Ecteinascidin derivative antibody-drug conjugate

Abstract

The present invention provides compounds, methods, and pharmaceutical compositions for use in the treatment of cancer. In certain embodiments, ecteinascidin derivative antibody-drug conjugate compounds are provided that exhibit significant efficacy and bioavailability for the treatment of cancer, for example, in humans.

Description

[Technical Field]

[0001] The present invention provides compounds, methods, and pharmaceutical compositions for use in the treatment of cancer. In certain embodiments, antibody-drug conjugates comprising ecteinascidin compounds are provided that exhibit remarkable efficacy, pharmacokinetic parameters, selectivity, and safety for the treatment of cancer, e.g., in humans.

[0002] cross reference

[0003] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is 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. [Background technology]

[0004] Antibody-drug conjugates (ADCs) are biopharmaceuticals being developed as targeted therapeutics for the treatment of cancer. In contrast to chemotherapy, which lacks selectivity for cancer cells, ADCs are designed to target and attack cancer cells while sparing healthy cells. ADCs achieve selectivity by attaching a cytotoxic payload, or drug, to an antibody via a linker. ADCs exploit the binding selectivity of antibodies to target the delivery of cytotoxic drugs to abnormal cells.

[0005] Ecteinascidins such as trabectedin and lurbinectedin are known to be cancer treatment drugs. For example, lurbinectedin is used to treat small cell lung cancer, and trabectedin is used to treat soft tissue sarcoma and ovarian cancer. However, trabectedin and lurbinectedin are toxic even at low concentrations.

[0006] Thus, there is a continuing need for targeted treatments that can optimize the effective dose of ecteinascidin therapeutics. Summary of the Invention

[0007] The present invention provides compounds, compositions and methods useful for treating proliferative disorders in a subject.

[0008] In one embodiment, the present invention provides a compound of formula (XI), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof: [ka] During the ceremony: R 1 and R 2 together form an aromatic ring or a bicyclic heteroaromatic ring; wherein the aromatic ring and the bicyclic heteroaromatic ring are C 1-10 -alkoxy, C 1-10 -optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, -SH, and -SO3H; R 3 is hydrogen or CH2OR 6 and; R 4 is H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, C(O)R 8 , C(O)OR 8 , C(O)NHR 8 , SO2R 8 , SO2NHR 8 ;where C 1-10 -alkyl or C 6-10 -Aryl is -OH, -F, -Cl, -Br, -C 1-6 --Alkyl-C 3-6 -cycloalkyl, and -C 3-6 -heterocyclyl; or L 1 and R 5 and R 6 is H, C 1-10 -Alkyl, C 6-10-aryl, phosphate, thiophosphate, phosphoramide, C(O)R 9 , C(O)OR 9 , and C(O)NHR 9 , SO3H, SO2R 9 wherein C 1-10 -alkyl or C 6-10 -aryl is -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 and R 5 or R 6 The phosphates and thiophosphates of 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C 5-10 -heteroaryl; and 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 The substituents on the phosphate and thiophosphate are optionally terminated with protecting groups; L 1 or L 2 is a reactive linker; R 8 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, 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; R 9 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, R 4 , R 5 , and R 6 One of the reactive groups R 10 or a linker to an antibody Ab; [ka] is either a single or double bond; and y is an integer selected from 0 to 32.

[0009] In certain embodiments, the present invention provides a compound of formula (XII), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, L 1 or L 2 An example of this is a reactive linker.

[0010] In certain embodiments, the present invention provides a compound of formula (XIII), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] R 1 and R 2 form at least one aromatic or bicyclic heteroaromatic ring, and in each case, C 1-10-alkoxy, C 1-10 -optionally substituted with 1 to 6 substituents independently selected from alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; [ka] is either a single or double bond; L 1 contains at least one of the following: (a)-H, but L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R 11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11ais 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 is -(A1) q -wherein A1 is an amino acid, the amino acid is a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; L 2 contains at least one of the following: (a)-H, but L 1 is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10-heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11)N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid is a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; Each L 2 independently contains at least one of the following: (a)-H, but L 1 is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid is a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0011] In certain embodiments, the present invention provides a compound of formula (XIV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, R 1 and R 2 form at least one aromatic or bicyclic heteroaromatic ring, and in each case, C 1-10 -alkoxy, C 1-10-optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; [ka] is either a single or double bond; L 1 or L 2 One example is a linker; L 1 teeth, 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 and; L 2 teeth, 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 -(-C2H4-O) t -(C 1-6- alkyl)-[(C(O)-] f -[OP(O)SH]; L 1 or L 2 One of them is not H; R 40 is a reactive group; A1 and A2, in each occurrence, are independently an amino acid; Subscript: b and j, at each occurrence, are independently selected from 0 to 4; c and t, in each occurrence, are independently selected from 0 to 32; e, f, g, h, and k are independently 0 or 1 in each occurrence.

[0012] In certain embodiments, the present invention provides a compound of Formula (XVa), (XVb), or (XVc), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, including: [ka] where Ab is a targeting agent; The subscript k is an integer from 1 to 10; In the formula, R 1 and R 2 form at least one aromatic or bicyclic heteroaromatic ring, and in each case, C 1-10 -alkoxy, C 1-10 -optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and B 1 is the linker; B 2 is the linker.

[0013] 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.

[0014] 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 explanation of the drawings]

[0015] The novel features of the invention are set forth with particularity 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 that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings in which: [Figure 1] FIG. 1 provides tumor volume measurements of female B-NDG mice subcutaneously injected with NCI-N87 cells followed by administration of either vehicle control (PBS) or 0.5 mg / kg body weight of trastuzumab-LD7. [Figure 2] FIG. 2 provides the body weight measurements of female B-NDG mice that were subcutaneously injected with NCI-N87 cells and then administered either vehicle control (PBS) or 0.5 mg / kg body weight of trastuzumab-LD7. [Figure 3] FIG. 3 provides the body weight measurements of male CD-1 mice injected intravenously with isotypic human IgG1 antibody conjugated to LD7 at dose rates of 6, 15 or 30 mg / kg body weight (mpk). Detailed Description of the Invention

[0016] The present invention provides compounds, compositions, and methods useful for treating proliferative disorders in a subject. Additionally, dosage forms useful for such methods are provided.

[0017] definition The following terms have the following meanings when referring to the compounds provided herein unless otherwise specified. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In the event that there are multiple definitions for a term herein, the definition in this section shall prevail unless otherwise specified.

[0018] All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety. In case of conflict, the present application controls.

[0019] As used herein, the articles "a," "an," and "the" may include not only particular embodiments having a single element, but also embodiments having multiple elements. For example, the aspect "comprising a compound of Formula Ib and an excipient" should be understood to provide particular embodiments having at least a second compound of Formula Ib, at least a second excipient, or both.

[0020] The term "or" as used herein is equally Boolean "or" unless the alternatives cannot be combined without logical inconsistency. For example, an aspect "comprising an excipient selected from A, B, or C" should be understood to apply to embodiments including A and B; B and C; A and C; or A, B, and C.

[0021] The term "about" used to modify a numerical value in the present invention indicates a range defined around that value. When "X" is a value, "about X" generally refers to a value of 0.95X to 1.05X. "About X" specifically refers to values ​​of at least 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 provide instruction and descriptive support for a claim limitation such as "0.98X." When "about" is applied to the beginning of a numerical range, it also applies to both ends of the numerical range. Thus, "about 5 to about 20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it also applies to all values ​​in that set. Thus, "about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%."

[0022] The words "comprise", "comprising", "include" and "including", when used in this specification and claims, are intended to specify the presence of stated features, integers, elements or steps, but do not exclude the presence or addition of one or more further of those features, integers, elements or steps.

[0023] The term "conjugate" as used herein refers to a compound having a multimeric antigen-binding compound or multimeric immunoglobulin, a linker, and a biologically active molecule.

[0024] The term "spacer" as used herein refers to a chemical building block of a linker used to spatially separate a multimeric antigen-binding compound or multimeric immunoglobulin from the biologically active molecule and to allow for catabolism of the linker within the cell.

[0025] The term "antibody" as used herein includes antigen-binding fragments of intact antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptides or glycoproteins that specifically bind to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from intact antibody molecules using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or conveniently available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA can be sequenced and manipulated, for example, by chemical or molecular biological techniques, to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0026] Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted using routine techniques available in the art to use the antigen-binding fragments of antibodies of the present disclosure.

[0027] As used herein, biologically active molecules (also referred to herein as "drugs," "toxins," "cytotoxic agents," "chemotherapeutic agents," etc.) include any molecule that has therapeutic utility in a mammal when targeted to a particular cell, cell type, or tissue. In typical embodiments, the molecule is advantageously delivered to a target within a mammal, particularly to a cell, and then delivered intracellularly (e.g., endocytosis), as compared to molecules released into the vascular or lymphatic system. In certain embodiments, a biologically active molecule is a compound that inhibits, slows, reduces, and / or prevents cell proliferation. A biologically active molecule may also cause cell death via necrosis or apoptosis.

[0028] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated straight-chain or branched-chain hydrocarbon. In certain embodiments, an alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkyl group contains 1 to 10 carbon atoms, i.e., C1 to C6. 10and 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, secbutyl, t-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 halogenated alkyl groups. In certain embodiments, the alkyl group is a fluorinated alkyl group. Non-limiting examples of moieties with which an alkyl group may be substituted are selected from the group consisting of halogen (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, or optionally protected, as known to those skilled in the art and as taught, for example, in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, incorporated herein by reference.

[0029] The term "lower alkyl," as used herein, unless otherwise specified, refers to a saturated straight or branched chain hydrocarbon having from 1 to 6 carbon atoms, i.e., a C1-C6 alkyl. In certain embodiments, a lower alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.

[0030] The term "cycloalkyl," as used herein, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, a cycloalkyl group can be saturated, and / or bridged, and / or unbridged, and / or fused bicyclic groups. In certain embodiments, a cycloalkyl group contains 3 to 10 carbon atoms, i.e., C3 to C6. 10In some embodiments, cycloalkyl includes 3 to 15 alkyl groups (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl.

[0031] The term "cycloalkenyl," as used herein, unless otherwise specified, refers to an unsaturated cyclic hydrocarbon. In certain embodiments, cycloalkenyl refers to a monocyclic or polycyclic ring system containing at least one double bond. In certain embodiments, cycloalkenyl groups can be bridged, unbridged, and / or fused bicyclic groups. In certain embodiments, cycloalkyl groups contain 3 to 10 carbon atoms, i.e., C3 to C6. 10 In some embodiments, the cycloalkenyl is a cycloalkyl group having 3 to 7 carbon atoms (C 3-10 ), or 4 to 7 (C 3-7 ) carbon atoms.

[0032] "Alkylene" specifically refers to a divalent saturated aliphatic hydrocarbon group having 1 to 11 carbon atoms which may be straight-chained or branched. In some embodiments, an alkylene group contains 1 to 6 carbon atoms. The term includes both substituted and unsubstituted moieties. This term is exemplified by groups such as methylene (-CH-), ethylene (-CHCH-), propylene isomers (e.g., -CHCHCH- and -CH(CH)CH-).

[0033] "Alkenyl" refers to a monovalent olefinically unsaturated hydrocarbon group, which in certain embodiments has up to about 11 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms, can be straight or branched, and has at least 1 or 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=CH), n-propenyl (-CHCH=CH), isopropenyl (-C(CH)=CH), and the like.

[0034] "Alkenylene" refers to a divalent olefinically unsaturated hydrocarbon group, which in certain embodiments has up to about 11 carbon atoms or 2 to 6 carbon atoms, can be straight or branched, and has at least 1 or 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), propenylene isomers (e.g., -CH=CHCH- and -C(CH)=CH- and -CH=C(CH)-).

[0035] "Alkynyl" refers to an acetylenically unsaturated hydrocarbon group, which in some embodiments has up to about 11 carbon atoms or 2 to 6 carbon atoms, may be straight or branched, and has at least 1 or 1 to 2 sites of alkynyl unsaturation. Non-limiting examples of alkynyl groups include acetylenyl, ethynyl (-C≡CH), propargyl (-CHC≡CH), and the like.

[0036] The term "aryl," as used herein, refers to phenyl, biphenyl, or naphthyl unless otherwise specified. This term includes both substituted and unsubstituted moieties. Aryl groups can be substituted with any moiety, including, but not limited to, one or more moieties selected from the group consisting of halogen (fluoro, chloro, bromo, or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate ester, phosphonic acid, phosphate ester, or phosphonate ester, and can be unprotected or protected as needed, 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, Second Edition, 1991.

[0037] "Alkoxy" refers to the group -OR', where R' is alkyl or cycloalkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0038] "Alkoxycarbonyl" refers to a radical -C(O)-alkoxy, where alkoxy is as defined herein.

[0039] "Amino" refers to the radical -NH2.

[0040] "Carbonyl" or "carboxy" refers to the radical --C(O)OH.

[0041] The terms "alkylamino" or "arylamino" refer to an amino group having one or two alkyl or aryl substituents, respectively. In certain embodiments, the alkyl substituent is lower alkyl. In other embodiments, the alkyl or lower alkyl is unsubstituted.

[0042] "Halogen" or "halo" refers to chloro, bromo, fluoro, or iodo.

[0043] "Monoalkylamino" refers to the group alkyl-NR'-, where R' is selected from hydrogen and alkyl or cycloalkyl.

[0044] "Thioalkoxy" refers to the group --SR', where R' is alkyl or cycloalkyl.

[0045] The terms "heterocyclyl" or "heterocycle" refer 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, a heterocyclyl or heterocycle group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. A heterocyclyl group is attached to the remainder of the molecule via a non-aromatic ring. In certain embodiments, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems, in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound.Examples of such heterocyclic radicals include azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, Examples of heterocycles include tetrahydrofuranyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocycle may also be optionally substituted as described herein.

[0046] The term "heteroaryl" refers to a monovalent monocyclic aromatic and / or 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 remainder of the molecule via the 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 1 carbon atom. In some embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, 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, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In some embodiments, heteroaryl may also be optionally substituted as described herein.

[0047] In certain embodiments, a heteroaryl group has a carbon skeleton containing C 1-3 - refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted by an alkyl group, wherein the 6-membered heteroaryl group contains 1, 2, or 3 nitrogen atoms, and the 5-membered heteroaryl group is C 1-3 -alkyl group or phenyl-C 1-3 - an imino group optionally substituted by an alkyl group, an oxygen atom or a sulfur atom, or C 1-3 -alkyl group or phenyl-C 1-3 - an imino group optionally substituted by an alkyl group or an oxygen atom or a sulfur atom, and further by a nitrogen atom, or C 1-3 -alkyl group or phenyl-C 1-3 - an imino group optionally substituted by an alkyl group and two nitrogen atoms, and the phenyl ring may be fused to the above monocyclic heterocyclic group through two adjacent carbon atoms, in which case the bond is through a nitrogen atom or a carbon atom of the heterocyclic moiety or the fused phenyl ring.

[0048] "Alkylaryl" refers to an aryl group with an alkyl substituent. The terms "aralkyl" or "arylalkyl" include alkyl groups with an aryl substituent.

[0049] "Alkylheterocyclyl" refers to a heterocyclyl group that has an alkyl substituent. The term alkylheterocyclyl includes alkyl groups that have a heterocyclyl substituent.

[0050] "Alkylheteroaryl" refers to a heteroaryl group that has an alkyl substituent. The term alkylheteroaryl includes alkyl groups that have a heteroaryl substituent.

[0051] As used herein, unless otherwise specified, the term "protecting group" refers to a group attached 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.

[0052] "Pharmaceutically acceptable salts" refers to salts of compounds provided herein that retain their biological properties, are non-toxic, and are not pharmaceutically undesirable. Such salts may be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, the following: (1) 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, and the like. Sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfone, benzenesulfone, 4-chlorobenzenesulfone, 2-naphthalenesulfone, 4-toluenesulfone, camphor, camphorsulfone, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexyl benzoate or (2) salts formed when an acidic proton present in the parent compound is either (a) substituted with a metal ion such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia, or an alkali metal or alkaline earth metal hydroxide, or (b) coordinated with an organic base such as an aliphatic, alicyclic, or aromatic organic amine, for example, ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc.

[0053] Pharmaceutically acceptable salts include, by way of example only, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, if the compound contains a basic functional group, hydrohalides such as hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, fluorosuccinate, fluoroisopropyl benzoate ... Included are non-toxic organic or inorganic salts such as talate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, and muconate.

[0054] "Purine" or "pyrimidine" bases are adenine, N 6 -Alkylpurines, N 6 -acylpurine (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -Benzylpurine, N 6 -Haloprin, N 6 -vinylpurine, N 6 -Acetylenylpurine, N 6 -Acylpurines, N 6 -Hydroxyalkylpurine, N 6 -Alkylaminopurine, N 6-thioalkylpurines, N 2 -Alkylpurines, N 2 -Alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidines including 6-azacytosine, 2- and / or 4-mercaptopyrimidines, uracil, 5-halouracils including 5-fluorouracil, C 5 -Alkylpyrimidines, C 5 -benzylpyrimidine, C 5 -Allopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenylpyrimidine, C 5 -Acylpyrimidine, C 5 -Hydroxyalkylpurine, C 5 -Amidopyrimidine, C 5 -cyanopyrimidine, C 5 -Iodopyrimidine, C 6 -iodo-pyrimidine, C 5 -Br-vinylpyrimidine, C 6 -Br-vinylpyrimidine, C 5 -Nitropyrimidine, C 5 -amino-pyrimidine, N 2 -Alkylpurines, N 2 This refers to, but is not limited to, -alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl.

[0055] The term "acyl" or "O-linked ester" refers to a group of formula C(O)R', where R' is alkyl or cycloalkyl (including lower alkyl), the carboxylate residue of an amino acid, aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, C1-C4 alkyl, or C1-C4 alkoxy, sulfonate ester such as alkyl or arylalkylsulfonyl including methanesulfonyl, mono-, di-, or tri-phosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. The aryl group in the ester optimally comprises a phenyl group.In particular, acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neoheptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chloro ... Difluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloroacetyl, dichloroacetyl, 7H-dodecafluoroheptanoyl, perfluoroheptanoyl, 7H-dodecafluoroheptanoyl, 7-chlorododecafluoroheptanoyl, 7H-dodecafluoroheptanoyl , 7H-dodecafluoroheptanoyl, nonafluoro-3,6-dioxaheptanoyl, nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, 1-benzenecarboxyl Examples of suitable alkyl esters include silyl, O-acetylmandelyl, pivaloylacetyl, 1-adamantanecarboxyl, cyclohexanecarboxyl, 2,6-pyridinedicarboxyl, cyclopropanecarboxyl, cyclobutanecarboxyl, perfluorocyclohexylcarboxyl, 4-methylbenzoyl, chloromethylisoxazolylcarbonyl, perfluorocyclohexylcarboxyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, and 4-phenylbenzoyl.

[0056] The term "amino acid" refers to naturally occurring and synthetic alpha, beta, gamma, or delta amino acids, including, but not limited to, those 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, valinyl, leucinyl, isorectinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isorectinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl, or β-histidinyl.

[0057] The terms "substantially free" or "substantially devoid" of a composition refer to a composition that contains at least 85% or 90% by weight, and in some 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 an enantiomer.

[0058] Similarly, the term "isolated" with respect to a composition refers to a composition that contains at least 85%, 90%, 95%, 98%, 99% to 100% by weight of a compound, with the remainder containing other species or enantiomers.

[0059] "Solvate" refers to a compound provided herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0060] "Isotopic composition" refers to the amount of each isotope present for a certain atom, and "natural isotopic composition" refers to the isotopic composition or abundance that naturally occurs for a certain atom. Atoms with natural isotopic composition are also referred to as "non-enriched" atoms in the present invention. Unless otherwise specified, atoms of compounds described in the present invention are meant to represent any stable isotope of that atom. For example, unless otherwise specified, if a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen with its natural isotopic composition.

[0061] "Isotopic enrichment" refers to the percentage of a molecule in which a certain atom incorporates a certain amount of a particular isotope, instead of the atom's natural isotopic abundance. For example, a deuterium enrichment of 1% at a certain position means that 1% of the molecules in a sample contain deuterium at the specified position. Since the distribution of naturally occurring deuterium is approximately 0.0156%, the deuterium enrichment at any position of 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 skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0062] "Isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0063] As used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl," "amino," "carboxyl," "alkylamino," "arylamino," "thioalkoxyoxy," "heterocyclyl," "heteroaryl," "alkylheterocyclyl," "alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine," "pyrimidine," "carboxyl," and "amino acid" groups optionally contain deuterium at one or more positions when a hydrogen atom is present, and the deuterium composition of the atoms or atoms differs from the natural isotopic composition.

[0064] Also, as used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl," "carboxyl," "alkylamino," "arylamino," "thioalkoxyoxy," "heterocyclyl," "heteroaryl," "alkylheterocyclyl," "alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine," "pyrimidine," "carboxyl," and "amino acid" groups optionally contain carbon-13 in an amount different from the natural isotopic composition.

[0065] In the present invention, EC 50 refers to the dose, concentration or amount of a particular test compound that induces a dose-dependent response at 50% of the maximum expression of the particular response induced, elicited or potentiated by the particular test compound.

