Einectin derivative antibody drug conjugates

Abstract

Provided herein are compounds, methods, and pharmaceutical compositions for the treatment of cancer. In certain embodiments, provided are ecteinin derivative antibody drug conjugate compounds that exhibit significant efficacy and bioavailability for the treatment of cancer, for example, in humans.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 480,285, filed January 17, 2023, which is hereby incorporated by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on January 10, 2024, is named 65657-702_601_SL.xml and is 20,721 bytes in size. Technical Field

[0005] Provided herein are compounds, methods, and pharmaceutical compositions for treating cancer. In certain embodiments, antibody drug conjugates comprising ecteinascidin compounds are provided that exhibit significant efficacy, pharmacokinetic parameters, selectivity, and safety for treating, for example, human cancer. Background Art

[0006] Antibody-drug conjugates (ADCs) are a class of biopharmaceuticals under development that are designed for targeted cancer therapy. Unlike chemotherapy, which lacks selectivity for cancer cells, ADCs are designed to target and attack cancer cells while leaving healthy cells unharmed. ADCs achieve selectivity by attaching a cytotoxic payload or drug to an antibody via a linker. ADCs leverage the binding selectivity of antibodies to deliver cytotoxic drugs to abnormal cells.

[0007] It is known that ecteinascidins such as trabectedin and lurbinectedin are cancer treatment drugs. For example, lurbinectedin has been used to treat small cell lung cancer and trabectedin has been used to treat soft tissue sarcoma and ovarian cancer. However, trabectedin and lurbinectedin are toxic even at low concentrations.

[0008] Therefore, there is a continuing need for targeted therapies that can optimize the effective dose of ecteinascidin therapy. Summary of the Invention

[0009] Provided herein are compounds, compositions, and methods useful for treating a proliferative disease in a subject.

[0010] In one embodiment, provided herein is a compound according to formula (XI), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof:

[0011]

[0012] in:

[0013] R 1 and R 2 Together they form an aromatic ring or a bicyclic heteroaromatic ring; wherein the aromatic ring and the bicyclic heteroaromatic ring are optionally substituted with 1 to 6 substituents independently selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, -SH and -SO3H;

[0014] R 3 is hydrogen or CH2OR 6 ;

[0015] R 4 It is H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 -Heterocycle, C(O)R 8 、C(O)OR 8 、C(O)NHR 8 、SO2R 8 、SO2NHR 8 ; among them C 1-10 -alkyl or C 6-10 -Aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -OH, -F, -Cl, -Br, -C 1-6 -alkyl, -C 3-6 -cycloalkyl and -C 3-6 -heterocyclyl; or L 1

[0016] R 5 and R 6 Each independently selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, phosphate, phosphorothioate, phosphoramide, C(O)R 9 、C(O)OR 9 , and C(O)NHR 9 、SO3H、SO2R 9 , where C 1-10 -alkyl or C 6-10 -aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -OH, -F, -Cl, -Br, optionally substituted -C 1-6 -alkyl, optionally substituted-C 3-6 -cycloalkyl, and optionally substituted -C 3-6-heterocyclyl; or L 2

[0017] where R 5 or R 6 The phosphates and phosphorothioates are optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl,

[0018] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and

[0019] wherein the substituents on the phosphate and phosphorothioate are optionally capped with protecting groups;

[0020] Among them L 1 or L 2 is a reactive linker;

[0021] R 8 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[0022] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H;

[0023] R 9 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[0024] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H;

[0025] where R 4 、R 5 , and R 6 One of them is the reactive group R 10 or a linker with an antibody Ab;

[0026] in is a single bond or a double bond; and

[0027] wherein y is an integer selected from 0 to 32.

[0028] In certain embodiments, provided herein are compounds according to formula (XII), or pharmaceutically acceptable salts, esters, stereoisomers, or tautomers thereof, comprising:

[0029]

[0030] Among them L 1 , or L 2 One of the reactive linkers is a reactive linker.

[0031] In certain embodiments, provided herein are compounds according to formula (XIII), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising:

[0032]

[0033] where R 1 and R 2 forming at least one aromatic ring or bicyclic heteroaromatic ring, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H;

[0034] in Is a single bond or a double bond;

[0035] Among them L 1 Contains at least one of the following:

[0036] (a)-H, if L 2 Not H;

[0037] (b) -CH3;

[0038] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0039] (d) optionally with at least one R 10 Substituted-(C0-6 -alkyl)-C 3-10 -cycloalkyl;

[0040] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0041] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0042] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0043] where R 10 It is R 10a -R 10b ,in

[0044] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0045] R 10b Selected from the group consisting of:

[0046] (i)-C(O)-R 11 ;

[0047] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0048] (iii)-NH-R 11 ;

[0049] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0050] (v)-C(O)-NH-R 11 ;

[0051] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0052] (vii)-C(O)-NH-NH-R 11 ;

[0053] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0054] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[0055] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[0056] (xi)-CH(NH2)-CO-R 11 ;

[0057] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[0058] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[0059] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[0060] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[0061] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0062] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0063] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6;

[0064] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0065] R 11d Selected from the group consisting of -O- and -NH;

[0066] Among them L 2 Contains at least one of the following:

[0067] (a)-H, if L 1 Not H;

[0068] (b) -PO3H-;

[0069] (c)-PO2SH-;

[0070] (d) -CH3;

[0071] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0072] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0073] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0074] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0075] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0076] where R 10 It is R 10a -R 10b ,in

[0077] R 10a Does not exist or is -(CH2)e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0078] R 10b Selected from the group consisting of:

[0079] (i)-C(O)-R 11 ;

[0080] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0081] (iii)-NH-R 11 ;

[0082] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0083] (v)-C(O)-NH-R 11 ;

[0084] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0085] (vii)-C(O)-NHNH-R 11 ;

[0086] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0087] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[0088] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0089] (xi)-CH(NH2)CO-R 11 ;

[0090] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0091] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0092] (xiv)-CH(CO-R 11)NH-R 11 ;

[0093] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0094] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0095] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0096] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6;

[0097] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0098] R 11d Selected from the group consisting of -O- and -NH.

[0099] Each L 2 Independently comprising at least one of the following:

[0100] (a)-H, if L 1 Not H;

[0101] (b) -PO3H-;

[0102] (c)-PO2SH-;

[0103] (d) -CH3;

[0104] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0105] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0106] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0107] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0108] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0109] where R 10 It is R 10a -R 10b ,in

[0110] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0111] R 10b Selected from the group consisting of:

[0112] (i)-C(O)-R 11 ;

[0113] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0114] (iii)-NH-R 11 ;

[0115] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0116] (v)-C(O)-NH-R 11 ;

[0117] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0118] (vii)-C(O)-NHNH-R 11 ;

[0119] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0120] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[0121] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0122] (xi)-CH(NH2)CO-R 11 ;

[0123] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0124] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0125] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0126] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0127] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0128] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0129] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6;

[0130] R 11c Yes - (CH2) x-, wherein the subscript x is an integer selected from 1 to 10; and

[0131] R 11d Selected from the group consisting of -O- and -NH.

[0132] In certain embodiments, provided herein are compounds according to formula (XIV), or pharmaceutically acceptable salts, esters, or tautomers thereof, comprising:

[0133]

[0134] where R 1 and R 2 forming at least one aromatic ring or bicyclic heteroaromatic ring, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H;

[0135] in Is a single bond or a double bond;

[0136] Among them L 1 , or L 2 One of them is the joint;

[0137] Among them L 1 yes:

[0138] H;

[0139] R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl) e -[(C(O)-] f ;or

[0140] R 40 -(-C2H4-O) c -C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H4-O) t -(C 1-6 alkyl)-[(C(O)-] k ;

[0141] Among them L 2 yes:

[0142] H;

[0143] R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl)-[(C(O)-NH] j -(-C2H-4-O) t -[OP(O)SH]; or

[0144] R 40 -(-C2H4-O) t -C(O)-(A1-A2) g -NH-(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H-4-O) t -(C 1-6 alkyl)-[(C(O)-] f -[OP(O)SH];

[0145] Among them L 1 or L 2 One of them is not H;

[0146] where R 40 It is a reactive group;

[0147] wherein A1 and A2 are independently in each instance an amino acid;

[0148] Where subscript:

[0149] b and j are independently selected at each occurrence from 0 to 4;

[0150] c and t are independently selected in each case from 0 to 32;

[0151] e, f, g, h and k are independently 0 or 1 in each instance.

[0152] In certain embodiments, the compound of Formula (XVa), (XVb), or (XVc), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprises:

[0153]

[0154]

[0155] Wherein Ab is a targeting agent;

[0156] Wherein the subscript k is an integer from 1 to 10;

[0157] where R 1 and R2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and

[0158] Among them B 1 It is a joint;

[0159] Among them B 2 It's a connector.

[0160] One embodiment provides a pharmaceutical composition comprising a compound of Formula (XI), (XII), (XIII), (XIV), (XVa), (XVb), (XVc), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient.

[0161] One embodiment provides a method of treating a disease or condition comprising administering a compound of Formula (XI), (XII), (XIII), (XIV), (XVa), (XVb), (XVc), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0162] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description and accompanying drawings, which set forth illustrative embodiments in which the principles of the invention are utilized, wherein:

[0163] Figure 1 Provided are tumor volume measurements of female B-NDG mice injected subcutaneously with NCI-N87 cells followed by dosing with vehicle control (PBS) or 0.5 mg / kg body weight of trastuzumab-LD7.

[0164] Figure 2 Provided are body weight measurements of female B-NDG mice injected subcutaneously with NCI-N87 cells followed by dosing with vehicle control (PBS) or 0.5 mg / kg body weight of trastuzumab-LD7.

[0165] Figure 3 Body weight measurements are provided for male CD-1 mice injected intravenously with an isotype human IgG1 antibody conjugated to LD7 at a dose rate of 6, 15, or 30 mg / kg body weight (mpk). DETAILED DESCRIPTION

[0166] Provided herein are compounds, compositions, and methods useful for treating a proliferative disease in a subject. Further provided are dosage forms useful for such methods.

[0167] definition

[0168] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. If multiple definitions exist for a term herein, those in this section prevail unless otherwise stated.

[0169] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present application will control.

[0170] As used herein, the articles "a," "an," and "the" include not only certain embodiments having a single member, but also embodiments having more than one member. For example, the aspect "comprising a compound of Formula Ib and an excipient" is understood to present certain embodiments having at least a second compound of Formula Ib, at least a second excipient, or both.

[0171] As used herein, the term "or" is similar to a Boolean "or," except that the alternatives cannot be combined without logical incompatibility. For example, the aspect "comprising an excipient selected from A, B, or C" should be understood to apply to embodiments comprising A and B; B and C; A and C; or A, B, and C.

[0172] As used herein, the term "about," which modifies a numerical value, indicates a limited range around that value. If "X" is a value, "about X" generally refers to a value from 0.95X to 1.05X. Any reference to "about X" explicitly refers to at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide written descriptive support for a claim limitation such as "0.98X." When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "from about 5 to 20%" is equivalent to "from about 5% to about 20%." When "about" is applied to the first value of a group of values, it applies to all values ​​in the group. Thus, "about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%."

[0173] When used in this specification and in the claims, the terms "comprise," "comprising," "include," and "including" are intended to specify the presence of stated features, integers, components or steps, but they do not preclude the presence or addition of one or more additional features, integers, components or steps.

[0174] As used herein, the term "conjugate" refers to a compound having a multimeric antigen-binding compound or multimeric immunoglobulin, a linker, and a biologically active molecule.

[0175] As used herein, the term "spacer" refers to a chemical building block of a linker that is used to spatially separate the multimeric antigen-binding compound or multimeric immunoglobulin from the biologically active molecule and allows for the cleavage of the linker inside the cell.

[0176] As used herein, the term "antibody" includes antigen-binding fragments of complete antibody molecules. As used herein, the term "antigen-binding portion" of an antibody, and "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of an antibody can be derived from complete antibody molecules, for example, using any suitable standard technique such as proteolytic digestion or recombinant genetic engineering techniques involving manipulation and expression of DNA encoding antibody variable and optional constant domains. Such DNA is known and / or can be easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA can be sequenced and chemically manipulated or by using molecular biology techniques, for example, one or more variable and / or constant domains can be arranged into a suitable configuration, or codons can be introduced to produce cysteine ​​residues, modify, add or delete amino acids, etc.

[0177] As with intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will generally comprise at least two different variable domains, each of which is capable of specifically binding to a separate antigen or a different epitope on the same antigen. Using conventional techniques available in the art, any multispecific antibody format can be adapted for use in the context of antigen-binding fragments of the antibodies of the present disclosure.

[0178] As used herein, biologically active molecules (also referred to herein as "drugs," "toxins," "cytotoxic agents," and "chemotherapeutic agents," etc.) include any molecule that has therapeutic use in a mammal when targeted to a specific cell, cell type, or tissue. In typical embodiments, the molecule is beneficially delivered to a target within a mammal and, in particular, beneficially delivered to a cell and then within the cell (e.g., endocytosis) compared to molecules released into the vascular or lymphatic system. In certain embodiments, the biologically active molecule is a compound that results in inhibition, delay, reduction, and / or prevention of cell growth. The biologically active molecule can also cause cell death via necrosis or apoptosis.

[0179] Unless otherwise indicated, the term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon. In certain embodiments, an alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkyl group comprises 1 to 10 carbon atoms, i.e., C1 to C2. 10 Alkyl. In certain embodiments, the alkyl group is selected from the group consisting of methyl, CF3, CCl3, CFCl2, CF2Cl, ethyl, CH2CF3, CF2CF3, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, including haloalkyl groups. In certain embodiments, the alkyl group is a fluorinated alkyl group. Non-limiting examples of moieties with which the alkyl group can be substituted are selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfuric acid, phosphonic acid, phosphate, or phosphonate, which are unprotected or protected as desired as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Edition, 1991, which is hereby incorporated by reference.

[0180] As used herein, the term "lower alkyl" refers to a saturated straight or branched chain hydrocarbon having 1 to 6 carbon atoms, i.e., a C1 to C6 alkyl group, unless otherwise indicated. In certain embodiments, the lower alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.

[0181] Unless otherwise indicated, the term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group can be a saturated, and / or bridged, and / or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl group comprises 3 to 10 carbon atoms, i.e., C3 to C 10 In some embodiments, the cycloalkyl group has from 3 to 15 (C 3-15 ), from 3 to 10 (C 3-10 ), or from 3 to 7 (C 3-7 ) carbon atoms. In certain embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, or adamantyl.

[0182] Unless otherwise indicated, the term "cycloalkenyl" as used herein refers to an unsaturated cyclic hydrocarbon. In certain embodiments, cycloalkenyl refers to a monocyclic ring or a polycyclic ring system comprising at least one double bond. In certain embodiments, a cycloalkenyl group can be a bridged, non-bridged, and / or fused bicyclic group. In certain embodiments, a cycloalkyl group comprises 3 to 10 carbon atoms, i.e., C3 to C 10 In some embodiments, the cycloalkenyl group has from 3 to 7 (C 3-10 ) or from 4 to 7 (C 3-7 ) carbon atoms.

[0183] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group, particularly having from 1 to 11 carbon atoms, which can be straight or branched. In certain embodiments, the alkylene group contains 1 to 6 carbon atoms. The term includes both substituted and unsubstituted moieties. The term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-).

[0184] "Alkenyl" refers to a monovalent olefinically unsaturated hydrocarbon radical, in certain embodiments, having up to about 11 carbon atoms, from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, which may be linear or branched and have at least one or from 1 to 2 sites of olefinic unsaturation. The term includes both substituted and unsubstituted moieties. Exemplary alkenyl groups include ethenyl (i.e., vinyl, or -CH=CH2), n-propenyl (-CH2CH=CH2), and isopropenyl (-C(CH3)=CH2), among others.

[0185] "Alkenylene" refers to a divalent olefinically unsaturated hydrocarbon radical, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms, which may be linear or branched and has at least one or from 1 to 2 sites of olefinic unsaturation. The term is exemplified by radicals such as ethenylene (-CH=CH-), and the propenylene isomers (e.g., -CH=CHCH2- and -C(CH3)=CH- and -CH=C(CH3)-).

[0186] "Alkynyl" refers to an acetylenically unsaturated hydrocarbon group, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms, which may be linear or branched and have at least one or from 1 to 2 sites of alkynyl unsaturation. Non-limiting examples of alkynyl groups include acetylenic, ethynyl (-C≡CH), and propargyl (-CH2C≡CH), and the like.

[0187] As used herein, term " aryl ", unless otherwise indicated, refers to phenyl, biphenyl or naphthyl.The term includes both substituted and unsubstituted moieties.Aryl groups can be substituted with any part of the description, including but not limited to, one or more parts selected from the group consisting of: halogen (fluorine, chlorine, bromine or iodine), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfuric acid, phosphonic acid, phosphate or phosphonate, which are unprotected or protected as needed, as known to those skilled in the art, for example, such as Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, second edition, taught in 1991.

[0188] "Alkoxy" refers to a group -OR', where R' is an alkyl or cycloalkyl group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0189] "Alkoxycarbonyl" refers to the radical -C(O)-alkoxy where alkoxy is as defined herein.

[0190] "Amino" refers to the free radical -NH2.

[0191] "Carboxyl" or "carboxy" refers to the free radical -C(O)OH.

[0192] The term "alkylamino" or "arylamino" refers to an amino group having one or two alkyl or aryl substituents, respectively. In certain embodiments, the alkyl substituent is a lower alkyl. In another embodiment, the alkyl or lower alkyl is unsubstituted.

[0193] "Halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0194] "Monoalkylamino" refers to the group alkyl-NR'-, where R' is selected from hydrogen and alkyl or cycloalkyl.

[0195] "Thioalkoxy" refers to the group -SR', where R' is alkyl or cycloalkyl.

[0196] The term "heterocyclyl" or "heterocycle" refers to a monovalent monocyclic non-aromatic ring system and / or polycyclic ring system containing at least one non-aromatic ring, wherein one or more non-aromatic ring atoms are heteroatoms independently selected from O, S or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7 or from 5 to 6 ring atoms. The heterocyclyl group is bonded to the rest of the molecule through the non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused or bridged ring system, and wherein the nitrogen or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl group may be attached to the main structure at any heteroatom or carbon atom, which results in the production of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, azepine, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyronyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothiophenyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolane, 1,4- Dithianyl, furanonyl, imidazolinyl, imidazolyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothiophenyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinone, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thimorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocycle may also be optionally substituted as described herein.

[0197] The term "heteroaryl" refers to a monovalent monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N in the ring. The heteroaryl group is bonded to the rest of the molecule through an aromatic ring. Each ring of the heteroaryl group can contain 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazopyrimidinyl, and thienopyridinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl groups may also be optionally substituted as described herein.

[0198] In certain embodiments, a heteroaryl group refers to a carbon skeleton optionally consisting of C 1-3 -alkyl group substituted monocyclic 5-membered or 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains 1, 2, or 3 nitrogen atoms, and the 5-membered heteroaryl group contains optionally C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, oxygen atom or sulfur atom substituted imino group, or optionally C 1-3 -alkyl or phenyl-C 1-3 -alkyl group or an imino group substituted with an oxygen atom or a sulfur atom, and additionally optionally with C 1-3 -alkyl or phenyl-C 1-3-alkyl groups and two nitrogen-substituted nitrogen atoms or imino groups, and wherein the phenyl ring may be fused to the above-mentioned monocyclic heterocyclic groups via two adjacent carbon atoms, wherein the bond occurs via the nitrogen atom or via a carbon atom of the heterocyclic moiety or the fused phenyl ring.

[0199] The term "alkylaryl" refers to an aryl group having an alkyl substituent. The term "aralkyl" or "arylalkyl" includes alkyl groups having an aryl substituent.

[0200] The term "alkylheterocyclyl" refers to a heterocyclyl group having an alkyl substituent. The term alkylheterocyclyl includes alkyl groups having a heterocyclyl substituent.

[0201] The term "alkylheteroaryl" refers to a heteroaryl group having an alkyl substituent. The term alkylheteroaryl includes alkyl groups having a heteroaryl substituent.

[0202] Unless otherwise defined, the term "protecting group" as used herein refers to a group added to an oxygen, nitrogen or phosphorus atom to prevent further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

[0203] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains its biological properties and that is non-toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from various organic and inorganic counterions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) Benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, benzoic acid or (2) salts formed when an acidic proton present in the parent compound is (a) replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, or by ammonia, or (b) coordinated by an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucaminepiperazine, tris(hydroxymethyl)-aminomethane, and tetramethylammonium hydroxide.

[0204] Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium and tetraalkylammonium and the like, and, when the compound contains essential functionality, salts of non-toxic organic or inorganic acids such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, salt, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, pivalate, tert-butylacetate, dodecyl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylaminosulfonate, quinate and muconate, among others.

[0205] The term "purine" or "pyrimidine" base refers to, but is not limited to, adenine, N 6 -alkylpurine, N 6 -acylpurine (wherein acyl is C(O)(alkyl, aryl, alkylaryl or arylalkyl), N 6 -Benzylpurine, N 6 -Halogenated purine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acylpurine, N 6 -Hydroxyalkylpurine, N 6 -alkylaminopurine, N 6 -thioalkylpurine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidines including 6-azacytosine, 2- and / or 4-mercaptopyrimidines, uracil, 5-halouracils including 5-fluorouracil, C 5 -alkylpyrimidine, C 5 -Benzylpyrimidine, C 5 -halogenated pyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acylpyrimidine, C 5-Hydroxyalkylpurine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -iodine, C 6 -iodine-pyrimidine, C 5 -Br-vinylpyrimidine, C 6 -Br-vinylpyrimidine, C 5 -nitropyrimidine, C 5 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracil, triazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6-diaminopurine and 6-chloropurine. As needed or desired, the functional oxygen and nitrogen groups on the base can be protected. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methylsulfonyl and p-toluenesulfonyl.

[0206] The term "acyl" or "O-linked ester" refers to a group of the formula C(O)R', where R' is an alkyl or cycloalkyl group (including lower alkyl), a carboxylate residue of an amino acid, an aryl group including phenyl, an alkaryl group, an arylalkyl group including benzyl, an alkoxyalkyl group including methoxymethyl, an aryloxyalkyl group such as phenoxymethyl, or a substituted alkyl group (including lower alkyl), an aryl group including phenyl optionally substituted with chlorine, bromine, fluorine, iodine, C1 to C4 alkyl or C1 to C4 alkoxy, a sulfonate such as alkyl or arylalkylsulfonyl, including methanesulfonyl, a mono-, di- or triphosphate, a trityl or monomethoxy-trityl group, a substituted benzyl group, an alkaryl group, an arylalkyl group including benzyl, an alkoxyalkyl group including methoxymethyl, an aryloxyalkyl group such as phenoxymethyl. The aryl group in the ester most preferably comprises a phenyl group. In particular, acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-phenylacetyl, 4-chloro-phenylacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, pivaloyl, chloro Difluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloroacetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodecafluoro-heptanoyl, 7-chlorododecafluoro-heptanoyl, 7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoro-heptanoyl, 7H-dodecafluoro-heptanoyl, nona- Fluoro-3,6-dioxaheptanoyl, nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxybenzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, pentadecanoyl, stearoyl, 3-cyclopentyl-propionyl , 1-phenyl-carboxyl, O-acetylmandelyl, pivaloylacetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexylcarboxyl, 4-methylbenzoyl, chloromethylisoxazolylcarbonyl, perfluorocyclohexylcarboxyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl.

[0207] The term "amino acid" refers to naturally occurring and synthetic α, β, γ or δ amino acids, and includes, but is not limited to, the amino acids found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine. In certain embodiments, the amino acid is in the L-configuration. Alternatively, the amino acid can be a derivative of alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, aspartyl, guamyl, lysyl, arginyl, histidyl, β-alanyl, β-valine acyl, β-leucyl, β-isoleucyl, β-prolyl, β-phenylalanyl, β-tryptophanyl, β-methionyl, β-glycyl, β-seryl, β-threonyl, β-cysteinyl, β-tyrosyl, β-asparaginyl, β-glutaminyl, β-aspartyl, β-gulinyl, β-lysyl, β-arginyl or β-histidyl.

[0208] The term "substantially free" or "substantially absent" with respect to a composition refers to a composition that includes at least 85% or 90% (in certain embodiments, 95%, 98%, 99%, or 100%) by weight of a specified enantiomer of the compound. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of enantiomers.

[0209] Similarly, the term "isolated" with respect to a composition refers to a composition that includes at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the compound, the remainder comprising other chemical species or enantiomers.

[0210] "Solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. In the case where the solvent is water, the solvate is a hydrate.

