Drug antibody conjugate containing an ectenacidin derivative

Abstract

A drug conjugate having the chemical formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab: wherein D is a drug moiety having the following chemical formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and (I) In the formula, D is covalently bonded to (X)b, or (AA)w, or (T)g, or (L) if present; and is useful for the treatment of cancer.

Description

Technology Field

[0001] The present invention relates to a novel drug conjugate, a drug linker compound, a method for preparing the same, a pharmaceutical composition containing said drug conjugate, and the use of the same as an antitumor agent. Background Technology

[0002] International patent application number PCT / EP2018 / 060868 discloses a novel ecteinascidin derivative exhibiting very promising antitumor activity. One of the compounds disclosed in this patent application is currently in Phase 1 clinical trials for the prevention and treatment of solid tumors.

[0003] Cancer treatment has advanced significantly in recent years due to the development of drugs that more efficiently target and kill cancer cells. Taking tumors as an example, researchers are developing pharmaceutical agents based on antibodies that bind to tumor-specific or tumor-associated antigens, utilizing cell surface receptors and antigens that are selectively expressed by target cells, such as cancer cells. To achieve these effects, cytotoxic molecules—such as chemotherapeutic drugs, bacteria, plant toxins, and radionuclides—are being chemically linked to monoclonal antibodies that bind to tumor-specific or tumor-associated cell surface antigens.

[0004] Therefore, while antibody-drug conjugates (ADCs) represent a challenging area for development considering their complex payloads, linkers, and antibody structures, there is still a need to develop additional ADC formulations. The problem to be solved

[0005] invention overview

[0006] There is a need to develop drug conjugates exhibiting novel activity. To this end, the present invention provides a novel drug linker compound for use in the manufacture of the drug conjugate of the present invention, a method for the manufacture of the novel drug conjugate of the present invention, a pharmaceutical composition containing said drug conjugate and its use as an antitumor agent, and a kit comprising the drug conjugate of the present invention for use in cancer treatment.

[0007] According to a first aspect of the present invention, the present invention provides a drug conjugate comprising a drug moiety covalently bonded to a remainder of the drug conjugate, wherein the drug conjugate is of the formula [D-(X) b -(AA) w -(T) g -(L)-] n It is represented by the chemical formula of -Ab, where:

[0008] D is a drug moiety having the following chemical formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and

[0009]

[0010] Here:

[0011] D is in (X)b if it exists, or in (AA)w if it exists, or in (T) if it exists g or covalently bonded to the linker group L via a hydroxyl group or an amine group;

[0012] Y is -NH- or -0- and;

[0013] R1 is -OH or -CN and;

[0014] R2 is -C(=0)Ra and;

[0015] R3 is a hydrogen or -ORb group;

[0016] R4 is hydrogen, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NHSelected from;

[0017] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0018] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl;

[0019] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0020] Prot NH is a protecting group for amino, and

[0021] However, if R4 is hydrogen, Y is -0- and,

[0022] X and T are extensions that may be the same or different;

[0023] Each AA is independently an amino acid unit;

[0024] L is a linker;

[0025] w is an integer in the range of 0 to 12;

[0026] b is an integer of 0 or 1;

[0027] g is an integer of 0 or 1;

[0028] Ab is a moiety comprising at least one antigen binding site; and

[0029] n is [D-(X) for a moiety containing at least one antigen-binding site b -(AA) w-(T) g -(L)-] is a ratio of 1 to 20.

[0030] According to a second aspect of the present invention, the present invention provides a drug conjugate comprising a drug moiety covalently bonded to a remainder of the drug conjugate, wherein the drug conjugate is of the formula [D-(X) b -(AA) w -(T) g -(L)-] n It is represented by the chemical formula of -Ab, where:

[0031] D is a drug moiety having the following chemical formula (IH) or a pharmaceutically acceptable salt, ester, solvate, tautomeric or stereoisomer thereof, and

[0032]

[0033] Here:

[0034] If the above dashed line exists (X) b A covalent bonding site for, or for (AA)w if present, or for linker L;

[0035] Each Y and Z is independently selected from -NH- and -0-;

[0036] R1 is -OH or -CN and;

[0037] R2 is the -C(=0)Ra group;

[0038] R3 is a hydrogen or -ORb group;

[0039] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl, wherein any substituent is one or more substituents Rx;

[0040] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl, wherein any substituent is one or more substituents Rx;

[0041] C1-C where substituent Rx can be arbitrarily substituted by at least one Ry group 12 C2-C that can be arbitrarily substituted by an alkyl group, at least one Ry group 12 C2-C that can be arbitrarily substituted by an alkenyl group, at least one Ry group 12 An aryl group having 6 to 18 carbon atoms in one or more rings that may be optionally substituted by one or more substituents that may be the same or different and selected from the group consisting of 'Ry, ORy, OCORy, OCOORy, CORy, COORy, OCONRyRz, CONRyRz, S(O)Ry, SO2Ry, P(O)(Ry)ORz, NRyRz, NRyCORz, NRyC(=O)NRyRz, NRyC(=NRy)NRyRz', an aralkyl group comprising an alkyl group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group as defined above, and as defined above A group selected from the group comprising an aralkyloxy group comprising an alkoxy group having 1 to 12 carbon atoms substituted by an optionally substituted aryl group, and a saturated or unsaturated heterocyclic group having one or more rings, comprising at least one oxygen, nitrogen, or sulfur atom within the ring(s), and optionally substituted by one or more substituents Ry; wherein if there are two or more optional substituents on any of the groups, the optional substituents Ry may be the same or different;

[0042] Each Ry and Rz independently consists of hydrogen, C1-C 12C1-C alkyl groups substituted by at least one halogen atom 12 C1-C alkyl groups substituted by aryl groups having 6 to 18 carbon atoms in one or more rings 12 C1-C groups substituted by an aralkyl group containing an alkyl group, and a saturated or unsaturated heterocyclic group of 5 to 14 having one or more rings. 12 Selected from the group consisting of heterocycloalkyl groups comprising an alkyl group and at least one oxygen, nitrogen, or sulfur atom within the ring(s);

[0043] X and Y are extending groups that may be the same or different;

[0044] Each AA is independently an amino acid unit;

[0045] L is a linker;

[0046] w is an integer in the range of 0 to 12;

[0047] b is an integer of 0 or 1;

[0048] g is an integer of 0 or 1;

[0049] Here, w+b+g is optionally not 0

[0050] Ab is a moiety comprising at least one antigen binding site; and

[0051] n is [D-(X) for a moiety containing at least one antigen-binding site b -(AA) w -(T) g -(L)-] is a ratio of 1 to 20.

[0052] According to another aspect of the present invention, the present invention provides a drug conjugate comprising a drug moiety covalently bonded to a remainder of the drug conjugate, wherein the drug conjugate is of the formula [D-(X) b -(AA)w -(T) g -(L)-] n It is represented by the chemical formula of -Ab, where:

[0053] D is a drug moiety having the following chemical formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and

[0054]

[0055] During the meal:

[0056] D is in (X)b if it exists, or in (AA)w if it exists, or in (T) if it exists g or covalently bonded to the linker group L via a hydroxyl group or an amine group;

[0057] Y is -NH- or -0- and;

[0058] R1 is -OH or -CN and;

[0059] R2 is -C(=0)Ra and;

[0060] R3 is a hydrogen or -ORb group;

[0061] R4 is hydrogen, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0062] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0063] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl;

[0064] Rc is a substituted or unsubstituted C1-C 12Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0065] Prot NH is a protecting group for amino, and

[0066] However, if R4 is hydrogen, Y is -0- and,

[0067] X and T are extensions that may be the same or different;

[0068] Each AA is independently an amino acid unit;

[0069] L is a linker;

[0070] w is an integer in the range of 0 to 12;

[0071] b is 1 and;

[0072] g is an integer of 0 or 1;

[0073] Ab is a moiety comprising at least one antigen binding site; and

[0074] n is [D-(X) for a moiety containing at least one antigen-binding site b -(AA) w -(T) g -(L)-] is a ratio of 1 to 20.

[0075] According to another aspect of the present invention, the present invention provides a drug conjugate comprising a drug moiety covalently bonded to a remainder of the drug conjugate, wherein the drug conjugate is of the formula [D-(X) b -(AA) w -(T) g -(L)-] n It is represented by the chemical formula of -Ab, where:

[0076] D is a drug moiety having the following chemical formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and

[0077]

[0078] During the meal:

[0079] D is in (X)b if it exists, or in (AA)w if it exists, or in (T) if it exists g or covalently bonded to the linker group L via a hydroxyl group or an amine group;

[0080] Y is -NH- or -0- and;

[0081] R1 is -OH or -CN;

[0082] R2 is -C(=0)Ra and;

[0083] R3 is a hydrogen or -ORb group;

[0084] R4 is hydrogen, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0085] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0086] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl;

[0087] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0088] Prot NH is a protecting group for amino, and

[0089] However, if R4 is hydrogen, Y is -0- and,

[0090] X and T are extensions that may be the same or different;

[0091] Each AA is independently an amino acid unit;

[0092] L is a linker;

[0093] w is 2 and;

[0094] b is 1 and;

[0095] g is an integer of 0 or 1;

[0096] Ab is a moiety comprising at least one antigen binding site; and

[0097] n is [D-(X) for a moiety containing at least one antigen-binding site b -(AA) w -(T) g -(L)-] is a ratio of 1 to 20.

[0098] As will be explained and illustrated in much greater detail below, the chemical formula [D-(X) of the present invention b -(AA) w -(T) g The drug conjugate of -(L)-]n-Ab is a breakthrough that resolves the aforementioned problem that additional drug conjugates are required in addition to formulations based on three major cytotoxic drug families that have been used as payloads to date and exhibit excellent antitumor activity.

[0099] According to a preferred embodiment of the present invention, the present invention provides a drug conjugate as defined herein, or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein D is a drug moiety selected from the formulas (IHa) and (IHb):

[0100]

[0101] Here, the dashed lines, R1, R2, R3, Y, and Z are as defined in the compound of [Formula IH].

[0102] According to another aspect of the present invention, the present invention has the formula D-(X) b -(AA) w -(T) g -L1 or D-(X) b -(AA) w -(T) g Provides a compound of -H, where:

[0103] L1 is a linker selected from the group of chemical formulas consisting of the following:

[0104]

[0105] If each dashed line exists (T) g Regarding, or if present (AA)w, or if present (X) b Indicates a covalent bonding site for, or for D if present;

[0106] G is halo, - O -Plum and - O -Selected from Tosil;

[0107] J stands for halo, hydroxy, - N -Suksin is already dead, - O -(4-nitrophenyl), - O -pentafluorophenyl, - O -Tetrafluorophenyl and -OC(O)-OR 20 Selected from;

[0108] R 19 is -C1-C 12 Alkylene-, -C3-C8 carbocyclo, -O-(C1-C 12 alkylene), one or more substituents R x -C6-C in one or more rings that can be arbitrarily substituted by 18 Aryllene, one or more substituents Rx -C1-C having an arylene group in one or more rings that can be arbitrarily substituted by 12 Alkylene-C6-C 18 Aryllene-, one or more substituents R x -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by 18 Aryllene-C1-C 12 Alkylene-, -C1-C 12 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 12 Alkylene-, -C5-C 14 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s), and the group is one or more substituents R x It is arbitrarily substituted by], -C1-C 12 Alkylene-(C5-C 14 Heterocyclo)- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s), and the group is one or more substituents R x It is arbitrarily substituted by], -(C5-C 14 Heterocyclo)-C1-C 12 Alkylene- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s), and said group is one or more substituents R x It is arbitrarily substituted by], -(OCH2CH2) r - and -CH2-(OCH2CH2) r - selected from, wherein each of the alkylene substituents, either alone or bonded to another moiety within the carbon chain, is one or more substituents R x It is something that can be arbitrarily substituted by;

[0109] R 20 C1-C 12 An aryl group having 6 to 18 carbon atoms within one or more alkyl or aromatic rings, wherein the aryl group is one or more substituents R x It is arbitrarily substituted by;

[0110] r is an integer in the range 1-10;

[0111] g is an integer of 0 or 1;

[0112] b is an integer of 0 or 1;

[0113] w is an integer from 0 to 12; and

[0114] Each D, R x , X, T, and AA are as defined in the first embodiment of the present invention.

[0115] In a preferred embodiment of the present invention, b+g+w is not 0. In another embodiment, b+w is not 0. In yet another embodiment, if w is not 0, b is 1. In yet another embodiment, if w is 0, b is 1.

[0116] According to another aspect of the present invention, formula D-(X) b -(AA) w -(T) g -L1 or D-(X) b -(AA) w -(T) g Provides a compound of -H, or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein D, X, AA, T, L1, b, g and w are each as defined herein; but additionally, a compound of formula D-(X) b -(AA) w -(T) g If it is a compound of -H, b+w+g is not 0.

[0117] In a preferred embodiment according to an aspect of the present invention, [D-(X) for a moiety comprising at least one antigen binding site b -(AA) w -(T) g The ratio of the -(L)-] group is in the range of 1 to 20. In additional embodiments, n is in the range of 1-12, 1-8, 3-8, 3-6, or 3-5, or is 1, 2, 3, 4, 5, or 6, preferably 3, 4, or 5, or 4.

[0118] According to another aspect of the present invention, the present invention provides a drug moiety D for use in an antibody-drug conjugate. In a further aspect of the present invention, the present invention provides a drug moiety D for use as a payload in an antibody-drug conjugate. In another aspect of the present invention, the present invention provides a use of the drug moiety D as described herein in the manufacture of an antibody-drug conjugate.

[0119] According to another aspect of the present invention, the present invention provides a drug conjugate according to the present invention for use as a pharmaceutical agent.

[0120] According to another aspect of the present invention, the present invention provides a drug conjugate according to the present invention for the treatment of cancer, more preferably selected from lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, kidney cancer, leukemia, multiple myeloma, lymphoma, gastric cancer and ovarian cancer. Most preferably, the cancer is breast cancer.

[0121] According to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising a drug conjugate according to the present invention and a pharmaceutically acceptable carrier.

[0122] According to another aspect of the present invention, the present invention provides a method for preventing or treating cancer, comprising administering an effective amount of the drug conjugate of the present invention to a patient in need thereof. Preferably, the cancer is selected from lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, kidney cancer, leukemia, multiple myeloma, lymphoma, gastric cancer, and ovarian cancer. Most preferably, the cancer is breast cancer.

[0123] According to another aspect of the present invention, the present invention provides a use of the drug conjugate of the present invention for manufacturing a drug for the treatment of cancer, more preferably selected from lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, renal cancer, leukemia, multiple myeloma, lymphoma, gastric cancer and ovarian cancer. Most preferably, the cancer is breast cancer.

[0124] According to another aspect of the present invention, the present invention provides a kit comprising a therapeutically effective amount of the drug conjugate of the present invention and a pharmaceutically acceptable carrier thereof. The kit is intended for use in the treatment of cancer, more preferably selected from lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, renal cancer, leukemia, multiple myeloma, lymphoma, and ovarian cancer. Most preferably, the cancer is breast cancer. The kit according to the present invention may comprise a therapeutically effective amount of the drug conjugate according to the present invention and optionally instructions for use of the drug conjugate in cancer treatment, in particular, use is preferred for cancer selected from lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, renal cancer, leukemia, multiple myeloma, lymphoma, gastric cancer, and ovarian cancer, and most preferably for breast cancer.

[0125] According to another aspect of the present invention, the present invention provides a method for preparing a drug conjugate according to the present invention, comprising conjugating a moiety Ab having at least one antigen binding site with a drug D, wherein the drug D, Ab, and D are as defined in the present invention. means of solving the problem

[0126] A detailed description of the preferred embodiment

[0127] The following applies to all aspects of the present invention:

[0128] In the compounds of the present invention, the alkyl group may be a linear or branched alkyl group having 1 to 12 carbon atoms. One preferred alkyl group class has 1 to 6 carbon atoms. A more preferred alkyl group has 1, 2, 3, or 4 carbon atoms. Methyl, ethyl, n-propyl, and isopropyl, n-butyl, isobutyl, Sec - Butyl and tert Butyl containing butyl is particularly preferred as an alkyl group used in the compound of the present invention.

[0129] In the compounds of the present invention, the alkenyl group is branched or unbranched, may have one or more double bonds, and has 2 to 12 carbon atoms. Preferably, these alkenyl groups may have 2 to 6 carbon atoms. More preferably, it is desirable for the alkenyl group to have 2, 3, or 4 carbon atoms. Ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, and 3-butenyl are particularly preferred alkenyl groups in the compounds of the present invention.

[0130] In the compounds of the present invention, the alkynyl group is branched or unbranched, may have one or more triple bonds, and has 2 to 12 carbon atoms. Preferably, these alkynyl groups may have 2 to 6 carbon atoms. More preferably, it is an alkynyl group having 2, 3, or 4 carbon atoms.

[0131] In the compounds of the present invention, preferred aryl groups are single or multiple cyclic compounds comprising a plurality of cyclic compounds containing spaced and / or fused aryl groups. A typical aryl group contains 1 to 3 spaced or fused rings and contains 6 to 12 carbon ring atoms. A preferred aryl group contains 6 to 10 carbon ring atoms. Particularly preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl, and substituted or unsubstituted anthryl.

[0132] Suitable heterocyclic groups comprise 1 to 3 separated and / or fused rings, and heteroaromatic groups and heteroalicyclic groups containing 5 to about 18 ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain 5 to 10 ring atoms, most preferably 5, 6, or 7 ring atoms. A suitable heteroaromatic group of the present invention contains one, two, or three heteroatoms selected from N, O, or S atoms, e.g., coumarinyl including 8-coumarinyl, quinoryl including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, furinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, Quinazolinyl, quinoxalinyl, naphthiridinyl, and furopyridyl are included herein. In the compounds of the present invention, a suitable heteroaliphatic group contains one, two, or three heteroatoms selected from N, O, or S atoms, e.g., pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyridyl, piperidyl, morpholinyl, thiomomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, tietanyl, homopiperidyl, oxephanyl, tiefanyl, oxazefinil, diazefinil, thiazefinil, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2 H -Piranil, 4 H-Pyranyl, Dioxanil, 1,3-Dioxolanil, Pyrazolidinil, Dithianil, Dithiolanil, Dihydropyranil, Dihydrothienyl, Dihydrofuranil, Pyrazolidinil, Imidazolidinil, Imidazolidinil, 3-Azabicyclo[3.1.0]hexyl, 3-Azabicyclo[4.1.0]heptyl, 3 H - Indolyl and quinoliginil are included here.

[0133] The groups mentioned above are OR', =O, SR', SOR', SO2R', NO2, NHR', NR'R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected OH, protected amino, protected SH, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 The group may be substituted at one or more suitable positions by one or more suitable groups, such as alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic, each R' group independently hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, COalkyl, CO2H, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic may be independently selected. If the group is substituted itself, the substituent may be selected from the above list. Additionally, if there is one or more R' groups in the substituent, each R' group may be the same or different from one another.

[0134] In the compounds of the present invention, the halogen substituents include F, Cl, Br, and I.

[0135] In particular, in the compound of the present invention, R 20 The alkyl groups in the definitions of , Ra, Rb, Rc, Rx, Ry, and Rz may be linear or branched alkyl groups having 1 to 12 carbon atoms, preferably alkyl groups having 1 to 6 carbon atoms, and more preferably methyl groups, ethyl groups, or i - It is a propyl group, most preferably a methyl group. In the definitions of M and Q, these may be linear or branched alkyl groups having 1 to 6 carbon atoms. Methyl, ethyl, n-propyl, and isopropyl, n-butyl, isobutyl, Sec - Butyl and tert Butyl containing butyl is particularly preferred as an alkyl group used in the compound of the present invention.

[0136] In the compounds of the present invention, the alkenyl groups defined by Ra, Rb, Rc, and Rx are branched or unbranched, may have one or more double bonds, and have 2 to 12 carbon atoms. Preferably, these alkenyl groups may have 2 to 6 carbon atoms, and more preferably, they are branched or unbranched alkenyl groups having 2, 3, or 4 carbon atoms. Ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, and 3-butenyl are particularly preferred alkenyl groups in the compounds of the present invention.

[0137] In the compounds of the present invention, the alkynyl groups defined by Ra, Rb, Rc, and Rx are branched or unbranched, may have one or more triple bonds, and have 2 to 12 carbon atoms. Preferably, these alkynyl groups may have 2 to 6 carbon atoms, and more preferably, are branched or unbranched alkynyl groups having 2, 3, or 4 carbon atoms.

[0138] In the compounds of the present invention, the halogen substituents in the definitions of Rx, Ry and Rz include F, Cl, Br and I, preferably Cl.

[0139] In the compounds of the present invention, the saturated or unsaturated heterocyclic group of 5 to 14 groups as defined in Rx is a heterocyclic group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s). The heterocyclic group may be a heteroaromatic group or a heteroaliphatic group, wherein the heteroaliphatic group may be partially unsaturated, and both the aromatic heterocyclic group and the aliphatic heterocyclic group contain 1 to 3 spaced or fused rings. Preferably, the heteroaromatic and heteroaliphatic groups contain 5 to 10 ring atoms. A suitable heteroaromatic group among the compounds of the present invention contains one, two, or three heteroatoms selected from N, O, or S atoms, for example, quinolyl including 8-quinolyl and isoquinolyl, coumarinyl including 8-coumarinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, furinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothiophenyl, benzothiazolyl. Benzoxazolyl, quinazolinil, quinoxalinil, naftiridinil, and puropyridyl are included here.In the compounds of the present invention, a suitable heteroaliphatic group contains 1, 2, or 3 heteroatoms selected from N, O, or S atoms, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morphollinyl, thiomomorphollinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, tietanyl, homopiperidyl, oxephanyl, tiefanyl, oxazefinyl, diazefinyl, thiazefinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, Dihydrothienyl, dihydrofuranil, pyrazolidinyl, imidazolidinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolidinyl are included herein.

[0140] In the compound of the present invention, Rx and R 20 The aryl group in the definition is a single or multiple cyclic compound containing a spaced and / or fused aryl group and 6 to 18 cyclic carbon atoms, optionally substituted. A typical aryl group contains 1 to 3 spaced or fused rings. A preferred aryl group contains 6 to 12 carbon cyclic atoms. Particularly preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl, and substituted or unsubstituted anthryl, most preferably including substituted or unsubstituted phenyl, wherein the substituents are as defined above.

[0141] In the compounds of the present invention, the aralkyl groups in the definitions of Rx, Ry, and Rz comprise the alkyl groups in the definitions and examples substituted by one or more aryl groups in the definitions and examples. Preferred examples include optionally substituted benzyl, optionally substituted phenylethyl, and optionally substituted naphthylmethyl.

[0142] In the compounds of the present invention, the aralkyloxy group in the definition of Rx comprises an alkoxy group having 1 to 12 carbon atoms substituted by one or more aryl groups as defined and exemplified above. Preferably, the alkoxy moiety has 1 to 6 carbon atoms, and the aryl group has a ring of 6 to 12 carbons, most preferably the aralkyloxy group is optionally substituted benzyloxy, optionally substituted phenylethoxy, and optionally substituted naphthylmethoxy.

[0143] In the compounds of the present invention, the heterocycloalkyl group in the definitions of Ry and Rz comprises an alkyl group as defined and exemplified by one or more heterocyclyl groups as defined and exemplified. Preferably, the heterocycloalkyl group comprises an alkyl group having 1 to 6 carbon atoms substituted by a heterocyclyl group having 5 to 10 ring atoms within 1 or 2 rings, and may be aromatic, or partially saturated or fully saturated. More preferably, the heterocycloalkyl group comprises a methyl or ethyl group substituted by a heterocyclyl group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, oxatyl, thianyl, 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiazolyl, tetrazolyl, isoxazolyl, oxazolyl, and benzimidazole.

[0144] In the compound of the present invention, R 19 The alkylene group in the definition is a straight-chain or branched alkylene group having 1 to 12 carbon atoms, and M, X, T, and R 30 The alkylene group in the definition is a linear or branched alkylene group having 1 to 6 carbon atoms. Preferably, R 19The alkylene group in the definition of is a linear or branched alkylene group having 1 to 8 carbon atoms, more preferably a linear or branched alkylene group having 1 to 6 carbon atoms. In the case of M, it is preferably a linear or branched alkylene group having 1 to 3 carbon atoms. In the definition of X, the alkylene group in the definition of X is preferably a linear or branched alkylene group having 2 to 4 carbon atoms. In the case of T, a linear or branched alkylene group having 2 to 4 carbon atoms is preferred. R 30 In the definition, a straight-chain or branched alkylene group having 2 to 4 carbon atoms is preferred, and a straight-chain or branched alkylene group having 3 carbon atoms is most preferred. To avoid confusion, the term "alkylene" is used to refer to alkanediyl groups.

[0145] In the compound of the present invention, R 19 The carbocyclo group in the definition of and M is a cycloalkyl group having 3 to 8 carbon atoms, having two covalent bonds at any position on the cycloalkyl ring that connect said cycloalkyl group to the remainder of the drug conjugate. Preferably, R 19 The carbocyclo group in the definition of and M is a cycloalkyl group having 3 to 7 carbon atoms, and more preferably a carbocyclo group having 5 to 7 carbon atoms.

[0146] In the compound of the present invention, R 19 The arylene group in the definition is an aryl group having 6 to 18 carbon atoms in one or more rings, having two covalent bonds at any position on the aromatic ring that connect said arylene group to the remainder of the drug conjugate. Preferably, R 19The arylene group in the definition is an aryl group having 6 to 12 carbon atoms within one or more rings having two covalent bonds at any position in an aromatic ring system, most preferably a phenylene group.

[0147] In the compound of the present invention, R 19 The heterocyclo group in the definition is a heterocyclyl group containing 1 to 3 spaced or fused rings having 5 to 14 ring atoms, comprising at least one oxygen, nitrogen, or sulfur atom within the ring(s), and having two covalent bonds at any position within the ring system of the heterocyclyl group. The heterocyclyl group may be a heteroaromatic group or a heteroaliphatic group, the latter of which may be partially unsaturated. Preferably, R 19 The heterocyclo group in the definition is a heterocyclyl group containing 1 to 3 spaced or fused rings having 5 to 12 ring atoms, comprising at least one oxygen, nitrogen, or sulfur atom within the ring(s), and having two covalent bonds at any position within the ring system of the heterocyclyl group.

[0148] If there are two or more arbitrary substituents Rx, Ry, or Rz on a substituent, each substituent Rx may be the same or different, each substituent Ry may be the same or different, and each substituent Rz may be the same or different.

[0149] According to one embodiment of the present invention, the above D is a chemical formula ( I ) or may be a pharmaceutically acceptable salt or ester thereof:

[0150]

[0151] I

[0152] During the meal:

[0153] Y is -NH- or -0- and;

[0154] R1 is -OH or -CN;

[0155] R2 is -C(=0)Ra and;

[0156] R3 is a hydrogen or -ORb group;

[0157] R4 is hydrogen, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0158] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0159] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl;

[0160] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0161] Prot NH is a protecting group for amino.

[0162] According to one aspect of the present invention, in the compound of formula I, when R4 is hydrogen, Y is -O-.

[0163] According to another embodiment of the present invention, the chemical formula I The compound of has the chemical formula IC It may be a compound, a pharmaceutically acceptable salt or ester thereof:

[0164]

[0165] IC

[0166] During the meal:

[0167] Y is -NH- and;

[0168] R1 is -OH or -CN;

[0169] R2 is -C(=0)Ra and;

[0170] R3 is a hydrogen or -ORb group;

[0171] R4 is -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0172] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0173] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl;

[0174] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0175] Prot NH is a protecting group for amino.

[0176] According to another embodiment of the present invention, the chemical formula I The compound of has the chemical formula ID It may be a compound, a pharmaceutically acceptable salt or ester thereof:

[0177]

[0178] ID

[0179] During the meal:

[0180] Y is -O- and;

[0181] R1 is -OH or -CN;

[0182] R2 is -C(=0)Ra and;

[0183] R3 is a hydrogen or -ORb group;

[0184] R4 is hydrogen, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0185] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0186] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl;

[0187] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0188] Prot NH is a protecting group for amino.

[0189] According to another embodiment of the present invention, the chemical formula I The compound of has the chemical formula IE It may be a compound, a pharmaceutically acceptable salt or ester thereof:

[0190]

[0191] IE

[0192] During the meal:

[0193] Y is -NH- or -O- and;

[0194] R1 is -OH or -CN;

[0195] R2 is -C(=0)Ra and;

[0196] R3 is a hydrogen or -ORb group;

[0197] R4 is -CH2NH 2, and -CH2NHProt NH Selected from;

[0198] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0199] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 alkenyl, and substituted or non-substituted C2-C 12 Selected from alkynyl; and

[0200] Prot NH is a protecting group for amino.

[0201] According to another embodiment of the present invention, the chemical formula I The compound of has the chemical formula IA It may be a compound, a pharmaceutically acceptable salt or ester thereof:

[0202]

[0203] IA

[0204] During the meal:

[0205] Y is -NH- or -O- and;

[0206] R1 is -OH or -CN;

[0207] R2 is -C(=0)Ra and;

[0208] R3 is hydrogen;

[0209] R4 is hydrogen, -CH2OH, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0210] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0211] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0212] Prot NH is a protecting group for amino.

[0213] According to one embodiment of the present invention, the chemical formula IA In the compound, if R4 is hydrogen, Y is -O-.

[0214] According to another embodiment of the present invention, the chemical formula I The compound of has the chemical formula IB It may be a compound, a pharmaceutically acceptable salt or ester thereof:

[0215]

[0216] IB

[0217] During the meal:

[0218] Y is -NH- or -O- and;

[0219] R1 is -OH or -CN;

[0220] R2 is -C(=0)Ra and;

[0221] R3 is -0Rb;

[0222] R4 is hydrogen, -CH2OH, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0223] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0224] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0225] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0226] Prot NH is a protecting group for amino.