[0066] In the present invention, IC 50 refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures such response.

[0067] The term "host" as used herein refers to any unicellular or multicellular organism in which a virus can replicate, including cell lines and animals, and in certain embodiments, humans. Alternatively, the host can harbor a portion of a Flaviviridae viral genome whose replication or function can be altered by a compound of the present invention. The term host specifically includes infected cells, cells transfected with all or part of a 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, veterinary applications in certain indications are clearly contemplated by the present invention (e.g., chimpanzees).

[0068] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals such as mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys such as cynomolgus monkeys and chimpanzees, and humans), and for example, humans. In one embodiment, the subject is refractory or non-responsive to current treatments for hepatitis C infection. In another embodiment, the subject is a livestock animal (e.g., horse, cow, pig, etc.) or a pet (e.g., dog or cat). In one embodiment, the subject is a human.

[0069] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent that can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In certain embodiments, a therapeutic agent is an agent that is known to be useful, has been used, or is currently being used, in the treatment or prevention of a disorder or one or more symptoms thereof.

[0070] A "therapeutically effective amount" refers to the amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effectively effect such treatment for the disease. A "therapeutically effective amount" can vary depending, inter alia, on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated.

[0071] "Treating" or "treatment" of a disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) 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 disorder.

[0072] As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to any agent that can be used in the prevention of 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 that is known to be useful, has been used, or is currently being used, for preventing or inhibiting the onset, development, progression, and / or severity of a disorder.

[0073] As used herein, the term "prophylactically effective amount" refers to an amount of a therapy (e.g., a prophylactic agent) sufficient to prevent or reduce the onset, recurrence, or occurrence of one or more symptoms associated with a disorder (or to enhance or improve the prophylactic efficacy of another therapy (e.g., another prophylactic agent)).

[0074] The term "reactive linker group" as used herein refers to functional groups used in conjugation, i.e., activated esters, haloacetamides, enzyme conjugation, and click chemistry. Conjugation sites are known in the art. For example, the conjugation moieties in Signal Transduction and Targeted Therapy (2022) 7:93; https: / / doi.org / 10.1038 / s41392-022-00947-7 are incorporated herein by reference in their entirety for all purposes. Linkers and antibody-drug conjugates are also described in Chemical Society Reviews (2019), 48(16), 4361-4374; and Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2017), 17(32), 3393-3424, which are incorporated herein by reference in their entirety for all purposes. As used in the present invention, a reactive linker or reactive linker group may comprise a non-reactive alkyl or heteroalkyl spacer segment, where the spacer segment is capped with a reactive group (e.g., R40). Examples of reactive groups include any group capable of forming a bond with an antibody. Specifically, examples of reactive groups include maleimide (configured to form a bond with the sulfur atom of a cysteine ​​side chain), N-hydroxysuccinimide (configured to form a bond with the nitrogen atom of a lysine side chain), or primary amine (configured to form a bond with the amide of a glutamine side chain via, for example, transglutaminase). Reactive linkers may also be peptide groups (e.g., cleavable peptides, e.g., Val-Cit), autoimmune groups (e.g., p-aminobenzyloxycarbonyl ("PABC") groups), polymer groups (e.g., polyethylene glycol (PEG)), alkyl groups (e.g., C 1-12The linker may further comprise a fused heteroaryl group formed from the reaction of a bicyclooctyne with a triazine (e.g., in a "click" reaction), or a cyclyl group formed from the reaction of a sulfur atom with a maleimide group.

[0075] antibody In some embodiments, the term "antibody" is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact 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 encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific antibodies, e.g., bispecific antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv, etc. Unless otherwise specified, 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 can comprise a human IgG1 constant region. The antibody can comprise a human IgG4 constant region.

[0076] The terms "complementarity-determining region" and "CDR," which are synonymous with "hypervariable region" or "HVR," are known in the art to refer to noncontiguous sequences of amino acids in an antibody variable region that confer antigen specificity and / or binding affinity. Generally, each heavy chain variable region has three CDRs (CDR-H1, CDR-H2, and CDR-H3), and each light chain variable region has three CDRs (CDR-L1, CDR-L2, and CDR-L3). The terms "framework region" and "FR" are known in the art to refer to the non-CDR portions of the heavy and light chain variable regions. Generally, each full-length heavy chain variable region has four FRs (FR-H1, FR-H2, FR-H3, and FR-H4), and each full-length light chain variable region has four FRs (FR-L1, FR-L2, FR-L3, and FR-L4). The precise amino acid sequence boundaries of a given CDR or FR can be determined using the methods described in 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 Plueckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J Mol Biol, 2001 Jun;309(3):657-70, ("Aho" numbering scheme); and Whitelegg NR and Rees AR, "WAM: an improved algorithm for modeling 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 using any of a number of well-known numbering schemes, including Kabat, IMGT, Chothia, AbM, Aho, contact numbering schemes, or any combination thereof. .

[0077] The term "variable region" or "variable domain" refers to the domain of an antibody's heavy or light chain that is involved in binding the antibody to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of native antibodies generally have similar structures, with each domain containing four conserved framework regions (FR) and three CDRs (see, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen may be isolated by using a VH or VL domain to screen a library of complementary VL or VH domains, respectively, from antibodies that bind the antigen (see, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0078] The term "heavy chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 50 to 70 kDa, containing a variable region of approximately 120 to 130 or more amino acids at its amino terminal end and a constant region at its carboxy terminal end. The constant region can be one of five different types (e.g., isotypes), designated α (alpha), δ (delta), ε (epsilon), γ (gamma), and μ (mu), based on the amino acid sequence of the heavy chain constant region. α, δ, and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. These different types of heavy chains, when combined with light chains, give rise to the five well-known antibody classes (e.g., isotypes): IgA, IgD, IgE, IgG, and IgM, respectively, including the four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0079] The term "light chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 25 kDa, the amino-terminal portion of which contains a variable region of about 100 to about 110 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two different types, called κ (kappa) or λ (lambda), based on the amino acid sequence of the constant domain. The amino acid sequences of light chains are well known in the art. The light chain may be a human light chain.

[0080] The provided antibodies also include antibody fragments. The terms "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 contain 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. Generally, an antibody fragment or antigen-binding fragment contains one or more CDRs from the parent antibody sufficient to confer binding specificity.

[0081] Generally, a humanized antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody may optionally contain at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of a non-human antibody refers to a variant of a non-human antibody that has typically been humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. In some embodiments, some FR residues of a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues were derived), e.g., to restore or improve antibody specificity or affinity. In some embodiments, humanized antibodies refer to non-human (e.g., murine) antibodies having specific immunoglobulin chains that contain minimal non-human (e.g., murine) sequence, chimeric immunoglobulins, or fragments thereof, or forms of antibodies that are not fully human.

[0082] Among the provided antibodies are human antibodies. A "human antibody" is an antibody having an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or non-human source, utilizing a human antibody repertoire or other human antibody coding sequence, including a human antibody library. The term excludes humanized forms of non-human antibodies that contain a non-human antigen-binding region, e.g., those in which all or substantially all CDRs are non-human.

[0083] Human antibodies can be prepared by administering immunogens to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or part of human immunoglobulin loci that replace endogenous immunoglobulin loci or that are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic animals, the endogenous immunoglobulin loci are generally inactivated. Human antibodies may also be derived or selected from human antibody libraries, including phage display libraries and cell-free libraries, that contain antibody coding sequences derived from the human repertoire. In certain embodiments, human antibodies can be subjected to successive rounds of selection, such as by phage display, to remove sequence debt or increase affinity.

[0084] Fc constant region Generally, the fragment crystallization (Fc) region or domain of an antibody mediates downstream effector functions through interaction with Fc receptors on immune cells (e.g., innate immune cells) or with the complement protein C1q, a recognition molecule of the complement system. Furthermore, interaction with Fc receptors can result in target cell killing through various immune effector mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), and antibody-mediated complement activation can result in complement-dependent cytotoxicity (CDC). Furthermore, both Fc receptor interaction and complement activation can exert a wide range of immunomodulatory functions.

[0085] Thus, in certain embodiments, mutations in the Fc region that reduce, inhibit, eliminate, and / or eliminate Fc-mediated functions are advantageous for reducing immune activation resulting from antibody binding to a target. In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody, thereby resulting in an Fc region variant. The Fc region may comprise the C-terminal region of an immunoglobulin heavy chain, including the hinge region, CH2 domain, CH3 domain, or any combination thereof. As used herein, the term "Fc region" includes native sequence Fc regions and variant Fc regions. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution, addition, or deletion) at one or more amino acid positions.

[0086] Pharmaceutical Composition The pharmaceutical compositions disclosed in the present invention can be administered to a subject by any suitable route of administration, including, but not limited to, parenteral administration (intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intravitreal, infusion, or topical), topical, oral, or nasal administration.

[0087] "Pharmaceutically acceptable" may refer to approved or approvable by a regulatory agency of the federal or state government, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, including humans. "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.

[0088] A "pharmaceutically acceptable excipient, carrier, or adjuvant" may refer to an excipient, carrier, or adjuvant that can be administered to a subject together with at least one antibody of the present disclosure, does not destroy its pharmacological activity, and is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[0089] 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.

[0090] Compounds, linker-drug conjugates, antibody-drug conjugates The present invention provides ecteinascidin derivative compounds useful for the treatment, diagnosis, or detection of pathological conditions. In one embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or polymorph thereof. The ecteinascidin derivative compounds may be useful as antibody-drug conjugates (ADCs), payload-linker compounds, and payloads in ADC compounds.

[0091] In some embodiments, the present disclosure provides a compound comprising a linker covalently attached to lurbinectedin via a secondary alcohol or a secondary amine. In some embodiments, the present disclosure provides a compound comprising a linker covalently attached to trabectedin via a secondary alcohol or a secondary amine. In some embodiments, provided herein are compounds comprising a linker covalently attached to ecteinascidin via a secondary alcohol or a secondary amine.

[0092] In one embodiment, provided herein is a compound according to Formula I: [ka]

[0093] R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 - can form at least one aromatic ring or bicyclic heterocycle optionally substituted with 1 to 6 substituents selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH), thiol, and -SOH. In one example, R 1 and R 2 can, together with the intervening atoms to which they are attached, form a monocyclic or bicyclic ring.

[0094] R 20 is one of the following: (a) H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, selected from the group consisting of C(O)R, C(O)OR, C(O)NHR, SO2R, and SO2NHR, wherein C 1-10 -alkyl may be substituted or unsubstituted, and C 6-10 -aryl is substituted or unsubstituted; or (b) L 1 where L 1 is a reactive group.

[0095] R 20 is, in each case independently, OH, F, Cl, Br, C 1-5 -Alkyl, C 3-6 -cycloalkyl, and C 3-6 -heterocyclyl, optionally substituted with 1 to 3 substituents selected from the group consisting of:

[0096] R 30 is one of the following: (c) H, C 1-10 -Alkyl, C 6-10- selected from the group consisting of aryl, phosphate, thiophosphate, phosphoramido, C(O)R6, C(O)OR6, and C(O)NHR6, sulfonyl, sulfonylamido, wherein C 1-10 -alkyl may be substituted or unsubstituted, and C 6-10 -aryl is substituted or unsubstituted, or (d) L 2 where L 2 is a reactive group.

[0097] In certain embodiments, the phosphates and thiophosphates are, in each case, H, C 1-6 -Alkyl, C 3-10 -cycloalkyl, poly(ethylene) glycol (PEG), C 6-10 -aryl, and C 5-10 -heteroaryl, optionally substituted with 1 to 2 substituents independently selected from the group consisting of -P(O)(OH), thiol, -OH, and -SO3H. The substituents on the phosphate and thiophosphate are optionally terminated with protecting groups.

[0098] In one embodiment, R 20 or R 30 At least one of is H.

[0099] In one embodiment, R 5 and R 6 are, in each case independently, C 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) 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), thiol, -OH, and -SOH. In some embodiments, the subscript y is an integer selected from 1 to 32. In some embodiments, R 5 and / or R 6 [PEG] y When comprising, the terminal PEG group may be terminated with any suitable moiety, including, but not limited to, -OH, -NH2, and / or -OMe.

[0100] L in formula (I) 1 may contain at least one of the following: (a)-H, but L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R10b where R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 10; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v)-CONH-R 11 ; (vi) -CON(C1-4-alkyl)-R 11 ; (vii)-CONHNH-R 11 ; (viii) -CONHN(C1-4-alkyl)-R 11 ; (ix) -CON(C1-4-alkyl)-NH-R 11 ; (x) -CON(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11dand combinations thereof. R 11a is 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 is -(A1-A2) q -, where A1 and A2, in each occurrence, are independently an amino acid, the amino acid being a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1-6. R 11c Ha-(CH2) x -, where the subscript x is an integer selected from 1 to 10. R 11d is selected from the group consisting of —O— and —NH. L in formula (I) 2 may contain at least one of the following: (a)-H, but L 1 is not H; (b)-PO3H-R 11 or -PO3H2; (c)-PO2SH-R 11 or -PO2SH2; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10-(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v)-CONH-R 11 ; (vi) -CON(C1-4-alkyl)-R 11 ; (vii)-CONHNH-R 11 ; (viii) -CONHN(C1-4-alkyl)-R 11 ; (ix) -CON(C1-4-alkyl)NH-R 11 ; (x) -CON(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 .

[0101] In one embodiment, R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1-A2) q -, wherein A1 and A2, independently at each occurrence, are an amino acid, the amino acid being a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; and R 11c Ha-(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.

[0102] In one embodiment, R 11 is 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 is selected from.

[0103] In one embodiment, L 1 and L 2 independently comprises at least one of the following divalent structures: (a)-C(O)-; (b) -C(O)-NH-; (c)-C(O)O-; (d)-[(C(O)-NH] n -; (e)-C(O)-; (f)-(A1-A2) q -; (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) m -or (j)-(C 1-6 -alkyl) p -.

[0104] In some embodiments of Formula (I), L 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)- and 0 to 3 of -(C2H4-O) m -Includes; L 1 is R 40 terminates at R 40 is a reactive group. In some embodiments, -(A1) q In some embodiments, one or more of L- is Val-Cit or Cit-Val. 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-R40 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 Ha-(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 -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 is.

[0105] In some embodiments of Formula (I), L 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -Includes; L 2 is R 40 terminates at R 40 is a reactive group. In one embodiment, L 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -Includes; L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 -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 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH2. In some embodiments, L 2is —PO3H2. In some embodiments, L 2 -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 -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 is.

[0106] In some embodiments of the antibody-drug conjugates derived from compounds of formula (I), B 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, -(A1) q - is selected from Val-Cit or Cit-Val. 1 is -C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m In some embodiments, B 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m-(C 1-6 In some embodiments, B 1 Ha-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 In some embodiments, B 1 comprises -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 comprises -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 is -C(O)-(C2H4-O) 12 In some embodiments, B 1 In some embodiments, B 1 is -C(O)-(CH2)-. In some embodiments, B 1 comprises -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 includes -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0107] In some embodiments of the antibody-drug conjugates derived from compounds of formula (I), B 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2 -PO2SH-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-. In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-NH-C(O)-O-CH-(CH)-NH-(Cit-Val)-C(O)-(CH-O)-(CH)-. In some embodiments, B 2 includes -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0108] In some embodiments of Formula (I), L 1 or L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, R 11 is R 40 terminates at R 40 is a reactive group. In some embodiments, the reactive group is -NHBoc (i.e., [ka] ) or —NH. In some embodiments, the reactive group is maleimide.

[0109] In some embodiments of Formula (I), R 20 If is H, then R 30 L 2 and R 30 If is H, then R 20 is L 1 In some embodiments of Formula (I), L 1 If is H, then L 2 At least one of is not H; and L 2 If all 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 -PO3H2, -PO2SH2, or L 2 and R 20 is H.

[0110] In some embodiments of the antibody-drug conjugates derived from compounds of formula (I), B 1 L so that a covalent bond is formed between them. 1 R seen in 40 In some embodiments of the antibody-drug conjugates derived from compounds of formula (I), B 2 L so that a covalent bond is formed between them. 2 R seen in 40 and Ab. Therefore, R 40 is a maleimide, Ab-B 1 - or Ab-B 2 - is independently [ka] It can be terminated with

[0111] In some embodiments of Formula (I), A1 and A2, at each occurrence, are independently an amino acid (eg, an amino acid residue), wherein the amino acid is selected from a natural amino acid or an unnatural amino acid.

[0112] In some embodiments, the subscript n is an integer selected from 0 to 4; the subscript m is an integer selected from 0 to 20; the subscript p is an integer 0 or 1; and the subscript t is an integer selected from 0 to 10. In some embodiments, each instance of the subscript n is independently an integer selected from 0 to 4; each instance of the subscript m is independently an integer selected from 1 to 20; each instance of the subscript p is independently an integer 0 or 1; each instance of the subscript q is independently an integer selected from 1 to 6; and each instance of the subscript n is independently an integer selected from 0 to 10.

[0113] In one embodiment, R 20 has at least one C 1-6 -C1-alkyl optionally substituted with heterocyclyl. 20 is a C1-alkyl optionally substituted with a bipyrrolidinyl substituent. 20 is a C1-alkyl optionally substituted with 1 to 2 pyrrolidonyl substituents.

[0114] In one embodiment, R 20 teeth, [ka] where: [ka] indicates the bond to which the illustrated substituent is attached. In some embodiments, R 20 is di(pyrrolidin-1-yl)methyl.

[0115] In one embodiment, R 30is a phosphate or a thiophosphate. 30 is a substituted phosphate or a substituted thiophosphate. In certain embodiments, R 30 teeth, [ka] where: [ka] indicates the bond to which the thiophosphate is attached.

[0116] In certain embodiments, the compound (e.g., a compound of Formula (I)) is [ka] wherein W is O or S; [ka] is either a single or double bond.

[0117] In certain embodiments, the compound (eg, a compound of Formula (I)) can be at least one of the compounds listed in Table A. [Table 1] JPEG2026502495000020.jpg234170

[0118] The present disclosure provides compounds of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, including: [ka] In the formula, L 1 or L 2 One of them is a reactive linker

[0119] L 1 contains at least one of the following: (a)-H, but L 1 or L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) At least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl. C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. R 10 is R 10a -R 10b where R 10a is absent or -(CH2) e - and e, at each occurrence, is independently selected from 1 to 4. R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 10; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R11 ; (v)-CONH-R 11 ; (vi) -CON(C1-4-alkyl)-R 11 ; (vii)-CONHNH-R 11 ; (viii) -CONHN(C1-4-alkyl)-R 11 ; (ix) -CON(C1-4-alkyl)-NH-R 11 ; (x) -CON(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ;

[0120] In some embodiments, R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof.

[0121] In some embodiments, R 11a is 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 is -(A1-A2) q-, wherein A1 and A2, in each occurrence, are independently an amino acid, the amino acid being a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(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.

[0122] In some embodiments of the compound of Formula (II), L 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -, where L 1 is R 40 terminates at R 40 is a reactive group. In some embodiments, -(A1) q In some embodiments, at least one of L is selected from Val-Cit or Cit-Val. 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)-R40 In some embodiments, L 1 Ha-(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 -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 is.

[0123] In some embodiments of the compound of Formula (II), L 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6-alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -, where L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -, where L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 -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 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH2. In some embodiments, L 2 is —PO3H2. In some embodiments, L 2 -PO2SH-(C2H4-O)3-(CH2)2-R 40 In some embodiments, L 2is -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 is.

[0124] In some embodiments of the antibody-drug conjugate derived from the compound of formula (II), B 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, -(A1) q - is selected from Val-Cit or Cit-Val. 1 is -C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m In some embodiments, B 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 1 Ha-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1)q -C(O)-(C 1-6 In some embodiments, B 1 comprises -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 comprises -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 is -C(O)-(C2H4-O) 12 In some embodiments, B 1 In some embodiments, B 1 In some embodiments, B 1 comprises -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 includes -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0125] In some embodiments of the antibody-drug conjugate derived from the compound of formula (II), B 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2-PO2SH-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-. In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-NH-C(O)-O-CH-(CH)-NH-(Cit-Val)-C(O)-(CH-O)-(CH)-. In some embodiments, B 2 includes -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0126] In one embodiment, L 1 or L 2 is R 40 terminates at R 40 is a reactive group. In one embodiment, R 11 is R 40 terminates at R 40 is a reactive group. In some embodiments, the reactive group is -NHBoc (i.e., [ka] ) or —NH. In some embodiments, the reactive group is maleimide.

[0127] In some embodiments of the compound of Formula (II), L 1 If is H, then L 2 At least one of is not H; and all L 2 If is H, then L 1 is not H.

[0128] In some embodiments of the antibody-drug conjugate derived from the compound of formula (II), B 1 L so that a covalent bond is formed between them. 1 R seen in 40 In some embodiments, B comprises the reaction product of B with Ab. 2 L so that a covalent bond is formed between them. 2 R seen in 40 and Ab. Therefore, R 40 is a maleimide, Ab-B 1 - or Ab-B 2 - is independently, [ka] It can be terminated with

[0129] In some embodiments of a compound of Formula (II) or an antibody-drug conjugate therefrom, A1 and A2 are, independently at each occurrence, 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, one or more -(A1) q - is defined throughout this disclosure as -(A1-A2) d -or-(A1-A2) g - (for example, the subscript d is 0 or 1, and the subscript g is 0 or 1).