[0211] "Isotopic composition" refers to the amount of each isotope present of a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, atoms of compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is explicitly designated as "H" or "hydrogen," that position is understood to have hydrogen at its natural isotopic composition.

[0212] "Isotopic enrichment" refers to the percentage of a given atom in a molecule at which a certain amount of a particular isotope is incorporated in place of the natural isotopic abundance of that atom. For example, a 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0213] "Isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of the atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of the atom.

[0214] As used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl," "amino," "carboxy," "alkylamino," "arylamino," "thioalkoxy," "heterocyclyl," "heteroaryl," "alkylheterocyclyl," "alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine," "pyrimidine," "carboxy," and "amino acid" groups optionally contain deuterium at one or more positions where hydrogen atoms are present, and the deuterium composition of one or more atoms is different from the natural isotopic composition.

[0215] Also as used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl," "carboxy," "alkylamino," "arylamino," "thioalkoxy," "heterocyclyl," "heteroaryl," "alkylheterocyclyl," "alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine," "pyrimidine," "carboxy," and "amino acid" groups optionally contain carbon-13 in an amount that differs from the natural isotopic composition.

[0216] As used herein, EC 50It refers to the dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximal expression of a particular response induced, stimulated or potentiated by the particular test compound.

[0217] As used herein, IC 50 It refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal response in an assay measuring such response.

[0218] As used herein, the term "host" refers to any unicellular or multicellular organism in which a virus can replicate, including cell lines and animals, and in certain embodiments, including humans. Alternatively, the host can carry a portion of a Flaviviridae viral genome, the replication or function of which can be altered by the compounds of the present invention. The term host specifically includes infected cells, cells transfected with all or part of the Flaviviridae genome, and animals, particularly primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. However, the present invention clearly contemplates veterinary applications (such as chimpanzees) in certain indications.

[0219] As used herein, the terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "subjects" refer to animals, such as mammals including non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys such as cynomolgus monkeys, chimpanzees, and humans), and for example, humans. In certain embodiments, the subject is refractory or unresponsive to current treatment for hepatitis C infection. In another embodiment, the subject is a farm animal (e.g., horse, cattle, pig, etc.) or a pet (e.g., dog or cat). In certain embodiments, the subject is a human.

[0220] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent that can be used to treat or prevent a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes a compound provided herein. In certain embodiments, a therapeutic agent is an agent known to be useful for treating or preventing a disorder or one or more symptoms thereof, or an agent that has been or is currently being used to treat or prevent a disorder or one or more symptoms thereof.

[0221] A "therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject for treatment of a disease, is sufficient to effect such treatment of the disease. A "therapeutically effective amount" may vary depending, inter alia, on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0222] In certain embodiments, "treating" or "treatment" of any disease or condition refers to alleviating the disease or condition present in a subject. In another embodiment, "treating" or "treatment" includes alleviating at least one physical parameter, which may be difficult to discern by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the disease or condition either physically (e.g., stabilization of identifiable symptoms) or physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" includes delaying the onset of the disease or condition.

[0223] As used herein, the terms "prophylactic agent" and "prophylactic agents" as used herein refer to any agent that can be used to prevent a disorder or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes a compound provided herein. In certain other embodiments, the term "prophylactic agent" does not refer to a compound provided herein. For example, a prophylactic agent is an agent known to be useful for preventing or hindering the onset, development, progression, and / or severity of a disorder, or an agent that has been or is currently being used to prevent or hinder the onset, development, progression, and / or severity of a disorder.

[0224] As used herein, the phrase "prophylactically effective amount" refers to an amount of a therapy (e.g., a prophylactic agent) sufficient to result in the prevention or reduction of the development, recurrence, or onset of one or more symptoms associated with a disorder (or an amount sufficient to enhance or improve the prophylactic effect of another therapy (e.g., another prophylactic agent)).

[0225] As used herein, the phrase "reactive linker group" refers to a functional group for conjugation, i.e., activated esters, haloacetamides, enzyme conjugation, click chemistry. The conjugation moiety can be known in the art. For example, the conjugation moiety in Signal Transduction and Targeted Therapy (2022) 7:93; https: / / doi.org / 10.1038 / s41392-022-00947-7 is incorporated herein by reference in its entirety for all purposes. Chemical Society Reviews (2019), 48(16), 4361-4374; and Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 17(32), 3393-3424; also describes linkers and antibody drug conjugates, which are incorporated herein by reference in their entirety for all purposes. As used herein, a reactive linker or reactive linker group may comprise an alkyl or heteroalkyl spacer segment that is not reactive, wherein the spacer segment is comprised of a reactive group (e.g., R 40 ) capping. Examples of reactive groups include any group capable of forming a bond with the antibody. Specifically, examples of reactive groups include maleimide (configured to form a bond with the sulfur atom of the cysteine ​​side chain), N-hydroxysuccinimide (configured to form a bond with the nitrogen atom of the lysine side chain), or a primary amine (configured to form a bond with the amide of the glutamine side chain, for example, via transglutaminase). The reactive linker may further comprise a peptide group (e.g., a cleavable peptide, e.g., Val-Cit), a self-immolative group (e.g., p-aminobenzyloxycarbonyl ("PABC") group), a polymeric group (e.g., polyethylene glycol (PEG)), an alkyl group (e.g., C 1-12 The linker may further comprise one or more cyclic groups. For example, the cyclic group may be a fused heteroaryl group formed by the reaction of a bicyclooctyne and a triazine (e.g., in a "click" reaction), or a cyclic group formed by the reaction between a sulfur atom and a maleimido group.

[0226] Antibody

[0227] In some embodiments, the term "antibody" is used in the broadest sense and includes polyclonal antibodies and monoclonal antibodies, including whole antibodies and functional (antigen-binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, single-chain antibody fragments, including single-chain variable fragments (sFv or scFv), and single domain antibody (e.g., sdAb, sdFv, nanobody) fragments. The term includes genetically engineered and / or otherwise modified immunoglobulin forms such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific antibodies such as bispecific antibodies, diabodies, triabodies, and tetrabodies, tandem bi-scFv, tandem tri-scFv. Unless otherwise stated, the term "antibody" should be understood to include functional antibody fragments thereof. The term also encompasses intact or full-length antibodies, including antibodies of any class or subclass, including IgG and its subclasses, IgM, IgE, IgA, and IgD. The antibody may comprise a human IgG1 constant region. The antibody may comprise a human IgG4 constant region.

[0228] The terms "complementarity determining region" and "CDR", which are synonymous with "hypervariable region" or "HVR", are known in the art to refer to non-contiguous sequences of amino acids within the variable region of an antibody that confer antigen specificity and / or binding affinity. Typically, there are 3 CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region, and 3 CDRs (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region. "Framework region" and "FR" are known in the art to refer to the non-CDR portions of the variable region of the heavy and light chains. Typically, there are 4 FRs (FR-H1, FR-H2, FR-H3, and FR-H4) in each full-length heavy chain variable region, and 4 FRs (FR-L1, FR-L2, FR-L3, and FR-L4) in each full-length light chain variable region.The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732-745. ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains," Dev Comp Immunol, 2003 Jan;27(1):55-77 ("IMGT" numbering scheme); Honegger A and Plückthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J Mol Biol, 2001 Jun 8;309(3):657-70, ("Aho" numbering scheme); and Whitelegg NR and Rees AR, "WAM: an improved algorithm for modelling antibodies on the WEB," Protein Eng. 2000 Dec;13(12):819-24 ("AbM" numbering scheme). The CDRs of the antibodies described herein can be defined by the Kabat, IMGT, Chothia, AbM, Aho, contact numbering schemes, or any combination thereof.

[0229] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding an antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (see, e.g., Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. In addition, VH or VL domains can be used to separate antibodies that bind to a specific antigen from antibodies that bind to the antigen to screen libraries of complementary VL or VH domains, respectively (see, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991)).

[0230] The term "heavy chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 50-70 kDa, wherein the amino-terminal portion includes a variable region of approximately 120 to 130 or more amino acids, and the carboxyl-terminal portion includes a constant region. Based on the amino acid sequence of the heavy chain constant region, the constant region can be one of five different types (e.g., isotypes) called alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ). The different heavy chains vary in size: α, δ, and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. When combined with a light chain, these different types of heavy chains give rise to the five well-known classes (e.g., isotypes) of antibodies, IgA, IgD, IgE, IgG, and IgM, including the four subclasses of IgG, IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0231] The term "light chain," when used in reference to an antibody, refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and the carboxyl-terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two different types, called kappa (κ) or lambda (λ), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. The light chain can be a human light chain.

[0232] Among the antibodies provided are antibody fragments. "Antibody fragment," "antigen-binding fragment," "antigen-binding domain," "antigen-binding region," "antigen binding fragment," "antigen binding domain," "antigen binding region," and similar terms refer to molecules other than intact antibodies that comprise a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); and multispecific antibodies formed from antibody fragments. In certain embodiments, the antibody is a single-chain antibody fragment, such as an scFv, comprising a variable heavy chain region and / or a variable light chain region. Typically, an antibody fragment or antigen-binding fragment will comprise one or more CDRs from a parent antibody sufficient to confer binding specificity.

[0233] In some embodiments, humanized antibody is an antibody that is derived from non-human CDR and all or all FR amino acid residues are derived from people FR. Humanized antibody optionally can include at least a portion of the antibody constant region derived from people's antibody. " humanized form " of non-human antibody refers to a variant of humanized non-human antibody, usually in order to reduce the immunogenicity to people, while retaining the specificity and avidity of parent non-human antibody. In some embodiments, some FR residues in humanized antibody are replaced with corresponding residues from non-human antibody (for example, the antibody from which CDR residues are derived), for example, in order to recover or improve antibody specificity or avidity. In some embodiments, humanized antibody refers to a non-human (for example, mouse) or incomplete humanized antibody form with specific immunoglobulin chain, chimeric immunoglobulin or its fragment, which contains minimum non-human (for example, mouse) sequence.

[0234] Among the antibodies provided are human antibodies. A "human antibody" is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell, or a non-human source utilizing a human antibody library or other human antibody encoding sequences (including human antibody libraries). The term does not include humanized forms of non-human antibodies that contain non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human.

[0235] Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce complete human antibodies or complete antibodies with human variable regions in response to antigenic stimulation. Such animals typically contain all or part of a human immunoglobulin locus, which replaces an endogenous immunoglobulin locus, or it exists outside the chromosome or is randomly integrated into the chromosome of the animal. In such transgenic animals, the endogenous immunoglobulin locus is typically inactivated. Human antibodies can also be derived from or selected from a human antibody library, including phage display and cell-free libraries containing antibody coding sequences derived from human libraries. In certain embodiments, human antibodies can be removed from sequence liability or increase their affinity by continuous rounds of selection using methods such as phage display.

[0236] Fc constant region

[0237] Typically, the fragment crystallizable (Fc) region or domain of an antibody mediates downstream effector functions via its interaction with Fc receptors on immune cells (e.g., innate immune cells) or with complement protein C1q (recognition molecules of the complement system). In addition, the interaction with Fc receptors can lead to the killing of targeted cells through a variety of immune effector mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), and antibody-mediated complement activation can lead to complement-dependent cytotoxicity (CDC). In addition, both Fc-receptor interactions and complement activation can play a wide range of immunomodulatory functions.

[0238] Therefore, in some cases, the mutation in the Fc region of the function of reducing, suppressing, ablating (ablate) and / or eliminating (abrogate) Fc mediation is conducive to reducing the immune activation caused by the combination of antibody and target. In some embodiments, one or more amino acid modifications can be introduced into the Fc region of antibody, thereby generating Fc region variants. The Fc region can include the C-terminal region of an immunoglobulin heavy chain, which includes a hinge region, a CH2 domain, a CH3 domain, or any combination thereof. As used herein, the Fc region includes a native sequence Fc region and a variant Fc region. The Fc region variant can include a human Fc region sequence (for example, human IgG1, IgG2, IgG3, or IgG4 Fc region), which is included in an amino acid modification (for example, substitution, addition, or deletion) at one or more amino acid positions.

[0239] Pharmaceutical composition

[0240] The pharmaceutical compositions disclosed herein can be administered to a subject by any suitable route of administration, including but not limited to parenteral (intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or local), topical, oral, or nasal administration.

[0241] "Pharmaceutically acceptable" may mean approved or approvable for use in animals, including humans, by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.

[0242] "Pharmaceutically acceptable salt" may refer to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.

[0243] A "pharmaceutically acceptable excipient, carrier, or adjuvant" may refer to an excipient, carrier, or adjuvant that can be administered to a subject with at least one antibody of the present disclosure and that does not destroy its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0244] A "pharmaceutically acceptable vehicle" may refer to a diluent, adjuvant, excipient, or carrier with which at least one antibody of the present disclosure is administered.

[0245] Compounds, linker-drug conjugates, and antibody-drug conjugates

[0246] Provided herein are ecteinascidin derivative compounds useful for the treatment, diagnosis, or detection of pathological conditions. In certain embodiments, provided herein are compounds or pharmaceutically acceptable salts, solvates, stereoisomeric forms, tautomeric forms, or polymorphic forms thereof. Ecteinascidin derivative compounds can be used as payloads in antibody drug conjugates (ADCs), payload-linker compounds, and ADC compounds.

[0247] In certain embodiments, the present disclosure provides a compound comprising a linker covalently bonded to rubectedin via a secondary alcohol or a secondary amine. In certain embodiments, the present disclosure provides a compound comprising a linker covalently bonded to trabectedin via a secondary alcohol or a secondary amine. In certain embodiments, provided herein is a compound comprising a linker covalently bonded to ecubectedin via a secondary alcohol or a secondary amine.

[0248] In certain embodiments, provided herein are compounds according to Formula I:

[0249]

[0250] R 1 and R 2At least one aromatic ring or bicyclic heterocycle may be formed, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol and -SO3H. In one embodiment, R 1 and R 2 Together with the intermediate atoms to which they are attached they may form a monocyclic or bicyclic ring.

[0251] R 20 (a) selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 -heterocyclic, C(O)R5, C(O)OR5, C(O)NHR5, SO2R5 and SO2NHR5, wherein C 1-10 -alkyl is substituted or unsubstituted, wherein C 6-10 - aryl is substituted or unsubstituted; or (b) L 1 , where L 1 is a reactive linker group.

[0252] R 20 Optionally substituted with 1-3 substituents independently selected in each case from the group consisting of OH, F, Cl, Br, C 1-5 -alkyl, C 3-6 -cycloalkyl and C 3-6 -heterocycle.

[0253] R 30 (c) selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, phosphate, phosphorothioate, phosphoramide, C(O)R6, C(O)OR6, and C(O)NHR6, sulfonyl, sulfonamide, wherein C 1-10 -alkyl is substituted or unsubstituted, wherein C 6-10 - aryl is substituted or unsubstituted, or (d) L 2 , where L 2 is a reactive linker group.

[0254] In certain embodiments, phosphates and phosphorothioates are optionally substituted with 1 to 2 substituents independently selected in each instance from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, polyethylene glycol (PEG), C 6-10 -aryl and C 5-10 -heteroaryl, wherein C 1-6-alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H. The substituents on the phosphates and phosphorothioates are optionally terminated with protecting groups.

[0255] In certain embodiments, R 20 or R 30 At least one of them is not H.

[0256] In certain embodiments, R 5 and R 6 Each is independently selected in each case from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 6-10 -heteroaryl, wherein C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H. In certain embodiments, subscript y is an integer selected from 1 to 32. In certain embodiments, when R 5 and / or R 6 Includes [PEG] y When PEG is used, the terminal PEG group can be capped with any suitable moiety, including but not limited to -OH, -NH2 and / or -OMe.

[0257] L in formula (I) 1 Can be at least one of the following:

[0258] (a)-H, if L 2 Not H;

[0259] (b) -CH3;

[0260] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0261] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0262] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10-heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0263] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0264] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 The -heteroaryl group optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S.

[0265] R 10 It can be R 10a -R 10b , where R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1-4 at each occurrence.

[0266] R 10b You can choose from the following groups:

[0267] (i)-CO-R 11 ;

[0268] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 10;

[0269] (iii)-NH-R 11 ;

[0270] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0271] (v)-CONH-R 11 ;

[0272] (vi)-CON(C 1-4 -alkyl)-R 11 ;

[0273] (vii)-CONHNH-R 11 ;

[0274] (viii)-CONHN(C 1-4 -alkyl)-R 11 ;

[0275] (ix)-CON(C 1-4-alkyl)NH-R 11 ;

[0276] (x)-CON(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0277] (xi)-CH(NH2)CO-R 11 ;

[0278] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0279] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0280] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0281] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0282] R 11 Can be selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d , and their combinations.

[0283] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-.

[0284] R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6.

[0285] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10.

[0286] R 11d Selected from the group consisting of -O- and -NH.

[0287] L in formula (I)2 Can be at least one of the following:

[0288] (a)-H, if L 1 Not H;

[0289] (b)-PO3H-R 11 or -PO3H2;

[0290] (c)-PO2SH-R 11 or -PO2SH2;

[0291] (d) -CH3;

[0292] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0293] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0294] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0295] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0296] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0297] where R 10 It is R 10a -R 10b ,in

[0298] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0299] R 10b Selected from the group consisting of:

[0300] (i)-CO-R11 ;

[0301] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 10;

[0302] (iii)-NH-R 11 ;

[0303] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0304] (v)-CONH-R 11 ;

[0305] (vi)-CON(C 1-4 -alkyl)-R 11 ;

[0306] (vii)-CONHNH-R 11 ;

[0307] (viii)-CONHN(C 1-4 -alkyl)-R 11 ;

[0308] (ix)-CON(C 1-4 -alkyl)NH-R 11 ;

[0309] (x)-CON(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0310] (xi)-CH(NH2)CO-R 11 ;

[0311] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0312] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0313] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0314] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 .

[0315] In certain embodiments, R 11 Can be selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; wherein R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

[0316] In certain embodiments, R 11 Selected from R 11a -R 11b -R 11c -R 11d ; R 11b -R 11c -R 11d ; R 11c -R 11d ; or R 11a -R 11c -R 11d .

[0317] In certain embodiments, L 1 and L 2 is independently at least one of the following divalent structures:

[0318] (a)-C(O)-;

[0319] (b) -C(O)-NH-;

[0320] (c)-C(O)O-;

[0321] (d)-[(C(O)-NH] n -;

[0322] (e)-C(O)-;

[0323] (f)-(A1-A2) q -;

[0324] (g) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)-, or -O-(C6H4)-CH2-O-;

[0325] (h)-(C 1-6 -alkyl)-;

[0326] (i)-(C2H4-O) m -;or

[0327] (j)-(C 1-6 -alkyl) p -.

[0328] In some embodiments of Formula (I), L 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 -(C2H4-O) m -; where L 1 R 40 End-capped, where R 40 Is a reactive group. In some embodiments, -(A1) q - is Val-Cit or Cit-Val. In some embodiments, L 1 is -C(O)-(C 1-6 -alkyl)-R 40 .

[0329] In some embodiments, L 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-R 40 .

[0330] In some embodiments, L 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R40 In some embodiments, L 1 Yes-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is di(pyrrolidin-1-yl)methyl. In some embodiments, L 1 Is -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(CH2)5-R 40 In some embodiments, L 1 is -C(O)-(CH2)-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 1 Is -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 .

[0331] In some embodiments of Formula (I), L 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 Alkyl)-NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 .

[0332] In some embodiments of the antibody drug conjugate derived from a compound of Formula (I), B 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, -(A1) q - is selected from the group consisting of: Val-Cit or Cit-Val. In some embodiments, B 1 Contains -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 1 Contains-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(CH2)5-. In some embodiments, B 1Contains -C(O)-(CH2)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2

[0333] -(CH2)2-. In some embodiments, B 1 Contains -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0334] In some embodiments of the antibody drug conjugate derived from a compound of Formula (I), B 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-. In some embodiments, B2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0335] In certain embodiments of the compound of Formula (I), L 1 or L 2 R 40 End-capped, where R 40 is a reactive group. In certain embodiments, R 11 R 40 End-capped, where R 40 In some embodiments, the reactive group is -NHBoc (i.e., ) or -NH2. In some embodiments, the reactive group is maleimide.

[0336] In some embodiments of the compound of Formula (I), when R 20 When it is H, then R 30 It's L 2 ; and when R 30 When it is H, then R 20 It's L 1 In some embodiments of the compound of formula (I), when L 1 When it is H, then L 2 At least one occurrence of is not H; and when L 2 When all occurrences of are H, then L 1 is not H. In some embodiments, R 20 is di(pyrrolidin-1-yl)methyl or L 1 , and R 30 is H. In some embodiments, R 30 Is -PO3H2, -PO2SH2, or L 2 ; and R 20 It’s H.

[0337] In some embodiments of the antibody drug conjugate derived from a compound of Formula (I), B 1 Contains as in L 1 R found in 40 The reaction product of α and α, such that a covalent bond is formed therebetween. In some embodiments of the antibody drug conjugate derived from a compound of formula (I), B 2 Contains as in L2 R found in 40 The reaction product with Ab forms a covalent bond between them. 40 When it is maleimide, Ab-B 1 - or Ab-B 2 - Can be used independently End-capping.

[0338] In certain embodiments of the compound of Formula (I), A1 and A2 are independently in each instance an amino acid (eg, an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid.

[0339] In certain embodiments, subscript n is an integer selected from 0 to 4; subscript m is an integer selected from 0 to 20; subscript p is an integer 0 or 1; and subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of subscript n is independently an integer selected from 0 to 4; each instance of subscript m is independently an integer selected from 1 to 20; each instance of subscript p is independently an integer 0 or 1; each instance of subscript q is independently an integer selected from 1 to 6; and each instance of subscript n is independently an integer selected from 0 to 10.

[0340] In certain embodiments, R 20 is optionally with at least one C 1-6 -heterocyclic substituted C1-alkyl. In certain embodiments, R 20 is a C1-alkyl optionally substituted with a dipyrrolidinyl substituent. In certain embodiments, R 20 is C1-alkyl optionally substituted with 1 to 2 pyrrolidonyl substituents.

[0341] In certain embodiments, R 20 yes in represents the bond through which the indicated substituent is bonded. In some embodiments, R 20 It is bis(pyrrolidin-1-yl)methyl.

[0342] In certain embodiments, R 30 is a phosphate or a thiophosphate. In certain embodiments, R 30 is a substituted phosphate or a substituted phosphorothioate. In certain embodiments, R 30 yes in Represents the bond through which the phosphorothioate is bonded.

[0343] In certain embodiments, the compound (eg, a compound of Formula (I)) is selected from

[0344]

[0345] Where W is O or S; Is a single bond or a double bond.

[0346] In certain embodiments, the compound (eg, a compound of Formula (I)) can be at least one of the compounds listed in Table A.

[0347] Table A

[0348]

[0349]

[0350]

[0351] The present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising:

[0352]

[0353] Among them L 1 or L 2 One of them is a reactive linker.

[0354] In certain embodiments, the reactive linker comprises a nucleophilic group that reacts with an electrophilic group on at least a portion of the targeting moiety.

[0355] In certain embodiments, L 1 Contains at least one of the following:

[0356] (a)-H, where L 1 or L 2 At least one of them is not H;

[0357] (b) -CH3;

[0358] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0359] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0360] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0361] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0362] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl,

[0363] C 5-10 The -heteroaryl group optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S.

[0364] R 10 It is R 10a -R 10b , where R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1-4 at each occurrence.

[0365] R 10b Selected from the group consisting of:

[0366] (i)-CO-R 11 ;

[0367] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 10;

[0368] (iii)-NH-R 11 ;

[0369] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0370] (v)-CONH-R 11 ;

[0371] (vi)-CON(C 1-4 -alkyl)-R 11 ;

[0372] (vii)-CONHNH-R 11 ;

[0373] (viii)-CONHN(C 1-4 -alkyl)-R 11 ;

[0374] (ix)-CON(C 1-4 -alkyl)NH-R 11 ;

[0375] (x)-CON(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0376] (xi)-CH(NH2)CO-R 11 ;

[0377] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0378] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0379] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0380] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0381] In certain embodiments, R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof.

[0382] In certain embodiments, R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

[0383] In some embodiments of the compound of Formula (II), L 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6-alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 1 R 40 End-capped, where R 40 Is a reactive group. In some embodiments, -(A1) q -at least one occurrence is selected from: Val-Cit or Cit-Val. In some embodiments, L 1 is -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 1 Yes-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is di(pyrrolidin-1-yl)methyl. In some embodiments, L 1 Is -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-R 40In some embodiments, L 1 Is -C(O)-(CH2)5-R 40 In some embodiments, L 1 is -C(O)-(CH2)-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 1 Is -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 .

[0384] In some embodiments of the compound of Formula (II), L 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 Alkyl)-NH-C(O)-O-CH2-(C6H4)-NH-(A1) q-C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 .