[0227] According to one aspect of the present invention, the chemical formula IB In the compound, if R4 is hydrogen, Y is -O-.

[0228] According to another embodiment of the present invention, the chemical formula I The compound of has the chemical formula IF It may be a compound, a pharmaceutically acceptable salt or ester thereof:

[0229]

[0230] IF

[0231] During the meal:

[0232] Y is -NH- or -O- and;

[0233] R1 is -OH and;

[0234] R2 is -C(=0)Ra and;

[0235] R3 is a hydrogen or -0Rb group;

[0236] R4 is hydrogen, -CH2OH, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0237] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0238] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0239] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0240] Prot NH is a protecting group for amino.

[0241] According to one aspect of the present invention, the chemical formula IF In the compound, if R4 is hydrogen, Y is -O-.

[0242] According to another aspect of the present invention, the chemical formula I The compound of has the chemical formula IG It may be a compound, a pharmaceutically acceptable salt or ester thereof:

[0243]

[0244] IG

[0245] During the meal:

[0246] Y is -NH- or -O- and;

[0247] R1 is -OH or -CN- and;

[0248] R2 is acetyl;

[0249] R3 is a hydrogen or -0Rb group;

[0250] R4 is hydrogen, -CH2OH, -CH2OH, -CH20C(=0)Rc, -CH2NH 2, and -CH2NHProt NH Selected from;

[0251] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl;

[0252] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0253] Prot NH is a protecting group for amino.

[0254] According to one aspect of the present invention, the chemical formula IG In the compound, if R4 is hydrogen, Y is -O-.

[0255] The above chemical formula I, IA, IB, IC, ID, IE, IF , or IG The preferred compound is the following chemical formula a or b It may be a compound, a pharmaceutically acceptable salt, or its ester:

[0256]

[0257] If the above compound is a compound of formula a or formula b, R4 may not be hydrogen.

[0258] The above chemical formula I, IA, IB, ID, IF , or IG The preferred compound is the following chemical formula c It may be a compound, a pharmaceutically acceptable salt, or its ester:

[0259] c

[0260] Here:

[0261] R1 is -OH or -CN- and;

[0262] R2 is -C(=O)Ra;

[0263] R3 is a hydrogen or -0Rb group;

[0264] Ra is hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 Selected from alkynyl; and

[0265] Rb is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, and substituted or unsubstituted C2-C 12 It is selected from alkinyl.

[0266] To avoid confusion, the above compound may be drug moiety D, and is attached by covalent bonding via a hydroxyl group or an amine group to (X)b if present, or (AA)w if present, or (T)g if present, or to linker group L. Thus, when conjugated, the covalent bond replaces the proton of the hydroxyl group or amine group in the compound.

[0267] A preferred compound of the present invention is the general formula I, IA, IB, IE, IF, IG, Ia, IAa, IBa, IEa, IFa, IGa, Ib, IAb, IBb, IEb, IFb , and IGb It includes a compound of, where:

[0268] Y is -NH- and;

[0269] And, R1; R2; R3; R4; R a ; Rb ; R c ; and Prot NH is as defined above.

[0270] A preferred compound of the present invention is the general formula I, IA, IB, IE, IF, IG, Ia, IAa, IBa, IEa, IFa, IGa, Ib, IAb, IBb, IEb, IFb , and IGb It includes a compound of, where:

[0271] Y is -O- and;

[0272] And, R1; R2; R3; R4; R a ; R b ; R c ; and Prot NH is as defined above.

[0273] A preferred compound of the present invention is the general formula I, IA, IB, IC, ID, IE, IG, Ia, IAa, IBa, ICa, IDa, IEa, IGa, Ib, IAb, IBb, ICb, IDb, IEb , and IGb It includes a compound of, where:

[0274] R1 is -OH and;

[0275] And, Y; R2; R3; R4; R a ; R b ; R c ; and Prot NH is as defined above.

[0276] A more preferred compound of the present invention is the general formula I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, Ib, IAb, IBb, ICb, IDb, IEb , and IFb It includes a compound of, where:

[0277] R2 is R a -C(=O)R is a substituted or unsubstituted C1-C6 alkyl a It is. A more desirable R a is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted Sec -butyl, and substituted or unsubstituted tert - It is butyl. The most desirable R2 is acetyl;

[0278] And, Y; R1; R3; R4; R b ; R c ; and Prot NH is as defined above.

[0279] A more preferred compound of the present invention is the general formula I, IB, IC, ID, IE, IF, IG, Ia, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IBb, ICb, IDb, IEb, IFb , and IGb It includes a compound of, where:

[0280] In compounds having the general formulas I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, or IGb, R3 is a hydrogen or -ORb group; in compounds having the formulas IB, IBa, or IBb, R3 is -OR b Giigo; R b is a substituted or unsubstituted C1-C6 alkyl. A more preferred R b is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It is butyl. More preferred R3s are hydrogen and methoxy, and hydrogen is most preferred in the R3 group;

[0281] And, Y; R1; R2; R4; R a ; R c ; and Prot NH is as defined above.

[0282] A more preferred compound of the present invention is the general formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0283] In compounds of general formulas I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)R c , -CH2NH2, and -CH2NHProt NH Selected from, where R4 in the compound of general formula IE, IEa, or IEb is -CH2NH2 and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted Sec -butyl, and substituted or unsubstituted tert -butyl. The most preferred Rc is methyl. A more preferred R4 is selected from -CH2OH and -CH2NH2. Even more preferably, R4 may be -CH2NH2. The most preferred R4 is -CH2OH;

[0284] And, Y; R1; R2; R3; Ra; and Rb are as defined above.

[0285] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0286] Y is -NH- and;

[0287] R1 is -OH and;

[0288] R2; R3; R4; Ra; Rb; Rc and Prot NH is as defined above.

[0289] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0290] Y is -NH- and;

[0291] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)Ra, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted Sec -butyl, and substituted or unsubstituted tert - It is butyl. The most desirable R2 is acetyl;

[0292] And, R1; R3; R4; Rb; Rc; and Prot NH is as defined above.

[0293] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0294] Y is -NH- and;

[0295] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -ORb; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; in compounds of general formulas IB, IBa, or IBb, R3 is -ORb; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. A more preferred R3 is hydrogen or methoxy, and the most preferred R3 group is hydrogen;

[0296] And, R1; R2; R4; Ra; Rc; and Prot NH is as defined above.

[0297] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb It includes a compound of, where:

[0298] Y is -NH- and;

[0299] In compounds of general formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from, where R4 in the compound of general formula IE, IEa, or IEb is -CH2NH2 and -CH2NHProt NHSelected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from -butyl. The most preferred Rc is methyl. A more preferred R4 is selected from -CH2OH and -CH2NH2. More preferably, R4 is -CH2NH2. The most preferred R4 is -CH2OH;

[0300] And, R1; R2; R3; Ra; and Rb are as defined above.

[0301] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0302] Y is -NH- and;

[0303] R1 is -OH and;

[0304] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a C(=O)Ra group, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from -butyl. The most preferred Rc is methyl. A more preferred R4 is selected from -CH2OH and -CH2NH2. The most preferred R2 is acetyl;

[0305] And, R3; R4; Rb; Rc; and Prot NH is as defined above.

[0306] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0307] Y is -NH- and;

[0308] R1 is -OH and;

[0309] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from butyl. The most preferred Rc is methyl. A more preferred R3 is selected from hydrogen and methoxy. The most preferred R3 is hydrogen;

[0310] And, R2; R4; Ra; Rc; and Prot NH is as defined above.

[0311] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0312] Y is -NH- and;

[0313] R1 is -OH and;

[0314] In compounds of general formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from, where R4 in the compound of general formula IE, IEa, or IEb is -CH2NH2 and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from -butyl. The most preferred Rc is methyl. A more preferred R4 is selected from -CH2OH and -CH2NH2. More preferably, R4 may be -CH2NH2. The most preferred R4 is -CH2OH;

[0315] And, R2; R3; Ra; and Rb are as defined above.

[0316] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0317] Y is -NH- and;

[0318] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0319] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0320] And, R1; R4; Rc; and Prot NH is as defined above.

[0321] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0322] Y is -NH- and;

[0323] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0324] In compounds of general formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from, where R4 in the compound of general formula IE, IEa, or IEb is -CH2NH2 and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from -butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2. A more preferred R4 may be -CH2NH2. The most preferred R4 is -CH2OH;

[0325] And, R1; R3; and Rb are as defined above.

[0326] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb It includes a compound of, where:

[0327] Y is -NH- and;

[0328] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group, and in compounds of general formulas IA, IAa, or IAb, R3 is an -ORb group; Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. A more preferred R3 is hydrogen or methoxy, and the most preferred R3 is hydrogen;

[0329] In compounds of general formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NHSelected from, where R4 in the compound of general formula IE, IEa, or IEb is -CH2NH2 and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from -butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2. More preferably, R4 can be -CH2NH2. The most preferred R4 is -CH2OH;

[0330] And, R1; R2; and Ra are as defined above.

[0331] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0332] Y is -NH- and;

[0333] R1 is -OH- and;

[0334] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0335] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from butyl. The most preferred Rc is methyl. More preferred R3 are hydrogen and methoxy, and the most preferred R3 group is hydrogen;

[0336] And, R4; Rc; and Prot NH is as defined above.

[0337] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb It includes a compound of, where:

[0338] Y is -NH- and;

[0339] R1 is -OH- and;

[0340] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0341] In compounds of general formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert -It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 is -CH2NH2, and most preferably R4 is -CH2OH;

[0342] And, R3; and Rb are as defined above.

[0343] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb , and IGb It includes a compound of, where:

[0344] Y is -NH- and;

[0345] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0346] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferably, Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0347] In compounds of general formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH;

[0348] And, R1 is as defined above.

[0349] A more preferred compound of the present invention is the general formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb It includes a compound of, where:

[0350] Y is -NH- and;

[0351] R1 is -OH- and;

[0352] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group, and in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0353] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0354] In compounds of general formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH.

[0355] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb , and IGb It includes a compound of, where:

[0356] Y is -O- and;

[0357] R1 is -OH- and;

[0358] And, R2; R3; R4; Ra; Rb; Rc; and Prot NH is as defined above.

[0359] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0360] Y is -O- and;

[0361] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0362] And, R1; R3; R4; Rb; Rc; and Prot NH is as defined above.

[0363] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb , and IGb It includes a compound of, where:

[0364] Y is -O- and;

[0365] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0366] And, R1; R2; R4; Ra; Rc; and Prot NH is as defined above.

[0367] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb , and IGb It includes a compound of, where:

[0368] Y is -O- and;

[0369] In compounds of general formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH;

[0370] And, R1; R2; R3; Ra; and Rb are as defined above.

[0371] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb , and IGb It includes a compound of, where:

[0372] Y is -O- and;

[0373] R1 is -OH- and;

[0374] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0375] And, R3; R4; Rb; Rc; and Prot NH is as defined above.

[0376] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb , and IGb It includes a compound of, where:

[0377] Y is -O- and;

[0378] R1 is -OH- and;

[0379] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0380] And, R2; R4; Ra; Rc; and Prot NH is as defined above.

[0381] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0382] Y is -O- and;

[0383] R1 is -OH- and;

[0384] In compounds of general formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NHSelected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH;

[0385] And, R2; R3; Ra; and Rb are as defined above.

[0386] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0387] Y is -O- and;

[0388] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0389] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0390] And, R1; R4; Rc; and Prot NH is as defined above.

[0391] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0392] Y is -O- and;

[0393] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0394] In compounds of general formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH;

[0395] And, R1; R3; and Rb are as defined above.

[0396] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0397] Y is -O- and;

[0398] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0399] In compounds of general formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH;

[0400] And, R1; R2; and Ra are as defined above.

[0401] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0402] Y is -O- and;

[0403] R1 is -OH and;

[0404] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0405] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0406] And, R4; Rc; and Prot NH is as defined above.

[0407] A more preferred compound of the present invention is general formula I , IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0408] Y is -O- and;

[0409] R1 is -OH and;

[0410] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n-Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0411] In compounds of general formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH;

[0412] And, R3; and Rb are as defined above.

[0413] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0414] Y is -O- and;

[0415] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0416] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0417] In compounds of general formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, even more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH;

[0418] And, R1 is as defined above.

[0419] A more preferred compound of the present invention is the general formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb It includes a compound of, where:

[0420] Y is -O- and;

[0421] R1 is -OH and;

[0422] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0423] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; and in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0424] In compounds of general formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH Selected from; in compounds of general formula IE, IEa, or IEb, R4 is -CH2NH2, and -CH2NHProt NH Selected from; Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2, more preferably R4 can be -CH2NH2, and most preferably R4 is -CH2OH.

[0425] A more preferred compound of the present invention is the general formula Ic, IAc, IBc, IDc, and IGc It includes a compound of, where:

[0426] R1 is -OH and;

[0427] And, R2; R3; Ra, and Rb are as defined above.

[0428] A more preferred compound of the present invention is the general formula Ic, IAc, IBc, IDc, IFc, and IGc It includes a compound of, where:

[0429] In compounds of general formula Ic, IAc, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0430] And, R1; R3; and Rb are as defined above.

[0431] A more preferred compound of the present invention is the general formula Ic, IAc, IBc, IDc, IFc and IGc It includes a compound of, where:

[0432] In compounds of general formula Ic, IDc, IFc, or IGc, R3 is hydrogen or an -ORb group; in compounds of general formula IAc, R3 is hydrogen; and in compounds of general formula IBc, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0433] And, R1; R2; and Ra are as defined above.

[0434] A more preferred compound of the present invention is the general formula Ic, IAc, IBc, IDc, IFc and IGc It includes a compound of, where:

[0435] R1 is -OH and;

[0436] In compounds of general formula Ic, IAc, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0437] And, R3; and Rb are as defined above.

[0438] A more preferred compound of the present invention is the general formula Ic, IAc, IBc, IDc, IFc and IGc It includes a compound of, where:

[0439] R1 is -OH and;

[0440] In compounds of general formula Ic, IDc, IFc, or IGc, R3 is hydrogen or an -ORb group; in compounds of general formula IAc, R3 is hydrogen; and in compounds of general formula IBc, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0441] And, R2; and Ra are as defined above.

[0442] A more preferred compound of the present invention is the general formula Ic, IAc, IBc, IDc, IFc and IGc It includes a compound of, where:

[0443] In compounds of general formula Ic, IAc, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0444] In compounds of general formula Ic, IDc, IFc, or IGc, R3 is hydrogen or an -ORb group; in compounds of general formula IAc, R3 is hydrogen; and in compounds of general formula IBc, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and most preferred R3 group is hydrogen;

[0445] And, R1 is as defined above.

[0446] A more preferred compound of the present invention is the general formula Ic, IAc, IBc, IDc, IFc and IGc It includes a compound of, where:

[0447] R1 is -OH and;

[0448] In compounds of general formula Ic, IAc, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is acetyl; and Ra is a substituted or unsubstituted C1-C6 alkyl. More preferably, Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most preferred R2 is acetyl;

[0449] In compounds of general formula Ic, IDc, IFc, or IGc, R3 is hydrogen or an -ORb group; in compounds of general formula IAc, R3 is hydrogen; and in compounds of general formula IBc, R3 is an -ORb group; and Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tertIt can be selected from butyl. More preferred R3s are hydrogen and methoxy, and the most preferred R3 group is hydrogen.

[0450] The following preferred substituents (where permitted by possible substituents) are in the chemical formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, Ic, IAc, IBc, IDc, IFc, and IGC Applies to the compound of:

[0451] In the compound of the present invention, a particularly preferred R1 is -OH.

[0452] In the compounds of the present invention, a particularly preferred R2 is a -C(=O)Ra group, wherein Ra is a substituted or unsubstituted C1-C6 alkyl. A more preferred Ra is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert - It can be selected from butyl. The most desirable R2 is acetyl.

[0453] In the compounds of the present invention, particularly preferred R3 is hydrogen or -ORb group, where Rb is a substituted or unsubstituted C1-C6 alkyl. More preferred Rb is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from butyl. More preferred R3s are hydrogen and methoxy, and the most preferred R3 group is hydrogen.

[0454] In the compounds of the present invention, particularly preferred R4 is hydrogen, -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NHSelected from, wherein Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from -butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from hydrogen, -CH2OH, and -CH2NH2. The most preferred R4 is -CH2OH.

[0455] chemical formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb In the compounds of I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IFb, or IGb, R4 is -CH2OH, -CH2OC(=O)Rc, -CH2NH2, and -CH2NHProt NH It is particularly preferable that it be selected from; and the R4 of the compound of IE, IEa or IEb is CH2NH2, and -CH2NHProt NH It may be selected from; where Rc is a substituted or unsubstituted C1-C6 alkyl. More preferred Rc is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted n -Propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n -Butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl, and substituted or unsubstituted tert It can be selected from -butyl. The most preferred Rc is methyl. A more preferred R4 can be selected from -CH2OH and -CH2NH2. The most preferred R4 is -CH2OH.

[0456] chemical formula Ia, IAa, IBa, ICa, IDa, IFa, IGa The compound is particularly preferred when R4 is -CH2OH or -CH2OC(=O)Rc, and the chemical formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb The compounds have R4 -CH2NH2 and -CH2NHProt NH It is particularly desirable in such cases.

[0457] In the compound of the present invention, it is particularly preferable that Y is -NH-.

[0458] Alternatively, in the compounds of the present invention, a particularly preferred Y is -O-.

[0459] A preferred compound according to the present invention comprises the following:

[0460] ㆍ chemical formula I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IFb, and IGb The compound of, here:

[0461] R4 is selected from -CH2OH and -CH2OC(=O)Rc;

[0462] A particularly desirable compound is a chemical formula Ia, IAa, IBa, ICa, IDa, IFa and IGa It is a compound of and / or a compound where R4 is -CH2OH.

[0463] ㆍ chemical formula I, IA, IB, IC, ID, IE IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb The compound of, here:

[0464] R4 is -CH2NH2 and -CH2NHProt NH Selected from; and

[0465] Prot NH is a protecting group for amino.

[0466] A particularly desirable compound is a chemical formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb It is a compound of and / or a compound in which R4 is -CH2NH2.

[0467] ㆍ chemical formula Ic, IAc, IBc, IDc, IFc, IGc The compound of, here:

[0468] In compounds of general formulas Ic, IAc, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is an acetyl group;

[0469] In compounds of general formulas Ic, IDc, IFc, and IGc, R3 is hydrogen or an -ORb group; in compounds of general formula IAc, R3 is hydrogen; or in compounds of general formula IBc, R3 is an -ORb group;

[0470] Ra is selected from hydrogen and is a substituted or unsubstituted C1-C6 alkyl; and

[0471] Rb is a substituted or unsubstituted C1-C6 alkyl.

[0472] A particularly preferred compound according to the present invention comprises the following:

[0473] ㆍ chemical formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, and IGb The compound of, here:

[0474] Y is -NH- and;

[0475] R4 is selected from -CH2OH and -CH2OC(=O)Rc;

[0476] and,

[0477] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C1-C 12 Alkenyl, and substituted or unsubstituted C1-C 12 Selected from alkinyl.

[0478] A more desirable compound is the chemical formula Ia, Ia, IBa, ICa, IFa, IGa It is a compound of and / or a compound where R4 is -CH2OH.

[0479] ㆍ chemical formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, and IGb The compound of, here:

[0480] Y is -O- and;

[0481] R4 is selected from -CH2OH and -CH2OC(=O)Rc;

[0482] and,

[0483] Rc is a substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C1-C 12 Alkenyl, and substituted or unsubstituted C1-C 12 Selected from alkinyl.

[0484] A more desirable compound is the chemical formula Ia, IAa, IBa, IDa, IFa, IGa It is a compound of and / or a compound where R4 is -CH2OH.

[0485] ㆍ chemical formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, and IGb The compound of, here:

[0486] Y is -NH- and;

[0487] R4 is -CH2NH2 and -CH2NHProt NH Selected from;

[0488] and,

[0489] Prot NH is a protecting group for amino.

[0490] A more desirable compound is the chemical formula Ib, IAb, IBb, ICb, IEb, IFb, IGb It is a compound of and / or a compound in which R4 is -CH2NH2.

[0491] ㆍ chemical formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, and IGb The compound of, here:

[0492] Y is -O- and;

[0493] R4 is -CH2NH2 and -CH2NHProt NH Selected from;

[0494] and,

[0495] Prot NH is a protecting group for amino.

[0496] A more desirable compound is the chemical formula Ib, IAb, IBb, IDb, IEb, IFb, IGb It is a compound of and / or a compound in which R4 is -CH2NH2.

[0497] ㆍ chemical formula I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IFb, IGb The compound of, here:

[0498] In compounds of general formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0499] In compounds of general formulas I, IC, ID, IF, IG, Ia, ICa, IDa, IFa, IGa, Ib, ICb, IDb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0500] R4 is selected from -CH2OH and -CH2OC(=O)Rc;

[0501] Ra is selected from hydrogen, and substituted or unsubstituted C1-C6 alkyls;

[0502] Rb is a substituted or unsubstituted C1-C6 alkyl; and

[0503] Rc is a substituted or unsubstituted C1-C6 alkyl.

[0504] A more desirable compound is the chemical formula Ia, IAa, IBa, ICa, IDa, IFa, IGa It is a compound of and / or a compound where R4 is -CH2OH.

[0505] ㆍ chemical formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb The compound of, here:

[0506] In compounds of general formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0507] In compounds of general formulas I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0508] R4 is -CH2NH2 and -CH2NHProt NH Selected from;

[0509] Ra is selected from hydrogen, and substituted or unsubstituted C1-C6 alkyls;

[0510] Rb is a substituted or unsubstituted C1-C6 alkyl; and

[0511] Prot NH is a protecting group for amino.

[0512] A more desirable compound is the chemical formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb It is a compound of and / or a compound in which R4 is CH2NH2.

[0513] ㆍCompounds of chemical formulas Ic, IAc, IBc, IDc, IFc, IGc, where:

[0514] In compounds of general formulas Ic, IAc, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is an acetyl group;

[0515] In compounds of general formulas Ic, IDc, IFc, and IGc, R3 is hydrogen or an -ORb group; in compounds of general formula IAc, R3 is hydrogen; or in compounds of general formula IBc, R3 is an -ORb group;

[0516] Ra is selected from substituted or unsubstituted C1-C6 alkyls;

[0517] Rb is selected from substituted or unsubstituted C1-C6 alkyls.

[0518] A more preferred compound according to the present invention comprises the following:

[0519] ㆍ chemical formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, and IGb The compound of, here:

[0520] Y is -NH- and;

[0521] In compounds of general formulas I, IA, IB, IC, IF, Ia, IAa, IBa, ICa, IFa, Ib, IAb, IBb, ICb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0522] In compounds of general formulas I, IC, IF, IG, Ia, ICa, IFa, IGa, Ib, ICb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0523] R4 is -CH2OH, and

[0524] Ra is selected from hydrogen, and substituted or unsubstituted C1-C6 alkyls; and

[0525] Rb is selected from substituted or unsubstituted C1-C6 alkyls.

[0526] A more desirable compound is the chemical formula Ia, IAa, or IBa, ICa, IFa, or IGa It is a compound of

[0527] ㆍ chemical formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, and IGb The compound of, here:

[0528] Y is -O- and;

[0529] In compounds of general formulas I, IA, IB, ID, IF, Ia, IAa, IBa, IDa, IFa, Ib, IAb, IBb, IDb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0530] In compounds of general formulas I, ID, IF, IG, Ia, IDa, IFa, IGa, Ib, IDb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0531] R4 is -CH2OH, and

[0532] Ra is selected from hydrogen, and substituted or unsubstituted C1-C6 alkyls; and

[0533] Rb is selected from substituted or unsubstituted C1-C6 alkyls.

[0534] A more desirable compound is the chemical formula Ia, Iaa, IBa, IDa, IFa, or IGa It is a compound of

[0535] ㆍ chemical formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb The compound of, here:

[0536] Y is -NH- and;

[0537] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0538] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0539] R4 is -CH2NH2 and -CH2NHProt NH Selected from,

[0540] Ra is selected from hydrogen, and substituted or unsubstituted C1-C6 alkyls;

[0541] Rb is selected from substituted or unsubstituted C1-C6 alkyls; and,

[0542] Prot NH is a protecting group for amino.

[0543] A more desirable compound is the chemical formula Ib, IAb, IBb, ICb, IEb, IFb, IGb It is a compound of and / or a compound in which R4 is -CH2NH2.

[0544] ㆍ chemical formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb The compound of, here:

[0545] Y is -O- and;

[0546] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0547] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0548] R4 is -CH2NH2 and -CH2NHProt NH Selected from,

[0549] Ra is selected from hydrogen, and substituted or unsubstituted C1-C6 alkyls;

[0550] Rb is selected from substituted or unsubstituted C1-C6 alkyls; and,

[0551] Prot NH is a protecting group for amino.

[0552] A more desirable compound is the chemical formula Ib, IAb, IBb, IDb, IEb, IFb, IGb It is a compound of and / or a compound in which R4 is -CH2NH2.

[0553] ㆍ chemical formula I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IFb, and IGb The compound of, here:

[0554] In compounds of general formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0555] In compounds of general formulas I, IC, ID, IF, IG, Ia, ICa, IDa, IFa, IGa, Ib, ICb, IDb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0556] R4 is -CH2OH and;

[0557] Ra is a substituted or unsubstituted C1-C6 alkyl; and

[0558] Rb is a substituted or unsubstituted C1-C6 alkyl.

[0559] Prot NH is a protecting group for amino.

[0560] A particularly more desirable compound is a chemical formula Ia, IAa, IBa, ICa, IDa, IFa, or IGa It is a compound.

[0561] ㆍ chemical formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb The compound of, here:

[0562] In compounds of general formulas I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, Ib, IAb, IBb, ICb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0563] In compounds of general formulas I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0564] R4 is -CH2NH2 and -CH2NHProt NH Selected from;

[0565] Ra is a substituted or unsubstituted C1-C6 alkyl;

[0566] Rb is a substituted or unsubstituted C1-C6 alkyl; and

[0567] Prot NH is a protecting group for amino.

[0568] A particularly more desirable compound is a chemical formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb It is a compound of and / or a compound in which R4 is -CH2NH2.

[0569] ㆍ chemical formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, and IGb The compound of, here:

[0570] Y is -NH- and;

[0571] In compounds of general formulas I, IA, IB, IC, IF, Ia, IAa, IBa, ICa, IFa, Ib, IAb, IBb, ICb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0572] In compounds of general formulas I, IC, IF, IG, Ia, ICa, IFa, IGa, Ib, ICb, IFb, or IGb, R3 is hydrogen or an -ORb group; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is an -ORb group;

[0573] R4 is -CH2OC(=O)Rc and;

[0574] Ra is selected from hydrogen and substituted or unsubstituted C1-C6 alkyls;

[0575] Rb is a substituted or unsubstituted C1-C6 alkyl; and

[0576] Rc is a substituted or unsubstituted C1-C6 alkyl.

[0577] The desirable compound is a chemical formula Ia, IAa, IBa, ICa, IFa, or IGa It is a compound.

[0578] ㆍ chemical formula Ic, IAc, IBc, IDc, IFc, and IGC The compound of, here:

[0579] In compounds of general formulas Ic, IAc, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is an acetyl group;

[0580] In compounds of general formulas Ic, IDc, IFc, or IGc, R3 is a hydrogen or methoxy group; in compounds of general formula IAc, R3 is hydrogen; or in compounds of general formula IBc, R3 is a methoxy; and

[0581] Ra is a substituted or unsubstituted C1-C6 alkyl.

[0582] A particularly more preferred compound according to the present invention comprises the following:

[0583] ㆍ chemical formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, and IGb The compound of, here:

[0584] Y is -NH- and;

[0585] In compounds of general formulas I, IA, IB, IC, IF, Ia, IAa, IBa, ICa, IFa, Ib, IAb, IBb, ICb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0586] In compounds of general formulas I, IC, IF, IG, Ia, ICa, IFa, IGa, Ib, ICb, IFb, or IGb, R3 is hydrogen or methoxy; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is methoxy;

[0587] R4 is -CH2OH and; and

[0588] Ra is a substituted or unsubstituted C1-C6 alkyl.

[0589] The desirable compound is a chemical formula Ia, Ia, IBa, ICa, IFa, IGa It is a compound of

[0590] ㆍ chemical formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, Ib, IAb, IBb, IDb, IFb, and IGb The compound of, here:

[0591] Y is -O- and;

[0592] In compounds of general formulas I, IA, IB, ID, IF, Ia, IAa, IBa, IDa, IFa, Ib, IAb, IBb, IDb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0593] In compounds of general formulas I, ID, IF, IG, Ia, IDa, IFa, IGa, Ib, IDb, IFb, or IGb, R3 is hydrogen or methoxy; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is methoxy;

[0594] R4 is -CH2OH and; and

[0595] Ra is a substituted or unsubstituted C1-C6 alkyl.

[0596] The desirable compound is a chemical formula Ia, IAa, IBa, IDa, IEa, IFa, IGa It is a compound of

[0597] ㆍ chemical formula I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb The compound of, here:

[0598] Y is -NH- and;

[0599] In compounds of general formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0600] In compounds of general formulas I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or methoxy; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is methoxy;

[0601] R4 is -CH2NH2 and -CH2NHProt NH Selected from;

[0602] Ra is a substituted or unsubstituted C1-C6 alkyl; and

[0603] Prot NH is a protecting group for amino.

[0604] The desirable compound is a chemical formula Ib, IAb, IBb, ICb, IEb, IFb, IGb It is a compound of, and / or a compound in which R4 is -CH2NH2.

