ S (M + Na): Calculated value: 283.12; Experimental value: 283.12.

Example 20 (3aR, 4R, 6S, 6aR) -6-((R) -2,2-dimethyl-1,3-dioxolane) -2,2-dimethylN- (2-methylpropylene) tetrahydrofuran [3,4 -d] [1,3] Dioxolane-4-ammonium oxide (64)

Compound 62 (10.0 g, 38.4 mmol) and hydroxylamine hydrochloride (25.01 g, 360.87 mmol) were dissolved in pyridine (150 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated, water (250 mL) is added, extracted with dichloromethane, combined with an organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and subjected to silica gel column chromatography. Separated (ethyl acetate), colorless, glassy compound 2,3: 5,6-O-dipropyl-D-growth oxime (63) (10.34 g, 98%), no need for purification, direct next reaction Can be used for). The obtained oxime (10.30 g, 37.43 mmol), isobutyraldehyde (3.00 g, 41.66 mmol) and magnesium sulfate (3 g, 25 mmol) were stirred at room temperature overnight. The reaction mixture was filtered, the mother liquor was concentrated, and then separated by silica gel column chromatography (ethyl acetate) to obtain a white solid compound (11.57 g, 94%). ESI MS m / z + C ₁₆ H ₂₇ NO ₆ (M + H): Calculated value: 329.18; Experimental value: 329.18.

Example 21 (3R, 5R) -2-((3aR, 4R, 6S, 6aR) -6-((R) -2,2-dimethyl-1,3-dioxolane) -2,2-dimethylN- (2) -Methylpropylene) tetrahydrofuran [3,4-d] [1,3] dioxocyclopentacene) -3-[(-)-10', 2'-camphorsultam]-N-propylisooxazole-5 − Carboxamide (65)

(3aR, 4R, 6S, 6aR, Z) -6-((R) -2,2-dimethyl-1,3-dioxolane) -2,2-dimethylN- (2-methylpropylene) tetrahydrofuran [3,4 -d] [1,3] Dioxocyclopentacene-4-amine (6.00 g, 18.22 mmol) and (2R) -N- (acryloyl) Bornan-10,2-sultam (5.10 g, 18.95 mmol) in dichloromethane ( After dissolving in 50 mL), the mixture was heated under reflux for 37 hours. The reaction mixture was concentrated, and after recrystallization with ethanol (30 mL), the target compound (8.72 g, 80%) was obtained. The mother liquor after recrystallization was separated by silica gel column chromatography (normal hexane / ethyl acetate = 7: 3) to obtain a larger amount of the target compound (0.47 g, 4%). ESI MS m / z + C ₂₉ H ₄₆ N ₂ NaO ₉ S (M + Na): Calculated value: 621.28; Experimental value: 621.28.

Example 22 (3 R, 5R) -2- (tert-butoxycarbonyl) -3-isopropylisooxazolidine-5-formamide acid (67)

(3R, 5R) -2-((3aR, 4R, 6S, 6aR) -6-((R) -2,2-dimethyl-1,3-dioxolan-4-yl-)-2,2-dimethyltetrahydrofuran [3,4-d] [1,3] Dioxocyclopentacene-4-yl) -3- [(-)-10', 2'-canfluin] -N-isopropyloxazole-5-formamide (30.0 g) , 48.2 mmol) in THF (100 mL) and methanol (60 mL), then an aqueous solution (60 mL) of lithium hydroxide (5.0 g, 208.7 mmol) was added at 45 ° C, and the mixture was stirred for 1 hour. , Concentrate the mixture, add water (150 mL), adjust the pH to 9 with 4M HCl, extract with ethyl acetate, then adjust the pH of the aqueous layer to 3 with 4M HCl, aqueous layer. Was extracted with ethyl acetate, combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. After stirring and washing the obtained product with normal hexane, (3R, 5R) -2-((3aR, 4R, 6S, 6aR) -6-((R) -2,2-dimethyl-1,3- Dioxolane) -2,2-dimethyltetrahydrofuran [3,4-d, 1,3] Dioxocyclopentacene-3-isopropyloxazole-5-formamide acid (66a) (17.1 g, 88%) was obtained for purification. It was not necessary and could be used as it was in the next reaction. ESI MS m / z + C ₁₉ H ₃₁ NNaO ₈ (M + Na): 424.19. The above obtained compound (8.0 g, 19.95 mmol) was used as acetonitrile. After dissolving in (80 mL), 60% HClO ₄ aqueous solution (6.0 mL, 35.77 mmol) was added at 45 ° C., and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and then 1,4-dioxane. After dissolving in (40 mL), _{an aqueous solution of LVDS 3} (25 g, 297 mmol) (32 mL) and Boc ₂ O (4.80 g, 22.00 mmol) were added at 4 ° C, and the reaction mixture was prepared at room temperature. After stirring for hours, the reaction mixture was concentrated, water and ethyl acetate / normal hexane (1: 1) were added to separate the layers, the pH of the aqueous layer was adjusted to 3 with 4M HCl, and the mixture was extracted with ethyl acetate. After merging with the organic phase, it was washed with saturated saline, dried with anhydrous sodium sulfate, filtered and concentrated, and then stirred and washed with normal hexane to (3 R, 5R) -2- (t-butoxycarbonyl)-. 3-Isopropyloxazole-5-formamide acid (4.91 g, 95%) was obtained. ESI MS m / z + C ₁₂ H ₂₁ NNaO ₅ (M + Na): Calculated value: 282.13; Experimental value: 282.13.

Example 23 (R) -2-[(3 R, 5R) -2- (t-butoxycarbonyl) -3-isopropyloxazole-5-formamide acid] -3- (triphenyl) Methyl propioate (68)

(3 R, 5R) -2- (t-butoxycarbonyl) -3-isopropyloxazole-5-formamic acid (1.01 g, 3.89 mmol) and 1- (S) -Tr-cysteine methyl hydrochloride (1.76 g, 4.27) mmol) was dissolved in dichloromethane (15 mL), iPr ₂ NEt (0.75 mL, 4.31 mmol) and TBTU (2.50 g, 7.78 mmol) were added at 4 ° C., and the reaction mixture was stirred at room temperature overnight. The reaction mixture _{was placed in an aqueous LVDS 3} solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered and concentrated. Separation was performed by silica gel column chromatography (normal hexane / ethyl acetate = 1: 2) to obtain the target compound (2.10 g, 87%). ESI MS m / z + C ₃₅ H ₄₂ N ₂ NaO ₆ S (M + Na): Calculated value: 641.27; Experimental value: 641.26.

Example 24 (3 R, 5R) -t-butyl-3-isopropyl-3-4- (methoxycarbonyl) thiazole) Isopropyloxazole-2 Methyl formate (69)

Ph ₃ P = O (4.10 g, 14.74 mmol) was dissolved in dichloromethane (40 mL), Tf ₂ O (2.0 mL, 12.0 mmol) was added, and the reaction mixture was stirred at -10 ° C. for 1 hour. Under temperature (R) -2-[(3 R, 5R) -2- (t-butoxycarbonyl) -3-isopropyloxazole-5-formamic acid] -3- (triphenyl) methyl propioate (68) ( A solution of 4.00 g, 6.47 mmol) in dichloromethane (20 mL) was added, and the reaction mixture was stirred at room temperature for 6 hours. _{Then, the reaction solution was put into a saturated aqueous solution of LVDS 3} at 4 ° C., extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated. Separation by silica gel column chromatography (normal hexane / ethyl acetate = 3: 2) gave the corresponding thiazolidine. The above obtained compound was dissolved in dichloromethane (60 mL), MnO ₂ (5.80 g, 66.7 mmol) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and concentrated, and then separated by silica gel column chromatography (normal hexane / ethyl acetate = 3: 2) to obtain the target compound (69) (1.75 g, 75%). ESI MS m / z + C ₁₆ H ₂₄ N ₂ NaO ₅ S (M + Na): Calculated value: 379.13; Experimental value: 379.14.

Example 25 2-((1R, 3 R -3- (t-butoxycarbonyl) -1 -hydrogen-4 -methylamine amyl) thiazole-4-methyl formate (70))

(3R, 5R) -t-butyl-3-isopropyl-3--4- (methoxycarbonyl) thiazole) Methyl isopropyloxazole-2 (69)) (1.00 g, 2.81 mmol) with acetonitrile (20 mL) and H ₂ It was dissolved in O (2 mL), Mo (CO) ₆ (1.10 g, 3.12 mmol) was added, and the reaction mixture was stirred at 70 ° C. for 16 hours. After concentrating the reaction solution, ethyl acetate (50 mL) and 10% aqueous citric acid solution (50 mL) were added, and NaIO ₄ was further added until the aqueous layer became transparent, and the mixture was extracted with ethyl acetate. The organic phase was _{washed with an aqueous Na 2} S ₂ O ₃ solution (10%) and saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated. Separation by silica gel column chromatography (normal hexane / ethyl acetate = 3: 2) gave a colorless solid compound (906 mg, 90%). ESI MS m / z + C ₁₆ H ₂₆ N ₂ NaO ₅ S (M + Na): Calculated value: 381.14; Experimental value: 381.14.

Example 26 2-((1R, 3 R-1 -acetoxyl-3- (t-butoxy-methylamine-4-pentyl) thiazole-4-methyl formate (71))

Compound 70 (900 mg, 2.51 mmol) was dissolved in pyridine (15 mL), acetate anhydride (0.5 mL, 5.29 mmol) was added, and the mixture was stirred overnight and then concentrated. Separation by silica gel column chromatography (normal hexane / ethyl acetate = 4: 1) gave a colorless solid compound (950 mg, 95%). ESI MS m / z + C ₁₈ H ₂₈ N ₂ NaO ₆ S (M + Na): Calculated value: 423.15; Experimental value: 423.16.

Example 27 2-((1R, 3 R-1 -acetoxyl-3- (t-butoxy-methylamine-4-pentyl) thiazole-4-formic acid (72))

Compound 71 (940 mg, 2.35 mmol) was dissolved in THF (15 mL), NaH (120 mg, 3.0 mmmol, 60%) was added at 4 ° C., the reaction mixture was stirred for 2 hours, and then CH ₃ I (0.155 mL, 2.49 mmol) was added and the reaction mixture was stirred overnight. After concentrating the reaction solution, it is dissolved in ethyl acetate, filtered, and concentrated to dryness. Pure 2-((1R, 3 R-1 -acetoxyl-3- (t-butoxy-methylamine-4-pentyl) thiazole) -4-Methyl formate (73a) was obtained. The obtained compound (73a) was dissolved in 1,2-dichloroethane (20 mL), and trimethyltin hydroxide (620 mg, 3.43 mmol) was added to the reaction. The mixed solution was stirred at 80 ° C. overnight. After concentrating the reaction solution, it was dissolved in ethanol / dichloromethane / acetic acid (1: 5: 0.01, 20 mL), filtered and concentrated, and toluene was added to the mother liquor to concentrate again. A dry compound was obtained. Then, the obtained compound was dissolved in pyridine (15 mL), acetate anhydride (0.4 mL, 4.23 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated. After that, the mixture was separated by silica gel column chromatography (methanol / dichloromethane / acetic acid = 10: 10: 0.01) to obtain an anhydrous solid compound (735 mg, 78%). ESI MS m / z + C ₁₈ H ₂₈ N ₂ NaO ₆ S (M + Na): Calculated value: 423.15; Experimental value: 423.16.

Example 28 2-((1R, 3 R --3- (t-butoxy (meth) amine-1-(3-1,3-dioxoisoindolin) -4-methylamine-pentyl) thiazole-4- Methyl formic acid (86)

Compound 70 (850 mg, 2.37 mmol) is dissolved in THF (15 mL), NaH (100 mg, 2.5 mmol, 60%) is added at -20 ° C, stirring at that temperature for 20 minutes, then N. -(3-Bromopropyl) phthalimide (655 mg, 2.4 mmol) was added, and the reaction mixture was stirred at -20 ° C. for 30 minutes, then warmed to room temperature and reacted for 4 hours. Methanol (0.5 mL) was added to the reaction solution to stop the reaction, dichloromethane (60 mL) was added, filtration and concentration were performed, and 2-(1R, 3 R-3- (t-butoxy-methylamine-1)-(t-butoxy-methylamine-1) was added. -(3-(1,3-Dioxoisodinolin-2 -Proxipo-4-pentyl) Thiazole-4-Methyl formic acid 85 was obtained. The obtained compound did not need to be purified, and the following reaction was carried out as it was. It was possible to use it in the step. After dissolving the above obtained compound 85 in THF (10 mL), NaH (170 mg, 4.25 mmol, 60%) was added at room temperature, and the mixture was stirred for 45 minutes. CH ₃ I (0.20 mL, 3.21 mmol) was added and the reaction was stirred at room temperature overnight. The _{reaction was stopped with NaH 2} PO ₄ (2.0 M, 2 mL) and then DMA (5 mL). ) Was added, concentrated under reduced pressure, and separated by silica gel column chromatography (ethyl acetate / dichloromethane = 10: 10 to 1: 4) to obtain the target compound (921 mg, 69%). ESI MS m / z +. C ₂₈ H ₃₇ N ₃ NaO ₇ S (M + Na): Calculated value: 582.22; Experimental value: 582.22.

Example 29 2-((1R, 3 R --3- (t-butoxy (meth) amine-1-(3-1,3-dioxoisoindolin) -4-methylamine-pentyl) thiazole-4- Formic acid (87)

Dry compound 86 (910 mg, 1.63 mmol) is dissolved in 1,2-dichloroethane (20 mL), tin trimethylhydroxide (400 mg, 2.21 mmol) is added, and the reaction mixture is stirred at 80 ° C. overnight. did. The reaction mixture was concentrated and then separated by silica gel column chromatography (methanol / dichloromethane / acetic acid = 10: 10: 0.01) to obtain the target compound (756 mg, 85%). ESI MS m / z + C ₂₇ H ₃₇ N ₃ O ₇ S (M + H): Calculated value: 546.22; Experimental value: 546.22.

Example 30 2-((1R, 3 R -1 -acetoxyl -3- (t-butoxy (3-1,3-dioxoisodinolin-2-pentamine) -4-methylamine-4-pentyl) thiazole- 4 --Methyl formate (89)

Compound 71 (800 mg, 2.00 mmol) is dissolved in THF (30 mL), NaH (150 mg, 3.75 mmol, 60%) is added at room temperature, stirred for 45 minutes, and then N- (3-bromopropyl). ) Phthalimide (655 mg, 2.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction _{was stopped with NaH 2} PO ₄ (2.0 M, 2 mL), then DMA (5 mL) was added, concentrated under reduced pressure, and separated by silica gel column chromatography (ethyl acetate / dichloromethane =). From 1:10 to 1: 4), the target compound was obtained (971 mg, 82%). ESI MS m / z + C ₂₉ H ₃₇ N ₃ NaO ₈ S (M + Na): Calculated value: 610.22; Experimental value: 610.22.

Example 31 2-((1R, 3 R -1 -acetoxyl -3- (t-butoxy (3-1,3-dioxoisodinolin-2-pentamine) -4-methylamine-4-pentyl) thiazole- 4 --Formic acid (90)

Dry compound 89 (900 mg, 1.53 mmol) is dissolved in 1,2-dichloroethane (35 mL), tin trimethylhydroxide (400 mg, 2.21 mmol) is added, and the reaction mixture is stirred at 80 ° C. overnight. did. After concentrating the reaction mixture, the obtained product was dissolved in pyridine (20 mL), acetate anhydride (3 mL) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated and then separated by silica gel column chromatography (methanol / dichloromethane / acetic acid = 10: 10: 0.01) to obtain the target compound (755 mg, 86%). ESI MS m / z + C ₂₈ H ₃₅ N ₃ NaO ₈ S (M + Na): Calculated value: 596.20; Experimental value: 596.20.

Example 32 (S) -5 -4- (benzyloxy) phenyl) -4- (t-butoxycarbonylamino) -2-ethyl ethylpentenate (185)

At -78 ° C, diisobutylaluminum hydride (40 ml, 40 mmol, 1.0 M) was added to (S) -3--4- (benzyloxy) phenyl) -4- (t-butoxycarbonylamino) methyl propioate 184 (8.00 g, It was slowly added to a 20.76 mmol) DCM (250 ml) solution, reacted for 2 hours and then stopped with MeOH (5 ml). After the reaction mixture reached room temperature, the pH was adjusted to 4 with 1M HCl and liquid separation was performed. The aqueous layer is extracted with DCM (2 x 150 ml), the organic layer is washed with water, the organic layer is merged _{, dried with anhydrous Na 2} SO ₄ , filtered and concentrated to obtain the first product of the aldehyde group intermediate. Obtained. The first product is dissolved in DCM and synthesized at room temperature with a solution of 1- (1-ethoxycarbonylethyl) triphenyl bromide phosphine (18.0 g, 40.64 mmol) and KOtBu (5.00 g, 44.64 mmol) in dichloromethane (80 ml). The prepared ylide solution was added, the mixture was reacted overnight, then concentrated and separated by column chromatography (ethyl acetate / normal hexane = 1: 8-1: 4) to produce the desired product (185) (6.90 g). , 76%). ESI: m / z: [M + Na] +, Ion peak: C ₂₆ H ₃₃ NNaO ₅ , 462.22, Experimental value, 462.22.

Example 33 (4R) -4- (t-butoxycarbonylamino-5-4-hydroxyphenyl) -2-methylethyl pentanoate (186)

In a hydrogen reaction bottle, (S) -5 -4- (benzyloxy) phenyl) -4- (t-butoxycarbonylamino) -2-ethyl ethylpentenate (185) (6.70 g, 15.26 mmol) and methanol ( 150 ml) and 10% Pd / C (0.3 g) are added, reacted in an atmosphere of 30 psi hydrogen gas for 6 hours, filtered and concentrated in diatomaceous soil, and recrystallized in ethanol / normal hexane to produce the desired product. (186) (4.61 g, 86%) was obtained. ESI: m / z: [M + Na] +, Ion peak: C ₁₉ H ₂₉ NNaO ₅ , 374.20, Experimental value, 374.30.

Example 34 (4R) -4- (t-butoxycarbonylamino-5-4-hydroxy-3-nitrophenyl) -2-methylethyl pentanoate (187)

_{Ac 2} O (2 ml, 21.16 mmol) and fuming nitric acid (0.65 ml, 14.07 mmol) were added to _{an anhydrous CH 2} Cl ₂ (200 ml) solution of compound (186) (4.50 g, 12.81 mmol) for 4 hours at room temperature. The mixture was stirred, diluted with water (150 ml), separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined _{, dried over anhydrous Na 2} SO ₄ , filtered and concentrated, separated by column chromatography (ethyl acetate / dichloromethane = 10: 10), and the desired product (187) (4.21 g, 83%). Got ESI: m / z: [M + Na] ⁺ , Ion peak: C ₁₉ H ₂₈ N _{2 NaO 7} , 419.19, Experimental value, 419.20.

Example 35 4- (t-butoxycarbonylamino) -2-methyl-5-(3-nitro-4-phosphonooxyphenyl) ethyl pentanoate (188)

Compound (187) (4.00 g, 10.09 mmol) was dissolved in acetonitrile (70 ml) and N, N-dimethylacetamide (30 ml) ^{, cooled to 0 o} C, and then N, N-diisopropyletyramine (4.00 ml, 23.00 mmol). ) Was added, and after 2 minutes, phosphorus oxychloride (2.00 ml, 21.45 mmol) was added. Stir at room temperature for 8 hours ^{, cool to 0 o} C, slowly add solution consisting of sodium hydrogen carbonate (3.5 g, 41.60 mmol) and water (20 ml), continue stirring overnight at 0 ° C to concentrate, C- Purified on 18 columns (20 x 4 cm), gradient elution conditions: 25 ml / min, A: 0.5% acetic acid, B: methanol. After washing with 100% A for 10 minutes, it became 75% A and 25% B (methanol) after 45 minutes. The target component was collected and concentrated to give the target compound (188) (3.89 g, 81%). ESI: m / z: [MH] ^- , Ion peak: C ₁₉ H ₂₈ N ₂ O ₁₀ P, 475.16, Experimental value, 475.20.

Example 36 (4R) -4- (t-butoxycarbonylamino) -2-methyl-5-(3-nitro-4-phosphonooxyphenyl) valeric acid (85)

A solution of lithium hydroxide (5.0 g, 208.7 mmol) in water (60 ml) was added to a solution of compound (188) (3.75 g, 7.87 mmol) in THF (100 ml) and ^{reacted at 0 o} C for 4 hours to give 4 M hydrochloric acid. Adjust to pH 6 with, concentrate, purify on C-18 column, perform gradient elution, i.e. hold 100% A (0.5% acetic acid) for 10 minutes at a rate of 25 ml / min, then 45 minutes. After that, it became 75% A and 25% B (methanol). The target component was collected to obtain the target compound (189) (2.82 g, 80%). ESI: m / z: [MH] ^- , Ion peak: C ₁₇ H ₂₄ N ₂ O ₁₀ P, 447.12, Experimental value, 447.20.

Example 37 (4R) -5-(3-amino-4-phosphonooxyphenyl) -4- (t-butoxycarbonylamino) -2-methyl pentanoate (190)

Compound (189) (2.6 g, 5.80 mmol), methanol (80 ml) and 10% Pd / C (0.2 g) were added to the hydrogen reaction bottle in this order. The reaction was carried out at a pressure of hydrogen gas at 35 psi for 6 hours. The mixture was filtered and concentrated on diatomaceous earth to give the assembly (190) (2.18 g, 90%). It did not need to be purified and could be used as is in the next reaction step. ESI: m / z: [MH] ^- , Ion peak: C ₁₇ H ₂₆ N ₂ O ₈ P, 417.15, Experimental value, 417.15.

Example 38 (S) -2- (t-butoxycarbonylamino-3- (4-hydroxy-3-nitrophenyl) -methyl propioate (196))

Acetic anhydride (4 ml) in a solution of (S) -2- (t-butoxycarbonylamino-3- (4-hydroxyphenyl) -methyl propioate (195) (4.5 g, 15.24 mmol) in anhydrous dichloromethane (240 ml)). , 42.32 mmol) and fuming nitric acid (0.85 ml, 18.40 mmol) were added. After stirring at room temperature for 4 hours, the mixture was diluted with water (150 ml), separated, and the aqueous phase was extracted with ethyl acetate. , Anhydrous sodium sulfate, filtered and concentrated, and separated by column chromatography (ethyl acetate / dichloromethane = 10: 10) to give the desired product (196) (4.30 g, 83%). m / z: [M + Na] ⁺ , ion peak: C ₁₅ H ₂₀ N _{2 NaO 7} , 363.13, experimental value, 363.20.

Example 39 (S) -2- (t-butoxycarbonylamino) -3- (3-nitro-4--phosphonooxyphenyl) -methyl propioate (197)

At 0 ^o C, add N, N'-diisopropylethylamine (4.00 ml, 23.00 mmol) to a solution of compound (196) (4.10 g, 12.05 mmol) in acetonitrile (90 ml), stir for 2 minutes, and then phosphoryl chloride. Add (2.00 ml, 21.45 mmol), stir the reaction mixture at room temperature for 8 hours, cool to 0 ° C., and slowly add a solution of sodium hydrogen carbonate (3.5 g, 41.60 mmol) and water (20 ml). Stir overnight at 0 ° C., then concentrate, purify on a C-18 column (20 x 4 cm) and perform gradient elution, ie 100% A (0.5% acetic acid) at a rate of 25 ml / min. After holding for 10 minutes, it became 75% A and 25% B (methanol) after 45 minutes. The target component was collected and concentrated to obtain the target compound (197) (4.20 g, 83%). ESI: m / z: [MH] ^- , Ion peak: C ₁₅ H ₂₀ N ₂ O ₁₀ P, 419.08, Experimental value, 419.10.