[0385] In some embodiments of the antibody drug conjugate derived from a compound of Formula (II), B 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, -(A1) q - is selected from Val-Cit or Cit-Val. In some embodiments, B 1 Contains -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 1 Contains-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(CH2)5-. In some embodiments, B 1 Contains -C(O)-(CH2)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2

[0386] -(CH2)2-. In some embodiments, B 1 Contains -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0387] In some embodiments of the antibody drug conjugate derived from a compound of Formula (II), B 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0388] In certain embodiments, L 1 or L 2 R 40 End-capped, where R 40 is a reactive group. In certain embodiments, R 11 R 40 End-capped, where R 40 In some embodiments, the reactive group is -NHBoc (i.e., ) or -NH2. In some embodiments, the reactive group is maleimide.

[0389] In some embodiments of the compound of Formula (II), when L 1 When it is H, then L 2 At least one occurrence of is not H; and when L 2 When all occurrences of are H, then L 1 Not H.

[0390] In some embodiments of the antibody drug conjugate derived from a compound of Formula (II), B 1 Contains as in L 1 R found in 40 The reaction product of with Ab such that a covalent bond is formed therebetween. 2 Contains as in L 2 R found in 40 The reaction product with Ab forms a covalent bond between them. 40 When it is maleimide, Ab-B 1 - or Ab-B 2 - Can be used independently End-capping.

[0391] In certain embodiments of the compound of formula (II) or an antibody drug conjugate derived therefrom, A1 and A2 are independently in each case an amino acid (e.g., an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[0392] In certain embodiments of the compound of Formula (II) or an antibody drug conjugate derived therefrom, subscript n is an integer selected from 0 to 4; subscript m is an integer selected from 0 to 20; subscript p is an integer 0 or 1; subscript q is an integer selected from 1 to 6; and subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of subscript n is independently selected from an integer selected from 0 to 4; each instance of subscript m is independently selected from an integer selected from 0 to 20; each instance of subscript p is independently selected from an integer 0 or 1; each instance of subscript q is independently selected from an integer selected from 1 to 6; and each instance of subscript n is independently selected from an integer selected from 0 to 10.

[0393] Provided herein are compounds of formula (III), or pharmaceutically acceptable salts, esters, stereoisomers or tautomers thereof, comprising

[0394]

[0395] where R1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, nitro, -P(O)(OH)2, thiol and -SO3H; wherein Is a single bond or a double bond.

[0396] In certain embodiments, L 1 Contains at least one of the following:

[0397] (a)-H, L 1 or L 2 At least one of them is not H;

[0398] (b) -CH3;

[0399] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0400] (d) optionally with at least one R 10 Substituted -C 2-8 -alkyl-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0401] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0402] (f) optionally with at least one R 10 Substituted -C 2-8 -alkyl-(C 0-6 alkyl)-phenyl;

[0403] (g) optionally with at least one R 10 Substituted -C 2-8 -alkyl-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 The -heteroaryl group optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S.

[0404] In certain embodiments, R 10 It is R 10a -R 10b , where R10a Does not exist or is -(CH2) e , wherein e is independently selected at each occurrence from 1 to 4; and R 10b Selected from the group consisting of:

[0405] (i)-CO-R 11 ;

[0406] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 10;

[0407] (iii)-NH-R 11 ;

[0408] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0409] (v)-CONH-R 11 ;

[0410] (vi)-CON(C 1-4 -alkyl)-R 11 ;

[0411] (vii)-CONHNH-R 11 ;

[0412] (viii)-CONHN(C 1-4 -alkyl)-R 11 ;

[0413] (ix)-CON(C 1-4 -alkyl)NH-R 11 ;

[0414] (x)-CON(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0415] (xi)-CH(NH2)CO-R 11 ;

[0416] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0417] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0418] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0419] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0420] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0421] where R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0422] R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0423] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0424] R 11d Selected from the group consisting of -O- and -NH.

[0425] In certain embodiments, L 2 Contains at least one of the following:

[0426] (a)-H, where L 1 or L 2 At least one of them is not H;

[0427] (b) -PO3H-;

[0428] (c)-PO2SH-;

[0429] (d) -CH3;

[0430] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0431] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0432] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 The -heterocyclyl group optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S.

[0433] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0434] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0435] where R 10 It is R 10a -R 10b ,in

[0436] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0437] R 10b Selected from the group consisting of:

[0438] (i)-CO-R 11 ;

[0439] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 10;

[0440] (iii)-NH-R 11 ;

[0441] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0442] (v)-CONH-R 11 ;

[0443] (vi)-CON(C 1-4 -alkyl)-R 11 ;

[0444] (vii)-CONHNH-R 11 ;

[0445] (viii)-CONHN(C 1-4 -alkyl)-R 11 ;

[0446] (ix)-CON(C 1-4 -alkyl)NH-R 11 ;

[0447] (x)-CON(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0448] (xi)-CH(NH2)CO-R 11 ;

[0449] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0450] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0451] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0452] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0453] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0454] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

[0455] In some embodiments of the compound of Formula (III), L 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 1 R 40 End-capped, where R 40 Is a reactive group. In some embodiments, -(A1) q -at least one occurrence is selected from: Val-Cit or Cit-Val. In some embodiments, L 1 is -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 1 Yes-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is di(pyrrolidin-1-yl)methyl. In some embodiments, L 1 Is -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1Is -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(CH2)5-R 40 In some embodiments, L 1 is -C(O)-(CH2)-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 1 Is -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 .

[0456] In some embodiments of the compound of Formula (III), L 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 Alkyl)-NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 .

[0457] In some embodiments of the antibody drug conjugate derived from a compound of formula (III), B 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, -(A1) q - is selected from the group consisting of: Val-Cit or Cit-Val. In some embodiments, B 1 Contains -C(O)-(C 1-6-alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 1 Contains-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(CH2)5-. In some embodiments, B 1 Contains -C(O)-(CH2)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 1 Contains -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0458] In some embodiments of the antibody drug conjugate derived from a compound of formula (III), B 2Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0459] In certain embodiments of the compound of formula (III), L 1 or L 2 R 40 End-capped, where R 40 is a reactive group. In certain embodiments, R 11 R 40End-capped, where R 40 In some embodiments, the reactive group is -NHBoc (i.e., ) or -NH2. In some embodiments, the reactive group is maleimide.

[0460] In some embodiments of the compound of formula (III), when L 1 When it is H, then L 2 At least one occurrence of is not H; and when L 2 When all occurrences of are H, then L 1 Not H.

[0461] In some embodiments of the antibody drug conjugate derived from a compound of formula (III), B 1 Contains as in L 1 R found in 40 The reaction product of with Ab such that a covalent bond is formed therebetween. 2 Contains as in L 2 R found in 40 The reaction product with Ab forms a covalent bond between them. 40 When it is maleimide, Ab-B 1 - or Ab-B 2 - Can be used independently End-capping.

[0462] In certain embodiments of the compound of formula (III) or an antibody drug conjugate derived therefrom, A1 and A2 are independently in each case an amino acid (e.g., an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[0463] In certain embodiments of the compound of formula (III), subscript n is an integer selected from 0 to 4; subscript m is an integer selected from 0 to 20; subscript p is an integer 0 or 1; subscript q is an integer selected from 1 to 6; and subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of subscript n is independently selected from an integer selected from 0 to 4; each instance of subscript m is independently selected from an integer selected from 0 to 20; each instance of subscript p is independently selected from an integer 0 or 1; each instance of subscript q is independently selected from an integer selected from 1 to 6; and each instance of subscript n is independently selected from an integer selected from 0 to 10.

[0464] In certain embodiments, the compound may be a compound of formula (IV) or a pharmaceutically acceptable salt, ester, or tautomer thereof, comprising:

[0465]

[0466] where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 Alkoxy, C 1-10 Alkyl, amino, hydroxy, nitro, -P(O)(OH)2, thiol and -SO3H; Is a single bond or a double bond.

[0467] In certain embodiments, L 1 It is R 40 - (C 1-6 alkyl)-[(C(O)-NH] n -(-C2H4-O) m -(C 1-6 alkyl) q -[(C(O)-] p ; or R 40 - (-C2H4-O) m -C(O)-(A1-A2) q -[-NH] n -(C6H4)-CH2-O-[(C(O)-NH] n -(-C2H-4-O) t -(C 1-6 alkyl)-[(C(O)-] p . L 2 It is R 40 -(C 1-6 alkyl)-[(C(O)-NH] n -(-C2H4-O) m -(C 1-6 alkyl)-[(C(O)-NH] p -(-C2H4-O) m -[OP(O)SH]; or R 40 - (-C2H-4-O) m -C(O)-(A1-A2) q -NH-(C6H4)-CH2-O-[(C(O)-NH] n -(-C2H4-O) t -(C 1-6alkyl)-[(C(O)-] p -[OP(O)SH]. In certain embodiments, L 1 It is R 40 -(C 1-6 alkyl)-C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -.

[0468] In certain embodiments, R 40 can be a reactive group; wherein A1 and A2 are independently at each occurrence an amino acid; wherein subscript n is independently at each occurrence selected from 0 to 4; wherein subscript m is independently at each occurrence selected from 0 to 20; wherein subscript p is independently at each occurrence 0 or 1; wherein subscript q is independently at each occurrence 0 or 1; and wherein subscript t is independently at each occurrence selected from 0 to 10. The linker can be cleavable or non-cleavable.

[0469] In certain embodiments, A1-A2 can be valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamate, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.

[0470] In some embodiments of the compound of Formula (IV), L 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 1 R 40 End-capped, where R 40 Is a reactive group. In some embodiments, -(A1) q -at least one occurrence is selected from: Val-Cit or Cit-Val. In some embodiments, L 1 is -C(O)-(C 1-6-alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 1 Yes-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is di(pyrrolidin-1-yl)methyl. In some embodiments, L 1 Is -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(CH2)5-R 40 In some embodiments, L 1 is -C(O)-(CH2)-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40In some embodiments, L 1 Is -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 .

[0471] In some embodiments of the compound of Formula (IV), L 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 Alkyl)-NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 In some embodiments, L 2 In some embodiments, L2 Is -PO2SH-(C2H4-O)3-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 .

[0472] In some embodiments of the antibody drug conjugate derived from a compound of Formula (IV), B 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 -(C2H4-O) m -. In some embodiments, -(A1) q - is selected from the group consisting of: Val-Cit or Cit-Val. In some embodiments, B 1 Contains -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6-alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(CH2)5-. In some embodiments, B 1 Contains -C(O)-(CH2)-.

[0473] In some embodiments, B 1 Contains -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2

[0474] -(CH2)2-. In some embodiments, B 1 Contains -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0475] In some embodiments of the antibody drug conjugate derived from a compound of Formula (IV), B 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 (C2H4-O) m -. In some embodiments, B 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m-NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0476] In certain embodiments of the compound of formula (IV), L 1 or L 2 R 40 End-capped, where R 40 is a reactive group. In certain embodiments, R 11 R 40 End-capped, where R 40是 Reactive group. In some embodiments, the reactive group is -NHBoc (i.e., ) or -NH2. In some embodiments, the reactive group is maleimide.

[0477] In some embodiments of the compound of Formula (IV), when L 1 When it is H, then L 2 At least one occurrence of is not H; and when L 2 When all occurrences of are H, then L 1 Not H.

[0478] In some embodiments of the antibody drug conjugate derived from a compound of Formula (IV), B 1 Contains as in L 1 R found in 40 The reaction product of with Ab such that a covalent bond is formed therebetween. 2 Contains as in L 2 R found in40 The reaction product with Ab forms a covalent bond between them. 40 When it is maleimide, Ab-B 1 - or Ab-B 2 - Can be used independently End-capping.

[0479] In certain embodiments of the compound of formula (IV) or an antibody drug conjugate derived therefrom, A1 and A2 are independently in each instance an amino acid (e.g., an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[0480] In certain embodiments of the compound of formula (IV), subscript n is an integer selected from 0 to 4; subscript m is an integer selected from 0 to 20; subscript p is an integer 0 or 1; subscript q is an integer selected from 1 to 6; and subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of subscript n is independently selected from an integer selected from 0 to 4; each instance of subscript m is independently selected from an integer selected from 0 to 20; each instance of subscript p is independently selected from an integer 0 or 1; each instance of subscript q is independently selected from an integer selected from 1 to 6; and each instance of subscript n is independently selected from an integer selected from 0 to 10.

[0481] In certain embodiments, the compound (e.g., a compound of Formula (IV), a compound of Formula (III)) is:

[0482]

[0483] In certain embodiments, the compound (e.g., a compound of Formula (IV), a compound of Formula (III)) is:

[0484]

[0485] In certain embodiments, linker L 1 or L 2 Independently contains:

[0486]

[0487] in Represents a compound of formula (IV) or L 1 or L 2wherein r is an integer selected from 1 to 12; and wherein s is an integer selected from 1 to 32.

[0488] In one example, the compound (e.g., a compound of formula (IV), a compound of formula (III)) can be

[0489]

[0490] wherein subscript v is an integer from 1 to 32, 1 to 14, or 1 to 8; and wherein subscript u is an integer between 0 and 11.

[0491] In one example, the compound (e.g., a compound of formula (III), a compound of formula (IV)) can be

[0492]

[0493] wherein the subscript e is an integer selected from 1 to 6, 1 to 4, or 1 to 3.

[0494] In certain embodiments, the compound of formula (III) or (IV) can be at least one of the compounds in Table B.

[0495] Table B

[0496]

[0497]

[0498]

[0499]

[0500] Also provided herein are compounds of Formula (Va) or (Vb), or pharmaceutically acceptable salts, esters, stereoisomers or tautomers thereof, comprising:

[0501]

[0502] wherein Ab is a targeting agent; wherein subscript k is an integer from 1 to 10;

[0503] where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 Alkoxy, C 1-10 alkyl, amino, hydroxy, nitro, -P(O)(OH)2, thiol, and -SO3H; and wherein B 1 or B 2One of the two is a linker. Ab can be an antibody, an antibody fragment, a protein or a peptide.

[0504] In certain embodiments, B 1 Contains at least one of the following:

[0505] (a)-H, if L 2 Not H;

[0506] (b) -CH3;

[0507] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0508] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0509] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0510] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0511] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0512] In certain embodiments, R 10 It is R 10a -R 10b , where R 10a Does not exist or is -(CH2) e , wherein e is independently selected from 1-4 at each occurrence.

[0513] In certain embodiments, R 10b Selected from the group consisting of:

[0514] (i)-CO-R 11 ;

[0515] (ii) -(C2H4-O) m -R11 , where subscript m is an integer from 1 to 10;

[0516] (iii)-NH-R 11 ;

[0517] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0518] (v)-CONH-R 11 ;

[0519] (vi)-CON(C 1-4 -alkyl)-R 11 ;

[0520] (vii)-CONHNH-R 11 ;

[0521] (viii)-CONHN(C 1-4 -alkyl)-R 11 ;

[0522] (ix)-CON(C 1-4 -alkyl)NH-R 11 ;

[0523] (x)-CON(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0524] (xi)-CH(NH2)CO-R 11 ;

[0525] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0526] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0527] (xiv)-CH(CO-R 11 )NH-R 11 ;and

[0528] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 .

[0529] In certain embodiments, R 11 Selected from the group consisting of: R 11a 、R 11b 、R11c 、R 11d and combinations thereof; wherein R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

[0530] In certain embodiments, B 2 Contains at least one of the following:

[0531] (a)-H, where L 1 or L 2 At least one of them is not H;

[0532] (b) -PO3H-;

[0533] (c)-PO2SH-;

[0534] (d) -CH3;

[0535] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0536] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0537] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0538] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0539] (j) optionally with at least one R 10 Substituted-(C0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 The -heteroaryl group optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S.

[0540] In certain embodiments, R 10 It is R 10a -R 10b ,in

[0541] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0542] R 10b Selected from the group consisting of:

[0543] (i)-CO-R 11 ;

[0544] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 10;

[0545] (iii)-NH-R 11 ;

[0546] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0547] (v)-CONH-R 11 ;

[0548] (vi)-CON(C 1-4 -alkyl)-R 11 ;

[0549] (vii)-CONHNH-R 11 ;

[0550] (viii)-CONHN(C 1-4 -alkyl)-R 11 ;

[0551] (ix)-CON(C 1-4 -alkyl)NH-R 11 ;

[0552] (x)-CON(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0553] (xi)-CH(NH2)CO-R 11 ;

[0554] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0555] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0556] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0557] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0558] In certain embodiments, R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; wherein R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x , wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

[0559] In certain embodiments, L 1 It is R 50 - (C 1-6 alkyl)-[(C(O)-NH] n -(-C2H4-O) m -(C 1-6 alkyl) q -[(C(O)-] p ; or R 40 -(-C2H-4-O) m -C(O)-(A1-A2) q -[-NH] n-(C6H4)-CH2-O-[(C(O)-NH] n -(-C2H4-O) t -(C 1-6 alkyl)-[(C(O)-] p In certain embodiments, L 2 It is R 50 -(C 1-6 alkyl)-[(C(O)-NH] n -(-C2H-4-O) m -(C 1-6 alkyl)-[(C(O)-NH] p -(-C2H4-O) m -[OP(O)SH]; or R 40 -(-C2H-4-O) m -C(O)-(A1-A2) q -NH-(C6H4)-CH2-O-[(C(O)-NH] n -(-C2H4-O) t -(C 1-6 alkyl)-[(C(O)-] p -[OP(O)SH]. R 50 It can be a conjugated unit.

[0560] In some embodiments of the compound of Formula (Va) or Formula (Vb), Ab is an antibody, antibody fragment, protein or peptide. In some embodiments, the antibody or antibody fragment comprises one or more of SEQ ID NOs. 1 to 20 as listed in Table 6. Non-limiting examples of antibodies include trastuzumab and brentuximab.

[0561] In some embodiments, the compound of formula (Va) or the compound of formula (Vb) is an antibody drug conjugate derived from a compound of formula (I). In some embodiments, the compound of formula (Va) or the compound of formula (Vb) is an antibody drug conjugate derived from a compound of formula (II). In some embodiments, the compound of formula (Va) or the compound of formula (Vb) is an antibody drug conjugate derived from a compound of formula (III). In some embodiments, the compound of formula (Va) or the compound of formula (Vb) is an antibody drug conjugate derived from a compound of formula (IV).

[0562] In certain embodiments, a compound (e.g., a compound of Formula (Va) or (Vb)) can be

[0563]

[0564] In certain embodiments, a compound (e.g., a compound of Formula (Va) or (Vb)) can be

[0565]

[0566] In certain embodiments, the compound (eg, a compound of Formula (Va) or (Vb)) can be at least one of the compounds listed in Table C.

[0567] Table C

[0568]

[0569]

[0570]

[0571]

[0572]

[0573] In certain embodiments, provided herein are compounds according to Formula (XI), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof:

[0574]

[0575] in:

[0576] R 1 and R 2 Together they form an aromatic ring or a bicyclic heteroaromatic ring; wherein the aromatic ring and the bicyclic heteroaromatic ring are optionally substituted with 1 to 6 substituents independently selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, -SH and -SO3H;

[0577] R 3 is hydrogen or CH2OR 6 ;

[0578] R 4 It is H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 -Heterocycle, C(O)R 8 、C(O)OR 8 、C(O)NHR 8 、SO2R 8 、SO2NHR 8 ; among them C 1-10 -alkyl or C 6-10-Aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -OH, -F, -Cl, -Br, -C 1-6 -alkyl, -C 3-6 -cycloalkyl and -C 3-6 -heterocyclyl; or L 1

[0579] R 5 and R 6 Each independently selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, phosphate, phosphorothioate, phosphoramide, C(O)R 9 、C(O)OR 9 , and C(O)NHR 9 、SO3H、SO2R 9 , among which C 1-10 -alkyl or C 6-10 -aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -OH, -F, -Cl, -Br, optionally substituted -C 1-6 -alkyl, optionally substituted-C 3-6 -cycloalkyl, and optionally substituted -C 3-6 -heterocyclyl; or L 2

[0580] where R 5 or R 6 The phosphates and phosphorothioates are optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl,

[0581] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and

[0582] wherein the substituents on the phosphate and phosphorothioate are optionally capped with protecting groups;

[0583] R 8 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C6-10 -aryl and C 6-10 -heteroaryl,

[0584] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H;

[0585] R 9 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[0586] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H;

[0587] where R 4 、R 5 , and R 6 One of them is the reactive group R 10 or a linker with an antibody Ab;

[0588] in is a single bond or a double bond; and

[0589] wherein y is an integer selected from 0 to 32.

[0590] In certain embodiments of Formula (XI), L 1 Contains at least one of the following:

[0591] (a)-H, if L 2 Not H;

[0592] (b) -CH3;

[0593] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0594] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0595] (e) optionally with at least one R 10 Substituted-(C0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0596] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; or

[0597] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0598] where R 10 It is R 10a -R 10b ,in

[0599] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0600] R 10b Selected from the group consisting of:

[0601] (i)-C(O)-R 11 ;

[0602] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0603] (iii)-NH-R 11 ;

[0604] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0605] (v)-C(O)-NH-R 11 ;

[0606] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0607] (vii)-C(O)-NH-NH-R 11 ;

[0608] (viii)-C(O)-NHN(C 1-4-alkyl)-R 11 ;

[0609] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[0610] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[0611] (xi)-CH(NH2)-CO-R 11 ;

[0612] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[0613] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[0614] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[0615] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[0616] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0617] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0618] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0619] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0620] R 11d Selected from the group consisting of -O- and -NH.

[0621] In certain embodiments of Formula (XI), L 2 Contains at least one of the following:

[0622] (a)-H, if L 1 Not H;

[0623] (b) -PO3H- or -PO3H2;

[0624] (c) -PO2SH- or -PO2SH2;

[0625] (d) -CH3;

[0626] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0627] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0628] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0629] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0630] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0631] where R 10 It is R 10a -R 10b ,in

[0632] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0633] R 10b Selected from the group consisting of:

[0634] (i)-C(O)-R 11 ;

[0635] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0636] (iii)-NH-R 11 ;

[0637] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0638] (v)-C(O)-NH-R 11 ;

[0639] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0640] (vii)-C(O)-NHNH-R 11 ;

[0641] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0642] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[0643] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0644] (xi)-CH(NH2)CO-R 11 ;

[0645] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0646] (xiii)-CH(N(C 1-4 - 11 )NH-R 11 ;

[0647] (xv)-CH(CO-alkyl)2)CO-R 11 ;

[0648] (xiv)-CH(CO-RR 11 )N(C 1-4 -alkyl)-R 11 ;

[0649] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0650] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0651] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0652] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0653] R 11d Selected from the group consisting of -O- and -NH.

[0654] In certain embodiments, R 11 Selected from:

[0655] R 11a -R 11b -R 11c -R 11d ;

[0656] R 11b -R 11c -R 11d ;

[0657] R 11c -R 11d ;or

[0658] R 11a -R 11c -R 11d .

[0659] In certain embodiments, R 11 With reactive group R 40 End-capping.

[0660] In certain embodiments, L 1 Contains at least one of the following bivalent structures:

[0661] (a)-C(O)-;

[0662] (b) -C(O)-NH-;

[0663] (c)-C(O)O-;

[0664] (d)-[(C(O)-NH] n -;

[0665] (e)-C(O)-;

[0666] (f)-(A1-A2) d -;

[0667] (g) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)-, or -O-(C6H4)-CH2-O-;

[0668] (h)-(C 1-6 -alkyl)-;

[0669] (i)-(C2H4-O) r- ;or

[0670] (j)-(C 1-6 -alkyl) p -;

[0671] Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group;

[0672] A1 and A2 are independently in each instance an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid;

[0673] Where subscript:

[0674] d is an integer selected from 0 to 1;

[0675] n is an integer selected from 0 to 4;

[0676] r is an integer selected from 0 to 32; and

[0677] p is an integer 0 or 1.

[0678] In certain embodiments of the compound of Formula (XI), L 1 Contains at least one of the following bivalent structures:

[0679] (a)-C(O)-;

[0680] (b) -C(O)-NH-;

[0681] (c)-C(O)O-;

[0682] (d)-[(C(O)-NH] n -;

[0683] (e)-C(O)-;

[0684] (f)-(A1) q -;

[0685] (g) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)-, or -O-(C6H4)-CH2-O-;

[0686] (h)-(C 1-6 -alkyl)-;

[0687] (i)-(C2H4-O) r- ;or

[0688] (j)-(C 1-6 -alkyl) p -;

[0689] Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group;

[0690] Each A1 is independently an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid;

[0691] Where subscript:

[0692] q is an integer selected from 1 to 6;

[0693] n is an integer selected from 0 to 4;

[0694] r is an integer selected from 0 to 32; and

[0695] p is an integer 0 or 1.