[0605] ㆍ chemical formula I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb The compound of, here:

[0606] Y is -O- and;

[0607] In compounds of general formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0608] In compounds of general formulas I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or methoxy; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is methoxy;

[0609] R4 is -CH2NH2 and -CH2NHProt NH Selected from;

[0610] Ra is a substituted or unsubstituted C1-C6 alkyl; and

[0611] Prot NH is a protecting group for amino.

[0612] A more desirable compound is the chemical formula Ib, IAb, IBb, IDb, IEb, IFb, IGb It is a compound of, and / or a compound in which R4 is -CH2NH2.

[0613] ㆍ chemical formula I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IFb, and IGb The compound of, here:

[0614] In compounds of general formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0615] In compounds of general formulas I, IC, ID, IF, IG, Ia, ICa, IDa, IFa, IGa, Ib, ICb, IDb, IFb, and IGb, R3 is hydrogen or methoxy; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is methoxy;

[0616] R4 is -CH2OH and;

[0617] Ra is methyl, ethyl, n -propyl, isopropyl and butyl, sec -Butyl, isobutyl, and tert - Selected from butyl containing butyl.

[0618] A more desirable compound is the chemical formula Ia, IAa, IBa, ICa, IDa, IEa, IFa, or IGa It is a compound of

[0619] ㆍ chemical formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb The compound of, here:

[0620] In compounds of general formulas I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, Ib, IAb, IBb, ICb, IDb, IEb, or IFb, R2 is a -C(=O)Ra group; in compounds of general formulas IG, IGa, or IGb, R2 is an acetyl group;

[0621] In compounds of general formulas I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, and IGb, R3 is hydrogen or methoxy; in compounds of general formulas IA, IAa, or IAb, R3 is hydrogen; or in compounds of general formulas IB, IBa, or IBb, R3 is methoxy;

[0622] R4 is -CH2NH2 and -CH2NHProt NH Selected from;

[0623] Ra is methyl, ethyl, n -propyl, isopropyl and butyl, sec -Butyl, isobutyl, and tert Selected from butyl containing butyl; and

[0624] Prot NH is a protecting group for amino.

[0625] A more desirable compound is the chemical formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb It is a compound of and / or a compound in which R4 is -CH2NH2.

[0626] ㆍ chemical formula Pregnancy or IAc, IDc, IFc, and IGc The compound of, here:

[0627] In compounds of general formulas Ic, IAc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is an acetyl group;

[0628] R3 is hydrogen; and

[0629] Ra is methyl, ethyl, n-propyl, isopropyl, and butyl, sec -Butyl, isobutyl, and cake - Selected from butyl containing butyl.

[0630] ㆍ chemical formula Ic, IBc, IDc, IFc, and IGc The compound of, here:

[0631] In compounds of general formulas Ic, IBc, IDc, or IFc, R2 is a -C(=O)Ra group; in compounds of general formula IGc, R2 is an acetyl group;

[0632] R3 is methoxy; and

[0633] Ra is methyl, ethyl, n -propyl, isopropyl, and butyl, sec -Butyl, isobutyl, and cake - Selected from butyl containing butyl.

[0634] A more preferred compound according to the present invention comprises the following:

[0635] ㆍ chemical formula I, IA, IC, IF, IG, Ia, IAa, ICa, IFa, IGa, Ib, IAb, ICb, IFb, and IGb of Compound, here:

[0636] Y is -NH- and;

[0637] R2 is acetyl;

[0638] R3 is hydrogen; and

[0639] R4 is -CH2OH.

[0640] The most desirable compound is the chemical formula Ia, IAa, ICa, IFa, or IGa It is a compound of

[0641] ㆍ chemical formula I, IA, ID, IF, IG, Ia, IAa, IDa, IFa, IGa, Ib, IAb, IDb, IFb, and IGb The compound of, here:

[0642] Y is -O- and;

[0643] R2 is acetyl;

[0644] R3 is hydrogen; and

[0645] R4 is -CH2OH.

[0646] The most desirable compound is the chemical formula Ia, IAa, IDa, IFa , or IGa It is a compound of

[0647] ㆍ chemical formula I, IA, IC, IE, IF, IG, Ia, IAa, ICa, IEa, IFa, IGa, Ib, IAb, ICb, IEb, IFb, and IGb The compound of, here:

[0648] Y is -NH- and;

[0649] R2 is acetyl;

[0650] R3 is hydrogen; and

[0651] R4 is -CH2NH2.

[0652] The most desirable compound is the chemical formula Ib, IAb, ICb, IEb, IFb , or IGb It is a compound of

[0653] ㆍ chemical formula I, IA, ID, IE, IF, IG, Ia, IAa, IDa, IEa, IFa, IGa, Ib, IAb, IDb, IEb, IFb, and IGb The compound of, here:

[0654] Y is -O- and;

[0655] R2 is acetyl;

[0656] R3 is hydrogen; and

[0657] R4 is -CH2NH2.

[0658] The most desirable compound is the chemical formula Ib, IAb, IDb, IEb, IFb , or IGb It is a compound of

[0659] ㆍ chemical formula I, IA, IC, ID, IF, IG, Ia, IAa, ICa, IDa, IFa, IGa, Ib, IAb, ICb, IDb, IFb, 및 IGb The compound of, here:

[0660] R2 is acetyl;

[0661] R3 is hydrogen; and

[0662] R4 is -CH2OH.

[0663] The most desirable compound is the chemical formula Ia, IAa, ICa, IDa, IFa or IGa It is a compound of

[0664] ㆍ chemical formula I, IA, IC, ID, IF, IG, Ia, IAa, ICa, IDa, IFa, IGa, Ib, IAb, ICb, IDb, IFb, and IGb The compound of, here:

[0665] R1 is -OH and;

[0666] R2 is acetyl;

[0667] R3 is hydrogen; and

[0668] R4 is -CH2OH.

[0669] The most desirable compound is the chemical formula Ia, IAa, ICa, IDa, IFa or IGa It is a compound of

[0670] ㆍ chemical formula I, IA, IC, ID, IE, IF, IG, Ia, IAa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, ICb, IDb, IEb, IFb, and IGb The compound of, here:

[0671] R2 is acetyl;

[0672] R3 is hydrogen; and

[0673] R4 is -CH2NH2.

[0674] The most desirable compound is the chemical formula Ib, IAb, ICb, IDb, IEb, IFb, or IGb It is a compound of

[0675] ㆍ chemical formula Pregnancy or IAc, IDc, IFc, IGc The compound of, here:

[0676] R2 is acetyl;

[0677] R3 is hydrogen.

[0678] ㆍ chemical formula Ic 또는 IBc, IDc, IFc, IGc The compound of, here:

[0679] R2 is acetyl; and

[0680] R3 is methoxy.

[0681] ㆍ Compound of the following chemical formula according to the present invention:

[0682]

[0683]

[0684]

[0685]

[0686] or its pharmaceutically acceptable salt or ester.

[0687] Compounds of particularly desirable chemical formulas:

[0688]

[0689]

[0690]

[0691] or its pharmaceutically acceptable salt or ester.

[0692] ㆍ Compound of the following chemical formula according to the present invention:

[0693]

[0694]

[0695] or its pharmaceutically acceptable salt or ester.

[0696] Compounds of particularly desirable chemical formulas:

[0697]

[0698]

[0699]

[0700] or its pharmaceutically acceptable salt or ester.

[0701] Compounds with a more desirable chemical formula:

[0702]

[0703]

[0704]

[0705] or its pharmaceutically acceptable salt or ester.

[0706] A more preferred compound according to the present invention is a compound of the following chemical formula:

[0707]

[0708] or its pharmaceutically acceptable salt or ester.

[0709] An additionally preferred compound according to the present invention is a compound of the following chemical formula:

[0710]

[0711] or its pharmaceutically acceptable salt or ester.

[0712] In a further embodiment, a preferred compound according to the present invention is a compound of the following chemical formula:

[0713]

[0714]

[0715] or its pharmaceutically acceptable salt or ester.

[0716] Additionally, a preferred compound includes a compound of the following chemical formula:

[0717]

[0718]

[0719] or its pharmaceutically acceptable salt or ester.

[0720] Additionally, a preferred compound includes a compound of the following chemical formula:

[0721]

[0722]

[0723] or its pharmaceutically acceptable salt or ester.

[0724] In a further preferred embodiment, the aforementioned preferences for different substituents are combined. The present invention also includes the formula according to the present invention. I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, Ic, IAc, IBc, IDc, IFc or IGcThis relates to such combinations of desirable substitutions (where permitted by possible substituents) in the compound.

[0725] To eliminate any doubt, the compound may be drug moiety D and is covalently bonded to (X)b (if present), or (AA)w (if present), or (T)g (if present), or (L) through a hydroxyl or amine group. Thus, when conjugated, the covalent bond replaces a proton of the hydroxyl or amine group of the compound.

[0726] Preferred drug moiety according to the present invention is as follows. The preferred definitions of (X)b, (AA)w, (T)g, and (L) presented below are applicable to all drug moiety D compounds described above. Preferred drug moiety according to the present invention includes the following:

[0727] ㆍ A drug moiety of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, wherein L is a linker group selected from the group consisting of the following:

[0728]

[0729] Here

[0730] The above dashed line is a covalent bonding point for Ab (rightward dashed line), and for (T)g if present, or for (AA)w if present, or for (X)b if present, or for linker L;

[0731] R 19 is -C1-C 12 Alkylene-, -C3-C8 carbocyclo, -O-(C1-C 12 (alkylene), -C6-C in one or more rings that can be arbitrarily substituted by one or more substituents Rx 18 Aryllene, -C1-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx 12 Alkylene-C6-C 18Aryllene-, -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx. 18 Aryllene-C1-C 12 Alkylene-, -C1-C 12 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 12 Alkylene-, -C5-C 14 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), said group is optionally substituted by one or more substituents Rx], -C1-C 12 Alkylene-(C5-C 14 Heterocyclo)- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), and said group is optionally substituted by one or more substituents Rx], -(C5-C 14 Heterocyclo)-C1-C 12 Alkylene- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s), and said group is optionally substituted by one or more substituents Rx], selected from -(OCH2CH2)r- and -CH2-(OCH2CH2)r-, wherein each of said alkylene substituents, either alone or bonded to other moiety within the carbon chain, can be optionally substituted by one or more substituents Rx;

[0732] R 20 is a -C1-C6 alkylene group;

[0733] M is selected from the group consisting of -C1-C6alkylene-, -C1-C6alkylene-(C3-C8carbocyclo)-, -(CH2CH2O)s-, -C1-C6alkylene-(C3-C8carbocyclo)-CON(H or C1-C6alkyl)-C1-C6alkylene-, phenylene which can be optionally substituted by one or more substituents Rx, phenylene-C1-C6alkylene- in which the phenylene moiety can be optionally substituted by one or more substituents Rx, and -C1-C6alkylene-CON(H or C1-C6alkyl)C1-C6alkylene-;

[0734] Q is selected from the group consisting of -N(H or C1-C6 alkyl)phenylene- and -N(H or C1-C6 alkyl)-(CH2)s;

[0735] r is an integer in the range of 1 to 10; and

[0736] s is an integer from 1 to 10.

[0737] ㆍ A drug moiety of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, wherein L is a linker group selected from the group consisting of the following:

[0738]

[0739] Here

[0740] The dashed lines above indicate covalent bonding points for Ab (right-facing dashed line), and for (AA)g if present, or for (X)b if present, or for the drug moiety (left-facing dashed line);

[0741] R 19 is -C1-C 12 Alkylene-, -O-(-C1-C 12 alkylene-), -C6-C in one or more rings that can be optionally substituted by one or more substituents Rx 12 Aryllene, -C1-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx 12 Alkylene-C6-C12 Aryllene-, -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx. 12 Aryllene-C1-C 12 Alkylene-, -C5-C 12 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), said group is optionally substituted by one or more substituents Rx], -C1-C 12 Alkylene-(C5-C 12 Heterocyclo)- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), and said group is optionally substituted by one or more substituents Rx], -(C5-C 12 Heterocyclo)-C1-C 12 Alkylene- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s), and said group is optionally substituted by one or more substituents Rx], selected from -(OCH2CH2)r- and -CH2-(OCH2CH2)r-, wherein each of said alkylene substituents, either alone or bonded to other moiety within the carbon chain, may optionally be substituted by one or more substituents Rx; and

[0742] R 30 is a -C1-C6 alkylene group;

[0743] M is selected from the group consisting of -C1-C6alkylene-, -C1-C6alkylene-(C3-C8carbocyclo)-, and phenylene which can be arbitrarily substituted by one or more substituents Rx; and

[0744] r is an integer in the range of 1 to 6.

[0745] ㆍ A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, selected from the following formulas (IV), (V), and (VI):

[0746]

[0747] During the meal:

[0748] X and Y are extensions as defined herein;

[0749] Each AA is an amino acid unit independently defined herein;

[0750] w is an integer in the range of 0 to 12;

[0751] b is an integer of 0 or 1;

[0752] g is an integer of 0 or 1;

[0753] Here, b + g + w is optionally not zero;

[0754] D is a drug moiety;

[0755] Ab is a moiety comprising at least one antigen-binding site;

[0756] n is the ratio of [D-(X)b-(AA)w-(T)g-(L)-] groups to a moiety containing at least one antigen-binding site (where L is as defined in formulas (IV), (V), or (VI)) in the range of 1 to 20;

[0757] R 19 -C1-C8alkylene-, -O-(C1-C8alkylene), -C1-C8alkylene-C6-C having an arylene group in one or more rings that can be optionally substituted by one or more substituents Rx 12 Aryllene-, -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx. 12Selected from arylene-C1-C8alkylene-, wherein each of the alkylene substituents, either alone or bonded to other moiety within the carbon chain, may be arbitrarily substituted by one or more substituents Rx; and

[0758] R 30 -C2-C4 alkylene- group; and

[0759] M is selected from the group consisting of -C1-C3alkylene- and -C1-C3alkylene-(C5-C7carbocyclo)-.

[0760] ㆍ A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, selected from the following formulas (IV), (V), and (VI):

[0761]

[0762] During the meal:

[0763] X and T are extensions that may be the same or different;

[0764] Each AA is an independently amino acid unit;

[0765] w is an integer from 0 to 12;

[0766] b is an integer of 0 or 1;

[0767] g is an integer of 0 or 1;

[0768] Here, b + g + w is optionally not zero;

[0769] D is a drug moiety;

[0770] Ab is a moiety comprising at least one antigen-binding site;

[0771] n is the ratio of [D-(X)b-(AA)w-(T)g-(L)-] groups to a moiety containing at least one antigen-binding site (where L is as defined in (IV), (V), or (VI)), ranging from 1 to 20;

[0772] R 19 is selected from -C1-C6alkylene-, phenylene-C1-C6alkylene-, wherein the phenylene group can be optionally substituted by one or more substituents Rx selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, halogen atoms, nitro groups, and cyano groups, wherein each of the alkylene substituents, either alone or bonded to other moiety within the carbon chain, can be optionally substituted by one or more substituents Rx selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, aryl groups having 6 to 12 carbon atoms, halogen atoms, nitro groups, and cyano groups, and preferably R 19 is a -C1-C6 alkylene group;

[0773] R 30 -C2-C4 alkylene- group; and

[0774] M is -C1-C3alkylene-(C5-C7carbocyclo)-.

[0775] ㆍ In the definition of the drug conjugate of the chemical formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab, L is as defined in the preferred definition for the above group and (AA)w preferably has the chemical formula (II):

[0776]

[0777] In the formula, dashed lines indicate covalent bonding points for (X)b, or for the drug moiety (left-facing dashed line), and for the linker (right-facing dashed line), if present; and

[0778] R 21 In the presence of hydrogen, methyl, isopropyl, isobutyl, sec -Butyl, Benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl,

[0779]

[0780] Selected from a group consisting of; and

[0781] w is an integer from 0 to 12.

[0782] ㆍ A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the first aspect of the present invention, wherein L in the formula is as defined in the preferred definition for the group and (AA)w is having the formula (II):

[0783] R in food 21 In the presence of hydrogen, methyl, isopropyl, sec -Selected from the group consisting of butyl, benzyl, indolylmethyl, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2 and -(CH2)4NHC(=NH)NH2; and

[0784] w is an integer from 0 to 6.

[0785] dotA drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the first aspect of the present invention, wherein L in the formula is as defined in the preferred definition for the group, w is 0 or 2, and if w is 2, (AA)w is a drug conjugate having the formula (III):

[0786]

[0787] Dashed lines indicate covalent bonding points for (X)b, or the drug moiety (left-facing dashed line), and for (T)g, or the linker (right-facing dashed line), if present;

[0788] R 22 is methyl, benzyl, isopropyl, sec -Selected from butyl and indolylmethyl; and

[0789] R 23 It is selected from methyl, -(CH2)4NH2, -(CH2)3NHCONH2 and -(CH2)3NHC(=NH)NH2.

[0790] dot In an embodiment of the present invention, b+g+w is not 0. In a further embodiment, b + w is not 0. In yet another embodiment, when w is not 0, b is 1. Additionally, in the drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab, L and (AA)w are as defined in the preferred definitions for the groups above, and X is preferably an extender selected from the group consisting of the following:

[0791] When D in the formula is conjugated through an amine group (e.g., when Z is -NH-):

[0792] -COO-(C1-C6alkylene)NH-;

[0793] -COO-CH2-(phenylene which can be arbitrarily substituted by one or more substituents Rx)-NH-;

[0794] -COO-(C1-C6alkylene)NH-COO-CH2-(phenylene which may be optionally substituted by one or more substituents Rx)-NH-;

[0795] -COCH2NH-COCH2-NH-;

[0796] -COCH2NH-;

[0797] -COO-(C1-C6alkylene)S-;

[0798] -COO-(C1-C6alkylene)NHCO(C1-C6alkylene)S-; or

[0799] When D in the formula is conjugated via a hydroxyl group (e.g., when Z is -O-):

[0800] -CONH-(C1-C6alkylene)NH-;

[0801] -COO-CH2-(phenylene which can be arbitrarily substituted by one or more substituents Rx)-NH-;

[0802] -CONH-(C1-C6alkylene)NH-COO-CH2-(phenylene which may be optionally substituted by one or more substituents Rx)-NH-;

[0803] -COCH2NH-COCH2-NH-;

[0804] -COCH2NH-;

[0805] -CONH-(C1-C6alkylene)S-;

[0806] -CONH-(C1-C6alkylene)NHCO(C1-C6alkylene)S-; and

[0807] b is 0 or 1, preferably 1.

[0808] dot A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, wherein L and (AA)w are as defined in the preferred definitions for the groups, and X is an extender selected from the group consisting of the following:

[0809] When D in the formula is conjugated through an amine group (e.g., when Z is -NH-):

[0810] -COO-(C2-C4alkylene)NH-;

[0811] -COO-CH2-phenylene-NH-, wherein the phenylene group in the formula may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, halogen atoms, nitro groups, and cyano groups;

[0812] -COO-(C2-C4alkylene)NH-COO-CH2-(phenylene that can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group)-NH-;

[0813] -COCH2NH-COCH2-NH-;

[0814] -COO-(C1-C6alkylene)S-;

[0815] -COO-(C1-C6alkylene)NHCO(C1-C6alkylene)S-; or

[0816] When D in the formula is conjugated via a hydroxyl group (e.g., when Z is -O-):

[0817] -CONH-(C2-C4alkylene)NH-;

[0818] -COO-CH2-phenylene-NH-, wherein the phenylene group in the formula may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, halogen atoms, nitro groups, and cyano groups;

[0819] -CONH-(C2-C4alkylene)NH-COO-CH2-(phenylene that can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group)-NH-;

[0820] -COCH2NH-COCH2-NH-;

[0821] -CONH-(C2-C4alkylene)S-;

[0822] -CONH-(C2-C4alkylene)NHCO(C1-C3alkylene)S-; and

[0823] b is 0 or 1, preferably 1.

[0824] dot A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, wherein L and (AA)w are as defined in the preferred definitions for the groups, and X is an extender selected from the group consisting of the following:

[0825] When D in the formula is conjugated through an amine group (e.g., when Z is -NH-):

[0826] -COO-CH2-phenylene-NH-

[0827] -COO(CH2)3NHCOOCH2-phenylene-NH-;

[0828] -COO(CH2)3NH-;

[0829] -COO(CH2)3-S-;

[0830] -COO(CH2)3NHCO(CH2)2S-; or

[0831] When D in the formula is conjugated via a hydroxyl group (e.g., when Z is -O-):

[0832] -COO-CH2-phenylene-NH-

[0833] -CONH(CH2)3NHCOOCH2-phenylene-NH-;

[0834] -CONH(CH2)3NH-;

[0835] -CONH(CH2)3-S-;

[0836] -CONH(CH2)3NHCO(CH2)2S-; and

[0837] b is 0 or 1, preferably 1.

[0838] dot A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, wherein L, (AA)w, and (X)b are as defined in the preferred definitions for the groups, and T is an extender selected from the group consisting of the following:

[0839] -CO-(C1-C6alkylene)-NH-;

[0840] -CO-(C1-C6alkylene)-[O-(C2-C6alkylene)]j-NH-;

[0841] -COO-(C1-C6alkylene)-[O-(C2-C6alkylene)]j-NH-;

[0842] j is an integer from 1 to 25, and

[0843] g is 0 or 1.

[0844] dot A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, wherein L, (AA)w, and (X)b are as defined in the preferred definitions for the groups, and T is an extender selected from the group consisting of the following:

[0845] -CO-(C1-C4alkylene)-NH-;

[0846] -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-;

[0847] -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-;

[0848] j is an integer from 1 to 10, and

[0849] g is 0 or 1.

[0850] dot A drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention, wherein L, (AA)w, and (X)b are as defined in the preferred definitions for the groups, and T is an extender selected from the group consisting of the following:

[0851] -CO-(C1-C4alkylene)-NH-;

[0852] -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-;

[0853] -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-;

[0854] j is an integer from 1 to 5, and

[0855] g is 0 or 1.

[0856] dotA preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is such that L, (AA)w, (X)b, and (T)g are defined as above, and D is a compound of the formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, (IH), (IHa), or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and is a compound of the formulas I, IA, IB, IC, ID, IE, IG, Ia, IAa, IBa, ICa, IDa, IEa, IGa, Ib, IAb, IBb, ICb, IDb, A drug conjugate in which R1 is CN or OH in compounds of IEb, IGb, (IH), (IHa) or (IHb), R1 is OH in compounds of the chemical formula IF, IFa and IFb, R1 is OH in compounds of the chemical formula IF, IFa and IFb, and more preferably R1 is CN.

[0857] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w, (X)b, and (T)g are defined as above, D is a compound of the formulas I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, (IH), (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and R2 is C(=O)Ra, where Ra is selected from hydrogen and substituted or unsubstituted C1-C6 alkyls, wherein any substituents are one or more substituents Rx, and more preferably R2 is acetyl.

[0858] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is as defined above, where L, (AA)w, (X)b, and (T)g are as defined above, and D is a compound of the formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, (IH), (IHa), or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and R3 is a compound of the general formulas I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, A drug conjugate in which the compound of IGb, (IH), (IHa) or (IHb) is hydrogen or -ORb group; the compound of general formula IA, IAa or IAb is hydrogen; the compound of general formula IB, IBa or IBb is -ORb group; Rb is a substituted or unsubstituted C1-C6 alkyl, wherein the optional substituents are one or more substituents Rx, more preferably R3 is hydrogen.

[0859] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w, (X)b, and (T)g are as defined above, D is a compound of the formula (IH), (IHa), or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer, or stereoisomer thereof, and Y is -NH- or -O-.

[0860] dotAnother preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w (X)b, and (T)g are as defined above, D is a compound of the formula (IH), (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, and Z is -NH- or -O-, more preferably Z is -NH-.

[0861] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is as defined above, where L, (AA)w, (X)b, and (T)g are a compound of the formula (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein:

[0862] R1 is -CN or -OH;

[0863] R2 is -C(=O)Ra, where Ra is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl, where optional substituents are one or more substituents Rx;

[0864] R3 is hydrogen or -ORb, where Rb is a substituted or unsubstituted C1-C6 alkyl group, where optional substituents are one or more substituents Rx;

[0865] Y is -NH- or -O- and; and

[0866] Z is a drug conjugate that is -NH- or -O-.

[0867] dotAnother preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is as defined above, where L, (AA)w, (X)b, and (T)g are a compound of the formula (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein:

[0868] R1 is -CN or -OH;

[0869] R2 is acetyl;

[0870] R3 is hydrogen or methoxy, more preferably hydrogen;

[0871] Y is -NH- or -O- and; and

[0872] Z is a drug conjugate that is -NH- or -O-.

[0873] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is as defined above, where L, (AA)w, (X)b, and (T)g are a compound of the formula (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein:

[0874] R1 is -CN and;

[0875] R2 is acetyl;

[0876] R3 is hydrogen;

[0877] Y is -NH- or -O- and; and

[0878] Z is a drug conjugate that is -NH-.

[0879] dotAnother preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is such that L, (AA)w, (X)b, and (T)g are defined as above, and D in the formula is selected from the following compounds:

[0880]

[0881] or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein the dashed line is a drug conjugate that is a covalent bonding site for (X)b if present, or for (AA)w if present, or for (T)g if present, or for linker group L.

[0882] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is such that L, (AA)w, (X)b, and (T)g are defined as above, and D in the formula is selected from the following compounds:

[0883]

[0884] or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein the dashed line is a drug conjugate that is a covalent bonding site for (X)b if present, or for (AA)w if present, or for (T)g if present, or for linker group L.

[0885] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w, (X)b, and (T)g and D are as defined above, and the moiety Ab comprising at least one antigen-binding site in the formula is an antigen-binding peptide.

[0886] dotAnother preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w, (X)b, and (T)g and D are as defined above, and the moiety Ab comprising at least one antigen-binding site is an antibody, a single-domain antibody, or an antigen-binding fragment thereof.

[0887] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w, (X)b, and (T)g and D are as defined above, and the moiety Ab comprising at least one antigen-binding site is a monoclonal, polyclonal antibody or bispecific antibody, and said antibody or its antigen-binding fragment is derived from any species, preferably human, mouse, or rabbit.

[0888] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w (X)b, and (T)g and D are as defined above, and the moiety Ab having at least one antigen-binding site is an antibody selected from the group consisting of a human antibody, an antigen-binding fragment of a human antibody, a humanized antibody, an antigen-binding fragment of a humanized antibody, a chimeric antibody, an antigen-binding fragment of a chimeric antibody, a glycosylated antibody, and a glycosylated antibody binding fragment, or an antigen-binding fragment thereof.

[0889] dotAnother preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w, (X)b, and (T)g and D are as defined above, and the moiety Ab having at least one antigen-binding site is an antibody or its antigen-binding fragment, wherein the antibody or its antigen-binding fragment is an antigen-binding fragment selected from the group consisting of a Fab fragment, a Fab' fragment, an F(ab')2 fragment, and an Fv fragment.

[0890] dot Another preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a drug conjugate in which L, (AA)w, (X)b, and (T)g and D are as defined above, and the moiety Ab having at least one antigen-binding site is an antibody or its antigen-binding fragment, wherein said antibody or its antigen-binding fragment is a cancer cell antigen, a viral antigen, an antigen of a cell producing an autoimmune antibody associated with an autoimmune disease, a monoclonal antibody that binds immunospecifically to a microbial antigen, and preferably a monoclonal antibody that binds immunospecifically to a cancer cell antigen.

[0891] dotAnother preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention is a moiety Ab having at least one antigen binding site, wherein L, (AA)w, (X)b, and (T)g and D are as defined above, a valence Ab having at least one antigen binding site, a valence Absicimab, alemtuzumab, anetuzumab, atezolizumab, avelumab, basilisimab, bevacizumab, blinatomumab, brentuximab, catumazomab, cetuximab, coltusimab, daclizumab, daratumumab, denintuzumab, denosumab, depatuxizumab, dinutuximab, durvalumab, elotuzumab, enfortumab, glembatuzumab, gemtuzumab, ibritumomab, indatusimab, indusatumab, innotuzumab, ipilimumab, labetuzumab, Radiratuzumab, Lapritusimab, Rifastuzumab, Lorrbotuzumab, Milatuzumab, Mirvetuzumab, Naratuzumab, Necitumumab, Nimotuzumab, Nivolumab, Obinutuzumab, Ofatumumab, Olaratuzumab, Omalizumab, Palivizumab, Panitumumab, Pembrolizumab, Pertuzumab, Finatuzumab, Polatuzumab, Ramucirumab, Rovalfituzumab, Sacituzumab, Finatuzumab, Polatuzumab, Ramucirumab, Rovalfituzumab, Sacituzumab, Siltusimab, Sirtratuzumab, Sofituzumab, Vadastuzumab, Borsetuzumab, Trastuzumab and anti-CD4 antibodies, anti-CD5 antibodies, anti-CD13 antibodies, and anti-CD30 antibodies, or antigen-binding fragments or their It comprises an antigen binding site for an antibody selected from an immunologically active portion, and more preferably absicimab, alemtuzumab, anetuzumab, atezolizumab, avelumab, basilisimab, bevacizumab, blinatomumab, brentuximab, catumazomab, cetuximab, daclizumab, daratumumab, denintuzumab, denosumab, depatuxizumab, dinutuximab, durvalumab, elotuzumab, enfortumab, glembatuzumab, gemtuzumab, ibritumomab, indatusimab, indusatumab, innotuzumab, ipilimumab, rabetuzumab, radiratuzumab, lapritusimab, mirvetusimab, naratuzumab, necitumumab, nimotuzumab, nivolumab, obinutuzumab, ofatumumab, olaratumab, Omalizumab, palivizumab, panitumumab,Pembrolizumab, pertuzumab, polatuzumab, ramucirumab, lovalfituzumab, sacituzumab, ciltusimab, sirtratumab, vadastuzumab, borcetuzumab, trastuzumab and an antigen-binding site for an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD13 antibody, and an anti-CD30 antibody, or an antibody selected from an antigen-binding fragment or its immunologically active portion, more preferably comprising apsiximab, alemtuzumab, atezolizumab, avelumab, basilisimab, bevacizumab, blinatomumab, brentuzimab, catumazomab, cetuximab, daclizumab, daratumumab, denosumab, dinutusimab, durvalumab, elotuzumab, gemtuzumab, ibritumomab, inotuzumab, ipilimumab, rabetuzumab, A drug conjugate comprising an antigen-binding site for an antibody selected from necitumumab, nimotuzumab, nivolumab, obinutuzumab, ofatumumab, olaratumab, omalizumab, palivizumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, lovalfituzumab, ciltusimab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody, and anti-CD30 antibody, or an antigen-binding fragment or its immunologically active portion. Among these, it is particularly preferred that it be brentuximab, gemtuzumab, inotuzumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody, and anti-CD30 antibody, or an antigen-binding fragment or its immunologically active portion; or trastuzumab and an anti-CD13 antibody or an antigen-binding fragment or its immunologically active portion, in particular an antigen selected from trastuzumab or the antigen-binding fragment or its immunologically active portion.