Example 40 3-(3-amino-4-phosphonooxyphenyl)-(2R) -2- (t-butoxycarbonylamino) -propioic acid (198)

Tin trimethylhydroxide in a solution of dried compound (197) (4.0 g, 9.52 mmol) in a mixed solvent consisting of 1,2-dichloroethane (50 ml) and N, N-dimethylacetamide (60 ml). (4.00 g, 22.1 mmol) was added. The mixture was reacted at 80 ° C. for 6 hours to concentrate, separated by column chromatography (water / acetonitrile = 1: 4), the target component was collected and concentrated, and (S) -2- (t-butoxycarbonylamino). ) -3- (3-Nitro-4-phosphonooxyphenyl) -propioic acid was obtained. The obtained compound, N, N-dimethylacetamide (70 ml) and 10% Pd / C (0.3 g) were put together in a hydrogen reaction bottle. The reaction was carried out at a pressure of hydrogen gas at 35 psi for 6 hours. The mixture was filtered through diatomaceous earth and concentrated to give the desired product (198) (2.86 g, 80%) after recrystallization. No further purification was required and it could be used as is in the next reaction step. ESI: m / z: [MH] ^- , Ion peak: C ₁₄ H ₂₀ N ₂ O ₈ P, 375.10, Experimental value, 375.10.

Example 41 3-(4-benzyloxyphenyl)-(2R) -2-[(t-butoxycarbonyl) -aminomethyl] -benzyl propioate (200)

Sodium hydride (430 mg, 10.75) in a solution of 3- (4-benzyloxyphenyl)-(2R) -2- (t-butoxycarbonylamino) -benzyl propioate (4.0 g, 8.67 mmol) in tetrahydrofuran (60 ml). After adding (mmol, 60% oil compound) and stirring at room temperature for 1 hour, iodine methane (1.82 g, 12.82 mmol) was added, the mixture was stirred overnight, and the reaction was stopped with methanol (0.5 ml). It was concentrated and separated by column chromatography (ethyl acetate / dichloromethane = 10: 10) to give the desired product (200) (3.83 g, 93%). MS ESI: m / z: [M + Na] ⁺ , Ion peak: C ₂₉ H ₃₃ NNaO ₅ , 498.24, Experimental value, 498.24.

Example 42 (2R) -2-[(t-butoxycarbonyl) -methylamino] -3- (4-hydroxy-2-nitrophenyl) propioic acid (201)

Compound (200) (3.8 g, 8.00 mmol), methanol (80 ml), and 10% Pd / C (0.3 g) were added to the hydrogen reaction bottle in this order. The reaction was carried out at a pressure of hydrogen gas at 35 psi for 6 hours, filtered through diatomaceous earth, concentrated, and the crude product (2R) -2-[(t-butoxycarbonyl) -methylamino] --3- (4--- Hydroxyphenyl) propioic acid (201 a) was obtained. The compound does not need to be purified. Add tin tetrachloride (1.5 ml, 12.75 mmol) and fuming nitric acid (0.60 ml, 12.98 mmol) dichloromethane (40 ml) to a solution of compound (201 a) in anhydrous dichloromethane (240 ml) at a temperature of -25 ° C. The mixture was stirred at -25 ° C for 75 minutes, the reaction was stopped with saturated sodium hydrogen carbonate, the pH was adjusted to 3-4, the aqueous layer was extracted with ethyl acetate, the organic layer was merged, and anhydrous sodium sulfate was added. The mixture was dried in, filtered and concentrated, and separated by column chromatography (MeOH / DCM / HOAc 1: 8: 0.01) to obtain the target compound (201) (1.98 g, 73%). ESI: m / z: [M + Na] ⁺ , Ion peak: C ₁₅ H ₂₀ N _{2 NaO 7} , 363.13, Experimental value, 363.13.

Example 43 (2R) -2-[(t-butoxycarbonyl) -methylamino] -3-(3-nitro-4-phosphonooxyphenyl) propioic acid (202)

N, N'-diisopropylethylamine (2.00 ml, 11.50 mmol) in a solution of compound (201) (1.98 g, 5.82 mmol) in acetonitrile (30 ml) and N, N-dimethylacetamide (30 ml) at 0 ° C. )) Was added and reacted at the temperature for 2 minutes, and then phosphoryl chloride (1.10 ml, 11.79 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours, cooled to 0 ° C., a solution consisting of sodium hydrogen carbonate (2.0 g, 23.80 mmol) and water (10 ml) was slowly added, and stirring was continued at 0 ° C. overnight. The mixture is concentrated, purified on a C-18 column (20 x 4 cm), gradient elution, holding 100% A (0.5% acetic acid) for 10 minutes at a rate of 25 ml / min, then 45 minutes to 75. It became% A and 25% B (methanol). The target component was collected and concentrated to give the target compound (202) (1.96, 80%). ESI: m / z: [MH] ^- , Ion peak: C ₁₅ H ₂₀ N ₂ O ₁₀ P, 419.09, Experimental value, 419.09.

Example 44 3-(3-amino-4-phosphonooxyphenyl)-(2R) -2-[(t-butoxycarbonyl) -methylamino] propioic acid (203) "

Compound (202) (1.96 g, 4.67 mmol), N, N-dimethylacetamine (60 ml) and 10% Pd / C (0.2 g) were placed in this order in a hydrogen reaction bottle. The reaction was carried out at a pressure of 30 psi hydrogen gas for 6 hours. The mixture was filtered through diatomaceous earth and concentrated to give the crude product (203) (1.74 g, 95%)). The crude product did not need to be purified and could be used as it is in the next reaction step. ESI: m / z: [MH]-, C ₁₅ H ₂₂ N ₂ O ₈ P, theoretical value, 389.12; experimental value, 389.12.

Example 45 Phenyl-2- (2R) -t-butoxycarbonylamino-1-acetone (204)

(1S, 2R)-(+)-Norephedrine (7.0 g, 46.29 mmol) is placed in a mixed solution of tetrahydrofuran (40 ml) and 1M sodium hydrogen carbonate (100 ml) at a temperature of 4 ° C. for 45 minutes. A solution of di-t-butyl dicarbonate (10.15 g, 46.53 mmol) in tetrahydrofuran (60 ml) was slowly added therein, and the reaction mixture was stirred at room temperature for 6 hours, concentrated, extracted with ethyl acetate, and anhydrous sodium sulfate. Dry with, filter, concentrate, separate by column chromatography (EtOAc / Hexane 1: 2), target components are collected, concentrated and crude product (1S) -phenyl-2- (2R). -T-butoxycarbonylamino-1-propanol (204b) (10.81, 93%) was obtained. The crude product does not need to be purified, MS ESI: m / z +: [M + Na] ⁺ , ion peak: C ₁₄ H ₂₁ NaNO ₃ , 274.15, experimental value, 274.15. A solution of compound (204b) in dichloroethane (50 ml) contains a solution of Des-Martin's reagent in dichloromethane (180 ml, 0.3 M), stirred for 1 hour, and then the mixture is frozen in sodium hydroxide solution (1 M). , 100 ml) is added and separated, the pH of the organic layer is adjusted to 6 with 1 M sodium dihydrogen phosphate (100 ml), dried with anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography. (EtOAc / hexane 1: 5), the desired product 204 (9.34 g, 81%, in two steps) was obtained. MS ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₁₄ H ₁₉ NaNO ₃ , 272.14, Experimental value, 272.14.

Example 46 (1R, 3 R -3-((2S, 3 S) -N-methyl-3-methyl-2- (R) -1 -methylpiperidin-2-formamide)-pentaamino-4-methyl-1 --4- (1-oxo-1 -phenylpropyl-2 -yl) carbamoyl) Thiazole-2-yl) -ethyl pentanoate (205)

After adding concentrated hydrochloric acid (1.0 ml, 37%) to a solution of compound 204 (180 mg, 0.722 mmol) in 1,4-dioxane (4 ml) at a temperature of 4 ° C. and stirring the mixture at room temperature for 40 minutes. , Concentrated, and toluene was added to carry out concentrated drying. The dried solid is dissolved in N, N-dimethylacetamine (7 ml) and compound 106 (251 mg, 0.466 mmol), 1-(3-dimethylaminopropyl) -3-ethylcarbon diimine hydrochloride (7-ethylcarbon diimine hydrochloride) is added to the solution. 305 mg, 1.56 mmol) and N, N'-diisopropylethylamine (0.13 ml, 0.747 mmol) were added in sequence, the reaction mixture was stirred for 8 hours, concentrated and separated by column chromatography (EtOAc / CH ₂ Cl). ₂ = 1: 4), the target product 205 (255.3 mg, 82%) was obtained. ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₃₅ H ₅₁ NaN ₅ O ₆ S, 692.36, Experimental value, 692.36.

Example 47 (1R, 3 R) -3-((2S, 3 S) -N, 3-dimethyl-2- (R) -1-methylpiperidin-2-formamide)-pentanoylamino-1- (4-- ((R) -1-(2,5-dioxo-2,5-dihydro-1H -pyrrole-1-yl) -12 -oxo-15 -phenyl-3,6,9 -trioxa-13,14-dia Zaheptadecyl-14 -alkenyl-16 -carbamoyl) thiazole-2-yl) -4-methylethyl valerate (206)

Compound 12 (50 mg HCl salt, 0.126 mmol) and acetic acid (3 ul, 0.052 mmol) were added to a solution of compound 205 (75 mg, 0.112 mmol) in methanol (5 ml) to allow the mixture to react overnight and then N. , N'-diisopropylethylamine (23 ul, 0.132 mmol) was added to neutralize, concentrate, separate by column chromatography (EtOAc / CH ₂ Cl ₂ = 1: 4-1: 3), compound of interest 206 (79.3 mg, 70%) was obtained. MS ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₅₀ H ₇₄ NaN ₈ O ₁₂ S, 1033.51, Experimental value, 1033.50.

Example 48 (1S, 2R) -2-(2-((1R, 3 R) -1 -acetoxyl-3- ((2S, 3 S) -N, 3-dimethyl-2-((R) -1-) Methylpiperidin-2-formamide) pentanoylamino) -4-methylamyl) thiazole-4-formamide group) -1 -phenylpropyl-3- (2- (2- (2- (2,5-dioxo-2,5)-) --Dihydro-1H -Pyrrole-1 -Il) ethoxy) ethoxy) ethoxy) Ethyl propioate (211)

Compounds 208a (95 mg, 0.141 mmol) and 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethoxy) ethoxy) propioic acid Dicyclohexylcarbodiimide (122 mg, 0.591 mmol) and 2,2-dimethylolpropionic acid (25 mg, 0.204 mmol) were added to a solution of (55 mg, 0.182 mmol) dichloroethane (5 ml) and the mixture was stirred overnight. After that, it was concentrated and separated by column chromatography (EtOAc / CH ₂ Cl ₂ = 1: 3) to obtain the target compound 211 (95.1 mg, 71%). MS ESI: m / z +: [M + Na] +, Ion peak: C ₄₈ H ₇₀ NaN ₆ O ₁₂ S, 977.47, Experimental value, 977.47.

Example 49 2,5-dioxopyrrolidine-1 -yl-2-((1R, 3 R) -1 -acetoxyl-3-((2S, 3 S) -N, 3-dimethyl-2-((R)) -1 -Methylpiperidin-2-formamide) pentanoylamino) -4-methylamyl) thiazole-4-ethyl carboxylate (234)

N-Hydroxysuccinimide (202.0 mg, 1.756 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in a solution of compound 106 (788.1 mg, 1.464 mmol) in N, N'-dimethylformamide (10 ml). Salt (980 mg, 5.104 mmol) was added and the mixture was stirred overnight, then concentrated and separated by column chromatography (EtOAc / CH ₂ Cl ₂ = 1: 3) to compound of interest 234 (762.8 mg, 82%). ) Was obtained. MS ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₃₀ H ₄₅ NaN ₅ O ₈ S, 658.30, Experimental value, 658.30.

Example 50 (4R) -4- (t-butoxycarbonylamino) -5-(3-(5-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) pentanoylamino-4 -(Phenyloxy) phenyl) -2-methyl pentanoate (235)

2,5-Dioxopyrrolidine-1 -yl-5-(2,5-dioxo-2,5-dihydro-) in a solution of compound 190 (825.1 mg, 1.973 mmol) in N, N'-dimethylformamide (7 ml) Add 1H-pyrrole-1-yl) ethyl pentanoate (23d) (711 mg, 2.417 mmol) and N, N'-diisopropylethylamine (0.250 ml, 1.438 mmol), stir the mixture overnight and then concentrate. Separated by C-18 column chromatography (from 100% 1% HOAc to 75% 1% HOAc / 25% MeOH in 4x25 cm, v = 15 ml / min, 45 min), compound of interest 235 (895.7 mg, 76%) was obtained. MS ESI: m / z-: [MH] ^- , Ion peak: C ₂₆ H ₃₅ N ₃ O ₁₁ P, 596.21, Experimental value, 596.21.

Example 51 (4R) -4- (t-butoxycarbonylamino) -5-(3-(3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrole-) 1-yl) ethoxy) ethoxy) ethoxy) propionamide-4- (phosphonooxy) phenyl) -2-methylpentanoate (236)

Compound 190 (632.5 mg, 1.512 mmol) in N, N'-dimethylformamide (7 ml) solution in 2,5-dioxopyrrolidine-1 -yl-3- (2-(2-(2- (2,5)-) --Dioxo-2,5-dihydro-1H -pyrrole-1 -yl) ethoxy) ethoxy) ethoxy) ethyl propionate (24c) (727 mg, 1.826 mmol) and N, N'-diisopropylethylamine (0.250 ml, 1.438 mmol) ) Is added, the mixture is stirred overnight, then concentrated and separated by C-18 column chromatography (4x25 cm, v = 15 ml / min, within 45 min 100% 1% HOAc to 75% 1). % HOAc / 25% MeOH) and the target compound 236 (763.2 mg, 72%) were obtained. MS ESI: m / z-: [MH] ^- , Ion peak: C ₃₀ H ₄₄ N ₃ O ₁₄ P, 700.25, Experimental value, 700.25.

Example 52 (4R) -4- (2-((1R, 3 R) -1 -acetoxyl-3-((2S, 3 S) -N, 3-dimethyl-2-((R) -1 -methylpiperidine) -2-formamide) pentanoylamino-4-methylpentyl) thiazole-4-formamide group)-5-(3-(5-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ) Pentanoylamino-4- (phosphonooxy) phenyl) -2-methylvaleric acid (239)

Concentrated hydrochloric acid (1.0 ml, 37%) was added to a solution of compound 235 (102 mg, 0.171 mmol) in 1,4-dioxane (4 ml), the mixture was stirred for 30 minutes, and then concentrated to dryness. I got the thing (237). Compound 234 (110 mg, 0.173 mmol) and N, N'-diisopropylethylamine (30 ul, 0.172 mmol) were added in this order to a solution of the crude product (237) in N, N-dimethylacetamine (5 ml). Addition, the mixture was stirred overnight, then concentrated and separated by column chromatography (1% HOAc-containing water / acetone, 1: 9-1: 4) to give the compound of interest 239 (123.2 mg, 71%). .. MS ESI: m / z-: [MH] ^- , Ion peak: C ₄₇ H ₆₇ N ₇ O ₁₄ PS, 1016.42, Experimental value, 1016.42.

Example 53 (4R) -4- (2-((1R, 3 R) -1 -acetoxyl-3-((2S, 3 S) -N, 3-dimethyl-2-((R) -1 -methylpiperidine) --2-formamide) pentanoylamino-4--4-methylpentyl) thiazole-4-formamide group)-3-(3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrol-) 1-yl) ethoxy) ethoxy) ethoxy) propionamide-4- (phosphonooxy) phenyl) -2-methylvaleric acid (240)

Concentrated hydrochloric acid (1.0 ml, 37%) was added to a solution of compound 236 (108 mg, 0.154 mmol) in 1,4-dioxane (4 ml), the mixture was stirred for 30 minutes, and then concentrated to dryness. I got the thing (238). Compound 234 (110 mg, 0.173 mmol) and N, N'-diisopropylethylamine (30 ul, 0.172 mmol) were added in this order to a solution of the crude product (238) in N, N-dimethylacetamine (5 ml). Addition, the mixture was stirred overnight, then concentrated and separated by column chromatography (1% HOAc-containing water / acetone, 1: 9-1: 4) to give the compound of interest 240 (131.2 mg, 76%). .. MS ESI: m / z-: [MH] ^- , Ion peak: C ₅₁ H ₇₅ N ₇ O ₁₇ PS, 1120.47, Experimental value, 1120.48.

Example 54 (4R) -4- (t-butoxycarbonylamino) -2-methyl-5-(4- (phosphonooxy) -3-(4-(pyridin-2-disulfide) butyrylamino) phenyl) valeric acid (244)

Succinimidyl 4- (pyridin-2-dimercapto) butyric acid (550.2 mg, 1.687 mmol) and N, N'-diisopropylethylamine (550.2 mg, 1.687 mmol) in a solution of compound 190 (548.3 mg, 1.311 mmol) in N, N'-dimethylformamide (10 ml). 0.18 ml, 1.03 mmol) was added, the mixture was stirred overnight, then concentrated, separated by column chromatography (1% HOAc-containing water / acetone, 1: 9-1: 4), compound of interest 244 (660.2 mg). , 80%). MS ESI: m / z-: [MH] ^- , Ion peak: C ₂₆ H ₃₅ N ₃ O ₉ PS ₂ , 628.16, Experimental value, 628.16.

Example 55 (4R) -4- (2-((1R, 3 R) -1 -acetoxyl-3-((2S, 3 S) -N, 3-dimethyl-2- ((R) -1 -methylpiperidin) -2-formamide) pentanoylamino) -4-methylpentyl) thiazole-4-formamide group)-2 -methyl-5-(4-(phosphonooxy) -3-(4-(pyridin-2-disulfide) butyrylamino)) Phenyl) Thiazole acid (248)

At room temperature of 4 ° C., concentrated hydrochloric acid (1.0 ml, 37%) was added to a solution of compound 244 (110.5 mg, 0.175 mmol) in 1,4-dioxane (4 ml), the mixture was stirred for 30 minutes, and then concentrated. The mixture was dried to obtain a crude product (246). Compound 234 (110 mg, 0.173 mmol) and N, N'-diisopropylethylamine (30 ul, 0.172 mmol) were added in this order to a solution of the crude product (246) in N, N-dimethylacetamine (5 ml). Addition, the mixture was stirred overnight, then concentrated and separated by column chromatography (1% HOAc-containing water / acetone, 1: 9-1: 4) to give the compound of interest 248 (129.1 mg, 71%). .. MS ESI: m / z-: [MH] ^- , Ion peak: C ₄₇ H ₆₇ N ₇ O ₁₂ PS ₃ , 1048.38, Experimental value, 1048.38.

Example 56 (4R) -4- (2-((1R, 3 R -1 -acetoxyl-3-((2S, 3 S) -N, 3--dimethyl-2-((R) -1 -methylpiperidin-) 2-formamide) pentanoylamino) -4-methylpentyl) thiazole-4-formamide group)-5-(3-(4-mercaptobutyrylamide group) -4- (phosphonooxy) phenyl) -2-methylvaleric acid (248b)

Dithiothreitol (20 mg, 0.129 mmol) was added to a mixture of compound 248 (30 mg, 0.0285 mmol) in N, N-dimethylacetamine (2 ml) and monosodium dihydrogen phosphate (0.1 M, pH 7). ) Was added. The mixture was stirred for 2 hours, concentrated and separated by column chromatography (1% HOAc-containing water / MeCN, 1: 9-1: 4) to give the desired compound 248b (22 mg, 85%). MS ESI: m / z-: [MH] ^- , Ion peak: C ₄₂ H ₆₄ N ₆ O ₁₂ PS ₂ , 939.38, Experimental value, 939.38.

Example 57 4- (4-Bromium Butyl) -10 -Oxa-4 -Azatricyclo [5.2.1.0 ^ {2, 6}] Deku-8 -En-3,5-Zeon (271)

10-Oxa-4-azatricyclo [5.2.1.0 ^ {2, 6}] Deku-8 -ene-3,5-dione (6.0 g, 36.35 mmol) and sodium hydride (60% oil, 1.50 g, 37.50 mmol) was added to N, N-dimethylacetamine (60 ml), and after stirring for 1 hour, 1,4-dibromobutane (35.0 g, 162.10 mmol) and sodium iodide (0.50 g, 3.33 mmol) were added. I joined. After stirring the mixture overnight, the reaction was stopped with methanol (0.5 ml), concentrated and separated by column chromatography (EtOAc / Hexanes). = 1: 8), the target compound 271 (9.34 g, 86%) was obtained. MS ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₁₂ H ₁₄ BrNaNO ₃ , 322.02, Experimental value, 322.02.

Example 58 Methyl-2-((1R, 3 R) -3- (t-butoxycarbonylamino) -1- [4'-(3'', 6''-endoxo-tetrahydrophthalacylamino) butoxy] -4 -Methylamyl) thiazole-4-methylcarboxylate (272)

Methyl-2-((1R, 3 R) -3- (t-butoxycarbonylamino) -1-hydroxy-4-methylamyl) thiazole-4-carboxylate (70) (1.0 g, 2.79 mmol) and hydrogenation Sodium (120 mg, 3.00 mmol, 60% oil) was added to tetrahydrofuran (30 ml), stirred for 30 minutes, then compound 271 (1.00 g, 3.34 mmol) and sodium iodide (50 mg, 0.33 mmol). Joined. After stirring the mixture overnight, the reaction was stopped with methanol (0.5 ml), concentrated, separated by column chromatography (EtOAc / CH ₂ Cl ₂ = 1:10), compound of interest 272 (1.36 g, 84%). Got MS ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₂₈ H ₃₉ NaN ₃ O ₈ S, 600.25, Experimental value, 600.25.

Example 59 Methyl 2-((1R, 3 R) -3- (N, N-t-butoxycarbonylmethylamino) -1- [4'-(3'', 6''-endoxo-tetrahydrophthalacylamino)) Butoxy] -4-methylamyl) thiazole-4-methylcarboxylate (273)

Compound 272 (1.30 g, 2.25 mmol) and sodium hydride (108 mg, 2.70 mmol, 60% oil) were added to N, N-dimethylformamine (80 ml), stirred for 1 hour, and then iodine methane. (460 mg, 3.24 mmol) was added. The mixture was stirred overnight and then concentrated and separated by column chromatography (EtOAc / CH ₂ Cl ₂ = 1: 12-1: 8) to give the compound of interest 273 (1.01 g, 76%). MS ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₂₉ H ₄₁ NaN ₃ O ₈ S, 614.26, Found, 614.26.

Example 60 2-((1R, 3R) -3- (N, N-t-butoxycarbonylmethylamino) -1- [4'-(3'', 6''-endoxo-tetrahydrophthalacylamino) butoxy] -4 -Methylamyl) Thiazole-4 -Carboxylic acid (274)

The dried compound 273 (900 mg, 1.52 mmol) was dissolved in a mixed solvent consisting of 1,2-dichloroethane (30 ml) and toluene, and tin trimethyl hydroxide (400 mg, 2.21 mmol) was added. The mixture was stirred at 100 ° C. overnight, concentrated and separated by column chromatography (MeOH / CH ₂ Cl ₂ / HOAc = 1: 10: 0.01) to give the compound of interest 274 (730 mg, 94%). ESI: m / z: [M + Na] ⁺ , Ion peak: C ₂₈ H ₃₉ N _{3 NaO 8} S, 600.22, Experimental value, 600.22.

Example 61 Methyl 2-((1R, 3 R) -1 -acetoxyl-3- (N, N-(t-butoxycarbonyl)) (4'-(3', 6''-endoxo-Δ-tetrahydro) butyl) Amino) -4-methylpentyl) Thiazole-4-carboxylic acid (275)

Compound 71 (1.50 g, 3.74 mmol) and sodium hydride (180 mg, 4.50 mmol, 60% oil) were added to N, N-dimethylformamide (80 ml), stirred for 1 hour, and then compound 271 (. 1.48 g, 4.94 mmol) and iodine methane (70 mg, 0.467 mmol) were added. The mixture was stirred overnight, concentrated and separated by column chromatography (EtOAc / CH ₂ Cl ₂ = 1: 10-1: 6) to give the compound of interest 275 (1.60 g, 69%). MS ESI: m / z +: [M + Na] ⁺ , Ion peak: C ₃₀ H ₄₁ NaN ₃ O ₉ S, 642.26, Experimental value, 642.26.

