Radionuclide coupling medicine as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a radionuclide coupling medicine and a medicine composition and application thereof. Specifically, the precursor of the radionuclide coupled drug has a structure as shown in a formula I, and LG represents a targeting ligand; s represents a spacer; l represents a linker; and C represents a chelating agent capable of containing a radionuclide. The radionuclide-conjugated drug may specifically deliver a radionuclide to a target cell. When the coupling drug contains one LG, the coupling drug can specifically deliver the radionuclide to a target cell; when the coupling medicine contains two LGs, the coupling medicine can play a role in various ways, so that the treatment effect is improved, and the toxic and side effects are reduced; meanwhile, due to the existence of the two LGs, the affinity of the coupling medicine to target cells is also enhanced, and the off-target toxicity is reduced. # imgabs0 #

Description

Radionuclide-coupled drug and its pharmaceutical composition and application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present invention claims priority to invention patent application No. 202211105422.6, entitled “Radionuclide-conjugated drugs, pharmaceutical compositions and applications thereof”, filed in China on September 9, 2022. The entire contents of the patent application are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of precision diagnosis and treatment, and specifically relates to a radionuclide-conjugated drug, a pharmaceutical composition based on the conjugated drug, and applications in the medical field. Background Art

[0004] Radiopharmaceuticals are specialized drugs that use particles or radiation emitted by radionuclides for medical diagnosis and treatment. Radionuclides and their labeled compounds used to study human physiology, pathology, and in vivo drug processes fall under this category. Radiopharmaceuticals are widely used in tumor diagnosis and treatment, myocardial imaging, early detection of neurodegenerative diseases, and imaging and diagnosis of inflammatory tissues. They enable rapid, non-destructive, real-time imaging of physiological and pathological processes and are a key cornerstone of molecular imaging and precision medicine, providing new means and approaches for truly early diagnosis and timely treatment.

[0005] As precision medicine advances, nuclear medicine is also moving toward precise targeting. Some physical methods or tissue uptake specificity can achieve partial precision targeting. For example, thyroid cancer and its metastases specifically absorb iodine, allowing for treatment with iodine-131 (I-131). Alternatively, minimally invasive placement of yttrium-90 (Y-90) microspheres can enable radioembolization. However, these targeted approaches are not feasible for widespread adoption and are limited to specific scenarios.

[0006] In recent years, with the widespread clinical application of ligands with targeted effects (e.g., antibody-drug conjugates / ADCs, peptide-drug conjugates / PDCs, small-molecule drug conjugates / SMDCs, etc.), the combination of these ligands and radioactive chelates has also formed a new track: radionuclide drug conjugates / RDCs. Similar to ADCs, RDCs use specific targeting mediated by antibodies, small molecules, or peptides to deliver radioactive / imaging factors to the target location, thereby concentrating the radiation generated by the radionuclide on local tissues, while reducing damage to other tissues caused by systemic exposure while providing efficient and precise diagnosis and treatment. Unlike ADCs, the radionuclides loaded in RDCs can be used for both diagnosis and treatment; in addition, RDCs are slightly different in structure from ADCs, requiring the introduction of specific structural fragments—chelates—to chelate the radionuclides.

[0007] Specifically, in terms of drug structure, RDCs are mainly composed of a ligand (e.g., an antibody, peptide, or small molecule) that mediates targeting, a linker, a chelator, and a radioisotope. Depending on the type of ligand, RDCs can be divided into antibody-targeted radionuclide antibody conjugates (RACs), small molecule (including peptide)-based radionuclide conjugates, and other types. Depending on the type of radionuclide, RDCs can perform different functions of imaging or treatment, and some nuclides even have both functions.

[0008] Currently, relatively few therapeutic RDCs have been approved for marketing, including Novartis' Lutathera (Lu-177dotatate, or 177Lu-dotatate, for the treatment of somatostatin receptor-positive gastrointestinal neuroendocrine tumors) and Pluvicto (Lu-177 vipivotide tetraxetan, or 177Lu-PSMA-617, for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer) and Biogen's Zevalin (Y-90 ibritumomab tiuxetan, or 90Y-ibritumomab tiuxetan, for the treatment of non-Hodgkin's lymphoma). There is an urgent need to develop more therapeutic or dual-purpose RDCs to meet the growing demand in the field of precision diagnosis and treatment.

[0009] Summary of the Invention

[0010] Problems to be solved by the invention

[0011] In response to the current problems of limited types of therapeutic RDCs and single targeting ligands, the present invention has discovered a series of new RDCs, including a variety of dual-ligand RDCs constructed based on dual-targeting technology, further enriching the types of therapeutic or dual-purpose RDCs.