[0696] In certain embodiments, L 2 Contains at least one of the following bivalent structures:

[0697] (a) -PO3H- or -PO3H2;

[0698] (b) -PO2SH- or -PO2SH2;

[0699] (c)-C(O)-;

[0700] (d)-C(O)-NH-;

[0701] (e)-C(O)O-;

[0702] (f)-[(C(O)-NH] n -;

[0703] (g)-C(O)-;

[0704] (h)-(A1-A2) d -;

[0705] (i) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)-, or -O-(C6H4)-CH2-O-;

[0706] (j)-(C 1-6 -alkyl)-;

[0707] (k)-(C2H4-O)r - ;or

[0708] (l)-(C 1-6 -alkyl) p -;

[0709] Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group;

[0710] A1 and A2 are independently in each instance an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid;

[0711] Where subscript:

[0712] d is an integer selected from 0 to 1;

[0713] n is an integer selected from 0 to 4;

[0714] r is an integer selected from 0 to 32; and

[0715] p is an integer 0 or 1.

[0716] In certain embodiments, R 4 is optionally with at least one C 1-6 -heterocyclic substituted C1-alkyl. In certain embodiments, R4 is C1-alkyl optionally substituted with 1 to 2 pyrrolidinyl substituents. In certain embodiments, R 4 yes in represents the bond through which the indicated substituent is bonded. In certain embodiments, R 5 is a phosphate or a thiophosphate. In certain embodiments, R 5 yes in represents the bond through which the phosphorothioate is bonded. In certain embodiments, R 6 is a substituted phosphate or a substituted thiophosphate. In certain embodiments, the compound of formula (XI) is selected from

[0717]

[0718] wherein W is O or S. In certain embodiments, W is O. In certain embodiments, W is S.

[0719] In certain embodiments, the compound of formula (XI) is selected from

[0720]

[0721]

[0722]

[0723]

[0724] In certain embodiments, the compound of formula (XII), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprises:

[0725]

[0726] Among them L 1 , or L 2 One of the reactive linkers is a reactive linker.

[0727] In certain embodiments, the compound of formula (XII), wherein L 1 Contains at least one of the following:

[0728] (a)-H, if L 2 Not H;

[0729] (b) -CH3;

[0730] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0731] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0732] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0733] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0734] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0735] where R 10 It is R 10a -R 10b ,in

[0736] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0737] R 10b Selected from the group consisting of:

[0738] (i)-C(O)-R 11 ;

[0739] (ii) -(C2H4-O) m , where subscript m is an integer from 1 to 32;

[0740] (iii)-NH-R 11 ;

[0741] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0742] (v)-C(O)-NH-R 11 ;

[0743] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0744] (vii)-C(O)-NH-NH-R 11 ;

[0745] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0746] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[0747] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[0748] (xi)-CH(NH2)-CO-R 11 ;

[0749] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[0750] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[0751] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[0752] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[0753] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0754] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0755] R 11b Yes-(A1-A2) q-, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0756] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0757] R 11d Selected from the group consisting of -O- and -NH.

[0758] In certain embodiments, the compound of formula (XII), wherein L 2 Contains at least one of the following:

[0759] (a)-H, if L 1 Not H;

[0760] (b) -PO3H- or -PO3H2;

[0761] (c) -PO2SH- or -PO2SH2;

[0762] (d) -CH3;

[0763] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0764] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0765] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0766] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0767] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0768] where R10 It is R 10a -R 10b ,in

[0769] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0770] R 10b Selected from the group consisting of:

[0771] (i)-C(O)-R 11 ;

[0772] (ii) -(C2H4-O) m , where subscript m is an integer from 1 to 32;

[0773] (iii)-NH-R 11 ;

[0774] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0775] (v)-C(O)-NH-R 11 ;

[0776] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0777] (vii)-C(O)-NHNH-R 11 ;

[0778] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0779] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[0780] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0781] (xi)-CH(NH2)CO-R 11 ;

[0782] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0783] (xiii)-CH(N(C1-4 -alkyl)2)CO-R 11 ;

[0784] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0785] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0786] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0787] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0788] R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0789] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0790] R 11d Selected from the group consisting of -O- and -NH.

[0791] In certain embodiments, R 11 With reactive group R 40 End-capping.

[0792] In certain embodiments,

[0793] L 1 Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 -Heterocycle, C(O)R 8 、C(O)OR 8 、C(O)NHR 8 、SO2R 8 , and SO2NHR8 ,

[0794] Among them C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or

[0795] Among them L 1 Optionally substituted with 1-3 substituents independently selected in each case from the group consisting of OH, F, Cl, Br, C 1-5 -alkyl, C 3-6 -cycloalkyl and C 3-6 -heterocycle;

[0796] where R 8 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[0797] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, and -SO3H;

[0798] At least one of the L 1 or L 2 is not H; and

[0799] wherein the subscript y is an integer selected from 0 to 32.

[0800] In certain embodiments,

[0801] L 2 Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, phosphate, phosphorothioate, phosphoramide, C(O)R 9 、C(O)OR 9 , and C(O)NHR 9 、SO3H、SO2R 9 ,

[0802] Among them C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or

[0803] wherein phosphate and phosphorothioate are optionally substituted with 1 to 2 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl,

[0804] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and

[0805] wherein the substituents on the phosphate and phosphorothioate are optionally capped with protecting groups;

[0806] where R 9 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[0807] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, and -SO3H;

[0808] At least one of the L 1 or L 2 is not H; and

[0809] wherein the subscript y is an integer selected from 0 to 32.

[0810] In certain embodiments, the compound of formula (XIII), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprises:

[0811]

[0812] where R 1 and R 2 forming at least one aromatic ring or bicyclic heteroaromatic ring, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H;

[0813] in Is a single bond or a double bond;

[0814] Among them L1 Contains at least one of the following:

[0815] (a)-H, if L 2 Not H;

[0816] (b) -CH3;

[0817] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0818] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0819] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0820] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0821] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0822] where R 10 It is R 10a -R 10b ,in

[0823] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0824] R 10b Selected from the group consisting of:

[0825] (i)-C(O)-R 11 ;

[0826] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0827] (iii)-NH-R 11 ;

[0828] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0829] (v)-C(O)-NH-R 11 ;

[0830] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0831] (vii)-C(O)-NH-NH-R 11 ;

[0832] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0833] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[0834] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[0835] (xi)-CH(NH2)-CO-R 11 ;

[0836] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[0837] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[0838] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[0839] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[0840] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0841] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0842] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0843] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0844] R 11d Selected from the group consisting of -O- and -NH;

[0845] Each L 2 Independently comprising at least one of the following:

[0846] (a)-H, if L 1 Not H;

[0847] (b) -PO3H-;

[0848] (c)-PO2SH-;

[0849] (d) -CH3;

[0850] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0851] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0852] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0853] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0854] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0855] where R 10 It is R 10a -R 10b ,in

[0856] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0857] R 10b Selected from the group consisting of:

[0858] (i)-C(O)-R 11 ;

[0859] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0860] (iii)-NH-R 11 ;

[0861] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0862] (v)-C(O)-NH-R 11 ;

[0863] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0864] (vii)-C(O)-NHNH-R 11 ;

[0865] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0866] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[0867] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0868] (xi)-CH(NH2)CO-R 11 ;

[0869] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0870] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0871] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0872] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0873] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0874] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0875] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0876] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0877] R 11d Selected from the group consisting of -O- and -NH.

[0878] Each L 2 Independently comprising at least one of the following:

[0879] (a)-H, if L 1 Not H;

[0880] (b) -PO3H-;

[0881] (c)-PO2SH-;

[0882] (d) -CH3;

[0883] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0884] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0885] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0886] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0887] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0888] where R 10 It is R 10a -R 10b ,in

[0889] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0890] R 10b Selected from the group consisting of:

[0891] (i)-C(O)-R 11 ;

[0892] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0893] (iii)-NH-R 11 ;

[0894] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0895] (v)-C(O)-NH-R 11 ;

[0896] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0897] (vii)-C(O)-NHNH-R 11 ;

[0898] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[0899] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[0900] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[0901] (xi)-CH(NH2)CO-R 11 ;

[0902] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[0903] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[0904] (xiv)-CH(CO-R 11 )NH-R 11 ;

[0905] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[0906] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[0907] R 11aSelected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[0908] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[0909] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[0910] R 11d Selected from the group consisting of -O- and -NH.

[0911] In certain embodiments, the compound of formula (XIV), or a pharmaceutically acceptable salt, ester, or tautomer thereof, comprises:

[0912]

[0913] where R 1 and R 2 forming at least one aromatic ring or bicyclic heteroaromatic ring, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H;

[0914] in Is a single bond or a double bond;

[0915] Among them L 1 or L 2 One is the joint;

[0916] Among them L 1 yes:

[0917] H;

[0918] R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl) e -[(C(O)-] f ;or

[0919] R 40-(-C2H4-O) c -C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H4-O) t -(C 1-6 alkyl)-[(C(O)-] k ;

[0920] Among them L 2 yes:

[0921] H;

[0922] R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl)-[(C(O)-NH] j -(-C2H4-O) t -[OP(O)SH]; or

[0923] R 40 -(-C2H4-O) t -C(O)-(A1-A2) g -NH-(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H-4-O) t -(C 1-6 alkyl)-[(C(O)-] f -[OP(O)SH];

[0924] Among them L 1 or L 2 One of them is not H;

[0925] where R 40 It is a reactive group;

[0926] wherein A1 and A2 are independently in each instance an amino acid;

[0927] Where subscript:

[0928] b and j are independently selected at each occurrence from 0 to 4;

[0929] c and t are independently selected in each case from 0 to 32;

[0930] e, f, g, h and k are independently 0 or 1 in each instance.

[0931] In certain embodiments, R40 is maleimido, -NH2, -COO-succinimide, halogen, or substituted alkyne (e.g., bicyclooctyne).

[0932] In certain embodiments of a compound of Formula (XI), a compound of Formula (XII), a compound of Formula (XIII), a compound of Formula (XIV), or an antibody drug conjugate derived from any of them, R 11b Yes-(A 1- A2) q In certain embodiments, A1-A2 are: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.

[0933] In some embodiments of a compound of Formula (XI), a compound of Formula (XII), a compound of Formula (XIII), a compound of Formula (XIV), or an antibody drug conjugate derived from any of them, R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, wherein the subscript q is 2, 3 or 4. In some embodiments, R 11b In some embodiments, R 11b is -(A1)4-. In some embodiments, R 11b -(A1) is selected from Val-Cit, Val-Ala, Phe-Lys or Gly-Gly-Phe-Gly q -, wherein q is 2 or 4. In certain embodiments, A1-A2 is selected from Val-Cit, Val-Ala or Phe-Lys. In certain embodiments, -(A1)4- (or alternatively written as -A1-A2-A3-A4-) is Gly-Gly-Phe-Gly. In certain embodiments, R 11b(e.g., A1-A2 or -A1-A2-A3-A4-) is selected from Val-Ala, or Gly-Gly-Phe-Gly. In certain embodiments, A1-A2 is selected from Val-Ala. In certain embodiments, A1-A2 is selected from Val-Cit. In certain embodiments, -A1-A2-A3-A4- is selected from Gly-Gly-Phe-Gly. In some embodiments, -(A1) q -(e.g., -(A1)4-, -A1-A2-A3-A4-) is selected from SEQ ID NO.: 21.

[0934] In some embodiments of a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), or an antibody drug conjugate derived therefrom, A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid. q In some embodiments of -, subscript q is 2, 3, or 4. In some embodiments, -(A1) q - is -(A1)2-. In some embodiments, -(A1) q - is -(A1)4-. In some embodiments, -(A1) q - is selected from Val-Cit, Val-Ala, Phe-Lys or Gly-Gly-Phe-Gly, wherein q is 2 or 4. In certain embodiments, -(A1) q - is -(A1-A2)-, wherein A1-A2 is selected from Val-Cit, Val-Ala or Phe-Lys. In some embodiments, -(A1)4- (or alternatively written as -A1-A2-A3-A4-) is Gly-Gly-Phe-Gly. In certain embodiments, -(A1) q -(e.g., A1-A2 or -A1-A2-A3-A4-) is selected from Val-Ala, or Gly-Gly-Phe-Gly. In certain embodiments, A1-A2 is selected from Val-Ala. In certain embodiments, A1-A2 is selected from Val-Cit. In certain embodiments, A1-A2-A3-A4- is selected from Gly-Gly-Phe-Gly. In some embodiments, -(A1) q -(e.g., -(A1)4-, -A1-A2-A3-A4-) is selected from SEQ ID NO.: 21.

[0935] In certain embodiments of the compound of formula (XI), the compound of formula (XII), the compound of formula (XIII), or the compound of formula (XIV), the compound is:

[0936]

[0937] In certain embodiments, L 1 or L 2 At least one of which independently comprises:

[0938]

[0939] in Represents a compound of formula (IV) or L 1 or L 2 The connection point of the rest of the

[0940] wherein r is an integer selected from 1 to 12; and

[0941] wherein s is an integer selected from 1 to 32.

[0942] In certain embodiments, r is an integer selected from 2 to 12; and

[0943] s is an integer selected from 2 to 32. In certain embodiments, r is 5. In certain embodiments, s is 3.

[0944] In some embodiments of the compound of formula (XI), the compound of formula (XII), the compound of formula (XIII), or the compound of formula (XIV), L 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 1 R 40 End-capped, where R 40 Is a reactive group. In some embodiments, -(A1) q - is Val-Cit or Cit-Val. In some embodiments, L 1 is -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 1 Yes-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is di(pyrrolidin-1-yl)methyl. In some embodiments, L 1 Is -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(CH2)5-R 40 In some embodiments, L 1 is -C(O)-(CH2)-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 1 Is -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g- (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[0945] In some embodiments of the compound of formula (XI), the compound of formula (XII), the compound of formula (XIII), or the compound of formula (XIV), L 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 2 R 40 End-capped, where R 40 is a reactive group. In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -(C 1-6 Alkyl)-NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 In some embodiments, L 2In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 2 Is -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 .

[0946] In some embodiments of the antibody drug conjugate derived from a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), or a compound of formula (XIV), B 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, -(A1) q - is Val-Cit or Cit-Val. In some embodiments, B 1 Contains -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 1 Contains-(A1)q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(CH2)5-. In some embodiments, B 1 Contains -C(O)-(CH2)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 1 Contains -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0947] In some embodiments of the antibody drug conjugate derived from a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), or a compound of formula (XIV), B 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0948] In certain embodiments of the compound of formula (XI), the compound of formula (XII), the compound of formula (XIII), or the compound of formula (XIV), L 1 , or L 2 One with R 40 End-capped, where R 40 is a reactive group. In certain embodiments, R 11 R 40 End-capped, where R 40 In some embodiments, the reactive group is -NHBoc (i.e., ) or -NH2. In some embodiments, the reactive group is maleimide.

[0949] In some embodiments of the compound of formula (XI), the compound of formula (XII), the compound of formula (XIII), or the compound of formula (XIV), when L 1 When it is H, then L 2 At least one occurrence of is not H; and when L 2 When all occurrences of are H, then L 1 Not H.

[0950] In some embodiments of the antibody drug conjugate derived from a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), or a compound of formula (XIV), B 1 Contains as in L 1 R found in 40 The reaction product of with Ab such that a covalent bond is formed therebetween. 2 Contains as in L 2 R found in 40 The reaction product with Ab forms a covalent bond between them. 40 When it is maleimide, Ab-B 1 - or Ab-B 2 - Can be used independently End-capping.

[0951] In certain embodiments of a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), or an antibody drug conjugate derived therefrom, A1 and A2 are independently in each instance an amino acid (e.g., an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[0952] In certain embodiments of a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), or an antibody drug conjugate derived from any of them, subscript n is an integer selected from 0 to 4; subscript m is an integer selected from 0 to 20; subscript p is an integer 0 or 1; subscript q is an integer selected from 1 to 6; and subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of subscript n is independently an integer selected from 0 to 4; each instance of subscript m is independently an integer selected from 1 to 20; each instance of subscript p is independently an integer 0 or 1; each instance of subscript q is independently an integer selected from 1 to 6; and each instance of subscript n is independently an integer selected from 0 to 10.

[0953] In certain embodiments, the compound (e.g., a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV)) is:

[0954]

[0955] wherein subscript v is an integer from 1 to 32; and wherein subscript u is an integer from 0 to 11. In certain embodiments, subscript v is an integer selected from 1 to 14.

[0956] In certain embodiments, the compound (e.g., a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV)) is

[0957]

[0958] wherein the subscript e is an integer selected from 1 to 6. In certain embodiments, e is an integer selected from 1 to 5. In certain embodiments, e is an integer selected from 1 to 4. In certain embodiments, e is an integer selected from 1 to 3.

[0959] In certain embodiments, the compound (e.g., a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV)) has the following structure:

[0960]

[0961]

[0962]

[0963] In certain embodiments, provided herein is a compound comprising a linker or reactive linker covalently bonded to rubectedin or ecubectedin via a secondary alcohol or secondary amine. In certain embodiments, the compound is covalently bonded to a targeting agent. In certain embodiments, the compound is covalently bonded to an antibody or antibody fragment thereof. In some embodiments, the antibody of the antibody fragment comprises at least one of SEQ ID NOs. 1-20 as listed in Table 6.

[0964] In certain embodiments, provided herein are compounds of Formula (XVa), (XVb), or (XVc), or pharmaceutically acceptable salts, esters, stereoisomers, or tautomers thereof, comprising:

[0965]

[0966]

[0967] Wherein Ab is a targeting agent;

[0968] Wherein the subscript k is an integer from 1 to 10;

[0969] where R 1 and R 2forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and

[0970] Among them B 1 It is a joint;

[0971] In some embodiments, B 2 It's a connector.

[0972] In some embodiments of the compound of Formula (XVa), (XVb), or (XVc), Ab is an antibody, antibody fragment, protein, or peptide. In some embodiments of the compound of Formula (XVa), (XVb), or (XVc), the compound is an antibody drug conjugate derived from a compound of Formula (XI), (XII), (XIII), or (XIV). In some embodiments, the antibody or antibody fragment comprises one or more of SEQ ID NOs. 1 to 20 as listed in Table 6. Non-limiting examples of antibodies include trastuzumab and brentuximab. Sequences associated with trastuzumab and brentuximab are listed in Table 6 below:

[0973] Table 6. Sequence ID NOs.

[0974]

[0975]

[0976]

[0977] In certain embodiments, for compounds of Formula (XVa), (XVb), or (XVc), B 1 Contains at least one of the following:

[0978] (a)-H;

[0979] (b) -CH3;

[0980] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[0981] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[0982] (e) optionally with at least one R 10Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[0983] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[0984] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[0985] where R 10 It is R 10a -R 10b ,in

[0986] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[0987] R 10b Selected from the group consisting of:

[0988] (i)-C(O)-R 11 ;

[0989] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[0990] (iii)-NH-R 11 ;

[0991] (iv)-N(C 1-4 -alkyl)-R 11 ;

[0992] (v)-C(O)-NH-R 11 ;

[0993] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[0994] (vii)-C(O)-NH-NH-R 11 ;

[0995] (viii)-C(O)-NHN(C1-4 -alkyl)-R 11 ;

[0996] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[0997] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[0998] (xi)-CH(NH2)-CO-R 11 ;

[0999] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[1000] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[1001] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[1002] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[1003] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1004] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1005] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1006] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1007] R 11d Selected from the group consisting of -O- and -NH;

[1008] Among them B 2 Contains at least one of the following:

[1009] (a)-H;

[1010] (b) -PO3H-;

[1011] (c)-PO2SH-;

[1012] (d) -CH3;

[1013] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1014] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1015] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1016] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1017] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1018] where R 10 It is R 10a -R 10b ,in

[1019] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1020] R 10b Selected from the group consisting of:

[1021] (i)-C(O)-R 11 ;

[1022] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1023] (iii)-NH-R 11 ;

[1024] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1025] (v)-C(O)-NH-R 11 ;

[1026] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1027] (vii)-C(O)-NHNH-R 11 ;

[1028] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1029] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[1030] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[1031] (xi)-CH(NH2)CO-R 11 ;

[1032] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[1033] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[1034] (xiv)-CH(CO-R 11 )NH-R 11 ;

[1035] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R11 ;

[1036] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1037] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1038] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1039] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1040] R 11d is selected from the group consisting of -O- and -NH; and

[1041] Among them B 1 or B 2 One of the is not H; and

[1042] Among them B 1 or B 2 One of the is bonded to Ab.

[1043] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, -(A1) q - is Val-Cit or Cit-Val. In some embodiments, B 1 Contains -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 1 Contains-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 Contains -C(O)-(CH2)5-. In some embodiments, B 1 Contains -C(O)-(CH2)-. In some embodiments, B 1 Contains -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2

[1044] -(CH2)2-. In some embodiments, B 1 Contains -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-. In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[1045] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 2 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains: i) -PO2SH-; and ii) 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-. In some embodiments, B 2 Contains -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, -(A1) q- one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[1046] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), L 1 or L 2 It’s H.

[1047] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 1 Contains as in L 1 R found in 40 The reaction product of with Ab such that a covalent bond is formed therebetween. In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 2 Contains as in L 2 R found in 40 The reaction product with Ab forms a covalent bond between them. 40 When it is maleimide, Ab-B 1 - or Ab-B 2 - Can be used independently End-capping.

[1048] In certain embodiments of the compounds of Formula (XVa), (XVb), or (XVc), A1 and A2 are independently, in each instance, an amino acid (e.g., an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[1049] In certain embodiments of compounds of Formula (XVa), (XVb), or (XVc), subscript n is an integer selected from 0 to 4; subscript m is an integer selected from 0 to 20; subscript p is an integer 0 or 1; subscript q is an integer selected from 1 to 6; and subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of subscript n is independently an integer selected from 0 to 4; each instance of subscript m is independently an integer selected from 1 to 20; each instance of subscript p is independently an integer 0 or 1; each instance of subscript q is independently an integer selected from 1 to 6; and each instance of subscript n is independently an integer selected from 0 to 10.

[1050] In certain embodiments, a compound (e.g., a compound of Formula (XVa), a compound of Formula (XVb), a compound of Formula (XVc)) is

[1051]

[1052] In certain embodiments of Formula (XVa), Formula (XVb), or Formula (XVc), B 1 or B 2 At least one of which independently comprises

[1053]

[1054] in Indicates the compound of formula (XVa), (XVb) or (XVc) or L 1 or L 2 The connection point of the rest of the

[1055] in indicates the point of attachment to the antibody or antibody fragment;

[1056] wherein the subscript r is an integer selected from 1 to 6; and

[1057] wherein the subscript s is an integer selected from 2 to 14. In certain embodiments, r is an integer selected from 2 to 6; and s is an integer selected from 2 to 14.

[1058] In certain embodiments, the compound is

[1059]

[1060] wherein a is an integer selected from 2 to 6. In certain embodiments, a is 4. In certain embodiments, a is 5.

[1061] In certain embodiments, the compound (e.g., a compound of Formula (XVa), a compound of Formula (XVb), a compound of Formula (XVc)) is selected from

[1062]

[1063]

[1064]

[1065]

[1066] Methods for preparing linker-drug conjugates

[1067] Disclosed herein is a method for the synthesis of compounds of formula (XVI) as outlined in Scheme A.

[1068] Plan A

[1069]

[1070] Disclosed herein is a method for the synthesis of compounds of formula (XVII) as outlined in Scheme B.

[1071] Plan B

[1072]

[1073] As disclosed herein, the variables for Scheme A and Scheme B are defined as follows: L 1 is a linker terminated with a reactive group. 1 As defined for compounds of Formula (I), (II), (III), (IV), or (XI). In some embodiments, L 1 is a linking group terminated with a reactive group; wherein the reactive group is selected from R 40 In some embodiments, L 1 is a linker terminated with a reactive group; wherein the reactive group is selected from maleimide or -NHBoc. In some embodiments, L 1 Contains 0-3 -C(O)-, 0-3 -C(O)-NH- or -NH-C(O)-, 0-3 -(A1) q -、0-3-(C 1-6 -alkyl)-, 0-2 -O-CH2-(C6H4)-NH-, and 0-3 -(C2H4-O) m -; where L 1 R 40 End-capped, where R 40 Is a reactive group. In some embodiments, -(A1) q -at least one occurrence is selected from: Val-Cit or Cit-Val. In some embodiments, L 1 is -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) m -(CH2)2-NH-C(O)-(CH2)2-R 40 .