Example 62 2-((1R, 3 R) -1 -acetoxyl-3- (N, N-(t-butoxycarbonyl) (4'-maleimidebutyl) amino) -4-methylpentyl) -thiazole-4-carboxylic Acid (276)

The dried compound 275 (800 mg, 1.29 mmol) was dissolved in a mixed solvent of 1,2-dichloroethane (40 ml) and toluene, and tin trimethyl hydroxide (400 mg, 2.21 mmol) was added. The mixture was stirred overnight, then concentrated, separated by column chromatography (MeOH / CH ₂ Cl ₂ / HOAc = 1: 5: 0.01), the composition was collected and concentrated to dryness. The resulting crude product is dissolved in pyridine (15 ml), acetic anhydride (0.3 ml, 3.17 mmol) is added to the solution at 0 ° C., the mixture is stirred overnight at room temperature, concentrated and column chromatographed. (MeOH / CH ₂ Cl ₂ / HOAc = 1: 10: 0.01) to obtain the target compound 276 (578.4 mg, 74%). ESI: m / z: [M + Na] ⁺ , Ion peak: C ₂₉ H ₃₉ N _{3 NaO 9} S, 628.24, Experimental value, 628.24.

Example 63 1-(2-methyl-2-epoxyethyl) -2-phenylethylamine

At a temperature of 0 ° C, 1-(2-methyl-2-epoxyethyl) -2-phenylethyl) butyl aminoate (Sun, L. et al, J. Mol. Catalysis A: Chem., 2005, 234 ( Add concentrated hydrochloric acid (37%, 2 mL) to a 1,4-dioxane (8 mL) solution of 1-2), 29-34) (300 mg, 1.08 mmol), and at that temperature, TLC is the starting material. Stirring was continued for 1 hour until none was indicated. The obtained mixture was diluted with toluene (10 ml), concentrated, and recrystallized from EtOH / hexane to obtain the target compound, hydrochloride (201 mg, 87%). ESI: m / z: [M + H] ⁺ , Ion peak: C ₁₁ H ₁₆ NO, 178.12, Experimental value, 178.12.

Example 64 (S, E) Ethyl-5 -Phenyl-4- (t-butoxycarbonylamino) -2-methyl-2-pentenoic acid (327)

Aluminum diisobutyl hydride (40 ml, 40 mmol, 1.0 M) at a temperature of -78 ° C (S) -3-phenyl-2- (t-butoxycarbonylamino) -methylpropioate 326 (5.60 g, 20.05 mmol) CH ₂ Cl ₂ (80 ml) solution was added and reacted for 45 minutes, then 1-(1-ethoxycarbonylethyl) triphenyl bromide phosphine (18.0 g, 40.64 mmol) and KOtBu (5.00 g) at that temperature. Add an ildo solution formed with a solution of dichloromethane (80 ml) of 44.64 mmol), react the mixture at -78 ° C, then stir overnight at room temperature, then add 1 L dihydrogen phosphate to the mixture. Add sodium solution, stir vigorously, separate, extract aqueous phase with dichloromethane, combine organic layers, dry with anhydrous sodium sulfate, concentrate and separate by column chromatography (ethyl acetate / normal hexane) = 1: 7-1: 5), the target product 327 (5.50 g, 83%) was obtained. ESI: m / z: [M + Na] ⁺ , Ion peak: C ₁₉ H ₂₇ NNaO ₄ , 356.19, Experimental value, 356.20.

Example 65 (S) -5 -Phenyl-4- (t-butoxycarbonylamino) -2,3-Epoxy ethyl-2-methylethyl valerate (328)

3-Chloroperbenzoic acid (5.5 g, 22.3 mmol) was added to a solution of compound 327 (5.0 g, 15.0 mmol) in dichloromethane (80 ml), the mixture was stirred overnight, and then sodium hydrogen carbonate (25 ml, sat. ) Dilute with solution, separate, extract aqueous phase with dichloromethane, combine organic layers, dry with anhydrous sodium sulphate, concentrate and separate by column chromatography (ethyl acetate / normal hexane = 1: 4) ), The target compound 328 (4.71 g, 90%) was obtained. ESI: m / z: [M + Na] ⁺ , Ion peak: C ₁₉ H ₂₇ NNaO ₅ , 372.19, Experimental value, 372.20.

Example 66 (S) -5 -Phenyl-4- (t-butoxycarbonylamino) -2,3-Epoxyethyl-2-methylpentanoate (329)

A solution of compound 328 (4.70 g, 13.45 mmol) in tetrahydrofuran (100 ml) was added to an aqueous solution (60 mL) of lithium hydroxide (5.0 g, 208.7 mmol), stirred for 1 hour, concentrated, and water (150 mL). ) Was added, and the pH was adjusted to 4 with 4M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated, separated by column chromatography (MeOH / DCM / HOAc = 10: 10: 0.01) and the compound of interest 329 (3.97 g, 92). %) Was obtained. ESI: m / z: [M + Na] ⁺ , Ion peak: C ₁₇ H ₂₃ NNaO ₅ , 344.16, Found 344.16.

Example 67 (S) -5 -Phenyl-4- (9 -Fluorenemethoxycarbonylamino) -2,3-Epoxyethyl-2-methylpentanoate (331)

At a temperature of 0 ° C., trifluoroacetic acid (10 ml) was added to a dichloromethane solution of compound (329) (3.90 g, 12.14 mmol), stirred at that temperature for 30 minutes, diluted with toluene, and concentrated to dryness. This was carried out to obtain trifluoroacetate 330, which is a crude product. Sodium carbonate (5.0 g, 47.16 mmol) was added to a mixed solvent of water (60 mL and ethanol (60 mL)) and compound 330 and 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) were added to the solution (3.70 g, 14.30 mmol) was added. After stirring for 6 hours, the mixture was concentrated, water (150 mL) was added, and the pH was adjusted to 4 with 4 M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, separated by column chromatography (MeOH / DCM / HOAc = 10: 10: 0.01) and the compound of interest (3.87 g, 72%). , Two-stage generation rate) was obtained. ESI: m / z: [M + Na] ⁺ , Ion peak: C ₂₇ H ₂₅ NNaO ₅ , 466.17, Found 466.17.

Example 68 General procedure for polypeptide condensation;
Amine hydrochloride is dissolved in dichloromethane or N, N-dimethylformamide (0.2 M), cooled to 4 ° C in an ice water bath, t-butoxycarbonyl protected amino acids (1.3 eq), EDC (2 eq), Alternatively, TBTU (2 eq), or PyBrOP (2 eq), HOBt (1.5 eq), and DIPEA (3.5 eq) were added in that order. After slowly raising the temperature to room temperature, the reaction was continued for 15 hours with stirring, and immediately after diluting with ethyl acetate, the mixture was washed with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution. Polypeptides combined with organic phase, dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure, separated by column chromatography (0% -20% MeOH: CH ₂ Cl ₂ ) and protected with t-butoxycarbonyl. Got

Example 69 General procedure for deprotection of t-butoxycarbonyl;
Dissolve t-butoxycarbonyl-protected amino acids in 20% trifluoroacetic acid-containing dichloromethane solution or 4 M hydrochloric acid-containing 1,4-dioxane solution, stir for 30 minutes, or determine if the reaction is complete by TLC follow-up. did. Concentration under reduced pressure gave the corresponding trifluoroacetic acid salt or hydrochloride polypeptide compound. The appropriate hydrochloride may be obtained by concentrating the trifluoroacetate-containing polypeptide in a 2% hydrochloric acid-containing dichloromethane / toluene solution 3 to 4 times.

Example 70 General procedure for solid phase peptide (SPPS) synthesis;
The Merrifield resin or modified PAM resin or MBHA resin was used for SPPS protected with t-butoxycarbonyl. Wang resin, 2-chlorotriphenylmethylchlorine resin, HMPB, and MBHA resin were used for SPPS protected with 9-fluorene methoxycarbonyl. Pretreatment (pre-expansion) and loading of amino compounds were performed on the resin according to the operation instructions of the resin manufacturer. The t-butoxycarbonyl-protected amino acid in the resin is deprotected with a dichloromethane solution of 20% trifluoroacetic acid or a 1,4-dioxane solution containing 4M hydrochloric acid (stir for 30 minutes), and then N, N-dimethyl. Formamide, methanol, dichloromethane of 50% N, N-diisopropylethylamine and pure dichloromethane were washed in order. For deprotection steps involving multiple free amines, the steps had to be repeated once prior to acylation due to the integrity of the reaction. Free amines are suspended in a solution of protected amino acids (3 eq of free amines), TBTU or PyBrOP (3 eq of free amines) and N, N-diisopropylethylamine (5 eq of free amines). After reacting the mixed solution for 4 hours, N, N-dimethylformamide, methanol and dichloromethane were washed in this order. For the acylation reactions involving many free amines, the pre-deprotection conjugate step was repeated once for the integrity of the reaction. It is common to repeat these steps before synthesizing the required peptide.

Example 71 General procedure for separating a peptide from a Wang resin or 2-chlorotriphenylchlorine resin A Wang resin to which a peptide is bound is mixed with 50% trifluoroacetic acid-containing dichloromethane and triisopropylsilane (1-5%), or , 2-Chlorotriphenyl chlorine resin-bound peptide and 1% trifluoroacetic acid-containing dichloromethane are mixed, filtered after 2 hours, eluted with dichloromethane (3x30 ml) and methanol (3x30 ml) in order, and the filtrate is prepared. After merging, concentrating and drying, cold ether was added and the resulting precipitate was a peptide to be deprotected.

Example 72 General procedure for separating peptides from Merrifield resin, modified PAM resin or MBHA resin Peptide-bound resin and HF / Me ₂ S / anisole (10: 1: 1) or CH ₃ SO ₃ H / Me ₂ S Mix anisole (20: 1: 1) (for cysteine-containing peptides, it _{should be mixed with HF / anisole / Me 2} S / p-thiocresol (10: 1: 1: 0.2)), after 2 hours , Concentrated in an atmosphere of nitrogen gas, diluted with trifluoroacetic acid and filtered. Then, the resin is eluted with dichloromethane (3x30 ml) and methanol (3x30 ml) in order, the filtrate is mixed, concentrated, dried, and then cold ether is added, and the obtained precipitate is a peptide to be deprotected. there were.

Example 73 Purification by Chromatography The crude polypeptide mixture is purified by silica gel column chromatography (10% to 25% methanol: eluted with dichloromethane) or purified by RP HPLC (0% to 70% methanol). Gradient elution with an aqueous solution (most preferably 1% acetic acid) was completed within 1 hour, the target components were mixed, and a sample was collected after evaporation.

Example 74 Preparation of Conjugates (Coupling Agents) As a class of binding molecules, antibodies can be conjugated to fission inhibitors via amides, sulfur ethers or disulfide bonds. The antibody was diluted with 50 mM sodium borate-containing PBS buffer (pH 8.0) (<5 mg / mL), dithiothreitol (final concentration 10 mM) was added, and treated at 35 ° C for 30 minutes to release the antibody. Was able to be released. Gel filtration chromatography (1 mM EDTA added to PBS buffer) on a G-25 column, then measured with Ellman's reagent [5,5'-dithiobis (2-nitrobenzoic acid)], approximately 8 per antibody. Two mercaptos have been conjugated. Antibodies and Traut's Reagent (2-iminthiophene) (Jue, R., et al. Biochem. 1978, 17 (25): 5399-5405) can release mercapto or under conditions of pH 7-8. , SATP (N-succinimidyl S-acetylthiopropionate) and SAT (PEG) 4 reacted with different conjugates to form mercapto by the action of hydroxylamine (Duncan, R, et al, Anal. Biochem. 1983, 132, 68-73, Fuji, N. et al, Chem. Pharm. Bull. 1985, 33, 362-367). Basically, about 5-8 mercaptos were bound to each antibody.

Under 4 ° C conditions, the antibody dimethylacetamide (DMA) (2-20% v / v) linked to cold free mercapto contains maleimide or bromineacetamide groups (0.5 M sodium borate solution (pH 9)). Necessary to promote alkylation of antibody and bromineacetamide) drug (connecting drug to mercapto-mol ratio is 1.2 to 1.5). After 1 to 2 hours, the reaction is terminated by over-adding cysteine, the conjugate product is filtered out, gel chromatography (G-25 outside, buffer is PBS), aseptic filtration and concentration. Get the conjugate product of. The protein concentration and the number of drugs connecting each antibody were measured by the absorbance of the conjugate product at 280 nm and 252 nm. Molecular sieving chromatography HPLC can be used to measure the specific gravity of a single form of a junction. Unbound drugs below 0.5% were measured by RP-HPLC. For monodrugs that form connections to sulfur ether keys, an average of 3.2-4.2 molecules were connected to a small molecule mitotic inhibitor for each antibody.

The conjugates were connected by linkers such as DMPS, SMDP, SMPT, SPP, SPDP, SPDB, SMCC or SM (PEG) n. The antibody (<5 mg / mL) was diluted with buffer (pH 6.5-7.5, 5 mM PBS, 50 mM NaCl, 1 mM EDTA), reacted and linked for 2 hours, and the molar ratio of linker to antibody was 6. ~ 10 times or more. The reaction mixture was separated by Sephadex G25 gel chromatography to remove low molecular weight molecules (if the linker contained pyridinethiol, the antibody concentration was measured spectrophotometrically. The extinction coefficient at 280 nm ahead of the antibody was 2067550 M- ¹ cm. ^-1 is. after the modified antibodies of excess dithiothreitol (20 times or more equivalents) process, the free 2-pyridine thiol was measured extinction coefficient of 343,280nm destination respectively 8080 and 5100M ^-1 cm ^-1 there were). A 1.2 to 1.5 equivalent mercapto group-bearing mitotic inhibitor molecule was added to the modified antibody. This reaction was carried out at room temperature for 5 to 18 hours. Unconnected drugs and other low molecular weight substances were removed from the reaction mixture by Sephadex G25 gel chromatography. In addition, the concentration of the connected product was measured by the absorbance at 280 nm and 252 nm. The resulting conjugate alone contained an average of 3.2 to 4.5 individual drug molecules per antibody molecule.

Example 75 Extracorporeal toxicity test
BJAB (Burkitt lymphoma cells), BT-474 (breast cancer cells), Namalwa (human Burkitt lymphoma cells), Ramos (human Burkitt lymphoma cells), COLO 205 (human colon adenocarcinoma cells), A375 (human malignant black) All tumor cells) were purchased from ATCC. The breast cancer cell line KPL-4 was obtained from Dr. J. Kurebayashi (Kurebayashi, J. et al. Br J Cancer 1999; 79: 707-17). All of the above cells were grown in RPMI 1640 medium containing 10% FBS, and the culture conditions were _{37 ° C. and 6% CO 2 incubator.} Cloning experiments can be used as a toxicity test method for detection, see the literature (Franken, et al, Nature Protocols 1, 2315-2319 (2006)). For test cells, 5000 cells per well were inoculated into a 6-well plate, a 1 pM to 50 nM gradient diluted drug (mitotic inhibitor or coupler) was added, and the cells were incubated for 72 hours. The original medium was replaced and the cells were subsequently cultured to form colonies after 7-10 days. Cells were fixed and then stained with 0.2% gentiana violet (diluted in 10% formalin or PBS) and cell colonies were counted. The number of untreated cells (medium only) was measured by colonies formed in the wells. Cell viability was calculated by the ratio of the number of colonies formed in the control and control (undrug-treated) holes to the drug-treated group.

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Fig. 1 Synthesis of branched linker for binding a drug to a cell-binding agent Fig. 2 Synthesis of maleimide linker and its use in drug-binding molecular linkage Fig. 3 Synthesis of bromomaleimide and dibromomaleimide linker and use in their drug-binding molecular linkage Fig. 4 Synthesis of amino acid (Val-Cit) linker for binding of anti-thread-dividing agent and cell-binding molecule Fig. 5 Synthesis of Tuv component of anti-thread-dividing agent Conditions: a): CuSO ₄ , H ₂ SO ₄ , Acetone, 95%; b): DIBAL-H, THF / Tol, -78 ^o C, 95%; c): NH ₂ OH, LVDS ₃ , CH ₃ OH / H ₂ O; d): Isobutylaldehyde, DDL ₄ , CH ₂ Cl ₂ , 85% (2 steps); e): (2R) -N- (Acryloyl) dichloromethane-10,2-Sultam (74), 40 ^o C, 48h, CH ₂ Cl ₂ 83%; f ): LiOH, THF / H ₂ O, 86%; g): HClO ₄ , CH ₃ CN / H ₂ O, 98%; h): BOC ₂ O, Na ₂ CO3, THF / H ₂ O, 95%; i): L- (S) -Tr-cysteine methyl ester, EDC, CH ₂ Cl ₂ , 85%; j): Ph ₃ P = O, Tf ₂ O, CH ₂ Cl ₂ ; k): MnO ₂ , CH ₂ Cl ₂ , 76% (2 steps); l): Mo (CO) ₆ , CH ₃ CN / H ₂ O, 87%; m): Ac ₂ O, Pyr., 95%; n): 1). NaH, THF, CH ₃ I, 85%; 2). HOSnMe ₃ , ClCH ₂ CH ₂ Cl, 80 ^o C, 95%, 3). Ac ₂ O / Pyr, 86%.
Fig. 6 Synthesis of Tuv component of anti-thread splitting agent Conditions: o): Fmoc-Cl, LVDS ₃ , THF / H ₂ O, 95%; p): L- (S) -Tr-cysteine methyl ester, EDC, CH ₂ Cl ₂ , 87%; q): Ph ₃ P = O, Tf ₂ O, CH ₂ Cl ₂ ; r): MnO ₂ , CH ₂ Cl ₂ , 76% (2 steps); s): Mo (CO) ) ₆ , CH ₃ CN / H ₂ O, 87%; t): TES-Cl, Pyr., 95%; u): NaH, THF, CH ₃ I, 90%; v): NaH, THF, BrCH ₂ COOtBu, 0 ^o C, 87%; w): HOSnMe ₃ , ClCH ₂ CH ₂ Cl, 80 ^o C, ~ 90%; x): Bu ₄ NF, THF; y): Ac ₂ O, Pyr. 81%.
Figure 7 Synthesis of some Boc-Tuv and conjugatable anti-mitotic agents Conditions: a): NaH, THF, N- (4-bromobutyl) phthalimide, NaI, ~ 83%; b); NaH, DMF, CH ₃ I, 90%; c): HOSnMe ₃ , ClCH ₂ CH ₂ Cl, 80 ^o C, ~ 85%; d): Ac ₂ O, Pyr .; e): (R)-(+) -b- Methylphenethylamine, EDC, DMA, 85%; f): 4M HCl, dichloromethane; g); Boc-Ile-OH, PyBroP, DMAP, DMA, 78%; h): D-Mep, PyBroP / CH ₂ Cl ₂ , 81%; i): NH ₂ NH ₂ , DMA; j); 58 (n = 3), EDC, DMA, k): Ac ₂ O, Pyr. 56%.
FIG. 8 Synthesis of some anti-thread-dividing agents Tuv, Ile-Tuv and Mep-Ile Fig. 9 Synthesis of anti-thread-dividing agents Ile-Tuv, Mep-Leu-Tuv, Val-Ile-Tuv and Val-Ile- Synthesis of a part of Tuv (O-alkyl) Fig. 10 Synthesis of bindable anti-mitotic agent and binding with antibody Fig. 11 Amino acid (Phe- (D) Lys) for binding of anti-mitogenic agent ) Linker synthesis Fig. 12 Synthesis of antibody-anti-thread-dividing agent conjugate Fig. 13 Synthesis of antibody-anti-thread-dividing agent conjugate Fig. 14 Synthesis of binding molecule-anti-thread-dividing agent conjugate Fig. 15 Binding molecule (antibody) )-Synthesis of anti-thread-dividing agent conjugate Fig. 16 Synthesis of antibody-anti-thread-dividing agent conjugate Fig. 17 Synthesis of antibody-anti-thread-dividing agent conjugate Fig. 18 Hydrophilic (phosphate prodrug) anti-presence Synthesis of hydrophilic Tut analogs for the synthesis of mitotic agents Figure 19 Synthesis of conjugates of anti-mitotic agents and antibodies Figure 20 BOC solid phase synthesis of bindable anti-mitotic agents Conditions: a): Piperazin (5 ~ 20 eq), CH ₂ Cl ₂ , 4h; b): Boc-Aa ₂ -OH (2 ~ 5 eq), PyBroP (2 ~ 5 eq), DIPEA (3 ~ 10 eq), DMF, 4 h c): 4M HCl / dioxane, 0.5h; then DIPEA (2-3 eq), washed with DMF; d): Boc-Aa1-OH (2-5 eq), TBTU (2-5 eq), DIPEA ( 3 to 10 eq), DMF, 4 h; e): BocNMe- Phe-OH, or Boc-Trp-OH, or BocNMe-Tyr (PO (OBz) OH) -OH (2 to 5 eq), or BocNMe- (Pyr) Ala-OH, or Boc- (thienyl) Ser-OH, or Boc- (thiazolyl) -Ala-OH, PyBroP (2-5 eq), DIPEA (3-10 eq), DMF, 4 h; f ): Boc-N (Me) -Tuv-OH (1.5 ~ 3 eq), PyBroP (2 ~ 5 eq), DIPEA (3 ~ 10 eq), DMF, 2 h; g): Boc-Ile-OH (2) ~ 5 eq), PyBroP (2 ~ 5 eq), DIPEA (3 ~ 10 eq), DMF, 3 h; h): NMe ₂ -Ile-OH, TBTU (2-5 eq), DIPEA (3-10 eq), DMF, 2h; i): TFA, anisole; j): 4-maleimidebutanoic acid NHS ester (1.5-2 eq), DIPEA (3-10 eq) ), DMF, 2 h; k): 4- (Methyldisulfanyl) butanoic acid NHS ester (1.5-2 eq), or 4,4-dimethyl 4- (methyldisulfanyl) -butanoic acid NHS ester (1.5-2 eq) eq), DIPEA (3-10 eq), DMF, 2 h; l): TCEP (3-10 eq), dioxane / buffer pH 7,0, then solid-supported guanidine.
Fig. 21 Fmoc solid phase synthesis of bindable anti-thread splitting agent Conditions: a) :( MeNCH ₂ ) ₂ (5 to 20 eq), DCM, 4h; b): Fmoc-Aa ₂ -OH (2 to 5 eq) ), PyBroP (2-5 eq), DIPEA (3-10 eq), DMF, 4 h; c): 20% piperidine, DMF, 2h; d): Fmoc-Aa1-OH (2-5 eq), TBTU (2-5 eq), DIPEA (3-10 eq), DMF, 4 h; e): (2-5 eq) FmocNMe-Tyr (SO ₃ H) -OH, or Fmoc-TrpOH-OH, or FmocNMe- Tyr (PO (OBz) -OH) -OH or FmocNMe _2- Tyr (glucose) -OH, or Boc- (quinolyl) Ala-OH, or Fmoc- (thienyl) Ser-OH, (phenyl) -Cys-OH, PyBroP (2-5 eq), DIPEA (3-10 eq), DMF, 4 h; f): Fmoc-N (Me) -Tuv-OH (1.5-3 eq), PyBroP (2-5 eq), DIPEA (3-10 eq), DMF, 4 h; g): Fmoc-Ile-OH (2-5 eq), PyBroP (2-5 eq), DIPEA (3-10 eq), DMF, 4 h; h) : Mep-OH (2-4 eq), or (R) -1-methylaziridine-2-carboxylet, TBTU (2-5 eq), DIPEA (3-10 eq), DMF, 2h; i): TFA , DCM, anisole; j): 4-maleimidebutanoic acid NHS ester (1.5-2 eq), DIPEA (3-10 eq), DMF, 4 h; k): 20% TFA, DCM; l): 4-( Methyldisulfanyl) butanoic acid NHS ester (1.5-2 eq), or 4,4-dimethyl 4- (methyldisulfanyl) -butanoic acid NHS ester (1.5-2 eq), DIPEA (3-10 eq), DMF, 4 h; m): TCEP (8 eq), dioxane, buffer pH 7,0, then solid Body-supported guanidine.
Figure 22 hydrophilic antimitotic agents and Synthesis of Figure 23 Tuv derivative conjugates with the antibody, and Mep-Ile-Tuv and _NMe 2 -Val-Ile-Tuv components of synthesis conditions: a): Compound 72 , DIPEA, CsI, DMF, 2 h; b): 20% TFA / DCM, 0.5 h, then washed with DIPEA, MeOH, DCM; c): Boc-Ile-OH (3-5 eq), PyBroP (3) ~ 5 eq), DIPEA (3 ~ 10 eq), DMF, 6 h; d): Mep-OH (2 ~ 4 eq), or NMe ₂ -Leu-OH, TBTU (2 ~ 5 eq), DIPEA (3) ~ 10 eq), DMF, 6 h; e): 95% TFA / Anisole / DCM.
Figure 24 antimitotic agent and the synthesis conditions of the conjugate of an _{antibody: a): (COCl) 2} 6 eq, DMF (cat), DCM, 1h; b): D - (+) - Boc- norephedrine 4 eq, DIPEA, DCM, 4 h; c): 20% TFA / DCM, 0.5 h, then washed with DIPEA, MeOH, DCM; d): Compound 274 (1.2 eq), TBTU (5 eq), DMF, 6 h; e): Boc-Ile-OH (3-5 eq), PyBroP (3-5 eq), DIPEA (3-10 eq), DMF, 4 h; f): Mep-OH (2-4 eq) ), Or NMe ₂ -Leu-OH, TBTU (2-5 eq), DIPEA (3-10 eq), DMF, 2h; g): HOSnMe ₃ , ClCH ₂ CH ₂ Cl, 80 ^o C, 8h.
Figure 25 Solid-phase synthesis of anti-thread-dividing agent and conjugate of its antibody Conditions: a): 20% TFA / DCM, 0.5 h, then washed with DIPEA, MeOH, DCM; b): Boc-thiazolyl-Ala -OH (2 eq), 2-thienyl -L-Cys-OH (2 eq) PyBroP (4 eq), DIPEA (4 eq), DMF, 6 h; c): Compound 276, TBTU (4 eq), DIPEA ( 4 eq), DMF, 6 h; d): Boc-Ile-OH (4 eq), PyBroP (4 eq), DIPEA (4 eq), DMF, 6 h; Condition: e): Mep-OH (2 ~ 4 eq), or NMe ₂ -Leu-OH, TBTU (2-5 eq), DIPEA (3-10 eq), DMF, 2h; f): TFA / DCM / anisole / p-thiocresol (95: 4: 4: 0.5: 0.5).)
FIG. 26 Solid phase synthesis of anti-thread-dividing agent and conjugate of its antibody Conditions: a: DMF / piperidine (4: 1); b: 331 / DMF / PyBroP (2-5 eq); c: Fmoc-Tuv- OH (1.2 eq), TBTU (5 eq), DMF; d: Fmoc-Ile-OH (4 eq), PyBroP (4 eq), DIPEA (4 eq), DMF; e: N, N (methyl, maleimide- Pentanoic acid)-Val-OH (2 eq), TBTU, DMF; f: N, N- (methyl, 2'-pyridinyl-disulfanylbutanoic acid)-Val-OH, TBTU (4 eq), DMF; g: 5% TFA / DCM / 1% TIS; i: DTT / pH 7.0 PBS buffer / DMF, then HPLC; j: N, N (methyl, maleimide-pentanoic acid)-Mep-OH (2 eq), TBTU, DMF k: N, N- (methyl, 2'-pyridinyl-disulfanylbutanoic acid)-Mep-OH, TBTU (4 eq), DMF.
Fig. 27 Synthesis of trans-2-arylcyclopropylamine, trans-2-arylcyclopropylcarboxylic acid, and trans-2-arylethylepoxycarboxylic acid Fig. 28 Synthesis of alkene amino acid and alkylepoxy amino acid Fig. 29 Anti-mitosis Synthesis of hydrophilic Tut analogs for the synthesis of hydrophilic prodrugs of agents Figure 30 Synthesis of hydrophilic prodrugs of antimitotic agents that bind to cell-binding agents Figure 31 Anti-presence that binds to cell-binding agents Synthesis of hydrophilic prodrugs of mitotic agents Figure 32 Synthesis of hydrophilic prodrugs of antimitotic agents that conjugately bind to an antibody Figure 33 Anti-CD22 antibody-anti with a drug / antibody ratio (D / A) of 3.0-4.3 Shows the cytotoxic effect of mitotic agents (TZ01-TZ09) conjugates on Ramos (Berkit lymphoma cell line). The cells were incubated for 5 days in the presence of the conjugate. The IC ₅₀ values are shown in FIG.
FIG. 34 shows the cytotoxic effect of trastuzumab-antimitotic (TZ03, TZ04 and TZ07) conjugates with a drug / antibody ratio (DAR) of 3.5-4.0 on KPL-4 (breast cancer cell line). Trastuzumab-TZ03 has particularly strong antiproliferative activity, respectively, in the absence of unconjugated trastuzumab, IC ₅₀ = 90 pM; in the presence of 1 micromol of trastuzumab (to saturate antigen binding), IC ₅₀ > 20nM ,. Special windows exceed 222 (IC ₅₀ > 20 nM / IC ₅₀ = 0.09 nM).
FIG. 35 shows the BJAB (Rituximab) of anti-CD22 antibody-anti-mitotic (TZ03, TZ04 and TZ07) conjugates and non-conjugated CD22 and CD20 antibodies (rituximab) with a drug / antibody ratio (D / A) of 3.8-4.2. It shows a cytotoxic effect on Burkitt lymphoma cell line). The conjugate (IC ₅₀ = 5-19 pM) has stronger antiproliferative activity than the non-conjugated CD22 antibody. Compared to non-conjugated _{compounds (IC 50} > 20 nM), it has stronger antiproliferative activity. When saturating antigen binding with 1 micromol of non-conjugated CD22 antibody, the special window for huCD22-TZ03 conjugation exceeds 660 (IC ₅₀ = 3.3 nm / IC ₅₀ = 0.005 nm) and for huCD22-TZ07 conjugation. The number of special windows exceeds 660 (IC ₅₀ = 15 nM / IC ₅₀ = 0.019 nM).
Tables 2-1 to 2-9 show the structures of antimitotic drugs produced by solid phase synthesis, their mass spectrometric ionic peaks, and their toxic effects on Ramos cells (ATCC, human Burkitt lymphoma cells) tested in vitro. The value of (IC ₅₀ ) is shown.
Tables 3-1 to 3-4 show the structural formulas of some antibody-antimitotic conjugates.