[0130] In certain embodiments of a compound of Formula (II) or an antibody-drug conjugate derived therefrom, the subscript n is an integer selected from 0 to 4; the subscript m is an integer selected from 0 to 20; the subscript p is an integer 0 or 1; the subscript q is an integer selected from 1 to 6; and the subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of the subscript n is independently selected from an integer selected from 0 to 4; each instance of the subscript m is independently selected from an integer selected from 0 to 20; each instance of the subscript p is independently selected from an integer 0 or 1; each instance of the subscript q is independently selected from an integer selected from 1 to 6; and each instance of the subscript n is independently selected from an integer selected from 0 to 10.

[0131] Provided herein are compounds of formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 - forms an aromatic or bicyclic heterocyclic ring optionally substituted with 1 to 6 substituents selected from alkylamino, hydroxy, nitro, -P(O)(OH)2, thiol, and -SO3H; [ka] is either a single or double bond.

[0132] In one embodiment, L 1 contains at least one of the following: (a)-H, but L 1 or L 2 at least one of which is not H; (b)-CH3; (c) at least one R 10-C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) At least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S.

[0133] In one embodiment, R 10 is R 10a -R 10b where R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; and R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 10; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v)-CONH-R 11 ; (vi) -CON(C1-4-alkyl)-R 11; (vii)-CONHNH-R 11 ; (viii) -CONHN(C1-4-alkyl)-R 11 ; (ix) -CON(C1-4-alkyl)-NH-R 11 ; (x) -CON(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1-A2) q wherein A1 and A2, at each occurrence, are independently an amino acid, the amino acid being selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(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.

[0134] In one embodiment, L 2 contains at least one of the following: (a)-H, but L 1 or L 2 at least one of which is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) At least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O)m -R 11 , where the subscript m is an integer from 1 to 10; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v)-CONH-R 11 ; (vi) -CON(C1-4-alkyl)-R 11 ; (vii)-CONHNH-R 11 ; (viii) -CONHN(C1-4-alkyl)-R 11 ; (ix) -CON(C1-4-alkyl)-NH-R 11 ; (x) -CON(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1-A2) q-wherein A1 and A2, in each occurrence, are independently an amino acid, the amino acid being selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0135] In some embodiments of the compound of Formula (III), L 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -, where L 1 is R 40 terminates at R 40 is a reactive group. In some embodiments, -(A1) q In some embodiments, at least one of L is selected from Val-Cit or Cit-Val. 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)-R40 In some embodiments, L 1 Ha-(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 -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 is.

[0136] In some embodiments of the compound of Formula (III), L 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6-alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -, where L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -, where L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 -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 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH2. In some embodiments, L 2 is —PO3H2. In some embodiments, L 2 -PO2SH-(C2H4-O)3-(CH2)2-R 40 In some embodiments, L 2is -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 -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 is.

[0137] In some embodiments of the antibody-drug conjugate derived from the compound of formula (III), B 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, -(A1) q - is selected from Val-Cit or Cit-Val. 1 is -C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m In some embodiments, B 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 1 Ha-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1)q -C(O)-(C 1-6 In some embodiments, B 1 comprises -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 comprises -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 is -C(O)-(C2H4-O) 12 In some embodiments, B 1 In some embodiments, B 1 In some embodiments, B 1 comprises -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 includes -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0138] In some embodiments of the antibody-drug conjugate derived from the compound of formula (III), B 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)- and 0 to 3 of -(C2H4-O) m In some embodiments, B 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)- and 0 to 3 of -(C2H4-O) m In some embodiments, B 2 -PO2SH-(C2H4-O) m -(C1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-. In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-NH-C(O)-O-CH-(CH)-NH-(Cit-Val)-C(O)-(CH-O)-(CH)-. In some embodiments, B 2 includes -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0139] In certain embodiments of the compound of Formula (III), L 1 or L 2 is R 40 where R 40 is a reactive group. In one embodiment, R 11 is R 40 where R 40 is a reactive group. In some embodiments, the reactive group is -NHBoc (i.e., [ka] ) or —NH. In some embodiments, the reactive group is maleimide.

[0140] In some embodiments of the compound of Formula (III), L1 If is H, then L 2 At least one of is not H; and L 2 If all of are H, then L 1 is not H.

[0141] In some embodiments of the antibody-drug conjugate derived from the compound of formula (III), B 1 L so that a covalent bond is formed between them. 1 R seen in 40 In some embodiments, B comprises the reaction product of B with Ab. 2 L so that a covalent bond is formed between them. 2 R seen in 40 and Ab. Therefore, R 40 is a maleimide, Ab-B 1 - or Ab-B 2 - is independently, [ka] It could be.

[0142] In some embodiments of a compound of Formula (III) or an antibody-drug conjugate derived therefrom, A1 and A2 are, independently in each occurrence, an amino acid (e.g., an amino acid residue), where the amino acid is selected from a natural amino acid or an unnatural amino acid. q -(A1-A2) d -or-(A1-A2) g - (for example, where the subscript d is 0 or 1 and the subscript g is 0 or 1).

[0143] In some embodiments of a compound of Formula (III), the subscript n is an integer selected from 0 to 4; the subscript m is an integer selected from 0 to 20; the subscript p is an integer 0 or 1; the subscript q is an integer selected from 1 to 6; and the subscript t is an integer selected from 0 to 10. In some embodiments, each instance of the subscript n is independently selected from an integer selected from 0 to 4; each instance of the subscript m is independently selected from an integer selected from 0 to 20; each instance of the subscript p is independently selected from an integer 0 or 1; each instance of the subscript q is independently selected from an integer selected from 1 to 6; and each instance of the subscript n is independently selected from an integer selected from 0 to 10.

[0144] Provided herein are compounds of formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 - forms an aromatic or bicyclic heterocyclic ring optionally substituted with 1 to 6 substituents selected from alkylamino, hydroxy, nitro, -P(O)(OH)2, thiol, and -SO3H; [ka] is either a single or double bond.

[0145] In one embodiment, L 1 is R 40 - (C 1-6- alkyl)-[(C(O)-NH] n -(-C2H4-O) m -(C 1-6- alkyl) q -[(C(O)-] p ; or R40 - (-C2H4-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 L 2 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 - (-C2H4-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]. In one embodiment, L 1 is R 40 -(C 1-6- alkyl)-C(O)-(A1-A2) g -[-NH] h -(C6H4)-CH2-O-[(C(O)-NH] j -It is.

[0146] In one embodiment, R 40can be a reactive group; A1 and A2, in each occurrence, are independently an amino acid; the subscript n, in each occurrence, is independently selected from 0 to 4; the subscript m, in each occurrence, is independently selected from 0 to 20; the subscript p, in each occurrence, is independently 0 or 1; the subscript q, in each occurrence, is independently 0 or 1; and the subscript t, in each occurrence, is independently selected from 0 to 10. The reactive group can be cleavable or non-cleavable.

[0147] 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-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.

[0148] In some embodiments of the compound of Formula (IV), L 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m - includes; where L 1 is R 40 terminates at R 40 is a reactive group. In some embodiments, -(A1) q In some embodiments, at least one of L is selected from Val-Cit or Cit-Val. 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 Ha-(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, L1 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 -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 is.

[0149] In some embodiments of the compound of Formula (IV), L 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)- and 0 to 3 of -(C2H4-O) m -, where L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)- and 0 to 3 of -(C2H4-O) m -, where L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 -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 40In some embodiments, L 2 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH2. In some embodiments, L 2 is —PO3H2. In some embodiments, L 2 -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 -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 is.

[0150] In some embodiments of the antibody-drug conjugate derived from the compound of formula (IV), B 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 3 -(C2H4-O) m In some embodiments, -(A1) q - is selected from Val-Cit or Cit-Val. 1 is -C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 In some embodiments, B1 Ha-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m In some embodiments, B 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 1 comprises -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 comprises -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 is -C(O)-(C2H4-O) 12 In some embodiments, B 1 In some embodiments, B 1 In some embodiments, B 1 comprises -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 includes -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0151] In some embodiments of the antibody-drug conjugate derived from the compound of formula (IV), B 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q-, 0~3 -(C 1-6 -alkyl)- and 0 to 3 of -(C2H4-O) m In some embodiments, B 2 i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)- and 0 to 3 of -(C2H4-O) m In some embodiments, B 2 -PO2SH-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-. In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-NH-C(O)-O-CH-(CH)-NH-(Cit-Val)-C(O)-(CH-O)-(CH)-. In some embodiments, B 2 includes -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0152] In certain embodiments of the compound of Formula (IV), L 1 or L 2 is R 40 where R 40is a reactive group. In one embodiment, R 11 is R 40 terminates at R 40 is a reactive group. In some embodiments, the reactive group is -NHBoc (i.e., [ka] ) or —NH. In some embodiments, the reactive group is maleimide.

[0153] In some embodiments of the compound of Formula (IV), L 1 If is H, then L 2 At least one of is not H; and all L 2 If is H, then L 1 is not H.

[0154] In some embodiments of the antibody-drug conjugate derived from the compound of formula (IV), B 1 L so that a covalent bond is formed between them. 1 R seen in 40 In some embodiments, B comprises the reaction product of B with Ab. 2 L so that a covalent bond is formed between them. 2 R seen in 40 and Ab. Therefore, R 40 is a maleimide, Ab-B 1 - or Ab-B 2 - is independently, [ka] It can be terminated with

[0155] In some embodiments of a compound of Formula (IV) or an antibody-drug conjugate derived therefrom, A1 and A2 are, independently in each occurrence, an amino acid (e.g., an amino acid residue), and the amino acid is selected from a natural amino acid or an unnatural amino acid. q -(A1-A2)d -or-(A1-A2) g - (for example, where the subscript d is 0 or 1 and the subscript g is 0 or 1).

[0156] In certain embodiments of a compound of Formula (IV), the subscript n is an integer selected from 0 to 4; the subscript m is an integer selected from 0 to 20; the subscript p is an integer 0 or 1; the subscript q is an integer selected from 1 to 6; and the subscript t is an integer selected from 0 to 10. In certain embodiments, each instance of the subscript n is independently selected from an integer selected from 0 to 4; each instance of the subscript m is independently selected from an integer selected from 0 to 20; each instance of the subscript p is independently selected from an integer 0 or 1; each instance of the subscript q is independently selected from an integer selected from 1 to 6; and each instance of the subscript n is independently selected from an integer selected from 0 to 10.

[0157] In some embodiments, the compound (eg, a compound of formula (IV), a compound of formula (III)) is: [ka]

[0158] In some embodiments, the compound (eg, a compound of formula (IV), a compound of formula (III)) is: [ka]

[0159] In one embodiment, the linker L 1 or L 2 are, independently, [ka] Includes: During the ceremony, [ka] to a compound of formula (IV), or L 1 Or L 2 indicates the point of attachment to the remainder of the group; r is an integer selected from 1 to 12; and s is an integer selected from 1 to 32.

[0160] In one example, the compound (e.g., a compound of formula (IV), a compound of formula (III)) can be: [ka] wherein the subscript v is an integer from 1 to 32, 1 to 14, or 1 to 8; and the subscript u is an integer from 0 to 11.

[0161] In one example, the compound (e.g., a compound of formula (III), a compound of formula (IV)) can be: [ka] In the formula, the subscript e is an integer selected from 1 to 6, 1 to 4, or 1 to 3.

[0162] In certain embodiments, the compound of formula (III) or (IV) can be at least one of the compounds in Table B. [Table 2] JPEG2026502495000039.jpg230170JPEG2026502495000040.jpg208170JPEG2026502495000041.jpg224170

[0163] Also provided herein are compounds of formula (Va) or (Vb), or pharmaceutically acceptable salts, esters, stereoisomers, or tautomers thereof, comprising: [ka] where Ab is a targeting agent; the subscript k is an integer from 1 to 10; R1 and R 2 are, in each case independently, C 1-10 Alkoxy, C 1-10 forming at least one aromatic ring or bicyclic heterocycle optionally substituted with 1 to 6 substituents selected from alkylamino, hydroxy, nitro, -P(O)(OH)2, thiol, and -SO3H; and B 1 or B 2 is a linker. The Ab can be an antibody, an antibody fragment, a protein, or a peptide.

[0164] In one embodiment, B 1 contains at least one of the following: (a)-H, but L 2 if is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) At least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S;

[0165] In some embodiments, R10 is R 10a -R 10b where R 10a is absent or -(CH2) e -, and e, at each occurrence, is independently selected from 1 to 4.

[0166] In one embodiment, R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 10; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v)-CONH-R 11 ; (vi) -CON(C1-4-alkyl)-R 11 ; (vii)-CONHNH-R 11 ; (viii) -CONHN(C1-4-alkyl)-R 11 ; (ix) -CON(C1-4-alkyl)-NH-R 11 ; (x) -CON(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 and (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 .

[0167] In one embodiment, R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; 11a is 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 is -(A1-A2) q -wherein A1 and A2, in each occurrence, are independently an amino acid, the amino acid being selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0168] In one embodiment, B 2 contains at least one of the following: (a)-H, but L 1 or L 2 at least one of which is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) At least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10-heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S.

[0169] In one embodiment, R 10 is R 10a -R 10b where R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 10; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v)-CONH-R 11 ; (vi) -CON(C1-4-alkyl)-R 11 ; (vii)-CONHNH-R 11 ; (viii) -CONHN(C1-4-alkyl)-R 11 ; (ix) -CON(C1-4-alkyl)-NH-R 11 ; (x) -CON(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 .

[0170] In some embodiments, R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; 11a is 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 is -(A1-A2) q -wherein A1 and A2, in each occurrence, are independently an amino acid, the amino acid being selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0171] In one embodiment, L 1 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 - (-C2H4-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 one embodiment, L 2 is R 50 - (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 - (-C2H4-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 can be a conjugation unit.

[0172] In some embodiments of a 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: 1-20 listed in Table 6. Non-limiting examples of antibodies include trastuzumab and brentuximab.

[0173] In some embodiments, the compound of Formula (Va) or Formula (Vb) is an antibody-drug conjugate derived from a compound of Formula (I). In some embodiments, the compound of Formula (Va) or Formula (Vb) is an antibody-drug conjugate derived from a compound of Formula (II). In some embodiments, the compound of Formula (Va) or Formula (Vb) is an antibody-drug conjugate derived from a compound of Formula (III). In some embodiments, the compound of Formula (Va) or Formula (Vb) is an antibody-drug conjugate derived from a compound of Formula (IV).

[0174] In certain embodiments, the compound (eg, a compound of Formula (Va) or Formula (Vb)) can be: [ka]

[0175] In certain embodiments, the compound (eg, a compound of Formula (Va) or Formula (Vb)) can be: [ka]

[0176] In certain embodiments, the compound (eg, a compound of Formula (Va) or Formula (Vb)) can be at least one of the compounds listed in Table C. [Table 3] JPEG2026502495000046.jpg178170JPEG2026502495000047.jpg217170JPEG2026502495000048.jpg223170

[0177] In certain embodiments, provided herein is a compound of formula (XI), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof: [ka] During the ceremony: R 1and R 2 together form an aromatic ring or a bicyclic heteroaromatic ring; the aromatic ring and the bicyclic heteroaromatic ring are 1-10 -alkoxy, C 1-10 -optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, -SH, and -SO3H; R 3 is hydrogen or CH2OR 6 and; R 4 is H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, C(O)R 8 , C(O)OR 8 , C(O)NHR 8 , SO2R 8 , SO2NHR 8 ;where C 1-10 -alkyl or C 6-10 -Aryl is -OH, -F, -Cl, -Br, -C 1-6 --Alkyl-C 3-6 -cycloalkyl, and -C 3-6 -heterocyclyl; or L 1 and R 5 and R 6 are H and C, respectively. 1-10 -Alkyl, C 6-10 -aryl, phosphate, thiophosphate, phosphoramide, C(O)R 9 , C(O)OR 9 , and C(O)NHR 9 , SO3H, SO2R 9 wherein C 1-10 -alkyl or C 6-10 -aryl is -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 and R 5 or R 6 The phosphates and thiophosphates of 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C 5-10 -heteroaryl; and 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 The substituents on the phosphate and thiophosphate are optionally terminated with protecting groups; R 8 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, 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 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, 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 4 , R 5 , and R 6 One of the reactive groups R 10 or a linker to an antibody Ab; [ka] is a single or double bond; and y is an integer selected from 0 to 32.

[0178] In some embodiments of Formula (XI), L 1 contains at least one of the following: (a)-H, but L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) At least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10-heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) -CH(N(C1-4- 11 )NH-R 11 ; (xiv) —CH(CO—alkyl)CO—R 11 ; (xv) -CH(CO-R R 11)N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1) q wherein A1 is an amino acid, independently at each occurrence, selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0179] In one embodiment, L 2 contains at least one of the following: (a)-H, but L 1 is not H; (b) -PO3H- or -PO3H2; (c) -PO2SH- or -PO2SH2; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) At least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10-heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) -CH(N(C1-4- 11 )NH-R 11 ; (xiv) —CH(CO—alkyl)CO—R 11 ; (xv) -CH(CO-R R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid is, at each occurrence, independently selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0180] In one embodiment, R 11 is selected from: R 11a -R 11b -R 11c -R 11d ; R 11b -R 11c -R 11d ; R11c -R 11d or R 11a -R 11c -R 11d .

[0181] In one embodiment, R 11 is the reactive group R 40 It is terminated at

[0182] In one embodiment, L 1 comprises at least one of the following divalent structures: (a)-C(O)-; (b) -C(O)-NH-; (c)-C(O)O-; (d)-[(C(O)-NH] n -; (e)-C(O)-; (f)-(A1-A2) d -; (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 -; L 1 or L 2 is R 40 where R 40 is a reactive group; A1 and A2, independently in each occurrence, are amino acids, wherein the amino acids are selected from natural amino acids or unnatural amino acids; 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 of 0 or 1.

[0183] In certain embodiments of the compound of Formula (XI), L 1 comprises at least one of the following divalent structures: (a)-C(O)-; (b) -C(O)-NH-; (c)-C(O)O-; (d)-[(C(O)-NH] n -; (e)-C(O)-; (f)-(A1) q -; (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 -; L 1 or L 2 is R 40 where R 40 is a reactive group; each A1 is independently an amino acid, wherein the amino acid is selected from a natural amino acid or an unnatural amino acid; Subscript: q is an integer selected from 1 to 6; n is an integer selected from 0 to 4; r is an integer selected from 0 to 32; and p is an integer of 0 or 1.

[0184] In one embodiment, L 2 comprises at least one of the following divalent 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)-; (h)-(A1-A2) d -; (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 - L 1 or L 2 is R 40 where R 40 is a reactive group; A1 and A2, independently in each occurrence, are amino acids, wherein the amino acids are selected from natural amino acids or unnatural amino acids; 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 of 0 or 1.

[0185] In one embodiment, R 4 At least one C 1-6 -C1-alkyl optionally substituted with heterocyclyl. 4 is C1-alkyl optionally substituted with 1 to 2 pyrrolidinyl substituents. 4 teeth, [ka] where: [ka] indicates the bond to which the illustrated substituent is attached. In certain embodiments, R 5 is a phosphate or a thiophosphate. 5 teeth, [ka] where: [ka] indicates the bond to which the thiophosphate is attached. In one embodiment, R 6 is a substituted phosphate or a substituted thiophosphate. In some embodiments, the compound of formula (XI) is selected from: [ka] W is O or S. In some embodiments, W is O. In some embodiments, W is S.

[0186] In some embodiments, the compound of formula (XI) is selected from: [ka] JPEG2026502495000057.jpg247170JPEG2026502495000058.jpg194170JPEG2026502495000059.jpg57170

[0187] In certain embodiments, a compound of formula (XII), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, L 1 or L 2 An example of a reactive linker is a reactive linker.

[0188] In one embodiment, a compound of formula (XII), wherein L 1 contains at least one of the following: (a)-H, but L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) At least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R 11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1-A2) q-wherein A1 and A2, at each occurrence, are independently an amino acid, the amino acid being a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0189] In one embodiment, a compound of formula (XII), wherein L 2 contains at least one of the following: (a)-H, but L 2 is not H; (b) -PO3H- or -PO3H2; (c) -PO2SH- or -PO2SH2; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) At least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R10 is R 10a -R 10b and R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1-A2) q -wherein A1 and A2, at each occurrence, are independently an amino acid, the amino acid being a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0190] In one embodiment, R 11 is the reactive group R 40 It is terminated at

[0191] In one embodiment, L 1 is H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, C(O)R 8 , C(O)OR 8 , C(O)NHR 8 , SO2R 8 , and SO2NHR 8 is selected from the group consisting of C 1-10 -alkyl and C 6-10 -aryl is, each independently, substituted or unsubstituted; or L 1 is, in each case independently, OH, F, Cl, Br, C 1-5 -Alkyl, C 3-6 -cycloalkyl, and C3-6 -heterocyclyl; R 8 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, 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 L 1 or L 2 is not H; and The subscript y is an integer selected from 0-32.