[0012] Solutions for solving problems

[0013] <First Aspect>

[0014] The present invention provides a radionuclide-conjugated drug precursor comprising a targeting ligand, a chelating agent, an optional linker and an optional spacer.

[0015] In the present invention, the radionuclide-conjugated drug precursor may have a structure as shown in Formula I,

[0016] in,

[0017] LG indicates targeting ligand;

[0018] S represents a spacer;

[0019] L represents a linker;

[0020] C represents a chelating agent;

[0021] m is 1 or 2;

[0022] n is 0 or 1;

[0023] p is 0 or 1; and

[0024] When p is 0, C is directly connected to S or LG;

[0025] When n is 0, LG is directly connected to L or C;

[0026] When m is 2, the two LGs are the same as or different from each other, and the two LGs are connected to S, L, or C at the same time, or the two LGs are connected to each other and then to S, L, or C.

[0027] In one embodiment of the present invention, the radionuclide-conjugated drug precursor having a structure as shown in Formula I may have a structure as shown in Formula I-1, LG-LC I-1

[0028] wherein LG, L and C are as defined in Formula I.

[0029] In another embodiment of the present invention, the radionuclide-conjugated drug precursor having a structure as shown in Formula I may have a structure as shown in Formula I-2, LG-C I-2

[0030] wherein LG and C are as defined in Formula I.

[0031] In another embodiment of the present invention, the radionuclide-conjugated drug precursor having a structure as shown in Formula I may have a structure as shown in Formula I-3,

[0032] wherein LG, S, L and C are as defined in Formula I.

[0033] In another embodiment of the present invention, the radionuclide-conjugated drug precursor having a structure as shown in Formula I may have a structure as shown in Formula I-4,

[0034] wherein LG, S and C are as defined in Formula I.

[0035] In another embodiment of the present invention, the radionuclide-conjugated drug precursor having a structure as shown in Formula I may have a structure as shown in Formula I-5,

[0036] wherein LG, L and C are as defined in Formula I.

[0037] In another embodiment of the present invention, the radionuclide-conjugated drug precursor having a structure as shown in Formula I may have a structure as shown in Formula I-6,

[0038] wherein LG, L and C are as defined in Formula I.

[0039] In one embodiment of the present invention, the targeting ligand (i.e., LG) can bind to the following cell surface proteins: PSMA, FORL1, TRPV6, FAPI, C-MET, CAIX, RGD, Hepsin or Sigma.

[0040] When containing only one targeting ligand, the conjugate prodrug containing it (for example, a conjugate prodrug as shown in Formula I-1 or Formula I-2) can bind to any one of the following cell surface proteins (single target single ligand), in particular PSMA, TRPV6, FAPI, C-MET or CAIX.

[0041] When containing two targeting ligands, a conjugate prodrug containing the same (for example, a conjugate prodrug as shown in Formula I-3, Formula I-4, Formula I-5 or Formula I-6) can bind to any one of the following cell surface protein combinations (single target dual ligand or dual target dual ligand), in particular PSMA / FORL1, FORL1 / TRPV6, PSMA / TRPV6, PSMA / FAPI, PSMA / RGD, PSMA / Hepsin, FAPI / RGD, FAPI / FAPI, FAPI / Hespin, PSMA / Sigma or FAPI / CAIX.

[0042] In one embodiment of the present invention, the targeting ligand may be formed by a polypeptide, an antibody or a small molecule.

[0043] In one embodiment of the present invention, each LG in the conjugated drug prosthesis shown in Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can be independently formed by any one of the ligand compounds of Formula LG-I, LG-II, LG-III, LG-IV, LG-V, LG-VI, LG-VII, LG-VIII, and LG-IX.

[0044] Preferred

[0045] In formula LG-I (or LG-I'),

[0046] R LG1 For amino,

[0047] in

[0048] R1 is hydrogen or an optionally substituted cycloalkylcarboxyl group (e.g., 4-(aminomethyl)cyclohexylcarboxyl, i.e. Preferred Or, 4-(6-aminohexanoylaminomethyl)cyclohexylcarbonyl, i.e. Preferred

[0049] R2 and R3 are each independently hydrogen or an optionally substituted C6-C 10 Aryl (e.g., phenyl, naphth-1-yl, naphth-2-yl, etc.);

[0050] R4 is hydroxy, optionally substituted C1-C6 alkylamino (e.g., 6-aminohexylamino, i.e. ), an amino acid derivative group (e.g., -NH-Asp-COOH) or an oligopeptide derivative group consisting of 2-6 amino acids (e.g., -NH-Asp-Asp-Lys-COOH);