[1074] In some embodiments, L 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 1 Yes-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 is -C(O)-(C2H4-O) 12 -(CH2)2-NH-C(O)-(CH2)2-R 40 In some embodiments, L 1 Is -C(O)-(CH2)5-R 40 In some embodiments, L 1 is -C(O)-(CH2)-R 40 In some embodiments, L 1 Is -C(O)-(C2H4-O)3-(CH2)2-NH-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(C2H4-O)2-(CH2)2-R 40 In some embodiments, L 1 Is -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 In some embodiments, R 40 is maleimide or -NHBoc. In some embodiments, R 40 is maleimide. In some embodiments, R 40 Yes -NHBoc.

[1075] In L 1In certain embodiments, A1 and A2 are independently in each case an amino acid (e.g., an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, -(A1) q - one or more of -(A1-A2) as defined throughout this disclosure d -or-(A1-A2) g - (e.g., where subscript d is 0 or 1, where subscript g is 0 or 1).

[1076] In L 1 In certain embodiments of the present invention, subscript n is an integer selected from 0 to 4; subscript m is an integer selected from 0 to 20; subscript p is an integer 0 or 1; subscript q is an integer selected from 1 to 6; and subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of subscript n is independently an integer selected from 0 to 4; each instance of subscript m is independently an integer selected from 1 to 20; each instance of subscript p is independently an integer 0 or 1; each instance of subscript q is independently an integer selected from 1 to 6; and each instance of subscript n is independently an integer selected from 0 to 10.

[1077] As disclosed herein, in some embodiments of Scheme A, step 1, the compound of formula (XVI) is prepared from lubide. In some embodiments, lubide is reacted with a suitable coupling reagent and a compound having structure L in a suitable solvent. 1 In some embodiments, rubitidine is reacted with a suitable coupling reagent, a suitable base, and a ligand having structure L in a suitable solvent. 1 -OH is contacted to produce a compound of formula (XVI). In some embodiments, a suitable coupling reagent is selected from fluoro-N, N, N', N'-bis (tetramethylene) formamidine hexafluorophosphate (BTFFH), tetramethylfluoroformamidine hexafluorophosphate (TFFH), or a combination thereof. In some embodiments, a suitable solvent comprises N, N-dimethylformamide (DMF). In some embodiments, a suitable base comprises diisopropylethylamine (DIPEA). In some embodiments, rubitidine is reacted with (i) BTFFH, TFFH, or a combination thereof; (ii) DIPEA; and (iii) a compound having structure L in DMF. 1 -OH to produce a compound of formula (XVI).

[1078] As disclosed herein, in some embodiments of Scheme B, step 1, the compound of formula (XVII) is prepared from trabectedin. In some embodiments, trabectedin is reacted with a suitable coupling reagent and a molecule having structure L in a suitable solvent. 1-OH is contacted to produce a compound of formula (XVII). In some embodiments, trabectedin is reacted with a suitable coupling reagent, a suitable base, and a hydroxyl radical having structure L in a suitable solvent. 1 -OH is contacted to produce a compound of formula (XVII). In some embodiments, a suitable coupling reagent is selected from fluoro-N, N, N', N'-bis (tetramethylene) formamidine hexafluorophosphate (BTFFH), tetramethylfluoroformamidine hexafluorophosphate (TFFH), or a combination thereof. In some embodiments, a suitable solvent comprises N, N-dimethylformamide (DMF). In some embodiments, a suitable base comprises diisopropylethylamine (DIPEA). In some embodiments, trabectedin is reacted with (i) BTFFH, TFFH, or a combination thereof; (ii) DIPEA; and (iii) a fluorocarbon having structure L in DMF. 1 -OH to produce a compound of formula (XVII).

[1079] In some embodiments of Scheme A, step 1 or Scheme B, step 1, L 1 -OH is selected from:

[1080]

[1081]

[1082] In some embodiments of the compound of Formula (I), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, the compound is a compound of Formula (XVI):

[1083]

[1084] or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof; wherein L 1 As defined for compounds of formula (I), formula (III), or formula (IV). 1 In some embodiments of -OH, L 1 As defined for compounds of formula (I), formula (III), or formula (IV).

[1085] In some embodiments of the compound of formula (XI), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, the compound is a compound of formula (XVI):

[1086]

[1087] or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof; wherein L 1As defined for compounds of formula (XI). 1 In some embodiments of -OH, L 1 As defined for the compound of formula (XI).

[1088] In some embodiments of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, the compound is a compound of Formula (XVII):

[1089]

[1090] or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, wherein L 1 As defined for compounds of formula (I), formula (II), formula (III), or formula (IV). 1 In some embodiments of -OH, L 1 As defined for compounds of Formula (I), Formula (II), Formula (III), or Formula (IV).

[1091] In some embodiments of the compound of formula (XI), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, the compound is a compound of formula (XVII):

[1092]

[1093] or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof; wherein L 1 As defined for compounds of formula (XI). 1 In some embodiments of -OH, L 1 As defined for the compound of formula (XI).

[1094] Optically active compounds

[1095] It should be understood that the compounds provided herein can have multiple chiral centers and can exist and be separated in optically active forms and racemic forms. Some compounds can exhibit polymorphism. It should be understood that any racemic form, optically active form, diastereomeric form, polymorphic form, or stereoisomeric form of the compounds provided herein having the useful properties described herein, or mixtures thereof, are within the scope of the present invention. It is well known in the art how to prepare optically active forms (e.g., by resolving racemic forms through recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[1096] Likewise, most amino acids are chiral (designated as L or D, with the L enantiomer being the naturally occurring configuration) and can exist as separate enantiomers.

[1097] Examples of methods for obtaining optically active materials are known in the art and include at least the following:

[1098] i) Physical separation of crystals - a technique in which macroscopic crystals of the individual enantiomers are artificially separated. This technique can be used if crystals of the individual enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct;

[1099] ii) simultaneous crystallization - a technique in which the individual enantiomers are crystallized separately from a solution of the racemate, which is possible only if the latter is an aggregate in the solid state;

[1100] iii) Enzymatic resolution - a technique in which racemates are partially or completely separated by virtue of the different reaction rates of the enantiomers with enzymes;

[1101] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

[1102] v) Chemical asymmetric synthesis - a synthetic technique in which the desired enantiomer is synthesized from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

[1103] vi) Diastereomeric separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization, by virtue of their now more distinct structural differences, followed by removal of the chiral auxiliary to yield the desired enantiomer;

[1104] vii) primary and secondary asymmetric transformations - techniques in which diastereomers from the racemate are allowed to equilibrate to produce a preponderance of the diastereomer from the desired enantiomer in solution, or in which preferential crystallization of the diastereomer from the desired enantiomer disturbs the equilibrium so that ultimately, in principle, all of the material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomers;

[1105] viii) Kinetic resolution - This technique involves the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by virtue of the unequal reaction rates of the enantiomers with a chiral non-racemic reagent or catalyst under kinetic conditions;

[1106] ix) Enantiospecific synthesis from non-racemic precursors - synthetic techniques in which the desired enantiomer is obtained from achiral starting materials and in which the stereochemical integrity is not or only minimally compromised during the synthesis;

[1107] x) Chiral liquid chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with the stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain additional chiral materials to stimulate different interactions;

[1108] xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the enantiomers are separated by virtue of their different interactions in the gaseous mobile phase with a column containing a stationary non-racemic chiral adsorbent phase;

[1109] xii) extraction with chiral solvents - a technique in which enantiomers are separated by virtue of preferential solubility of one enantiomer in a specific chiral solvent;

[1110] xiii) Transport across chiral membranes - a technique in which a racemate is placed in contact with a thin membrane barrier. This barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the membrane barrier. The separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[1111] In some embodiments, the composition of the compound is substantially free of a specified enantiomer of the compound. In certain embodiments, in the methods and compounds of the present invention, the compound is substantially free of enantiomers. In some embodiments, the composition comprises at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the compound, with the remainder comprising other chemical species or enantiomers.

[1112] Geometric isomers and tautomers

[1113] In addition, in some embodiments, the compounds described herein exist as "geometric isomers". In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, E (entgegen, E) and Z (zusammen, Z) isomers and their corresponding mixtures. In some cases, the compounds exist as tautomers.

[1114] "Tautomer" refers to a molecule in which a proton transfer from one atom of the molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In cases where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[1115]

[1116] Isotopically enriched compounds

[1117] Also provided herein are isotopically enriched compounds, including but not limited to isotopically enriched compounds.

[1118] Isotopic enrichment (e.g., deuteration) of drugs to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles has previously been demonstrated for several classes of drugs. See, e.g., Lijinsky et al., Food Cosmet. Toxicol., 20:393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et al., Mutation Res. 308:33 (1994); Gordon et al., Drug Metab. Dispos., 15:589 (1987); Zello et al., Metabolism, 43:487 (1994); Gately et al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[1119] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) reduce the number of doses required to achieve a desired effect, (4) reduce the amount of dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any active metabolites are formed, and / or (6) reduce the production of harmful metabolites in specific tissues and / or create more effective drugs and / or safer drugs for use in combination therapy, whether or not the combination therapy is intended.

[1120] Replacing an atom with one of its isotopes often results in a change in the reaction rate of a chemical reaction. This phenomenon is called the kinetic isotope effect (" KIE "). For example, if a C-H bond breaks during the rate-determining step (i.e., the step with the highest transition state energy) of a chemical reaction, the replacement of the hydrogen by deuterium will result in a decrease in the reaction rate, and the process will be slowed down. This phenomenon is called the deuterium kinetic isotope effect (" DKIE "). (See, for example, Foster et al., Adv. Drug Res., Vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., Vol. 77, pp. 79-88 (1999)).

[1121] The magnitude of the DKIE can be expressed as the ratio between the rate of a given reaction in which a C-H bond is broken and the rate of the same reaction in which deuterium replaces hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, which means that when deuterium replaces hydrogen, the reaction can be 50 times slower or more. High DKIE values ​​can be due in part to a phenomenon called tunneling, which is a result of the uncertainty principle. Tunneling is attributed to the small mass of the hydrogen atom and occurs because transition states involving protons can sometimes form in the absence of the required activation energy. Because deuterium has a larger mass than hydrogen, it statistically has a much lower probability of experiencing this phenomenon.

[1122] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with 2 neutrons in the nucleus and an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly as T2O. Tritium decays slowly (half-life = 12.3 years) and emits low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, however, it must be ingested in large quantities to pose a significant health risk. Compared to deuterium, smaller amounts of tritium must be consumed before dangerous levels of tritium are reached. Substitution of tritium ("T") for hydrogen still produces a stronger bond than deuterium and gives a numerically larger isotope effect. Similarly, substitution of isotopes for other elements, including but not limited to, 13 C or 14 C substitution for carbon, 33 S. 34 S, or 36 S replaces sulfur, 15 N substitution for nitrogen, and 17 O or 18 The substitution of O for oxygen can lead to a similar kinetic isotope effect.

[1123] For example, DKIE is used to reduce the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching holds that when isolated by phase I enzymes, xenogens can instantaneously bind and re-bind in various conformations before a chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large size of the binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can result in different ratios of known metabolites as well as completely new metabolites. This new metabolic signature may confer more or less toxicity.

[1124] Animals express a variety of enzymes for the purpose of removing foreign substances such as therapeutic agents from their circulatory systems. Examples of such enzymes include cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) π bonds. The resulting metabolites can be stable or unstable under physiological conditions and can have substantially different pharmacokinetics, pharmacodynamics, and acute and long-term toxicity characteristics relative to the parent compound. For many drugs, such oxidation is rapid. Therefore, these drugs often require multiple doses or high daily doses.

[1125] Thus, isotopic enrichment at certain positions of the compounds provided herein will result in a detectable KIE compared to a similar compound having a natural isotopic composition, which will affect the pharmacokinetic, pharmacological, and / or toxicological properties of the compounds provided herein.

[1126] Preparation of compounds and pharmaceutical compositions

[1127] In certain embodiments, the preparation methods described in the examples may include one or more protection or deprotection steps.

[1128] The present compounds can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein.Any compound disclosed herein can be provided in an appropriate pharmaceutical composition and administered via a suitable route of administration.

[1129] The methods provided herein comprise administering a pharmaceutical composition containing at least one compound as described herein, in salt form, if appropriate, alone or in combination with one or more compatible and pharmaceutically acceptable carriers (such as a diluent or adjuvant) or with another agent.

[1130] In certain embodiments, the second agent can be formulated or packaged together with the compound provided herein. Of course, when, according to the judgment of those skilled in the art, such co-formulation should not interfere with the activity or administration method of any agent, the second agent will only be formulated together with the compound provided herein. In certain embodiments, the compound provided herein and the second agent are formulated separately. For the convenience of those skilled in the art, they can be packaged together, or individually packaged.

[1131] In clinical practice, the active agents provided herein can be administered by any conventional route, in particular parenterally, rectally, or by inhalation (eg, in the form of an aerosol).

[1132] It can be used as a solid composition in the form of a powder or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch.

[1133] Compositions for parenteral administration may be emulsions or sterile solutions. These compositions may also contain adjuvants, particularly wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization may be carried out in several ways, for example using a bacterial filter, by radiation or by heating. They may also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or any other injectable sterile medium when used.

[1134] In certain embodiments, provided herein are compositionss or single unit dosage forms. Provided herein are pharmaceutical compositions and single unit dosage forms comprising one or more preventive or therapeutic agents (e.g., compounds provided herein, or other preventive or therapeutic agents) of a preventive or therapeutically effective amount, and more than one typical pharmaceutically acceptable carrier or excipient. In a specific embodiment and in this context, the term "pharmaceutically acceptable" means approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more particularly for humans. The term "carrier" includes diluents, adjuvants (e.g., Freund's adjuvant (complete and incomplete)), excipients, or solvents for use in treatment thereof. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including liquids of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. When the pharmaceutical composition is administered intravenously, water can be used as a carrier. Saline solutions and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described by EW Martin in "Remington's Pharmaceutical Sciences".

[1135] Typical pharmaceutical compositions and dosage forms contain more than one excipient. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be administered to a subject and the specific active ingredient in the dosage form. If desired, the composition or single unit dosage form may also contain a small amount of a wetting agent or emulsifier, or a pH buffer.

[1136] The lactose-free compositions provided herein can include excipients well known in the art and listed, for example, in U.S. Pharmacopoeia (USP) SP (XXI) / NF (XVI). Typically, the lactose-free compositions include active ingredients, binders / fillers, and lubricants in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms include active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[1137] Further included herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, as water can promote the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means of simulating long-term storage in order to determine characteristics such as shelf life or the stability of a formulation over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of water on a formulation can be significant because moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipment, and use of a formulation.

[1138] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[1139] Anhydrous pharmaceutical compositions should be prepared and stored so that their anhydrous nature is maintained. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[1140] Further provided are pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which an active ingredient decomposes. Such compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[1141] Pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsions and powders etc. Such compositions and dosage forms will contain a preventive or therapeutically effective amount of a prophylactic or therapeutic agent (in purified form in certain embodiments) and a suitable amount of a carrier to provide a form for appropriate administration to a subject. The preparation should be suitable for the mode of administration. In certain embodiments, the pharmaceutical composition or single unit dosage form is sterile and is used for administration to a subject, for example, an animal subject, such as a mammalian subject, for example, a human subject, in a suitable form.

[1142] The pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of route of administration include, but are not limited to, parenteral administration, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, intrasynovial and rectal administration. In a specific embodiment, the composition is formulated as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, intranasal or topical administration to the human race according to conventional procedures. In one embodiment, the pharmaceutical composition is formulated according to conventional procedures for subcutaneous administration to the human race. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to alleviate pain at the injection site.

[1143] Examples of dosage forms include, but are not limited to, dispersions; suppositories; ointments; poultices; pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for mucosal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to a subject.

[1144] The composition, shape, and type of dosage forms provided herein will generally vary depending on their intended use. For example, a dosage form used for the initial treatment of a viral infection may contain a greater amount of one or more of the active ingredients contained therein than a dosage form used in the maintenance treatment of the same infection. These and other ways in which the specific dosage forms contained herein may vary from one another will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing, Easton PA (2000).

[1145] Typically, the ingredients of the composition are supplied separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate in an airtight sealed container such as an ampoule or sachette indicating the amount of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is to be administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed before administration.

[1146] Typical dosage forms include a compound as provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in a range of from about 0.01 mg to about 1000 mg per day, administered as a single once-daily dose in the morning, or as divided doses throughout the day taken with food. Specific dosage forms can have about 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of active compound.

[1147] Parenteral dosage forms

[1148] In certain embodiments, provided is a parenteral dosage form. Parenteral dosage forms can be administered to a subject by various approaches, including but not limited to subcutaneous, intravenous (including push injection), intramuscular and intra-arterial. Because their administration usually bypasses the subject's natural defenses to pollutants, parenteral dosage forms are typically sterile or can be sterilized before being administered to a subject. Examples of parenteral dosage forms include but are not limited to, i.e., injection-type (ready for injection) solutions, ready-to-use dissolution or suspension in a pharmaceutically acceptable injection vehicle, i.e., injection-type suspensions, and emulsions.

[1149] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to, Water for Injection, USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[1150] Compounds that increase the solubility of one or more active ingredients disclosed herein can also be incorporated into parenteral dosage forms.

[1151] Dosage and unit dosage form

[1152] In human therapeutics, the doctor will determine what he considers to be the most appropriate posology based on prophylactic or curative treatment and based on the age, weight, stage of infection and other factors specific to the subject to be treated. In certain embodiments, the dosage is from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day for an adult, or from about 10 to 50 mg per day. In certain embodiments, the dosage is from about 5 to about 400 mg per day or from 25 to 200 mg per day for each adult. In certain embodiments, a dosage rate of from about 50 to about 500 mg per day is also contemplated.

[1153] In a further aspect, provided is a method for treating or preventing cancer in a subject, which is by administering an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. The amount of the compound or composition effective in preventing or treating a disease or one or more of its symptoms will vary with the nature and severity of the disease or condition and the approach by which the active ingredient is administered. Frequency and dosage will also vary according to factors specific to each subject, depending on the specific therapy (e.g., treatment or preventive agent) administered, the severity of the disease, disease or condition, route of administration, and the age, weight, response, and past medical history of the subject. The effective dose can be inferred from a dose-response curve derived from an in vitro or animal model test system.

[1154] In certain embodiments, the exemplary dosage of the composition includes milligrams or micrograms of active compound in the subject or sample weight per kilogram (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 micrograms per kilogram to about 10 milligrams per kilogram). For compositions provided herein, in certain embodiments, based on the weight of the active compound, the dosage administered to the subject is 0.140 mg / kg to 3 mg / kg of the subject's body weight. In certain embodiments, the dosage administered to the subject is between 0.20 mg / kg and 2.00 mg / kg of the subject's body weight, or between 0.30 mg / kg and 1.50 mg / kg.

[1155] In certain embodiments, the recommended daily dose range of the compositions provided herein for conditions described herein is located in the range of from about 0.1 mg to about 1000 mg every day, as a single daily dose or as a divided dose throughout the day. In certain embodiments, the daily dose is applied twice daily with equal divided doses. In certain embodiments, the daily dose range should be from about 10 mg to about 200 mg every day, in other embodiments, between about 10 mg and about 150 mg every day, in further embodiments, between about 25 and about 100 mg every day. In some cases, it may be necessary to use the dosage of the active ingredient outside the scope disclosed herein, which will be apparent to those of ordinary skill in the art. In addition, it should be noted that clinicians or attending physicians will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[1156] Different therapeutically effective amounts can be applicable to different diseases and conditions, which will be readily known to those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or alleviate such conditions but insufficient to cause or sufficient to reduce the adverse reactions associated with compositions provided herein are also included in the above-mentioned dosage amounts and dosage frequency tables. Further, when a subject administers multiple dosages of compositions provided herein, not all of the dosages need to be the same. For example, the dosage administered to a subject can be increased to improve the preventive or therapeutic effect of the compositions, or it can be reduced to reduce more than one side effect that a particular subject is experiencing.

[1157] In certain embodiments, the dosage of the compositions provided herein administered to a subject to prevent, treat, manage, or alleviate a disorder or one or more symptoms thereof is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of the subject's body weight, based on the weight of the active compound. In another embodiment, the dosage of the composition or the composition provided herein administered to prevent, treat, manage, or alleviate a disorder or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[1158] In certain embodiments, treatment or prevention can be started with one or more loading doses of compound or composition provided herein, followed by one or more maintenance doses. In such embodiments, loading dose can be, for example, about 60 to about 400mg every day, or about 100 to about 200mg every day, for one day to five weeks. Loading dose can then be one or more maintenance doses. In certain embodiments, each maintenance dose is independently about from about 10mg to about 200mg every day, between about 25mg and about 150mg every day, or between about 25 and about 80mg every day. Maintenance dose can be applied daily, and can be used as a single dose or as a divided dose.

[1159] In certain embodiments, the dosage of compound provided herein or compositions can be used to reach the steady-state concentration of active ingredient in the blood or serum of the experimenter.Steady-state concentration can be determined by measuring according to the available technology of technical personnel, or can be determined based on the physical characteristics of the experimenter such as height, weight and age.In certain embodiments, a sufficient amount of compound provided herein or compositions are used to reach the steady-state concentration in the blood or serum of the experimenter from about 300 to about 4000ng / mL, from about 400 to about 1600ng / mL or from about 600 to about 1200ng / mL.In some embodiments, loading dose can be used to reach the steady-state blood or serum concentration of about 1200 to about 8000ng / mL or about 2000 to about 4000ng / mL, for 1 to 5 days.In certain embodiments, maintenance dose can be used to reach the steady-state concentration in the blood or serum of the experimenter from about 300 to about 4000ng / mL, from about 400 to about 1600ng / mL or from about 600 to about 1200ng / mL.

[1160] In certain embodiments, administration of the same composition can be repeated, and administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent can be repeated, and administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[1161] In some aspects, provided herein is a unit dose comprising a compound or a pharmaceutically acceptable salt thereof in a form suitable for administration. Such forms are described in detail above. In certain embodiments, the unit dose comprises 1 to 1000 mg, 5 to 250 mg, or 10 to 50 mg of active ingredient. In a specific embodiment, the unit dose comprises about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of active ingredient. Such unit doses can be prepared according to techniques familiar to those skilled in the art.

[1162] The dosage of the second agent is to be used in the combination therapy provided herein. In certain embodiments, a dosage lower than that which has been or is currently being used to prevent or treat cancer is used in the combination therapy provided herein. The recommended dosage of the second agent can be obtained from the knowledge of the technician. For those second agents approved for clinical use, the recommended dosage is described in, for example, Hardman et al., ed., 1996, Goodman & Gilman's The Pharmacological Basis of Basis of Therapeutics 9th Edition, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Edition, 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in their entirety.

[1163] In various embodiments, the therapy (e.g., a compound provided herein and a second agent) is administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 hours apart to about 3 hours apart, about 3 hours apart to about 4 hours apart, about 4 hours apart to about 5 hours apart, about 5 hours apart to about 6 hours apart, about 6 hours apart to about 7 hours apart, about 7 hours apart to about 8 hours apart, about 8 hours apart to about 9 hours apart, about 9 hours apart to about 10 hours apart, about 10 hours apart to about 11 hours apart, about 11 hours apart to about 12 hours apart, about 12 hours apart to 18 hours apart, 18 hours apart to 24 hours apart, 24 hours apart to 36 hours apart, 36 hours apart to 48 hours apart, 48 hours apart to 52 hours apart, 52 hours apart to 60 hours apart, 60 hours apart to 72 hours apart, 72 hours apart to 84 hours apart, 84 hours apart to 96 hours apart, or 96 hours apart to 120 hours apart. In various embodiments, the therapy is administered no more than 24 hours apart or no more than 48 hours apart. In certain embodiments, two or more therapies are administered within the same patient visit.In other embodiments, a compound provided herein and a second agent are administered simultaneously.

[1164] In other embodiments, the compound provided herein and the second agent are administered about 2 to 4 days apart, about 4 to 6 days apart, about 1 week apart, about 1 to 2 weeks apart, or more than 2 weeks apart.

[1165] In certain embodiments, administration of the same agent can be repeated, and administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same agent can be repeated, and administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[1166] In certain embodiments, provided herein is a compound and a second agent, administered to a patient, for example, a mammal, such as a human, in sequence and within a time interval, so that provided herein is a compound that can act together with other agents to provide an increased benefit than if they were administered in other ways. For example, the second active agent can be administered simultaneously or continuously in any order at different time points; however, if they cannot be administered simultaneously, they should be administered close enough in time to provide the desired treatment or preventive effect. In certain embodiments, provided herein is a compound and a second active agent that exert their effects at overlapping times. Each second active agent can be administered separately in any appropriate form and by any suitable route. In other embodiments, provided herein is a compound that is administered before, simultaneously, or after the second active agent is administered.