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが独立して括弧内構造における分子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０であり；
括弧内の構造体が効果的な抗有糸分裂剤・薬物であり、そのうち、Ｒ^１、Ｒ^２、Ｒ^３とＲ⁴が独立して、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；C₂〜C₈のヘテロ環、炭素環、アルキルシクロアルキル、複素環アルキル、Ｃ_３〜Ｃ_８のアリール、アラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル；又は２つのＲ基（例えば、Ｒ^１Ｒ^２ _、 Ｒ^２Ｒ^３ _、 Ｒ^３Ｒ^４、Ｒ^５Ｒ^６、Ｒ^１２Ｒ^１３という各組合せが炭素数３〜７の炭素環基、シクロアルキル、または複素環基とヘテロシクロアルキルなど環係基であってもいい）をそれぞれ表し、ＹがＮまたはＣＨであり；また、Ｒ^１、Ｒ^３とＲ^４はＨであってもよく、かつ、Ｒ²は欠如していてもよく；
Ｒ^５、Ｒ^６、Ｒ^８と Ｒ^１０はそれぞれ、独立してＨ又はＣ_１〜Ｃ_４のアルキルまたはヘテロアルキルであり；
Ｒ^７ は独立してＨ、Ｒ^１４、あるいは−Ｒ^１４Ｃ（＝Ｏ）Ｘ^１Ｒ^１５又は−Ｒ^１４Ｘ^１Ｒ^１５から選択され；そのうち、Ｒ^１４ とＲ^１５ はそれぞれ独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル；複素環、炭素環、シクロアルカン；Ｃ_３−Ｃ_８アリール、復素環アルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり、Ｘ^１はＯ、Ｓ、Ｓ−Ｓ、ＮＨ又はＮＲ^１４であり；
Ｒ^９は独立してＨ、−Ｏ−、−ＯＲ^１４、−ＯＣ（＝Ｏ）Ｒ^１４−、−ＯＣ（＝Ｏ）ＮＨＲ^１４−、−ＯＣ（＝Ｏ）Ｒ¹⁴ＳＳＲ^１５−、ＯＰ（＝Ｏ）（ＯＲ^１４）−またはＯＲ^１４ＯＰ（＝Ｏ）（ＯＲ^１５）であり、そのうち、Ｒ^１４ とＲ^１５はそれぞれ独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１１はＨ、Ｒ^１４、−Ｒ^１４Ｃ（＝Ｏ）Ｒ^１６、−Ｒ^１４Ｘ^２Ｒ^１６、−Ｒ^１４Ｃ（＝Ｏ）Ｘ^２であり、そのうち、Ｘ^２は−Ｏ−、−Ｓ−、−ＮＨ−、−Ｎ（Ｒ^１４）−、−Ｏ−Ｒ^１４−、−Ｓ−Ｒ^１４−、−Ｓ（＝Ｏ）−Ｒ^１４−または−ＮＨＲ^１４−であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル、Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環、又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；Ｒ^１６は Ｈ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１２は独立してＲ^１４、−Ｏ−、−Ｓ−、−Ｎ−、＝Ｎ−、＝ＮＮＨ−、−ＮＨ（Ｒ^１４）、−ＯＲ^１４、−Ｃ（Ｏ）Ｏ−Ｃ（Ｏ）Ｏ−Ｒ^１6−、Ｃ（Ｏ）ＮＨ-、Ｃ（Ｏ）ＮＨＲ^１４、−ＳＲ^１４−、−Ｓ（＝Ｏ）Ｒ^１４−、−Ｐ(=Ｏ)（ＯＲ^１６）−、−ＯＰ（＝Ｏ）（ＯＲ^１６）−、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１６）、−Ｃ（Ｏ)ＯＰ（＝Ｏ）（ＯＲ^１６）、又は−ＳＯ_２Ｒ¹⁶であり；Ｒ^１４は独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり、Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１３はＣ_１−Ｃ_１０アルキル、ヘテロアルキル、アルキル酸、アルキルアミド、アルキルアミン又はＡｒであり、そのうち、Ａｒとは、１員環又は複数員環からなる芳香族環又は複素芳香族環であり、芳香族環又は複素芳香族環が４〜１０個の炭素原子を含み、最も好ましくは４〜６つの炭素原子を含み、複素芳香族環とは、１つ又はいくつかの炭素原子が他の原子によって置換された芳香族環を意味し、最も好ましくは、１つ、２つ又は３つの炭素原子がＯ、Ｎ、Ｓｉ、Ｓｅ、ＰまたはＳによって置換され、最も好ましくはＯ、Ｓ、Ｎによって置換され；アリールまたはＡｒとは、１つ又はいくつかの水素原子が置換された芳香族環を意味し、水素原子を置換するこれらの基は、Ｒ^１７、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^１６、ＳＲ^１６、ＮＲ^１６Ｒ^１７、Ｎ＝ＮＲ^１６、Ｎ＝Ｒ^１６、ＮＲ^１６Ｒ¹⁷、ＮＯ_２、ＳＯＲ^１６Ｒ^１７、ＳＯ_２Ｒ^１６、ＳＯ_３Ｒ^１６、ＯＳＯ_３Ｒ^１６、ＰＲ^１６Ｒ^１７、ＰＯＲ^１６Ｒ^１7、ＰＯ_２Ｒ^１６Ｒ^１７、ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣＨ_２ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＰＯ（ＯＲ^１６）（ＯＲ^１７）、ＯＰ（Ｏ）（ＯＲ^１７）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）Ｒ^１７ またはＯＣ（Ｏ）ＮＨＲ^１７を含み、そのうち、Ｒ^１６とＲ^１７はそれぞれ、独立してＨ−、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニル或いはＣ_４−Ｃ_１２グリコシド又は医薬用塩であり；
また、Ｒ^１０がＨでない場合、或いは、Ｒ^１３が下記の基である場合、Ｒ^１２はＨであってもよく；

ここで、Ｚ^１はＨ、ＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＰＯ（ＯＲ^１８）_２、Ｐ（Ｏ）（ＯＲ^１８）ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）Ｒ^１８、Ｃ（Ｏ）ＮＨＲ^１８、ＳＯ_２（ＯＲ^１８）、Ｃ_４−Ｃ₁₂のグリコシド、又は、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、複素環であり；Ｒ^１８は、Ｈ、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、ヘテロアルキル；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；又は、Ｃ_３〜Ｃ_８のアリール、アルキルカルボニルであり；Ｒ^１９はＨ、ＯＨ、ＮＨ_２、ＯＳＯ_２（ＯＲ^１８）、ＸＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＰＯ（ＯＲ^１８）_２、ＸＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＣ（Ｏ）Ｒ^１８、ＸＣ（Ｏ）ＮＨＲ^１８、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル、カルボン酸誘導体；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニル；又は医薬用塩であり；ＸはＯ、Ｓ、又はＮＨであり；Ｙ^１とＹ^２はそれぞれＮ又はＣＨであり；
或いは、Ｒ^１１が下記の基である場合、Ｒ^１２はＨであってもよく；

Ｘ^２がＯ、Ｓ、Ｎ−Ｒ^８であり、Ｒ^８がＨ、Ｃ_１〜Ｃ_６のアルキル又はヘテロアルキルである。） (Additional note)
(Appendix 1)
Conjugates having the structure represented by Structural Formula (I) and pharmaceutically acceptable salts and solvates.

(However, where T is the target or binding ligand, L is the dissociable linker,

Is a link bond where L independently connects to the molecule in parenthesized structure, n is 1-20, m is 1-10;
The structures in parentheses are effective anti-thread splitting agents / drugs, of which R ¹ , R ² , R ³ and R ⁴ are independent, C _{1 to} C ₈ alkyl, heteroalkyl; C ₂ heterocycle, carbocycle -C _8, alkyl cycloalkyl, _{heterocycloalkyl,} aryl C 3 -C _8, aralkyl, heteroalkyl cycloalkyl, alkylcarbonyl; or two R groups ^(e.g., R ¹ _{R 2,} R ^{Each combination of 2} R ³ _, R ³ R ⁴ , R ⁵ R ⁶ , and R ¹² R ¹³ is a ring-related group such as a carbocyclic group having 3 to 7 carbon atoms, a cycloalkyl group, or a heterocyclic group and a heterocycloalkyl group. Y is N or CH; R ¹ , R ³ and R ⁴ may be H, and R ² may be absent;
R ⁵ , R ⁶ , R ⁸ and R ¹⁰ are each independently alkyl or heteroalkyl H or _C 1 -C _4;
R ⁷ is independently selected from H, R ¹⁴ or -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ ; of which R ¹⁴ And R ¹⁵ Are independently C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl; heterocycle, carbocycle, cycloalkane; C _3- C ₈ aryl, condensing ring alkyl, heteroaralkyl, Heteroalkylcycloalkyl, alkylcarbonyl, where X ¹ is O, S, SS, NH or NR ¹⁴ ;
R ⁹ is independently ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15 -, OP ( = O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ), of which R ¹⁴ And R ¹⁵ are independently C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, respectively. Heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
R ¹¹ is H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² , of which X ² is -O-,- ^{S -, - NH -, -} N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - a ^{and; R 14} is C _{1 to} C ₈ alkyl, heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl , Heteroaralkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹² independently R ¹⁴ , -O-, -S-, -N-, = N-, = NNH-, -NH (R ¹⁴ ), -OR ¹⁴ , -C (O) OC (O) ^{) OR 16 -, C (O} ) NH-, C (O) NHR 14, -SR 14 -, - S (= O) R 14 -, - P (= O) (OR 16) -, - OP (= O) (OR ¹⁶ )-, -CH ₂ OP (= O) (OR ¹⁶ ), -C (O) OP (= O) (OR ¹⁶ ), or -SO ₂ R ¹⁶ ; R ¹⁴ is Independently C _1- C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero Alkyne, heteroalkylcycloalkyl, alkylcarbonyl, R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkylamines or Ar, of which, the Ar, aromatic ring or heteroaromatic ring consisting of 1-membered ring or more membered ring Yes, the aromatic ring or heteroaromatic ring contains 4 to 10 carbon atoms, most preferably 4 to 6 carbon atoms, and the heteroaromatic ring is one or several other carbon atoms. Means an aromatic ring substituted with an atom of, most preferably one, two or three carbon atoms are substituted with O, N, Si, Se, P or S, most preferably O, S, Substituted by N; aryl or Ar means an aromatic ring in which one or several hydrogen atoms are substituted, and these groups substituting hydrogen atoms are R ¹⁷ , F, Cl, Br, I. , OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) (OR ¹⁷⁾ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ¹⁷ , of which R ¹⁶ and R ¹⁷ are independently H-, C _1- C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; or C _3- C ₈ aryl, cycloalkyl, respectively. , alkylcycloalkyl, heteroaryl cycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or C ₄ -C ₁₂ glycoside or pharmaceutical salts;
Also, if R ¹⁰ is not H, or if R ¹³ is the following group, then R ¹² may be H;

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP. (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ glycosides, or C _{1 to} C ₈ alkyls, carboxyalkyls. The group is a heterocycle; R ¹⁸ is an alkyl of H, C _{1 to} C ₈ , a carboxyalkyl group, a heteroalkyl; an alkenyl, an alkynyl, a heterocycle of _{C 2 to} C ₈ ; or an aryl of _{C 3 to} C _8. , Alkylcarbonyl; R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C ₃ ~ C ₈ aryl, alkylcarbonyl; or medicinal salt; X is O, S, or NH; Y ¹ and Y ² are N or CH, respectively;
Alternatively, if R ¹¹ is the following group, then R ¹² may be H;

X ² is O, S, N-R ⁸ and R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6. )

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが独立して括弧内構造における分子と接続するリンク結合、ｎは１〜２０、mは１〜１０であり；
括弧内の構造体が効果的な抗有糸分裂剤・薬物であり、そのうち、Ｒ^１、Ｒ^２、Ｒ^３とＲ⁴がＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；C₂〜C₈のヘテロ環、炭素環、アルキルシクロアルキル、ヘテロシクロアルキル、Ｃ_３〜Ｃ_８のアリール、アラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル；又は２つのＲ^１基（例えば、Ｒ^１Ｒ^２ _、 Ｒ^２Ｒ^３ _、Ｒ^３Ｒ^４、Ｒ^５Ｒ^６、Ｒ^１２Ｒ^１３という各組合せが炭素数３〜７の炭素環基、シクロアルキル、あるいは複素環基とヘテロシクロアルキルなど環係基であってもいい）をそれぞれ表し、ＹがＮまたはＣＨであり；また、Ｒ^１、Ｒ^３とＲ^４はＨであってもよく、かつ、Ｒ²は欠如していてもよく、
Ｒ^５、Ｒ^６、Ｒ^８とＲ^１０はそれぞれ、独立してＨ又はＣ_１〜Ｃ_４（炭素数１〜４）のアルキルまたはヘテロアルキルであり；
Ｒ^７は独立してＨ、Ｒ^１４ _、あるいは−Ｒ^１４Ｃ（＝Ｏ）Ｘ^１Ｒ^１５又は−Ｒ^１４Ｘ^１Ｒ^１５から選択され、そのうち、Ｒ^１４とＲ^１５はそれぞれ独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル；複素環、炭素環、シクロアルカン；又はＣ_３−Ｃ_８アリール、復素環アルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり、Ｘ^１はＯ、Ｓ、Ｓ−Ｓ、ＮＨ又はＮＲ^１４であり；
Ｒ^９は独立してＨ、−Ｏ−、−ＯＲ^１４、−ＯＣ（＝Ｏ）Ｒ^１４−、−ＯＣ（＝Ｏ）ＮＨＲ^１４−、−ＯＣ（＝Ｏ） Ｒ¹⁴ＳＳＲ^１５、ＯＰ（＝Ｏ）（ＯＲ^１４）−またはＯＲ^１４ＯＰ（＝Ｏ）（ＯＲ^１５）であり；そのうち、Ｒ^１４とＲ^１５ はそれぞれ独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１１は独立してＨ、Ｒ^１４、−Ｒ^１４Ｃ（＝Ｏ）Ｒ^１６、−Ｒ^１４Ｘ^２Ｒ^１６、−Ｒ^１４Ｃ（＝Ｏ）Ｘ^２であり；そのうち、Ｘ^２は−Ｏ−、−Ｓ−、−ＮＨ−、−Ｎ（Ｒ^１４）−、−Ｏ−Ｒ^１４−、−Ｓ−Ｒ^１４−、−Ｓ（＝Ｏ）−Ｒ^１４−または−ＮＨＲ^１４−であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１２は独立してＲ^１４、−ＯＨ、−ＳＨ、−ＮＨ_２、＝ＮＨ、＝ＮＮＨ_２、−ＮＨ（Ｒ^１４）、−ＯＲ^１４、−ＣＯＲ^１６、−ＣＯＯＲ^１４−、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１４、−ＳＲ^１４、−Ｓ（＝Ｏ）Ｒ^１４、−Ｐ(=Ｏ)（ＯＲ^１６）_２、−ＯＰ（＝Ｏ）（ＯＲ^１６）_２、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１６）_２、又は−ＳＯ_２Ｒ¹⁶であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１３はＣ_１−Ｃ_１０アルキル、ヘテロアルキル、アルキル酸、アルキルアミド、アルキルアミン又はＡｒであり；そのうち、Ａｒとは、１員環又は複数員環からなる芳香族環又は複素芳香族環であり、芳香族環又は複素芳香族環ごとに４〜１０個の炭素原子を含み、最も好ましくは４〜６つの炭素原子を含み；複素芳香族環とは、１つ又はいくつかの炭素原子が他の原子によって置換された芳香族環を意味し、最も好ましくは、１つ、２つ又は３つの炭素原子がＯ、Ｎ、Ｓｉ、Ｓｅ、ＰまたはＳによって置換され、最も好ましくは、Ｏ、Ｓ、Nによって置換され；アリールまたはＡｒとは、１つ又はいくつかの水素原子が置換された芳香族環を意味し、水素原子を置換するこれらの基は、Ｒ^１７、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^１６、ＳＲ^１６、ＮＲ^１６Ｒ^１７、Ｎ＝ＮＲ^１６、Ｎ＝Ｒ^１６、ＮＲ^１６Ｒ¹⁷、ＮＯ_２、ＳＯＲ^１６Ｒ^１７、ＳＯ_２Ｒ^１６、ＳＯ_３Ｒ^１６、ＯＳＯ_３Ｒ^１６、ＰＲ^１６Ｒ^１７、ＰＯＲ^１６Ｒ^１7、ＰＯ_２Ｒ^１６Ｒ^１７、ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣＨ_２ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＰＯ（ＯＲ^１６）（ＯＲ^１７）、ＯＰ（Ｏ）（ＯＲ^１７）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）Ｒ^１７ またはＯＣ（Ｏ）ＮＨＲ^１７を含み、そのうち、Ｒ^１６とＲ^１７はそれぞれ、独立してＨ、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニル或いはＣ_４−Ｃ_１２グリコシド又は医薬用塩であり；
また、Ｒ^１０がＨでない場合、或いは、Ｒ^１３が下記の基である場合、Ｒ^１２はＨであってもよく、

ここで、Ｚ^１はＨ、ＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＰＯ（ＯＲ^１８）_２、Ｐ（Ｏ）（ＯＲ^１８）ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）Ｒ^１８、Ｃ（Ｏ）ＮＨＲ^１８、ＳＯ_２（ＯＲ^１８）、Ｃ_４−Ｃ₁₂のグリコシド、又は、アルキル、カルボキシアルキル基、複素環であり；Ｒ^１８は、Ｈ、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、ヘテロアルキル；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；又は、Ｃ_３〜Ｃ_８のアリール、アルキルカルボニルであり；Ｒ^１９はＨ、ＯＨ、ＮＨ_２、ＯＳＯ_２（ＯＲ^１８）、ＸＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＰＯ（ＯＲ^１８）_２、ＸＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＣ（Ｏ）Ｒ^１８、ＸＣ（Ｏ）ＮＨＲ^１８、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル、カルボン酸誘導体；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニル又は医薬用塩であり；ＸはＯ、Ｓ、又はＮＨであり；Ｙ^１とＹ^２はそれぞれＮ又はＣＨであり；
或いは、Ｒ^１１が下記の基である場合、Ｒ^１２はＨであってもよく、

Ｘ^２がＯ、Ｓ、Ｎ−Ｒ^８であり、Ｒ^８がＨ、Ｃ_１〜Ｃ_６のアルキル又はヘテロアルキルである。） (Appendix 2)
The conjugate and pharmaceutically acceptable salt and solvate according to Appendix 1, which has the structure represented by Structural Formula (II).