[0892] dot A particularly preferred drug conjugate of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab according to the present invention comprises the following:

[0893] (a) Drug conjugate according to the present invention:

[0894] L is selected from the group consisting of the following:

[0895]

[0896] During the meal:

[0897] The dashed lines indicate covalent bonding points for Ab (right-facing dashed line), and for (T)g if present, or for (AA)w if present, or for (X)b if present, or for the drug moiety (left-facing dashed line);

[0898] R 19 is -C1-C 12 Alkylene-, -O-(C1-C 12 (alkylene), -C6-C in one or more rings that can be arbitrarily substituted by one or more substituents Rx 12 Aryllene, -C1-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx 12 Alkylene-C6-C 12 Aryllene-, -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx. 12 Aryllene-C1-C 12 Alkylene-, -C5-C 12 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), said group is optionally substituted by one or more substituents Rx], -C1-C 12 Alkylene-(C5-C 12 Heterocyclo)- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), and said group is optionally substituted by one or more substituents Rx], -(C5-C 12 Heterocyclo)-C1-C 12Alkylene- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s), and said group is optionally substituted by one or more substituents Rx], selected from -(OCH2CH2)r- and -CH2-(OCH2CH2)r-, wherein each of said alkylene substituents, either alone or bonded to other moiety within the carbon chain, can be optionally substituted by one or more substituents Rx;

[0899] R 30 is a -C1-C6 alkylene group;

[0900] M is selected from the group consisting of -C1-C6alkylene-, -C1-C6alkylene-(C3-C8carbocyclo)-, and phenylene, which can be substituted by one or more substituents Rx;

[0901] r is an integer from 1 to 6;

[0902] (AA)w has the chemical formula (II):

[0903]

[0904] In the formula, dashed lines indicate covalent bonding points for (X)b, or for the drug moiety (left-facing dashed line), if present, and for (T)g, or for the linker (right-facing dashed line), if present; and

[0905] R 21 In the presence of hydrogen, methyl, isopropyl, isobutyl, sec -Butyl, Benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl,

[0906]

[0907] Selected from a group consisting of;

[0908] w is an integer from 0 to 12;

[0909] In the formula, X is an extender selected from the following, and

[0910] Here, when D is conjugated via an amine group (e.g., when Z is -NH-): -COO-(C1-C6alkylene)NH-, -COO-CH2-(phenylene which may be optionally substituted by one or more substituents Rx)-NH-, -COO-(C1-C6alkylene)NH-COO-CH2-(phenylene which may be optionally substituted by one or more substituents Rx)-NH-, -COCH2NH-COCH2-NH-, -COCH2NH-, -COO-(C1-C6alkylene)S-, -COO-(C1-C6alkylene)NHCO(C1-C6alkylene)S-; or

[0911] When D is conjugated via a hydroxyl group (e.g., when Z is -O-): -CONH-(C1-C6alkylene)NH-, -COO-CH2-(phenylene which can be optionally substituted by one or more substituents Rx)-NH-, -CONH-(C1-C6alkylene)NH-COO-CH2-(phenylene which can be optionally substituted by one or more substituents Rx)-NH-, -COCH2NH-COCH2-NH-, -COCH2NH-, -CONH-(C1-C6alkylene)S-, -CONH-(C1-C6alkylene)NHCO(C1-C6alkylene)S-;

[0912] b is 0 or 1, preferably 1;

[0913] In the formula, T is an extender selected from -CO-(C1-C6alkylene)-NH-, -CO-(C1-C6alkylene)-[O-(C2-C6alkylene)]j-NH-, and -COO-(C1-C6alkylene)-[O-(C2-C6alkylene)]j-NH-, where j is an integer from 1 to 25;

[0914] g is 0 or 1 and;

[0915] D is a drug moiety of the chemical formula I, IA, IB, IC, ID, IE, IF, IG, IH, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, where:

[0916] R2 is -C(=O)Ra in compounds of general formulas I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, (IH), (IHa) or (IHb); is acetyl in compounds of general formulas IG, IGa or IGb; Ra is selected from hydrogen and substituted or unsubstituted C1-C6 alkyl, wherein any substituents are one or more substituents Rx;

[0917] R3 is a hydrogen or -ORb group in a compound of general formula I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, IGb, (IH), (IHa) or (IHb); is a hydrogen in a compound of general formula IA, IAa or IAb; is a -ORb group in a compound of general formula IB, IBa or IBb; Rb is a substituted or unsubstituted C1-C6 alkyl, wherein any substituents are one or more substituents Rx;

[0918] A moiety Ab having at least one antigen-binding site in the formula is an antibody or its antigen-binding fragment selected from the group consisting of a human antibody, an antigen-binding fragment of a human antibody, a humanized antibody, an antigen-binding fragment of a humanized antibody, a chimeric antibody, an antigen-binding fragment of a chimeric antibody, a glycosylated antibody, and a glycosylated antibody-binding fragment; and

[0919] n is the ratio of [D-(X)b-(AA)w-(T)g-(L)-] groups to a moiety Ab containing at least one antigen-binding site, ranging from 1 to 12.

[0920] (b) A drug conjugate according to the present invention selected from chemical formulas (IV), (V) and (VI):

[0921]

[0922] During the meal:

[0923] R 19 -C1-C8alkylene-, -O-(C1-C8alkylene), -C1-C8alkylene-C6-C having an arylene group in one or more rings that can be optionally substituted by one or more substituents Rx 12 -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx, and an arylene group in one or more rings that can be arbitrarily substituted by arylene-, and one or more substituents Rx. 12Selected from arylene-C1-C8 alkylene-, wherein each of the alkylene substituents, either alone or bonded to other moiety within the carbon chain, may be arbitrarily substituted by one or more substituents Rx;

[0924] R 30 is a -C2-C4 alkylene group;

[0925] M is selected from the group consisting of -C1-C3alkylene- and -C1-C3alkylene-(C5-C7carbocyclo) which can be substituted by one or more substituents Rx;

[0926] (AA)w has the chemical formula (II):

[0927]

[0928] During the meal:

[0929] The dashed lines indicate covalent bonding points for (X)b, or the drug moiety (left-facing dashed line), if present, and for (T)g, or the linker (right-facing dashed line), if present;

[0930] R 21 In the presence of hydrogen, methyl, isopropyl, sec Selected from the group consisting of -butyl, benzyl, indolylmethyl, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2, and -(CH2)4NHC(=NH)NH2;

[0931] w is an integer from 0 to 6;

[0932] In the formula, X is an extender selected from the following, and

[0933] When D is conjugated via an amine group (e.g., when Z is -NH-): -COO-(C2-C4alkylene)NH-, -COO-CH2-phenylene-NH- (wherein the phenylene group may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group), -COO-(C2-C4alkylene)NH-COO-CH2- (phenylene which may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group)-NH-, -COCH2NH-COCH2-NH-, -COO-(C2-C4alkylene)S-, and -COO-(C2-C4alkylene)NHCO(C1-C6alkylene)S-; or

[0934] When D is conjugated via a hydroxyl group (e.g., when Z is -O-): -CONH-(C2-C4alkylene)NH-, -COO-CH2-phenylene-NH- (wherein the phenylene group may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group), -CONH-(C2-C4alkylene)NH-COO-CH2-(phenylene which may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group)-NH-, -COCH2NH-COCH2-NH-, -CONH-(C2-C4alkylene)S-, and -CONH-(C2-C4alkylene)NHCO(C1-C3alkylene)S-;

[0935] b is 0 or 1, preferably 1;

[0936] In the formula, T is an extender selected from -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, where j is an integer from 1 to 10;

[0937] g is 0 or 1 and;

[0938] D is a drug moiety of the chemical formula I, IA, IB, IC, ID, IE, IF, IG, IH, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, where:

[0939] R2 is acetyl;

[0940] R3 is hydrogen or methoxy in compounds of general formulas I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, IGb, (IH), (IHa) or (IHb); is hydrogen in compounds of general formulas IA, IAa, or IAb; is methoxy in compounds of general formulas IB, IBa, or IBb; preferably, R3 is hydrogen;

[0941] The moiety Ab having at least one antigen-binding site in the formula is an antibody or its antigen-binding fragment selected from cancer cell antigens, viral antigens, antigens of cells producing autoimmune antibodies associated with autoimmune diseases, monoclonal antibodies that immunospecifically bind to microbial antigens, and preferably monoclonal antibodies that immunospecifically bind to cancer cell antigens; and

[0942] n is the ratio of [D-(X)b-(AA)w-(T)g-(L)-] groups (where L is as defined in formulas (IV), (V), and (VI)) to a moiety Ab containing at least one antigen-binding site, ranging from 3 to 8.

[0943] (c) A drug conjugate according to the present invention selected from chemical formulas (IV), (V) and (VI):

[0944]

[0945] During the meal:

[0946] R 19 is selected from -C1-C6alkylene-, phenylene-C1-C6alkylene-, wherein the phenylene group can be optionally substituted by one or more substituents Rx selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, halogen atoms, nitro groups, and cyano groups, wherein each of the alkylene substituents, either alone or bonded to other moiety within the carbon chain, can be optionally substituted by one or more substituents Rx selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, aryl groups having 6 to 12 carbon atoms, halogen atoms, nitro groups, and cyano groups, and preferably R 19 is a -C1-C6 alkylene group;

[0947] R 30 -C2-C4 alkylene group;

[0948] M is -C1-C3alkylene-(C5-C7carbocyclo)-;

[0949] w is 0 or 2, wherein if w is 2, (AA)w has the chemical formula (III):

[0950]

[0951] In the formula, dashed lines indicate covalent bonding points for (X)b, or for the drug moiety (left-facing dashed line), and for (T)g, or for the linker (right-facing dashed line), if present;

[0952] R 22 is selected from methyl, benzyl, isopropyl, sec-butyl, and indolylmethyl;

[0953] R 23 It is selected from methyl, -(CH2)4NH2, -(CH2)3NHCONH2 and -(CH2)3NHC(=NH)NH2;

[0954] X is -COO-(C2-C4alkylene)NH-, -COO-CH2-phenylene-NH-[the phenylene group may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group], -COO-(C2-C4alkylene)NH-COO-CH2-(phenylene which may be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group)-NH-, -COCH2NH-COCH2-NH-, -COO-(C1-C6alkylene)S-, -COO-(C1-C6alkylene)NHCO(C1-C6alkylene)S-;

[0955] b is 0 or 1, preferably 1;

[0956] In the above formula, T is selected from the group consisting of -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH- and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, and j is an integer from 1 to 5;

[0957] g is 0 or 1, and

[0958] D is a drug moiety of the formula I, IA, IC, ID, IE, IG, IH, Ia, IAa, ICa, IDa, IEa, IGa, Ib, IAb, ICb, IDb, IEb, IGb, (IHa) or (IHb), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, where:

[0959] R1 is CN and;

[0960] R2 is acetyl;

[0961] R3 is hydrogen;

[0962] Y is -NH- or -O- and;

[0963] Z is -NH-;

[0964] dotMoiety antibodies having at least one antigen-binding site are apsiximab, alemtuzumab, anetuzumab, atezolizumab, avelumab, bacilisimab, bevacizumab, blinatomumab, brentuximab, catumazomab, cetuximab, coltusimab, daclizumab, daratumumab, denintuzumab, denosumab, depatuxizumab, dinutuximab, durvalumab, elotuzumab, enfortumab, glembatuzumab, gemtuzumab, ibritumomab, indatusimab, indusatumab, inozutumab, ipilimumab, rabetuzumab, radiratuzumab, lapritusimab, rifastuzumab, lorbotuzumab, milatuzumab, mirvetusimab, naratuzumab, necitumumab, nimotuzumab, nivolumab, obinutuzumab, ofatumumab, olaratumab, omalizumab, palivizumab, panitumumab, pembrolizumab, pertuzumab, finatuzumab, polatuzumab, ramucirumab, lovalfituzumab, sacituzumab, finatuzumab, polatuzumab, ramucirumab, lovalfituzumab, sacituzumab, ciltusimab, sirtratumab, sofituzumab, vadastuzimab, borsetuzumab, trastuzumab and comprising an antigen-binding site for an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD13 antibody, and an anti-CD30 antibody, or an antibody selected from an antigen-binding fragment or its immunologically active portion, more preferably apsiximab, alemtuzumab, anetuzumab, atezolizumab, avelumab, basilisimab, bevacizumab, Blinatomumab, Brentuximab, Cathumazomab, Cetuximab, Daclizumab, Daratumumab, Denintuzumab, Denosumab, Depatuzizumab, Dinutuximab, Durvalumab, Elotuzumab, Enfortumab, Glembatumumab, Gemtuzumab, Ibritumomab, Indatusimab, Indusatumab, Inozutumab, Ipilimumab, Ravetuzumab, Radiratuzumab, Lapritusimab, Mirvetuzimab, Naratuzimab, Necitumumab, Nimotuzumab, Nivolumab, Obinutuzumab, Ofatumumab, Olaratumab, Omalizumab, Palivizumab, Panitumumab, Pembrolizumab, Pertuzumab, Folatuzumab, Ramucirumab, Rovalfituzumab, Sacituzumab, Siltuximab, Sirtratumab, Vadastuximab, Borsetuzumab, Trastuzumab and anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody,and includes an antigen-binding site for an anti-CD30 antibody, or a monoclonal antibody selected from an antigen-binding fragment or its immunologically active portion, more preferably comprising apsiximab, alemtuzumab, atezolizumab, avelumab, baciliximab, bevacizumab, blinatomumab, brentuximab, catumazomab, cetuximab, daclizumab, daratumumab, denosumab, dinutuximab, durvalumab, elotuzumab, gemtuzumab, ibritumomab, inozutumab, ipilimumab, rabetuzumab, necitumumab, nimotuzumab, nivolumab, obinutuzumab, ofatumumab, olaratumab, omalizumab, palivizumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rovalfituzumab, ciltusimab, A moiety Ab comprising an antigen-binding site for a monoclonal antibody selected from trastuzumab, an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD13 antibody, and an anti-CD30 antibody, or an antigen-binding fragment or its immunologically active portion. Among these, a moiety Ab comprising an antigen-binding site for a monoclonal antibody selected from brentuximab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD13 antibody, and an anti-CD30 antibody, or an antigen-binding fragment or its immunologically active portion, or trastuzumab and an anti-CD13 antibody or an antigen-binding fragment or its immunologically active portion, in particular trastuzumab or an antigen-binding fragment or its immunologically active portion; and,

[0965] n is the ratio of [D-(X)b-(AA)w-(T)g-(L)-] groups (where L is as defined in formulas (IV), (V), and (VI)) to a moiety Ab containing at least one antigen-binding site, ranging from 3 to 5.

[0966] (d) A drug conjugate according to the present invention selected from chemical formulas (IV), (V) and (VI):

[0967]

[0968] During the meal:

[0969] R 19 is -C2-C6alkylene-;

[0970] R 30 -C2-C4alkylene- ;

[0971] M is -C1-C3alkylene-(C5-C7carbocyclo)-;

[0972] If w is 0 or 2, and w is 2, then (AA)w is a drug conjugate having the chemical formula (III):

[0973]

[0974] R in food 22 is isopropyl, R 23 -(CH2)3NHCONH2, and the dashed line indicates the covalent bonding site for (X)b if present, or for the drug moiety, and the covalent bonding site for (T)g if present (left-facing dashed line) or the covalent bonding site for the linker (right-facing dashed line);

[0975] -COO-CH2-phenylene-NH-, -COO-(C2-C4alkylene)NH-, where X is -CONH-(C2-C4alkylene)NH-, -COO-(C2-C4alkylene)NH-COO-CH2-(phenylene which can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group), -COO-(C2-C4alkylene)NH-COO-CH2-(phenylene which can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group), -COCH2NH-COCH2-NH-, -COO-(C2-C4alkylene)S-, and An extender selected from the group consisting of -COO-(C2-C4alkylene)NHCO(C1-C3alkylene)S-;

[0976] b is 0 or 1, preferably 1; in the formula, T is an extender selected from -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, where j is an integer from 1 to 5;

[0977] g is 0 or 1 and;

[0978] D is a drug moiety selected from the following:

[0979]

[0980] or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein the dashed line is a covalent bonding site for (X)b if present, or for (AA)w if present, or for (T)g if present, or for linker group L;

[0981] A moiety Ab comprising at least one antigen-binding site is selected from brentuximab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody, and anti-CD30 antibody, or an antigen-binding fragment or its immunologically active portion, or more preferably selected from trastuzumab and anti-CD13 antibody or an antigen-binding fragment or its immunologically active portion, in particular from trastuzumab or an antigen-binding fragment or its immunologically active portion; and

[0982] n is the ratio of [D-(X)b-(AA)w-(T)g-(L)-] groups (wherein L is defined in formula (IV), (V), or (VI)) to a moiety Ab containing at least one antigen-binding site, ranging from 3 to 5.

[0983] (e) A drug conjugate according to the present invention selected from chemical formulas (IV), (V) and (VI):

[0984]

[0985] During the meal:

[0986] R 19 is -C2-C6alkylene-;

[0987] R 30 -C2-C4alkylene- ;

[0988] M is -C1-C3alkylene-(C5-C7carbocyclo)-;

[0989] If w is 0 or 2, and w is 2, then (AA)w is a drug conjugate having the chemical formula (III):

[0990]

[0991] R in food 22 is isopropyl, R 23 ... is selected from methyl and -(CH2)3NHCONH2, and the dashed line indicates a covalent bonding site for (X)b if present, or for a drug moiety, and a covalent bonding site for (T)g if present (left-facing dashed line), or a covalent bonding site for a linker (right-facing dashed line);

[0992] -COO-CH2-phenylene-NH-, -COO-(C2-C4alkylene)NH-, where X is -COO-(C2-C4alkylene)NH-, where the phenylene group can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group; -COO-(C2-C4alkylene)NH-COO-CH2-(phenylene, which can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group); -COCH2NH-COCH2-NH-, -COO-(C2-C4alkylene)S-, and An extender selected from the group consisting of -COO-(C2-C4alkylene)NHCO(C1-C3alkylene)S-;

[0993] b is 0 or 1, preferably 1;

[0994] In the formula, T is an extender selected from -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, where j is an integer from 1 to 5;

[0995] g is 0 or 1 and;

[0996] D is a drug moiety selected from the following:

[0997]

[0998] or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein the dashed line is a covalent bonding site for (X)b if present, or for (AA)w if present, or for (T)g if present, or for linker group L;

[0999] A moiety Ab comprising at least one antigen-binding site is selected from brentuximab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody, and anti-CD30 antibody, or an antigen-binding fragment or its immunologically active portion, or more preferably selected from trastuzumab and anti-CD13 antibody or an antigen-binding fragment or its immunologically active portion, in particular from trastuzumab or an antigen-binding fragment or its immunologically active portion; and

[1000] n is the ratio of [D-(X)b-(AA)w-(T)g-(L)-] groups (wherein L is defined in formula (IV), (V), or (VI)) to a moiety Ab containing at least one antigen-binding site, ranging from 3 to 5.

[1001] (f) Drug conjugate according to chemical formula (IV):

[1002]

[1003] During the meal:

[1004] R 19 -C2-C5alkylene-;

[1005] If w is 0 or 2, and w is 2, then (AA)w has the chemical formula (III):

[1006]

[1007] R in food 22 is isopropyl, R 23 ... is selected from methyl or -(CH2)3NHCONH2, and the dashed lines indicate a covalent bonding site for (X)b if present, or for a drug moiety, and a covalent bonding site for (T)g if present (left-facing dashed line), or a covalent bonding site for a linker (right-facing dashed line); and

[1008] X is a -COOCH2-phenylene-NH group, and

[1009] b is 1 and;

[1010] T is an extender of the chemical formula -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]4-NH-;

[1011] g is 0 or 1 and;

[1012] or of the chemical formula (V)

[1013]

[1014] M is -methyl-cyclohexylene- and;

[1015] b is 1 and;

[1016] w is 0 and;

[1017] X is an extender selected from -(CH2)3S- and -(CH2)3NHCO(CH2)2S-;

[1018] g is 0 and;

[1019] or of the chemical formula (VI)

[1020]

[1021] R in food 19 -C2-C5alkylene-;

[1022] R 30 is -C3alkylene-;

[1023] If w is 0 or 2, and w is 2, then (AA)w is the formula (III) and:

[1024]

[1025] R in food 22 is isopropyl, R 23 ... is selected from methyl and -(CH2)3NHCONH2, and the dashed lines indicate a covalent bonding site for (X)b if present, or for a drug moiety, and a covalent bonding site for (T)g if present (left-facing dashed line), or a covalent bonding site for a linker (right-facing dashed line); and

[1026] X is a -COOCH2-phenylene-NH- group;

[1027] b is 1 and;

[1028] T is an extender of the chemical formula -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]4-NH-;

[1029] g is 0 or 1 and;

[1030] D is a drug moiety selected from the following:

[1031]

[1032] or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein the dashed line is a covalent bonding site for (X)b if present;

[1033] A moiety Ab comprising at least one antigen-binding site is selected from brentuzimab, gemtuzumab, inotuzumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody, and anti-CD30 antibody, or an antigen-binding fragment or its immunologically active portion, or more preferably selected from trastuzumab and anti-CD13 antibody or an antigen-binding fragment or its immunologically active portion, in particular from trastuzumab or an antigen-binding fragment or its immunologically active portion; and

[1034] n is the ratio of the [D-(X)b-(AA)w-(T)g-(L)-] group (wherein L is defined in formula (IV)) to the moiety Ab containing at least one antigen-binding site, ranging from 3 to 5, preferably 4.

[1035] g) Antibody-drug conjugate according to the present invention, selected from the group consisting of the following:

[1036]

[1037]

[1038]

[1039]

[1040] In the formula, n is 2-6, more preferably 3, 4, or 5, and each and The is independently selected from brentuzimab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody and anti-CD30 antibody, or antigen-binding fragment or its immunologically active portion, and more preferably from trastuzumab and anti-CD13 antibody or its antigen-binding fragment or its immunologically active portion, particularly preferably from trastuzumab or antigen-binding fragment or its immunologically active portion.

[1041] In one embodiment, the antibody-drug conjugate according to the present invention excludes the following:

[1042]

[1043] More preferably, the antibody-drug conjugate is selected from the group consisting of the following:

[1044]

[1045] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is selected from trastuzumab and an anti-CD13 antibody or its antigen-binding fragment or its immunologically active portion, more preferably trastuzumab or its antigen-binding fragment or its immunologically active portion, and

[1046]

[1047] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is selected from trastuzumab or its antigen-binding fragment or its immunologically active portion, and

[1048]

[1049] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is selected from trastuzumab and an anti-CD13 antibody or an antigen-binding fragment or its immunologically active portion, more preferably trastuzumab or an antigen-binding fragment or its immunologically active portion, and

[1050]

[1051] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab or an antigen-binding fragment or its immunologically active part, and

[1052]

[1053] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab or an antigen-binding fragment or its immunologically active part, and

[1054]

[1055] In the formula, n is 2-6, more preferably 3, 4, or 5, and, The is selected from trastuzumab and an anti-CD13 antibody or an antigen-binding fragment or its immunologically active portion, more preferably trastuzumab or an antigen-binding fragment or its immunologically active portion.

[1056] h) Antibody-drug conjugate according to the present invention selected from the group consisting of the following:

[1057]

[1058]

[1059]

[1060]

[1061]

[1062] In the formula, n is 2-6, more preferably 3, 4, or 5, and each and is independently selected from brentuximab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody and anti-CD30 antibody, or antigen-binding fragment or its immunologically active portion, and more preferably selected from trastuzumab and anti-CD13 antibody or its antigen-binding fragment or its immunologically active portion, particularly preferably from trastuzumab or antigen-binding fragment or its immunologically active portion; or

[1063]

[1064] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is an anti-CD13 antibody, or an antigen-binding fragment or its immunologically active part.

[1065] More preferably, the antibody-drug conjugate is selected from the group consisting of the following:

[1066]

[1067] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is an anti-CD13 antibody, or an antigen-binding fragment or its immunologically active part.

[1068]

[1069] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1070]

[1071] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1072]

[1073] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1074]

[1075] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1076]

[1077] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1078]

[1079] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1080]

[1081] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1082]

[1083] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1084]

[1085] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part, and

[1086]

[1087] In the formula, n is 2-6, more preferably 3, 4, or 5, and, is trastuzumab, or an antigen-binding fragment or its immunologically active part.

[1088] Particularly preferably, the antibody drug conjugate according to the present invention should be in an isolated or purified form.

[1089] Preferred compounds according to the formula D-(X)b-(AA)w-(T)g-L1 or the formula D-(X)b-(AA)w-(T)gH according to the present invention include the following:

[1090] dot According to the present invention, the compound of formula D-(X)b-(AA)w-(T)g-L1 or formula D-(X)b-(AA)w-(T)gH is defined as D, X, AA, T, L1, b, g, and w in the formula as defined in the present invention; additionally, if the compound is a compound of formula D-(X)b-(AA)w-(T)gH, b+w+g≠0.

[1091] dot As a compound of the formula D-(X)b-(AA)w-(T)g-L1 or the formula D-(X)b-(AA)w-(T)gH according to the present invention, among the formulas:

[1092] L1 is a linker of the following chemical formula:

[1093]

[1094] During the meal:

[1095] The dashed line indicates the covalent bonding site for (T)g, if present, or for (AA)w, or for (X)b, or for D;

[1096] R 19 is -C1-C 12 Alkylene-, -O-(-C1-C 12 alkylene-), -C6-C in one or more rings that can be optionally substituted by one or more substituents Rx 12 Aryllene, -C1-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx 12 Alkylene-C6-C 12 Aryllene-, -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx. 12 Aryllene-C1-C 12 Alkylene-, -C5-C12 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), said group is optionally substituted by one or more substituents Rx], -C1-C 12 Alkylene-(C5-C 12 Heterocyclo)- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within said ring(s), and said group is optionally substituted by one or more substituents Rx], -(C5-C 12 Heterocyclo)-C1-C 12 Alkylene- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s), and said group is optionally substituted by one or more substituents Rx], selected from -(OCH2CH2)r- and -CH2-(OCH2CH2)r-, wherein each of said alkylene substituents, either alone or bonded to other moiety within the carbon chain, can be optionally substituted by one or more substituents Rx;

[1097] r is an integer in the range 1-6; and

[1098] Each of D, Rx, X, AA, T, b, g, and w is as defined in the present invention; however, additionally, if the compound is a compound of the formula D-(X)b-(AA)w-(T)gH, b+w+g≠0.

[1099] dot As a compound of the formula D-(X)b-(AA)w-(T)g-L1 or the formula D-(X)b-(AA)w-(T)gH according to the present invention, among the formulas:

[1100] L1 is a linker of the following chemical formula:

[1101]

[1102] During the meal:

[1103] The dashed line indicates the covalent bonding site for (T)g, if present, or for (AA)w, or for (X)b, or for D;

[1104] R 19 -C1-C8alkylene-, -O-(-C1-C8alkylene-), -C1-C8alkylene-C6-C having an arylene group in one or more rings that can be optionally substituted by one or more substituents Rx 12 Aryllene-, -C6-C having an arylene group in one or more rings that can be arbitrarily substituted by one or more substituents Rx. 12 Selected from arylene-C1-C8 alkylene-, wherein each of the alkylene substituents, either alone or bonded to other moiety within the carbon chain, may be arbitrarily substituted by one or more substituents Rx;

[1105] (AA)w has the chemical formula (II):

[1106]

[1107] In the formula, dashed lines indicate covalent bond points for (X)b or D (left-facing dashed line) if present, and for (T)g or L1 or hydrogen atoms (right-facing dashed line) if present;

[1108] R in food 21 Where present, is selected from the group consisting of hydrogen, methyl, isopropyl, sec-butyl, benzyl, indolylmethyl, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2 and -(CH2)4NHC-(=NH)NH2, and w represents an integer from 0 to 6;

[1109] It is preferable that X is an extension selected from the group consisting of the following:

[1110] When D in the formula is conjugated through an amine group (e.g., when Z is -NH-): -COO-(C2-C4alkylene)NH-, -COO-CH2-phenylene)-NH, in which the phenylene group can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group, -COO-(C2-C4alkylene)NH-COO-CH2-(phenylene)-NH-, in which the phenylene group can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group, -COCH2NH-COCH2-NH-, -COO-(C2-C4alkylene)S-, and -COO-(C2-C4alkylene)NHCO(C1-C3alkylene)S-; or

[1111] When D in the formula is conjugated via a hydroxyl group (e.g., when Z is -O-): -CONH-(C2-C4alkylene)NH-, -COO-CH2-phenylene-NH- where the phenylene group can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group, -CONH-(C2-C4alkylene)NH-COO-CH2-(phenylene which can be optionally substituted by 1 to 4 substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group)-NH-, -COCH2NH-COCH2-NH-, -CONH-(C2-C4alkylene)S-, and -CONH-(C2-C4alkylene)NHCO(C1-C3alkylene)S-;

[1112] T is an extender selected from the group consisting of -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, where j is an integer from 1 to 10;

[1113] b is 0 or 1 and;

[1114] g is 0 or 1 and;

[1115] Here, if the compound is of the chemical formula D-(X)b-(AA)w-(T)gH, b+w+g≠0; and

[1116] D is a drug moiety of chemical formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb; and is covalently bonded through a hydroxyl or amine group; or

[1117] As a drug moiety of the chemical formula (IHa) or the chemical formula (IHb), or as a pharmaceutically acceptable salt, ester, solvate, tautomeric or stereoisomer thereof:

[1118]

[1119] The dashed lines in (IHa) and (IHb) in the formula indicate covalent bonding sites for (X)b, if present, (AA)w, if present, (T)g, or L1;

[1120] R1 is -OH or -CN;

[1121] R2 is a -C(=O)Ra group, where Ra is selected from hydrogen and substituted or unsubstituted C1-C6 alkyls, where optional substituents are one or more substituents Rx;

[1122] R3 is a hydrogen or -C(=O)Rb group, where Rb is selected from hydrogen and substituted or unsubstituted C1-C6 alkyls, where optional substituents are one or more substituents Rx;

[1123] Y is -NH- or -O-; and

[1124] Z is -NH- or -O-.