[1167] In certain embodiments, provided herein is a compound and a second agent, administered in cycles to the patient. Cycling therapy involves administering a first agent (e.g., a first preventive or therapeutic agent) for a period of time, followed by administering a second agent and / or a third agent (e.g., a second and / or third preventive or therapeutic agent) for a period of time and repeating the sequence. Cycling therapy can reduce the development of resistance to more than one therapy, avoid or reduce the side effects of one of the therapies, and / or improve the efficacy of the treatment.

[1168] In certain embodiments, provided herein is a compound and a second active agent with a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days, or about once a week. A cycle can be included in each cycle of about 90 minutes, about 1 hour, or about 45 minutes per cycle by infusion administration of a compound and a second agent provided herein. Each cycle can include at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.

[1169] In other embodiments, multiple courses of treatment are administered to the patient simultaneously, i.e., a single dose of the second agent is administered separately but at intervals such that the compound provided herein can act together with the second active agent. For example, one component can be administered once a week in combination with other components that can be administered once every 2 weeks or once every 3 weeks. In other words, even if the treatments are not administered simultaneously or during the same day, the dosing regimen can be performed simultaneously.

[1170] The second agent can be added or synergistic with the compound provided herein. In certain embodiments, provided herein is a compound and one or more second agents in the same pharmaceutical composition are administered simultaneously. In another embodiment, provided herein is a compound and one or more second agents in a separate pharmaceutical composition are administered simultaneously. In still another embodiment, provided herein is a compound administered before or after the second agent is administered. It is also contemplated that the compound provided herein and the second agent are administered by the same or different routes of administration (e.g., parenteral). In certain embodiments, when provided herein is a compound and a second agent that may produce adverse side effects including but not limited to toxicity are administered simultaneously, the second active agent can advantageously be administered with a dose lower than the threshold value that causes adverse side effects.

[1171] Reagent test kit

[1172] Also provided is a kit for the method for treating cancer.Kit may include compound or composition provided herein, the second medicament or composition and provide instructions for the information for treating illness to a health care provider.Instructions can be provided in printed form or in the form of electronic media such as floppy disks, CDs or DVDs, or in the form of a website address in which such instructions can be obtained.The unit dose of compound or composition provided herein or the second medicament or composition may include such that when administered to a subject, the treatment or prevention effective plasma level of compound or composition can maintain the dosage of at least 1 day in the subject. In some embodiments, compound or composition can be included as sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.

[1173] In some embodiments, suitable packaging is provided. As used herein, " packaging " includes a solid matrix or material that is generally used in systems and can keep a compound provided herein and / or a second medicament suitable for administration to a subject within fixed limits. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil laminated envelopes, etc. If electron beam sterilization technology is adopted, packaging should have a sufficiently low density to allow the sterilization of contents.

[1174] How to use

[1175] In certain embodiments, provided herein are methods for treating and / or preventing cancer, comprising administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, provided herein are methods for treating cancer in a subject. In certain embodiments, the method includes administering to a subject in need thereof a compound effective for treating or preventing cancer in an amount combined with a second agent effective for treating or preventing infection. The compound may be any compound as described herein, and the second agent may be any second agent described in the art or herein. In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form as described elsewhere herein.

[1176] In certain embodiments, the subject has received cancer therapy and stopped the therapy before administering the methods provided herein. In further embodiments, the subject has received therapy and continues to receive the therapy and administer the methods provided herein. According to the judgment of those skilled in the art, the method can be co-administered with other therapies for cancer. In certain embodiments, the methods or compositions provided herein can be co-administered with other therapies for cancer at a reduced dose.

[1177] Second therapeutic agent

[1178] In certain embodiments, provided herein are compounds and compositions useful in a method for treating cancer, the method comprising further administering a second medicament effective for treating a condition. The second medicament can be any medicament known to those skilled in the art effective for treating a condition, including those currently approved by the FDA.

[1179] In certain embodiments, the compounds provided herein are administered in combination with one second agent. In further embodiments, the second agent is administered in combination with two second agents. In still further embodiments, the second agent is administered in combination with two or more second agents.

[1180] As used herein, the term "combination" includes the use of more than one therapy (e.g., more than one prophylactic and / or therapeutic agent). The use of the term "combination" does not limit the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered to a subject having a disorder prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy (e.g., a prophylactic or therapeutic agent).

[1181] As used herein, the term "synergistic" includes a combination of a compound provided herein with another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently being used to prevent, manage, or treat a condition that is more effective than the additive effects of these therapies. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) allows the use of lower doses of more than one therapy and / or a lower frequency of administering the therapy to a subject with a condition. The ability to utilize lower doses of therapies (e.g., a prophylactic or therapeutic agent) and / or administer the therapy less frequently reduces the toxicity associated with administering the therapy to the subject without reducing the efficacy of the therapy in preventing or treating the condition. In addition, synergy can result in improved efficacy of the agent in preventing or treating the condition. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce the adverse or unwanted side effects associated with the use of any one therapy alone.

[1182] The active compounds provided herein can be combined or administered alternately with another therapeutic agent. In combination therapy, two or more medicaments of an effective dose are administered together, while in alternating or sequential step therapy, the effective dose of each medicament is administered continuously or sequentially. The dosage given will depend on the absorption, inactivation and excretion rate of the drug and other factors known to those skilled in the art. It should be noted that the dosage value will also vary with the severity of the condition to be alleviated. It should be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time based on individual needs and the professional judgment of the individual administering or supervising the administration of the composition.

[1183] Some embodiments of the present disclosure

[1184] Provided below are some non-limiting embodiments of the present disclosure.

[1185] Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof:

[1186]

[1187] where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H;

[1188] where R 20 for:

[1189] (a) Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 - heterocycle, C(O)R5, C(O)OR5, C(O)NHR5, SO2R5 and SO2NHR5,

[1190] Among them C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or

[1191] (b)L 1 , where L 1 is a reactive linker group;

[1192] Among them, R 20 Optionally substituted with 1-3 substituents independently selected in each case from the group consisting of OH, F, Cl, Br, C 1-5 -alkyl, C 3-6 -cycloalkyl and C 3-6 -heterocycle;

[1193] where R 30 for:

[1194] (c) selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 - aryl, phosphate, phosphorothioate, phosphoramide, C(O)R6, C(O)OR6, and C(O)NHR6, sulfonyl, sulfonamide,

[1195] Among them C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or

[1196] (d)L 2 , where L 2 is a reactive linker group;

[1197] wherein phosphate and phosphorothioate are optionally substituted with 1 to 2 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl,

[1198] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and

[1199] wherein the substituents on the phosphate and phosphorothioate are optionally capped with protecting groups;

[1200] where R 5 and R 6 Each is independently selected in each case from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[1201] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H;

[1202] where R 20 or R 30 At least one of them is not H;

[1203] in is a single bond or a double bond; and

[1204] wherein the subscript y is an integer selected from 0 to 32.

[1205] Embodiment 2. The compound of embodiment 1, wherein L 1 Contains at least one of the following:

[1206] (a)-H, if L 2 Not H;

[1207] (b) -CH3;

[1208] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1209] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1210] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1211] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; or

[1212] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1213] where R 10 It is R 10a -R 10b ,in

[1214] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1215] R 10b Selected from the group consisting of:

[1216] (i)-C(O)-R 11 ;

[1217] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1218] (iii)-NH-R 11 ;

[1219] (iv)-N(C 1-4 -alkyl)-R 11;

[1220] (v)-C(O)-NH-R 11 ;

[1221] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1222] (vii)-C(O)-NH-NH-R 11 ;

[1223] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1224] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[1225] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[1226] (xi)-CH(NH2)-CO-R 11 ;

[1227] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[1228] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[1229] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[1230] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[1231] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1232] R 11aSelected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1233] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1234] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1235] R 11d Selected from the group consisting of -O- and -NH.

[1236] Embodiment 3. The compound of embodiment 1 or 2, wherein L 2 Contains at least one of the following:

[1237] (a)-H, if L 1 Not H;

[1238] (b) -PO3H- or -PO3H2;

[1239] (c) -PO2SH- or -PO2SH2;

[1240] (d) -CH3;

[1241] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1242] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1243] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1244] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1245] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1246] where R 10 It is R 10a -R 10b ,in

[1247] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1248] R 10b Selected from the group consisting of:

[1249] (i)-C(O)-R 11 ;

[1250] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1251] (iii)-NH-R 11 ;

[1252] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1253] (v)-C(O)-NH-R 11 ;

[1254] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1255] (vii)-C(O)-NHNH-R 11 ;

[1256] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1257] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[1258] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[1259] (xi)-CH(NH2)CO-R 11 ;

[1260] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[1261] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[1262] (xiv)-CH(CO-R 11 )NH-R 11 ;

[1263] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[1264] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1265] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1266] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1267] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1268] R 11d Selected from the group consisting of -O- and -NH.

[1269] Embodiment 4. The compound of embodiment 2 or 3, wherein R 11 Selected from:

[1270] R 11a -R 11b -R 11c -R 11d ;

[1271] R 11b -R 11c -R 11d ;

[1272] R 11c -R 11d ;or

[1273] R 11a -R 11c -R 11d .

[1274] Embodiment 5. The compound of any one of Embodiments 2-4, wherein R 11 With reactive group R 40 Embodiment 6. The compound of any one of Embodiments 1-5, wherein L 1 Contains at least one of the following bivalent structures:

[1275] (a)-C(O)-;

[1276] (b) -C(O)-NH-;

[1277] (c)-C(O)O-;

[1278] (d)-[(C(O)-NH] n -;

[1279] (e)-C(O)-;

[1280] (f)-(A1-A2) d -;

[1281] (g) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)-, or -O-(C6H4)-CH2-O-;

[1282] (h)-(C 1-6 -alkyl)-;

[1283] (i)-(C2H4-O) r- ;or

[1284] (j)-(C 1-6 -alkyl) p -;

[1285] Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group;

[1286] A1 and A2 are independently in each instance an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid;

[1287] Where subscript:

[1288] d is an integer selected from 0 to 1;

[1289] n is an integer selected from 0 to 4;

[1290] r is an integer selected from 0 to 32; and

[1291] p is an integer 0 or 1.

[1292] Embodiment 7. The compound of any one of Embodiments 1-5, wherein L 2 Contains at least one of the following bivalent structures:

[1293] (a) -PO3H- or -PO3H2;

[1294] (b) -PO2SH- or -PO2SH2;

[1295] (c)-C(O)-;

[1296] (d)-C(O)-NH-;

[1297] (e)-C(O)O-;

[1298] (f)-[(C(O)-NH] n -;

[1299] (g)-C(O)-;

[1300] (h)-(A1-A2) d -;

[1301] (i) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)-, or -O-(C6H4)-CH2-O-;

[1302] (j)-(C 1-6 -alkyl)-;

[1303] (k)-(C2H4-O) r- ;or

[1304] (l)-(C 1-6 -alkyl) p -;

[1305] Among them L 1 or L 2 R 40 End-capped, where R40 It is a reactive group;

[1306] A1 and A2 are independently in each instance an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid;

[1307] Where subscript:

[1308] d is an integer selected from 0 to 1;

[1309] n is an integer selected from 0 to 4;

[1310] r is an integer selected from 0 to 32; and

[1311] p is an integer 0 or 1.

[1312] Embodiment 8. The compound of any one of Embodiments 1-7, wherein R 20 is optionally with at least one C 1-6 -heterocyclic-substituted C1-alkyl.

[1313] Embodiment 9. The compound of any one of Embodiments 1-8, wherein R 20 is C1-alkyl optionally substituted with a dipyrrolidinyl substituent.

[1314] Embodiment 10. The compound of any one of Embodiments 1-9, wherein R 20 is C1-alkyl optionally substituted with 1 to 2 pyrrolidinyl substituents.

[1315] Embodiment 11. The compound of any one of Embodiments 1-10, wherein R 20 yes in represents the bond through which the indicated substituent is bonded.

[1316] Embodiment 12. The compound of any one of Embodiments 1-11, wherein R 30 It is a phosphate or a thiophosphate.

[1317] Embodiment 13. The compound of any one of Embodiments 1-11, wherein R 30 is a substituted phosphate or a substituted phosphorothioate.

[1318] Embodiment 14. The compound of embodiment 12, wherein R 30 yes in Represents the bond through which the phosphorothioate is bonded.

[1319] Embodiment 15. The compound of embodiment 1, wherein the compound is selected from

[1320]

[1321] Where W is O or S.

[1322] Embodiment 16. The compound of embodiment 1, wherein the compound is selected from

[1323]

[1324]

[1325]

[1326] Embodiment 17. A compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising:

[1327]

[1328] Among them L 1 or L 2 One of them is a reactive linker.

[1329] Embodiment 18. The compound of embodiment 17, wherein L 1 Contains at least one of the following:

[1330] (a)-H, if L 2 Not H;

[1331] (b) -CH3;

[1332] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1333] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1334] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1335] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1336] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1337] where R 10 It is R 10a -R 10b ,in

[1338] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1339] R 10b Selected from the group consisting of:

[1340] (i)-C(O)-R 11 ;

[1341] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1342] (iii)-NH-R 11 ;

[1343] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1344] (v)-C(O)-NH-R 11 ;

[1345] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1346] (vii)-C(O)-NH-NH-R 11 ;

[1347] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1348] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[1349] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[1350] (xi)-CH(NH2)-CO-R 11 ;

[1351] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[1352] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[1353] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[1354] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[1355] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1356] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1357] R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1358] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1359] R 11d Selected from the group consisting of -O- and -NH.

[1360] Embodiment 19. The compound of embodiment 17 or 18, wherein L 2 Contains at least one of the following:

[1361] (a)-H, if L 1 Not H;

[1362] (b) -PO3H- or -PO3H2;

[1363] (c) -PO2SH- or -PO2SH2;

[1364] (d) -CH3;

[1365] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1366] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1367] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1368] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1369] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1370] where R 10 It is R 10a -R 10b ,in

[1371] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1372] R 10b Selected from the group consisting of:

[1373] (i)-C(O)-R 11 ;

[1374] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1375] (iii)-NH-R 11 ;

[1376] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1377] (v)-C(O)-NH-R 11 ;

[1378] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1379] (vii)-C(O)-NHNH-R 11 ;

[1380] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1381] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[1382] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[1383] (xi)-CH(NH2)CO-R 11 ;

[1384] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[1385] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[1386] (xiv)-CH(CO-R 11 )NH-R 11 ;

[1387] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[1388] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1389] R 11aSelected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1390] R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1391] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1392] R 11d Selected from the group consisting of -O- and -NH.

[1393] Embodiment 20. The compound of embodiment 18 or 19, wherein R 11 Selected from:

[1394] R 11a -R 11b -R 11c -R 11d ;

[1395] R 11b -R 11c -R 11d ;

[1396] R 11c -R 11d ;or

[1397] R 11a -R 11c -R 11d .

[1398] Embodiment 21. The compound of any one of Embodiments 18-20, wherein R 11 With reactive group R 40 End-capping.

[1399] Embodiment 22. The compound of any one of Embodiments 17-21, wherein L 1 Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 - heterocycle, C(O)R5, C(O)OR5, C(O)NHR5, SO2R5, and SO2NHR5,

[1400] Among them C 1-10-alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or

[1401] Among them, L 1 Optionally substituted with 1-3 substituents independently selected in each case from the group consisting of OH, F, Cl, Br, C 1-5 -alkyl, C 3-6 -cycloalkyl and C 3-6 -heterocycle;

[1402] where R 5 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[1403] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, and -SO3H;

[1404] At least one of the L 1 or L 2 is not H; and

[1405] wherein the subscript y is an integer selected from 0 to 32.

[1406] Embodiment 23. The compound of any one of Embodiments 17-21, wherein L 2 Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 - aryl, phosphate, phosphorothioate, phosphoramide, C(O)R6, C(O)OR6, and C(O)NHR6, sulfonyl, sulfonamide,

[1407] Among them C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or

[1408] wherein phosphate and phosphorothioate are optionally substituted with 1 to 2 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl,

[1409] Among them C1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and

[1410] wherein the substituents on the phosphate and phosphorothioate are optionally capped with protecting groups;

[1411] where R 6 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl,

[1412] Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, and -SO3H;

[1413] At least one of the L 1 or L 2 is not H; and

[1414] wherein the subscript y is an integer selected from 0 to 32.

[1415] Embodiment 24. A compound of formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising:

[1416]

[1417] where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H;

[1418] in Is a single bond or a double bond;

[1419] Among them L 1 Contains at least one of the following:

[1420] (a)-H, if L 2 Not H;

[1421] (b) -CH3;

[1422] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1423] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1424] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1425] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1426] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1427] where R 10 It is R 10a -R 10b ,in

[1428] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1429] R 10b Selected from the group consisting of:

[1430] (i)-C(O)-R 11 ;

[1431] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1432] (iii)-NH-R 11 ;

[1433] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1434] (v)-C(O)-NH-R 11 ;

[1435] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1436] (vii)-C(O)-NH-NH-R 11 ;

[1437] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1438] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[1439] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[1440] (xi)-CH(NH2)-CO-R 11 ;

[1441] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[1442] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[1443] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[1444] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ;

[1445] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1446] R 11aSelected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1447] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1448] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1449] R 11d Selected from the group consisting of -O- and -NH;

[1450] Among them L 2 Contains at least one of the following:

[1451] (a)-H, if L 1 Not H;

[1452] (b) -PO3H-;

[1453] (c)-PO2SH-;

[1454] (d) -CH3;

[1455] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1456] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1457] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1458] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1459] (j) optionally with at least one R 10 Substituted-(C 0-6alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1460] where R 10 It is R 10a -R 10b ,in

[1461] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1462] R 10b Selected from the group consisting of:

[1463] (i)-C(O)-R 11 ;

[1464] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1465] (iii)-NH-R 11 ;

[1466] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1467] (v)-C(O)-NH-R 11 ;

[1468] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1469] (vii)-C(O)-NHNH-R 11 ;

[1470] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1471] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[1472] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[1473] (xi)-CH(NH2)CO-R 11 ;

[1474] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[1475] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[1476] (xiv)-CH(CO-R 11 )NH-R 11 ;

[1477] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[1478] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1479] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1480] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1481] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1482] R 11d Selected from the group consisting of -O- and -NH.

[1483] Embodiment 25. A compound of formula (IV) or a pharmaceutically acceptable salt, ester, or tautomer thereof, comprising:

[1484]

[1485] where R 1 and R 2forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H;

[1486] in Is a single bond or a double bond;

[1487] Among them L 1 or L 2 One is the joint;

[1488] Among them L 1 yes:

[1489] H;

[1490] R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl) e -[(C(O)-] f ;or

[1491] R 40 -(-C2H4-O) c -C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H4-O) t -(C 1-6 alkyl)-[(C(O)-] k ;

[1492] Among them L 2 yes:

[1493] H;

[1494] R 40 - (C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl)-[(C(O)-NH] j -(-C2H-4-O) t -[OP(O)SH]; or

[1495] R 40 - (-C2H4-O)t -C(O)-(A1-A2) g -NH-(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H-4-O) t -(C 1-6 alkyl)-[(C(O)-] f -[OP(O)SH];

[1496] Among them L 1 or L 2 One of them is not H;

[1497] where R 40 It is a reactive group;

[1498] wherein A1 and A2 are independently in each instance an amino acid;

[1499] Where subscript:

[1500] b and j are independently selected at each occurrence from 0 to 4;

[1501] c and t are independently selected in each case from 0 to 32;

[1502] e, f, g, h and k are independently 0 or 1 in each instance.

[1503] Embodiment 26. The compound of any one of Embodiments 21-25, wherein R 40 It is a maleimide group.

[1504] Embodiment 27. The compound of any one of Embodiments 18-26, wherein R 11b Yes-(A 1- A2) q -, wherein A1-A2 is: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine or asparagine-alanine.

[1505] Embodiment 28. The compound of Embodiment 27, wherein A1-A2 is selected from Val and Cit.

[1506] Embodiment 29. The compound of any one of Embodiments 24-28, wherein the compound is:

[1507]

[1508] Embodiment 30. The compound of Embodiments 24-28, wherein the compound is:

[1509]

[1510] Embodiment 31. The compound of any one of Embodiments 17-30, wherein L 1 or L 2 At least one of which independently comprises:

[1511]

[1512] in Represents a compound of formula (IV) or L 1 or L 2 The connection point of the rest of the

[1513] wherein r is an integer selected from 1 to 12; and

[1514] wherein s is an integer selected from 1 to 32.

[1515] Embodiment 32. The compound of embodiment 31, wherein

[1516] wherein r is an integer selected from 2 to 12; and

[1517] wherein s is an integer selected from 2 to 32.

[1518] Embodiment 33. The compound of Embodiment 29, wherein the compound is:

[1519]

[1520] wherein subscript v is an integer from 1 to 32; and

[1521] where subscript u is an integer from 0 to 11.

[1522] Embodiment 34. The compound of Embodiment 33, wherein subscript v is an integer selected from 1 to 14.

[1523] Embodiment 35. The compound of embodiment 33 or 34, wherein the compound is

[1524]

[1525] wherein the subscript e is an integer selected from 1 to 6.

[1526] Embodiment 36. The compound of Embodiment 35, wherein subscript e is an integer from 1 to 4.

[1527] Embodiment 37. The compound of Embodiment 17, wherein the compound has the following structure:

[1528]

[1529]

[1530]

[1531]

[1532]

[1533] Embodiment 38. A compound comprising a linker or reactive linker covalently bonded to lubidene via a secondary alcohol or a secondary amine.

[1534] Embodiment 39. A compound comprising a linker or reactive linker covalently bonded to trabectedin via a secondary alcohol, or a secondary amine.

[1535] Embodiment 40. The compound of Embodiment 38 or 39, wherein the compound is covalently bonded to the targeting agent.

[1536] Embodiment 41. The compound of any one of Embodiments 38-40, wherein the compound is covalently bonded to an antibody or antibody fragment thereof.

[1537] Embodiment 42. A compound of Formula (Va) or (Vb), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising:

[1538]

[1539] Wherein Ab is a targeting agent;

[1540] Wherein the subscript k is an integer from 1 to 10;

[1541] where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and

[1542] Among them B 1 It is a joint;

[1543] Among them B 2 It's a connector.

[1544] Embodiment 43. The compound of embodiment 42, wherein Ab is an antibody, antibody fragment, protein or peptide.

[1545] Embodiment 44. The compound of embodiment 42 or 43, wherein

[1546] Among them B 1 Contains at least one of the following:

[1547] (a)-H, if B 2 Not H;

[1548] (b) -CH3;

[1549] (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1550] (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1551] (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1552] (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1553] (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1554] where R 10 It is R 10a -R 10b ,in

[1555] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1556] R 10b Selected from the group consisting of:

[1557] (i)-C(O)-R 11 ;

[1558] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1559] (iii)-NH-R 11 ;

[1560] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1561] (v)-C(O)-NH-R 11 ;

[1562] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1563] (vii)-C(O)-NH-NH-R 11 ;

[1564] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1565] (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ;

[1566] (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ;

[1567] (xi)-CH(NH2)-CO-R 11 ;

[1568] (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ;

[1569] (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ;

[1570] (xiv)-CH(CO-R 11 )-NH-R 11 ;

[1571] (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R11 ;

[1572] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1573] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1574] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1575] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1576] R 11d Selected from the group consisting of -O- and -NH;

[1577] Among them B 2 Contains at least one of the following:

[1578] (a)-H, if B 1 Not H;

[1579] (b) -PO3H-;

[1580] (c)-PO2SH-;

[1581] (d) -CH3;

[1582] (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl;

[1583] (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl;

[1584] (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein C 3-10-heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S;

[1585] (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl;

[1586] (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;

[1587] where R 10 It is R 10a -R 10b ,in

[1588] R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence;

[1589] R 10b Selected from the group consisting of:

[1590] (i)-C(O)-R 11 ;

[1591] (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32;

[1592] (iii)-NH-R 11 ;

[1593] (iv)-N(C 1-4 -alkyl)-R 11 ;

[1594] (v)-C(O)-NH-R 11 ;

[1595] (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ;

[1596] (vii)-C(O)-NHNH-R 11 ;

[1597] (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ;

[1598] (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ;

[1599] (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ;

[1600] (xi)-CH(NH2)CO-R 11 ;

[1601] (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ;

[1602] (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ;

[1603] (xiv)-CH(CO-R 11 )NH-R 11 ;

[1604] (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ;

[1605] where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof;

[1606] R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-;

[1607] R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6;

[1608] R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and

[1609] R 11d is selected from the group consisting of -O- and -NH; and

[1610] Among them B 1 or B 2 One of them is not H; and

[1611] Among them B 1 or B 2 One of them is bonded to Ab.