(However, where T is the target or binding ligand, L is the dissociable linker,

Is a link bond where L independently connects to the molecule in parenthesized structure, n is 1-20, m is 1-10;
The structures in parentheses are effective anti-thread-dividing agents / drugs, of which R ¹ , R ² , R ³ and R ⁴ are C _{1 to} C ₈ alkyl and heteroalkyl; C _{2 to} C ₈ heterocycle, carbocycle, alkyl cycloalkyl, _{heterocycloalkyl,} aryl C 3 -C _8, aralkyl, heteroalkyl cycloalkyl, alkylcarbonyl; or two ^{R 1} groups ^(e.g., R ¹ _R ^2, R 2 ^{R 3} _, R ³ R ⁴ , R ⁵ R ⁶ , R ¹² R ¹³ may be a carbocyclic group having 3 to 7 carbon atoms, a cycloalkyl group, or a heterocyclic group and a heterocycloalkyl group.) represent each, Y is N or CH; ^also, R 1, ^{R 3} and ^{R 4} can be H, and may also be R ² is absent,
R ^{5, R} 6, respectively ^{R 8} and ^{R 10} is an alkyl or heteroalkyl independently H or _C 1 _{~C 4 (1~4} carbon atoms);
R ⁷ is independently selected from ^{H, R 14} or ^{-R 14 C (= O) X} 1 R 15 or ^-R 14 ^X 1 ^{R _15,,} of ^{which, R 14} and ^{R 15} are each independently _{C 1} alkyl -C _{8, heteroalkyl;} alkenyl C 2 -C _8, alkynyl; heterocycle, carbocycle, cycloalkane; or _C 3 -C ₈ aryl, Fukumotowa alkyl, heteroaralkyl, heteroalkyl cycloalkyl, alkyl It is a carbonyl and X ¹ is O, S, SS, NH or NR ¹⁴ ;
R ⁹ is independently ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ); of which R ¹⁴ and R ¹⁵ Are independently C _{1 to C 8} alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl. , Heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
R ¹¹ are independently H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² ; of which X ² is -O. ^{-, - S -, - NH} -, - N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - a and; R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero. Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹² is independently _{^{R 14, -OH, -SH, -NH}} 2, = NH, = NNH 2, -NH (R 14), - OR 14, -COR 16, -COOR 14 -, C (O) NH ₂ , C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (= O) (OR ¹⁶ ) ₂ or -SO ₂ R ¹⁶ ; R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; Or C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units. ;
R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or Ar; them, and Ar, aromatic ring or heteroaromatic ring consisting of 1-membered ring or more membered ring There are 4 to 10 carbon atoms per aromatic or heteroaromatic ring, most preferably 4 to 6 carbon atoms; a heteroaromatic ring is one or several carbon atoms. It means an aromatic ring substituted with other atoms, most preferably one, two or three carbon atoms are substituted with O, N, Si, Se, P or S, most preferably O, Substituted by S, N; aryl or Ar means an aromatic ring in which one or several hydrogen atoms are substituted, and these groups substituting hydrogen atoms are R ¹⁷ , F, Cl, Br. , I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) ( Includes OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ^17. , R ¹⁶ and R ¹⁷ are independently H, C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; or C _3- C ₈ aryl, cyclo, respectively. alkyl, alkylcycloalkyl, heteroaryl cycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or C ₄ -C ₁₂ glycoside or pharmaceutical salts;
Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP. (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ glycosides, or alkyl, carboxyalkyl groups, heterocycles. R ¹⁸ is an alkyl, carboxyalkyl group, heteroalkyl of H, C _{1 to} C ₈ ; an alkenyl, alkynyl, heterocycle of _{C 2 to} C ₈ ; or an aryl, alkyl carbonyl of _{C 3 to} C _8; R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivatives; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C _{3 to} C ₈ aryl, alkylcarbonyl or pharmaceutical salt; X is O, S, or be NH; ^{Y 1} and ^{Y 2} are each N or CH;
Alternatively, if R ¹¹ is the following group, then R ¹² may be H.

X ² is O, S, N-R ⁸ and R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6. )

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが独立して括弧内構造における分子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０であり；
括弧内の構造体が効果的な抗有糸分裂剤・薬物であり、そのうち、Ｒ^１、Ｒ^２、Ｒ^３とＲ⁴が独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；C₂〜C₈のヘテロ環、炭素環、アルキルシクロアルキル、ヘテロシクロアルキル、Ｃ_３〜Ｃ_８のアリール、アラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、又は２つのＲ基（例えば、Ｒ^１Ｒ^２ _、 Ｒ^２Ｒ^３ _、 Ｒ^３Ｒ^４、Ｒ^５Ｒ^６、Ｒ^１２Ｒ^１３という各組合せが炭素数３〜７の炭素環基、シクロアルキル、または複素環基とヘテロシクロアルキルなど環係基であってもいい）をそれぞれ表し、ＹがＮまたはＣＨであり；また、Ｒ^１、Ｒ^３とＲ^４はＨであってもよく、かつ、Ｒ²は欠如していてもよく、
Ｒ^５、Ｒ^６、Ｒ^８とＲ^１０はそれぞれ、独立してＨ又はＣ_１〜Ｃ_４のアルキルまたはヘテロアルキルであり；
Ｒ^７は独立してＲ^１４、あるいは−Ｒ^１４Ｃ（＝Ｏ）Ｘ^１Ｒ^１５又は−Ｒ^１４Ｘ^１Ｒ^１５から選択され、そのうち、Ｒ^１４ とＲ^１５ はそれぞれ、独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環、シクロアルカン；又はＣ_３−Ｃ_８アリール、復素環アルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり、Ｘ^１はＯ、Ｓ、Ｓ−Ｓ、ＮＨ又はＮＲ^１４であり；
Ｒ^９は独立してＨ、−Ｏ−、−ＯＲ^１４、−ＯＣ（＝Ｏ）Ｒ^１４−、−ＯＣ（＝Ｏ）ＮＨＲ^１４−、−ＯＣ（＝Ｏ）Ｒ¹⁴ＳＳＲ^１５、ＯＰ（＝Ｏ）（ＯＲ^１４）−またはＯＲ^１４ＯＰ（＝Ｏ）（ＯＲ^１５）であり；そのうち、Ｒ^１４とＲ^１５はそれぞれＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１１は独立して、Ｈ、Ｒ^１４、−Ｒ^１４Ｃ（＝Ｏ）Ｒ^１６、−Ｒ^１４Ｘ^２Ｒ^１６、−Ｒ^１４Ｃ（＝Ｏ）Ｘ^２であり；そのうち、Ｘ^２ は−Ｏ−、−Ｓ−、−ＮＨ−、−Ｎ（Ｒ^１４）−、−Ｏ−Ｒ^１４−、−Ｓ−Ｒ^１４−、−Ｓ（＝Ｏ）−Ｒ^１４−または−ＮＨＲ^１４−であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１２は独立して、Ｒ^１４、−ＯＨ、−ＳＨ、−ＮＨ_２、＝ＮＨ、＝ＮＮＨ_２、−ＮＨ（Ｒ^１４）、−ＯＲ^１４、−ＣＯＲ^１６、−ＣＯＯＲ^１４−、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１４、−ＳＲ^１４、−Ｓ（＝Ｏ）Ｒ^１４、−Ｐ(=Ｏ)（ＯＲ^１６）_２、−ＯＰ（＝Ｏ）（ＯＲ^１６）_２、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１６）_２、−ＳＯ_２Ｒ¹⁶であり；Ｒ^１４は独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１３はＣ_１−Ｃ_１０アルキル、ヘテロアルキル、アルキル酸、アルキルアミド、アルキルアミン又はＡｒであり；そのうち、Ａｒとは、１員環又は複数員環からなる芳香族環又は複素芳香族環であり、芳香族環又は複素芳香族環ごとに４〜１０個の炭素原子を含み、最も好ましくは４〜６つの炭素原子を含み、複素芳香族環とは、１つ又はいくつかの炭素原子が他の原子によって置換された芳香族環を意味し、最も好ましくは、１つ、２つ又は３つの炭素原子がＯ、Ｎ、Ｓｉ、Ｓｅ、ＰまたはＳによって置換され、最も好ましくは、Ｏ、Ｓ、Nによって置換され；アリールまたはＡｒとは、１つ又はいくつかの水素原子が置換された芳香族環を意味し、水素原子を置換するこれらの基は、独立してＲ^１７、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^１６、ＳＲ^１６、ＮＲ^１６Ｒ^１７、Ｎ＝ＮＲ^１６、Ｎ＝Ｒ^１６、ＰＲ^１６Ｒ¹⁷、ＰＯＲ^１６Ｒ^１7、ＰＯ_２Ｒ^１６Ｒ^１７、ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣＨ_２ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＰＯ（ＯＲ^１６）（ＯＲ^１７）、ＯＰ（Ｏ）（ＯＲ^１７）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）Ｒ^１７またはＯＣ（Ｏ）ＮＨＲ^１７を含み、そのうち、Ｒ^１６とＲ^１７はそれぞれ、独立してＨ−、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニル或いはＣ_４−Ｃ_１２グリコシド又は医薬用塩であり；
また、Ｒ^１０がＨでない場合、或いは、Ｒ^１３が下記の基である場合、Ｒ^１２はＨであってもよく、

ここで、Ｚ^１はＨ、ＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＰＯ（ＯＲ^１８）_２、Ｐ（Ｏ）（ＯＲ^１８）ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）Ｒ^１８、Ｃ（Ｏ）ＮＨＲ^１８、ＳＯ_２（ＯＲ^１８）、Ｃ_４−Ｃ₁₂のグリコシド、又は、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、複素環であり；Ｒ^１８は、Ｈ、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、ヘテロアルキル；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニルであり；Ｒ^１９はＨ、ＯＨ、ＮＨ_２、ＯＳＯ_２（ＯＲ^１８）、ＸＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＰＯ（ＯＲ^１８）_２、ＸＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＣ（Ｏ）Ｒ^１８、ＸＣ（Ｏ）ＮＨＲ^１８、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル、カルボン酸誘導体；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニル；又は医薬用塩であり；ＸはＯ、Ｓ、ＮＨであり；Ｙ^１とＹ^２はそれぞれＮ又はＣＨであり；
或いは、Ｒ^１１が下記の基である場合、Ｒ^１２はＨであってもよく、

Ｘ^２がＯ、Ｓ、Ｎ−Ｒ^８であり、Ｒ^８がＨ、Ｃ_１〜Ｃ_６のアルキル又はヘテロアルキルである。） (Appendix 3)
The conjugate and pharmaceutically acceptable salt and solvate according to Appendix 1, having the structure represented by Structural Formula (III).

(However, where T is the target or binding ligand, L is the dissociable linker,

Is a link bond where L independently connects to the molecule in parenthesized structure, n is 1-20, m is 1-10;
The structures in parentheses are effective anti-thread splitting agents / drugs, of which R ¹ , R ² , R ³ and R ⁴ are independently C _{1 to} C ₈ alkyl and heteroalkyl; C ₂ to heterocycle, carbocycle C _8, alkyl cycloalkyl, _{heterocycloalkyl,} aryl C 3 -C _8, aralkyl, heteroalkyl cycloalkyl, alkylcarbonyl, or two R groups ^(e.g., R ¹ _R 2, ^{R 2} Even if ^{each combination of R 3} _, R ³ R ⁴ , R ⁵ R ⁶ , and R ¹² R ¹³ is a carbocyclic group having 3 to 7 carbon atoms, a cycloalkyl group, or a heterocyclic group and a heterocycloalkyl group. (Good), respectively, where Y is N or CH; and R ¹ , R ³ and R ⁴ may be H, and R ² may be absent.
R ^{5, R} 6, each ^{R 8} and ^{R 10,} independently is an alkyl or heteroalkyl H or _C 1 -C _4;
R ⁷ is independently selected from R ¹⁴ or -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ , of which R ¹⁴ And R ¹⁵ Alkyl of _C 1 -C ₈ each, independently, _heteroalkyl; alkenyl C 2 -C _8, alkynyl, heterocyclic, carbocyclic, cycloalkane; or _C 3 -C ₈ aryl, Fukumotowa alkyl, hetero Alkyne, heteroalkylcycloalkyl, alkylcarbonyl, where X ¹ is O, S, SS, NH or NR ¹⁴ ;
R ⁹ is independently ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ); of which R ¹⁴ and R ¹⁵ are C _1- C ₈ alkyl and heteroalkyl; C _2- C ₈ alkenyl, respectively. Alkynyl, heterocycle, carbocycle; or C _3- C _8- aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
R ¹¹ are independently H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² ; of which X ^{2 is- O -, - S -, -} NH -, - N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - a and R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹² is _{^{independently, R 14, -OH, -SH,}} -NH 2, = NH, = NNH 2, -NH (R 14), - OR 14, -COR 16, -COOR 14 -, C (O ) NH ₂ , C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (= O) (OR ¹⁶ ) ₂ , -SO ₂ R ¹⁶ ; R ¹⁴ is independently C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, Carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1-4 amino acid units Is;
R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or Ar; them, and Ar, aromatic ring or heteroaromatic ring consisting of 1-membered ring or more membered ring There are 4 to 10 carbon atoms per aromatic or heteroaromatic ring, most preferably 4 to 6 carbon atoms, and a heteroaromatic ring is one or several carbon atoms. It means an aromatic ring substituted with other atoms, most preferably one, two or three carbon atoms are substituted with O, N, Si, Se, P or S, most preferably O, Substituted by S, N; aryl or Ar means an aromatic ring in which one or several hydrogen atoms are substituted, and these groups substituting hydrogen atoms are independently ^R17 , F, Cl, Br, I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR) ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP ( O) (OR ¹⁷ ) ₂ , including OC (O) R ¹⁷ or OC (O) NHR ¹⁷ , of which R ¹⁶ and R ¹⁷ are independently H-, C _{1 to} C ₈ alkyl and heteroalkyl, respectively. ; alkenyl _C 2 -C _8, alkynyl, heterocyclic, _carbocyclic, C 3 -C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or _C 4 -C ₁₂ Glycosides or medicinal salts;
Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP. (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ glycosides, or C _{1 to} C ₈ alkyl, carboxyalkyl Group, heterocycle; R ¹⁸ is H, C _{1 to} C ₈ alkyl, carboxyalkyl group, heteroalkyl; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C _{3 to} C ₈ aryl, alkyl It is a carbonyl; R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR). ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C _{3 to} C ₈ aryl, alkylcarbonyl; be or pharmaceutical salt; X is O, S, NH; ^{Y 1} and ^{Y 2} are each N or CH;
Alternatively, if R ¹¹ is the following group, then R ¹² may be H.

X ² is O, S, N-R ⁸ and R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6. )

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが括弧内構造における分子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０であり；
括弧内の構造体が効果的な抗有糸分裂剤・薬物であり、そのうち、Ｒ^１、Ｒ^２、Ｒ^３とＲ⁴が独立して、Ｃ_１〜Ｃ_８のアルキル、へテロアルキル；C₂〜C₈ヘテロ環、炭素環、アルキルシクロアルキル、複素環アルキル；Ｃ_３〜Ｃ_８のアリール、アラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル；２つのＲ基（例えば、Ｒ^１Ｒ^２ _、 Ｒ^２Ｒ^３ _、 Ｒ^３Ｒ^４、Ｒ^５Ｒ^６、Ｒ^１２Ｒ^１３という各組合せが炭素数３〜７の炭素環基、シクロアルキル、または複素環基とヘテロシクロアルキルなど環係基であってもいい）をそれぞれ表し；ＹがＮまたはＣＨであり；また、Ｒ^１、Ｒ^３とＲ^４はＨであってもよく、かつ、Ｒ²は欠如していてもよく、
Ｒ^５、Ｒ^６、Ｒ^８とＲ^１０はそれぞれ、独立してＨ又はＣ_１〜Ｃ_４のアルキルまたはヘテロアルキルであり；
Ｒ^７は独立してＨ、Ｒ^１４、あるいは−Ｒ^１４Ｃ（＝Ｏ）Ｘ^１Ｒ^１５又は−Ｒ^１４Ｘ^１Ｒ^１５から選択され、そのうち、Ｒ^１４とＲ^１５はそれぞれＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル；複素環、炭素環、シクロアルカン；又はＣ_３−Ｃ_８アリール、復素環アルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｘ^１はＯ、Ｓ、Ｓ−Ｓ、ＮＨ又はＮＲ^１４であり；
Ｒ^９は独立して、−Ｏ−、−ＯＲ^１４、−ＯＣ（＝Ｏ）Ｒ^１４−、−ＯＣ（＝Ｏ）ＮＨＲ^１４−、−ＯＣ（＝Ｏ）Ｒ¹⁴ＳＳＲ^１５−、ＯＰ（＝Ｏ）（ＯＲ^１４）−であり、そのうち、Ｒ^１４とＲ^１５はそれぞれＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；又はＣ_３−Ｃ_８アリール、ヘテロアリール、複素環、炭素環、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１１は独立して、Ｈ、Ｒ^１４、−Ｒ^１４Ｃ（＝Ｏ）Ｒ^１６、−Ｒ^１４Ｘ^２Ｒ^１６、−Ｒ^１４Ｃ（＝Ｏ）Ｘ^２であり；そのうち、Ｘ^２ は−Ｏ−、−Ｓ−、−ＮＨ−、−Ｎ（Ｒ^１４）−、−Ｏ−Ｒ^１４−、−Ｓ−Ｒ^１４−、−Ｓ（＝Ｏ）−Ｒ^１４−または−ＮＨＲ^１４−であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１２は独立して、Ｒ^１４、−ＯＨ、−ＳＨ、−ＮＨ_２、＝ＮＨ、＝ＮＮＨ_２、−ＮＨ（Ｒ^１４）、−ＯＲ^１４、−ＣＯＲ^１６、−ＣＯＯＲ^１４−、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１４、−ＳＲ^１４、−Ｓ（＝Ｏ）Ｒ^１４、−Ｐ(=Ｏ)（ＯＲ^１６）_２、−ＯＰ（＝Ｏ）（ＯＲ^１６）_２、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１６）_２、又は−ＳＯ_２Ｒ¹⁶であり；Ｒ^１４は独立して、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１３はＣ_１−Ｃ_１０アルキル、ヘテロアルキル、アルキル酸、アルキルアミド、アルキルアミン又はＡｒであり；そのうち、Ａｒとは、１員環又は複数員環からなる芳香族環又は複素芳香族環であり、芳香族環又は複素芳香族環ごとに４〜１０個の炭素原子を含み、最も好ましくは４〜６つの炭素原子を含み、複素芳香族環とは、１つ又はいくつかの炭素原子が他の原子によって置換された芳香族環を意味し、最も好ましくは、１つ、２つ又は３つの炭素原子がＯ、Ｎ、Ｓｉ、Ｓｅ、Ｐ またはＳによって置換され、最も好ましくは、Ｏ,Ｓ、Nによって置換され；アリールまたはＡｒとは、１つ又はいくつかの水素原子が置換された芳香族環を意味し、水素原子を置換するこれらの基は、Ｒ^１７、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^１６、ＳＲ^１６、ＮＲ^１６Ｒ^１７、Ｎ＝ＮＲ^１６、Ｎ＝Ｒ^１６、ＮＲ^１６Ｒ¹⁷、ＮＯ_２、ＳＯＲ^１６Ｒ^１７、ＳＯ_２Ｒ^１６、ＳＯ_３Ｒ^１６、ＯＳＯ_３Ｒ^１６、ＰＲ^１６Ｒ^１７、ＰＯＲ^１６Ｒ^１7、ＰＯ_２Ｒ^１６Ｒ^１７、ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣＨ_２ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＰＯ（ＯＲ^１６）（ＯＲ^１７）、ＯＰ（Ｏ）（ＯＲ^１７）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）Ｒ^１７ またはＯＣ（Ｏ）ＮＨＲ^１７を含み；そのうち、Ｒ^１６とＲ^１７はそれぞれ、独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニル或いはＣ_４−Ｃ_１２グリコシド又は医薬用塩であり；
また、Ｒ^１０がＨでない場合、或いは、Ｒ^１３が下記の基である場合、Ｒ^１２はＨであってもよく、

ここで、Ｚ^１はＨ、ＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＰＯ（ＯＲ^１８）_２、Ｃ（Ｏ）Ｒ^１８、Ｃ（Ｏ）ＮＨＲ^１８、ＳＯ_２（ＯＲ^１８）、Ｃ_４−Ｃ₁₂のグリコシド、又は、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、複素環であり；Ｒ^１８は、Ｈ、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニルであり；Ｒ^１９はＨ、ＯＨ、ＮＨ_２、ＯＳＯ_２（ＯＲ^１８）、ＸＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＰＯ（ＯＲ^１８）_２、ＸＣ（Ｏ）Ｒ^１８、ＸＣ（Ｏ）ＮＨＲ^１８、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル、カルボン酸誘導体；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニル又は医薬用塩であり；ＸはＯ、Ｓ、又はＮＨであり；Ｙ^１とＹ^２はそれぞれＮ又はＣＨであり；
或いは、Ｒ^１１が下記の基である場合、Ｒ^１２はＨであってもよく、

Ｘ^２がＯ、Ｓ、Ｎ−Ｒ^８であり、Ｒ^８がＨ、Ｃ_１〜Ｃ_６のアルキル又はヘテロアルキルである。） (Appendix 4)
The conjugate and pharmaceutically acceptable salt and solvate according to Appendix 1, having the structure represented by Structural Formula (IV).