[1125] dot As a compound of the formula [D-(X)b-(AA)w-(T)g-(L)-]n-Ab or the formula D-(X)b-(AA)w-(T)gH according to the present invention, among the formulas:

[1126] L1 is a linker of the following chemical formula:

[1127]

[1128] During the meal:

[1129] The dashed line indicates the covalent bonding site for (T)g, if present, or for (AA)w, or for (X)b, or for D;

[1130] R 19 is selected from phenylene-C1-C6alkylene-, wherein the phenylene group can be optionally substituted by one or more substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group, wherein each of the alkylene substituents, either alone or bonded to another moiety in the carbon chain, can be optionally substituted by one or more substituents Rx selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, a halogen atom, a nitro group, and a cyano group, and preferably R 19 is a C1-C6 alkylene group;

[1131] w is 0 or 2, and when w is 2, (AA)w has the chemical formula (III):

[1132]

[1133] In the formula, dashed lines indicate covalent bond points for X (left-facing dashed line) if present and for (T)g if present, or for L1 or hydrogen atoms (right-facing dashed line);

[1134] R 22 is selected from methyl, benzyl, isopropyl, sec-butyl, and indolylmethyl;

[1135] R 23 It is selected from methyl, -(CH2)4NH2, -(CH2)3NHCONH2 and -(CH2)3NHC(=NH)NH2;

[1136] X is an extender selected from the group consisting of the following:

[1137] When D in the formula is conjugated through an amine group (e.g., when Z is -NH-): -COO-CH2-phenylene-NH-, -COO(CH2)3NHCOO-CH2-phenylene-NH, -COO-(CH2)3)NH-, -COO(CH2)3-S-, and -COO-(CH2)3NHCO-(CH2)2S- ; or

[1138] When D in the formula is conjugated through a hydroxyl group (e.g., when Z is -O-): -COO-CH2-phenylene-NH-, -CONH(CH2)3NHCOOCH2-phenylene-NH-, -CONH(CH2)3NH-, -CONH(CH2)3-S-, and -CONH(CH2)3NHCO(CH2)2S-,

[1139] In the formula, T is an extender selected from the group consisting of -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, where j is an integer from 1 to 5;

[1140] b is 0 or 1 and;

[1141] g is 0 or 1 and;

[1142] Here, if the compound is of the chemical formula D-(X)b-(AA)w-(T)gH, b+w+g≠0; and

[1143] D is a drug moiety of chemical formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb; and is covalently bonded through a hydroxyl or amine group; or

[1144] As a drug moiety of the chemical formula (IHa) or the chemical formula (IHb), or as a pharmaceutically acceptable salt, ester, solvate, tautomeric or stereoisomer thereof:

[1145]

[1146] The dashed lines in (IHa) and (IHb) in the formula indicate covalent bond points;

[1147] R1 is -CN or -OH;

[1148] R2 is acetyl;

[1149] R3 is hydrogen or methoxy, preferably hydrogen;

[1150] Y is -NH- or -O-; and

[1151] Z is -NH- or -O-.

[1152] dot As a compound of the formula D-(X)b-(AA)w-(T)g-L1 or the formula D-(X)b-(AA)w-(T)gH according to the present invention, among the formulas:

[1153] L1 is a linker of the following chemical formula:

[1154]

[1155] During the meal:

[1156] The dashed line indicates the covalent bonding site for (T)g, if present, or for (AA)w, or for (X)b, or for D;

[1157] R 19 is -C2-C6alkylene- and,

[1158] w is 0 or 2, and when w is 2, (AA)w has the chemical formula (III):

[1159]

[1160] R 22 is isopropyl, and R 23 is selected from methyl and -(CH2)3NHCONH2, where dashed lines indicate covalent bonding points for X (left-handed dashed line) and, if present, for (T)g, or for L1 or hydrogen atoms (right-handed dashed line);

[1161] X is an extender selected from the group consisting of -COO-CH2-phenylene-NH-, -COO(CH2)3NHCOO-CH2-phenylene-NH, -COO-(CH2)3)NH-, -COO(CH2)3-S-, and -COO-(CH2)3NHCO-(CH2)2S-:

[1162] In the formula, T is an extender selected from the group consisting of -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)]j-NH-, where j is an integer from 1 to 5;

[1163] b is 0 or 1 and;

[1164] g is 0 or 1 and;

[1165] Here, if the compound is of the chemical formula D-(X)b-(AA)w-(T)gH, b+w+g≠0; and

[1166] D is a drug moiety selected from the following, or a pharmaceutically acceptable salt, ester, solvate, tautomer, or stereoisomer thereof.

[1167]

[1168] The dashed lines in the equation represent covalent bond points.

[1169] dot As a compound of the formula D-(X)b-(AA)w-(T)g-L1 or the formula D-(X)b-(AA)w-(T)gH according to the present invention, among the formulas:

[1170] L1 is a linker of the following chemical formula:

[1171]

[1172] During the meal:

[1173] The dashed line indicates the covalent bonding site for (T)g, if present, or for (AA)w, or for (X)b, or for D;

[1174] R 19 is -C2-C5alkylene- and,

[1175] w is 0 or 2, and when w is 2, (AA)w has the chemical formula (III):

[1176]

[1177] R 22 is isopropyl, and R 23 is selected from methyl and -(CH2)3NHCONH2, where dashed lines indicate covalent bonding points for X (left-handed dashed line) and, if present, for (T)g, or for L1 or hydrogen atoms (right-handed dashed line);

[1178] X is a -COO-CH2-phenylene-NH- group, and

[1179] T is the -CO-(CH2)2-[O-(CH2)2]4-NH- group;

[1180] b is 0 or 1 and;

[1181] g is 0 or 1 and;

[1182] Here, if the compound is of the chemical formula D-(X)b-(AA)w-(T)gH, b+w+g≠0; and

[1183] D is a drug moiety selected from the following, or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof;

[1184]

[1185] The dashed lines in the equation represent covalent bond points.

[1186] dot Compounds of the chemical formula DX-(AA)w-(T)g-L1 selected from the following:

[1187]

[1188]

[1189]

[1190] dot Compounds of the chemical formula DX-(AA)w-(T)g-L1 selected from the following:

[1191]

[1192]

[1193]

[1194] In the drug conjugate of the present invention, the term "pharmaceutically acceptable salt, ester, solvate, tautomeric or stereoisomer" refers to any pharmaceutically acceptable form of salt, ester, solvate, hydrate, or stereoisomer, or any other compound capable of providing the aforementioned compound directly or indirectly upon administration to a patient. However, pharmaceutically unacceptable salts are also included within the scope of the present invention, as they may be used to produce pharmaceutically acceptable salts. The preparation of salts, prodrugs, and derivatives can be carried out by known technical methods.

[1195] For example, pharmaceutically acceptable salts of the compounds provided in the present invention are synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, these salts are prepared, for example, by reacting the free acid or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Examples of acid addition salts include inorganic acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, and organic acid addition salts, such as acetate, trifluoroacetate, malate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p -Toluenesulfonate can be cited. Examples of alkali addition salts include inorganic salts such as sodium, potassium, calcium, and ammonium salts, and, for example, ethylenediamine, ethanolamine, N,N Examples include organic alkali salts such as dialkylene ethanolamine, triethanolamine, and basic amino acid salts.

[1196] The drug conjugate of the present invention may be in a crystalline form, such as a free compound or a solvate (e.g., a hydrate), and both of these forms are included within the scope of the present invention. Solvation methods are generally known in the art.

[1197] All compounds that are prodrugs of the drug conjugates of the present invention are also included in the scope and spirit of the present invention. The term "prodrug" is used in the broadest sense and includes derivatives that are converted into the compounds of the present invention in vivo. These derivatives are terms familiar to those skilled in the art, and include, for example, compounds in which a free hydroxyl group is converted into an ester derivative. Many suitable prodrugs are well known to those skilled in the art and are described, for example, in the literature [Burger "Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers)], the contents of which are incorporated by reference into the present invention.

[1198] With respect to the compounds of the present invention, pharmaceutically acceptable esters are not particularly limited and can be selected by a person skilled in the art. In the case of such esters, these esters are in vivo ( in vivo It is desirable that it can be degraded by biological processes such as hydrolysis. The group constituting the ester (the group denoted as R when the ester is denoted as -COOR) is, for example, a C1-C4 alkoxy C1-C4 alkyl group such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, or t-butoxymethyl; a C1-C4 alkoxylated C1-C4 alkoxy C1-C4 alkyl group such as 2-methoxyethoxymethyl; or a C6-C group such as phenoxymethyl. 10Aryloxy C1-C4 alkyl groups; halogenated C1-C4 alkoxy C1-C4 alkyl groups such as, e.g., 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; C1-C4 alkoxycarbonyl C1-C4 alkyl groups such as, e.g., methoxycarbonylmethyl; cyano C1-C4 alkyl groups such as, e.g., cyanomethyl or 2-cyanoethyl; C1-C4 alkylthiomethyl groups such as, e.g., methylthiomethyl or ethylthiomethyl; C6-C groups such as, e.g., phenylthiomethyl or naphthylthiomethyl 10 Arylthiomethyl group; C1-C4 alkylsulfonyl C1-C4 lower alkyl groups that can be arbitrarily substituted by halogen atom(s), such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; C6-C groups, such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl. 10arylsulfonyl C1-C4 alkyl group; For example, formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, C1-C7 aliphatic acyloxy C1-C4 alkyl groups such as 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, or 1-pivaloyloxyhexyl; a C5-C6 cycloalkylcarbonyl oxy C1-C4 alkyl group, such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, or 1-cyclohexylcarbonyloxybutyl; C6-C, such as benzoyloxymethyl 10arylcarbonyloxy C1-C4 alkyl group; For example, methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, C1-C6 alkoxycarbonyloxymethyl, such as 1-(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl, or 1-(hexyloxycarbonyloxy)propyl. C1-C4 alkyl group; C5-C6 cycloalkyloxycarbonyl hydroxy C1-C4 alkyl group such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)propyl, or 1-(cyclohexyloxycarbonyloxy)butyl;[5-(C1-C4alkyl)-2-oxo-1,3-dioxolene-4-yl]methyl group, such as (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolene-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolene-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolene-4-yl)methyl, or (5-butyl-2-oxo-1,3-dioxolene-4-yl)methyl; [5-(phenyl which can be arbitrarily substituted by C1-C4 alkyl, C1-C4 alkoxy or halogen atom(s))-2-oxo-1,3-dioxolene-4-yl]methyl group e.g. (5-phenyl-2-oxo-1,3-dioxolene-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolene-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolene-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolene-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo-1,3-dioxolene-4-yl]methyl; or a phthalidyl group that can be optionally substituted by a C1-C4 alkyl or C1-C4 alkoxy group(s), such as phthalidyl, dimethylphthalidyl, or dimethoxyphthalidyl, preferably a pivaloyloxymethyl group, a phthalidyl group, or a (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl group, and more preferably a (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl group.

[1199] All compounds referred to in the present invention are intended to represent not only such specific compounds but also their variants or related forms. In particular, since the compounds of the present invention may have asymmetric centers, they may exist as different enantiomeric forms. All optical isomers and stereoisomers of the compounds referred to in the present invention and mixtures thereof are considered to be encompassed within the scope of the present invention. Accordingly, any compound given in the present invention is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. In particular, drug conjugates of the formula [D-(X)b-(AA)w-(T)g-(L)]n-Ab and compounds of the formulas DX-(AA)w-(T)g-L1 or DX-(AA)w-(T)gH may contain enantiomers depending on their asymmetry or diastereomers. Since stereoisomerism related to double bonds is also possible, in some cases, the corresponding molecule may exist as an (E)-isomer or a (Z)-isomer. If the molecule contains multiple double bonds, each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of other double bonds of the molecule. Monoisomers of isomers and mixtures thereof are also included within the scope of the present invention.

[1200] Furthermore, the compounds referred to in the present invention may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropes. In particular, a tautomer refers to one of two or more structural isomers of a compound existing in equilibrium, which is easily converted from one isomer form to the other isomer form. Examples of common tautomer pairs include amine-amine, amide-amide, keto-enol, lactam-lactim, etc. Additionally, any compound referred to in the present invention is intended to represent its hydrates, solvates, polymorphs, and mixtures, if such forms exist in the medium. Furthermore, all geometric isomers, tautomers, atropes, hydrates, solvates, polymorphs, and isotope-labeled forms of the compounds referred to in the present invention, as well as mixtures thereof, are also considered to be included within the scope of the present invention.

[1201] The protected forms of the compounds disclosed in this invention are considered to be within the scope of this invention. Suitable protecting groups are well known to those skilled in the art. A general review of protecting groups in organic chemistry can be found in the literature [Wuts, PGM and Greene TW in Protecting Groups in Organic Synthesis, 4 th Ed. Wiley-Interscience] and literature [Kocienski PJ in Protecting Groups, 3 rd It is listed in Ed. Georg Thieme Verlag. These references provide sections on protecting OH, amino, and SH groups. All these references are included by reference in their entirety.

[1202] Within the scope of the present invention, an OH protecting group is defined as an O-bond moiety resulting from the protection of OH through the formation of a suitably protected OH group. Examples of such protected OH groups include ethers, silyl ethers, esters, sulfons, sulfenates and sulfinates, carbonates, and carbamates. In the case of ethers, the protecting groups for OH include methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p -Methoxybenzyloxymethyl, [(3,4-dimethoxybenzyl)oxy]methyl, p - Nitrobenzyloxymethyl, o -Nitrobenzyloxymethyl, [( R )-1-(2-nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, [( p -phenylphenyl)oxy]methyl, t -Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2-Cyanothoxymethyl, Bis(2-Chloroethoxy)methyl, 2,2,2-Trichloroethoxymethyl, 2-(Trimethylsilyl)ethoxymethyl, Menthoxymethyl, O-Bis(2-acetoxy-ethoxy)methyl, tetrahydropyranil, fluorine tetrahydropyranil, 3-bromotetrahydropyranil, tetrahydrothiopyranil, 1-methoxycyclohexyl, 4-methoxytetrahydropyranil, 4-methoxy-tetrahydrothiopyranil, 4-methoxytetrahydrothiopyranil S,S-dioxide, 1-[(2-chloro-4-methyl)-phenyl]-4-methoxypiperidin-4-yl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1-(4-chlorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxane-2-yl, tetrahydrofuranil, tetrahydrothiopyranil, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-hydroxyethyl, 2-bromoethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl, 1,1-dianisil-2,2,2-trichloroethyl, 1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 1-(2-cyanoethoxy)ethyl, 2-trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, t -Butyl, Cyclohexyl, 1-Methyl-1'-Cyclopropylmethyl, Allyl, Prenyl, Cinnamyl, 2-Phenalyl, Propargyl, p -chlorophenyl, p -Methoxyphenyl, p -Nitrophenyl, 2,4-Dinitrophenyl, 2,3,5,6-Tetrafluoro-4-(Trifluoromethyl)phenyl, Benzyl, p -Methoxybenzyl, 3,4-Dimethoxybenzyl, 2,6-Dimethoxybenzyl, o - Nitrobenzyl, p - Nitrobenzyl, Pentadienylnitrobenzyl, Pentadienylnitropiferonyl, Halobenzyl, 2,6-Dichlorobenzyl, 2,4-Dichlorobenzyl, 2,6-Difluorobenzyl, p -Cyanobenzyl, fluorobenzyl, 4-fluoroalkoxybenzyl, trimethylsilylxyl, p-phenylbenzyl, 2-phenyl-2-propyl, p-acylaminobenzyl, p-azidobenzyl, 4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, p-(methylsulfinyl)benzyl, p-siletanylbenzyl, 4-acetoxybenzyl, 4-(2-trimethylsilyl)ethoxymethoxybenzyl, 2-naphthylmethyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, 2-quinolinylmethyl, 6-methoxy-2-(4-methylphenyl)-4-quinolinemethyl, 1-pyrenylmethyl, diphenylmethyl, 4-methoxydiphenylmethyl, 4-phenyldiphenylmethyl, p,p' -Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, Tris(4- t -butylphenyl)methyl, α -Naphthyldiphenylmethyl, p -Methoxyphenyldiphenylmethyl, di( p -methoxyphenyl)phenyl-methyl, tri( p -methoxyphenyl)methyl, 4-(4'-bromopenacyloxy)phenyldiphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 4,4'-dimethoxy-3''-[N-(imidazolylmethyl)]trityl, 4,4'-dimethoxy-3''-[N-(imidazolylethyl)carbamoyl]trityl, bis(4-methoxyphenyl)-1'-pyrenylmethyl, 4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4''-dimethoxytrityl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-phenylthioxantyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, 4,5-bis(ethoxycarbonyl)-[1,3]-dioxolane-2-yl, benzisothiazolyl S,S - It can be selected from dioxides. In the case of silyl ethers, the protecting group for OH is trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2-norbornyldimethylsilyl, t -butyldimethylsilyl, t -butyldiphenylsilyl, tribenzylsilyl, tri- p -Xylsilyl, Tri- p-xylsilyl, diphenylmethylsilyl, di- t -Butylmethylsilyl, bis( t -butyl)-1-pyrenylmethoxysilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, t -butylmethoxyphenylsilyl, t - Butoxydiphenylsilyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl and fluorosilyl. In the case of esters, the protecting group for OH may be selected from formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetamidate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p -Chlorophenoxyacetate, Phenylacetate, Diphenylacetate, 3-Phenylpropionate, Bisfluoroate, 4,4-(Propanoyl,4-PentenoateEthylenedithio)Pentanoate, 5[3-Bis(4-Methoxyphenyl)Hydro-Oxymethylphenoxy]Rebulinate, Pivaloate, 1-Adamanthoate, Crotonate, 4-Methoxycrotonate, Benzoate, p -phenylbenzoate, 2,4,6-trimethylbenzoate, 4-bromobenzoate, 2,5-difluorobenzoate, p- Nitrobenzoate, picolinate, nicotinate, 2-(azidomethyl)benzoate, 4-azido-butyrate, (2-azidomethyl)phenylacetate, 2-{[(tritylthio)oxy]methyl}benzoate, 2-{[(4-methoxytritylthio)oxy]methyl}benzoate, 2-{[methyl(tritylthio)amino]methyl}benzoate, 2-{{[(4-methoxytrityl)thio]methylamino}methyl}benzoate, 2-(allyloxy)phenylacetate, 2-(prenyloxymethyl)benzoate, 6-(levulinyloxymethyl)-3-methoxy-2-nitrobenzoate, 6-(levulinyloxymethyl)-3-methoxy-4-nitrobenzoate, 4-Benzyloxybutyrate, 4-Trialkylsilyloxy-butyrate, 4-Acetoxy-2,2-Dimethylbutyrate, 2,2-Dimethyl-4-Pentenoate, 2-Iodobenzoate, 4-Nitro-4-Methylpentanoate, o -(Dibromomethyl)benzoate, 2-formylbenzenesulfonate, 4-(methylthio-methoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2-(chloroacetoxymethyl)benzoate, 2-[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate, 2-[2-(4-methoxybenzyl-oxy)ethyl]benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenyl-acetate, isobutyrate, monosuccinoate, ( E )-2-methyl-2-butenoate, o -(Methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'- Forms an ester with the oxygen atom of the unprotected OH to which it is attached, which can be selected from tetramethylphosphorodiamidate and 2-chlorobenzoate. In the case of sulfonates, sulfenates, and sulfinates, it forms a sulfonate, sulfenate, or sulfinate with the oxygen atom of the unprotected OH to which a protecting group is attached, which can be selected from sulfate, allylsulfonate, methanesulfonate, benzylsulfonate, tosylate, 2-[(4-nitrophenyl)ethyl]sulfonate, 2-trifluoromethylbenzenesulfonate, 4-monomethoxytritylsulfenate, alkyl 2,4-dinitrophenylsulfenate, 2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinate, and dimethylphosphinothioil. In the case of carbonates, the protecting groups for OH are methyl carbonate, methoxymethyl carbonate, 9-fluorenylmethyl carbonate, ethyl carbonate, bromoethyl carbonate, 2-(methylthiomethoxy)ethyl carbonate, 2,2,2-trichloroethyl carbonate, 1,1-dimethyl-2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-[dimethyl(2-naphthylmethyl)silyl]ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, 2-(triphenylphosphonio)ethyl carbonate, cis-[4-[[(methoxytrityl)sulfphenyl]oxy]tetrahydrofuran-3-yl]oxy carbonate, isobutyl carbonate, t - Butyl carbonate, vinyl carbonate, allyl carbonate, cinnamyl carbonate, propargyl carbonate, p -Chlorophenyl carbonate, p - Nitrophenyl carbonate, 4-ethoxy-1-naphthyl carbonate, 6-bromo-7-hydroxycoumarin-4-ylmethyl carbonate, benzyl carbonate, o - Nitrobenzyl carbonate, p - Nitrobenzyl carbonate, p-Methoxybenzyl carbonate, 3,4-Dimethoxybenzyl carbonate, Anthraquinone-2-ylmethyl carbonate, 2-Danylethyl carbonate, 2-(4-Nitrophenyl)ethyl carbonate, 2-(2,4-Dinitrophenyl)ethyl carbonate, 2-(2-Nitrophenyl)propyl carbonate, 2-(3,4-Methylenedioxy-6-Nitrophenyl)propyl carbonate, 2-Cyano-1-phenylethyl carbonate, 2-(2-Pyridyl)amino-1-phenylethyl carbonate, 2-[ N -methyl- N -(2-pyridyl)]amino-1-phenylethyl carbonate, phenacyl carbonate, 3',5'-dimethoxybenzoin carbonate, methyl dithiocarbonate and S - It forms a carbonate with the oxygen atom of the unprotected OH to which it is attached, which can be selected from benzylthiocarbonate. And in the case of carbamates, the protecting group for the OH is dimethylthiocarbamate, N -Phenyl carbamate and N -methyl- N -( o -) It forms a carbamate with the oxygen atom of the unprotected OH to which it is attached, which can be selected from nitrophenyl) carbamate.