[0192] In one embodiment, L 2 is H, C 1-10 -Alkyl, C 6-10 -aryl, phosphate, thiophosphate, phosphoramide, C(O)R 9 , C(O)OR 9 , and C(O)NHR 9 , SO3H, SO2R 9 is selected from the group consisting of C 1-10 -alkyl and C 6-10 -aryl is, each independently, substituted or unsubstituted; or The phosphates and thiophosphates may in each case independently be H, C 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C 5-10 -optionally substituted with 1 to 2 substituents selected from the group consisting of heteroaryl; 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 phosphate and thiophosphate are optionally terminated with protecting groups; R 9 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, C 1-6 - alkyl is optionally substituted with 1 to 3 substituents independently selected from methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH)2, thiol, and -SO3H; At least one L 1 or L 2 is not H; and The subscript y is an integer selected from 0-32.

[0193] In certain embodiments, a compound of Formula (XIII), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 - forming at least one aromatic or bicyclic heteroaromatic ring optionally substituted with 1 to 6 substituents selected from alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; [ka] is either a single or double bond; L 1contains at least one of the following: (a)-H, but L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) At least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R 11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1-A2) q -wherein A1 is an amino acid, the amino acid being a natural or unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) xwhere the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; Each L 2 independently includes at least one of the following: (a)-H, but L 2 is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) At least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid being a natural or unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH. Each L 2 independently includes at least one of the following: (a)-H, but L 2 is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) At least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10band R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11dand combinations thereof; R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid being a natural or unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH.

[0194] In certain embodiments, a compound of Formula (XIV), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 - forming at least one aromatic or bicyclic heteroaromatic ring optionally substituted with 1 to 6 substituents selected from alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; [ka] is either a single or double bond; L 1 or L 2 is the linker; L 1 teeth: 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 and; L 2 teeth: 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 -(-C2H4-O) t -(C 1-6- alkyl)-[(C(O)-] f -[OP(O)SH]; L 1 or L 2 One of them is not H; R 40 is a reactive group; A1 and A2 are independently in each occurrence an amino acid; Subscript: b and j, in each occurrence, are independently selected from 0 to 4; c and t, in each occurrence, are independently selected from 0 to 32; e, f, g, h, and k are independently 0 or 1 in each occurrence.

[0195] In one embodiment, R 40 is maleimide, -NH2, -COO-succinimide, halogen or substituted alkyne (e.g., bicyclooctyne).

[0196] 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 one of these, R 11b Ha-(A 1- A2) q A1-A2 are as follows: 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.

[0197] 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 one of these, R 11b Ha-(A1) q -, A1 is an amino acid, the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is 2, 3, or 4. In some embodiments, R 11b is -(A1)2-. In some embodiments, R 11bis -(A1)4-. In some embodiments, R 11b is selected from Val-Cit, Val-Ala, Phe-Lys or Gly-Gly-Phe-Gly - (A1) q -, and q is 2 or 4. In some embodiments, 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 some embodiments, R 11b (e.g., A1-A2 or -A1-A2-A3-A4-) is selected from Val-Ala, or Gly-Gly-Phe-Gly. In some embodiments, A1-A2 is selected from Val-Ala. In some embodiments, A1-A2 is selected from Val-Cit. In some 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.

[0198] 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 one of these, R 11b Ha-(A1) q -(A1) -, wherein A1 is an amino acid, and the amino acid is selected from natural amino acids or unnatural amino acids. q In some embodiments of -, the 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, and q is 2 or 4. In one embodiment, -(A1) q- is -(A1-A2)-, where 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 some embodiments, -(A1) q -(e.g., A1-A2 or -A1-A2-A3-A4-) is selected from Val-Ala, or Gly-Gly-Phe-Gly. In some embodiments, A1-A2 is selected from Val-Ala. In some embodiments, A1-A2 is selected from Val-Cit. In some 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.

[0199] In certain embodiments of a compound of Formula (XI), a compound of Formula (XII), a compound of Formula (XIII), or a compound of Formula (XIV), the compound is as follows: [ka]

[0200] In one embodiment, L 1 or L 2 At least one of: [ka] Including, During the ceremony, [ka] to a compound of formula (IV), or L 1 Or L 2 indicates the point of attachment to the rest of the r is an integer selected from 1 to 12; and s is an integer selected from 1 to 32.

[0201] In some embodiments, r is an integer selected from 2 to 12; and s is an integer selected from 2 to 32. In some embodiments, r is 5. In some embodiments, s is 3.

[0202] 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 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -Includes; L 1 is R 40 terminates at R 40 is a reactive group. In some embodiments, one or more -(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 Ha-(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 -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-R 40 In some embodiments, one or more -(A1) q - is defined throughout this disclosure as -(A1-A2) d -or-(A1-A2) g - (for example, the subscript d is 0 or 1, and the subscript g is 0 or 1).

[0203] 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 2represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -Includes; L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 are: i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -Includes; L 2 is R 40 terminates at R 40 is a reactive group. In some embodiments, L 2 -PO2SH-(C2H4-O) m -(C 1-6 -alkyl)-R 40 In some embodiments, L 2 -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 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 -alkyl)-R 40 In some embodiments, L 2 is -PO2SH2. In some embodiments, L 2 is —PO3H2. In some embodiments, L 2-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 -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-R 40 is.

[0204] 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 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, one or more -(A1) q - is Val-Cit or Cit-Val. In some embodiments, B 1 is -C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m In some embodiments, B 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C1-6 In some embodiments, B 1 Ha-(A1) q -C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 In some embodiments, B 1 comprises -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 comprises -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 is -C(O)-(C2H4-O) 12 In some embodiments, B 1 In some embodiments, B 1 In some embodiments, B 1 comprises -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 includes -(Gly)-C(O)-O-CH2-(C6H4)-NH-(Cit-Val)-C(O)-(CH2)5-.

[0205] 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 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2are: 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 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2 -PO2SH-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-. In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-NH-C(O)-O-CH-(CH)-NH-(Cit-Val)-C(O)-(CH-O)-(CH)-. In some embodiments, B 2 includes -PO2SH-(C2H4-O)3-(CH2)2-NH-C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-.

[0206] 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 or L 2 An example of this is R 40 terminates at R 40 is a reactive group. In one embodiment, R 11 is R40 terminates at R 40 is a reactive group. In some embodiments, the reactive group is -NHBoc (e.g., [ka] ) or —NH. In some embodiments, the reactive group is maleimide.

[0207] 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 If is H, then at least one L 2 is not H; and all L 2 If is H, then L 1 is not H.

[0208] 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 L so that a covalent bond is formed between them. 1 R seen in 40 In some embodiments, B comprises the reaction product of B with Ab. 2 L so that a covalent bond is formed between them. 2 R seen in 40 and Ab. Therefore, R 40 is a maleimide, Ab-B 1 - or Ab-B 2 - is independently, [ka] It can be terminated with

[0209] 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 one of these, A1 and A2, in each occurrence, are independently an amino acid (e.g., an amino acid residue), and the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, one or more -(A1) q - is defined throughout this disclosure as -(A1-A2) d -or-(A1-A2) g - (for example, the subscript d is 0 or 1, and the subscript g is 0 or 1).

[0210] 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 one of these, the subscript n is an integer selected from 0 to 4; the subscript m is an integer selected from 0 to 20; the subscript p is an integer selected from the integers 0 or 1; the subscript q is an integer selected from 1 to 6; and the subscript t is an integer selected from 0 to 10. In certain embodiments, each subscript n is independently an integer selected from 0 to 4; each subscript m is independently an integer selected from 1 to 20; each subscript p is independently an integer 0 or 1; each subscript q is independently an integer selected from 1 to 6; and each subscript n is independently an integer selected from 0 to 10.

[0211] 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: [ka] and wherein the subscript v is an integer selected from 1 to 32; and the subscript u is an integer selected from 0 to 11. In some embodiments, the subscript v is an integer selected from 1 to 14.

[0212] 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: [ka] In the formula, the subscript e is an integer selected from 1 to 6. In some embodiments, the subscript e is an integer selected from 1 to 5. In some embodiments, the subscript e is an integer selected from 1 to 4. In some embodiments, the subscript e is an integer selected from 1 to 3.

[0213] In certain embodiments, the compound (eg, a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV)) has the following structure: [ka] JPEG2026502495000073.jpg229170

[0214] In some embodiments, the present invention provides a compound comprising a linker or reactive linker covalently attached to lurbinectin or ecteinascidin via a secondary alcohol or a secondary amine. In some embodiments, the compound is covalently attached to a targeting agent. In some embodiments, the compound is covalently attached 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 listed in Table 6.

[0215] In certain embodiments, there is provided a compound of Formula (XVa), (XVb), or (XVc), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] where Ab is a targeting agent; The subscript k is an integer from 1 to 10; R 1 and R2 are, in each case independently, C 1-10 -alkoxy, C 1-10 - forming at least one aromatic ring or bicyclic heterocycle optionally substituted with 1 to 6 substituents selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and B 1 is the linker.

[0216] In some embodiments, B 2 is the linker.

[0217] In some embodiments of a compound of Formula (XVa), Formula (XVb), or Formula (XVc), Ab is an antibody, antibody fragment, protein, or peptide. In some embodiments of a compound of Formula (XVa), Formula (XVb), or Formula (XVc), the compound is an 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). In some embodiments, the antibody or antibody fragment comprises one or more of SEQ ID NOs: 1-20 listed in Table 6. Non-limiting examples of antibodies include trastuzumab and brentuximab. The sequences for trastuzumab and brentuximab are listed in Table 6 below:

[0218] [Table 4] JPEG2026502495000076.jpg242170JPEG2026502495000077.jpg239170JPEG2026502495000078.jpg123170

[0219] In certain embodiments, for a compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 1 contains at least one of the following: (a)-H; (b)-CH3; (c) at least one R 10-C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) At least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R 11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1) q wherein A1 is an amino acid, the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; B2 independently includes at least one of the following: (a)-H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) At least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid being a natural or unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; B 1 or B 2 one of which is not H; and B 1 or B 2 One of them is bound to Ab.

[0220] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, -(A1) q - is Val-Cit or Cit-Val. 1 is -C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m -(C 1-6 -alkyl)-NH-C(O)-(C 1-6 In some embodiments, B 1 is -C(O)-(C2H4-O) m In some embodiments, B 1 is -C(O)-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 1 Ha-(A1) q-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C 1-6 In some embodiments, B 1 comprises -C(O)-(C2H4-O)2-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 comprises -C(O)-(C2H4-O)4-(CH2)2-NH-C(O)-(CH2)2-. In some embodiments, B 1 is -C(O)-(C2H4-O) 12 In some embodiments, B 1 In some embodiments, B 1 In some embodiments, B 1 comprises -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 comprises -(Gly)-C(O)-O-CH-(C6H)-NH-(Cit-Val)-C(O)-(CH)-. In some embodiments, -(A1) q -(A1-A2) d -or-(A1-A2) g - (for example, the subscript d is 0 or 1, and the subscript g is 0 or 1).

[0221] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 2 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2are: i) -PO2SH-; and ii) 0 to 3 -C(O)-, 0 to 3 -C(O)-NH- or -NH-C(O)-, 0 to 3 -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m In some embodiments, B 2 -PO2SH-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-O-CH2-(C6H4)-NH-(A1) q -C(O)-(C2H4-O) m -(C 1-6 In some embodiments, B 2 -PO2SH-(C2H4-O) m -NH-C(O)-(C2H4-O) m -NH-C(O)-(C 1-6 In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-. In some embodiments, B 2 comprises -POSH-(CH-O)-(CH)-NH-C(O)-O-CH-(CH)-NH-(Cit-Val)-C(O)-(CH-O)-(CH)-. In some embodiments, B 2 includes -POSH-(CH-O)-(CH)-NH-C(O)-(CH-O)-(CH)-NH-C(O)-(CH)-. In some embodiments, -(A1) q -(A1-A2) d -or-(A1-A2) g - (for example, the subscript d is 0 or 1, and the subscript g is 0 or 1).

[0222] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), L 1 or L 2 is H.

[0223] In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 1 L so that a covalent bond is formed between them. 1 R seen in 40 In some embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 2 L so that a covalent bond is formed between them. 2 R seen in 40 and Ab. Therefore, R 40 is a maleimide, Ab-B 1 - or Ab-B 2 - is independently, [ka] It can be terminated with

[0224] In some embodiments of a compound of Formula (XVa), Formula (XVb), or Formula (XVc), A1 and A2, at each occurrence, are independently an amino acid (e.g., an amino acid residue), and the amino acid is selected from a natural amino acid or an unnatural amino acid. In some embodiments, one or more -(A1) q - is defined throughout this disclosure as -(A1-A2) d -or-(A1-A2) g - (for example, the subscript d is 0 or 1, and the subscript g is 0 or 1).

[0225] In some embodiments of a compound of Formula (XVa), Formula (XVb), or Formula (XVc), the subscript n is an integer selected from 0 to 4; the subscript m is an integer selected from 0 to 20; the subscript p is an integer selected from the integers 0 or 1; the subscript q is an integer selected from 1 to 6; and the subscript t is an integer selected from 0 to 10. In some embodiments, each subscript n is independently an integer selected from 0 to 4; each subscript m is independently an integer selected from 1 to 20; each subscript p is independently an integer 0 or 1; each subscript q is independently an integer selected from 1 to 6; and each subscript n is independently an integer selected from 0 to 10.

[0226] In certain embodiments, the compound (a compound of formula (XVa), a compound of formula (XVb), a compound of formula (XVc)) is as follows: [ka]

[0227] In certain embodiments of the compound of Formula (XVa), Formula (XVb), or Formula (XVc), B 1 or B 2 At least one of: [ka] Including, During the ceremony, [ka] to a compound of formula (XVa), formula (XVb), or formula (XVc), or L 1 Or L 2 indicates the point of attachment to the rest of the [ka] indicates the point of attachment to the antibody or antibody fragment; the subscript r is an integer selected from 1 to 6; and The subscript s is an integer selected from 2 to 14. In some embodiments, r is an integer selected from 2 to 6; and s is an integer selected from 2 to 14.

[0228] In one embodiment, the compound is [ka] and In the formula, a is an integer selected from 2 to 6. In one embodiment, a is 4. In one embodiment, a is 5.

[0229] In certain embodiments, the compound (a compound of formula (XVa), a compound of formula (XVb), a compound of formula (XVc)) is selected from: [ka] JPEG2026502495000086.jpg229170JPEG2026502495000087.jpg115170

[0230] Methods for preparing linker-drug conjugates Disclosed in the present invention is a method for the synthesis of compounds of formula (XVI) as outlined in Scheme A. [ka]

[0231] Disclosed in the present invention is a method for the synthesis of compounds of formula (XVII) as outlined in Scheme B. [ka]

[0232] As disclosed herein, the variables in Scheme A and Scheme B are defined as follows: 1 is a linker group terminated with a reactive group. In some embodiments, L 1is as defined for compounds of formula (I), formula (II), formula (III), formula (IV), or formula (XI). In some embodiments, L 1 is a linker group terminated in a reactive group; the reactive group is R 40 In some embodiments, L 1 is a linker group terminated in a reactive group; the reactive group is selected from maleimide or -NHBoc. In some embodiments, L 1 represents 0 to 3 of -C(O)-, 0 to 3 of -C(O)-NH- or -NH-C(O)-, 0 to 3 of -(A1) q -, 0~3 -(C 1-6 -alkyl)-, 0 to 2 -O-CH2-(C6H4)-NH-, and 0 to 3 -(C2H4-O) m -Includes; L 1 is R 40 terminates at R 40 is a reactive group. In some embodiments, -(A1) q - is selected from: Val-Cit or Cit-Val. 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, L1 Ha-(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 -(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 is -NHBoc.

[0233] L 1 In some embodiments, A1 and A2 are independently in each occurrence an amino acid (e.g., an amino acid residue), and the amino acid is selected from a natural amino acid or an unnatural amino acid.q -(A1-A2) d -or-(A1-A2) g - (for example, the subscript d is 0 or 1, and the subscript g is 0 or 10 or 1).

[0234] L 1 In some embodiments, the subscript n is an integer selected from 0 to 4; the subscript m is an integer selected from 0 to 20; the subscript p is an integer selected from the integers 0 or 1; the subscript q is an integer selected from 1 to 6; and the subscript t is an integer selected from 0 to 10. In some embodiments, each subscript n is independently an integer selected from 0 to 4; each subscript m is independently an integer selected from 1 to 20; each subscript p is independently an integer 0 or 1; each subscript q is independently an integer selected from 1 to 6; and each subscript n is independently an integer selected from 0 to 10.

[0235] As disclosed herein, in some embodiments of Scheme A, Step 1, a compound of formula (XVI) is prepared from lurbinectedin. In some embodiments, lurbinectedin is reacted with a suitable coupling reagent in a suitable solvent to form a compound of structure L 1 In some embodiments, lurbinectedin is contacted with a compound having the structure L 1and a compound having —OH to obtain a compound of formula (XVI). In some embodiments, a suitable coupling reagent is selected from fluoro-N,N,N′,N′-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH), tetramethylfluoroaluminamidinium 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, lurbinectedin is reacted in DMF with (i) BTFFH, TFFH, or a combination thereof; (ii) DIPEA; or (iii) a compound of structure L 1 and a compound having an —OH group to obtain a compound of formula (XVI).

[0236] As disclosed herein, in some embodiments of Scheme B, Step 1, a compound of formula (XVII) is prepared from trabectedin. In some embodiments, trabectedin is reacted with a suitable coupling reagent in a suitable solvent to form a compound of structure L 1 In some embodiments, trabectedin is contacted with a compound having the structure L 1 and a compound having —OH to obtain a compound of formula (XVII). In some embodiments, a suitable coupling reagent is selected from fluoro-N,N,N′,N′-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH), tetramethylfluoroaluminamidinium 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 in DMF with (i) BTFFH, TFFH, or a combination thereof; (ii) DIPEA; or (iii) a compound of structure L 1and a compound having an —OH group to obtain a compound of formula (XVII).

[0237] In some embodiments of Scheme A, Step 1 or Scheme B, Step 1, L 1 -OH is selected from: [ka] JPEG2026502495000091.jpg27170

[0238] In some embodiments of a 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 (XVI), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof; [ka] In the formula, L 1 is as defined for compounds of formula (I), formula (II), formula (III), or formula (IV). 1 In some embodiments of —OH, L 1 is as defined for compounds of formula (I), formula (II), formula (III), or formula (IV).

[0239] 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), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof; [ka] In the formula, L 1 is as defined for compounds of formula (XI). 1 In some embodiments of —OH, L 1 is as defined for compounds of formula (XI).

[0240] In some embodiments of a 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), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof; [ka] In the formula, L 1 is as defined for compounds of formula (I), formula (II), formula (III), or formula (IV). 1 In some embodiments of —OH, L 1 is as defined for compounds of formula (I), formula (II), formula (III), or formula (IV).

[0241] 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), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof; [ka] In the formula, L 1 is as defined for compounds of formula (XI). 1 In some embodiments of —OH, L 1 is as defined for compounds of formula (XI).

[0242] optically active compound It is understood that the compounds provided herein may have multiple chiral centers and may exist and be isolated in optically active and racemic forms. The compounds may exhibit polymorphism. It is understood that any racemic, optically active, diastereomeric, polymorphic, or stereoisomer of the compounds provided herein, or mixtures thereof, that possess the useful properties described herein, are within the scope of the present invention. Methods for preparing optically active forms (e.g., separation of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases) are well known in the art.

[0243] Similarly, most amino acids are chiral (designated L or D, with the L enantiomer being the naturally occurring configuration) and can exist as separate enantiomers.

[0244] Examples of methods for obtaining optically active materials are known in the art and include at least the following: i) Physical separation of crystals - a technique in which macroscopic crystals of individual enantiomers are separated manually. This technique can be used when crystals of separate enantiomers are present, i.e., the material is an aggregate and the crystals are visually distinguishable; ii) simultaneous crystallization - a technique in which the individual enantiomers are crystallized separately from a solution of the racemate, which is only possible if the latter are aggregates in the solid state; iii) Enzymatic resolution - a technique that utilizes the different reaction rates of enantiomers and enzymes to partially or completely separate the racemate; iv) Enzymatic asymmetric synthesis - a synthetic technique that utilizes an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enriched synthetic precursor of a desired enantiomer; v) Chemical asymmetric synthesis - a synthetic technique in which a desired enantiomer is synthesized from an achiral precursor under conditions that result in asymmetry (i.e., chirality) in the product, which can be achieved using a chiral catalyst or chiral auxiliary; vi) Diastereomeric separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are separated by their structural differences, by chromatography or crystallization, and the chiral auxiliary is removed to give the desired enantiomer; vii) Primary and secondary asymmetric transformations - either the diastereomers from the racemate equilibrate and the diastereomer from the desired enantiomer predominates in solution, or preferential crystallization of the diastereomer from the desired enantiomer disrupts the equilibrium, ultimately converting essentially all of the material to the crystalline diastereomer from the desired enantiomer, after which the desired enantiomer is released from the diastereomer; viii) Kinetic resolution - this technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the unequal reaction rates of enantiomers using chiral non-racemic reagents or catalysts under kinetic conditions; ix) Enantiospecific synthesis from non-racemic precursors - a synthetic technique that obtains the desired enantiomer from non-chiral starting materials, in which the stereochemical integrity is not compromised or is compromised only to a minimum extent during the synthesis; x) Chiral liquid chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase due to their different interactions with the stationary phase. The stationary phase can be made of a chiral substance or chiral substances can be added to the mobile phase to cause different interactions; xi) Chiral gas chromatography - a technique in which the racemate is volatilized and enantiomers are separated by their different interactions in the gaseous mobile phase using a column containing a fixed non-racemic chiral adsorbent phase; xii) Extraction using chiral solvents - a technique for separating enantiomers by preferential dissolution of the enantiomers in a particular chiral solvent; xiii) Transport through chiral membranes - This technique involves contacting a racemate with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, which is preferentially transported across the membrane barrier by a driving force such as a concentration or pressure difference. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0245] In some embodiments, compositions of compounds are 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 an enantiomer. 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 species or enantiomers.