(However, where T is the target or binding ligand, L is the dissociable linker,

Is the link bond where L connects to the molecule in the parenthesized structure, n is 1-20, m is 1-10;
The structures in parentheses are effective anti-thread splitting agents / drugs, of which R ¹ , R ² , R ³ and R ⁴ are independent, C _{1 to} C ₈ alkyl, heteroalkyl; C. ₂ -C ₈ heterocycle, carbocycle, alkyl cycloalkyl, heterocyclic _alkyl; aryl C 3 -C _8, aralkyl, heteroalkyl cycloalkyl, alkylcarbonyl; two R groups ^(e.g., R ¹ _R 2, ^{R 2} Even if ^{each combination of R 3} _, R ³ R ⁴ , R ⁵ R ⁶ , and R ¹² R ¹³ is a carbocyclic group having 3 to 7 carbon atoms, a cycloalkyl group, or a heterocyclic group and a heterocycloalkyl group. (Good), respectively; Y is N or CH; and R ¹ , R ³ and R ⁴ may be H, and R ² may be absent.
R ^{5, R} 6, each ^{R 8} and ^{R 10,} independently is an alkyl or heteroalkyl H or _C 1 -C _4;
R ⁷ is independently selected from H, R ¹⁴ or -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ , of which R ¹⁴ and R ¹⁵ are C _{1 to} C _{8 respectively.} with or _C 3 -C ₈ aryl, Fukumotowa alkyl, heteroaralkyl, heteroalkyl cycloalkyl, alkylcarbonyl, alkyl, _heteroalkyl, alkenyl C 2 -C _8, alkynyl; heterocycle, carbocycle, cycloalkane X ¹ is O, S, SS, NH or NR ¹⁴ ;
R ⁹ is ^{independently, -O -, - OR 14,} -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15 -, OP (= O) (OR ¹⁴ )-, of which R ¹⁴ and R ¹⁵ are C _1- C ₈ alkyl, heteroalkyl; or C _3- C ₈ aryl, heteroaryl, heterocyclic, carbocycle, alkylcycloalkyl, respectively. , Heterocycloalkyl, Heteroalkylcycloalkyl, Heteroaralkyl, Alkylcarbonyl;
R ¹¹ are independently H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² ; of which X ^{2 is- O -, - S -, -} NH -, - N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - a and R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, hetero Alkylcycloalkyl, heteroaralkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹² is _{^{independently, R 14, -OH, -SH,}} -NH 2, = NH, = NNH 2, -NH (R 14), - OR 14, -COR 16, -COOR 14 -, C (O ) NH ₂ , C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (= O) (OR ¹⁶ ) ₂ or -SO ₂ R ¹⁶ ; R ¹⁴ is independently C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, hetero Rings, carbocycles; C _3- C _8- aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1-4 It is an amino acid unit;
R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or Ar; them, and Ar, aromatic ring or heteroaromatic ring consisting of 1-membered ring or more membered ring There are 4 to 10 carbon atoms per aromatic ring or heteroaromatic ring, most preferably 4 to 6 carbon atoms, and a heteroaromatic ring is one or several carbon atoms. It means an aromatic ring substituted with another atom, most preferably one, two or three carbon atoms are substituted with O, N, Si, Se, P or S, most preferably O, Substituted by S, N; aryl or Ar means an aromatic ring in which one or several hydrogen atoms are substituted, and these groups substituting hydrogen atoms are R ¹⁷ , F, Cl, Br. , I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) ( Includes OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ¹⁷ ; , R ¹⁶ and R ¹⁷ are independently C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, alkyl, respectively. cycloalkyl alkyl, heterocycloalkyl, heterocycloalkyl alkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or C ₄ -C ₁₂ glycoside or pharmaceutical salts;
Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C ( _{^{O) NHR 18, SO 2 (}} oR 18), glycosides C 4 -C _12, or _alkyl of C 1 -C _8, carboxyalkyl group, a ^{heterocyclic; R 18} is, _H, C 1 -C ₈ alkyl, _heteroalkyl, alkenyl C 2 -C _8, alkynyl, _heterocycle; aryl C 3 -C _8, ^{alkylcarbonyl;} R ₁₉ is ^{_{H, OH, NH 2, OSO}} 2 (OR 18), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid _derivatives; alkenyl C 2 -C _8, alkynyl, _heterocycle; aryl of C 3 -C _8, alkyl carbonyl or pharmaceutical salt; X is O, S, or NH Yes; Y ¹ and Y ² are N or CH, respectively;
Alternatively, if R ¹¹ is the following group, then R ¹² may be H.

X ² is O, S, N-R ⁸ and R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6. )

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが独立して括弧内構造における分子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０であり；
括弧内の構造体が効果的な抗有糸分裂剤・薬物であり、そのうち、Ｒ^１、Ｒ^２、Ｒ^３とＲ⁴が独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；C₂〜C₈のヘテロ環、炭素環、アルキルシクロアルキル、ヘテロシクロアルキル；Ｃ_３〜Ｃ_８のアリール、アラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル；２つのＲ基（例えば、Ｒ^１Ｒ^２ _、Ｒ^２Ｒ^３ _、Ｒ^３Ｒ^４、Ｒ^５Ｒ^６、Ｒ^１２Ｒ^１３という各組合せが炭素数３〜７の炭素環基、シクロアルキル、複素環基とヘテロシクロアルキルなど環係基であってもいい）をそれぞれ表し、ＹがＮまたはＣＨであり；また、Ｒ^１、Ｒ^３とＲ^４はＨであってもよく、かつ、Ｒ²は欠如していてもよく、
Ｒ^５、Ｒ^６、Ｒ^８と Ｒ^１０はそれぞれ、独立してＨ又はＣ_１〜Ｃ_４のアルキルまたはヘテロアルキルであり；
Ｒ^７は独立してＨ、Ｒ^１４、あるいは−Ｒ^１４Ｃ（＝Ｏ）Ｘ^１Ｒ^１５又は−Ｒ^１４Ｘ^１Ｒ^１５から選択され、そのうち、Ｒ^１４ とＲ^１５はそれぞれ、独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環、シクロアルカン；Ｃ_３−Ｃ_８アリール、復素環アルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり、Ｘ^１はＯ、Ｓ、Ｓ−Ｓ、ＮＨ又はＮＲ^１４であり；
Ｒ^９は独立してＨ、−Ｏ−、−ＯＲ^１４、−ＯＣ（＝Ｏ）Ｒ^１４−、−ＯＣ（＝Ｏ）ＮＨＲ^１４−、−ＯＣ（＝Ｏ）Ｒ¹⁴ＳＳＲ^１５、ＯＰ（＝Ｏ）（ＯＲ^１４）−またはＯＲ^１４ＯＰ（＝Ｏ）（ＯＲ^１５）であり；そのうち、Ｒ^１４とＲ^１５はそれぞれ、独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１１は独立して−Ｒ^１４、−Ｒ^１４Ｃ（＝Ｏ）Ｒ^１7、−Ｒ^１４Ｘ^２Ｒ^１7、−Ｒ^１４Ｃ（＝Ｏ）Ｘ^２であり；そのうち、Ｒ^１7は独立してＨ、ＯＨ、Ｃ_１〜Ｃ_８のアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、ヘテロアルキル；Ｃ_３−Ｃ_８アリール，アリレン、複素環、炭素環、ヘテロシクロシクロアルキル；または１つあるいは二つのアミノ酸単位であり；Ｒ^１４又は１〜４つのアミノ酸単位であり；Ｘ^２は−Ｏ−、−Ｓ−、−ＮＨ−、−Ｎ（Ｒ^１４）−、−Ｏ−Ｒ^１４−、−Ｓ−Ｒ^１４−、−Ｓ（＝Ｏ）−Ｒ^１４−または−ＮＨＲ^１４−であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル；Ｃ_３−Ｃ_８アリール、複素環、炭素環、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１２は独立してＲ^１４、−ＯＨ、−ＳＨ、−ＮＨ_２、＝ＮＨ、＝ＮＮＨ_２、−ＮＨ（Ｒ^１４）、−ＯＲ^１４、−ＣＯＲ^１６、−ＣＯＯＲ^１４−、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１４、−ＳＲ^１４、−Ｓ（＝Ｏ）Ｒ^１４、−Ｐ(=Ｏ)（ＯＲ^１６）_２、−ＯＰ（＝Ｏ）（ＯＲ^１６）_２、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１６）_２、又は−ＳＯ_２Ｒ¹⁶であり；Ｒ^１４は独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１３はＣ_１−Ｃ_１０アルキル、ヘテロアルキル、アルキル酸、アルキルアミド、アルキルアミン又はＡｒであり；そのうち、Ａｒとは、１員環又は複数員環からなる芳香族環又は複素芳香族環であり、芳香族環又は複素芳香族環ごとに４〜１０個の炭素原子を含み、最も好ましくは４〜６つの炭素原子を含み；複素芳香族環とは、１つ又はいくつかの炭素原子が他の原子によって置換された芳香族環を意味し、最も好ましくは、１つ、２つ又は３つの炭素原子がＯ、Ｎ、Ｓｉ、Ｓｅ、ＰまたはＳによって置換され、最も好ましくは、Ｏ、Ｓ、Nによって置換され；アリールまたはＡｒとは、１つ又はいくつかの水素原子が置換された芳香族環を意味し、水素原子を置換するこれらの基は、独立してＲ^１７、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^１６、ＳＲ^１６、ＮＲ^１６Ｒ^１７、Ｎ＝ＮＲ^１６、Ｎ＝Ｒ^１６、ＮＲ^１６Ｒ¹⁷、ＮＯ_２、ＳＯＲ^１６Ｒ^１７、ＳＯ_２Ｒ^１６、ＳＯ_３Ｒ^１６、ＯＳＯ_３Ｒ^１６、ＰＲ^１６Ｒ^１７、ＰＯＲ^１６Ｒ^１7、ＰＯ_２Ｒ^１６Ｒ^１７、ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣＨ_２ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＰＯ（ＯＲ^１６）（ＯＲ^１７）、ＯＰ（Ｏ）（ＯＲ^１７）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）Ｒ^１７ またはＯＣ（Ｏ）ＮＨＲ^１７を含み；そのうち、Ｒ^１６とＲ^１７はそれぞれ、独立してＣ_１〜Ｃ_８のＨ、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニル或いはＣ_４−Ｃ_１２グリコシド又は医薬用塩であり；
また、Ｒ^１０がＨでない場合、或いは、Ｒ^１３が下記の基である場合、Ｒ^１２はＨであってもよく、

ここで、Ｚ^１はＨ、ＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＰＯ（ＯＲ^１８）_２、Ｐ（Ｏ）（ＯＲ^１８）ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）Ｒ^１８、Ｃ（Ｏ）ＮＨＲ^１８、ＳＯ_２（ＯＲ^１８）、Ｃ_４−Ｃ₁₂のグリコシド、又は、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、複素環であり；Ｒ^１８は、Ｈ、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、ヘテロアルキル；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；又は、Ｃ_３〜Ｃ_８のアリール、アルキルカルボニルであり；Ｒ^１９はＨ、ＯＨ、ＮＨ_２、ＯＳＯ_２（ＯＲ^１８）、ＸＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＰＯ（ＯＲ^１８）_２、ＸＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＣ（Ｏ）Ｒ^１８、ＸＣ（Ｏ）ＮＨＲ^１８、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル、カルボン酸誘導体；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環、Ｃ_３〜Ｃ_８のアリール、アルキルカルボニル又は医薬用塩であり；ＸはＯ、Ｓ、又はＮＨであり；Ｙ^１とＹ^２はそれぞれＮ又はＣＨであり；
或いは、Ｒ^１１が下記の基である場合、Ｒ^１２はＨであってもよく、

Ｘ^２がＯ、Ｓ、Ｎ−Ｒ^８であり；Ｒ^８がＨ、Ｃ_１〜Ｃ_６のアルキル又はヘテロアルキルである。） (Appendix 5)
The conjugate and pharmaceutically acceptable salt and solvate according to Appendix 1, which has the structure represented by Structural Formula (V).

(However, where T is the target or binding ligand, L is the dissociable linker,

Is a link bond where L independently connects to the molecule in parenthesized structure, n is 1-20, m is 1-10;
The structures in parentheses are effective anti-thread splitting agents / drugs, of which R ¹ , R ² , R ³ and R ⁴ are independently C _{1 to} C ₈ alkyl and heteroalkyl; C ₂ to heterocycle, carbocycle C _8, alkyl cycloalkyl, _{heterocycloalkyl;} aryl C 3 -C _8, aralkyl, heteroalkyl cycloalkyl, alkylcarbonyl; two R groups ^(e.g., R ¹ _R ^{2, R} 2 R ^{Each combination of 3} _, R ³ R ⁴ , R ⁵ R ⁶ , and R ¹² R ¹³ may be a ring-related group such as a carbocyclic group having 3 to 7 carbon atoms, a cycloalkyl group, a heterocyclic group and a heterocycloalkyl group). represent each, Y is N or CH; ^also, R 1, ^{R 3} and ^{R 4} can be H, and may also be R ² is absent,
R ⁵ , R ⁶ , R ⁸ and R ¹⁰ are each independently alkyl or heteroalkyl H or _C 1 -C _4;
R ⁷ is independently selected from H, R ¹⁴ or -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ , of which R ¹⁴ And R ¹⁵ are independently C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, cycloalkane; C _3- C ₈ aryl, condensate ring alkyl, respectively. , Heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl, where X ¹ is O, S, SS, NH or NR ¹⁴ ;
R ⁹ is independently ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ); of which R ¹⁴ and R ¹⁵ are independently C _{1 to} C ₈ alkyl and heteroalkyl; C _2- C. ₈ alkenyl, alkynyl, heterocyclic, carbocyclic, C ₃ -C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl;
R ¹¹ is independently -R ¹⁴ , -R ¹⁴ C (= O) R ¹⁷ , -R ¹⁴ X ² R ¹⁷ , and -R ¹⁴ C (= O) X ² ; of which R ¹⁷ is independent. H, OH, C _{1 to} C ₈ alkyl; C _2- C ₈ alkenyl, alkynyl, heteroalkyl; C _3- C ₈ aryl, arylene, heterocycle, carbocycle, heterocyclocycloalkyl; or one or two one of an amino acid ^{unit; R 14} or be a one to four amino acid units; ^{X 2} is -O -, - S -, - NH -, - N (R 14) -, - O-R 14 -, - S ^{-R 14 -, - S (=} O) -R 14- or -NHR ¹⁴ - a ^is; alkyl ^{R 14} is _C 1 -C _{8, heteroalkyl;} alkenyl C 2 -C _8, alkynyl; _{C 3} - C ₈ aryl, heterocycle, carbocycle, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl;
R ¹² is independently _{^{R 14, -OH, -SH, -NH}} 2, = NH, = NNH 2, -NH (R 14), - OR 14, -COR 16, -COOR 14 -, C (O) NH ₂ , C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (= O) (OR ¹⁶ ) ₂ or -SO ₂ R ¹⁶ ; R ¹⁴ is independently C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, Carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1-4 amino acid units Is;
R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or Ar; them, and Ar, aromatic ring or heteroaromatic ring consisting of 1-membered ring or more membered ring Yes, each aromatic ring or heteroaromatic ring contains 4-10 carbon atoms, most preferably 4-6 carbon atoms; a heteroaromatic ring is one or several carbon atoms. It means an aromatic ring substituted with other atoms, most preferably one, two or three carbon atoms are substituted with O, N, Si, Se, P or S, most preferably O, Substituted by S, N; aryl or Ar means an aromatic ring in which one or several hydrogen atoms are substituted, and these groups substituting hydrogen atoms are independently ^R17 , F, Cl, Br, I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP ( O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ or OC (O) NHR ¹⁷ Included; of which, R ¹⁶ and R ¹⁷ are independently C _{1 to} C ₈ H, C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle, respectively; C ₃ -C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkyl carbonyl or _C 4 _{-C 12} glycoside or pharmaceutical salts;
Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP. (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ glycosides, or C _{1 to} C ₈ alkyl, carboxyalkyl The group is a heterocycle; R ¹⁸ is an alkyl of H, C _{1 to} C ₈ , a carboxyalkyl group, a heteroalkyl; an alkenyl, an alkynyl, a heterocycle of _{C 2 to} C ₈ ; or an aryl of _{C 3 to} C _8. , Alkylcarbonyl; R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle, C ₃ aryl -C _8, alkylcarbonyl or pharmaceutical salt; X is O, S, or be NH; ^{Y 1} and ^{Y 2} is N or CH, respectively;
Alternatively, if R ¹¹ is the following group, then R ¹² may be H.

X ² is O, S, N-R ⁸ ; R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6. )

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが独立して括弧内構造における分子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０であり；
括弧内の構造体が効果的な抗有糸分裂剤・薬物であり、そのうち、Ｒ^１、Ｒ^２、Ｒ^３とＲ⁴がＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；C₂〜C₈のヘテロ環、炭素環、アルキルシクロアルキル、ヘテロシクロアルキル；Ｃ_３〜Ｃ_８のアリール、アラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル；２つのＲ基（例えば、Ｒ^１Ｒ^２ _、 Ｒ^２Ｒ^３ _、Ｒ^３Ｒ^４、Ｒ^５Ｒ^６、Ｒ^１２Ｒ^１３という各組合せが炭素数３〜７の炭素環基、シクロアルキル、複素環基とヘテロシクロアルキルなど環係基であってもいい）をそれぞれ表し；ＹがＮまたはＣＨであり；また、Ｒ^１、Ｒ^３とＲ^４はＨであってもよく、かつ、Ｒ²は欠如していてもよく、
Ｒ^５、Ｒ^６、Ｒ^８とＲ^１０はそれぞれ、独立してＨ又はＣ_１〜Ｃ_４のアルキルまたはヘテロアルキルであり；
Ｒ^７ は独立してＨ、Ｒ^１４、あるいは−Ｒ^１４Ｃ（＝Ｏ）Ｘ^１Ｒ^１５又は−Ｒ^１４Ｘ^１Ｒ^１５から選択され；そのうち、Ｒ^１４ とＲ^１５ はそれぞれ、独立してＣ_１〜Ｃ_８のアルキル又はヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル；複素環、炭素環、シクロアルカン；Ｃ_３−Ｃ_８アリール、復素環アルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｘ^１はＯ、Ｓ、Ｓ−Ｓ、ＮＨ又はＮＲ^１４であり；
Ｒ^９は独立してＨ、−Ｏ−、−ＯＲ^１４、−ＯＣ（＝Ｏ）Ｒ^１４−、−ＯＣ（＝Ｏ）ＮＨＲ^１４−、−ＯＣ（＝Ｏ）Ｒ¹⁴ＳＳＲ^１５、ＯＰ（＝Ｏ）（ＯＲ^１４）−またはＯＲ^１４ＯＰ（＝Ｏ）（ＯＲ^１５）であり；そのうち、Ｒ^１４ とＲ^１５ はそれぞれ、独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１１は独立してＨ、Ｒ^１４、−Ｒ^１４Ｃ（＝Ｏ）Ｒ^１６、−Ｒ^１４Ｘ^２Ｒ^１６、−Ｒ^１４Ｃ（＝Ｏ）Ｘ^２であり；そのうち、Ｘ^２は−Ｏ−、−Ｓ−、−ＮＨ−、−Ｎ（Ｒ^１４）−、−Ｏ−Ｒ^１４−、−Ｓ−Ｒ^１４−、−Ｓ（＝Ｏ）−Ｒ^１４−または−ＮＨＲ^１４−であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；Ｒ^１６はＨ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１２は独立してＲ^１４、−Ｏ-、−Ｓ-、−ＮＨ−、＝Ｎ-、＝ＮＮＨ、−Ｎ（Ｒ^１４）-、−ＯＲ^１４-、Ｃ（Ｏ）Ｏ−、Ｃ（Ｏ）ＮＨ−、Ｃ（Ｏ）ＮＲ^１４、−ＳＲ^１４、−Ｓ（＝Ｏ）Ｒ^１４、ＮＨＲ^１４、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１5）−、−Ｐ(=Ｏ)（ＯＲ^１5）―、−Ｃ（Ｏ）ＯＰ（＝Ｏ）（ＯＲ^１5）−、−ＯＰ(=Ｏ)（ＯＲ^１5）Ｏ―、−ＳＯ_２Ｒ¹⁴であり；Ｒ^１４、Ｒ^１5、は独立して、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル；Ｃ_３−Ｃ_８アリール、複素環、炭素環、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；
Ｒ^１３はＣ_１−Ｃ_１０アルキル、ヘテロアルキル、アルキル酸、アルキルアミド、アルキルアミン又はＡｒであり；そのうち、Ａｒとは、１員環又は複数員環からなる芳香族環又は複素芳香族環であり、芳香族環又は複素芳香族環ごとに４〜１０個の炭素原子を含み、最も好ましくは４〜６つの炭素原子を含み、複素芳香族環とは、１つ又はいくつかの炭素原子が他の原子によって置換された芳香族環を意味し、最も好ましくは、１つ、２つ又は３つの炭素原子がＯ、Ｎ、Ｓｉ、Ｓｅ、Ｐ またはＳによって置換され、最も好ましくは、Ｏ,Ｓ、Nによって置換され；アリールまたはＡｒとは、１つ又はいくつかの水素原子が置換された芳香族環を意味し、水素原子を置換するこれらの基は、Ｒ^１７、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^１６、ＳＲ^１６、ＮＲ^１６Ｒ^１７、Ｎ＝ＮＲ^１６、Ｎ＝Ｒ^１６、ＮＲ^１６Ｒ¹⁷、ＮＯ_２、ＳＯＲ^１６Ｒ^１７、ＳＯ_２Ｒ^１６、ＳＯ_３Ｒ^１６、ＯＳＯ_３Ｒ^１６、ＰＲ^１６Ｒ^１７、ＰＯＲ^１６Ｒ^１7、ＰＯ_２Ｒ^１６Ｒ^１７、ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣＨ_２ＯＰ（Ｏ）（ＯＲ^１７）_２、ＰＯ（ＯＲ^１６）（ＯＲ^１７）、ＯＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１７）_２、ＯＣ（Ｏ）Ｒ^１７ またはＯＣ（Ｏ）ＮＨＲ^１７を含み；そのうち、Ｒ^１６とＲ^１７はそれぞれ、独立してＨ―、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニル或いはＣ_４−Ｃ_１２グリコシド又は医薬用塩であり；
また、Ｒ^１０がＨでない場合、或いは、Ｒ^１３が下記の基である場合、Ｒ^１２はＨであってもよく、

ここで、Ｚ^１はＨ、ＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＰＯ（ＯＲ^１８）_２、Ｐ（Ｏ）（ＯＲ^１８）ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）Ｒ^１８、Ｃ（Ｏ）ＮＨＲ^１８、ＳＯ_２（ＯＲ^１８）、Ｃ_４−Ｃ₁₂のグリコシド、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、複素環であり；Ｒ^１８は、Ｈ、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、ヘテロアルキル；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニルであり；Ｒ^１９はＨ、ＯＨ、ＮＨ_２、ＯＳＯ_２（ＯＲ^１８）、ＸＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＰＯ（ＯＲ^１８）_２、ＸＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＣ（Ｏ）Ｒ^１８、ＸＣ（Ｏ）ＮＨＲ^１８、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル、カルボン酸誘導体；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニル；または医薬用塩であり；ＸはＯ、Ｓ、又はＮＨであり；Ｙ^１とＹ^２はそれぞれＮ又はＣＨであり；
或いは、Ｒ^１１が下記の基である場合、Ｒ^１２はＨであってもよく、

Ｘ^２がＯ、Ｓ、Ｎ−Ｒ^８であり、Ｒ^８がＨ、Ｃ_１〜Ｃ_６のアルキル又はヘテロアルキルであり；
Ｒ^１２は独立してＲ^１４、−Ｏ-、−Ｓ-、−ＮＨ−、＝Ｎ-、＝ＮＮＨ、−Ｎ（Ｒ^１４）-、−ＯＲ^１４-、Ｃ（Ｏ）Ｏ−、−ＣＯＲ^１6−、−ＣＯＯＲ^１4−、Ｃ（Ｏ）ＮＨ−、Ｃ（Ｏ）ＮＲ^１４、−ＳＲ^１４、−Ｓ（＝Ｏ）Ｒ^１４、−Ｐ(=Ｏ)（ＯＲ^１6）―、−ＯＰ(=Ｏ)（ＯＲ^１6）―、ＯＰ(=Ｏ)（ＯＲ^１6）Ｏ―、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１6）−、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１6）Ｏ−、−ＳＯ_２Ｒ¹⁴であり；Ｒ^１４は独立して、Ｃ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；；Ｒ^１６は Ｈ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位である。） (Appendix 6)
The conjugate and pharmaceutically acceptable salt and solvate according to Appendix 1, having the structure represented by Structural Formula (VI).