[1203] Within the scope of the present invention, an amino protecting group is generated from the protection of an amino group through the formation of a suitably protected amino group. N - Defined by a binding moiety. Examples of protected amino groups include carbamates, ureas, amides, heterocyclic systems, N -alkyl amine, N -Alkenylamine, N -alkynylamine, N - Includes aryl amines, imines, enamines, N-metal derivatives, NN derivatives, NP derivatives, N-Si derivatives, and NS derivatives. In the case of carbamates, the protecting group of the amino group, together with the amino group to which it is attached, includes methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate, 2,6-di-t -butyl-9-fluorenylmethyl carbamate, 2,7-bis(trimethylsilyl)fluorenylmethyl carbamate, 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 17-tetrabenzo[ a,c,g,i ]Fluorenylmethyl carbamate, 2-chloro-3-indenylmethyl carbamate, benz[ f ]Indene-3-ylmethyl carbamate, 1,1-dioxobenzo[ b ]-thiophene-2-ylmethyl carbamate, 2-methylsulfonyl-3-phenyl-1-prop-2-enyl carbamate, 2,7-di-t-butyl-[9,(10,10-dioxo-10,10,10,10-tetrahydrothioxantyl)]methyl carbamate, 2,2,2-trichloroethyl carbamate, 2-trimethylsilylethyl carbamate, (2-phenyl-2-trimethylsilyl)ethyl carbamate, 2-phenylethyl carbamate, 2-chloroethyl carbamate, 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate, 1,1-dimethyl-2,2,2-trichloroethyl carbamate, 2-(2'-pyridyl)ethyl carbamate, 2-(4'-pyridyl)ethyl carbamate, 2,2-bis(4'-nitrophenyl)ethyl carbamate, 2-[(2-nitrophenyl)dithio]-1-phenylethyl carbamate, 2-( N,N -Dicyclohexylcarboxamido)ethyl carbamate, t -Butyl carbamate, Fluorus BOC carbamate, 1-Adamantyl carbamate, 2-Adamantyl carbamate, 1-(1-Adamantyl)-1-methylethyl carbamate, 1-methyl-1-(4-biphenylyl)ethyl carbamate, 1-(3,5-di- t-butylphenyl)-1-methylethyl carbamate, triisopropylsilyloxycarbamate, vinyl carbamate, allyl carbamate, prenyl carbamate, 1-isopropylallyl carbamate, cinnamyl carbamate, 4-nitrocinnamyl carbamate, 3-(3'-pyridyl)prop-2-enyl carbamate, hexadienyl carbamate, propargyl carbamate, 1,4-but-2-enyl biscarbamate, 8-quinolyl carbamate, N -Hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate, 3,5-di- t -Butylbenzyl carbamate, p -Methoxybenzyl carbamate, p - Nitrobenzyl carbamate, p -Bromobenzyl carbamate, p -Chlorobenzyl carbamate, 2,4-Dichlorobenzyl carbamate, 4-Methylsulfinylbenzyl carbamate, 4-Trifluoromethylbenzyl carbamate, Fluorus benzyl carbamate, 2-Naphthylmethyl carbamate, 9-Anthrylmethyl carbamate, Diphenylmethyl carbamate, 4-Phenylacetoxybenzyl carbamate, 4-Azidobenzyl carbamate, 4-Azido-methoxybenzyl carbamate, m -Chloro- p -Acyloxybenzyl carbamate, p -(Dihydroxyboryl)-benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-( p-Toluenesulfonyl)ethyl carbamate, 2-(4-nitrophenylsulfonyl)ethyl carbamate, 2-(2,4-dinitrophenylsulfonyl)ethyl carbamate, 2-(4-trifluoromethylphenylsulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate, 2-phosphonioethyl carbamate, 2-[phenyl(methyl)sulfonio]ethyl carbamate, 1-methyl-1-(triphenylphosphonio)ethyl carbamate, 1,1-dimethyl-2-cyanoethyl carbamate, 2-dansylethyl carbamate, 2-(4-nitrophenyl)ethyl carbamate, 4-methylthiophenyl carbamate, 2,4-dimethylthiophenyl carbamate, m - Nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, α -Methylnitropiferonyl carbamate, o -Nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl( o -Nitrophenyl)methyl carbamate, 2-nitrophenylethyl carbamate, 6-nitroveratrile carbamate, 4-methoxyphenacyl carbamate, 3',5'-dimethoxybenzoin carbamate, 9-xanthenylmethyl carbamate, N -methyl- N -( o -Nitrophenyl) Carbamate, t -Amyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, cyclobutyl carbamate, cyclopentyl carbamate, cyclohexyl carbamate, isobutyl carbamate, isobornyl carbamate, cyclopropylmethyl carbamate, p - Decyloxybenzyl carbamate, diisopropylmethyl carbamate, 2,2-dimethoxy-carbonylvinyl carbamate, o -( N,N -dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-( N,N-dimethyl-carboxamido)propyl carbamate, butynyl carbamate, 1,1-dimethylpropynyl carbamate, 2-iodoethyl carbamate, 1-methyl-1-(4'-pyridyl)ethyl carbamate, 1-methyl-1-( p -phenylazophenyl)ethyl carbamate, p -( p -methoxyphenylazo)benzyl carbamate, p -(phenylazo)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, isonicotinyl carbamate, 4-(trimethyl-ammonium)benzyl carbamate, p -Cyanobenzyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, phenyl carbamate, 2,4,6-tri- t - Forms a carbamate that can be selected from butylphenyl carbamate, 1-methyl-1-phenylethyl carbamate, and S-benzyl thiocarbamate. In the case of urea, the protecting group of the amino group is phenothiazinyl-(10)-carbonyl, N - p -Toluenesulfonylaminocarbonyl, N '-phenylaminothiocarbonyl, 4-hydroxyphenylaminocarbonyl, 3-hydroxytryptaminocarbonyl and N It may be selected from '-phenylaminothiocarbonyl. In the case of amides, the protecting group of the amino group, together with the amino group to which it is attached, is formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, pent-4-enamide, picolinamide, 3-pyridylcarboxamide, N -Benzoylphenylalanylamide, Benzamide, p -Phenylbenzamide, o -Nitrophenylacetamide, 2,2-dimethyl-2-( o -Nitrophenyl)acetamide, o -Nitrophenoxyacetamide, 3-( o -nitrophenyl)propanamide, 2-methyl-2-( o- Nitrophenoxy)propanamide, 3-methyl-3-nitrobutanamide, o - Nitrocinnamide, o -Nitrobenzamide, 3-(4- t -butyl-2,6-dinitrophenyl)-2,2-dimethylpropanamide, o -(benzoyloxymethyl)benzamide, 2-(acetoxymethyl)benzamide, 2-[( t -butyldiphenylsiloxy)methyl]benzamide, 3-(3',6'-dioxo-2',4',5'-trimethylcyclohexa-1',4'-diene)-3,3-dimethylpropionamide, o -hydroxy-trans-cinnamid, 2-methyl-2-( o -phenylazophenoxy)propanamide, 4-chlorobutanamide, aceto-acetamide, 3-( p -hydroxyphenyl)propanamide, ( N' - dithiobenzyloxycarbonylamino)acetamide and N - Forms an amide that can be selected from acetylmethionine amides. In the case of heterocyclic systems, the protecting group of the amino group, together with the amino group to which it is attached, is 4,5-diphenyl-3-oxazolin-2-one, N -Phthalimide, N -Dichlorophthalimide, N -Tetrachlorophthalimide, N -4-Nitrophthalimide, N -Thiodiglycolloyl, N -Daithiasuccinimide, N -2,3-diphenylmaleimide, N -2,3-dimethylmaleimide, N -2,5-dimethylpyrrole, N -2,5-bis(triisopropylsiloxy)pyrrole, N -1,1,4,4-tetramethyldisyl azacyclopentane adduct, N -1,1,3,3-tetramethyl-1,3-disylasedoin, N -Diphenylsilyldiethylene, N -5-substituted-1,3-dimethyl-1,3,5-triazcyclohexane-2-one, NIt forms a heterocyclic system that can be selected from -5-substituted-1,3-benzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone and 1,3,5-dioxazine. N -alkyl, N - In the case of alkenyl, N-alkynyl, or N-aryl amines, the protecting group of the amino group N -methyl, N - t -butyl, N -Alil, N -Frenil, N -Cinnamil, N -phenylallyl, N -Propargil, N -Methoxymethyl, N -[2-(trimethylsilyl)ethoxy]methyl, N -3-acetoxypropyl, N -cyanomethyl, N -2- Azanorbornen, N -benzyl, N -4-methoxybenzyl, N -2,4-dimethoxybenzyl, N -2-hydroxybenzyl, N -ferrosenylmethyl, N -2,4-dinitrophenyl, o -Methoxyphenyl, p -Methoxyphenyl, N -9-phenylfluorenyl, N -Fluorenyl, N -2-Picolylamine N -Oxide, N -7-methoxycouma-4-ylmethyl, N -Diphenylmethyl, N -Bis(4-methoxyphenyl)methyl, N -5-Dibenzosuberyl, N -triphenylmethyl, N -(4-methylphenyl)diphenylmethyl and N -(4-methoxyphenyl)diphenylmethyl can be selected from. In the case of an imine, the protecting group of the amino group N -1,1-dimethylthiomethylene, N -Benzylidene, N -p-methoxybenzylidene, N -Diphenylmethylene,N -[2-pyridyl)methyl]methylene, N -( N ', N '-dimethylaminomethylene), N -( N ', N -Dibenzylaminomethylene), N -( N - t -butylaminomethylene), N , N -isopropylidene, N - p - Nitrobenzylidene, N -Salicylidene, N -5-chlorosalicylidene, N -(5-chloro-2-hydroxyphenyl)phenylmethylene, N -Cyclohexylidene and N - t - It can be selected from butylidene. In the case of enamin, the protecting group of the amino group N -(5,5-dimethyl-3-oxo-1-cyclohexenyl), N -2,7-dichloro-9-fluorenylmethylene, N -1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, N -(1,3-dimethyl-2,4,6-(1 H ,3 H ,5 H )-trioxopyrimidine-5-ylidene)-methyl, N -4,4,4-trifluoro-3-oxo-1-butenyl and N -It can be selected from -(1-isopropyl-4-nitro-2-oxo-3-pyrroline-3-yl). In the case of N-metal derivatives, the protecting group of the amino group is N-borane, N - Diphenylboric acid ester, N -Diethylboric acid ester, N -9-Bora bicyclononan, N - May be selected from difluoroboric acid esters and 3,5-bis(trifluoromethyl)phenylboronic acid; also N -Phenyl(pentacarbonylchrome)carbenyl, N-Phenyl(pentacarbonyl-tungsten)carbenyl, N -Methyl(pentacarbonylchrome)carbenyl, N -Methyl(pentacarbonyltungsten)carbenyl, N - Copper chelate, N - Includes zinc chelates and 18-crown-6 derivatives. In the case of NN derivatives, the protecting group of the amino group, together with the amino group to which it is attached, N- nitroamino, N -Nitrosamino, amine N - Oxide, azide, triagen derivatives and N -Trimethylsilylmethyl- N - Forms NN derivatives that can be selected from benzylhydrazine. In the case of NP derivatives, the protecting group of the amino group, together with the amino group to which it is attached, forms NP derivatives that can be selected from diphenylphosphinamide, dimethylthiophosphinamide, diphenylthiophosphinamide, dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, and iminotriphenylphosphorane. In the case of N-Si derivatives, the protecting group of NH2 t - It can be selected from butyldiphenylsilyl and triphenylsilyl. In the case of NS derivatives, the protected amino group N -sulfenyl or N - It may be selected from sulfonyl derivatives. N-sulfphenyl derivatives are benzenesulfenamide, 2-nitrobenzenesulfenamide, 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfenamide and N It can be selected from -3-nitro-2-pyridinesulfenamide. N-sulfonyl derivatives include methanesulfonamide, trifluoromethanesulfonamide, t -Butylsulfonamide, Benzylsulfonamide, 2-(Trimethylsilyl)ethanesulfonamide, p -Toluenesulfonamide, Benzenesulfonamide, o- Anisylsulfonamide, 2-Nitrobenzenesulfonamide, 4-Nitrobenzenesulfonamide, 2,4-Dinitrobenzenesulfonamide, 2-Naphthalenesulfonamide, 4-(4',8'-Dimethoxynaphthylmethyl)benzenesulfonamide, 2-(4-Methylphenyl)-6-Methoxy-4-Methylsulfonamide, 9-Anthracenesulfonamide, Pyridine-2-sulfonamide, Benzothiazole-2-sulfonamide, Phenacylsulfonamide, 2,3,6-Trimethyl-4-Methoxybenzenesulfonamide, 2,4,6-Trimethoxybenzenesulfonamide, 2,6-Dimethyl-4-Methoxy-Benzenesulfonamide, Pentamethylbenzenesulfonamide, 2,3,5,6-Tetramethyl-4-Methoxybenzenesulfonamide, 4-Methoxybenzenesulfonamide, 2,4,6-trimethylbenzenesulfonamide, 2,6-dimethoxy-4-methylbenzenesulfonamide, 3-methoxy-4- t - It can be selected from butylbenzenesulfonamide and 2,2,5,7,8-pentamethylchroman-6-sulfonamide.

[1204] Within the scope of the present invention, the protector of SH is formed due to the protection of the SH group through the formation of a suitable protected SH group. S - It is defined as a bonded portion. Examples of such protected SH groups include thioethers, disulfides, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates. In the case of thioethers, the protecting group of SH is S -alkyl, S -benzyl, S - p -Methoxybenzyl, S - o -Hydroxybenzyl, S - p -Hydroxybenzyl, S - o -Acetoxybenzyl, S - p -Acetoxybenzyl, S - p - Nitrobenzyl, S - o - Nitrobenzyl, S -2,4,6-trimethylbenzyl, S -2,4,6,-trimethoxybenzyl, S -4-Piccolil,S -2-Piccolil- N -Oxide, S -2-quinolinylmethyl, S -9-Anthrylmethyl, S -9-fluorenylmethyl, S -Zantenil, S -ferrosenylmethyl, S -Diphenylmethyl, S -Bis(4-methoxyphenyl)methyl, S -5-Dibenzosuberyl, S -Triphenylmethyl, 4-methoxytrityl, S -Diphenyl-4-pyridylmethyl, S -phenyl, S -2,4-dinitrophenyl, S -2-quinolyl, S - t -butyl, S -1-Adamantyl, S -Methoxymethyl, S -isobutoxymethyl, S -Benzyloxymethyl, S -1-ethoxyethyl, S -2-tetrahydropyranil, S -Benzylthiomethyl, S -phenylthiomethyl, S -Acetamidomethyl (Acm), S -Trimethylacetamidomethyl, S -Benzamidomethyl, S -allyloxycarbonylaminomethyl, S - N -[2,3,5,6-tetrafluoro-4-( N -piperidino)-phenyl- N -allyloxycarbonylaminomethyl, S -phthalimidomethyl, S -phenylacetamidomethyl, S -Acetylmethyl, S -Carboxymethyl, S -cyanomethyl, S -(2-nitro-1-phenyl)ethyl, S -2-(2,4-dinitrophenyl)ethyl, S -2-(4'-pyridyl)ethyl, S -2-cyanoethyl, S -2-(trimethylsilyl)ethyl,S -2,2-bis(carboethoxy)ethyl, S -(1- m -nitrophenyl-2-benzoyl)ethyl, S -2-phenylsulfonylethyl, S -1-(4-methylphenylsulfonyl)-2-methylprop-2-yl and S - p - It can be selected from hydroxyphenacyl. In the case of disulfide, the protected SH group S -ethyl disulfide, S - t -Butyl disulfide, S -2-nitrophenyl disulfide, S -2,4-dinitrophenyl disulfide, S -2-phenylazophenyl disulfide, S -2-carboxyphenyl disulfide and S It can be selected from -3-nitro-2-pyridyl disulfide. In the case of silyl thioethers, the SH protecting group can be selected from the list of groups listed above for the protection of OH by the silyl ether. In the case of thioesters, the SH protecting group S -Acetyl, S -Benzoyl, S -2-Methoxyisobutyryl, S -Trifluoroacetyl, S - N -[[ p -biphenylyl)-isopropyloxy]carbonyl]- N -methyl-γ-aminothiobutyrate and S - N -( t -Butoxycarbonyl)- N It can be selected from methyl-γ-aminothiobutyrate. In the case of thiocarbonate, the SH protecting group S -2,2,2-trichloroethoxycarbonyl, S - t - Butoxycarbonyl, S -Benzyl oxycarbonyl, S - p -Methoxybenzyl oxycarbonyl and SIt can be selected from fluorenylmethylcarbonyl. In the case of thiocarbamate, the protected SH group S -( N -ethyl carbamate) and S -( N It can be selected from methoxymethylcarbamate.

[1205] Although references to such groups are given as simple examples of protecting groups such as OH, amino, and SH groups, additional groups having the above functions may be known to those skilled in the art, and therefore should not be interpreted as limiting the scope of the invention and should also be understood as being included in the invention.

[1206] To provide a more concise explanation, some of the quantitative expressions given in this specification are not defined by the term “about.” Whether or not the term “about” is explicitly used, all quantities given in this specification are understood to refer to actual given values, and also to approximations of such given values ​​that would be reasonably inferred by those skilled in the art, including equivalents and approximations resulting from experimental and / or measurement conditions for such given values.

[1207] "Antibody-drug conjugates (ADCs)" represent a targeted strategy for delivering cytotoxic molecules to cancer cells (e.g., international patent applications WO-A-2004 / 010957, WO-A-2006 / 060533, and WO-A-2007 / 024536). These compounds are generally referred to as drug, toxin, and radionuclide "conjugates." Tumor cell death occurs when a drug conjugate binds to a tumor cell and releases and / or activates the cytotoxic activity of the drug moiety. The selectivity provided by drug conjugates improves patient drug tolerance by minimizing toxicity to normal cells. Three examples of this type of drug antibody conjugate that have received market approval are gemtuzumab ozogamicin for acute myeloid leukemia, brentuximab vedotin for relapsed and refractory Hodgkin lymphoma and anaplastic large cell lymphoma, and ado-trastuzumab emtansine for breast cancer, particularly HER2+.

[1208] In cancer treatment, the efficacy of drugs generally depends on differences in growth rates, biochemical pathways, and physiological characteristics between cancerous and normal tissues. Consequently, most standard chemotherapy regimens are relatively non-specific and exhibit dose-limited toxicity, producing suboptimal therapeutic effects. One approach to selectively targeting malignant cells rather than healthy tissue is the use of specific monoclonal antibodies (mAbs) that recognize tumor-associated antigens expressed on the surface of tumor cells [Meyer, DL & Senter, PD (2003) Recent advances in antibody drug conjugates for cancer therapy. Annu. Rep. Med. Chem., 38, 229-237; Chari, RV (2008) Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc. Chem. Res. 41, 98-107]. mAbs and their derivatives are currently experiencing rapid growth within the field of therapeutic molecules. Over the past 25 years, more than 30 types of G-type immunoglobulin (IgG) and related agents have been approved for cancer and inflammatory diseases.

[1209] An alternative strategy is to chemically ionize small anti-neoplastic molecules onto monoclonal antibodies (mAbs) used as carriers (increasing half-life) and targeting agents (selectivity). Due to their high selectivity for tumor-associated antigens, excellent pharmacodynamics, and relatively low intrinsic toxicity, there have been extensive attempts to utilize mAbs for delivering targeted drugs. mAb-drug conjugates (ADCs) are formed by covalently linking anticancer drugs to mAbs, usually through a conditionally stabilized linker system. Upon binding to a cell surface antigen, the mAbs used in most ADCs are actively transported to lysosomes or other intracellular compartments where enzymes, low pH, or reducing agents facilitate drug release. However, the number of ADCs currently under development is limited.

[1210] Antigens must have high selectivity for tumor cells to limit toxicity and off-target effects. Too many tumor-related antigens have been investigated in preclinical models and clinical trials, including those overexpressed in B cells (e.g., CD20, CD22, CD40, CD79), T cells (CD25, CD30), carcinoma cells (HER2, EGFR, EpCAM, EphB2, PSMA), endothelium (endoglin), or stromal cells (fibroblast-activating protein) [Teicher BA. Antibody-drug conjugate targets. Curr Cancer Drug Targets 9(8):982-1004, 2009]. A major and important feature of ADC targets is their ability to be internalized; this ability may be an inherent characteristic of the antigen itself or may be induced by the binding of an antibody to the antigen. In fact, ADC internalization is crucial for reducing toxicity associated with the extracellular delivery of drug payloads.

[1211] In contrast to conjugated small molecules and numerous putative antigen targets, the cytotoxic drugs used as payloads in ADCs are currently in active clinical trials in a limited number of families, examples of which include: caliceamycin (Pfizer), duocarmycin (Synthon), pyrrolobenzodiazepine (Spirogen), irinotecan (Immunomedics), metansinoids (DM1 and DM4; ImmunoGen + Genentech / Roche, Sanofi-Aventis, Biogen Idec, Centocor / Johnson & Johnson, Millennium / Takeda), and auristatin (MMAE and MMAF; Seattle Genetics + Genentech / Roche, MedImmune / AstraZeneca, Bayer-Schering, Celldex, Progenics, Genmab). Caliceamycin, duocarmycin, and pyrrolobenzodiazepine are DNA minor groove binders, and irinotecan is a topoisomerase I inhibitor, whereas metansinoids and auristatin are tubulin depolarizers.

[1212] Interestingly, three representative cytotoxicity-induced ADCs have reached the late clinical trial stage: Trastuzumab emtansine (T-DM1), which is trastuzumab linked to a semi-synthetic metansinoid drug by a stable linker (FDA approved on February 22, 2013, for advanced HER2-positive breast cancer); and Inotuzumab ozogamicin (CMC-544), a humanized anti-CD22 mAb (G5 / 44, IgG4) conjugated to caliceamicin by an acid-unstable linker (acetylphenoxy-butanoic acid) (B-cell non-Hodgkin lymphoma). Brentuximab vedotin, a humanized anti-CD30 mAb linked to monomethylauristatin E (MMAE) via a maleimidecaproyl-valyl-citrullinyl-p-aminobenzylcarbamate linker (FDA approved on August 19, 2011, for anaplastic large cell lymphoma and Hodgkin lymphoma).

[1213] Linkers are a key component of the ADC structure. Several classes of second-generation linkers have been investigated, including acid-unstable hydrazone linkers (lysosomes) (e.g., gemtuzumab and inotuzumab ozogamicin); These include disulfide-based linkers (reductive intracellular environment) (reductive intracellular; non-degradable thioether linkers (catabolic degradation in lysosomes) (e.g., trastuzumab emtansine); and peptide linkers (e.g., citrulline-valine) (lysosomal proteases such as cathepsin-B) (e.g., brentuximab vedotin): see, for example, WO-A-2004 / 010957, WO-A-2006 / 060533, and WO-A-2007 / 024536. Purification of antibody-drug conjugates by size exclusion chromatography (SEC) has also been described [e.g., Liu et al., Proc. Natl. Acad. Set (USA), 93: 8618-8623 (1996), and Chari et al., Cancer Research, 52: 127-131 (1992)].

[1214] Trastuzumab (Herceptin) is a monoclonal antibody that interferes with the HER2 / neu receptor. Its primary use is to treat certain types of breast cancer. The HER receptor is a protein embedded in the cell membrane that transmits molecular signals from outside the cell into the cell and plays a role in activating or deactivating genes. HER proteins promote cell proliferation. In some cases, HER2 is overexpressed, particularly in certain types of breast cancer, causing cancer cells to proliferate uncontrollably.

[1215] The HER2 gene is amplified in 20–30% of early-stage breast cancers, leading to the overexpression of epidermal growth factor (EGF) receptors on the cell membrane. In some types of cancer, HER2 can signal without the growth factor reaching and binding to the receptor, thereby structurally rendering its effect on the cell; however, trastuzumab is ineffective in this case.

[1216] The HER2 pathway promotes cell growth and division when functioning normally; however, if it is overexpressed, cell growth accelerates beyond normal limits. In some types of cancer, this pathway is utilized to promote rapid cell growth and proliferation, and consequently, tumor formation. In cancer cells, the HER2 protein can be expressed 100 times more than in normal cells (2 million vs. 20,000 per cell). Such overexpression leads to strong and constant proliferation signaling, ultimately resulting in tumor formation. Overexpression of HER2 can also induce checkpoint inactivation, which can further intensify proliferation.

[1217] In the compounds of the present invention, Ab is a moiety comprising at least one antigen-binding site. In separate embodiments, Ab may be any suitable substance capable of binding to target cells, preferably animal cells and more preferably human cells. Examples of such substances include lymphokines, hormones, growth factors, and nutrient-transferring molecules (e.g., transferrin). In other examples, Ab may be an aptamer and may include nucleic acid or peptide aptamers.

[1218] Where Ab is a moiety having at least one antigen-binding site, the moiety is preferably an antigen-binding peptide or polypeptide. In a preferred embodiment, this moiety is an antibody or its antigen-binding fragment.

[1219] In the drug conjugate of the present invention, the term “antibody” refers to any immunoglobulin, preferably a full-length immunoglobulin. Preferably, the term encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies, such as bispecific antibodies and their antibody fragments, insofar as they exhibit the intended biological activity. The antibody may be of any species, but is preferably of rodent origin, such as rat or mouse, or of human or rabbit origin. Alternatively, the antibody, preferably a monoclonal antibody, may be its humanized antibody, chimeric antibody, or its antibody fragment. “Chimerative antibody” may also include “primatised” antibodies comprising a variable domain antigen-binding sequence derived from non-human primates (e.g., Old World monkey, ape) and a human constant domain sequence. Immunoglobulins may also be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2), or any subclass of immunoglobulin molecules.

[1220] The term 'monoclonal antibody' refers to a substantially homogeneous population of antibody molecules produced by a single clone of a B lineage cell, often a hybridoma (i.e., the antibodies of the individuals containing the population are identical except for a small amount of possible naturally occurring mutations). Importantly, each monoclonal has the same antigenic specificity—that is, it is directed to a single determinant on the antigen.

[1221] The production of monoclonal antibodies can be carried out by known methods. However, as an example, monoclonal antibodies can be produced by the hybridoma method (Kohler et al. (1975) Nature 256:495), human B cell hybridoma technology (Kozbor et al., 1983, Immunology Today 4: 72), or EBV-hybridoma technology (Cole et al., 1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Alternatively, monoclonal antibodies can be produced by the recombinant DNA method (see US 4816567) or [Clackson et al. (1991) Nature, 352:624-628; Marks et al. (1991) J. MoI. It can be isolated from a phage antibody library using the technique described in Biol., 222:581-597.

[1222] Polyclonal antibodies are antibodies directed toward different determinants (epitopes). This heterogeneous antibody population can be derived from the serum of immunized animals using various processes known in the art.

[1223] The term 'bispecific antibody' refers to an artificial antibody composed of two different monoclonal antibodies. By being able to bind to either of two adjacent epitopes on a single antigen, they increase both antibody avidity and specificity, or bind to two different antigens for numerous applications, particularly the recruitment of cytotoxic T-cells and natural killer (NK) cells or the retargeting of cytotoxic drugs, radionuclides, or toxins for cancer treatment (Holliger & Hudson, Nature Biotechnology, 2005, 9, 23). Bispecific antibodies may have a hybrid immunoglobulin heavy chain with primary binding specificity on one arm and a hybrid immunoglobulin heavy-to-light chain pair (providing secondary binding specificity) on the other arm. This asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of the immunoglobulin light chain on only half of the bispecific molecule provides an easy separation method (WO 94 / 04690; Suresh et al., Methods in Enzymology, 1986, 121:210; Rodrigues et al., 1993, J. of Immunology 151:6954-6961; Carter et al., 1992, Bio / Technology 10:163-167; Carter et al., 1995, J. of Hematotherapy 4:463-470; Merchant et al., 1998, Nature Biotechnology 16:677-681).

[1224] Methods for producing hybrid or bispecific antibodies are known. In one method, a bispecific antibody is produced by fusing two hybridomas into a single "quadroma" by genetic fusion or chemical crosslinking of two different Fab or scFv modules (Holliger & Hudson, Nature Biotechnology, 2005, 23(9), 1126-1136).

[1225] The term 'chimeric' antibody refers to an antibody in which different parts within the antibody originate from different animals. For example, a chimeric antibody can be derived from the variable region of a mouse and the constant region of a human. In contrast, a 'humanized antibody' refers to one that is primarily derived from humans, even if it contains a non-human part. Specifically, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the hypervariable region of the receptor are replaced by residues from the hypervariable region of a non-human species (donor antibody), such as mice, rats, rabbits, or non-human primates, which possess the desired specificity, affinity, and efficacy. In some instances, residues from the framework region (FR) of the human immunoglobulin are replaced by corresponding non-human residues. Additionally, humanized antibodies may contain residues not found in the recipient or donor antibody. These modifications are designed to further refine antibody performance. Generally, the humanized antibody actually comprises at least one, or generally two, variable domains in which all or actually all of the hypervariable loops correspond to those of non-human immunoglobulin and all or actually all of the FR corresponds to that of the human immunoglobulin sequence. The humanized antibody also optionally comprises at least a portion of the immunoglobulin constant portion (Fc), generally at least a portion of the human immunoglobulin.

[1226] Recombinant antibodies, such as chimeric and humanized monoclonal antibodies, can be produced by known recombinant DNA technology. Completely human antibodies can be produced using transgenic mice that cannot express endogenous immunoglobulin heavy and light chain genes but can express human heavy and light chain genes. Transgenic mice are immunized with selected antigens in the usual manner. Antigen-directed monoclonal antibodies can be obtained using conventional hybridoma technology. Human immunoglobulin transgenes produced by transgenic mice rearrange during B cell differentiation, followed by class switching and somatic mutation. Thus, therapeutically useful IgG, IgA, IgM, and IgE antibodies can be produced using these technologies. An overview of the technology for producing human antibodies can be found, for example, in the literature [Lonberg and Huszar (1995, Int. Rev. Immunol. 13:65-93)]. For technologies for manufacturing human antibodies and human monoclonal antibodies and protocols for manufacturing such antibodies, reference may be made to, for example, U.S. Patents Nos. 5625126; 5633425; 5569825; 5661016; and 5545806, the entire contents of which are incorporated by reference into the present invention. Other human antibodies are also available for purchase, for example, from Abgenix, Inc. (Freemont, CA) and Genpharm (San Jose, CA).

[1227] In the drug conjugate of the present invention, the term 'antigen-binding fragment' refers to a portion of a full-length antibody, wherein such antigen-binding fragment of the antibody retains the antigen-binding function of the corresponding full-length antibody. The antigen-binding fragment may comprise a portion of a variable portion of an antibody, said portion may comprise at least one, two, or preferably three CDRs selected from CDR1, CDR2, and CDR3. The antigen-binding fragment may also comprise a portion of an immunoglobulin light chain and a heavy chain. Examples of antibody fragments include Fab, Fab', F(ab')2, scFv, di-scFv, sdAb, and BiTE (particularly T cell engagers), nanobodies, diabodies, diabody-Fc fusions, tribodies, and tetrabodies; minibodies; and linear antibodies. Examples include fragments produced by a Fab expression library, anti-idiotype (anti-ID) antibodies, CDRs (complementary determining region), and epitope-binding fragments of the aforementioned that bind immunospecifically to target antigens such as cancer cell antigens, viral antigens, or microbial antigens, such as single-chain or single-domain antibody molecules containing only heavy chains, such as camelid VHH domains and shark V-NARs; and multispecific antibodies formed from antibody fragments. For comparison, a full-length antibody referred to as an ‘antibody’ includes not only VL and VH domains but also complete light chain and heavy chain constant domains.

[1228] Antibodies may also possess one or more effector functions that confer biological activity attributable to the antibody's Fc region (either the original sequence Fc region or an amino acid variant Fc region engineered according to methods in the art to modify receptor binding). Examples of antibody effector functions include CIq binding: complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and downregulation of cell surface receptors (e.g., B cell receptors; BCR).

[1229] The antibody may also be a functionally active fragment (also referred to herein as the immunologically active portion), derivative, or analog of an antibody that binds immunely to a target antigen, such as, for example, a cancer cell antigen, a viral antigen, or a microbial antigen, or other antibody that binds to tumor cells. In this regard, being functionally active means that the fragment, derivative, or analog can elicit an anti-idiotype antibody that recognizes the same antigen as the antigen recognized by the antibody from which the fragment, derivative, or analog is derived. In particular, in an exemplary embodiment, the antigenicity of the idiotype of the immunoglobulin molecule may be enhanced by deleting the CDR sequence and framework, which is the C-terminus of the CDR sequence that specifically recognizes the antigen. To determine which CDR sequence binds to the antigen, a synthetic peptide containing the CDR sequence can be used with the antigen in a binding assay by a known binding assay (e.g., BIA core assay) [see, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. of Immunology 125(3):961-969)].

[1230] The term ‘antibody’ may also include a fusion protein of an antibody or its functionally active fragment that is fused through a covalent bond (e.g., a peptide bond) with the amino acid sequence of another protein (or part thereof, e.g., at least 10, 20, or 50 amino acid portions of that protein) that is not the antibody, for example, at the N-terminus or C-terminus. The antibody or its fragment may also be covalently bound to another protein at the N-terminus of an invariant domain.

[1231] Additionally, the antibodies or antigen-binding fragments of the present invention may also include analogs or derivatives of the antibodies or their antigen-binding fragments modified by covalent bonding of any type of molecule (provided that such covalent bonding allows the antibody to have its antigen-binding immunospecificity). Examples of such modifications include glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic hydrolysis, binding to cellular antibody units or other proteins, etc. As non-limiting examples, numerous chemical modifications may be performed by known techniques such as specific chemical degradation, acetylation, formylation, and metabolic synthesis in the presence of tunicamycin. In addition, the analogs or derivatives may contain one or more non-natural amino acids.

[1232] The antibody or antigen-binding fragment of the present invention may have modifications (e.g., substitution, deletion, or addition) to the Fc domain of the antibody. In particular, such modifications may be present at the Fc-hinge site to increase binding to the FcRn receptor (WO 97 / 34631).

[1233] In one embodiment, the antibody in the drug conjugate of the present invention may be an antibody or its antigen-binding fragment useful for treating a disease, preferably cancer, preferably a monoclonal antibody. The cancer may be breast cancer, colorectal cancer, endometrial cancer, renal cancer, melanoma, leukemia, lung cancer, multiple myeloma, lymphoma (e.g., Hodgkin's disease and non-Hodgkin's lymphoma), solid tumors such as sarcoma and carcinoma, melanoma, mesothelioma, osteosarcoma, ovarian cancer, and renal cancer. In a preferred embodiment, the cancer may be lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, renal cancer, leukemia, multiple myeloma, lymphoma, gastric cancer, and ovarian cancer. In a more preferred embodiment, the cancer may be colorectal cancer, breast cancer, leukemia, lymphoma, and ovarian cancer.