[0246] Geometric Isomers and Tautomers Furthermore, in some embodiments, the compounds described herein exist as "geometric isomers." In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusanmen (Z) isomers, as well as corresponding mixtures thereof. In some cases, the compounds exist as tautomers.

[0247] "Tautomer" refers to a molecule capable of proton shift from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds described in the present invention exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Examples of tautomeric equilibrium include: [ka]

[0248] isotopically enriched compounds Also provided in the present invention are isotopically enriched compounds, including but not limited to isotopically enriched compounds.

[0249] Isotopic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles has previously been demonstrated for several classes of drugs. For example, 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).

[0250] Isotopic enrichment of drugs can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of administrations required to achieve a desired effect, (4) decrease the dosage required to achieve a desired effect, (5) increase the formation of active metabolites, if formed, and / or (6) decrease the production of harmful metabolites in specific tissues, and / or to create more effective and / or safer drugs, whether or not combination therapy is intended.

[0251] Substituting an atom with one of its isotopes often changes the rate of a chemical reaction. This phenomenon is known as the isotope effect. For example, if a C-H bond is broken at the rate-determining step of a chemical reaction (i.e., the step with the highest energy transition state), substituting deuterium for that hydrogen will decrease the reaction rate, slowing the process. This phenomenon is known as the deuterium isotope effect ("DKIE"). (See, e.g., 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)).

[0252] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken and the same reaction in which deuterium is replaced by hydrogen. The DKIE ranges from approximately 1 (no isotope effect) to very large values, such as over 50, meaning that the reaction slows down by more than 50 times when deuterium is replaced by hydrogen. High DKIE values ​​are thought to be due in part to a phenomenon known as tunneling, a consequence of the uncertainty principle. Tunneling occurs because the small mass of the hydrogen atom allows the formation of a transition state containing a proton without the necessary activation energy. Because deuterium is more massive than hydrogen, this phenomenon is statistically much less likely to occur.

[0253] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with two neutrons in its nucleus and an atomic weight close to three. It occurs naturally in the environment at very low concentrations, most commonly as T2O. Tritium decays slowly (half-life = 12.3 years), emitting low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the primary hazard associated with this isotope, but large amounts must be ingested to pose a significant health risk. Compared to deuterium, a smaller amount of tritium must be ingested to reach dangerous levels. Substituting tritium ("T") for hydrogen results in a stronger bond than deuterium, resulting in a numerically larger isotope effect. Similarly, the substitution of carbon 3 C or 14 C, sulfur 33 S, 34 S, or 36 S, nitrogen 15 N, oxygen 17 O or 18 Substitution of isotopes of other elements, including but not limited to O, may result in similar isotope effects.

[0254] For example, DKIEs have been used to reduce the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride. However, this method is not applicable to all drugs. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching proposes that heterologous substances sequestered by phase I enzymes may bind transiently and rebind in various conformations prior to chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large size of the binding pockets of many phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can alter the ratio of known metabolites to entirely new metabolites. This new metabolic profile can result in stronger or weaker toxicity.

[0255] Animals express a variety of enzymes designed to remove foreign substances, such as therapeutic drugs, from the circulatory system. Examples of such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases. These enzymes react with these contaminants, converting them into more polar intermediates or metabolites for renal excretion. The most common metabolic reaction of pharmaceutical compounds involves the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) π bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have significantly different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles compared to the parent compound. For many drugs, this oxidation process occurs rapidly. Consequently, these drugs often require multiple daily or large doses.

[0256] Thus, isotopic enrichment at specific positions of the compounds provided herein results in detectable KIEs that affect the pharmacokinetic, pharmacological, and / or toxicological profiles of the compounds provided herein compared to analogous compounds with natural isotopic composition.

[0257] Preparation of Compounds and Pharmaceutical Compositions In certain embodiments, one or more protection or deprotection steps may be included in the preparation methods described in the Examples.

[0258] The compounds can be formulated into pharmaceutical compositions using methods available in the art and methods disclosed in the present invention. Any of the compounds disclosed in the present invention can be provided in a suitable pharmaceutical composition and administered by a suitable route of administration.

[0259] The methods provided herein include administering a pharmaceutical composition containing at least one compound described herein, either alone or in combination with one or more compatible pharmaceutically acceptable carriers or other agents, such as a diluent or adjuvant.

[0260] In some embodiments, the second agent can be formulated or packaged together with the compound provided herein.Of course, the second agent will only be formulated together with the compound provided herein if, according to the judgment of those skilled in the art, such co-formulation will not inhibit the activity or administration method of either agent.In some embodiments, the compound provided herein and the second agent are formulated separately.They can be packaged together or separately for the convenience of those skilled in the art.

[0261] In clinical practice, the active agents provided herein may be administered by any conventional route, particularly parenterally, rectally, or by inhalation (eg, in the form of an aerosol).

[0262] It may also be used as a powder or granular solid composition in which the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.

[0263] Compositions for parenteral administration can be in the form of emulsions or sterile solutions. These compositions can also contain adjuvants, particularly wetting agents, isotonicity adjusting agents, emulsifying agents, dispersing agents, and stabilizing agents. Sterilization can be carried out in several ways, for example, by using a bacteriological filter, by irradiation, or by heat. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or other injectable sterile medium at the time of use.

[0264] In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein or other prophylactic or therapeutic agent), and typically one or more pharmaceutically acceptable carriers or excipients. In specific embodiments, and in this context, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can include sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions, aqueous dextrose and aqueous glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.

[0265] Typical pharmaceutical compositions and dosage forms contain one or more excipients.Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, the way the dosage form is administered to a subject and the specific active ingredients in the dosage form.The composition or single preparation can also contain, if desired, minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0266] The lactose-free composition provided in the present invention can contain excipients that are well known in the art and are described in, for example, US Pharmacopoeia (USP) SP (XXI) / NF (XVI). Generally, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in pharmaceutically compatible and pharmaceutically acceptable amounts. An exemplary lactose-free dosage form contains active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0267] Furthermore, because water can accelerate the degradation of compounds, the present invention encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage to determine properties such as shelf life or stability over time of a formulation. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the degradation of certain compounds. Therefore, the effect of moisture on a formulation is very important because moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipping, and use of formulations.

[0268] 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 that include lactose and at least one active ingredient that includes a primary or secondary amine can be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0269] Anhydrous pharmaceutical compositions should be prepared and stored so as to maintain their anhydrous nature.Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, so that they can be included in suitable prescription 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.

[0270] Additionally, pharmaceutical compositions and dosage forms are provided that comprise one or more compounds that reduce the rate at which the active ingredient decomposes. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0271] Pharmaceutical compositions and unitary dosage forms can take the form of a solution, suspension, emulsion, powder, etc. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in some embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to a subject. The formulation should suit the mode of administration. In some embodiments, the pharmaceutical composition or unitary dosage form is sterile and in suitable form for administration to a subject, e.g., an animal subject, such as a mammalian subject, e.g., a human subject.

[0272] A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral administration, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, intrasynovial, and rectal administration. In certain embodiments, the composition is routinely formulated as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, intranasal, or topical administration to humans. In one embodiment, the pharmaceutical composition is routinely formulated for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Optionally, the composition may include a solubilizing agent and a local anesthetic, such as lignocamune, to ease pain at the injection site.

[0273] Examples of dosage forms include, but are not limited to, liquid dispersions; suppositories; ointments; cataplasms (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 liquid dosage forms suitable for parenteral administration to a subject.

[0274] The composition, shape, and type of dosage forms provided herein typically vary depending on their intended use. For example, a dosage form used for the initial treatment of a viral infection may contain a higher amount of one or more of its constituent active ingredients than a dosage form used for the maintenance treatment of the same infection. These and other ways in which specific dosage forms encompassed by the present invention differ from one another will be readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000).

[0275] Generally, the components of the composition are supplied in unit dosage form, either separately or mixed together, in a sealed container such as an ampoule or sachet indicating the quantity of active agent, for example, as a dry lyophilized powder or a water-free concentrate. When the composition is administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed before administration.

[0276] Typical dosage forms contain about 0.01 mg to about 1000 mg of a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, per day, administered as a single dose once daily in the morning or in divided doses throughout the day with meals. Particular 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.

[0277] Parenteral dosage forms In some embodiments, a parenteral dosage form is provided. The parenteral dosage form can be administered to a subject by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because the administration generally bypasses the subject's natural defenses against contaminants, the parenteral dosage form is generally sterile or can be sterilized before administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready for dissolution or suspension in a pharmaceutically acceptable injection vehicle, suspensions ready for injection, and emulsions.

[0278] 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, aqueous vehicles such as, but not limited to, Water for Injection USP; 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, ethyl alcohol, polyethylene glycol, 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.

[0279] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms.

[0280] Dosage and Unit Dose In treating humans, a physician will determine the most appropriate dosing regimen according to whether prophylactic or therapeutic treatment is desired, as well as the age, weight, stage of infection, and other factors specific to the subject being treated. In certain embodiments, the dosage is about 1 to about 1000 mg per adult per day, or about 5 to about 250 mg per adult per day, or about 10 to about 50 mg per adult per day. In certain embodiments, the dosage is about 5 to about 400 mg per adult per day, or 25 to 200 mg per adult per day. In certain embodiments, dosage rates of about 50 to about 500 mg per day are also contemplated.

[0281] In a further aspect, a method for treating or preventing cancer in a subject is provided 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 a compound or composition effective for preventing or treating a disease or one or more symptoms thereof may vary depending on the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage may also vary according to factors specific to each subject, depending on the particular therapy (e.g., therapeutic or prophylactic agent) administered, the severity of the disorder, disease, or condition, the route of administration, and the subject's age, physical condition, weight, response, and past medical history. Effective amounts may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0282] In some embodiments, exemplary dosages of the compositions include milligram or microgram amounts of active compound per kg of subject or sample body weight (e.g., from about 10 micrograms per kg to about 50 milligrams per kg, from about 100 micrograms per kg to about 25 milligrams per kg, or from about 100 micrograms per kg to about 10 milligrams per kg). For compositions provided herein, in some embodiments, the dosage administered to a subject is 0.140 mg / kg to 3 mg / kg of the subject's body weight, based on the weight of the active compound. In some embodiments, the dosage administered to a subject is 0.20 mg / kg to 2.00 mg / kg, or 0.30 mg / kg to 1.50 mg / kg of the subject's body weight.

[0283] In one embodiment, the recommended daily dosage range of the compositions provided herein for the conditions described herein is within the range of about 0.1 mg to about 1000 mg per day, administered as a single dose once daily or in divided doses throughout the day. In one embodiment, the daily dosage is administered twice daily in equally divided doses. In one embodiment, the daily dosage range should be about 10 mg to about 200 mg per day, in other embodiments, about 10 mg to about 150 mg per day, and in further embodiments, about 25 mg to about 100 mg per day. As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredient outside the ranges disclosed in the present invention. Furthermore, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate treatment in conjunction with the subject's response.

[0284] Various therapeutically effective amounts may be applied to various diseases and conditions, as will be readily known to those skilled in the art.Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause or reduce side effects associated with the compositions provided herein, are also encompassed by the above dosage and administration frequency schedules.Furthermore, when a subject is administered multiple doses of the compositions provided herein, not all doses need to be the same.For example, the dose administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or may be decreased to reduce one or more side effects experienced by a particular subject.

[0285] In certain embodiments, the dosage of the compositions provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof, in a subject 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 certain embodiments, the dosage of a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof, in a subject is from 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 The unit dose is in mg.

[0286] In some embodiments, treatment or prevention can begin with one or more loading doses of a compound or composition provided herein, followed by one or more maintenance doses. In such embodiments, the loading dose can be, for example, about 60 to about 400 mg per day, or about 100 to about 200 mg per day, for one to five weeks. The loading dose can be followed by one or more maintenance doses. In some embodiments, each maintenance dose is independently about 10 mg to about 200 mg per day, about 25 mg to about 150 mg per day, or about 25 mg to about 80 mg per day. The maintenance dose can be administered daily, in a single dose or in divided doses.

[0287] In certain embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in the blood or serum of a subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill in the art, or can be based on the subject's physical characteristics, such as height, weight, and age. In certain embodiments, a sufficient amount of a compound or composition provided herein is administered to achieve a steady-state concentration in the subject's blood or serum of about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 200 ng / mL. In some embodiments, a loading dose can be administered to achieve a steady-state blood or serum concentration of about 1200 to about 8000 ng / mL, or about 2000 to about 4000 ng / mL over 1 to 5 days. In certain embodiments, the maintenance dose can be administered to achieve a steady-state concentration in the subject's blood or serum of about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 1200 ng / mL.

[0288] In certain embodiments, repeated administrations of the same composition may be administered, and the administrations may be 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 apart. In other embodiments, repeated administrations of the same prophylactic or therapeutic agent may be administered, and the administrations may be 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 apart.

[0289] In some aspects, the present invention provides a unit dose comprising a compound or a pharmaceutically acceptable salt thereof in a form suitable for administration. In some embodiments, the unit dose comprises 1-1000 mg, 5-250 mg, or 10-50 mg of the active ingredient. In specific embodiments, the unit dose comprises about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of the active ingredient. Such unit doses can be prepared according to techniques well known to those skilled in the art.

[0290] The dosage of the second agent used in the combination therapy provided herein is lower than the dosage that has been or is currently used to prevent or treat cancer. The recommended dosage of the second agent can be obtained from the knowledge of those skilled in the art. For second agents approved for clinical use, the recommended dosage is described, for example, in Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis of Basis of Therapeutics 9th Ed., Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in their entirety.

[0291] In various embodiments, the therapeutic agents (e.g., a compound provided herein and a second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, about 1 hour apart, about 1 to 2 hours apart, about 2 to 3 hours apart, about 3 to 4 hours apart, about 4 to 5 hours apart, about 5 to 6 hours apart, about 6 to 7 hours apart, about 7 to 8 hours apart, about 8 to 9 hours apart, about 9 to 10 hours apart, about 10 to 11 hours apart, about 11 to 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or 96 to 120 hours apart. In various embodiments, the therapeutic agents are administered less than 24 hours apart or less than 48 hours apart. In some embodiments, two or more therapeutic agents are administered within the same patient visit. In other embodiments, a compound provided herein and a second agent are administered simultaneously.

[0292] 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 2 weeks or more apart.

[0293] In some embodiments, administration of the same agent may be repeated and the administration may 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 may be repeated and the administration may 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.

[0294] In some embodiments, the compound provided herein and the second agent are administered to a patient, e.g., a mammal, such as a human, in an order and at a time interval such that the compound provided herein can act together with the other agent to provide an enhanced benefit compared to when they are administered in other ways. For example, the second agent can be administered simultaneously at different times or sequentially in any order, but if not administered simultaneously, they should be administered sufficiently close in time to provide the desired therapeutic or prophylactic effect. In some embodiments, the compound provided herein and the second agent exert their effects at overlapping times. Each second agent can be administered separately in any suitable form and by any suitable route. In other embodiments, the compound provided herein is administered before, simultaneously with, or after the administration of the second agent.

[0295] In some embodiments, a compound provided herein and a second agent are cyclically administered to a patient. Cycling therapy involves administering a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by administration of a second agent and / or a third agent (e.g., a second and / or third prophylactic or therapeutic agent) for a period of time, repeating this sequential administration. Cycling therapy can prevent the development of resistance to one or more therapies, avoid or reduce side effects of one therapy, and / or improve the efficacy of the treatment.

[0296] In some embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about three weeks, about once every two weeks, about once every 10 days, or about once a week. One cycle can include administration of the compound provided herein and the second agent by infusion about every 90 minutes, about every hour, or about every 45 minutes. Each cycle can include at least one week off, at least two weeks off, or at least three weeks off. The number of administration cycles is about 1 to about 12, more typically about 2 to about 10, and even more typically about 2 to about 8.

[0297] In other embodiments, the courses of treatment are administered simultaneously to the patient, i.e., individual doses of the second agent are administered separately within a time interval that allows the compound provided herein to cooperate with the second active agent. For example, one component can be administered once a week, with the other component being administered once every two weeks or once every three weeks. In other words, the dosing regimen is performed simultaneously, even if the therapeutic agents are not administered at the same time or on the same day.

[0298] The second agent can act additively or synergistically with the compound provided herein. In some embodiments, the compound provided herein is administered simultaneously with one or more second agents in the same pharmaceutical composition. In another embodiment, the compound provided herein is administered simultaneously with one or more second agents in separate pharmaceutical compositions. In yet another embodiment, the compound provided herein is administered before or after the administration of the second agent. It is also contemplated that the compound provided herein and the second agent may be administered by the same or different routes of administration, for example, parenterally. In some embodiments, when the compound provided herein is administered simultaneously with a second agent that potentially causes side effects, including but not limited to toxicity, the second active agent may be advantageously administered at a dose below the threshold at which side effects occur.

[0299] kit Kits for use in methods for treating cancer are also provided. The kits can include instructions providing a healthcare provider with information about the compounds or compositions provided herein, the second agent or composition, and how to use them to treat a disorder. The instructions can be provided in printed form, or in the form of electronic media such as a floppy disk, CD, or DVD, or in the form of a website address where such instructions can be obtained. A unit dosage of the compounds or compositions or second agent or composition provided herein can include an amount that, when administered to a subject, can maintain a therapeutically or prophylactically effective plasma level of the compound or composition in the subject for at least one day. In some embodiments, the compounds or compositions can be included as a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0300] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes solid matrices or materials that are commonly used in systems and can hold the compound provided herein and / or a second agent suitable for administration to a subject within a certain limit. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil-laminated envelopes, etc. When using electron beam sterilization technology, the packaging should have a sufficiently low density to allow sterilization of the contents.

[0301] How to use In some embodiments, the present invention provides a method for treating and / or preventing cancer, comprising administering an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for treating cancer in a subject. In some embodiments, the method comprises administering to a subject in need thereof an amount of a compound effective for treating or preventing cancer in combination with a second agent effective for treating or preventing an infectious disease. The compound can be any compound described in the present invention, and the second agent can be any second agent described in the art or herein. In some embodiments, the compound is in the form of a pharmaceutical composition or dosage form as described elsewhere herein.

[0302] In some embodiments, the subject is undergoing cancer treatment and has discontinued that therapy prior to administration of the methods provided herein. In further embodiments, the subject is undergoing treatment and continues to receive that treatment while administering the methods provided herein. The methods can be co-administered with other therapies for cancer, according to the judgment of one of skill in the art. In some embodiments, the methods or compositions provided herein can be co-administered with reduced doses of other therapies for cancer.

[0303] Second therapeutic agent In certain embodiments, the compounds and compositions provided herein are useful in methods for treating cancer, including the further administration of a second agent effective in treating the disorder. The second agent can be any agent known to those skilled in the art to be effective in treating the disorder, including those currently approved by the FDA.

[0304] In some 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 yet further embodiments, the second agent is administered in combination with two or more second agents.

[0305] As used herein, the term "in combination" includes the use of more than one therapies (e.g., one or more prophylactic and / or therapeutic agents). As used herein, the use of the term "in combination" does not restrict the order in which 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 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 subsequent 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 after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.

[0306] As used herein, the term "synergistic effect" includes a combination of a compound provided herein with another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently used to prevent, manage, or treat a disorder, and is more effective than the additive effects of the therapies. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may allow for lower dosages of one or more therapeutic agents and / or less frequent administration of the therapeutic agents to a subject with a disorder. The ability to utilize lower doses of a therapy (e.g., a prophylactic or therapeutic agent) and / or administer the therapy less frequently reduces the toxicity associated with administering the therapy to a subject without reducing the efficacy of the therapy in preventing or treating the disorder. Furthermore, a synergistic effect improves the efficacy of the agents in preventing or treating the disorder. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or undesirable side effects associated with the use of either therapy alone.

[0307] The active compounds provided herein can be administered in combination or alternation with other therapeutic agents. In combination therapy, effective amounts of two or more agents are administered together, while in alternation therapy or sequential step therapy, effective amounts of each agent are administered sequentially or sequentially. The dosage depends on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​also vary depending on the severity of the condition to be alleviated. Furthermore, it should be understood that for any particular subject, the specific dosage regimen and schedule should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0308] Some embodiments of the present disclosure Below are some non-limiting embodiments of the present disclosure.