[1612] Embodiment 45. The compound of any one of Embodiments 41-43, wherein the compound is

[1613]

[1614] Embodiment 46. The compound of any one of Embodiments 41-43, wherein the compound is

[1615]

[1616]

[1617] Embodiment 47. The compound of any one of Embodiments 42-46, wherein B 1 or B 2 At least one of which independently comprises

[1618]

[1619] in Represents a compound of formula (Va) or (Vb) or L 1 or L 2 The connection point of the rest of the

[1620] in indicates the point of attachment to the antibody or antibody fragment;

[1621] wherein the subscript r is an integer selected from 1 to 6; and

[1622] wherein the subscript s is an integer selected from 2 to 14.

[1623] Embodiment 48. The compound of embodiment 47, wherein

[1624] wherein the subscript r is an integer selected from 2 to 6; and

[1625] wherein the subscript s is an integer selected from 2 to 14.

[1626] Embodiment 49. The compound of embodiment 47 or 48, wherein the compound is

[1627]

[1628] wherein a is an integer selected from 2 to 6.

[1629] Embodiment 50. The compound of embodiment 42, wherein the compound is selected from

[1630]

[1631]

[1632]

[1633] Embodiment 51. A pharmaceutical composition comprising a compound according to any one of embodiments 1-16 or 38-49 and a pharmaceutically acceptable excipient.

[1634] Embodiment 52. A method of treating a disease or condition comprising administering a compound of embodiments 1-16 or 38-49.

[1635] Example

[1636] Unless otherwise stated, the following analytical methods were used.

[1637] Analytical method A.

[1638] Instrument: Agilent 1260 Infinity Lab LC / MSD. Column: Agilent Zorbax C18, 5 mm, 4.6 x 50 mm. Column temperature: 45°C. Mobile phase A: 0.1% trifluoroacetic acid (TFA) in water. Mobile phase B: 0.1% TFA in acetonitrile. Gradient from 5% to 95% mobile phase B over 3 minutes, hold at 95% B for 3 minutes, and column wash for 4 minutes. UV traces were monitored at 210 nm and 254 nm. Molecular ions between 115 and 1200 Da were monitored in positive and negative ionization modes.

[1639] Analytical method B.

[1640] Instrument: Agilent 6230TOF LC / MS. Column: Agilent Zorbax 300SB-C8, 5 mm, 4.6 x 50 mm. Column temperature: 45°C. Mobile phase A: 0.1% FA in water. Mobile phase B: 0.1% TFA in acetonitrile. Gradient from 5% to 95% mobile phase B over 10 min, hold at 95% B for 5 min, column rinse for 5 min. UV traces monitored at 210 nm and 254 nm.

[1641] As used herein, the symbols and conventions used in the procedures, schemes, and examples are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry, whether or not certain abbreviations are specifically defined. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromolar); Hz (hertz); MHz (megahertz); mmol (millimole); hr or hour (hour); min (minute); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); THF (tetrahydrofuran); CDCl3 (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EtOAc (ethyl acetate); MeOH (methanol); and BOC (tert-butyloxycarbonyl).

[1642] For all of the following examples, standard workup and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. Unless otherwise indicated, all reactions are carried out at room temperature. The synthetic methodologies presented herein are intended to illustrate applicable chemistry through the use of specific examples and do not limit the scope of this disclosure.

[1643] Example 1

[1644] Preparation of LD1

[1645]

[1646] This example provides the synthesis of lubitidin LD1.

[1647] Maleimido-(PEG)2-carboxylic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 minutes before the addition of rubitidine (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using flash reverse phase chromatography on a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water with 0.1% formic acid. LCMS analysis methods A, R t =4.8min, expected [M+H] + 1095.40, measured [M+H] + 1095.4, [M+2H]2+ 548.5, off-white solid.

[1648] Example 2

[1649] Preparation of LD2

[1650]

[1651] This example provides the synthesis of lubitidin LD2.

[1652] Maleimido-(PEG)4-carboxylic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 minutes before the addition of rubitidine (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using flash reverse phase chromatography on a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water with 0.1% formic acid. LCMS analysis methods A, R t =4.92min, expected [M+H] + 1183.45, measured [M+H] + 1184.0, [M+2H] 2+ 592.5, off-white solid.

[1653] Example 3

[1654] Preparation of LD3

[1655]

[1656] This example provides the synthesis of lubitidin LD3.

[1657] Maleimido-(PEG) 12 -carboxylic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 minutes before the addition of rubitidine (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using flash reverse phase chromatography on a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water with 0.1% formic acid. LCMS analysis methods A, R t=4.63min, expected [M+H] + 1535.66, found [M+2H] 2+ 768.4, off-white solid. High-resolution TOF-MS expected [M+H] + 1535.6637, measured [M+H] + 1535.7737.

[1658] Example 4

[1659] Preparation of LD4

[1660]

[1661] This example provides the synthesis of lubitidin LD4.

[1662] Maleimido-hexanoic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 minutes before the addition of rubitidine (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using flash reverse phase chromatography on a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water with 0.1% formic acid. LCMS analysis methods A, R t =5.2min, expected [M+H] + 978.35, measured [M+H] + 978.4, [M+2H] 2+ 490, off-white solid.

[1663] Example 5

[1664] Preparation of LD5

[1665]

[1666] This example provides the synthesis of lubitidin LD5.

[1667] Maleimido-glycine (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 minutes before the addition of rubitidine (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using flash reverse phase chromatography on a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water with 0.1% formic acid. LCMS analysis methods A, R t =4.75min, expected [M+H] + 922.29, measured [M+H] + 922.3, [M+2H] 2+ 461.6, off-white solid.

[1668] Example 6

[1669] Preparation of LD6

[1670]

[1671] This example provides the synthesis of Lubitidin LD6

[1672] Maleimido-Val-Cit-PAB-PNP (1 eq) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M, followed by the addition of amino-(PEG) 2-carboxylic acid (1.5 eq) and DIPEA (5 eq). The reaction was stirred at room temperature for 24 hours, and then the crude product was purified by flash reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS analysis methods A, R t =4.86min, expected [M+H] + 1589.65, found [M+2H] 2+ 795.4, [M-OH+H] 2+ 786.4, off-white solid.

[1673] Maleimido-Val-Cit-PAB-amido-(PEG)2-carboxylic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 minutes before the addition of rubitidine (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using flash reverse phase chromatography on a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water with 0.1% formic acid. LCMS analysis methods A, R t =4.86min, expected [M+H] + 1589.66, measured [M+H] + 795.4, [M-OH+H]2 + 786.4, off-white solid.

[1674] Example 7

[1675] Preparation of LD7

[1676]

[1677]

[1678] This example provides the synthesis of trabectedin LD7.

[1679] Maleimido-(PEG)4-carboxylic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 min before the addition of trabectedin (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS analysis methods A, R t =4.54min, expected [M+H] + 1160.44, measured [M+H] + 1160.4, [M+2H] 2+ 580.7, light yellow solid.

[1680] Example 8

[1681] Preparation of LD8

[1682]

[1683]

[1684] This example provides the synthesis of Trabectedin LD8.

[1685] 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 min before the addition of trabectedin (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid) using fast reverse phase chromatography. LCMS analysis methods A, R t =4.32min, expected [M+H] + 899.28, measured [M+H] + 899.3, red solid.

[1686] Example 9

[1687] Preparation of LD9

[1688]

[1689]

[1690] This example provides the synthesis of trabectedin LD9.

[1691] Maleimidocaproic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 min before the addition of trabectedin (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr). The crude product was purified using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS analysis methods A, R t =4.9min, expected [M+H]+ 955.34, measured [M+H] + 955.9, yellow solid.

[1692] Example 10

[1693] Preparation of LD10

[1694]

[1695]

[1696] This example provides the synthesis of trabectedin LD10.

[1697] Maleimido-Val-Cit-PAB-PNP (1 eq) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M, followed by the addition of amino-(PEG) 2-carboxylic acid (1.5 eq) and DIPEA (5 eq). The reaction was stirred at room temperature for 24 hours, and then the crude product was purified by flash reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS analysis methods A, R t =4.56min, expected [M+H] + 822.39, measured [M+H] + 822.4, off-white solid.

[1698] Maleimido-Val-Cit-PAB-amido-(PEG)2-carboxylic acid (1.5 eq) was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.1 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 5 eq) and diisopropylethylamine (DIPEA; 10 eq). The reaction mixture was stirred at room temperature for 10 min before the addition of trabectedin (1 eq). The reaction mixture was stirred at room temperature for 16 hours (hr) and the crude product was purified using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water with 0.1% formic acid using fast reverse phase chromatography. LCMS analysis methods A, R t =4.96min, expected [M+H] + 1565.63, found [M+2H] 2+ 783.4, [M-OH+H] 2+ 774.2, light yellow solid.

[1699] Example 11

[1700] Preparation of Lubitidine Derivative 1

[1701]

[1702] This example provides the synthesis of the above compounds.

[1703] Lubiquinone was dissolved in anhydrous dimethylformamide (DMF) at a concentration of 0.01 M, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)formamidine hexafluorophosphate (BTFFH; 10 equivalents) and diisopropylethylamine (DIPEA; 20 equivalents). The reaction mixture was stirred at room temperature overnight. The crude product was purified using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS analysis methods A, R t =4.81min, expected [M+H] + 937.41, measured [M+H] + 937.4, red solid.

[1704] Example 12

[1705] Preparation of lubitidine derivative 2.

[1706]

[1707] This example provides the synthesis of the above compounds.

[1708] To a solution of lubide (1 eq) in dimethylformamide (DMF) was added (-)PSI reagent (4 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5 eq) and the reaction was stirred at room temperature for 1 hour followed by addition of water and reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column, 5%-95% acetonitrile / water (with 0.1% formic acid) gradient. LCMS Analytical Methods A, R t =4.64min, expected [M+H] + 881.22, measured [M+H] + 881.2, yellow solid.

[1709] Example 13

[1710] Preparation of lubitidine derivative 3.

[1711]

[1712] This example provides the synthesis of the above compounds.

[1713] To a solution of rubitidine (1 eq) was added (-)PSI reagent (4 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5 eq) and the reaction was stirred at room temperature for 1 hour, followed by the addition of N-Boc amino-(PEG)4-ol (5 eq) and stirring for 1 hour. The crude product was purified by reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS analysis methods A, R t =4.52min, expected [M+H] + 1156.40, measured [M+H] + 1155.4, [M+2H] 2+ 578.5, yellow solid.

[1714] The structure of the (-)PSI reagent is as follows:

[1715]

[1716] Example 14

[1717] Preparation of trabectedin derivative 4.

[1718]

[1719] This example provides the synthesis of the above compounds.

[1720] To a solution of trabectedin (1 eq) in dimethylformamide (DMF) was added (-)PSI reagent (4 eq) and diazabicyclo[5.4.0]undec-7-ene (DBU) (5 eq) and the reaction was stirred at room temperature for 1 hour, followed by addition of water and reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column, a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS Analytical Methods A, R t =4.42min, expected [M+H] + 858.21, measured [M+H] + 858.2, light yellow solid.

[1721] Example 15

[1722] Preparation of trabectedin derivative 5.

[1723]

[1724] This example provides the synthesis of the above compounds.

[1725] To a solution of trabectedin (1 eq) was added (-)PSI reagent (4 eq) and diazabicyclo[5.4.0]undec-7-ene (DBU) (5 eq) and the reaction was stirred at room temperature for 1 hour, followed by the addition of N-Boc amino-(PEG)4-ol (5 eq) and stirring for 1 hour. The crude product was purified by reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column, a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid). LCMS analysis methods A, R t =4.52min, expected [M+H] + 1133.38, measured [M+H] + 1133.4, [M+2H] 2+ 567.0, yellow solid.

[1726] Example 16

[1727] Preparation of LD11

[1728]

[1729]

[1730] This example provides the synthesis of lubitidine LD11.

[1731] The lubidine derivative 3 was dissolved in 10% TFA / DCM and stirred at room temperature for 30 minutes. The reaction mixture was concentrated on a rotary evaporator. The crude lubidine amine product was used in the next step.

[1732] The crude rutile amine was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equivalents) and Mal-(PEG)4-NHS (2 equivalents) reagents. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid).

[1733] The structure of Mal-(PEG)4-NHS (i.e., Mal-PEG4-NHS) as used in the examples of the present disclosure is shown below:

[1734]

[1735] Example 17

[1736] Preparation of LD12

[1737]

[1738]

[1739] This example provides the synthesis of trabectedin LD12.

[1740] Trabectedin derivative 5 was dissolved in 10% TFA / DCM and stirred at room temperature for 30 minutes.The reaction mixture was concentrated on a rotary evaporator and the crude trabectedin amine product was used in the next step.

[1741] The crude trabectedin amine was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equivalents) and Mal-(PEG)4-NHS (2 equivalents) reagents. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column, a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid).

[1742] Example 18

[1743] Preparation of LD13

[1744]

[1745]

[1746] This example provides the synthesis of lubitidin LD13.

[1747] The lubidine derivative 3 was dissolved in 10% TFA / DCM (TFA = trifluoroacetic acid) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated on a rotary evaporator and the crude lubidine amine product was used in the next step.

[1748] The crude rutabaga was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equivalents, DIPEA = diisopropylethylamine) and Mal-(PEG)2-Val-Cit-PAB-PNP (2 equivalents) reagents. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column and a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid).

[1749] The structure of Mal-(PEG)2-Val-Cit-PAB-PNP (i.e., Mal-PEG2-Val-Cit-PAB-PNP) as used in the examples of the present disclosure is shown below:

[1750]

[1751] Example 19

[1752] Preparation of LD14

[1753]

[1754] This example provides the synthesis of trabectedin LD14.

[1755] Trabectedin derivative 5 was dissolved in 10% TFA / DCM and stirred at room temperature for 30 minutes.The reaction mixture was concentrated on a rotary evaporator and the crude trabectedin amine product was used in the next step.

[1756] The crude trabectedin amine was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equivalents) and Mal-(PEG)2-Val-Cit-PAB-PNP (2 equivalents) reagents. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by reverse phase chromatography using a Biotage Isolera chromatograph equipped with a Biotage Sfar C18 column, a gradient of 5%-95% acetonitrile / water (with 0.1% formic acid).

[1757] Example 20

[1758] Antibody-drug conjugate generation and characterization

[1759] Conjugation

[1760] mAb was pH adjusted with 200 mM Tris, 5 mM EDTA, pH 8.5 (10% if in PBS, 30% if in proA) and then reduced with 4-10 equivalents of TCEP at 37°C for 1 hour. The number of free thiols was quantified using the Ellman test. 10% DMSO and 2M excess linker-drug (LD, e.g., LD1) per mol of free thiol were added, the solution was vortexed and allowed to stand at room temperature for 2 hours. Then, 1.2 mol of N-acetylcysteine ​​(NAC) per mol of linker-drug was added, the solution was vortexed and allowed to stand at room temperature for 20 minutes. The resulting antibody drug conjugate (ADC) was then buffered with PBS pH 7.4 3 times to remove free linker-drug.

[1761] The drug-to-antibody ratio (DAR) was determined by hydrophobic interaction chromatography (HIC) or mass spectrometry using intact ADC. Aggregates were determined by size exclusion chromatography (SEC).

[1762] Complete characterization data are presented in Table 1 below.

[1763] Characterization of hydrophobic interactions of ADCs

[1764] Hydrophobic interaction characterization (HIC) was performed using a PolyPropyl A column (PolyLC) with 1.5 M ammonium sulfate and 25 mM potassium phosphate in water as mobile phase A and 0.25% w / v CHAPS and 25 mM potassium phosphate in water as mobile phase B. The sample was injected directly onto the column using a gradient of 0-100% mobile phase B over 15 min. UV signals were collected at 280 nm and the chromatograms were analyzed for unconjugated antibody and higher DAR species. DAR calculations were performed by integrating the area under the HIC curve for the previously established peaks (DAR = 0, DAR = 1, DAR = 2, DAR = 4, etc.) and calculating the % for each peak.

[1765] Mass spectrometric characterization of intact ADC

[1766] The non-reduced masses of the antibody-drug conjugates were determined on an Agilent 6230TOF LC / MS equipped with an electrospray ionization (ESI) source directly coupled to an Agilent 1260 high performance liquid chromatography system. Samples were first diluted to 1 mg / mL and then analyzed in their non-reduced form. Proteins were separated on a reversed-phase column (Zorbax 300SB-C8, 5 mm, 4.6 x 50 mm) with a denaturing mobile phase system. Mobile phase A was 0.1% (v / v) formic acid in water. Mobile phase B was 0.1% (v / v) formic acid (mobile phase B) in 80% (v / v) 2-propanol, 10% (v / v) acetonitrile, and 10% (v / v) water. The MS spectra of each protein were averaged, and then deconvolution was performed to obtain average mass and monoisotopic mass.

[1767] Size exclusion chromatography characterization of aggregates

[1768] Size exclusion chromatography (SEC) was used to characterize the size heterogeneity of the antibody-drug conjugates. The analysis was performed using an Acquity 1.7 μm, 4.6 x 300 mm UPLC BEH200 SEC column with 25 mM sodium phosphate, pH 6.5, 500 mM L-arginine, and 10% isopropyl alcohol (IPA) in water as the mobile phase. The sample was injected neat and the mobile phase was applied isocratically at 0.2 mL / min for 22 min. The UV signal at 280 nm was collected and the peak area was used to calculate the degree of aggregation and fragmentation of the ADC.

[1769] Table 1. Characterization of ecteinascidin ADCs.

[1770]

[1771]

[1772] In vitro plasma stability

[1773] Trastuzumab-LD3 ADC was spiked into macaque, rat, and mouse plasma at a concentration of 50 μg / mL and incubated at 37°C for 7 days. Cells were collected at different time points, including 0, 24, 72, and 168 hours. TM MS-compatible magnetic IP kits subjected all time points to a two-step immunoaffinity enrichment. The first step involved fixing a biotinylated anti-human IgG capture reagent to streptavidin magnetic beads, followed by a second step of affinity purification of the sample. The eluted sample was injected onto an Agilent 1260 high performance liquid chromatography system connected to an Agilent 6230 TOF LC / MS system. Analyzed using a reversed-phase column (Zorbax 300SB-C8, 5 mm, 4.6 x 50 mm) with a denaturing mobile phase system. Mobile phase A was 0.1% (v / v) formic acid in water. Mobile phase B was 0.1% (v / v) formic acid (mobile phase B) in acetonitrile. The MS spectra of each protein were averaged and then deconvoluted to obtain average mass and monoisotopic mass. MS was operated under denaturing conditions using an m / z range of 300-3500 and a capillary voltage of 4.5 kV. The MS data were analyzed in MassHunter software using a maximum entropy deconvolution algorithm. The percent conjugate remaining at each time point was calculated based on the time-0 reference value, assuming the time 0 value was 100%. The assay imprecision was + / - 25%.

[1774] The results are summarized in Table 2.

[1775] Table 2. In vitro plasma stability results

[1776]

[1777] In vitro ecteinascidin ADC cytotoxicity-adherent cell cytotoxicity assay

[1778] Adherent cells are cultured to 50-80% confluence in T75 flasks and harvested into single cell suspensions with trypsin. 3 to 5,000 (3,000-5,000) cells per well are seeded in a tissue culture plate of 50 μL / well culture medium and incubated at 37°C for 18-24 hours. Serial dilutions of ADC in the culture medium are then distributed to the plate in 50 μL / wells. After plating and processing, the cells are returned to the incubator for an additional 3 to 5 days. CellTiter-Glo reagent is prepared according to the manufacturer's instructions and added to the culture at 100 μL / well. CellTiter-Glo allows relative counting of metabolically active cells by quantifying intracellular ATP concentration. After incubation with CellTiter-Glo for 5 minutes at ambient room temperature, the transparent bottom black assay plate is then read in a photometer within 30 minutes, or the Cell Titer Glo / cell lysate solution of 125 μL / well is transferred to a black assay plate and read. The luminescent reading obtained from the culture that has not received any treatment (cell culture medium only) is set to 100% control, and all other luminescent values ​​are normalized to these controls (e.g., normalized RLU, relative luminescent units). Luminescent signals are detected using a standard plate reader, and IC50 is calculated by logistic nonlinear regression using GraphPad Prism (GraphPad Software, San Diego, CA).

[1779] Suspension cell cytotoxicity assay

[1780] Suspension cells were cultured as single cell suspensions in T75 flasks. Three to five thousand (3,000-5,000) cells per well were seeded in 50 μL / well of culture medium in tissue culture plates and incubated at 37° C. for 18-24 hours.

[1781] The serial dilutions of ADC in the culture medium are then distributed to the plate with 50 μ L / wells. After plating and processing, the cells are returned to the incubator for an additional 3-5 days. CellTiter-Glo reagent is prepared according to the manufacturer's instructions and added to the culture with 100 μ L / wells. CellTiter-Glo allows relative counting of metabolically active cells by quantifying intracellular ATP concentration. After incubation with CellTiter-Glo for 5 minutes at ambient room temperature, the transparent bottom black assay plate is then read in a photometer within 30 minutes, or the Cell Titer Glo / cell lysate solution of 125 μ L / wells is transferred to a black assay plate and read. The luminescent readings obtained from the culture (only cell culture medium) that has never received any treatment are set to 100% control, and all other luminescent values ​​are normalized to these controls (e.g., normalized RLU, relative luminescent units). Standard microplate reader is used to detect luminescent signals, and GraphPad Prism (GraphPad Software, San Diego, CA) is used to calculate IC50 by logistic nonlinear regression. Human neutrophil cytotoxicity assay.

[1782] Human CD34+ myeloid progenitor cells were seeded in 96-well plates at 3,000 cells per well and supplemented with 10 ng / ml human recombinant IL-3 and 30 ng / ml human recombinant G-CSF (both Peprotech, Cranbury, NJ) growth medium. Test ADC or free drug was added to each well in duplicate or triplicate at a specified final concentration. After 3-4 days of cultivation, half of the culture medium (100 μl) was carefully removed, and CellTiter-Glo 2.0 (Promega, Madison, WI) viability assay was performed according to the manufacturer's protocol. Luminescent signals were detected using a standard microplate reader, and IC was calculated using GraphPad Prism (GraphPad Software, San Diego, CA) by logistic nonlinear regression. 50 .

[1783] The results are summarized in Tables 3-5 below. All experiments were repeated at least 3 times, with each data point in duplicate. As used in the following tables, n / t means "not tested."

[1784] Table 3. In vitro cytotoxicity of ecteinascidin ADC and small molecule derivative 1 in HCC1954 (Her2 positive), confluent HCC1954 (Her2 positive), SKBR3 (Her2 positive) and SUDHL1 (CD30 positive) cell lines.

[1785]

[1786]

[1787] Table 4. In vitro cytotoxicity of ecteinascidin ADCs in SKOV3 (Her2 positive) and NCI-N87 (Her2 positive) cell lines.

[1788]

[1789]

[1790]

[1791] Table 5. In vitro cytotoxicity of ecteinascidin ADCs in primary human neutrophils.

[1792] sample <![CDATA[Human Neutrophil IC 50 , nM]]> Trastuzumab-LD1 66.32 Trastuzumab-LD2 54.05 Trastuzumab-LD3 120 Trastuzumab-LD4 68.02 Trastuzumab-LD6 100 Trastuzumab-LD7 100 Trastuzumab-LD8 28.01 Trastuzumab-LD10 94.48 Trastuzumab-LD15 >100

[1793] Example 21

[1794] Antibody Drug Conjugate Efficacy and Tolerability

[1795] In vivo efficacy studies

[1796] Female B-NDG mice aged 6-8 weeks were injected subcutaneously with 5x10 6 NCI-N87 cells (ATCC CRL-5822). The volume of subcutaneously grown tumors was measured twice a week using a caliper and calculated using the modified ellipsoid formula: tumor volume (TV) = 0.5 x length x width 2 The body weights of the animals were also recorded twice a week to monitor the tolerance of the test article. Five days after cell inoculation, when the average tumor volume was approximately 150 mm 3 On day 0, mice (n=5 per group) received their first dose of vehicle control (PBS) or 0.5 mg / kg body weight trastuzumab-LD7 antibody drug conjugate (ADC) by intravenous injection into the tail vein (day 0). On day 10, mice received a second dose of vehicle control or trastuzumab-LD7. ...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof: where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; where R 20 for: (a) Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 - heterocycle, C(O)R5, C(O)OR5, C(O)NHR5, SO2R5 and SO2NHR5, wherein the C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or (b)L 1 , where L 1 is a reactive linker group; in, R 20 Optionally substituted with 1-3 substituents independently selected in each case from the group consisting of OH, F, Cl, Br, C 1-5 -alkyl, C 3-6 -cycloalkyl and C 3-6 -heterocycle; where R 30 for: (c) selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 - aryl, phosphate, phosphorothioate, phosphoramide, C(O)R6, C(O)OR6, and C(O)NHR6, sulfonyl, sulfonamide, wherein the C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or (d)L 2 , where L 2 is a reactive linker group; wherein the phosphates and phosphorothioates are optionally substituted with 1 to 2 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and wherein the substituents on the phosphate and phosphorothioate are optionally blocked with protecting groups; where R 5 and R 6 Each is independently selected in each case from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; where R 20 or R 30 At least one of them is not H; in is a single bond or a double bond; and wherein the subscript y is an integer selected from 0 to 32.