[1234] Examples of antibodies that may be useful for cancer treatment include, but are not limited to, antibodies against the following antigens: CA125 (ovary), CA15-3 (carcinoma), CA19-9 (carcinoma), L6 (carcinoma), Lewis Y (carcinoma), Lewis X (carcinoma), alpha-fetoprotein (carcinoma), CA 242 (colon), placental alkaline phosphatase (carcinoma), prostate-specific antigen (prostate), prostatic acid phosphatase (prostate), epidermal growth factor (carcinoma), e.g., EGF receptor 2 protein (breast cancer), MAGE-I (carcinoma), MAGE-2 (carcinoma), MAGE-3 (carcinoma), MAGE-4 (carcinoma), anti-transferrin receptor (carcinoma), p97 (melanoma), MUCl-KLH (breast cancer), CEA (colon), gplOO (melanoma), MARTl (melanoma), PSA (prostate), IL-2 receptor (T-cell leukemia Examples include CD20 (non-Hodgkin lymphoma), CD52 (leukemia), CD33 (leukemia), CD22 (lymphoma), human chorionic gonadotropin (carcinoma), CD38 (multiple myeloma), CD40 (lymphoma), mucin (carcinoma), P21 (carcinoma), MPG (melanoma), and Neu oncogene product (carcinoma). Examples of some specific and useful antibodies include, but are not limited to, BR96 mAb (Trail, PA, et al Science (1993) 261, 212-215), BR64 (Trail, PA, et al Cancer Research (1997) 57, 100-105), mAb against CD40 antigen, such as S2C6 mAb (Francisco, JA, et al Cancer Res. (2000) 60:3225-3231), mAb against CD70 antigen, such as 1F6 mAb, and mAb against CD30 antigen, such as AClO (Bowen, MA, et al (1993) J. Immunol., 151:5896-5906; Wahl et al., 2002 Cancer Res. 62(13):3736-42).Many other internalizing antibodies that bind to tumor-associated antigens are available and have also been reviewed (Franke, AE, et al Cancer Biother Radiopharm. (2000) 15:459-76; Murray, JL, (2000) Semin Oncol, 27:64-70; Breitling, F., and Dubel, S., Recombinant Antibodies, John Wiley, and Sons, New York, 1998).

[1235] The present invention includes cancer treatment related to these antibodies.

[1236] Non-limiting examples of other tumor-associated antigens include BMPR1B, E16, STEAP1, STEAP2, 0772P, MPF, Napi3b, Sema5b, PSCA hlg, ETBR, MSG783, TrpM4, CRIPTO, CD21, CD79b, FcRH2, HER2, NCA, MDP, IL20Rα, Brevican, EphB2R, ASLG659, PSCA, GEDA, BAFF-R, CD79A, CXCR5, HLA-DOB, P2X5, CD72, LY64, FCRH1, IRTA2, and TENB2.

[1237] In another embodiment, the antibody of the drug conjugate of the present invention may be an antibody or its antigen-binding fragment that specifically binds to a viral antigen, a microbial antigen, or an antigen of a cell producing an autoimmune antibody associated with an autoimmune disease, preferably a monoclonal antibody.

[1238] Viral antigens include any viral peptide, polypeptide, or protein capable of eliciting an immune response, such as HIV gpl20, HIV nef, RSV F glycoprotein, influenza virus neuraminidase, influenza virus hemagglitinin, HTLV tax, herpes simplex virus glycoproteins (e.g., Gb, Gc, Gd, and Ge) and hepatitis B surface antigen.

[1239] Examples of microbial antigens include, but are not limited to, any microbial peptide, polypeptide, protein, saccharide, polysaccharide, or lipid molecule capable of eliciting an immune response (e.g., bacterial, fungal, pathogenic protozoal, or yeast polypeptides, e.g., LPS and encapsulated polysaccharides).

[1240] In another embodiment, the antibody or antigen-binding fragment binds to an epitope present in a cell such as a tumor cell. Preferably, when the cell is a tumor cell, the tumor cell epitope is not present in non-tumor cells or is present at a lower concentration or in a different stereocomposition than in tumor cells.

[1241] In one embodiment, the antibody or antigen-binding fragment binds to an epitope present in relation to one of the following antigens: CA125, CA15-3, CA19-9 L6, Lewis Y, Lewis X, alpha-fetoprotein, CA 242, placental alkaline phosphatase, prostate-specific antigen, prostate acid phosphatase, epidermal growth factor, e.g., EGF receptor 2 protein, MAGE-I, MAGE-2, MAGE-3, MAGE-4, anti-transferrin receptor, p97, MUCl-KLH, CEA, gplOO, MARTl, PSA, IL-2 receptor, CD20, CD52, CD33, CD22, human chorionic gonadotropin, CD38, CD40, mucin, P21, MPG, Neu oncogene product, BMPR1B, E16, STEAP1, STEAP2, 0772P. MPF, Napi3b, Sema5b, PSCA hlg, ETBR, MSG783, TrpM4, CRIPTO, CD21, CD79b, FcRH2, HER2, NCA, MDP, IL20Rα, Brevican, EphB2R, ASLG659, PSCA, GEDA, BAFF-R, CD79A, CXCR5, HLA-DOB, P2X5, CD72, LY64, FCRH1, IRTA2, TENB2, viral antigens (e.g., viral peptides, polypeptides, or HIV gpl20, HIV nef, RSV F glycoprotein, influenza virus neuraminidase, influenza virus hemagglitinin, HTLV tax, herpes simplex virus glycoproteins (e.g., Gb, Gc, Gd, and Ge) and hepatitis B surface antigen), microorganisms capable of eliciting an immune response Antigens (all microbial peptides, polypeptides, proteins, saccharides, polysaccharides, or lipid molecules (e.g., bacteria, fungi, pathogenic protozoa, or yeast polypeptides, e.g., LPS and encapsulated polysaccharides)) or antigens of cells that produce autoimmune antibodies associated with autoimmune diseases.

[1242] In one embodiment, when the antigen is ErBB2 (also known as ERBB2, CD340, or HER2; these terms may be used interchangeably), the antibody or antigen-binding fragment may bind to one or more of the following epitopes: ARHC L (SEQ No. 1), QNGS (SEQ No. 2), and PPFCVARC PSG (SEQ No. 3). These epitopes correspond to positions 557-561, 570-573, and 593-603 of the human HER2 polypeptide sequence, respectively (Accession: NM_004448, Version: NM_004448.3).

[1243] In other embodiments, the antibody may be any antibody known for the treatment or prevention of a viral or microbial infection, i.e., an infectious disease. Examples of such antibodies include, but are not limited to, PRO542 (Progenies), a CD4 fusion antibody useful for the treatment of HIV infection; OsTAVIR (Protein Design Labs, Inc., CA), a human antibody useful for the treatment of hepatitis B virus; PROTOVIR (Protein Design Labs, Inc., CA), a humanized IgG1 antibody useful for the treatment of cytomegalovirus (CMV); and anti-LPS antibodies.

[1244] Other antibodies useful for the treatment of infectious diseases include, but are not limited to, the following: pathogenic bacteria (Streptococcus pyrogenes, Streptococcus pneumoniae, Neisseria gonorea, Neisseria meningitidis, Corynebacterium diphtheria, Clostridium botulinum, Clostridium furfringens, Clostridium tetani, Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella ozenas, Klebsiella rhinocereromitis, Staphylococcus aureus, Vibrio cholerae, Escherichia coli, Pseudomonas eruginosa, Campylobacter (Vibrio) fetus, Aeromonas hydrophila, Bacillus cereus, Edwardsiella tarda, Yersinia enterocolitica, Yersinia pestis, Yersinia Pseudotuberculousis, Shigella discenteria, Shigella flexneri, Shigella sonnei, Salmonella typhimurium, Treponema pallidum, Treponema pertenu, Treponema caratenum, Borrelia vincentii, Borrelia burgdorferi, Leptospira ecterohernorazi, Mycobacterium tuberculousis, Pneumocytis carnii, Franciscola tularensis, Brucella arbortus, Brucella suis, Brucella melitensis, Mycoplasma spp., Rickettsia prowazekii, Rickettsia tsutsugamushi, Chlamydia spp.Antibodies against antigens from ); antibodies against antigens from pathogenic fungi (Coccidioides imitis, Aspergillus fumigatus, Candida albicans, Blastomyces damertitidis, Cryptococcus neoformans, Histoplasma capsulatum); antibodies against antigens from protozoa (Entomoeba histolytica, Toxoplasma gondii, Trichomonas tenas, Trichomonas hominis, Trichomonas vaginalis, Trioanosoma gambiens, Trypanosoma rhodesiens, Trypanosoma cruchii, Leyssimania donovani, Leyssimania tropica, Leyssimania brasiliensis, Pneumocytis pneumoniae, Plasmodium bibox, Plasmodium falciferum, Plasmodium malaria); or antibodies against antigens from parasites (Enterobius vermicularis, Trichuris trichiura, Ascaris lumbricoides, Trichinella spiralis, Strongiloides stercoralis, Systozoma jamonicum, Systozoma mansoni, Systozoma hematobium, and hookworms).

[1245] Examples of other antibodies useful for the treatment of viral diseases include, but are not limited to, antibodies against antigens of the following non-limiting pathogenic viruses: poxviridae, herpesviridae, herpes simplex virus 1, herpes simplex virus 2, adenoviridae, parpoviridae, enteroviridae, picornaviridae, parvoviridae, reoviridae, retroviridae, influenza virus, parainfluenza virus, mumps, measles, respiratory syncytial virus, rubella, arboviridae, labdoviridae, arenaviridae, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, non-A / non-B hepatitis virus, rhinoviridae, coronavirusidae, rotoviridae, and human immunodeficiency virus.

[1246] In another embodiment, the antibody of the drug conjugate of the present invention may be an antibody known for the prophylactic treatment of autoimmune diseases, examples thereof, but not limited to: Th2-lymphocyte-related diseases (e.g., atopic dermatitis, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omen syndrome, systemic sclerosis, and graft-versus-host disease); Th1-lymphocyte-related diseases (e.g., rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome, Hashimoto's thyroiditis, Graves' disease, primary biliary cirrhosis, Wegener's granulomatosis, and tuberculosis); activated B-lymphocyte-related diseases (e.g., systemic lupus erythematosus, Goodpasture syndrome, rheumatoid arthritis, and type I diabetes); and active chronic hepatitis, Addison's disease, allergic alveolitis, allergic reaction, allergic rhinitis, Alport syndrome, anaphylaxis, ankylosing spondylitis, anti-phospholipid syndrome, arthritis, roundworm infection, aspergillosis, atopic allergy, atopic dermatitis, atopic rhinitis, Behcet's disease, Bird-Fancier's Lung, bronchial asthma, Kaplan syndrome, cardiomyopathy, celiac disease, Chagas disease, chronic glomerulonephritis, Cogan's Syndrome, cold agglutininism, congenital rubella infection, CREST syndrome, Crohn's disease, cryoglobulinemia, Cushing's syndrome, dermatomyositis, discoid lupus, Dressler syndrome, Eaton-Lambert syndrome, echovirus infection, encephalomyelitis, endocrine ophthalmopathy, Epstein-Barr virus infection, Equine Heaves' emphysema, Lupus erythematosus, Ivan syndrome, Felty syndrome, Fibromyalgia, Fuchs's cyclitis, Gastric atrophy, Gastrointestinal allergy, Giant cell arteritis, Glomerulonephritis, Goodpasture syndrome, Graf-versus-host disease, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Idiopathic adrenal atrophy, Idiopathic pulmonary fibrosis, IgA nephropathy, Inflammatory bowel disease, Insulin-dependent diabetes mellitus,Juvenile arthritis, Juvenile diabetes mellitus (Type I), Lambert-Eaton syndrome, laminitis, lichen planus, lupoid hepatitis, lupus lymphopenia, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyneoplastic syndrome, early-onset dementia, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, recurrent miscarriage, Reiter syndrome, rheumatic fever, rheumatoid arthritis, Sampter syndrome, schistosomiasis, Schmidt syndrome, scleroderma, Shulman's syndrome, Sjögren's syndrome, rigidity syndrome, sympathetic ophthalmitis, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thyroiditis, thrombocytopenia, thyrotoxicosis, toxic Epidermolysis, insulin resistance type B, diabetes mellitus type I, ulcerative colitis, uveitis, vitiligo, Waldenström macroglobulinemia, Wegener's granulomatosis.

[1247] Immunospecific antibodies against antigens of cells responsible for producing autoimmune antibodies can be obtained by methods known to a person skilled in the art, such as chemical synthesis or recombinant expression techniques. Non-limiting examples of autoimmune antibodies include anti-nuclear antibodies; anti-ds DNA; anti-ss DNA; anti-cardiolipin antibodies IgM, IgG; anti-phospholipid antibodies IgM, IgG; anti-SM antibodies; anti-mitochondrial antibodies; thyroid antibodies; microbody antibodies; thyroglobulin antibodies; anti-SCL-70; anti-Jo; anti-U1RNP; anti-La / SSB; anti-SSA; anti-SSB; anti-fertilizer cell antibodies; anti-histone; anti-RNP; C-ANCA; P-ANCA; anti-kinetochore; anti-fibrillarin and anti-GBM antibodies.

[1248] In another embodiment, the antibody of the drug conjugate of the present invention may be capable of binding to both a receptor or a receptor complex expressed on activated lymphocytes, for example, an antibody associated with an autoimmune disease. The receptor or receptor complex may include an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, an interleukin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein. Non-limiting examples of suitable immunoglobulin superfamily members include CD2, CD3, CD4, CD5, CD8, CD13, CD19, CD22, CD28, CD79, CD90, CD152 / CTLA-4, PD-I, and ICOS. Non-limiting examples of appropriate TNF receptor superfamily members include CD27, CD40, CD95 / Fas, CD134 / OX40, CD137 / 4-1BB, TNF-Rl, TNFR-2, RANK, TACI, BCMA, osteoprotegerin, Apo2 / TRAEL-Rl, TRAIL-R2, TRAIL-R3, TRABL-R4, and APO-3. Non-limiting examples of appropriate integrins include CD1 Ia, CD1Ib, CD1Ic, CD18, CD29, CD41, CD49a, CD49b, CD49c, CD49d, CD49e, CD49f, CD103, and CD104. Non-limiting examples of appropriate lectins include type C, type S, and type I lectins.

[1249] An antibody that binds to a molecular target or target antigen, such as the ErbB2 antigen, is an antibody capable of binding to the antigen with sufficient affinity to be useful for targeting cells expressing said antigen. If the antibody binds to ErbB2, it will usually bind preferentially to ErbB2 as opposed to other ErbB receptors and may be an antibody that does not significantly cross-react with other proteins such as EGFR, ErbB3, or ErbB4. In these embodiments, the degree of binding of the antibody to these non-ErbB2 proteins (e.g., cell surface binding to endogenous receptors) will be less than 10% when measured by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA). Sometimes, anti-ErbB2 antibodies will not significantly cross-react with rat neu proteins, as described in the literature [Schecter et al., Nature 312:513 (1984) and Drebin et al., Nature 312:545-548 (1984)].

[1250] In another embodiment, the antibody of the target or drug conjugate of the present invention may be selected from the antibodies or targets in the table below. Such antibodies are immunospecific to the target antigen and may be commercially available or may be manufactured by known methods in the art, such as recombinant expression technology.

[1251] designation Product Name Target 3F8 GD2 ganglioside 8H9 B7-H3 Abagovomab CA-125 (Imitation) Abciximab ReoPro CD41 7E3 Abituzumab CD51 Abrilumab Integrin a4β7 Actoxumab Clostridium difficile Clostridium difficile ) Adalimumab Humira TNF-α Adecatumumab EpCAM Atidortoxumab Streptococcus aureus alpha toxin ( Staphylococcus aureus alpha toxin) Aducanumab Beta-amyloid Afasevikumab IL17A and IL17F Afutuzumab CD20 Alemtuzumab Campath, Lemtrada CD52 Alirocumab Praluent PCSK9 Altumomab Hybri-ceaker CEA Amatuximab Mesothelin Andecaliximab gelatinase B Anetumab MSLN Anifrolumab Interferon α / β receptors Anrukinzumab IL-13 Apolizumab HLA-DR β-chain Aprutumab FGFR2 Ascrinvacumab Activin receptor-like kinase 1 Aselizumab L-Selectin (CD62L) Atezolizumab Tecentriq PD-L1 Atidortoxumab Streptococcus aureus alpha toxin Atinumab RTN4 Atorolimumab Rhesus factor Avelumab Bavencio PD-L1 Azintuxizumab CD319 Bapineuzumab Beta-amyloid Basiliximab Simulect CD25 (α chain of IL-2 receptor) Bavituximab phosphatidylserine BCD-100 PD-1 Bectumomab LymphoScan CD22 Begelomab DPP4 Belantamab BCMA Belimumab Benlysta BAFF Bemarituzumab FGFR2 Benralizumab Fasenra CD125 Berlimatoxumab Streptococcus aureus bi-component leukocidin Bersanlimab ICAM-1 Bertilimumab CCL11 (eotaxin-1) Besilesomab Scintimun CEA-associated antigens Bevacizumab Avastin VEGF-A Bezlotoxumab Zinplava Clostridium difficile Blinatomumab Blincyto CD19, CD3 Bimagrumab ACVR2B Bimekizumab IL 17A and IL17F Birtamimab Serum amyloid A protein Bivatuzumab CD44 v6 BIVV009 C1s Bleselumab CD40 Blontuvetmab Blontress CD20 Blosozumab SOST Bococizumab Neural apoptosis-regulated proteinase 1 Brazikumab IL23 Brentuximab Adcentris CD30 (TNFRSF8) Briakinumab IL-12, IL-23 Brodalumab Siliz IL-17 Brontictuzumab Notch 1 Burosumab Crysvita FGF 23 Cabiralizumab CSF1R Camidanlumab CD25 Camrelizumab Programmed cell death 1 Canakinumab Ilaris IL-1 Cantuzumab MUC-1 Capromab Prostascint Prostate carcinoma cells Carlumab MCP-1 Carotuximab Endoglin Catumaxomab Removal EpCAM, CD3 CC49 TAG-72 cBR96 Lewis-Y antigen Cedelizumab CD4 Cemiplimab PCDC1 Cergutuzumab IL2 Cetrelimab Programmed cell death 1 Cetuximab Erbitux EGFR Cibisatamab CEACAM5 Cixutumumab IGF-1 receptor (CD221) Clazakizumab IL6 Clenoliximab CD4 Clivatuzumab hPAM4-Cide MUC1 Codrituzumab Glypican 3 Cofetuzumab PTK7 Coltuximab CD19 Conatumumab TRAIL-R2 Concizumab TFPI Cosfroviximab ZMapp Ebola virus glycoprotein CR6261 Influenza A hemagglutinin Crenezumab 1-40-β-amyloid Crizanlizumab Selectin P Crotedumab GCGR Cusatuzumab CD70 Dacetuzumab CD40 Daclizumab Zenapax CD25 (α chain of the IL-2 receptor) Dalotuzumab IGF-1 receptor (CD221) Dapirolizumab pegol CD154 (CD40L) Daratumumab Darzalex CD38 Dectrekumab IL-13 Demcizumab DLL4 Denintuzumab CD19 Denosumab Prolia RANKL Depatuxizumab EGFR Derlotuximab Histone complex Detumomab B lymphoma cells Dezamizumab Serum amyloid P component Dinutuximab Unituxin GD2 ganglioside Diridavumab Hemagglutinin Domagrozumab GDF-8 Drozitumab DR5 Duligotuzumab ERBB3 (HER3) Dupilumab Dupixent IL4 Durvalumab Imfinzi PD-L1 Dusigitumab ILGF2 Ecromeximab GD3 ganglioside Eculizumab Soliris C5 Edobacomab Endotoxin Edrecolomab Panorex EpCAM Efalizumab Raptiva LFA-1 (CD11a) Eldelumab Interferon gamma-inducing protein Elezanumab RGMA Elgemtumab ERBB3 (HER3) Elotuzumab Empliciti SLAMF7 Elsilimomab IL-6 Emactuzumab CSF1R Emapalumab Gamifant Interferon gamma Emibetuzumab HHGFR Emicizumab Hemlibra Activate F9, F10 Enapotamab AXL Enavatuzumab TWEAK receptor Enfortumab Nectin-4 Enlimomab pegol ICAM-1 (CD54) Enoblituzumab CD276 Enokizumab IL9 Enoticumab DLL4 Ensituximab 5AC Epitumomab Epiciarin Epratuzumab CD22 Eptinezumab calcitonin gene-related peptide Erenumab Aimovig CGRP Ertumaxomab Rexomun HER2 / neu, CD3 Etaracizumab Abegrin Integrin α v β3 Etigilimab TIGIT Etrolizumab Integrin β7 Evinacumab Angiopoietin 3 Evolocumab Repatha PCSK9 Exbivirumab Hepatitis B surface antigen Fanolesomab NeutroSpec CD15 Faralimomab Interferon receptor Faricimab VEGF-A and Ang-2 Farletuzumab Folic acid receptor 1 Fasinumab HNGF FBTA05 Lymphomun CD20 Felvizumab RS virus Fezakinumab IL-22 Fibatuzumab Ephrin receptor A3 Ficlatuzumab HGF Figitumumab IGF-1 receptor (CD221) Firivumab Influenza A virus hemagglutinin Flanvotumab TYRP1 (glycoprotein 75) Fletikumab IL-20 Fontolizumab HuZAF IFN-γ Foralumab CD3 epsilon Foravirumab Rabies virus glycoprotein Fremanezumab calcitonin gene-related peptide alpha Fresolimumab TGF-β Frunevetmab NGF Fulranumab NGF Futuximab EGFR Galcanezumab calcitonin Galiximab CD80 Ganitumab 1 receptor (CD221) Gantenerumab Beta-amyloid Gatipotuzumab MUC1 Gavilimomab CD147 (branch) Gedivumab Hemagglutinin HA Gemtuzumab Mylotarg CD33 Gevokizumab IL-1β Gilvetmab PCDC1 Gimsilumab CSF2 Girentuximab Rencarex Carbonic anhydrase 9 (CA-IX) Glembatumumab GPNMB Golimumab Simponi TNF-α Gomiliximab CD23 (IgE receptor) Gosuranemab tau protein Guselkumab Tremfya IL23 Ianalumab BAFF-R Ibalizumab Trogarzo CD4 Ibritumomab Zevalin CD20 Icrucumab VEGFR-1 Idarucizumab Praxbind dabigatran (dabigatran) Ifabotuzumab EPHA3 Iladatuzumab CD97B IMAB362 CLDN18.2 Imalumab MIF Imaprelimab MCAM Imciromab Myoscint cardiac myosin Imgatuzumab EGFR Inclacumab सेलेक्तिन P Indatuximab SDC1 indusatumab GUCY2C inebilizumab CD19 Infliximab Remicade TNF-α Inolimomab CD25 (IL-2 receptor α chain) Inotuzumab Sponsor CD22 Intetumubab CD51 Ipilimumab Yervoy CD152 Iomab-B CD45 Iratumumab CD30 (TNFRSF8) Isatuximab CD38 Iscalimab CD40 Istiratumab IGF1R, CD221 Itolizumab Alzumab CD6 Ixekizumab Taltz IL-17A Keliximab CD4 Labetuzumab CEA-Cide CEA Lacnotuzumab CSF1, MCSF Ladiratuzumab LIV-1 Lanadelumab ショルレークン(kallikrein) Landogrozumab GDF-8 Laprituximab EGFR Larcaviximab Ebola virus glycoprotein Lebrikizumab IL-13 Lemalesomab NCA-90 Lendalizumab C5 Lenvervimab B형 간에 하원 하원 Lenzilumab CSF2 Lerelimumab TGF beta 2 Leronlimab CCR5 Lesofavumab HA Lexatumumab TRAIL-R2 Libivirumab B형 간에 하원 하원 Lifastuzumab Phosphate-sodium co-transporter Ligelizumab TIME Lilotomab CD37 Lintuzumab CD33 Lirilumab KIR2D Lodelcizumab PCSK9 Lokivetmab Cytopoint Canis lupus familiaris Canis lupus familiaris IL31 Loncastuximab CD19 Losatuxizumab EGFR, ERBB1 HER1 Lorvotuzumab CD56 Lucatumumab CD40 Lulizumab pegol CD28 Lumiliximab CD23 (IgE receptor) Lumretuzumab ERBB3 (HER3) Lupartumab LYPD3 Lutikizumab интерлукин 1 אלפא MABp1 Xilonix IL1A Mapatumumab TRAIL-R1 Margetuximab HER2 Marstacimab TFPI Maslimomab T-cell receptors Mavrilimumab GMCSF α-α-α-γαα α-αα α-β Matuzumab EGFR Mepolizumab Bosatria IL-5 Metilimumab TGF beta 1 Milatuzumab CD74 Minretumomab TAG-72 Mirikizumab IL23A Mirvetuximab 정산 사지체 아파 Mitumomab GD3 ganglioside Modotuximab EGFR extracellular domain III Mogamulizumab Poteligeo CCR4 Monalizumab NKG2A Morolimumab Rhesus factor Mosunetuzumab CD3E, MS4A1, CD20 Motavizumab Numax RS virus (respiratory syncytial virus) Moxetumomab CD22 Muromonab-CD3 Orthoclone OKT3 CD3 Namilumab CSF2 Naratuximab CD37 Narnatumab RON Natalizumab Tysabri α4 integrin Navicixizumab DLL4 Navivumab Influenza A virus 하마글기לוטינין HA Naxitamab C-Met Nebacumab 내동소(endotoxin) Necitumumab Portrazza EGFR Nemolizumab IL31RA Nerelimomab TNF-α Nesvacumab 2 Netakimab Interleukins 17A Nimotuzumab Theracim, Theraloc EGFR Nirsevimab RSVFR Nivolumab Opdivo PD-1 Obiltoxaximab Anthem Bacillus anthracis anthracnose Obinutuzumab Gazyva CD20 Ocaratuzumab CD20 Ocrelizumab Ocrevus CD20 Odulimomab LFA-1 (CD11a) Ofatumumab Arzerra CD20 Olaratumab Lartruvo PDGF-R α Oleclumab 5'-nucleotidase Olendalizumab Complement C5a Olokizumab IL6 Omalizumab Xolair IgE Fc region OMS721 MASP-2 Onartuzumab Human Scatter Factor Receptor Kinase Ontuxizumab TEM1 Onvatilimab VSIR Opicinumab LINGO-1 Oregovomab OvaRex CA-125 Orticumab oxLDL Otelixizumab CD3 Otilimab GMCSF Otlertuzumab CD37 Oxelumab OX-40 Ozanezumab NOGO-A Ozoralizumab TNF-α Pagibaximab lipoteichoic acid Palivizumab Synagis, Abbosynagis F protein of respiratory syncytial virus Pamrevlumab CTGF Panitumumab Vectibix EGFR Pankomab Tumor specific glycosylation of MUC1 Panobacumab Pseudomonas aeruginosa ( Pseudomonas aeruginosa ) Parsatuzumab EGFL7 Pascolizumab IL-4 Pasotuxizumab 정산 가자분해현소 Patelizumab LTA Patritumab ERBB3 (HER3) Pembrolizumab Keytruda PD1 Pemtumomab Theragyn MUC1 Perakizumab IL17A Pertuzumab Omnitarg HER2 / neu Pidilizumab PD-1 Pinatuzumab CD22 Pintumomab Adenocarcinoma antigen Placulumab Human TNF Plozalizumab CCR2 Pogalizumab TNFR Superfamily Member 4 Polatuzumab CD79B Ponezumab human beta-amyloid Porgaviximab Zaire Ebola virus glycoprotein Prasinezumab NACP Prezalizumab ICOSL Priliximab CD4 Pritoxaximab E. coli Shiga toxin type 1 Pritumumab Vimentin PRO 140 CCR5 Quilizumab IGHE Racotumomab Vaxira NGNA ganglioside Radretumab Fibronectin extra domain-B Rafivirumab Rabies virus glycoprotein Ralpancizumab Neuronal apoptosis regulatory proteolytic enzyme 1 Ramucirumab Cyramza VEGFR2 Ranevetmab NGF Ravagalimab CD40 Ravulizumab C5 Raxibacumab Anthrax toxin, protective antigen Refanezumab Myelin-associated glycoprotein Regavirumab cytomegalovirus glycoprotein B Relatlimab LAG3 Remtolumab Interleukin 17 alpha, TNF Reslizumab Cinqair IL-5 Rilotumumab HGF Rinucumab Platelet-derived growth factor receptor beta. Risankizumab IL23A Rituximab MabThera, Rituxan CD20 Rivabazumab pegol Pseudomonas aeruginosa type 3 secretory system ( Pseudomonas aeruginosa type III secretion system Robatumumab IGF-1 receptor (CD221) Rmab RabiShield Rabies virus G glycoprotein Roledumab RHD Romilkimab Interleukin 13 Romosozumab Evenity Sclerostin Rontalizumab IFN-α Rosmantuzumab Root plate-specific spondin 3 Rovalpituzumab DLL3 Rovelizumab LeukArrest CD11, CD18 Rozanolixizumab FCGRT Ruplizumab Antova CD154 (CD40L) SA237 IL-6R Sacituzumab TROP-2 Samalizumab CD200 Samrotamab LRRC15 Sapelizumab IL6R Sarilumab Kevzara IL6 Satralizumab IL6 receptor Satumomab TAG-72 Secukinumab Cosentyx IL-17A Selicrelumab CD40 Seribantumab ERBB3 (HER3) Setoxaximab E. coli Shiga toxin type 2 Setrusumab SOST Sevirumab cytomegalovirus Sibrotuzumab FAP SGN-CD19A CD19 SHP647 Mucosal address cell adhesion molecules Sifalimumab IFN-α Siltuximab Sylvant IL-6 Simtuzumab LOXL2 Sintilimab PD-1 Siplizumab CD2 Sirtratumab SLITRK6 Sirukumab IL-6 Sofituzumab CA-125 Solanezumab Beta-amyloid Sonepcizumab Sphingosine-1-phosphate Sontuzumab episiarin Spartalizumab PDCD1, CD279 Stamulumab myostatin Suptavumab RSVFR Sutimlimab C1S Suvizumab HIV-1 Suvratoxumab Staphylococcus aureus alpha toxin ( Staphylococcus aureus alpha toxin) Tabalumab BAFF Tacatuzumab AFP-Cide alpha-fetoprotein Talacotuzumab CD123 Talizumab IgE Tamtuvetmab Tactress CD52 Tanezumab NGF Taplitumomab CD19 Tarextumab Notch receptor Tavolimab CD134 Tefibazumab Aurexis Clumping factor A Telisotuzumab HGFR Tenatumomab tenascin C Teneliximab CD40 Teplizumab CD3 Tepoditamab Dendritic cell-associated lectin 2 Teprotumumab IGF-1 receptor (CD221) Tesidolumab C5 Tetulomab CD37 Tezepelumab TSLP Tibulizumab BAFF Tildrakizumab Light IL23 Tigatuzumab TRAIL-R2 Timigutuzumab HER2 Timolumab AOC3 Tiragotumab TIGIT Tislelizumab PCDC1, CD279 Tisotumab Coagulation factor III Tocilizumab Actemra, RoActemra IL-6 receptors Tomozotuximab EGFR, HER1 Toralizumab CD154 (CD40L) Tosatoxumab 황사 들상 구근 Tositumomab Bexxar CD20 Tovetumab CD140a Tralokinumab IL-13 Trastuzumab Herceptin HER2 / neu TRBS07 Ectomorph GD2 ganglioside Tregalizumab CD4 Tremelimumab CTLA-4 Trevogrumab 8 Tucotuzumab EpCAM Tuvirumab B-type hepatitis virus Ublituximab MS4A1 Ulocuplumab CXCR4 (CD184) Urelumab 4-1BB (CD137) Urtoxazumab 대장균 Ustekinumab Stelara IL-12, IL-23 Utomilumab 4-1BB (CD137) Vadastuximab CD33 Vanalimab CD40 Vandortuzumab STEAP1 Vantictumab Frizzled receptor Vanucizumab Angiopoietin 2 Vapaliximab AOC3 (VAP-1) Varisacumab VEGF-A Varlilumab CD27 Vatelizumab ITGA2 (CD49b) Vedolizumab Entyvio Integrin α4β7 Veltuzumab CD20 Vepalimomab AOC3 (VAP-1) Vesencumab NRP1 Visilizumab Nuvion CD3 Volociximab Integrin α5β1 Vonlerolizumab CD134 Vopratelimab ICOS Vorsetuzumab CD70 Votumumab HumaSPECT Tumor antigen CTAA16.88 Vunakizumab Interleukin 17 alpha Xentuzumab IGF1, IGF2 XMAB-5574 CD19 Zalutumumab HuMax-EGFr EGFR Zanolimumab HuMax-CD4 CD4 Zatuximab HER1 Zenocutuzumab ERBB3, HER3 Ziralimumab CD147 (branch) Zolbetuximab CLDN18 Zolimomab CD5

[1252] In addition to the above description, the antibody of the drug antibody conjugate of the present invention may be Vitaxin, a humanized antibody for the treatment of sarcoma; Smart IDlO, a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin lymphoma; Oncolym, a radiolabeled rat anti-HLA-DRlO antibody for the treatment of non-Hodgkin lymphoma; and Allomune, a humanized anti-CD2 mAb for the treatment of Hodgkin's disease or non-Hodgkin lymphoma.