[0309] Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof: [ka] In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 - forming at least one aromatic or bicyclic heterocyclic ring optionally substituted with 1 to 6 substituents selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; R 20 is one of the following: (a) H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, selected from the group consisting of C(O)R, C(O)OR, C(O)NHR, SO2R, and SO2NHR, wherein C 1-10 -alkyl and C 6-10 -each aryl is independently substituted or unsubstituted; or (b)L 1 , where L 1 is a reactive group; R 20 is, in each case independently, OH, F, Cl, Br, C 1-5 -Alkyl, C 3-6 -cycloalkyl, and C 3-6 -heterocyclyl; R 30 is one of the following: (c) H, C 1-10 -Alkyl, C 6-10 - selected from the group consisting of aryl, phosphate, thiophosphate, phosphoramide, C(O)R6, C(O)OR6, and C(O)NHR6, sulfonyl, sulfonylamide; where C 1-10 -alkyl and C 6-10 - each aryl is independently substituted or unsubstituted, or (d)L 2 , where L 2 is a reactive group; Phosphates and thiophosphates are in each case H, C 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C 5-10 -heteroaryl; and where 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; wherein the substituents on the phosphate and thiophosphate are optionally terminated with protecting groups; R 5 and R 6 are, in each case independently, C1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, where 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 20 or R 30 at least one of is H; [ka] is either a single or double bond; and The subscript y is an integer selected from 0-32.

[0310] Embodiment 2. L 1 contains at least one of the following: (a)-H, but L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with (g) at least one R10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R 11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid, at each occurrence, is independently selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; The compound of embodiment 1.

[0311] Embodiment 3. L 2 contains at least one of the following: (a)-H, but L 1 is not H; (b)-PO3H-R 11 or -PO3H2; (c) -PO2SH- or -PO2SH2; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6-alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) —C(O)—NH—R 11 ; (iv) —C(O)—N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is 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 is -(A1) q -wherein A1 is an amino acid, the amino acid, at each occurrence, is independently selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; The compound of embodiment 1 or 2.

[0312] Embodiment 4. R 11The compound of embodiment 2 or 3, wherein is 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 .

[0313] Embodiment 5. R 11 is a reactive group R 40 The compound of any one of embodiments 2-4, wherein the compound is terminated in

[0314] Embodiment 6. L 1 and L 2 independently comprises at least one of the following divalent structures: (a)-C(O)-; (b) -C(O)-NH-; (c)-C(O)O-; (d)-[(C(O)-NH] n -; (e)-C(O)-; (f)-(A1-A2) q -; (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 -; L 1 or L 2 is R 40 terminates at R 40 is a reactive group; A1 and A2, independently in each occurrence, are amino acids, wherein the amino acids are selected from natural amino acids or unnatural amino acids; 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 of 0 or 1; A compound according to any one of embodiments 1 to 5.

[0315] Embodiment 7. L 2 comprises at least one of the following divalent 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)-; (h)-(A1-A2) d -; (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 - L 1 or L 2 is R 40 where R 40 is a reactive group; A1 and A2, independently in each occurrence, are amino acids, wherein the amino acids are selected from natural amino acids or unnatural amino acids; 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 of 0 or 1; A compound according to any one of embodiments 1 to 5.

[0316] Embodiment 8. R 20 But there is at least one C 1-6 The compound of any one of embodiments 1-7, wherein - is C1-alkyl optionally substituted with heterocyclyl.

[0317] Embodiment 9. R 20 The compound of any one of embodiments 1-8, wherein is C1-alkyl optionally substituted with a bipyrrolidinyl substituent.

[0318] Embodiment 10. R 20 The compound of any one of embodiments 1-9, wherein is C1-alkyl optionally substituted with 1-2 pyrrolidinyl substituents.

[0319] Embodiment 11. R 20 but, [ka] where: [ka] The compound of any one of embodiments 1-10, wherein represents the bond to which the illustrated substituent is attached.

[0320] Embodiment 12. R 30 The compound of any one of embodiments 1-11, wherein is a phosphate or thiophosphate.

[0321] Embodiment 13. R 30 The compound of any one of embodiments 1-11, wherein is a substituted phosphate or a substituted thiophosphate.

[0322] Embodiment 14. R 30 but, [ka] where: [ka] 13. The compound of embodiment 12, wherein: denotes the bond to which the thiophosphate is attached.

[0323] Embodiment 15. The compound is selected from: [ka] The compound of embodiment 1, wherein W is O or S.

[0324] Embodiment 15. The compound of embodiment 1, wherein the compound is selected from the following: [ka] JPEG2026502495000105.jpg190170

[0325] Embodiment 17. A compound of Formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, L 1 or L 2 is a reactive linker,

[0326] Embodiment 18. L 1 contains at least one of the following: (a)-H, but L 1 or L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8- alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e and e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R 11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is 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 is -(A1-A2) q -wherein A1 and A2, at each occurrence, are independently an amino acid, the amino acid being a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(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; The compound of embodiment 17.

[0327] Embodiment 19. L 2 contains at least one of the following: (a)-H, but L 1 is not H; (b)-PO3H-R 11 or -PO3H2; (c) -PO2SH- or -PO2SH2; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is 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—; R11b is -(A1-A2) q wherein A1 and A2, independently in each occurrence, are an amino acid, the amino acid being selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; A compound according to embodiment 17 or 18.

[0328] Embodiment 20. R 11 The compound of embodiment 18 or 19, wherein is 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 .

[0329] Embodiment 21. R 11 is a reactive group R 40 The compound of any one of embodiments 18-20, wherein

[0330] Embodiment 22. L 1 But H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 - selected from the group consisting of heterocyclyl, C(O)R5, C(O)OR5, C(O)NHR5, SO2R5, and SO2NHR5; C 1-10 -alkyl and C 6-10 -each aryl is independently substituted or unsubstituted; or L 1 is, in each case independently, OH, F, Cl, Br, C 1-5 -Alkyl, C 3-6 -cycloalkyl, and C 3-6 -heterocyclyl; R 5 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, 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 L 1 or L 2 is not H; and The subscript y is an integer selected from 0 to 32. A compound according to any one of embodiments 17 to 21.

[0331] Embodiment 23. L 2 But H, C 1-10 -Alkyl, C 6-10 - selected from the group consisting of aryl, phosphate, thiophosphate, phosphoramide, C(O)R6, C(O)OR6, and C(O)NHR6, sulfonyl, sulfonylamide; where C 1-10 -alkyl and C 6-10 -each aryl is independently substituted or unsubstituted; or The phosphates and thiophosphates may in each case independently be H, C 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C5-10 -optionally substituted with 1 to 2 substituents selected from the group consisting of heteroaryl; C 1-6 -alkyl is optionally substituted with 1 to 2 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 The substituents on the phosphate and thiophosphate are optionally terminated with reactive groups; R 6 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, 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 L 1 or L 2 is not H; and The subscript y is an integer selected from 0 to 32. A compound according to any one of embodiments 17 to 21.

[0332] Embodiment 24. A compound of Formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10- forms an aromatic or bicyclic heteroaromatic ring optionally substituted with 1 to 6 substituents independently selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, -SH, and -SO3H; [ka] is either a single or double bond; L 1 contains at least one of the following: (a)-H, but L 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R 11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11ais 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 is -(A1) q -wherein A1 is an amino acid, the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; L 2 contains at least one of the following: (a)-H, but L 1 is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10-heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11)N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is 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 is -(A1) q wherein A1 is an amino acid, the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0333] Embodiment 25. A compound of Formula (IV), or a pharmaceutically acceptable salt, ester, or tautomer thereof, comprising: [ka] In the formula, L 1 teeth: 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 and; L 2 teeth: 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 -(-C2H4-O) t -(C 1-6 -alkyl)-[(C(O)-] f -[OP(O)SH]; L 1 or L 2 One of them is not H; R 40 is a reactive group; A1 and A2, in each occurrence, are independently an amino acid; Subscript: b and j, at each occurrence, are independently selected from 0 to 4; c and t, in each occurrence, are independently selected from 0 to 32; e, f, g, h, and k, at each occurrence, are independently 0 or 1; The compound, or a pharmaceutically acceptable salt, ester, or tautomer thereof.

[0334] Embodiment 26. R 40The compound of any one of embodiments 21-25, wherein is maleimide.

[0335] Embodiment 27. R 11b A 1- A2) q 27. The compound of any one of embodiments 18-26, 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, glutamate-asparagine, asparagine-glutamate, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.

[0336] Embodiment 28. The compound of embodiment 27, wherein A1-A2 is selected from Val and Cit.

[0337] Embodiment 29. The compound comprises: [ka] The compound of any one of embodiments 24-28, wherein

[0338] Embodiment 30. The compound comprises: [ka] The compound of any one of embodiments 24-28, wherein

[0339] Embodiment 31. L 1 or L 2 At least one of the following is independently [ka] Includes: During the ceremony, [ka] to a compound of formula (IV), or L 1 Or L 2 indicates the point of attachment to the rest of the r is an integer selected from 1 to 12; and s is an integer selected from 1 to 32; A compound according to any one of embodiments 17 to 30.

[0340] Embodiment 32. r is an integer selected from 2 to 12; and s is an integer selected from 2 to 32; The compound of embodiment 31.

[0341] Embodiment 33. The compound comprises: [ka] and wherein the subscript v is an integer from 1 to 32; and The subscript u is an integer between 0 and 11. The compound of embodiment 29.

[0342] Embodiment 34. A compound of embodiment 33, wherein the subscript v is an integer selected from 1-14.

[0343] Embodiment 35. The compound is: [ka] wherein the subscript e is an integer selected from 1 to 6. A compound according to embodiment 33 or 34.

[0344] Embodiment 36. The compound of embodiment 35, wherein the subscript e is an integer from 1 to 4.

[0345] Embodiment 37 The compound of embodiment 17, wherein the compound has the following structure: [ka] JPEG2026502495000117.jpg211170JPEG2026502495000118.jpg217170JPEG2026502495000119.jpg207170JPEG2026502495000120.jpg68170

[0346] Embodiment 38. A compound comprising a linker or reactive linker covalently attached to lurbinectedin via a secondary alcohol or a secondary amine.

[0347] Embodiment 39. A compound comprising a linker or reactive linker covalently attached to trabectedin via a secondary alcohol or a secondary amine.

[0348] Embodiment 40 The compound of embodiment 38 or 39, wherein the compound is covalently attached to a targeting agent.

[0349] Embodiment 41. The compound of any one of embodiments 38-40, wherein the compound is covalently attached to an antibody or antibody fragment thereof.

[0350] Embodiment 42. A compound of Formula (Va) or (Vb), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: [ka] where Ab is a targeting agent; The subscript k is an integer from 1 to 10; R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10- forming at least one aromatic ring or bicyclic heterocycle optionally substituted with 1 to 6 substituents selected from the group consisting of alkylamino, hydroxy, halogen, nitro, -P(O)(OH)2, thiol, and -SO3H; and B 1 is the linker; B 2 is the linker, The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

[0351] Embodiment 43 The compound of embodiment 42, wherein Ab is an antibody, antibody fragment, protein, or peptide.

[0352] Embodiment 44.B 1 contains at least one of the following: (a)-H, but B 2 is not H; (b)-CH3; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (g) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10-heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NH-NH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)N(C1-4-alkyl)-NH—R 11 ; (x) -C(O)N(C1-C4-alkyl)-N-(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)-CO-R 11 ; (xii) —CH(NH(C1-4-alkyl))—CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)—CO—R 11 ; (xiv) -CH(CO-R 11 )-NH-R 11 ; (xv) -CH(CO-R11 )-N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is 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 is -(A1) q wherein A1 is an amino acid, the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of -O- and -NH; B 2 independently includes at least one of the following: (a)-H, but B 1 is not H; (b) -PO3H-; (c)-PO2SH-; (d)-CH3; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10-heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 -(C0-6 alkyl)-phenyl optionally substituted with; (j) at least one R 10 -(C0-6 alkyl)-C optionally substituted with 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH2) e - wherein e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii) -(C2H4-O) m -R 11 , where the subscript m is an integer from 1 to 32; (iii) -NH-R 11 ; (iv) —N(C1-4-alkyl)-R 11 ; (v) -C(O)-NH-R 11 ; (vi) —C(O)—N(C1-4-alkyl)-R 11 ; (vii) -C(O)-NHNH-R 11 ; (viii) —C(O)—NHN(C1-4-alkyl)-R 11 ; (ix) —C(O)—N(C1-4-alkyl)NH—R 11 ; (x)—C(O)—N(C1-C4-alkyl)N(C1-4 alkyl)-R 11 ; (xi) -CH(NH2)CO-R11 ; (xii) —CH(NH(C1-4-alkyl))CO—R 11 ; (xiii) —CH(N(C1-4-alkyl)2)CO—R 11 ; (xiv) -CH(CO-R 11 )NH-R 11 ; (xv) -CH(CO-R 11 )N(C1-4-alkyl)-R 11 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is 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 is -(A1) q wherein A1 is an amino acid, the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH2) x where 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 B 1 or B 2 One of is not H; and B 1 or B 2 One of them is bound to Ab, A compound according to embodiment 42 or 43.

[0353] Embodiment 45. The compound is: [ka] 44. The compound of any one of embodiments 41-43, wherein

[0354] Embodiment 46. The compound is: [ka] 44. The compound of any one of embodiments 41-43, wherein

[0355] Embodiment 47.B 1 or B 2 At least one of: [ka] Including, During the ceremony, [ka] to a compound of formula (Va) or formula (Xb), or L 1 Or L 2 indicates the point of attachment to the rest of the [ka] indicates the point of attachment to the antibody or antibody fragment; the subscript r is an integer selected from 1 to 6; and The subscript s is an integer selected from 2 to 14. A compound according to any one of embodiments 42 to 46.

[0356] Embodiment 48. r is an integer selected from 2 to 6; and s is an integer selected from 2 to 14; The compound of embodiment 47.

[0357] Embodiment 49. The compound is: [ka] and In the formula, a is an integer selected from 2 to 6. A compound according to embodiment 47 or 48.

[0358] Embodiment 50 The compound of embodiment 42, wherein the compound is selected from the following: [ka] JPEG2026502495000129.jpg236170JPEG2026502495000130.jpg219170JPEG2026502495000131.jpg165170

[0359] Embodiment 51. A pharmaceutical composition comprising a compound of any one of embodiments 1-16 or 38-49 and a pharmaceutically acceptable excipient.

[0360] Embodiment 52. A method of treating a disease or condition comprising administering a compound of any one of Embodiments 1-16 or 38-49. [Example]

[0361] Unless otherwise specified, the following analytical methods were used:

[0362] Analysis method A 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: 5% to 95% mobile phase B, 3 min, hold at 95% B for 3 min, column wash for 4 min. UV trace monitor at 210 nm and 254 nm. Positive and negative ionization modes monitoring molecular ions from 115 Da to 1200 Da.

[0363] Analysis method B Instrument: Agilent 6230 TOF 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: 5% to 95% mobile phase B, 10 min, hold at 95% B for 5 min, column wash for 5 min. UV trace monitoring at 210 nm and 254 nm.

[0364] When used in the present invention, the symbols and conventions used in these processes, schemes and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, but not exclusively, the following abbreviations can be used in the examples and throughout this specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimolar); μM (micromolar); Hz (Hertz); MHz (Megahertz); mmol (millimolar); hr or hours (hours); 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 (t-butyloxycarbonyl).

[0365] For all of the following examples, standard workup and purification methods known to those skilled in the art can be utilized. Unless otherwise specified, all temperatures are in °C (Celsius). All reactions are performed at room temperature unless otherwise specified and indicated. The synthetic methodologies exemplified in this invention are intended to illustrate applicable chemistry through the use of specific examples and are not intended to limit the scope of the present disclosure.

[0366] Example 1 Preparation of LD1 [ka]

[0367] This example provides the synthesis of lurbinectedin LD1.

[0368] Maleimide-(PEG)2-carboxylic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which lurbinectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours (hrs). The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.8 minutes, expected [M+H] + 1095.40, measurement [M+H] + 1095.4, [M+2H] 2+ 548.5, off-white solid.

[0369] Example 2 Preparation of LD2 [ka]

[0370] This example provides the synthesis of lurbinectedin LD2.

[0371] Maleimide-(PEG)4-carboxylic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which lurbinectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.92 minutes, expected [M+H] + 183.45, measurement [M+H] + 1184.0, [M+2H] 2+ 592.5, off-white solid.

[0372] Example 3 Preparation of LD3 [ka]

[0373] This example provides the synthesis of lurbinectedin LD3.

[0374] Maleimide-(PEG) 12The carboxylic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which lurbinectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.63 minutes, expected [M+H] + 1535.66, measurement [M+2H] 2+ 768.4, off-white solid. High-resolution TOF-MS [M+H] + 1535.6637, measurement [M+H] + 1535.7737.

[0375] Example 4 Preparation of LD4 [ka]

[0376] This example provides the synthesis of lurbinectedin LD4.

[0377] Maleimidohexanoic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which lurbinectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =5.2 minutes, expected [M+H] + 978.35, measurement [M+H] + 978.4, [M+2H] 2+ 490, off-white solid.

[0378] Example 5 Preparation of LD5 [ka]

[0379] This example provides the synthesis of lurbinectedin LD5.

[0380] Maleimido-glycinic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which lurbinectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, Rt =4.75 min, predicted [M+H] + 922.29, Measurement [M+H] + 922.3, [M+2H] 2+ 461.6, off-white solid.

[0381] Example 6 Preparation of LD6 [ka]

[0382] This example provides the synthesis of lurbinectedin LD6.

[0383] Maleimido-Val-Cit-PAB-PNP (1 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of amino-(PEG)2-carboxylic acid (1.5 equiv.) and DIPEA (5 equiv.). The reaction was stirred at room temperature for 24 h, and the crude product was subsequently purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.86 minutes, expected [M+H] + 1589.65, measurement [M+2H] 2+ 795.4, [M-OH+H] 2+ 786.4, off-white solid.

[0384] Maleimido-Val-Cit-PAB-amide-(PEG)2-carboxylic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which lurbinectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.86 minutes, expected [M+H] + 1589.66, measurement [M+H] + 795.4, [M-OH+H]2 + 786.4, off-white solid.

[0385] Example 7 Preparation of LD7 [ka]

[0386] This example provides the synthesis of trabectedin LD7.

[0387] Maleimide-(PEG)4-carboxylic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which trabectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.54 minutes, expected [M+H] + 1160.44, measurement [M+H] + 1160.4, [M+2H] 2+ 580.7, pale yellow solid.

[0388] Example 8 Preparation of LD8 [ka]

[0389] This example provides the synthesis of trabectedin LD8.

[0390] 2-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N′,N′-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which trabectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.32 minutes, expected [M+H] + 899.28, measurement [M+H] + 899.3, red solid.

[0391] Example 9 Preparation of LD9 [ka]

[0392] This example provides the synthesis of trabectedin LD9.

[0393] Maleimidohexanoic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which trabectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t=4.9 minutes, expected [M+H] + 955.34, measurement [M+H] + 955.9, yellow solid.

[0394] Example 10 Preparation of LD10 [ka]

[0395] This example provides the synthesis of trabectedin LD10.

[0396] Maleimido-Val-Cit-PAB-PNP (1 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of amino-(PEG)2-carboxylic acid (1.5 equiv.) and DIPEA (5 equiv.). The reaction was stirred at room temperature for 24 h, after which the crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column and a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.56 minutes, expected [M+H] + 822.39, Measurement [M+H] + 822.4, off-white solid.

[0397] Maleimido-Val-Cit-PAB-amide-(PEG)2-carboxylic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of fluoro-N,N,N',N'-bis(tetramethylene)aluminamidinium hexafluorophosphate (BTFFH; 5 equiv.) and diisopropylethylamine (DIPEA; 10 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, after which trabectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.96 minutes, expected [M+H] + 1565.63, measurement [M+2H] 2+ 783.4, [M-OH+H] 2+ 774.2, pale yellow solid.

[0398] Example 11 Preparation of lurbinectedin derivative 1 [ka]

[0399] This example provides the synthesis of the above compound.

[0400] Lurbinectedin 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)aluminum amidinium hexafluorophosphate (BTFFH; 10 equivalents) and diisopropylethylamine (DIPEA; 20 equivalents). The reaction mixture was stirred overnight at room temperature. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical methods A and R t=4.81 minutes, expected [M+H] + 937.41, Measurement [M+H] + 937.4, red solid.

[0401] Example 12 Preparation of lurbinectedin derivative 2 [ka]

[0402] This example provides the synthesis of the above compound.

[0403] To a solution of lurbinectedin (1 equiv.) in dimethylformamide (DMF), (-)PSI reagent (4 equiv.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5 equiv.) were added. The reaction was stirred at room temperature for 1 hour, followed by the addition of water. The resulting product was subjected to flash reversed-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.64 minutes, expected [M+H] + 881.22, measurement [M+H] + 881.2, yellow solid.

[0404] Example 13 Preparation of lurbinectedin derivative 3 [ka]

[0405] This example provides the synthesis of the above compound.