2. The compound according to claim 1, wherein L 1 Contains at least one of the following: (a)-H, if L 2 Not H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; or (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

3. The compound according to claim 1 or 2, wherein L 2 Contains at least one of the following: (a)-H, if L 1 Not H; (b) -PO3H- or -PO3H2; (c) -PO2SH- or -PO2SH2; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

4. The compound according to claim 2 or 3, wherein R 11 Selected from: R 11a -R 11b -R 11c -R 11d ; R 11b -R 11c -R 11d ; R 11c -R 11d ;or R 11a -R 11c -R 11d 。 5. The compound according to any one of claims 2 to 4, wherein R 11 With reactive group R 40 End-capping.

6. The compound according to any one of claims 1 to 5, wherein L 1 Contains at least one of the following bivalent structures: (a)-C(O)-; (b) -C(O)-NH-; (c)-C(O)O-; (d)-[(C(O)-NH] n -; (e)-C(O)-; <h2 style=";text-align:left;direction:ltr">(f)-(A1-A2)<h2 style=";text-align:left;direction:ltr"> d <h2 style=";text-align:left;direction:ltr"> -; (g)[-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- or -O-(C6H4)-CH2-O-; (h)-(C 1-6 -alkyl)-; (i)-(C2H4-O) r- ;or (j)-(C 1-6 -alkyl) p -; Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group; A1 and A2 are independently, in each instance, an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid; in Subscript: d is an integer selected from 0 to 1; n is an integer selected from 0 to 4; r is an integer selected from 0 to 32; and p is an integer 0 or 1.

7. The compound according to any one of claims 1 to 5, wherein L 2 Contains at least one of the following bivalent structures: (a) -PO3H- or -PO3H2; (b) -PO2SH- or -PO2SH2; (c)-C(O)-; (d) -C(O)-NH-; (e)-C(O)O-; (f)-[(C(O)-NH] n -; (g)-C(O)-; <h2 style=";text-align:left;direction:ltr">(h)-(A1-A2)<h2 style=";text-align:left;direction:ltr"> d <h2 style=";text-align:left;direction:ltr"> -; (i) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- or -O-(C6H4)-CH2-O-; (j)-(C 1-6 -alkyl)-; (k)-(C2H4-O) r- ;or (l)-(C 1-6 -alkyl) p -; Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group; A1 and A2 are independently, in each instance, an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid; in Subscript: d is an integer selected from 0 to 1; n is an integer selected from 0 to 4; r is an integer selected from 0 to 32; and p is an integer 0 or 1.

8. A compound according to any one of claims 1 to 7, wherein R 20 yes in represents the bond through which the indicated substituent is bonded.

9. The compound according to any one of claims 1 to 8, wherein R 30 yes in Represents the bond through which the phosphorothioate is bonded.

10. The compound according to claim 1, wherein the compound is selected from 11. A compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising: Among them L 1 or L 2 One of them is a reactive linker.

12. The compound according to claim 11, wherein L 1 Contains at least one of the following: (a)-H, if L 2 Not H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

13. The compound according to claim 11 or 12, wherein L 2 Contains at least one of the following: (a)-H, if L 1 Not H; (b) -PO3H- or -PO3H2; (c) -PO2SH- or -PO2SH2; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

14. The compound according to claim 12 or 13, wherein R 11 Selected from: R 11a -R 11b -R 11c -R 11d ; R 11b -R 11c -R 11d ; R 11c -R 11d ;or R 11a -R 11c -R 11d 。 15. The compound according to any one of claims 12 to 14, wherein R 11 With reactive group R 40 End-capping.

16. A compound of formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising: where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; in Is a single bond or a double bond; Among them L 1 Contains at least one of the following: (a)-H, if L 2 Not H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH; Among them L 2 Contains at least one of the following: (a)-H, if L 1 Not H; (b) -PO3H-; (c)-PO2SH-; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

17. A compound of formula (IV) or a pharmaceutically acceptable salt, ester, or tautomer thereof, comprising: where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; in Is a single bond or a double bond; Among them L 1 or L 2 One is the joint; Among them L 1 yes: H； R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl) e -[(C(O)-] f ; R 40 -(-C2H4-O) c -C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H4-O) t -(C 1-6 alkyl)-[(C(O)-] k ;or R 40 -(C 1-6 alkyl)-C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -; Among them L 2 yes: H； R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl)-[(C(O)-NH] j -(-C2H4-O) t -[OP(O)SH]; or R 40 -(-C2H4-O) t -C(O)-(A1-A2) g -NH-(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H-4-O) t -(C 1-6 alkyl)-[(C(O)-] f -[OP(O)SH]; Among them L 1 or L 2 One of them is not H; where R 40 It is a reactive group; wherein A1 and A2 are independently in each instance an amino acid; Where subscript: b and j are independently selected at each occurrence from 0 to 4; c and t are independently selected in each case from 0 to 32; e, f, g, h and k are independently 0 or 1 in each instance.

18. A compound according to any one of claims 15 to 17, wherein R 40 It is a maleimide group.

19. The compound according to any one of claims 12 to 18, wherein R 11b Yes-(A 1- A2) q -, wherein each occurrence of A1-A2 is independently: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamate-asparagine, asparagine-glutamate, citrulline-asparagine, asparagine-citrulline, alanine-asparagine or asparagine-alanine.

20. The compound according to claim 19, wherein -(A 1- A2) q - is Val-Cit or Cit-Val.

21. The compound according to any one of claims 16 to 20, wherein the compound is:

22. The compound according to any one of claims 16-20, wherein the compound is:

23. The compound according to any one of claims 11 to 22, wherein L 1 or L 2 At least one of which independently comprises: or in Represents a compound of formula (IV) or L 1 or L 2 The connection point of the rest of the wherein r is an integer selected from 1 to 12; and wherein s is an integer selected from 1 to 32.

24. The compound according to claim 23, wherein wherein r is an integer selected from 2 to 12; and wherein s is an integer selected from 2 to 32.

25. The compound according to any one of claims 16 to 24, wherein L 1 is H; or L 2 It’s H.

26. The compound of claim 21, wherein the compound is: wherein subscript v is an integer from 1 to 32; and where subscript u is an integer from 0 to 11.

27. The compound of claim 26, wherein subscript v is an integer selected from 1 to 14.

28. The compound of claim 21, wherein the compound is wherein the subscript e is an integer selected from 1 to 6.

29. The compound of claim 28, wherein subscript e is an integer from 1 to 4.

30. The compound according to claim 16 or 17, wherein the compound has the following structure:

31. A compound comprising a linker or reactive linker covalently bonded to lubidine via a secondary alcohol or a secondary amine.

32. A compound comprising a linker or reactive linker covalently bonded to trabectedin via a secondary alcohol or a secondary amine.

33. The compound of claim 31 or 32, wherein the compound is covalently bonded to a targeting agent.

34. The compound of any one of claims 31-33, wherein the compound is covalently bonded to an antibody or antibody fragment thereof.

35. A compound of formula (Va) or (Vb), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising: Wherein Ab is a targeting agent; Wherein the subscript k is an integer from 1 to 10; where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and Among them B 1 It is a joint; Among them B 2 It's a connector.

36. The compound of claim 35, wherein Ab is an antibody, antibody fragment, protein or peptide.

37. The compound according to claim 35 or 36, wherein Among them B 1 Contains at least one of the following: (a)-H, if B 2 Not H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH; Among them B 2 Contains at least one of the following: (a)-H, if B 1 Not H; (b) -PO3H-; (c)-PO2SH-; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; and Among them B 1 or B 2 One of them is not H; and Among them B 1 or B 2 One of them is bonded to Ab.

38. A compound according to any one of claims 34-37, wherein the compound is 39. The compound according to any one of claims 34-37, wherein the compound is 40. A compound according to any one of claims 35-39, wherein B 1 or B 2 At least one of which independently comprises or in Represents a compound of formula (Va) or (Vb) or L 1 or L 2 The connection point of the rest of the in indicates the point of attachment to the antibody or antibody fragment; wherein the subscript r is an integer selected from 1 to 6; and wherein the subscript s is an integer selected from 2 to 14.

41. The compound according to claim 40, wherein wherein the subscript r is an integer selected from 2 to 6; and wherein the subscript s is an integer selected from 2 to 14.

42. The compound according to claim 40 or 41, wherein the compound is wherein a is an integer selected from 2 to 6.

43. The compound according to claim 35, wherein the compound is selected from 44. A pharmaceutical composition comprising a compound according to any one of claims 1-10 or 31-43 and a pharmaceutically acceptable excipient.

45. A method of treating a disease or condition comprising administering a compound according to claims 1-10 or 31-43.

46. ​​A compound of formula (XI), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof: in: R 1 and R 2 Together they form an aromatic ring or a bicyclic heteroaromatic ring; wherein the aromatic ring and the bicyclic heteroaromatic ring are optionally substituted with 1 to 6 substituents independently selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, -SH and -SO3H; R 3 is hydrogen or CH2OR 6 ; R 4 It is H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 -Heterocycle, C(O)R 8 、C(O)OR 8 、C(O)NHR 8 、SO2R 8 、SO2NHR 8 ; wherein said C 1-10 -alkyl or C 6-10 -Aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -OH, -F, -Cl, -Br, -C 1-6 -alkyl, -C 3-6 -cycloalkyl and -C 3-6 -heterocyclyl; or L 1 ; R 5 and R 6 Each independently selected from: i) H, C 1-10 -alkyl, C 6-10 -aryl, phosphate, phosphorothioate, phosphoramide, C(O)R 9 、C(O)OR 9 , and C(O)NHR 9 、SO3H、SO2R 9 The group consisting of 1-10 -alkyl or C 6-10 -aryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -OH, -F, -Cl, -Br, optionally substituted -C 1-6 -alkyl, optionally substituted-C 3-6 -cycloalkyl and optionally substituted-C 3-6 -heterocyclyl; and ii) L 2 ; where R 5 or R 6 The phosphates and phosphorothioates are optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and wherein the substituents on the phosphate and phosphorothioate are optionally blocked with protecting groups; R 8 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; R 9 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; where R 4 、R 5 and R 6 One of them is the reactive group R 10 or a linker with an antibody Ab; in is a single bond or a double bond; and wherein y is an integer selected from 0 to 32.

47. The compound according to claim 46, wherein L 1 Contains at least one of the following: (a)-H, if L 2 Not H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; or (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

48. The compound according to claim 46 or 47, wherein L 2 Contains at least one of the following: (a)-H, if L 1 Not H; (b) -PO3H- or -PO3H2; (c) -PO2SH- or -PO2SH2; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is independently selected at each occurrence from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

49. The compound according to claim 47 or 48, wherein R 11 Selected from: R 11a -R 11b -R 11c -R 11d ; R 11b -R 11c -R 11d ; R 11c -R 11d ;or R 11a -R 11c -R 11d 。 50. A compound according to any one of claims 47-49, wherein R 11 With reactive group R 40 End-capping.

51. according to the compound described in any one of claims 46-50, wherein L 1 Contains at least one of the following bivalent structures: (a)-C(O)-; (b) -C(O)-NH-; (c)-C(O)O-; (d)-[(C(O)-NH] n -; (e)-C(O)-; <h2 style=";text-align:left;direction:ltr">(f)-(A1-A2)<h2 style=";text-align:left;direction:ltr"> d <h2 style=";text-align:left;direction:ltr"> -; (g)[-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- or -O-(C6H4)-CH2-O-; (h)-(C 1-6 -alkyl)-; (i)-(C2H4-O) r- ;or (j)-(C 1-6 -alkyl) p -; Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group; A1 and A2 are independently, in each instance, an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid; in Subscript: d is an integer selected from 0 to 1; n is an integer selected from 0 to 4; r is an integer selected from 0 to 32; and p is an integer 0 or 1.

52. A compound according to any one of claims 46-50, wherein L 2 Contains at least one of the following bivalent structures: (a) -PO3H- or -PO3H2; (b) -PO2SH- or -PO2SH2; (c)-C(O)-; (d) -C(O)-NH-; (e)-C(O)O-; (f)-[(C(O)-NH] n -; (g)-C(O)-; <h2 style=";text-align:left;direction:ltr">(h)-(A1-A2)<h2 style=";text-align:left;direction:ltr"> d <h2 style=";text-align:left;direction:ltr"> -; (i) [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- or -O-(C6H4)-CH2-O-; (j)-(C 1-6 -alkyl)-; (k)-(C2H4-O)r - ;or (l)-(C 1-6 -alkyl) p -; Among them L 1 or L 2 R 40 End-capped, where R 40 It is a reactive group; A1 and A2 are independently, in each instance, an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid; in Subscript: d is an integer selected from 0 to 1; n is an integer selected from 0 to 4; r is an integer selected from 0 to 32; and p is an integer 0 or 1.

53. according to the compound described in any one of claim 46-52, wherein R 4 yes in represents the bond through which the indicated substituent is bonded.

54. according to the compound described in any one of claims 46-53, wherein R 5 yes in Represents the bond through which the phosphorothioate is bonded.

55. according to the compound described in any one of claims 46-54, wherein R 6 yes in Represents the bond through which the phosphorothioate is bonded.

56. The compound of claim 46, wherein the compound is selected from 57. A compound of formula (XII) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising: Among them L 1 , or L 2 One of the reactive linkers is a reactive linker.

58. The compound according to claim 57, wherein L 1 Contains at least one of the following: (a)-H, if L 2 Neither of the two is H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

59. The compound according to claim 57 or 58, wherein each L 2 Independently comprising at least one of the following: (a)-H, if L 1 Not H; (b) -PO3H- or -PO3H2; (c) -PO2SH- or -PO2SH2; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1-A2) q -, wherein A1 and A2 are independently in each case an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

60. The compound according to claim 58 or 59, wherein R 11 Selected from: R 11a -R 11b -R 11c -R 11d ; R 11b -R 11c -R 11d ; R 11c -R 11d ;or R 11a -R 11c -R 11d 。 61. according to the compound described in any one of claims 58-60, wherein R 11 With reactive group R 40 End-capping.

62. according to the compound described in any one of claims 57-61, wherein L 1 Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, C 3-10 -Heterocycle, C(O)R 8 、C(O)OR 8 、C(O)NHR 8 、SO2R 8 and SO2NHR 8 , wherein the C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or Among them L 1 Optionally substituted with 1-3 substituents independently selected in each case from the group consisting of OH, F, Cl, Br, C 1-5 -alkyl, C 3-6 -cycloalkyl and C 3-6 -heterocycle; where R 8 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, and -SO3H; At least one of the L 1 or L 2 is not H; and wherein the subscript y is an integer selected from 0 to 32.

63. according to the compound described in any one of claims 57-62, wherein L 2 Selected from the group consisting of: H, C 1-10 -alkyl, C 6-10 -aryl, phosphate, phosphorothioate, phosphoramide, C(O)R 9 、C(O)OR 9 , and C(O)NHR 9 、SO3H、SO2R 9 , wherein the C 1-10 -alkyl and C 6-10 - aryl groups are each independently substituted or unsubstituted; or wherein the phosphates and phosphorothioates are optionally substituted with 1 to 2 substituents independently selected in each case from the group consisting of: H, C 1-6 -alkyl, C 3-10 -cycloalkyl, (polyethylene glycol) y ([PEG] y ), C 6-10 -aryl and C 5-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, -OH, and -SO3H; and wherein the substituents on the phosphate and phosphorothioate are optionally blocked with protecting groups; where R 9 Selected from the group consisting of: C 1-6 -alkyl, C 3-10 -cycloalkyl, [PEG] y 、C 6-10 -aryl and C 6-10 -heteroaryl, Among them C 1-6 -alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, and -SO3H; At least one of the L 1 or L 2 is not H; and wherein the subscript y is an integer selected from 0 to 32.

64. A compound of formula (XIII), or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof, comprising: where R 1 and R 2 forming at least one aromatic ring or bicyclic heteroaromatic ring, optionally substituted with 1 to 6 substituents independently selected in each case from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; in Is a single bond or a double bond; Among them L 1 Contains at least one of the following: (a)-H, if L 2 Neither of the two is H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH; Each L 2 Contains at least one of the following: (a)-H, if L 1 Not H; (b) -PO3H-; (c)-PO2SH-; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

65. A compound of formula (XIV) or a pharmaceutically acceptable salt, ester, or tautomer thereof, comprising: where R 1 and R 2 forming at least one aromatic ring or bicyclic heteroaromatic ring, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; in Is a single bond or a double bond; Among them L 1 , or L 2 One of them is the joint; Among them L 1 yes: H； R 40 - (C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c- (C 1-6 alkyl) e -[(C(O)-] f ;or R 40 - (-C2H4-O) c -C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H4-O) t -(C 1-6 alkyl)-[(C(O)-] k ; Each L 2 Independently it is: H； R 40 -(C 1-6 alkyl)-[(C(O)-NH] b -(-C2H4-O) c -(C 1-6 alkyl)-[(C(O)-NH] j -(-C2H4-O) t -[OP(O)SH]; or R 40 -(-C2H4-O) t -C(O)-(A1-A2) g -NH-(C6H4)-CH2-O-[(C(O)-NH] j -(-C2H-4-O) t -(C 1-6 alkyl)-[(C(O)-] f -[OP(O)SH]; Among them L 1 or L 2 One of them is not H; where R 40 It is a reactive group; wherein A1 and A2 are independently in each instance an amino acid; Where subscript: b and j are independently selected at each occurrence from 0 to 4; c and t are independently selected in each case from 0 to 32; e, f, g, h and k are independently 0 or 1 in each instance.

66. A compound according to any one of claims 61-65, wherein R 40 is maleimido, -NH2, -COO-succinimide, halogen or substituted alkyne.

67. A compound according to any one of claims 58-66, wherein R 11b Yes-(A 1- A2) q -, wherein A1-A2 is: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine or asparagine-alanine.

68. The compound according to any one of claims 67, wherein -(A 1- A2) q - is selected from Val-Cit, Val-Ala, Phe-Lys or Gly-Gly-Phe-Gly.

69. The compound of any one of claims 64-68, wherein the compound is:

70. A compound according to any one of claims 57-69, wherein L 1 or L 2 At least one of which independently comprises: or in Represents a compound of formula (IV) or L 1 or L 2 wherein r is an integer selected from 1 to 12; and wherein s is an integer selected from 1 to 32.

71. The compound according to claim 70, wherein wherein r is an integer selected from 2 to 12; and wherein s is an integer selected from 2 to 32.

72. The compound of claim 69 or 70, wherein the compound is: wherein subscript v is an integer from 1 to 32; wherein subscript u is an integer from 0 to 11.

73. The compound of claim 72, wherein subscript v is an integer selected from 1 to 14.

74. The compound according to claim 69 or 70, wherein the compound is wherein the subscript e is an integer selected from 1 to 6.

75. The compound of claim 74, wherein subscript e is an integer from 1 to 4.

76. The compound of claim 69, wherein the compound has the structure:

77. A compound comprising a linker or reactive linker covalently bonded to lubectedin or ecubectedin via a secondary alcohol or a secondary amine.

78. The compound of claim 77, wherein the compound is covalently bonded to a targeting agent.

79. The compound of claim 77 or 78, wherein the compound is covalently bonded to an antibody or antibody fragment thereof.

80. A compound of Formula (XVa), (XVb), or (XVc), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: Wherein Ab is a targeting agent; Wherein the subscript k is an integer from 1 to 10; where R 1 and R 2 forming at least one aromatic ring or bicyclic heterocycle, optionally substituted with 1 to 6 substituents independently in each case selected from the group consisting of: C 1-10 -alkoxy, C 1-10 -alkyl, amino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and Among them B 1 It is a joint; Among them B 2 It's a connector.

81. The compound of claim 80, wherein Ab is an antibody, antibody fragment, protein or peptide.

82. The compound according to claim 80 or 81, Among them B 1 Contains at least one of the following: (a)-H; (b) -CH3; (c) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (d) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (f) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (g) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NH-NH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)N(C 1-4 -alkyl)-NH-R 11 ; (x)-C(O)N(C1-C4-alkyl)-N-(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)-CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))-CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)-CO-R 11 ; (xiv)-CH(CO-R 11 )-NH-R 11 ; (xv)-CH(CO-R 11 )-N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH; Among them B 2 Contains at least one of the following: (a)-H; (b) -PO3H-; (c)-PO2SH-; (d) -CH3; (e) optionally with at least one R 10 Substituted -C 2-8 -alkyl; (f) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) optionally with at least one R 10 Substituted-(C 0-6 -alkyl)-C 3-10 -heterocyclic group, wherein the C 3-10 -heterocyclyl optionally contains 1-3 heteroatoms independently selected from the group consisting of N, O and S; (h) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-phenyl; (j) optionally with at least one R 10 Substituted-(C 0-6 alkyl)-C 5-10 -heteroaryl, wherein the C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; where R 10 It is R 10a -R 10b ,in R 10a Does not exist or is -(CH2) e -, wherein e is independently selected from 1 to 4 at each occurrence; R 10b Selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where subscript m is an integer from 1 to 32; (iii)-NH-R 11 ; (iv)-N(C 1-4 -alkyl)-R 11 ; (v)-C(O)-NH-R 11 ; (vi)-C(O)-N(C 1-4 -alkyl)-R 11 ; (vii)-C(O)-NHNH-R 11 ; (viii)-C(O)-NHN(C 1-4 -alkyl)-R 11 ; (ix)-C(O)-N(C 1-4 -alkyl)NH-R 11 ; (x)-C(O)-N(C1-C4-alkyl)N(C 1-4 alkyl)-R 11 ; (xi)-CH(NH2)CO-R 11 ; (xii)-CH(NH(C 1-4 -alkyl))CO-R 11 ; (xiii)-CH(N(C 1-4 -alkyl)2)CO-R 11 ; (xiv)-CH(CO-R 11 )NH-R 11 ; (xv)-CH(CO-R 11 )N(C 1-4 -alkyl)-R 11 ; where R 11 Selected from the group consisting of: R 11a 、R 11b 、R 11c 、R 11d and combinations thereof; R 11a Selected from the group consisting of: [-NH]-(C6H4)-CH2-O-, [-NH]-(C6H4)-CH2-OC(O)-, -O-(C6H4)-CH2-OC(O)- and -O-(C6H4)-CH2-O-; R 11b Yes-(A1) q -, wherein A1 is an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid, and wherein the subscript q is an integer selected from 1 to 6; R 11c Yes - (CH2) x -, wherein the subscript x is an integer selected from 1 to 10; and R 11d Selected from the group consisting of -O- and -NH.

83. according to the compound described in any one of claims 79-82, wherein said compound is 84. according to the compound described in any one of claims 80-83, wherein B 1 or B 2 At least one of which independently comprises or in represents a compound of formula (XVa), (XVb) or (XVc) or a compound of formula (XVa), (XVb) or (XVc) 1 or L 2 The connection point of the rest of the in indicates the point of attachment to the antibody or antibody fragment; wherein the subscript r is an integer selected from 1 to 6; and wherein the subscript s is an integer selected from 2 to 14.

85. The compound of claim 84, wherein wherein the subscript r is an integer selected from 2 to 6; and wherein the subscript s is an integer selected from 2 to 14.

86. The compound according to claim 84 or 85, wherein the compound is wherein a is an integer selected from 2 to 6.

87. The compound of claim 80, wherein the compound is selected from 88. A pharmaceutical composition comprising a compound according to any one of claims 46-56 or 77-87 and a pharmaceutically acceptable excipient.

89. A method of treating a disease or condition comprising administering a compound according to any one of claims 46-56 or 77-87 or a pharmaceutical composition according to claim 88.

90. A method for preparing a linker-drug compound of formula (XVI): Among them L 1 is a linking group terminated with a reactive group; The method comprises reacting rubitidine with a suitable coupling reagent and a ligand having the structure L 1 -OH compound is contacted in a suitable solvent to provide a linker-drug compound of formula (XVI); wherein L 1 is a linking group terminated with a reactive group.

91. A method for preparing a linker-drug compound of formula (XVII): Among them L 1 is a linking group terminated with a reactive group; The method comprises reacting trabectedin with a suitable coupling reagent and a ligand having structure L 1 -OH compound is contacted in a suitable solvent to provide a linker-drug compound of formula (XVII); wherein L 1 is a linking group terminated with a reactive group.

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