[1253] The antibody of the drug conjugate of the present invention may be any antibody fragment known to be used in the treatment of any disease, preferably cancer. Again, such antibody fragments are immunospecific to the target antigen and may be commercially available or manufactured by known methods, such as recombinant expression technology. Examples of such available antibodies include those listed in the table below.

[1254] Fragment type / format Name Trade name Target Fab / chimeric abciximab ReoPro CD41 (integrin alpha-IIb) Fab / humanised abrezekimab Interleukin 13 F(ab')2 / mouse Afelimomab TNF-a F(ab')2 / humanised Alacizumab pegol VEGFR2 Fab / mouse Anatumomab TAG-72 Fab / ovine CroFab Snake venom Fab / ovine DigiFab Digoxin Fab / ovine Digibind Digoxin Fab' / mouse arcitumomab CEA-scan CEA Fab' / mouse bectumomab LymphoScan CD22 Fab' / mouse biciromab FibriScint Fibrin II, beta chain BiTE / mouse Blinatumomab Blincyto CD19 scFv / humanised brolucizumab VEGFA sdAb / humanised caplacizumab Cablivi VWF Fab' / PEGylatedhumanised certolizumab pegol Cimzia TNF-α Fab / humanised citatuzumab EpCAM F(ab')2 / mouse dorlimomab Unknown scFv / chimerichumanised duvortuxizumab CD19, CD3E scFv / human efungumab Mycograb Hsp90 F(ab')2 / humanised erlizumab ITGB2 (CD18) Di-scFy flotetuzumab IL-3 수용체 scFv / human gancotamab 미상 F(ab')2 / mouse igovomab Indimacis-125 CA-125 Fab / humanised lampalizumab CFD scFv / humanised letolizumab TRAP Fab / mouse nacolomab C242 항원 Fab / mouse naptumomab 5T4 Fab / mouse nofetumomab 미상 scFv / humanised oportuzumab Vicinium EpCAM Fab / humanised ranibizumab Lucentis VEGF-A BiTE / mouse Solitomab EpCAM Fab' / mouse sulesomab LeukoScan NCA-90 (과립구 항원) Fab Tadocizumab Integrin α IIb β3 Fab / mouse Telimomab 미상 scFv / humanised Vobarilizumab IL6R Fab / humanised Thromboview D-이량체 Fab / PEGylatedhumanised CDP791 VEGF Fab / bispecifichumanised MDX-H210 Her2 / Neu &CD64 (γFcR1) scFv / humanised Pexelizumab 보체 C5 (ScFv)4fused tostreptavidin mouse CC49 TAG-72범 암종 항원 ScFv fused to β-lactamasehuman SGN-17 P97 항원 ScFv fused to PEGhuman F5 scFv-PEGImmunoliposome Her2 Diabody(V H -V L )2human C6.5K-A Her2 / Neu Diabody(V H -V L )2human L19L19-γIFN 피브로넥틴 EDB 도메인 Diabody(V L -V H )2human T84.66 CEA Minibody(scF v -C H 3)2murine-human chimera(minibody) T84.66 CEA Minibodymurine-human chimera(minibody) 10H8 Her2 S c F v dimer Fc(S c F v )2-Fcmurine-human chimera(minibody) T84.66 CEA Bispecific scFv(V L -V H -V H -V L )mouse r28M CD28 및 MAP Bispecific scFv(V L -V H -V H -V L )origin unknown BiTE MT103 CD19 및 CD3 Bispecific scFv(V L -V H -V H -V L )origin unknown BiTE Ep-CAM 및 CD3 Bispecific tandem diabody(VH-VL- VH -VL) (mouse) Tandab CD19 and CD3 VhH-β-lactamase fusioncamelid Nanobody CEA Dab / human Anti-TNFα dAb TNFα VhH / camelid Nanobody TNFα VhH / camelid Nanobody von Willybrand factor

[1255] Fab fragment, antigen-binding (one cancer)

[1256] F(ab')2 fragment, antigen-binding, includes hinge portion (both arms)

[1257] Fab' fragment, antigen-binding, including hinge portion (both arms)

[1258] scFv single-chain variable fragment

[1259] di-scFv dimeric, single-chain variable fragment

[1260] (Holliger & Hudson, Nature Biotechnology, 2005, 23(9), 1126-1136).

[1261] In a preferred embodiment, the antibody of the drug conjugate of the present invention targets a cell surface antigen.

[1262] In a preferred embodiment, the antibody of the drug conjugate of the present invention may bind to a receptor encoded by the ErbB gene. This antibody may specifically bind to an ErbB receptor selected from EGFR, HER2, HER3, and HER4. Preferably, the antibody in the drug conjugate may specifically bind to the extracellular domain of the HER2 receptor to inhibit the growth of tumor cells overexpressing the HER2 receptor. The antibody of the drug conjugate may be a monoclonal antibody, e.g., a mouse monoclonal antibody, a chimeric antibody, or a humanized antibody. Preferably, the humanized antibody may be huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7, or huMAb4D5-8 (trastuzumab), particularly preferably trastuzumab. Antibodies can also be antibody fragments, such as Fab fragments.

[1263] Other desirable antibodies include the following:

[1264] (i) Anti-CD4 antibodies. The antibody of the drug conjugate may be a monoclonal antibody, e.g., a rat monoclonal antibody, a chimeric antibody, or a humanized antibody;

[1265] (ii) Anti-CD5 antibodies. The antibody of the drug conjugate may be a monoclonal antibody, e.g., a rat monoclonal antibody, a chimeric antibody, or a humanized antibody;

[1266] (iii) Anti-CD13 antibodies. The antibody of the drug conjugate may be a monoclonal antibody, e.g., a rat monoclonal antibody, a chimeric antibody, or a humanized antibody; and

[1267] (iv) Anti-CD20 antibodies. The antibody of the drug conjugate may be a monoclonal antibody, e.g., a rat monoclonal antibody, a chimeric antibody, or a humanized antibody. Preferably, the humanized antibody is rituximab or its antibody fragment, e.g., a Fab fragment; and

[1268] (v) Anti-CD30 antibodies. The antibody of the drug conjugate may be a monoclonal antibody, e.g., a rat monoclonal antibody, a chimeric antibody, or a humanized antibody. Preferably, the humanized antibody is rituximab or its antibody fragment, e.g., a Fab fragment.

[1269] In one embodiment of the present invention, a drug antibody conjugate may embody one or more of the following: the drug antibody conjugate may embody (i) increased cytotoxicity (or reduced cell survival), (ii) increased cell proliferation inhibitory activity (cell retention), (iii) increased binding affinity for a target antigen or epitope, (iv) increased internalization of the conjugate, (v) reduced patient side effects, and / or (vi) improved toxicity profile. Such increases may be relative to drug antibody conjugates known in the art that bind to the same or different epitopes or antigens.

[1270] Method for manufacturing drug antibody conjugates

[1271] The drug-antibody conjugate of the present invention may be manufactured according to techniques well known in the art. Processes for conjugating a moiety comprising at least one antigen-binding site to an antibody, e.g., an antibody against several different drugs, using different processes have been previously described and are exemplified, e.g., WO-A-2004 / 010957, WO-A-2006 / 060533, and WO-A-2007 / 024536, the contents of which are incorporated by reference into the present invention. These processes involve using a linker group capable of inducing a drug, toxin, or radionuclide to attach to a moiety, e.g., an antibody. Binding to a moiety, e.g., an antibody, generally occurs via one of the following three routes: via a free thiol group in cysteine ​​following partial reduction of a disulfide group in the antibody; via a free amino group in lysine in the antibody; and via a free hydroxyl group in serine and / or threonine in the antibody. Binding methods vary depending on the binding site on the moiety, such as an antibody. Purification of antibody-drug conjugates by size exclusion chromatography (SEC) has also been described [e.g., Liu et al., Proc. Natl. Acad. Set (USA), 93: 8618-8623 (1996), and Chari et al., Cancer Research, 52: 127-131 (1992)].

[1272] As previously mentioned, the drug payload of the drug conjugate of the present invention is an ecteinascidin derivative disclosed in or included within the scope of international patent application no. PCT / EP2018 / 060868 (the contents of which are incorporated by reference into the present invention). These compounds are synthesized according to the method described in the present application.

[1273] As described above, a method for preparing a drug conjugate according to the present invention is provided, comprising conjugating a moiety Ab having at least one antigen-binding site according to the present invention with a drug D having the chemical formula (IH), (IHa) or (IHb) as defined in the present invention, and Ab and D.

[1274] An example of a method for preparing a drug conjugate of the present invention comprises preparing a drug antibody conjugate of the formula (G) or (G') of the present invention as follows:

[1275]

[1276] The above method includes the following steps:

[1277] (i) Drugs with the chemical formula (IH)-H (DH):

[1278]

[1279] In the definition of (IH)-H in the formula, the substituent is as defined above for the formula (IH) and reacts with a compound of formula (D') or (E):

[1280]

[1281] Obtain a compound of chemical formula (F) or (F'), respectively:

[1282]

[1283] (ii) partially reduce one or more disulfide bonds in the antibody to be conjugated to obtain a reduced antibody Ab-SH having free thiol groups:

[1284] and

[1285] (iii) react the partially reduced antibody Ab-SH having a free thiol group with the compound of formula (F) or (F') produced in step (i) to obtain the desired drug antibody conjugate of formula (G) or (G'), respectively:

[1286]

[1287] In another preferred embodiment of this process, the antibody is selected from brentuzimab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody and anti-CD30 antibody or antigen-binding fragment or its immunologically active portion, or is selected from trastuzumab and anti-CD4 antibody or antigen-binding fragment or its immunologically active portion, preferably trastuzumab or antigen-binding fragment or its immunologically active portion. Additionally, partial reduction of this monoclonal antibody is performed using tris[2-carboxyethyl]phosphine hydrochloride (TCEP).

[1288] ...

Claims

Claim 1 Chemical formula [D-(X) b -(AA) w -(T) g -(L)-] n As a drug conjugate of -Ab, in the above formula, D is a drug moiety having the formula (IH) or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and (IH) Formula: If the above dashed line exists (X) b Regarding, or if present (AA) w Regarding, or if present (T) g A covalent bonding site for, or for the linker group (L); Y is -NH- or -O-; R1 is -OH or -CN; R2 is acetyl; R3 is hydrogen; Z is selected from -O- and -NH-; X is an extender selected from -COO-(C1-C6alkylene)NH-; -COO-CH2-(phenylene)-NH-; -COO-(C1-C6alkylene)NH-COO-CH2-(phenylene)-NH-; -COCH2NH-COCH2-NH-; -COCH2NH-; -COO-(C1-C6alkylene)S-; and -COO-(C1-C6alkylene)NHCO(C1-C6alkylene)S- when Z is -NH-; and -CONH-(C1-C6alkylene)NH- when Z is -O-; An extender selected from -COO-CH2-(phenylene)-NH-; -CONH-(C1-C6alkylene)NH-COO-CH2-(phenylene)-NH-; -COCH2NH-COCH2-NH-; -COCH2NH-; -CONH-(C1-C6alkylene)S-; and -CONH-(C1-C6alkylene)NHCO(C1-C6alkylene)S-; b is 0 or 1; and T is -CO-(C1-C6alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C6alkylene)] j -NH-, -COO-(C1-C6alkylene)-[O-(C2-C4alkylene)] j An extender selected from the group consisting of -NH-; where j is an integer from 1 to 25, and g is 0 or 1; (AA) w is chemical formula (II) and: If the above dashed line exists (X) b or indicates a covalent bonding site for the drug moiety (dashed line to the right) and if present (T) g or indicates the covalent bonding point for the linker group (dashed line in the left direction); R 21 In the presence of hydrogen, methyl, isopropyl, isobutyl, sec -Butyl, Benzyl, p -hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl, Selected from the group consisting of; and w are integers in the range of 0 to 12; and L is a linker selected from the group consisting of: The dashed line above indicates the covalent bonding point for Ab (dashed line in the right direction), and if present (T) g , or if present (AA) w , or if it exists (X) b Or indicating the covalent bonding point for D (leftward dashed line); R 19 is -C1-C 12 Alkylene-, -C3-C8 carbocyclo, -O-(C1-C 12 alkylene), -C6-C in one or more rings 18 Arrylene, C1-C with arylene groups within one or more rings 12 Alkylene-C6-C 18 Arrylene, C6-C with arylene groups within one or more rings 18 Aryllene-C1-C 12 Alkylene, -C1-C 12 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 12 Alkylene-, -C5-C 14 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings, and at least one oxygen, nitrogen, or sulfur atom is included within the ring(s)], -C1-C 12 Alkylene-(C5-C 14 Heterocyclo)-[wherein the heterocyclo group is a saturated or unsaturated group having one or more rings, and at least one oxygen, nitrogen, or sulfur atom is included within the ring(s)], -(OCH2CH2) r - and -CH2-(OCH2CH2) r Selected from, R 30 is a -C1-C6 alkylene- group; M is -C1-C6 alkylene-, -C1-C6 alkylene-(C3-C8 carbocyclo)-, -(CH2CH2O) s -, selected from the group consisting of -, -C1-C6alkylene-(C3-C8carbocyclo)-CON(H or C1-C6alkyl)-C1-C6alkylene-, phenylene, phenylene-C1-C6alkylene-, and -C1-C6alkylene-CON(H or C1-C6alkyl)C1-C6alkylene-; Q is selected from -N(H or C1-C6alkyl)phenylene- and -N(H or C1-C6alkyl)-(CH2) s Selected from the group consisting of; r is an integer in the range of 1 to 10; s is an integer in the range of 1 to 10; Ab is a monoclonal antibody or an antigen-binding fragment thereof that binds immunospecifically to cancer cell antigens; and n is [D-(X) for the Ab moiety b -(AA) w -(T) g -(L)-] A drug conjugate with a ratio of 1 to 20. Claim 2 In claim 1, the above D is a drug moiety selected from the chemical formulas (IHa) and (IHb), or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof: Here, the dashed lines R1, R2, R3, Y, and Z are the same as defined in the chemical formula (IH), for the drug conjugate. Claim 3 In paragraph 1, the above D is the following compound: , and or a pharmaceutically acceptable salt, solvate, tautomeric or stereoisomer thereof, wherein the dashed line is present (X) b , or if present (AA) w , or if present (T) g or a drug conjugate that is a covalent bonding site for (L). Claim 4 In paragraph 1, the above D is the following compound:, or a pharmaceutically acceptable salt, solvate, tautomeric or stereoisomer thereof, wherein the dashed line is present (X) b , or if present (AA) w , or if present (T) g or a drug conjugate that is a covalent bonding site for (L). Claim 5 In claim 1, the salt is hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, maleate, mandelate, methanesulfonate, p -Toluenesulfonate, Sodium, Potassium, Calcium, Ammonium, Ethylenediamine, Ethanolamine, N,N - Drug conjugate selected from dialkylene ethanolamine, triethanolamine, and basic amino acids. Claim 6 A drug conjugate according to claim 1, wherein L is a linker group selected from the group consisting of the following: In the formula: The dashed line above indicates the covalent bonding point for Ab (dashed line in the right direction), and if present (T) g , or if present (AA) w , or (X) b Indicates the covalent bonding point for (dashed line pointing to the left); R 19 is -C1-C 12 Alkylene-, -O-(C1-C 12 alkylene), -C6-C in one or more rings 12 Arrylene, -C1-C with arylene groups in one or more rings 12 Alkylene-C6-C 12 Arrylene-, -C6-C having an arylene group in one or more rings 12 Allylene-C1-C 12 Alkylene-, -C5-C 12 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings, and at least one oxygen, nitrogen, or sulfur atom is included within the ring(s)], -C1-C 12 Alkylene-(C5-C 12 Heterocyclo)-[wherein the heterocyclo group is a saturated or unsaturated group having one or more rings, and the ring(s) contain at least one oxygen, nitrogen, or sulfur atom], -(C5-C 12 Heterocyclo)-C1-C 12 Alkylene-[wherein the heterocyclo group is a saturated or unsaturated group having one or more rings, and at least one oxygen, nitrogen, or sulfur atom is included within the ring(s)], -(OCH2CH2) r - and -CH2-(OCH2CH2) r Selected from;R 30 is a -C1-C6 alkylene- group; M is selected from the group consisting of -C1-C6 alkylene-, -C1-C6 alkylene-(C3-C8 carbocyclo)-, and phenylene; and r is an integer in the range of 1 to 6. Claim 7 In claim 1, a drug conjugate selected from chemical formulas (IV), (V), and (VI): In the formula: X, T, AA, w, b, g, D, Ab, and n are as defined in Claim 1; R 19 -C1-C8alkylene-, -O-(C1-C8alkylene), -C1-C8alkylene-C6-C having an arylene group in one or more rings 12 arylene-, and -C6-C having one or more arylene groups within the ring 12 Selected from arylene-C1-C8 alkylene-; R 30 is a -C2-C4 alkylene group; and M is selected from the group consisting of -C1-C3 alkylene and -C1-C3 alkylene (C5-C7 carbocyclo)-; or a drug conjugate selected from chemical formulas (IV), (V), and (V): In the formula: X, T, AA, w, b, g, D, Ab, and n are as defined in Claim 1; R 19 is selected from -C1-C6alkylene- and phenylene-C1-C6alkylene, and R 30 is a -C2-C4 alkylene- group; and M is a -C1-C3 alkylene-(C5-C7 carbocyclo)- group. Claim 8 In Paragraph 7, R 19 is a drug conjugate that is a -C1-C6 alkylene group: Claim 9 In paragraph 1, R 21 In the presence of hydrogen, methyl, isopropyl, sec Selected from the group consisting of -butyl, benzyl, indolylmethyl, -(CH2)3NHCONH2, -(CH2)4NH2, -(CH2)3NHC(=NH)NH2 and -(CH2)4NHC(=NH)NH2; and w is an integer in the range of 0 to 6; or w is 0 or 2, and if w is 2, (AA) w is a drug conjugate of chemical formula (III): In the formula: If a dashed line exists (X) b or indicates a covalent bonding site for the drug moiety (dashed line to the left) and if present (T) g or indicates the covalent bonding point for the linker (dashed line to the right); R 22 is methyl, benzyl, isopropyl, sec -Selected from butyl and indolylmethyl; and R 23 It is selected from methyl, -(CH2)4NH2, -(CH2)3NHCONH2 and -(CH2)3NHC(=NH)NH2. Claim 10 In claim 1, X is a drug conjugate that is an extender selected from the group consisting of the following: where Z in the formula is -NH-: -COO-(C2-C4alkylene)NH-; -COO-CH2-phenylene-NH-; -COO-(C2-C4alkylene)NH-COO-CH2-(phenylene)-NH-; -COCH2NH-COCH2-NH-; -COO-(C2-C4alkylene)S-; -COO-(C2-C4alkylene)NHCO(C1-C3alkylene)S-; or where Z in the formula is -O-: -CONH-(C2-C4alkylene)NH-; -COO-CH2-phenylene-NH-; -CONH-(C2-C4alkylene)NH-COO-CH2-(phenylene)-NH-; -COCH2NH-COCH2-NH-; -CONH-(C2-C4alkylene)S-; -CONH-(C2-C4alkylene)NHCO(C1-C3alkylene)S-; or X is an extender selected from the group consisting of the following drug conjugates: where Z in the formula is -NH-: -COO-CH2-phenylene-NH- -COO(CH2)3NHCOOCH2-phenylene-NH-; -COO(CH2)3NH-; -COO(CH2)3-S-; -COO(CH2)3NHCO(CH2)2S-; or where Z in the formula is -O-: -COO-CH2-phenylene-NH- -CONH(CH2)3NHCOOCH2-phenylene-NH-; -CONH(CH2)3NH-; -CONH(CH2)3-S-; -CONH(CH2)3NHCO(CH2)2S-. Claim 11 In paragraph 10, b is a drug conjugate that is 1: Claim 12 In claim 1, the above T is -CO-(C1-C4alkylene)NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)] j -NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)] j An extender selected from the group consisting of -NH-; where j is an integer from 1 to 10, and g is 0 or 1; or T is -CO-(C1-C4alkylene)-NH-, -CO-(C1-C4alkylene)-[O-(C2-C4alkylene)] j -NH-, and -COO-(C1-C4alkylene)-[O-(C2-C4alkylene)] j A drug conjugate selected from the group consisting of -NH-, wherein j is an integer from 1 to 5 and g is 0 or 1. Claim 13 In claim 1, the moiety Ab comprising at least one antigen-binding site is apsiximab, alemtuzumab, anetuzumab, atezolizumab, avelumab, bacilisimab, bevacizumab, blinatomumab, brentuximab, catumazomab, cetuximab, coltusimab, daclizumab, daratumumab, denintuzumab, denosumab, depatuxizumab, dinutuximab, durvalumab, elotuzumab, enfortumab, glembatuzumab, gemtuzumab, ibritumomab, indatusimab, indusatumab, inozutumab, ipilimumab, rabetuzumab, radiratuzumab, lapritusimab, rifastuzumab, lorbotuzumab, milatuzumab, mirvetusimab, naratuzumab, necitumumab, nimotuzumab, A drug conjugate selected from nivolumab, obinutuzumab, ofatumumab, olaratumab, omalizumab, palivizumab, panitumumab, pembrolizumab, pertuzumab, finatuzumab, polatuzumab, ramucirumab, rovalfituzumab, sacituzumab, ciltusimab, sirtratumab, sofituzumab, vadastuzimab, borsetuzumab, trastuzumab, and anti-CD4 antibodies, anti-CD5 antibodies, anti-CD13 antibodies, and anti-CD30 antibodies, or antigen-binding fragments thereof. Claim 14 A drug conjugate according to claim 1, wherein the Ab is an antibody selected from the group consisting of brentuximab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody, and anti-CD30 antibody, or an antigen-binding fragment thereof. Claim 15 A drug conjugate according to claim 1, wherein the Ab is an antibody selected from trastuzumab and anti-CD13 antibodies or an antigen-binding fragment thereof. Claim 16 A drug conjugate according to claim 1, wherein the Ab is trastuzumab or an antigen-binding fragment thereof. Claim 17 In paragraph 1, a drug conjugate that is an antibody-drug conjugate selected from the group consisting of the following: , , , , ' In the equation, n is 2-6, and each and is independently selected from brentuximab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody and anti-CD30 antibody, or their antigen-binding fragments; or a drug conjugate selected from the group consisting of the following: , In the expression, n is 2-6, and each and is independently selected from brentuximab, gemtuzumab, inozutumab, lovalfituzumab, trastuzumab, anti-CD4 antibody, anti-CD5 antibody, anti-CD13 antibody and anti-CD30 antibody, or their antigen-binding fragments; or a drug conjugate of the following formula In the equation, n is 2-6, and is an anti-CD13 antibody, or its antigen-binding fragment. Claim 18 In claim 17, the above Ab is selected from trastuzumab and an anti-CD13 antibody or an antigen-binding fragment thereof; or the above Ab is a drug conjugate selected from trastuzumab or an antigen-binding fragment thereof. Claim 19 In paragraph 17, n is a drug conjugate of 3, 4, or 5. Claim 20 In paragraph 1, a drug conjugate that is an antibody drug conjugate in an isolated or purified form. Claim 21 Chemical formula D-(X) b -(AA) w -(T) g - As a compound of -L1, where:L1 is a linker selected from the group of chemical formulas consisting of the following: , if each dashed line in the equation exists (T) g , or if present (AA) w , or if it exists (X) b , or indicates a covalent bonding site for D; G is a halo, - O -Plum and - O -Selected from tosyl; J is halo, hydroxy, - N -Suksin is already dead, - O -(4-nitrophenyl), - O -pentafluorophenyl, - O -Tetrafluorophenyl and -OC(O)-OR 20 Selected from;R 19 is -C1-C 12 Alkylene-, -C3-C8 carbocyclo, -O-(C1-C 12 alkylene), -C6-C in one or more rings 18 Arrylene, -C1-C with arylene groups in one or more rings 12 Alkylene-C6-C 18 Arrylene-, -C6-C having an arylene group in one or more rings 18 Aryllene-C1-C 12 Alkylene-, -C1-C 12 Alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C 12 Alkylene-, -C5-C 14 Heterocyclo- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s)], -C1-C 12 Alkylene-(C5-C 14 Heterocyclo)- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s)], -(C5-C 14 Heterocyclo)-C1-C 12 Alkylene- [wherein the heterocyclo group is a saturated or unsaturated group having one or more rings and containing at least one oxygen, nitrogen, or sulfur atom within the ring(s)], -(OCH2CH2) r - and -CH2-(OCH2CH2) r Selected from;R 20 C1-C 12 It is an aryl group having 6 to 18 carbon atoms within one or more alkyl or aromatic rings; r is an integer in the range of 1 to 10; b is an integer of 0 or 1; g is an integer of 0 or 1; w is an integer in the range of 0 to 12; and each of D, R x , X, T, and AA are as defined in claim 1; or chemical formula DX-(AA) w -(T) g - The compound of -L1 is a compound selected from the following: Claim 22 Chemical formula D-(X) b -(AA) w -(T) g - Compound of L1: In the above formula, D, X, AA, T, b, g, and w are each as defined in Claim 1, and L1 is as defined in Claim 21. Claim 23 A drug conjugate according to claim 1, wherein b+w+g is not 0; or b+w is not 0; or where w is not 0, b is 1. Claim 24 A compound of claim 21 in which b+w+g is not 0; or b+w is not 0; or where w is not 0, b is 1. Claim 25 A pharmaceutical composition for treating cancer comprising a drug conjugate according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier thereof. Claim 26 A pharmaceutical composition according to claim 25, wherein the cancer is selected from lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, kidney cancer, leukemia, multiple myeloma, lymphoma, gastric cancer, and ovarian cancer. Claim 27 A kit for treating cancer selected from lung cancer, colorectal cancer, breast cancer, pancreatic carcinoma, renal cancer, leukemia, multiple myeloma, lymphoma, urinary cancer, and ovarian cancer, comprising a therapeutically effective amount of a drug conjugate according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier. Claim 28 A drug conjugate according to claim 1, wherein n is an integer from 1 to 12. Claim 29 In paragraph 28, n is a drug conjugate of 3, 4, or 5. Claim 30 In paragraph 29, n is a drug conjugate of 4. Claim 31 A method for preparing a drug antibody conjugate of the following chemical formula (G) or (G'), comprising the following steps: (i) Drug DH of the following chemical formula (IH)-H [In the definition of (IH)-H in the formula, the substituent is as defined in Paragraph 1] React with a compound of the following formula (D') or (E): Step to obtain a compound of chemical formula (F) or (F'), respectively: (ii) A step of partially reducing one or more disulfide bonds in the antibody to be conjugated to obtain a reduced antibody Ab-SH having free thiol groups: ; and (iii) reacting a partially reduced antibody Ab-SH having a free thiol group with a compound of formula (F) or (F') produced in step (i) to obtain a desired drug antibody conjugate of formula (G) or (G'), respectively; . 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