[0406] To a solution of lurbinectedin (1 equiv.), (-)PSI reagent (4 equiv.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5 equiv.) were added, and the reaction was stirred at room temperature for 1 hour. Subsequently, N-Boc amino-(PEG)4-alcohol (5 equiv.) was added and stirred for 1 hour. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.52 minutes, expected [M+H] + 1156.40, measurement [M+H] + 1155.4, [M+2H] 2+ 578.5, yellow solid.

[0407] The structure of the (-)PSI reagent is shown below: [ka]

[0408] Example 14 Preparation of trabectedin derivative 4 [ka]

[0409] This example provides the synthesis of the above compound.

[0410] To a solution of trabectedin (1 equiv.) in dimethylformamide (DMF), (-)PSI reagent (4 equiv.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5 equiv.) were added. The reaction was stirred at room temperature for 1 hour. Water was then added, stirred for 1 hour, and subjected to flash reversed-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column and a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.42 minutes, expected [M+H]+ 858.21, Measurement [M+H] + 858.2, pale yellow solid.

[0411] Example 15 Preparation of trabectedin derivative 5 [ka]

[0412] This example provides the synthesis of the above compound.

[0413] To a solution of trabectedin (1 equiv.), (-)PSI reagent (4 equiv.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5 equiv.) were added, and the reaction was stirred at room temperature for 1 h. Subsequently, N-Boc amino-(PEG)4-alcohol (5 equiv.) was added and stirred for 1 h. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.52 minutes, expected [M+H] + 1133.38, measurement [M+H] + 1133.4, [M+2H] 2+ 567.0, yellow solid.

[0414] Example 16 Preparation of LD11 [ka]

[0415] This example provides the synthesis of lurbinectedin LD11.

[0416] Lurbinectedin 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 lurbinectedin amine product was used in the next step.

[0417] Crude lurbinectedin amine was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equiv.) and Mal-(PEG)4-NHS (2 equiv.) reagents. The reaction mixture was stirred at room temperature for 16 h. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid.

[0418] The structure of Mal-(PEG)-NHS (i.e., Mal-PEG-NHS) used in the examples of the present disclosure is shown below: [ka]

[0419] Example 17 Preparation of LD12 [ka]

[0420] This example provides the synthesis of trabectedin LD12.

[0421] 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.

[0422] Crude trabectedin amine was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equiv.) and Mal-(PEG)4-NHS (2 equiv.) reagents. The reaction mixture was stirred at room temperature for 16 h. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid.

[0423] Example 18 Preparation of LD13 [ka]

[0424] This example provides the synthesis of lurbinectedin LD13.

[0425] The lurbinectedin 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. The crude lurbinectedin amine product was used in the next step.

[0426] Crude lurbinectedin amine was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equiv.) and Mal-(PEG)4-NHS (2 equiv.) reagents. The reaction mixture was stirred at room temperature for 16 h. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid.

[0427] The structure of Mal-(PEG)2-Val-Cit-PAB-PNP (i.e., Mal-PEG2-Val-Cit-PAB-PNP) used in the examples of the present disclosure is shown below: [ka]

[0428] Example 19 Preparation of LD14 [ka]

[0429] This example provides the synthesis of trabectedin LD14.

[0430] 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.

[0431] Crude trabectedin amine was dissolved in anhydrous dimethylformamide (DMF), followed by the addition of DIPEA (10 equiv.) and Mal-(PEG)2-Val-Cit-PAB-PNP (2 equiv.). The reaction mixture was stirred at room temperature for 16 h. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid.

[0432] Example 20 Generation and Characterization of Antibody Drug Conjugates Conjugation The mAb was pH adjusted with 200 mM Tris, 5 mM EDTA, pH 8.5 (10% in PBS, 30% in proA) and reduced with 4–10 equivalents of TCEP at 37°C for 1 h. The number of free thiols was quantified using an Ellman test. 10% DMSO and a 2 M excess of linker-drug (LD, e.g., LD1) per mole of free thiol were added, the solution was vortexed, and the mixture was left at room temperature for 2 h. Next, 1.2 mol of N-acetylcysteine ​​(NAC) per mole of linker-drug was added, the solution was vortexed, and the mixture was left at room temperature for 20 min. The resulting antibody-drug conjugate (ADC) was buffer-exchanged 3x into PBS pH 7.4 to remove free linker-drug.

[0433] Drug-antibody conjugation ratios (DARs) were determined using either hydrophobic interaction chromatography (HIC) or mass spectrometry of the intact ADC. Aggregation was determined by size exclusion chromatography (SEC).

[0434] Complete characterization data is shown in Table 1 below.

[0435] Characterization of hydrophobic interactions in ADCs 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, and a gradient of 0 to 100% mobile phase B was applied over 15 min. The UV signal at 280 nm was collected, and the chromatogram was analyzed for unconjugated antibody and high DAR species. The DAR was calculated by integrating the area under the HIC curve for predefined peaks (DAR = 0, DAR = 1, DAR = 2, DAR = 4, etc.) and calculating the % of each peak.

[0436] Mass spectrometric characterization of intact ADCs The non-reduced mass of the antibody-drug conjugates was measured using an Agilent 6230 TOF 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 analyzed in their non-reduced form. Proteins were separated on a reversed-phase column (Zorbax 300SB-C8, 5 mm, 4.6 x 50 mm) using a denaturing mobile phase system. Mobile phase A was 0.1% (v / v) formic acid in water. Mobile phase B was 80% (v / v) 2-propanol, 10% (v / v) acetonitrile, and 0.1% (v / v) formic acid in 10% (v / v) water (mobile phase B). MS spectra for each protein were averaged and deconvoluted to obtain the mean and monoisotopic masses.

[0437] Characterization of ADC aggregation by size exclusion chromatography Size-exclusion chromatography (SEC) was used to assess 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 a mobile phase of 25 mM sodium phosphate in water, pH 6.5, 500 mM L-arginine, and 10% isopropanol (IPA). The sample was injected neat, and the mobile phase was applied isocratically at 0.2 mL / min for 22 minutes. The UV signal at 280 nm was collected, and the extent of ADC aggregation and fragmentation was calculated from the peak areas.

[0438] [Table 5]

[0439] In Vitro Plasma Stability Trastuzumab-LD3 ADC was added to cynomolgus monkey, rat, and mouse plasma at a concentration of ~50 μg / mL and incubated at 37°C for 7 days. Various time points were collected: 0, 24, 72, and 168 hours. After incubation, all time points were analyzed by Pierce TMA two-step immunoaffinity enrichment was performed using an MS-Compatible Magnetic IP Kit. In the first step, biotinylated anti-human IgG capture reagent was immobilized on streptavidin magnetic beads, followed by affinity purification of the sample. The eluted sample was injected into an Agilent 1260 high-performance liquid chromatography system connected to an Agilent 6230 TOF LC / MS system. Analysis was performed 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 in acetonitrile (mobile phase B). MS spectra for each protein were averaged and then deconvoluted to obtain the mean mass and monoisotopic mass. MS was operated under denaturing conditions with an m / z range of 300–3500 and a capillary voltage of 4.5 kV. MS data were analyzed in MassHunter software using a maximum entropy deconvolution algorithm. The remaining percentage of conjugate at each time point was calculated relative to time 0, assuming a time zero value of 100%. The assay imprecision is ±25%.

[0440] The results are summarized in Table 2.

[0441] [Table 6]

[0442] In Vitro Ecteinascidin ADC Cytotoxicity - Adhesion Cytotoxicity Assay Adherent cells were cultured in T75 flasks until 50–80% confluent and harvested into a single-cell suspension with trypsin. 3,000–5,000 cells per well were seeded into tissue culture plates in 50 μL / well of medium and incubated at 37°C for 18–24 hours. ADCs were then serially diluted in culture medium and dispensed into the plates at 50 μL / well. After plating and treatment, the cells were returned to the incubator and cultured for an additional 3–5 days. CellTiter-Glo reagent was prepared according to the manufacturer's instructions and added to the culture medium at 100 μL / well. CellTiter-Glo allows for the relative enumeration of metabolically active cells by quantifying intracellular ATP concentration. After a 5-minute incubation with CellTiter-Glo at room temperature, the clear-bottom black assay plate was read in a luminometer within 30 minutes, or 125 μL / well of CellTiter-Glo / cell lysate was transferred to the black assay plate and read. Luminescence measurements from untreated cultures (cell culture medium only) were used as 100% controls, and all other luminescence values ​​were normalized to these controls (e.g., normalized RLU, relative luminescence units). Luminescence signals were detected using a standard plate reader, and IC50 values ​​were calculated by logistic nonlinear regression using GraphPad Prism (GraphPad Software, San Diego, CA).

[0443] Suspension cytotoxicity assay Suspension cells were cultured as single cell suspensions in T75 flasks. 3,000–5,000 cells were seeded per well of tissue culture plates in 50 μL of medium per well and incubated at 37°C for 18–24 hours.

[0444] Serial dilutions of ADC in culture medium were then dispensed into the plates at 50 μL / well. After plating and treatment, the cells were returned to the incubator and cultured for an additional 3–5 days. CellTiter-Glo reagent was prepared according to the manufacturer's instructions and added to the culture medium at 100 μL / well. CellTiter-Glo allows for the relative enumeration of metabolically active cells by quantifying intracellular ATP concentration. After a 5-minute incubation with CellTiter-Glo at room temperature, the clear-bottom black assay plate was either read in a luminometer within 30 minutes, or 125 μL / well of CellTiter-Glo / cell lysate was transferred to the black assay plate and read. Luminescence measurements obtained from cultures that received no treatment (cell culture medium only) were used as the 100% control, and all other luminescence values ​​were normalized (e.g., normalized RLU, relative luminescence units) to these controls. Luminescent signals were detected using a standard plate reader, and IC50 values ​​were calculated by logistic nonlinear regression using GraphPad Prism (GraphPad Software, San Diego, CA).

[0445] Human neutrophil cytotoxicity assay. Human CD34+ myeloid progenitor cells were seeded at 3,000 cells per well in growth medium supplemented with 10 ng / ml human recombinant IL-3 and 30 ng / ml human recombinant G-CSF (both Peprotech, Cranberry, NJ) in 96-well plates. Test ADCs or free drugs were added to each well in duplicate or triplicate at the indicated final concentrations. After 3–4 days of culture, half of the medium (100 μl) was carefully removed, and a viability assay was performed using CellTiter-Glo 2.0 (Promega, Madison, WI) according to the manufacturer's protocol. Luminescent signals were detected using a standard plate reader, and IC values ​​were calculated by logistic nonlinear regression using GraphPad Prism (GraphPad Software, San Diego, CA). 50 was calculated.

[0446] The results are summarized in Tables 3-5 below. All experiments were repeated at least three times with each data point in duplicate. As used in the tables below, n / t indicates "not tested."

[0447] [Table 7]

[0448] [Table 8]

[0449] [Table 9]

[0450] Example 21 Efficacy and Tolerability of Antibody Drug Conjugates In vivo efficacy studies Six to eight week old female B-NDG mice were treated with 5x10 6 NCI-N87 cells (ATCC CRL-5822) were injected subcutaneously. The volume of the subcutaneously grown tumor was measured twice a week using a vernier caliper and calculated using the modified ellipsoid formula: tumor volume (TV) = 0.5 × length × width. 2 Animal body weights were also recorded twice weekly to monitor test article tolerance. Five days after cell inoculation, the mean tumor volume was approximately 150 mm. 3 At this time, mice (n = 5 per cohort) were given their first dose of either vehicle control (PBS) or 0.5 mg / kg body weight of trastuzumab-LD7 antibody-drug conjugate (ADC) via tail vein injection (Day 0). On Day 10, mice received a second dose of vehicle control or trastuzumab-LD7.

[0451] The antibody moiety, trastuzumab, is predicted to bind to HER2 (ERBB2) on the surface of NCI-N87 cells. If the ADC is functional in vivo, it can be internalized into the cells and deliver the LD7 payload to induce cytotoxicity. The significant reduction in tumor volume compared to vehicle control, along with no change in body weight, demonstrates that trastuzumab-LD7 is a functional ADC in vivo without causing any adverse events in the administered animals. Figure 1 shows tumor volume measurements for each cohort of mice throughout the study. Figure 2 shows body weight measurements for each cohort of mice throughout the study.

[0452] In vivo tolerability study An isotype human IgG1 antibody conjugated to LD7 was intravenously injected via the tail vein into 5-7 week-old male CD-1 mice. Three mice per group were administered either 6, 15, or 30 mg / kg body weight (mpk). Animal weights and clinical observations were recorded every other day for 15 days after administration. All animals continued to gain weight throughout the study, with no significant differences observed among the three dose levels. No clinical observations were also performed during the study. Body weight gain and the absence of any obvious adverse events suggested that the LD7 ADC was well tolerated by mice, even at the highest dose tested in this study.

[0453] The maximum tolerated dose (MTD) of trabectedin, the payload of LD7, has previously been reported to be 0.15 mg / kg in male mice. For an ADC with a drug-to-antibody ratio (DAR) of 2, this means the expected tolerated dose is 15 mg / kg. The fact that animals received LD7 at twice the normalized free payload dose without any signs of adverse events suggests that trabectedin delivered as an ADC is better tolerated and can be administered at higher drug levels. Figure 3 shows the body weight measurements of each cohort of mice throughout the study.

[0454] Example 22 Synthesis of LD15 [ka]

[0455] This example provides the synthesis of lurbinectedin LD15.

[0456] MC-vc-PAB-glycine carboxylic acid (1.3 equiv.) was dissolved in anhydrous dimethylformamide (DMF) at 0.1 M concentration, followed by the addition of tetramethylfluoroformamidinium hexafluorophosphate (TFFH; 1.5 equiv.) and diisopropylethylamine (DIPEA; 4.5 equiv.). The reaction mixture was stirred at room temperature for 30 minutes, after which lurbinectedin (1 equiv.) was added. The reaction mixture was stirred at room temperature for 2 hours. The crude product was purified by flash reverse-phase chromatography using a Biotage Isolera chromatography system equipped with a Biotage Sfar C18 column, with a gradient of 5% to 95% acetonitrile / water with 0.1% formic acid. LCMS analytical method A, R t =4.79 minutes, expected [M+H] + 1440.58, measurement [M+H-OH] 2+ 711.9, [M+2H-OH] 3+ 475, off-white solid.

[0457] The structure of MC-vc-PAB-glycine carboxylic acid used in the examples of the present disclosure is shown below: [ka]

[0458] All publications, patents, and applications cited in this specification are incorporated by reference herein as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. While the claimed subject matter has been described in terms of various embodiments, those skilled in the art will understand that various modifications, substitutions, omissions, and changes can be made therein without departing from the spirit thereof. Accordingly, it is intended that the scope of the subject matter be limited only by the scope of the following claims, including equivalents thereof.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof: 【Chemistry 1】 In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, halogen, nitro, -P(O)(OH) 2 , thiol, and -SO 3 forming at least one aromatic or bicyclic heterocyclic ring optionally substituted with 1 to 6 substituents selected from the group consisting of H; R 20 is one of the following: (a) H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, C(O)R 5 , C(O)OR 5 , C(O)NHR 5 , SO 2 R 5 , and SO 2 NHR 5 wherein C 1-10 -alkyl and C 6-10 -each aryl is independently substituted or unsubstituted; or (b) L 1 , where L 1 is a reactive group; R 20 is, in each case independently, OH, F, Cl, Br, C 1-5 -Alkyl, C 3-6 -cycloalkyl, and C 3-6 -heterocyclyl; R 30 is one of the following: (c) H, C 1-10 -Alkyl, C 6-10 -aryl, phosphate, thiophosphate, phosphoramide, C(O)R 6 , C(O)OR 6 , and C(O)NHR 6 , sulfonyl, sulfonylamide; where C 1-10 -alkyl and C 6-10 - each aryl is independently substituted or unsubstituted, or (d) L 2 , where L 2 is a reactive linker group; Phosphates and thiophosphates are in each case H, C 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C 5-10 -heteroaryl; where C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, -OH, and -SO 3 and optionally substituted with 1 to 3 substituents independently selected from the group consisting of H; wherein the substituents on the phosphate and thiophosphate are optionally terminated with protecting groups; R 5 and R 6 are, in each case independently, C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, where C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, -OH, and -SO 3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of H; R 20 or R 30 at least one of is H; 【Chemistry 2】 is either a single or double bond; and The subscript y is an integer selected from 0 to 32; The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

2. L 1 includes at least one of the following: (a) -H, where L 2 is not H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; or (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid, at each occurrence, is independently selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; The compound of claim 1.

3. L 2 includes at least one of the following: (a) -H, where L 1 is not H; (b)-PO 3 H- or -PO 3 H 2 ; (c)-PO 2 SH- or -PO 2 SH 2 ; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, which, in each occurrence, is independently a natural amino acid or an unnatural amino acid, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; 3. The compound according to claim 1 or 2.

4. R 11 but: 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 Selected from:

4. The compound according to claim 2 or 3.

5. R 11 is a reactive group R 40 The compound according to any one of claims 2 to 4, wherein the compound is terminated in

6. L 1 comprises at least one of the following divalent structures: (a) —C(O)—; (b) —C(O)—NH—; (c) —C(O)O—; (d)-[(C(O)-NH] n -; (e) —C(O)—; (f)-(A 1 -A 2 ) d -; (g) [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -O-C(O)-, -O-(C 6 H 4 )-CH 2 -O-C(O)-, or -O-(C 6 H 4 )-CH 2 -O-; (h)-(C 1-6 -alkyl)-; (i)-(C 2 H 4 -O) r or (j)-(C 1-6 -alkyl) p -; L 1 or L 2 But R 40 where R 40 is a reactive group; A 1 and A 2 is, independently in each occurrence, an amino acid, where the amino acid is selected from a natural amino acid or an unnatural amino acid; 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 of 0 or 1; The compound according to any one of claims 1 to 5.

7. L 2 comprises at least one of the following divalent structures: (a)-PO 3 H- or -PO 3 H 2 ; (b)-PO 2 SH- or -PO 2 SH 2 ; (c) —C(O)—; (d) —C(O)—NH—; (e) —C(O)O—; (f)-[(C(O)-NH] n -; (g) —C(O)—; (h)-(A 1 -A 2 ) d -; (i) [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -O-C(O)-, -O-(C 6 H 4 )-CH 2 -O-C(O)-, or -O-(C 6 H 4 )-CH 2 -O-; (j)-(C 1-6 -alkyl)-; (k)-(C 2 H 4 -O) r- or (l)-(C 1-6 -alkyl) p - L 1 or L 2 But R 40 where R 40 is a reactive group; A 1 and A 2 is, independently in each occurrence, an amino acid, where the amino acid is selected from a natural amino acid or an unnatural amino acid; 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 of 0 or 1; The compound according to any one of claims 1 to 5.

8. R 20 but, 【Transformation 3】 where: 【Chemistry 4】 indicates the bond to which the illustrated substituent is attached; The compound according to any one of claims 1 to 7.

9. R 30 but, 【Transformation 5】 where: 【Transformation 6】 indicates the bond to which the thiophosphate is attached, The compound according to any one of claims 1 to 8.

10. The compound is 【Transformation 7】 【change】

11. A compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof: 【Transformation 8】 In the formula, L 1 or L 2 is a reactive group, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

12. L 1 includes at least one of the following: (a) -H, where L 2 is not H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; or (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 -A 2 ) q -, where A 1 and A 2 is, independently at each occurrence, an amino acid, wherein the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; The compound of claim 11.

13. L 2 includes at least one of the following: (a) -H, where L 1 is not H; (b)-PO 3 H- or -PO 3 H 2 ; (c)-PO 2 SH- or -PO 2 SH 2 ; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 -A 2 ) q -, where A 1 and A 2 is, independently at each occurrence, an amino acid, wherein the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; 13. A compound according to claim 11 or 12.

14. R 11 but: 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 Selected from:

14. A compound according to claim 12 or 13.

15. R 11 is a reactive group R 40 The compound according to any one of claims 12 to 14, wherein the compound is terminated in

16. A compound of formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, comprising: 【Chemistry 9】 In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, nitro, -P(O)(OH) 2 , thiol, and -SO 3 H; where: 【Chemistry 10】 is either a single or double bond; L 1 includes at least one of the following: (a) -H, where L 2 is not H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 and A 2 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) x -, where the subscript x is an integer selected from 1 to 10; and R 11d is selected from the group consisting of —O— and —NH; L 2 includes at least one of the following: (a) -H, where L 1 is not H; (b)-PO 3 H-; (c)-PO 2 SH-; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the subscript m is an integer from 1 to 10; (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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; A compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

17. A compound of formula (IV), or a pharmaceutically acceptable salt, ester, or tautomer thereof, comprising: 【Chemistry 11】 In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, halogen, nitro, -P(O)(OH) 2 , thiol, and -SO 3 H; where: 【Chemistry 12】 is either a single or double bond; L 1 teeth: H； R 40 -(C 1-6- alkyl)-[(C(O)-NH] b -(-C 2 H 4 -O) c- (C 1-6 -alkyl) e -[(C(O)-] f ; R 40 -(-C 2 H 4 -O) c -C(O)-(A 1 -A 2 ) g -[-NH] h -(C 6 H 4 )-CH 2 -O-[(C(O)-NH] j -(-C 2 H 4 -O) t -(C 1-6 -alkyl)-[(C(O)-] k or R 40 -(C 1-6 -alkyl)-C(O)-(A 1 -A 2 ) g -[-NH] h -(C 6 H 4 )-CH 2 -O-[(C(O)-NH] j - and; L 2 teeth: H； R 40 -(C 1-6 -alkyl)-[(C(O)-NH] b -(-C 2 H 4 -O) c- (C 1-6 -alkyl)-[(C(O)-NH] j -(-C 2 H 4 -O) t -[OP(O)SH]; or R 40 -(-C 2 H 4 -O) t -C(O)-(A 1 -A 2 ) g -NH-(C 6 H 4 )-CH 2 -O-[(C(O)-NH] j -(-C 2 H 4 -O) t -(C 1-6 -alkyl)-[(C(O)-] f -[OP(O)SH]; L 1 or L 2 is not H; R 40 is a reactive group; A 1 and A 2 is independently in each occurrence an amino acid; Subscript: b and j, in each occurrence, are independently selected from 0 to 4; c and t, in each occurrence, are independently selected from 0 to 32; e, f, g, h, and k are independently in each occurrence 0 or 1; The compound, or a pharmaceutically acceptable salt, ester, or tautomer thereof.