(However, where T is the target or binding ligand, L is the dissociable linker,

Is a link bond where L independently connects to the molecule in parenthesized structure, n is 1-20, m is 1-10;
The structures in parentheses are effective anti-thread-dividing agents / drugs, of which R ¹ , R ² , R ³ and R ⁴ are C _{1 to} C ₈ alkyl and heteroalkyl; C _{2 to} C ₈ heterocycle, carbocycle, alkyl cycloalkyl, _{heterocycloalkyl;} aryl C 3 -C _8, aralkyl, heteroalkyl cycloalkyl, alkylcarbonyl; two R groups ^(e.g., R ¹ _R ^2, R ² _{R 3,} R ^{Each combination of 3} R ⁴ , R ⁵ R ⁶ , and R ¹² R ¹³ may be a carbocyclic group having 3 to 7 carbon atoms, a cycloalkyl group, a heterocyclic group, a heterocycloalkyl group, or the like). Y is N or CH; and R ¹ , R ³ and R ⁴ may be H and R ² may be absent.
R ^{5, R} 6, each ^{R 8} and ^{R 10,} independently is an alkyl or heteroalkyl H or _C 1 -C _4;
R ⁷ is independently selected from H, R ¹⁴ or -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ ; of which R ¹⁴ And R ¹⁵ Each is alkyl or heteroalkyl _C 1 -C _{8 independently;} alkenyl C 2 -C _8, alkynyl; heterocycle, carbocycle, _cycloalkane; C 3 -C ₈ aryl, Fukumotowa alkyl, heteroaralkyl , Heteroalkylcycloalkyl, alkylcarbonyl; X ¹ is O, S, SS, NH or NR ¹⁴ ;
R ⁹ is independently ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ); of which R ¹⁴ And R ¹⁵ Are independently C _{1 to C 8} alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, respectively. , Heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
R ¹¹ are independently H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² ; of which X ² is -O. ^{-, - S -, - NH} -, - N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - a and; R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl. Cycloalkyl, heteroaralkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹² is independently ^{R 14, -O -, - S} -, - NH -, = N -, = NNH, -N (R 14) -, - OR 14 -, C (O) O-, C ( O) NH-, C (O) NR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , NHR ¹⁴ , -CH ₂ OP (= O) (OR ¹⁵ )-, -P (= O) (OR) ¹⁵ )-, -C (O) OP (= O) (OR ¹⁵ )-, -OP (= O) (OR ¹⁵ ) O-, -SO ₂ R ¹⁴ ; R ¹⁴ , R ¹⁵ are independent. C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl; C _3- C ₈ aryl, heterocycle, carbocycle, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, Heteroalkylcycloalkyl, alkylcarbonyl;
R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or Ar; them, and Ar, aromatic ring or heteroaromatic ring consisting of 1-membered ring or more membered ring There are 4 to 10 carbon atoms per aromatic or heteroaromatic ring, most preferably 4 to 6 carbon atoms, and a heteroaromatic ring is one or several carbon atoms. It means an aromatic ring substituted with other atoms, most preferably one, two or three carbon atoms are substituted with O, N, Si, Se, P or S, most preferably O, Substituted by S, N; aryl or Ar means an aromatic ring in which one or several hydrogen atoms are substituted, and these groups substituting hydrogen atoms are R ¹⁷ , F, Cl, Br. , I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR ¹⁷ ) , OC (O) OP (O) (OR ¹⁷ ) ₂ , including OC (O) R ¹⁷ or OC (O) NHR ¹⁷ , of which R ¹⁶ and R ¹⁷ are independently H-, C _{1-, respectively.} alkyl of C _{8, heteroalkyl;} alkenyl C 2 -C _8, alkynyl, heterocyclic, _carbocyclic, C 3 -C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl cycloalkyl, heteroaralkyl, alkylcarbonyl or _C 4 _{-C 12} glycoside or pharmaceutical salts;
Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP. (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ glycosides, C _{1 to} C ₈ alkyl, carboxyalkyl groups, Heterocycle; R ¹⁸ is H, C _{1 to} C ₈ alkyl, carboxyalkyl group, heteroalkyl; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C _{3 to} C ₈ aryl, alkylcarbonyl. Yes; R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C _{3 to} C ₈ aryl, alkylcarbonyl; be or pharmaceutical salt; X is O, S, or be NH; ^{Y 1} and ^{Y 2} are each N or CH;
Alternatively, if R ¹¹ is the following group, then R ¹² may be H.

X ² is O, S, N-R ⁸ and R ⁸ is H, C _{1 to} C ₆ alkyl or heteroalkyl;
R ¹² is independently ^{R 14, -O -, - S} -, - NH -, = N -, = NNH, -N (R 14) -, - OR 14 -, C (O) O -, - COR ^{16 -, - COOR 14 -,} C (O) NH-, C (O) NR 14, -SR 14, -S (= O) R 14, -P (= O) (OR 16) -, - OP ( = O) (OR ¹⁶ )-, OP (= O) (OR ¹⁶ ) O-, -CH ₂ OP (= O) (OR ¹⁶ )-, -CH ₂ OP (= O) (OR ¹⁶ ) O-, -SO ₂ R ¹⁴ ; R ¹⁴ is independently C _1- C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cyclo They are alkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl ;; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units. )

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが独立して括弧内構造における分子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０であり；
括弧内の構造体が効果的な抗有糸分裂剤・薬物であり、そのうち、Ｒ^１、Ｒ^２、Ｒ^３とＲ⁴が独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；C₂〜C₈のヘテロ環、炭素環、アルキルシクロアルキル、複素環アルキル、Ｃ_３〜Ｃ_８のアリール、アラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル；又は２つのＲ基（例えば、Ｒ^１Ｒ^２ _、Ｒ^２Ｒ^３ _、Ｒ^３Ｒ^４、Ｒ^５Ｒ^６、Ｒ^１２Ｒ^１３という各組合せが炭素数３〜７の炭素環基、シクロアルキル、または複素環基とヘテロシクロアルキルなど環係基であってもいい）をそれぞれ表し、ＹがＮまたはＣＨであり；また、Ｒ^１、Ｒ^３とＲ^４はＨであってもよく、かつ、Ｒ²は欠如していてもよく、
Ｒ^５、Ｒ^６、Ｒ^８とＲ^１０はそれぞれ、独立してＨ又はＣ_１〜Ｃ_４のアルキルまたはヘテロアルキルであり；
Ｒ^７ は独立して独立してＨ、Ｒ^１４、あるいは−Ｒ^１４Ｃ（＝Ｏ）Ｘ^１Ｒ^１５又は−Ｒ^１４Ｘ^１Ｒ^１５から選択され；そのうち、Ｒ^１４とＲ^１５はそれぞれ独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環、シクロアルカン；Ｃ_３−Ｃ_８アリール、復素環アルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｘ^１はＯ、Ｓ、Ｓ−Ｓ、ＮＨ又はＮＲ^１４であり；
Ｒ^９は独立してＨ、−Ｏ−、−ＯＲ^１４、−ＯＣ（＝Ｏ）Ｒ^１４−、−ＯＣ（＝Ｏ）ＮＨＲ^１４−、−ＯＣ（＝Ｏ）Ｒ¹⁴ＳＳＲ^１５、ＯＰ（＝Ｏ）（ＯＲ^１４）−またはＯＲ^１４ＯＰ（＝Ｏ）（ＯＲ^１５）であり；そのうち、Ｒ^１４ とＲ^１５ はそれぞれ、独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；
Ｒ^１１は独立してＨ、Ｒ^１４、−Ｒ^１４Ｃ（＝Ｏ）Ｒ^１６、−Ｒ^１４Ｘ^２Ｒ^１６、−Ｒ^１４Ｃ（＝Ｏ）Ｘ^２であり；そのうち、Ｘ^２ は−Ｏ−、−Ｓ−、−ＮＨ−、−Ｎ（Ｒ^１４）−、−Ｏ−Ｒ^１４−、−Ｓ−Ｒ^１４−、−Ｓ（＝Ｏ）−Ｒ^１４−または−ＮＨＲ^１４−であり；Ｒ^１４はＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；Ｃ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロアラルキル、アルキルカルボニルであり；Ｒ^１６は Ｈ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１２は独立してＲ^１４、−ＯＨ、−ＳＨ、−ＮＨ_２、＝ＮＨ、＝ＮＮＨ_２、−ＮＨ（Ｒ^１４）、−ＯＲ^１４、−ＣＯＲ^１６、−ＣＯＯＲ^１４−、Ｃ（Ｏ）ＮＨ_２、Ｃ（Ｏ）ＮＨＲ^１４、−ＳＲ^１４、−Ｓ（＝Ｏ）Ｒ^１４、−Ｐ(=Ｏ)（ＯＲ^１６）_２、−ＯＰ（＝Ｏ）（ＯＲ^１６）_２、−ＣＨ_２ＯＰ（＝Ｏ）（ＯＲ^１６）_２、−Ｃ（Ｏ）ＯＰ（＝Ｏ）（ＯＲ^１６）_２、又は−ＳＯ_２Ｒ¹⁶であり；Ｒ^１４は独立してＣ_１〜Ｃ_８のアルキル、ヘテロアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、複素環、炭素環；又はＣ_３−Ｃ_８アリール、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニルであり；Ｒ^１６は Ｈ、ＯＨ、Ｒ^１４又は１〜４つのアミノ酸単位であり；
Ｒ^１３はＣ_１−Ｃ_１０アルキル、ヘテロアルキル、アルキル酸、アルキルアミド、アルキルアミン又はＡｒであり；そのうち、Ａｒとは、１員環又は複数員環からなる芳香族環又は複素芳香族環であり、芳香族環又は複素芳香族環ごとに４〜１０個の炭素原子を含み、最も好ましくは４〜６つの炭素原子を含み、複素芳香族環とは、１つ又はいくつかの炭素原子が他の原子によって置換された芳香族環を意味し、最も好ましくは、１つ、２つ又は３つの炭素原子がＯ、Ｎ、Ｓｉ、Ｓｅ、ＰまたはＳによって置換され、最も好ましくは、Ｏ、Ｓ、Nによって置換され；アリールまたはＡｒとは、１つ又はいくつかの水素原子が置換された芳香族環を意味し、水素原子を置換するこれらの基は、Ｒ^１8、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^１６、ＳＲ^１６、ＮＲ^１６Ｒ^１8、Ｎ＝ＮＲ^１６、Ｎ＝Ｒ^１６、ＮＲ^１６Ｒ¹⁸、ＮＯ_２、ＳＯＲ^１６Ｒ^１8、ＳＯ_２Ｒ^１６、ＳＯ_３Ｒ^１６、ＯＳＯ_３Ｒ^１６、ＰＲ^１６Ｒ^１8、ＰＯＲ^１６Ｒ^１8、ＰＯ_２Ｒ^１６Ｒ^１8、ＯＰＯ₃Ｒ^１６Ｒ^１8 _、ＣＨ_２ＯＰＯ₃Ｒ^１６Ｒ^１8、ＯＰ（Ｏ）（ＯＲ^１6）ＯＰ（Ｏ）（ＯＲ^１8）_２、Ｃ（Ｏ）ＯＰＯ₃Ｒ^１６Ｒ^１8またはＰＯ₃Ｒ^１６Ｒ^１8を含み、そのうち、Ｒ^１６とＲ^１8はそれぞれ、独立してＨ、Ｃ_１〜Ｃ_８のアルキル；Ｃ_２−Ｃ_８のアルケニル、アルキニル、ヘテロアルキル；Ｃ_３−Ｃ_８アリール、複素環、炭素環、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル或いはＣ_４−Ｃ_１２グリコシド又は医薬用塩であり；
また、Ｒ^１０がＨでない場合、或いは、Ｒ^１３が下記の基である場合、Ｒ^１２はＨであってもよく、

ここで、Ｚ^１はＨ、ＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＰＯ（ＯＲ^１８）_２、Ｃ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｐ（Ｏ）（ＯＲ^１８）ＯＰ（Ｏ）（ＯＲ^１８）_２、Ｃ（Ｏ）Ｒ^１８、Ｃ（Ｏ）ＮＨＲ^１８、ＳＯ_２（ＯＲ^１８）、Ｃ_４−Ｃ₁₂のグリコシド、又は、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、複素環であり；Ｒ^１８は、Ｈ、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル基、ヘテロアルキル；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニルであり；Ｒ^１９はＨ、ＯＨ、ＮＨ_２、ＯＳＯ_２（ＯＲ^１８）、ＸＣＨ_２ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＣ（Ｏ）ＯＰ（Ｏ）（ＯＲ^１８）_２、ＸＰＯ（ＯＲ^１８）_２、ＸＣ（Ｏ）Ｒ^１８、ＸＣ（Ｏ）ＮＨＲ^１８、Ｃ_１〜Ｃ_８のアルキル、カルボキシアルキル、カルボン酸誘導体；Ｃ_２〜Ｃ_８のアルケニル、アルキニル、複素環；Ｃ_３〜Ｃ_８のアリール、アルキルカルボニル又は医薬用塩であり；ＸはＯ、Ｓ、又はＮＨであり；Ｙ^１とＹ^２はそれぞれＮ又はＣＨであり；
或いは、Ｒ^１１が下記の基である場合、Ｒ^１２はＨであってもよく、

Ｘ^２がＯ、Ｓ、Ｎ−Ｒ^８であり；Ｒ^８がＨ、Ｃ_１〜Ｃ_６のアルキル又はヘテロアルキルである。） (Appendix 7)
The conjugate and pharmaceutically acceptable salt and solvate according to Appendix 1, having the structure represented by Structural Formula (VII).

(However, where T is the target or binding ligand, L is the dissociable linker,

Is a link bond where L independently connects to the molecule in parenthesized structure, n is 1-20, m is 1-10;
The structures in parentheses are effective anti-thread splitting agents / drugs, of which R ¹ , R ² , R ³ and R ⁴ are independently C _{1 to} C ₈ alkyl and heteroalkyl; C ₂ to heterocycle, carbocycle C _8, alkyl cycloalkyl, _{heterocycloalkyl,} aryl C 3 -C _8, aralkyl, heteroalkyl cycloalkyl, alkylcarbonyl; or two R groups ^(e.g., R ¹ _R 2, ^{R 2} Even if ^{each combination of R 3} _, R ³ R ⁴ , R ⁵ R ⁶ , and R ¹² R ¹³ is a carbocyclic group having 3 to 7 carbon atoms, a cycloalkyl group, or a heterocyclic group and a heterocycloalkyl group. (Good), respectively, where Y is N or CH; and R ¹ , R ³ and R ⁴ may be H, and R ² may be absent.
R ^{5, R} 6, each ^{R 8} and ^{R 10,} independently is an alkyl or heteroalkyl H or _C 1 -C _4;
R ⁷ is independently and independently selected from H, R ¹⁴ or -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ ; of which R ¹⁴ and R ¹⁵ are independent, respectively. alkyl of _C 1 -C ₈ Te, _heteroalkyl; alkenyl C 2 -C _8, alkynyl, heterocyclic, carbocyclic, _cycloalkane; C 3 -C ₈ aryl, Fukumotowa alkyl, heteroaralkyl, heteroalkyl cycloalkyl , Alkynecarbonyl; X ¹ is O, S, SS, NH or NR ¹⁴ ;
R ⁹ is independently ^{H, -O -, - OR 14} , -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ); of which R ¹⁴ And R ¹⁵ Are independently C _{1 to C 8} alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, respectively. , Heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
R ¹¹ are independently H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , -R ¹⁴ C (= O) X ² ; of which X ² is -O. ^{-, - S -, - NH} -, - N (R 14) -, - O-R 14 -, - S-R 14 -, - S (= O) -R 14- or -NHR ¹⁴ - a and; R ¹⁴ is C _{1 to} C ₈ alkyl, heteroalkyl; C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkyl. Cycloalkyl, heteroaralkyl, alkylcarbonyl; R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹² is independently _{^{R 14, -OH, -SH, -NH}} 2, = NH, = NNH 2, -NH (R 14), - OR 14, -COR 16, -COOR 14 -, C (O) NH ₂ , C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (= O) (OR ¹⁶ ) ₂ , -C (O) OP (= O) (OR ¹⁶ ) ₂ , or -SO ₂ R ¹⁶ ; R ¹⁴ is an independently C _{1 to} C ₈ alkyl, _heteroalkyl; be or _C 3 -C ₈ aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkyl cycloalkyl, alkylcarbonyl; alkenyl C 2 -C _8, alkynyl, heterocyclic, carbocyclic R ¹⁶ is H, OH, R ¹⁴ or 1 to 4 amino acid units;
R ¹³ is _C 1 _{-C 10} alkyl, heteroalkyl, alkyl acid, alkyl amides, alkyl amine or Ar; them, and Ar, aromatic ring or heteroaromatic ring consisting of 1-membered ring or more membered ring There are 4 to 10 carbon atoms per aromatic or heteroaromatic ring, most preferably 4 to 6 carbon atoms, and a heteroaromatic ring is one or several carbon atoms. It means an aromatic ring substituted with other atoms, most preferably one, two or three carbon atoms are substituted with O, N, Si, Se, P or S, most preferably O, S, is replaced by N; aryl or Ar, 1 or several of the hydrogen atoms means an aromatic ring substituted, these groups substituting a hydrogen atom, R ^18, F, Cl, Br , I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁸ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁸ , NO ₂ , SOR ¹⁶ R ¹⁸ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ^{16, PR 16 R 18, POR} 16 R 18, PO 2 R 16 R 18, OPO 3 R 16 R 18, CH 2 OPO 3 R 16 R 18, OP (O) (OR 16) OP (O) (OR 18 ) ₂ , C (O) OPO ₃ R ¹⁶ R ¹⁸ or PO ₃ R ¹⁶ R ¹⁸ , of which R ¹⁶ and R ¹⁸ are independently H, C _{1 to} C ₈ alkyl; C _2- C. ₈ alkenyl, alkynyl, _heteroalkyl; C 3 -C ₈ aryl, heterocycle, carbocycle, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkyl cycloalkyl, alkylcarbonyl or _C 4 _{-C 12} glycoside Or a medicinal salt;
Further, when R ¹⁰ is not H, or when R ¹³ is the following group, R ¹² may be H.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP. (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ glycosides, or C _{1 to} C ₈ alkyls, carboxyalkyls. Group, heterocycle; R ¹⁸ is H, C _{1 to} C ₈ alkyl, carboxyalkyl group, heteroalkyl; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C _{3 to} C ₈ aryl, alkyl It is a carbonyl; R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ¹⁸ ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ _{) 2} , XPO (OR 18). ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, carboxyalkyl, carboxylic acid derivative; C _{2 to} C ₈ alkenyl, alkynyl, heterocycle; C _{3 to} C ₈ aryl, alkylcarbonyl or pharmaceutical salt; X is O, S, or be NH; ^{Y 1} and ^{Y 2} are each N or CH;
Alternatively, if R ¹¹ is the following group, then R ¹² may be H.

X ² is O, S, N-R ⁸ ; R ⁸ is an alkyl or heteroalkyl of H, C _{1 to} C _6. )

（ただし、ここで、Tは標的又は結合リガンド、Lは解離可能なリンカー、

はＬが独立して括弧内構造における分子と接続するリンク結合、ｎは１〜２０、ｍは１〜１０、ｑは１〜５であり； Z¹はH, CH₂OP(O)(OR¹⁸ ₎₂, PO(OR¹⁸)_2, C(O)OP(O)(OR¹⁸)₂, P(O)(OR¹⁸)OP(O)(OR¹⁸)₂, C(O)R¹⁸, C(O)NHR¹⁸, SO₂(OR¹⁸), C₄₋C₁₂グリコシド、またはC₁₋C₈アルキル基、カルボキシアルキル基、複素環基；R¹⁸は、H、C₁₋C₈アルキル、カルボキシアルキル、ヘテロアルキル；C₂₋C₈アルケニル基、アルキニル基、複素環基；C₃₋C₈のアリール基、アルキルカルボニル基；R²⁴はHまたはCH₃である。） (Appendix 8)
Most preferably, the conjugate and pharmaceutically acceptable salt and solvate according to Appendix 7, having the structure represented by Structural Formula (VIII).

(However, where T is the target or binding ligand, L is the dissociable linker,

Is a link bond where L independently connects to the molecule in the parenthesized structure, n is 1-20, m is 1-10, q is 1-5; Z ¹ is H, CH ₂ OP (O) (OR) ¹⁸ _{) 2} , PO (OR ¹⁸ ) _2, C (O) OP (O) (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ) OP (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _4- C ₁₂ glycoside, or C _1- C ₈ alkyl group, carboxyalkyl group, heterocyclic group; R ¹⁸ is H, C _1- C ₈ alkyl , Carboxylalkyl, heteroalkyl; C _2- C ₈ alkenyl group, alkynyl group, heterocyclic group; C _3- C ₈ aryl group, alkylcarbonyl group; R ²⁴ is H or CH ₃ . )

（ただし、-W-は拡張単位であり、Aaが存在する場合、１つの目標分子単位（Ｔ）を１つのアミノ酸単位（Aa）に接続させ、又は、Aaが存在しない場合、ＷはＶ単位に接続され；Ｗは独立して１つの自己絶滅間隔単位、１つのペプチドベース単位、１つのヒドラゾン、１つのジスルフィド結合、１つのチオエーテル結合、１つのエステルまたは１つのアミド結合を含有していてもよく、ｗは０又は１であってもよく；Aaは１つの天然又は非天然のアミノ酸単位を単独で示し、ｒは０〜１２の整数を単独で示し、(Aa)_rは天然又は非天然のアミノ酸、ジペプチド、トリペプチド、テトラペプチド、ペンタペプチド、ヘキサペプチド、ヘプタペプチド、オクタペプチド、ノナペプチド、デカペプチド、ウンデカペプチドまたはドデカペプチドを示し、
Ｖは間隔単位であり、H、O、NH、S、C₁−C₈アルキル又はヘテロアルキル、C₂−C₈アルケニル、アルキニル、複素環、炭素環；C₃−C₈アリール、シクロアルキル、アルキルシクロアルキル基、ヘテロシクロアルキル、ヘテロアリール、ヘテロアルキルシクロアルキル、アルキルカルボニル、又は1−4個のアミノ酸単位を単独で示し；ｖは０、１又は２である。） (Appendix 9)
The linker L according to any one of Appendix 1 to 8, which has the following molecular formula.

(However, -W- is an expansion unit, and if Aa is present, one target molecular unit (T) is connected to one amino acid unit (Aa), or if Aa is not present, W is a V unit. Connected to; W independently contains one self-extinguishing interval unit, one peptide-based unit, one hydrazone, one disulfide bond, one thioether bond, one ester or one amide bond. Well, w may be 0 or 1; Aa represents one natural or unnatural amino acid unit alone, r represents an integer from 0 to 12 alone, and (Aa) _r represents natural or unnatural. Amino acids, dipeptides, tripeptides, tetrapeptides, pentapeptides, hexapeptides, heptapeptides, octapeptides, nonapeptides, decapeptides, undecapeptides or dodecapeptides.
V is an interval unit, H, O, NH, S, C _1- C ₈ alkyl or heteroalkyl, C _2- C ₈ alkenyl, alkynyl, heterocycle, carbocycle; C _3- C ₈ aryl, cycloalkyl, Alkylcycloalkyl groups, heterocycloalkyls, heteroaryls, heteroalkylcycloalkyls, alkylcarbonyls, or 1-4 amino acid units are shown alone; v is 0, 1 or 2. )

(Appendix 10)
Cell conjugate T can bind to an antibody, a single-stranded antibody or an antibody fragment capable of binding to a target cell, a monoclonal antibody, a single-chain monoclonal antibody, a single-chain monoclonal antibody fragment capable of binding to a target cell, a chimeric antibody, or a target cell. Chimeric antibody fragment, domain antibody, domain antibody fragment that can bind to target cells, analog antibody (adnectin), DAPRins (designed ankyrin repeat protein), lymphocaine, hormones, vitamins, growth factors, colony stimulators, nutrient transport Any of Appendix 1-8, selected from molecules (transferases), binding peptides, proteins, small molecules attached to albumin, high molecular weight polymers, artificially synthesized polymers, liposomes, nanoparticles, vesicles, and (viral) capsids. The conjugate according to item 1.

(Appendix 11)
The structural formulas of the anti-mitotic conjugates are IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, IIi, IIj, IIk, IIl, IIm, IIn, IIo, IIp, IIq, IIr, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IVa, IVb, IVc, IVd, IVe, IVf, Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, VIa, VIb, VIc, VIe, VIf, VIg, VIh, VIi, VIIa, VIIb, VIIc, VIId, VIIe, VIIf, VIIg, VIIh, VIIi, VIIj, VIIk, VIIl, VIIm, VIIn, VIIo, VIIp, VIIr, VIIs, and VIIt The conjugate according to Appendix 1, which is indicated by.

(Appendix 12)
The structural formulas of the anti-mitotic molecules constituting the conjugate are 232a, 232b, 232c, 232d, 232e, 232f, 232g, 232h, 232i, 232j, 232k, 232l, 232m, 232n, 232o, 232p, 232q, 232r, 232s, 232t, 221a, 221b, 233a, 233b, 233c, 233d, 222a, 308a, 308b, 309a, 309b, 290, 299a, 299b, 241, 242, 247, 248, 206, 211, 346, 350, 354, 357, 361, 366, 371 and 376, the conjugate according to any one of Appendix 1-8.