18. R 40 The compound according to any one of claims 15 to 17, wherein is maleimide.

19. R 11b Ha-(A 1- A 2 ) q -, where A in each case 1 -A 2 are 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; The compound according to any one of claims 12 to 18.

20. -(A 1- A 2 ) q 20. The compound of claim 19, wherein - is Val-Cit or Cit-Val.

21. The compound is: 【Chemistry 13】 The compound according to any one of claims 16 to 120,

22. The compound is: 【Chemistry 14】 The compound according to any one of claims 16 to 20,

23. L 1 or L 2 at least one of, independently, 【Chemistry 15】 Includes: During the ceremony, 【Chemistry 16】 to a compound of formula (IV), or L 1 Or L 2 indicates the point of attachment to the remainder of the r is an integer selected from 1 to 12; and s is an integer selected from 1 to 32; The compound according to any one of claims 11 to 22.

24. r is an integer selected from 2 to 12; and s is an integer selected from 2 to 32; 24. The compound of claim 23.

25. L 1 is H; or L 2 The compound of any one of claims 16 to 24, wherein is H.

26. The compound is: 【Chemistry 17】 and where the subscript v is an integer from 1 to 32; and The subscript u is an integer between 0 and 11.

22. The compound of claim 21.

27. 27. The compound of claim 26, wherein the subscript v is an integer selected from 1 to 14.

28. The compound is: [Chemistry 18] and 22. The compound of claim 21, wherein the subscript e is an integer selected from 1 to 6.

29. 29. The compound of claim 28, wherein the subscript e is an integer from 1 to 4.

30. 18. The compound of claim 16 or 17, wherein the compound has the structure: 【Chemistry 19】 【change】 【change】 【change】 【change】

31. A compound comprising a linker or reactive linker covalently attached to lurbinectedin via a secondary alcohol or a secondary amine.

32. A compound comprising a linker or reactive linker covalently attached to trabectedin via a secondary alcohol or a secondary amine.

33. 33. The compound of claim 31 or 32, wherein the compound is covalently attached to a targeting agent.

34. The compound of any one of claims 31 to 33, wherein the compound is covalently attached 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: 【Chemistry 20】 where Ab is a targeting agent; The subscript k is an integer from 1 to 10; R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, halogen, nitro, -P(O)(OH) 2 , thiol, and -SO 3 forming at least one aromatic ring or bicyclic heterocycle optionally substituted with 1 to 6 substituents selected from the group consisting of H; and B 1 is a linker; B 2 is the linker, The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

36. 36. The compound of claim 35, wherein Ab is an antibody, antibody fragment, protein, or peptide.

37. B 1 includes at least one of the following: (a)-H, but B 2 is not H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; B 2 includes at least one of the following: (a)-H, but B 1 is not H; (b)-PO 3 H-; (c)-PO 2 SH-; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and where R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; where R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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 B 1 or B 2 one of which is not H; and B 1 or B 2 One of them is bound to Ab, 37. A compound according to claim 35 or 36.

38. The compound is 【Chemistry 21】 The compound according to any one of claims 34 to 37,

39. The compound is 【Chemistry 22】 The compound according to any one of claims 34 to 37,

40. B 1 or B 2 At least one of: 【Chemistry 23】 Including, During the ceremony, 【Chemistry 24】 to a compound of formula (Va) or formula (Xb), or L 1 Or L 2 indicates the point of attachment to the remainder of the 【Chemistry 25】 indicates the point of attachment to the antibody or antibody fragment; the subscript r is an integer selected from 1 to 6; and The subscript s is an integer selected from 2 to 14; The compound according to any one of claims 35 to 39.

41. r is an integer selected from 2 to 6; and s is an integer selected from 2 to 14; 41. The compound of claim 40.

42. The compound is 【Chemistry 26】 and wherein a is an integer selected from 2 to 6.

42. A compound according to claim 40 or 41.

43. The compound is 【Chemistry 27】 【change】 【change】 【change】 36. The compound of claim 35, selected from:

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or 31 to 43 and a pharmaceutically acceptable excipient.

45. 44. A method of treating a disease or condition comprising administering a compound of any one of claims 1-10 or 31-43.

46. A compound of formula (XI) or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof: 【Chemistry 28】 During the ceremony: R 1 and R 2 together form an aromatic ring or a bicyclic heteroaromatic ring; Aromatic rings and bicyclic heteroaromatic rings are C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, halogen, nitro, -P(O)(OH) 2 , -SH, and -SO 3 optionally substituted with 1 to 6 substituents independently selected from the group consisting of H; R 3 is hydrogen or CH 2 OR 6 and R 4 is H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, C(O)R 8 , C(O)OR 8 , C(O)NHR 8 , SO 2 R 8 , SO 2 NHR 8 ; where C 1-10 -alkyl or C 6-10 -Aryl is -OH, -F, -Cl, -Br, -C 1-6 --Alkyl-C 3-6 -cycloalkyl, and -C 3-6 -heterocyclyl; or L 1 and R 5 and R 6 i) H, C 1-10 -Alkyl, C 6-10 -aryl, phosphate, thiophosphate, phosphoramide, C(O)R 9 , C(O)OR 9 , and C(O)NHR 9 , SO 3 H, SO 2 R 9 The group consisting of: 1-10 -alkyl or C 6-10 -aryl is -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 are independently selected from R 5 or R 6 The phosphates and thiophosphates of 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C 5-10 -heteroaryl; C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, -OH, and -SO 3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of H; and The substituents on the phosphate and thiophosphate are optionally terminated with protecting groups; R 8 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, -OH, and -SO 3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of H; R 9 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, -OH, and -SO 3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of H; R 4 , R 5 , and R 6 One of the reactive groups R 10 or a linker to an antibody Ab; 【Chemistry 29】 is either a single or double bond; and y is an integer selected from 0 to 32; The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

47. L 1 includes at least one of the following: (a) -H, where L 2 is not H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; or (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-CO-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid, at each occurrence, is independently selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; 47. The compound of claim 46.

48. L 2 includes at least one of the following: (a) -H, where L 1 is not H; (b)-PO 3 H- or -PO 3 H 2 ; (c)-PO 2 SH- or -PO 2 SH 2 ; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid, at each occurrence, is independently selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; 48. A compound according to claim 46 or 47.

49. R 11 but: 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 Selected from:

49. A compound according to claim 47 or 48.

50. R 11 is a reactive group R 40 50. The compound according to any one of claims 47 to 49, wherein

51. L 1 comprises at least one of the following divalent structures: (a) —C(O)—; (b) —C(O)—NH—; (c) —C(O)O—; (d)-[(C(O)-NH] n -; (e) —C(O)—; (f)-(A 1 -A 2 ) d -; (g) [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -O-C(O)-, -O-(C 6 H 4 )-CH 2 -O-C(O)-, or -O-(C 6 H 4 )-CH 2 -O-; (h)-(C 1-6 -alkyl)-; (i)-(C 2 H 4 -O) r or (j)-(C 1-6 -alkyl) p -; L 1 or L 2 But R 40 where R 40 is a reactive group; A 1 and A 2 is, independently in each occurrence, an amino acid, where the amino acid is selected from a natural amino acid or an unnatural amino acid; 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 of 0 or 1; The compound according to any one of claims 47 to 48.

52. L 2 comprises at least one of the following divalent structures: (a)-PO 3 H- or -PO 3 H 2 ; (b)-PO 2 SH- or -PO 2 SH 2 ; (c) —C(O)—; (d) —C(O)—NH—; (e) —C(O)O—; (f)-[(C(O)-NH] n -; (g) —C(O)—; (h)-(A 1 -A 2 ) d -; (i) [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -O-C(O)-, -O-(C 6 H 4 )-CH 2 -O-C(O)-, or -O-(C 6 H 4 )-CH 2 -O-; (j)-(C 1-6 -alkyl)-; (k)-(C 2 H 4 -O) r- or (l)-(C 1-6 -alkyl) p -; L 1 or L 2 But R 40 where R 40 is a reactive group; A 1 and A 2 is, independently in each occurrence, an amino acid, where the amino acid is selected from a natural amino acid or an unnatural amino acid; 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 of 0 or 1; The compound according to any one of claims 46 to 50.

53. R 4 but, 【Transformation 30】 where: 【Chemistry 31】 indicates the bond to which the illustrated substituent is attached; The compound according to any one of claims 46 to 52.

54. R 5 but, 【Chemistry 32】 where: 【Transformation 33】 indicates the bond to which the thiophosphate is attached, The compound according to any one of claims 46 to 53.

55. R 6 but, 【Transformation 34】 where: 【Chemistry 35】 indicates the bond to which the thiophosphate is attached, The compound according to any one of claims 46 to 54.

56. The compound is 【Transformation 36】 【change】 【change】 【change】 47. The compound of claim 46, selected from:

57. Provided is a compound of formula (XII), or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof, which comprises: 【Chemistry 37】 In the formula, L 1 or L 2 is a reactive linker: The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

58. L 1 includes at least one of the following: (a) -H, where L 2 is not H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; or (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 -A 2 ) q -, where A 1 and A 2 is independently, at each occurrence, an amino acid, wherein the amino acid is selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; 58. The compound of claim 57.

59. Each L 2 independently comprising at least one of: (a) -H, where L 1 is not H; (b)-PO 3 H- or -PO 3 H 2 ; (c)-PO 2 SH- or -PO 2 SH 2 ; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group N, O, and S; where R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 -A 2 ) q -, where A 1 and A 2 is independently in each occurrence an amino acid, the amino acid being selected from natural amino acids or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; 59. A compound according to claim 57 or 58.

60. R 11 but: 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 Selected from:

60. The compound of claim 58 or 59.

61. R 11 is a reactive group R 40 The compound according to any one of claims 58 to 60, wherein

62. L 1 is H, C 1-10 -Alkyl, C 6-10 -aryl, C 3-10 -heterocyclyl, C(O)R 8 , C(O)OR 8 , C(O)NHR 8 , SO 2 R 8 , and SO 2 NHR 8 is selected from the group consisting of C 1-10 -alkyl and C 6-10 -aryl is, independently, substituted or unsubstituted; or L 1 is, in each case independently, OH, F, Cl, Br, C 1-5 -Alkyl, C 3-6 -cycloalkyl, and C 3-6 -heterocyclyl; R 8 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, and -SO 3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of H; At least one L 1 or L 2 is not H; and The subscript y is an integer selected from 0 to 32; The compound according to any one of claims 57 to 61.

63. L 2 is H, C 1-10 -Alkyl, C 6-10 -aryl, phosphate, thiophosphate, phosphoramide, C(O)R 9 , C(O)OR 9 , and C(O)NHR 9 , SO 3 H, SO 2 R 9 is selected from the group consisting of C 1-10 -alkyl and C 6-10 -aryl is, independently, substituted or unsubstituted; or The phosphates and thiophosphates may in each case independently be H, C 1-6 -Alkyl, C 3-10 -cycloalkyl, (poly(ethylene) glycol) y ([PEG] y ), C 6-10 -aryl, and C 5-10 - optionally substituted with 1 to 2 substituents selected from the group consisting of heteroaryl; C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, -OH, and -SO 3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of H; The substituents on the phosphate and thiophosphate are optionally terminated with protecting groups; R 9 is C 1-6 -Alkyl, C 3-10 -cycloalkyl, [PEG] y , C 6-10 -aryl, and C 6-10 -heteroaryl, C 1-6 -Alkyl is methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, amino, nitro, -P(O)(OH) 2 , thiol, and -SO 3 optionally substituted with 1 to 3 substituents independently selected from H; At least one L 1 or L 2 is not H; and The subscript y is an integer selected from 0 to 32 The compound according to any one of claims 57 to 62.

64. Compounds of formula (XIII), or pharmaceutically acceptable salts, esters, stereoisomers, or tautomers thereof, including: 【Transformation 38】 In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, halogen, nitro, -P(O)(OH) 2 , thiol, and -SO 3 forming at least one aromatic or bicyclic heteroaromatic ring optionally substituted with 1 to 6 substituents selected from H; 【Chemistry 39】 is either a single or double bond; L 1 includes at least one of the following: (a) -H, where L 2 is not H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; Each L 2 includes at least one of the following: (a) -H, where L 1 is not H; (b)-PO 3 H-; (c)-PO 2 SH-; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

65. Compounds of formula (XIV), or pharmaceutically acceptable salts, esters, stereoisomers, or tautomers thereof, including: 【Chemistry 40】 In the formula, R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, halogen, nitro, -P(O)(OH) 2 , thiol, and -SO 3 forming at least one aromatic or bicyclic heteroaromatic ring optionally substituted with 1 to 6 substituents selected from the group consisting of H; 【Chemistry 41】 is either a single or double bond; L 1 or L 2 An example of the linker is: L 1 teeth: H； R 40 - (C 1-6 -alkyl)-[(C(O)-NH] b -(-C 2 H 4 -O) c- (C 1-6 -alkyl) e -[(C(O)-] f or R 40 - (-C 2 H 4 -O) c -C(O)-(A 1 -A 2 ) g -[-NH] h -(C 6 H 4 )-CH 2 -O-[(C(O)-NH] j -(-C 2 H 4 -O) t -(C 1-6 -alkyl)-[(C(O)-] k and Each L 2 independently: H； R 40 -(C 1-6 -alkyl)-[(C(O)-NH] b -(-C 2 H 4 -O) c -(C 1-6 -alkyl)-[(C(O)-NH] j -(-C 2 H 4 -O) t -[OP(O)SH]; or R 40 -(-C 2 H 4 -O) t -C(O)-(A 1 -A 2 ) g -NH-(C 6 H 4 )-CH 2 -O-[(C(O)-NH] j -(-C 2 H 4 -O) t -(C 1-6 -alkyl)-[(C(O)-] f -[OP(O)SH]; L 1 or L 2 One of them is not H; R 40 is a reactive group; A 1 and A 2 is independently in each occurrence an amino acid; Subscript: b and j, in each occurrence, are independently selected from 0 to 4; c and t, in each occurrence, are independently selected from 0 to 32; e, f, g, h, and k are independently in each occurrence 0 or 1; The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

66. R 40 is maleimide, -NH 2 , -COO-succinimide, halogen or substituted alkyne.

67. R 11b A 1- A 2 ) q - and A 1 -A 2 but: 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. The compound according to any one of claims 58 to 66.

68. -(A 1- A 2 ) q 68. The compound of any one of claims 67, wherein - is selected from Val-Cit, Val-Ala, Phe-Lys, or Gly-Gly-Phe-Gly.

69. The compound is: 【Chemistry 42】 The compound according to any one of claims 64 to 68, wherein

70. L 1 or L 2 At least one of: 【Chemistry 43】 Including, During the ceremony, 【Chemistry 44】 to a compound of formula (IV), or L 1 Or L 2 indicates the point of attachment to the remainder of the the subscript r is an integer selected from 1 to 12; and The subscript s is an integer selected from 1 to 32; 70. The compound according to any one of claims 57 to 69.

71. r is an integer selected from 2 to 12; and s is an integer selected from 2 to 32; 71. The compound of claim 70.

72. The compound is: 【Chemistry 45】 and wherein the subscript v is an integer from 1 to 32; and the subscript u is an integer from 0 to 11.

71. The compound of claim 69 or 70.

73. 73. The compound of claim 72, wherein the subscript v is an integer selected from 1 to 14.

74. The compound is 【Chemistry 46】 and wherein the subscript e is an integer selected from 1 to 6.

71. The compound of claim 69 or 70.

75. 75. The compound of claim 74, wherein the subscript e is an integer from 1 to 4.

76. 70. The compound of claim 69, wherein the compound has the structure: 【Chemistry 47】 【change】 【change】

77. A compound comprising a linker or reactive linker covalently attached to lurbinectedin via a secondary alcohol or a secondary amine.

78. 78. The compound of claim 77, wherein the compound is covalently attached to a targeting agent.

79. 79. The compound of claim 77 or 78, wherein the compound is covalently attached 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: 【Chemistry 48】 where Ab is a targeting agent; The subscript k is an integer from 1 to 10; R 1 and R 2 are, in each case independently, C 1-10 -alkoxy, C 1-10 -Alkylamino, hydroxy, halogen, nitro, -P(O)(OH) 2 , thiol, and -SO 3 forming at least one aromatic ring or bicyclic heterocycle optionally substituted with 1 to 6 substituents selected from the group consisting of H; and B 1 is a linker; B 2 is the linker, The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer thereof.

81. 81. The compound of claim 80, wherein Ab is an antibody, antibody fragment, protein, or peptide.

82. B 1 includes at least one of the following: (a)-H; (b)-CH 3 ; (c) at least one R 10 -C optionally substituted with 2-8 - alkyl; (d) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (e) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (f) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (g) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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(C 1 -C 4 -alkyl)-N-(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )-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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; B 2 includes at least one of the following: (a)-H; (b)-PO 3 H-; (c)-PO 2 SH-; (d)-CH 3 ; (e) at least one R 10 -C optionally substituted with 2-8 - alkyl; (f) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -cycloalkyl; (g) at least one R 10 optionally substituted with -(C 0-6 -alkyl)-C 3-10 -heterocyclyl, where C 3-10 -heterocyclyl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; (h) at least one R 10 optionally substituted with -(C 0 - 6 alkyl)-phenyl; (j) at least one R 10 optionally substituted with -(C 0 - 6 Alkyl)-C 5-10 -heteroaryl, where C 5-10 -heteroaryl optionally contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; R 10 is R 10a -R 10b and R 10a is absent or -(CH 2 ) e - where e, at each occurrence, is independently selected from 1 to 4; R 10b is selected from the group consisting of: (i)-C(O)-R 11 ; (ii)-(C 2 H 4 -O) m -R 11 , where the 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 ; (viii)-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(C 1 -C 4 -alkyl)N(C 1 - 4 alkyl)-R 11 ; (xi)-CH(NH 2 )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 ; R 11 is R 11a , R 11b , R 11c , R 11d and combinations thereof; R 11a is [-NH]-(C 6 H 4 )-CH 2 -O-, [-NH]-(C 6 H 4 )-CH 2 -OC(O)-, -O-(C 6 H 4 )-CH 2 -OC(O)- and -O-(C 6 H 4 )-CH 2 -O-; R 11b is -(A 1 ) q -, where A 1 is an amino acid, wherein the amino acid is selected from natural or unnatural amino acids, and the subscript q is an integer selected from 1 to 6; R 11c Ha-(CH 2 ) 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; 82. The compound of claim 80 or 81.

83. The compound is 【Chemistry 49】 The compound according to any one of claims 79 to 82,

84. B 1 or B 2 At least one of: [Transformation 50] Including, During the ceremony, 【Chemistry 51】 to a compound of formula (XVa), (XVb), or (XVc), or L 1 Or L 2 indicates the point of attachment to the remainder of the 【Chemistry 52】 indicates the point of attachment to the antibody or antibody fragment; the subscript r is an integer selected from 1 to 6; and The subscript s is an integer selected from 2 to 14; The compound according to any one of claims 80 to 83.

85. the subscript r is an integer selected from 2 to 6; and the subscript s is an integer selected from 2 to 14; 85. The compound of claim 84.

86. The compound is 【Chemistry 53】 and 86. The compound according to claim 84 or 85, wherein a is an integer selected from 2 to 6.

87. 81. The compound of claim 80, wherein the compound is selected from the following: 【Chemistry 54】 【change】 【change】

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): 【Transformation 55】 In the formula, L 1 is a linker group terminated in a reactive group; The method comprises reacting lurbinectedin with a suitable coupling reagent in a suitable solvent to form a compound of the structure L 1 and a compound having an —OH group to obtain a linker-drug compound of formula (XVI).

91. A method for preparing a linker-drug compound of formula (XVII): 【Transformation 56】 in the formula, in the formula, L 1 is a linker group terminated in a reactive group; The method comprises reacting trabectedin with a suitable coupling reagent in a suitable solvent to form a compound of the structure L 1 and a compound having an —OH group to obtain a linker-drug compound of formula (XVII).

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