(Appendix 13)
The structural formulas of the antibody conjugated with the anti-mitotic agent are mAb-TZ01, mAb-TZ02, mAB-TZ03, mAb-TZ04, mAb-TZ05, mAb-TZ06, mAb-TZ07, mAb-TZ08, mAb- TZ09, mAb-TZ10a, mAb-TZ10b, mAb-TZ11, mAb-TZ12, mAb-TZ13, mAb-TZ14, mAb-TZ15, mAb-TZ16, mAb-TZ17, mAb-TZ18, mAb-TZ19, mAb-TZ20, The conjugate according to any one of Appendix 1 to 8, represented by mAb-TZ21, mAb-TZ22, mAb-TZ23, mAb-TZ24, and mAb-TZ25.

(Appendix 14)
Target cells that bind to cell surface conjugate T are tumor cells, virus-infected cells, microbial-infected cells, parasite-infected cells, autoimmune cells, activated cells, bone marrow cells, activated T cells and B cells, or melanin cells. Apo2, ASLG659, BAFF-R, BMPR1B (bone-forming protein), IGF-IR, CA125, CanAg, E16, EGFR, EphA2 receptor; ErbB2, MUC1, MUC16, NaPi3b (synonyms: NAPI-3B, NPTIIb, SLC34A2) , Solute carrier family 34 II, II type sodium-dependent phosphate transporter 3B), VEGF, TF, MY9, antiB4, EpCAM, FcRH2, C242, CD2, CD3, CD4, CD5, CD6, CD11, CD 11a, CD18 , CD19, CD20, CD21, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD70, CD72, CD79, CD79a, CD79b, CD105, CD138, CRIPTO (CR, CR1, CRGF, CRIPTO, CXCR5) , LY64, TDGF1, morphoma-derived growth factor), EphA receptor, EphB receptor, EGFR, EGFRvIII, ETBR (ET), FCRH1, HER2 / neu, HER3, HLA-DOB (MHCII molecule Ia antigen), Integrin, IRTA2, MPF (MPF, MSLN, SMR, giant nucleus growth factor, mesoterin), GEDA, sema 5B (FLJ10372, KIAA1445, Mm42015, SEMA5B, 5EMAG, semaphoring 5 bHlog, sema domain, 7 One of the thrombospondinic repeats and cytoplasmic domain), PSCA, STEAP1 (six transmembrane epidermal growth factor of prostate 1), and STEAP2 (, HGNC 8639, IPCA-1, PCANP1, STAMP1, STEAP2, STMP, prostate) Or the antibody-drug conjugate according to any one of Appendix 1-8, comprising cells representing one or more; and cells expressing insulin-like growth factor, epidermal growth factor, or folic acid receptor.

（ただし、RはC₁−C₈ アルキル又はC₂H₄(OC₂H₄)_n、ｎは1〜20であり;X³はH又はBrである。） (Appendix 15)
The linker according to Appendix 9, which has the structure of a 3-bromo-maleimide group or a 3,4-dibromo-maleimide group below when one linker of the conjugate binds to two cytotoxic molecules.

(However, R is C _{1 −} C ₈ alkyl or C ₂ H ₄ (OC ₂ H ₄ ) _n , n is 1 to 20; X ³ is H or Br.)

（ここで、RはC₁〜C₈ アルキル又はC₂H₄(OC₂H₄)_n, nは1〜20であり; Dは細胞毒素分子/薬物，Tは細胞結合分子である。） (Appendix 16)
When two cytotoxins in a conjugate are conjugated to one linker, the conjugate and pharmaceutically acceptable as described in any one of Appendix 1-8, wherein the conjugate that binds to the cytotoxin molecule has the following structure: Salts and solvates to be added.

(Here, R is C _{1 to} C ₈ alkyl or C ₂ H ₄ (OC ₂ H ₄ ) _n , n is 1 to 20; D is a cytotoxic molecule / drug, T is a cell binding molecule.)

（ここで、RはC₁〜C₈ アルキル又はC₂H₄(OC₂H₄)_n, nは1〜20であり;Dは細胞毒素分子/薬物，Tは細胞結合分子である。） (Appendix 17)
When two cytotoxins in a conjugate are conjugated to one linker, the conjugate and pharmaceutically acceptable as described in any one of Appendix 1-8, wherein the conjugate that binds to the cytotoxin molecule has the following structure: Salts and solvates to be added.

(Here, R is C _{1 to} C ₈ alkyl or C ₂ H ₄ (OC ₂ H ₄ ) _n , n is 1 to 20; D is a cytotoxic molecule / drug, T is a cell binding molecule.)

(Appendix 18)
The cytotoxic drug D is a pharmaceutical such as calikeamycin, auristatins, maytancinoids, drastatin, CC-1065 analogs, doxorubicin, taxanes, lorobenzodiazepine dimers, siRNAs or mixtures of these molecules. The conjugate according to Appendix 16 or 17, selected from any of these salts, acids or derivatives that are permissible in.

(Appendix 19)
A conjugate to which the anti-thread fission agent according to any one of Appendix 1 to 8 is conjugated at a therapeutically effective dose for the treatment or prevention of cancer, autoimmune disease or infectious disease. , Or a drug composition comprising a suitable pharmaceutically acceptable salt, carrier, diluent, excipient, or mixture thereof.

(Appendix 20)
For use in the synergistically effective treatment or prevention of cancer, autoimmune disease or infectious disease, at a therapeutically effective dose, the conjugate according to any one of Appendix 1-8 can be used with other drugs (eg, for example. A drug composition comprising a drug component in combination with a chemotherapy, radiotherapy, immunotherapy, anti-autoimmune disease agent, anti-infective agent, or other antibody-drug conjugate).

Claims (5)

A conjugate having the structure represented by the structural formula (I) or a pharmaceutically acceptable salt or solvate thereof.

(However, here,
T is an antibody, a single-stranded antibody, an antibody fragment capable of binding to a target cell, a monoclonal antibody, a single-chain monoclonal antibody, a single-chain monoclonal antibody fragment capable of binding to a target cell, a chimeric antibody, or a chimeric antibody capable of binding to a target cell. Fragments, domain antibodies, domain antibody fragments that can bind to target cells, antibody-like adnectin, DARPin (designed ankyrin repeat protein), lymphocaine, hormones, vitamins, growth factors, colony stimulators, nutrient transport molecules (transferases), binding A cell-binding ligand selected from peptides, proteins, small molecules attached to albumin, high molecular weight polymers, artificially synthesized polymers, liposomes, nanoparticles, vesicles, and (viral) capsids.
L is

(However, W is an expansion unit, and if Aa is present, W connects the molecule having the structure in parentheses to the amino acid unit (Aa), or if Aa is not present, W is connected to the V unit and W. May independently contain one self-destructive spacer, one peptide-based unit, one hydrazone, one disulfide bond, one thioether bond, one ester or one amide bond, where w It may be 0 or 1
Aa independently represents one natural or unnatural amino acid unit, r independently represents an integer from 0 to 12, (Aa) _r is a natural or unnatural amino acid, dipeptide, tripeptide, tetrapeptide, Peptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide,
V is an interval unit and is independently H, O, NH, S, C _{1 to} C ₈ alkyl, C _{2 to} C ₈ heteroalkyl, C _{2 to} C ₈ alkenyl, C _{2 to} C ₈ alkynyl, C. _{3 to} C ₈ aryl, C _{3 to} C ₈ heterocycle, C _{3 to} C ₈ carbocycle, C _{3 to} C ₈ cycloalkyl, C _{3 to} C ₈ alkylcycloalkyl, C _{3 to} C ₈ heterocycloalkyl, C ₃ ~ C ₈ heteroaryl, C ₃ ~ C ₈ heteroaralkyl, C ₃ ~ C ₈ heteroalkylcycloalkyl, C ₃ ~ C ₈ alkylcarbonyl, (CH ₂ CH ₂ O) _k (k is an integer from 0 to 12), Or it indicates 1 to 4 amino acid units, and v is 0, 1 or 2. )
It is a dissociable linker having the formula

Is a link bond in which L independently connects to the molecule in parenthesized structure,
n is 1 to 20, m is 1 to 10, and
R ¹ , R ³ , and R ⁴ are independently hydrogen, C _{1 to} C ₈ alkyl, C _{2 to} C ₈ heteroalkyl, C _{2 to} C ₈ heterocycle, C _{3 to} C ₈ carbon ring, C ₃ to. C ₈ alkyl cycloalkyl, C _{3 to} C ₈ heterocyclic alkyl, C _{3 to} C ₈ aryl, C _{3 to} C ₈ aralkyl, C _{3 to} C ₈ heteroalkyl cycloalkyl, or C _{3 to} C ₈ alkylcarbonyl. R ² is independently absent or C _{1 to} C ₈ alkyl, C _{2 to} C ₈ heteroalkyl, C _{2 to} C ₈ heterocycle, C _{3 to} C ₈ carbocycle, C ₃ to C. ₈ alkyl _cycloalkyl, C 3 -C _{8 heterocycloalkyl,} C 3 -C _{8 aryl,} C 3 -C _{8 aralkyl,} C 3 -C ₈ heteroalkyl cycloalkyl, or _C 3 -C ₈ alkylcarbonyl, or , R ¹ R ² , R ² R ³ , or R ³ R ^{4 form} a carbocyclic, cycloalkyl, heterocyclic, or heterocycloalkyl ring system having 3 to 7 carbon atoms.
Y is N or CH,
R ⁵ , R ⁶ , R ⁸ , and R ¹⁰ are independently H, C _{1 to} C ₄ alkyl, or C _{1 to} C ₄ heteroalkyl, respectively, or R ⁵ R ⁶ has 3 carbon atoms. Form a carbocyclic, cycloalkyl, heterocyclic, or heterocycloalkyl ring system of ~ 7.
R ⁷ are independently H, R ¹⁴ , -R ¹⁴ C (= O) X ¹ R ¹⁵ or -R ¹⁴ X ¹ R ¹⁵ , where X ¹ is O, S, SS, NH, Or NR ¹⁴
R ⁹ is ^{independently, H, -O -, - OR} 14, -OC (= O) R 14 -, - OC (= O) NHR 14 -, - OC (= O) R 14 SSR 15 -, OP (= O) (OR ¹⁴ )-or OR ¹⁴ OP (= O) (OR ¹⁵ ).
R ¹¹ is H, R ¹⁴ , -R ¹⁴ C (= O) R ¹⁶ , -R ¹⁴ X ² R ¹⁶ , or -R ¹⁴ C (= O) NHR ¹⁴ , of which X ² is -O. ^{-, - S -, - NH} -, - N (R 14) -, - O-R 14 -, - S-R 14 -, or -S (= O) ^{-R 14} - is and,
R ¹² independently has R ¹⁴ , H, -OH, -SH, -NH ₂ , = NH, = NNH ₂ , -NH (R ¹⁴ ), -OR ¹⁴ , -COR ¹⁶ , C (O) NH. ₂ , C (O) NHR ¹⁴ , -SR ¹⁴ , -S (= O) R ¹⁴ , -P (= O) (OR ¹⁶ ) ₂ , -OP (= O) (OR ¹⁶ ) ₂ , -CH ₂ OP (= O) (OR ¹⁶ ) ₂ or -SO ₂ R ¹⁶
R ¹³ is C _{1 to} C ₁₀ alkyl, C _{1 to} C ₁₀ heteroalkyl, C _{1 to} C ₁₀ alkyl acid, C _{1 to} C ₁₀ alkyl amide, C _{1 to} C ₁₀ alkyl amine, or Ar, of which Ar is an aromatic ring or a complex aromatic ring containing 4 to 10 carbon atoms and consisting of a 1-membered ring or a multi-membered ring, wherein the heteroaromatic ring is one or several carbon atoms. Means an aromatic ring substituted with another atom, where one or several hydrogen atoms of Ar are optionally R ¹⁷ , F, Cl, Br, I, OR ¹⁶ , SR ¹⁶ , NR ¹⁶ R ¹⁷ , N = NR ¹⁶ , N = R ¹⁶ , NR ¹⁶ R ¹⁷ , NO ₂ , SOR ¹⁶ R ¹⁷ , SO ₂ R ¹⁶ , SO ₃ R ¹⁶ , OSO ₃ R ¹⁶ , PR ¹⁶ R ¹⁷ , POR ¹⁶ R ¹⁷ , PO ₂ R ¹⁶ R ¹⁷ , OP (O) (OR ¹⁷ ) ₂ , OCH ₂ OP (O) (OR ¹⁷ ) ₂ , OC (O) OP (O) (OR ¹⁷ ) ₂ , PO (OR ¹⁶ ) (OR) ¹⁷ ), OP (O) (OR ¹⁷ ) OP (O) (OR ¹⁷ ) ₂ , OC (O) R ¹⁷ , or OC (O) NHR ¹⁷ may be substituted.
R ¹⁴ and R ¹⁵ are independently C _{1 to} C ₈ alkyl, C _{2 to} C ₈ alkenyl, C _{2 to} C ₈ alkynyl, C _{2 to} C ₈ heterocycle, C _{3 to} C ₈ aryl, C ₃ to. C ₈ Heterocycloalkyl, C _{3 to} C ₈ Heteroalkyl Cycloalkyl, C _{3 to} C ₈ Heteroalkyl, C _{3 to} C ₈ Carbocycles, C _{3 to} C ₈ Cycloalkyl, C _{3 to} C ₈ Heteroaralkyl, or C _{3 to} C ₈ alkylcarbonyl,
R ¹⁶ and R ¹⁷ are independently H, C _{1 to} C ₈ alkyl, C _{2 to} C ₈ alkenyl, C _{2 to} C ₈ alkynyl, C _{2 to} C ₈ heterocycle, and C _{3 to} C ₈ aryl, respectively. , C _{3 to} C ₈ cycloalkyl, C _{3 to} C ₈ alkyl cycloalkyl, C _{3 to} C ₈ carbocycles, C _{3 to} C ₈ heteroalkyl, C _{3 to} C ₈ heterocycloalkyl, C _{3 to} C ₈ heteroalkyl Cycloalkyl, C _{3 to} C ₈ heteroaralkyl, C _{3 to} C ₈ alkylcarbonyl, or C _{4 to} C ₁₂ glycosides or medicinal salts.
Alternatively, R ¹² R ¹³ forms a carbocyclic, cycloalkyl, heterocyclic, or heterocycloalkyl ring system having 3 to 7 carbon atoms.
(I) If R ¹³ is the following group, R ¹ R ³ _{may be a C 3 to} C ₇ heterocycle or heterocycloalkyl instead of the options described above.

Here, Z ¹ is H, CH ₂ OP (O) (OR ¹⁸ ) ₂ , C (O) OP (O) (OR ¹⁸ ) ₂ , PO (OR ¹⁸ ) ₂ , P (O) (OR ¹⁸ ). OP (O) (OR ¹⁸ ) ₂ , C (O) R ¹⁸ , C (O) NHR ¹⁸ , SO ₂ (OR ¹⁸ ), C _{4 to} C ₁₂ glycosides, or C _{1 to} C ₈ alkyl, C ₂ to C ₈ carboxyalkyl or C _{2 to} C ₈ heterocycle, R ¹⁸ is H, C _{1 to} C ₈ alkyl, C _{1 to} C ₈ heteroalkyl, C _{2 to} C ₈ carboxyalkyl, C _{2 to} C ₈ Alkyne, C _{2 to} C ₈ alkynyl, C _{2 to} C ₈ heterocycle, C _{3 to} C ₈ aryl, or C _{3 to} C ₈ alkylcarbonyl, where R ¹⁹ is H, OH, NH ₂ , OSO ₂ (OR ^18). ), XCH ₂ OP (O) (OR ¹⁸ ) ₂ , XPO (OR ¹⁸ ) ₂ , XC (O) OP (O) (OR ¹⁸ ) ₂ , XC (O) R ¹⁸ , XC (O) NHR ¹⁸ , C _{1 to} C ₈ alkyl, C _{1 to} C ₈ carboxylic acid derivative, C _{2 to} C ₈ alkenyl, C _{2 to} C ₈ alkynyl, C _{2 to} C ₈ heterocycle, C _{2 to} C ₈ carboxyalkyl, C _{3 to} C ₈ Aryl, C _{3 to} C ₈ alkylcarbonyl, or medicinal salts, where X is O, S, or NH, and Y ¹ and Y ² are N or CH, respectively.
(Ii) If R ¹¹ is the following group, R ¹ R ³ _{may be a C 3 to} C ₇ heterocycle or heterocycloalkyl instead of the options described above.

X ² is O, S, N-R ⁸ , R ⁸ is H, C _{1 to} C ₆ alkyl or C _{1 to} C ₆ heteroalkyl, and R 8'and R 8'' are R8, respectively. Or, it is the following group.

) The conjugate according to claim 1, which has a structure represented by the structural formula (V), or a pharmaceutically acceptable salt or solvate thereof.

(However, here,
R ⁹ is independently -OH, -OR ¹⁴ , -OC (= O) R ¹⁴ , -OC (= O) NHR ¹⁴ , -OC (= O) R ¹⁴ SSR ¹⁵ , or OP (= O). (OR ¹⁴ ) OH, where R ¹⁴ and R ¹⁵ are independently C _{1 to} C ₈ alkyl, C _{1 to} C ₈ heteroalkyl, C _{3 to} C ₈ aryl, and C _{3 to} C, respectively. _{8 heteroaryl,} C 3 -C _{8 heterocycle,} C 3 -C _{8 carbocycle,} C 3 -C _{8 alkylcycloalkyl,} C 3 -C _{8 heterocycloalkyl,} C 3 -C ₈ heteroalkyl cycloalkyl, _{C 3} -C ₈ heteroaralkyl, or _C 3 are -C ₈ alkylcarbonyl R ¹¹ is ^{independently, -R 14 -, - R 14} C (= O) R 17, -R 14 X 2 R 17, or - R ¹⁴ C (= O) X ² , where R ¹⁷ is independently H, OH, C _{1 to} C ₈ alkyl, C _{2 to} C ₈ alkenyl, C _{2 instead of the options described above.} ~ C ₈ alkynyl, C ₂ ~ C ₈ heteroalkyl, C ₃ ~ C ₈ aryl, C ₃ ~ C ₈ arylene, C ₃ ~ C ₈ heterocycle, C ₃ ~ C ₈ carbocycle, C ₃ ~ C ₈ heterocyclo Alkyl, or 1 or 2 amino acids, X ² is an alternative to the options described above ^{-O-, -S-, -NH-, -N (R 14} )-, ^{-O-R 14} -,- ^{S-R 14 -, - S} (= O) -R 14 -, or -NHR ¹⁴ - a and, ^{wherein, R 14,} instead of the above alternatives, _{independently,} C 1 -C ₈ alkyl, C _{2 to} C ₈ heteroalkyl, C _{2 to} C ₈ alkenyl, C _{2 to} C ₈ alkynyl, C _{3 to} C ₈ aryl, C _{3 to} C ₈ heterocycle, C _{3 to} C ₈ carbocycle, C _{3 to} C ₈ Cycloalkyl, C _{3 to} C ₈ alkyl cycloalkyl, C _{3 to} C ₈ heterocycloalkyl, C _{3 to} C ₈ heteroalkyl cycloalkyl, C _{3 to} C ₈ heteroaralkyl, or C _{3 to} C ₈ alkylcarbonyl.
(I) If R ¹³ is the basis of claim 1, the R ¹ R ³ and R ² R ³ _{may be C 3 to} C ₇ heterocycles or heterocycloalkyls instead of the options described above. Often,
(Ii) If R ¹¹ is the basis of claim 1, even if R ¹ R ³ and R ² R ³ _{are C 3 to} C ₇ heterocycles or heterocycloalkyls instead of the options described above. Good. ) The conjugate according to claim 1, which has a structure represented by the structural formula (VI), or a pharmaceutically acceptable salt or solvate thereof.

(However, here,
R ⁷ is R ¹⁴ , -R ¹⁴ C (= O) X ¹ R ¹⁵ , or -R ¹⁴ X ¹ R ¹⁵ , where R ¹⁴ and R ¹⁵ are independently C ₁ to R 15, respectively. C ₈ alkyl, C _{1 to} C ₈ heteroalkyl, C _{2 to} C ₈ alkenyl, C _{2 to} C ₈ alkynyl, C _{2 to} C ₈ heterocycle, C _{3 to} C ₈ aryl, C _{3 to} C ₈ heterocycloalkyl, C _{3 to} C ₈ heteroalkylcycloalkyl, C _{3 to} C ₈ heteroalkyl, C _{3 to} C ₈ carbocycles, C _{3 to} C ₈ cycloalkyl, or C _{3 to} C ₈ alkylcarbonyl, where X ¹ is O, S, SS, NH, or NR ¹⁴
R ⁹ is independently H, -OH, -OR ¹⁴ , -OC (= O) R ¹⁴ , -OC (= O) NHR ¹⁴ , -OC (= O) R ¹⁴ SSR ¹⁵ , OP (= O). ) (OR ¹⁴ ) ₂ or OR ¹⁴ OP (= O) (OR ¹⁵ ) ₂ .
R ^12, instead of the above alternatives, ^{independently, R 14, -O -, -} S -, - N -, = N -, = NNH -, - N (R 14) -, - OR 14 - ^{, -C (O) O -,} - C (O) NH-, C (O) NR 14 -, - SR 14 -, - S (= O) R 14 -, - NHR 14 -, - CH 2 OP ( = O) (OR ¹⁶ )-, -P (= O) (OR ¹⁶ )-, -C (O) OP (= O) (OR ¹⁶ )-, -OP (= O) (OR ¹⁶ )-, or -SO ₂ R ¹⁴ where R ¹⁴ and R ¹⁵ are independently C _{1 to} C ₈ alkyl, C _{1 to} C ₈ heteroalkyl, C _{2 to} C ₈ alkenyl, and C _{2 to} C, respectively. ₈ alkynyl, C _{3 to} C ₈ aryl, C _{3 to} C ₈ heterocycle, C _{3 to} C ₈ carbocycle, C _{3 to} C ₈ cycloalkyl, C _{3 to} C ₈ alkylcycloalkyl, C _{3 to} C ₈ heterocyclo Alkyne, C _{3 to} C ₈ heteroaralkyl, C _{3 to} C ₈ heteroalkylcycloalkyl, or C _{3 to} C ₈ alkylcarbonyl. ) The conjugate according to claim 1, which has a structure represented by the structural formula (VII), or a pharmaceutically acceptable salt or solvate thereof.

(However, here,
R ⁹ is an independent alternative to the above options: -OH, -OR ¹⁴ , -OC (= O) R ¹⁴ , -OC (= O) NHR ¹⁴ , -OC (= O) R ¹⁴ SSR ¹⁵ , Or OP (= O) (OR ¹⁴ ) OR ¹⁵ , where R ¹⁴ and R ¹⁵ are independently C _{1 to} C ₈ alkyl, C _{1 to} C ₈ heteroalkyl, and C ₃ to, respectively. C ₈ aryl, C _{3 to} C ₈ heteroaryl, C _{3 to} C ₈ heterocycle, C _{3 to} C ₈ carbocycle, C _{3 to} C ₈ alkylcycloalkyl, C _{3 to} C ₈ heterocycloalkyl, C _{3 to} C ₈ heteroalkylcycloalkyl, C _{3 to} C ₈ heteroaralkyl, or C _{3 to} C ₈ alkylcarbonyl.
(I) If R ¹³ is the basis of claim 1, the R ¹ R ³ and R ² R ³ _{may be C 3 to} C ₇ heterocycles or heterocycloalkyls instead of the options described above. Often,
(Ii) If R ¹¹ is the basis of claim 1, even if R ¹ R ³ and R ² R ³ _{are C 3 to} C ₇ heterocycles or heterocycloalkyls instead of the options described above. Good. ) The conjugate according to claim 1, which has a structure represented by the structural formula (VIII), or a pharmaceutically acceptable salt or solvate thereof.

(However, ^where, R 24, ^{R 24 'is} H or CH _3.)

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