[0051] R5 is an optionally substituted C1-C6 alkyl group; when substituted, the substituent is an amino-substituted C1-C6 alkanoyl group, an amino-substituted C6-C 10 Aroyl or an acyl group derived from an amidation reaction of the two (e.g., 4-(6-aminohexanoylaminomethyl)benzoyl);

[0052] Formula LG-II is pteroic acid or folic acid or an analog thereof; preferably, the folic acid analog is selected from 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 10-formylfolate, methotrexate, 5,10-methylenetetrahydrofolate, aminopterin and raltitrexed;

[0053] Formula LG-III comprises all or part of the amino acids in the polypeptide EGKLSSNDTEGGLCKEFLHPSKVDLPR; preferably, formula LG-III comprises 9 to 27 amino acids in the above polypeptide; more preferably, formula LG-III is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the polypeptide KEFLHPSKVDLPR;

[0054] Preferred

[0055] In formula LG-IV (or LG-IV'),

[0056] R LG2 is halogen (e.g., bromine), amino,

[0057] in

[0058] R8 is hydrogen, in

[0059] R 8’ is a carboxy-substituted C1-C6 alkylamino group (e.g., 5-amino-5-carboxypentylamino), a carboxy-substituted C3-C8 cycloalkylmethylamino group (e.g., (trans-4-carboxycyclohexyl)methylamino), or a carboxy-substituted C1-C2 alkoxy group (e.g., 2-(2-(carboxymethyloxy)ethoxy)ethylamino);

[0060] R 8”is hydrogen, amino-substituted C1-C6 alkanoyl (e.g., 6-aminohexanoyl), amino-substituted C1-C2 alkoxy C1-C2 alkoxy C1-C2 alkanoyl (e.g., 2-(2-(2-aminoethoxy)ethoxy)acetyl), carboxyl-substituted C1-C6 alkanoyl (e.g., 3-carboxypropionyl), or carboxyl-substituted C1-C2 alkoxy C1-C2 alkoxy C1-C2 alkanoyl (e.g., 2-(2-(carboxymethyloxy)ethoxy)acetyl);

[0061] R9 is in

[0062] R 9’ is a carbonyl group or a methylene group;

[0063] In the LG-V model,

[0064] X is a single bond or -(CH2CH2O) n CH2CONH-, where

[0065] n is 0, 1, 2, or 3;

[0066] R LG3 For hydrogen or in

[0067] R 10 is a C1-C6 alkylamino group substituted with a hydroxy group or a carboxyl group (e.g., 5-amino-5-carboxypentylamino group);

[0068] In formula LG-VI,

[0069] B1 to B5 are each independently an amino acid fragment formed by any one of the following amino acids: phenylalanine (Phe), glutamic acid (Glu), arginine (Arg), glycine (Gly) and aspartic acid (Asp); preferably, formula LG-VI is and

[0070] optionally introducing an optionally substituted alkanoyl group (e.g., 3-amino-3-carboxypropanoyl) and / or an optionally substituted amino group (e.g., 5-amino-5-carboxypentylamino) into at least one of the residues of B1 to B5;

[0071] In formula LG-VII,

[0072] C1 to C4 each independently represent an amino acid fragment, wherein the C-terminus of C1 is connected to a benzothiazolyl group, the N-terminus of C4 is connected to an acetyl group, and

[0073] optionally introducing an optionally substituted alkanoyl group (e.g., 3-carboxypropionyl) into at least one of the C1-C4 residues;

[0074] In formula LG-VIII,

[0075] Y is One end marked by * is connected to the carboxyl group (COOH), and the other end is connected to the ring Z;

[0076] Ring Z is C6-C 10 Aromatic ring (e.g., benzene ring, naphthalene ring, etc.) or 5-9 membered heteroaromatic ring (e.g., furan ring, benzofuran ring, etc.);

[0077] R LG4 is hydrogen, C1-C6 alkyl or C1-C6 alkoxy;

[0078] Formula LG-IX comprises a polypeptide Cys a -X1-Cys c -X2-Gly-Pro-Pro-X3-Phe-Glu-Cys d -Trp-Cys b -Tyr-X4-X5-X6, wherein: X1 is Asn, His or Tyr; X2 is Gly, Ser, Thr or Asn; X3 is Thr or Arg; X4 is Ala, Asp, Glu, Gly or Ser; X5 is Ser or Thr; X6 is Asp or Glu; Cys a-d are each independently a cysteine ​​residue; preferably, the residue Cys a With Cys b and Cys c With Cys d Further, the formula LG-IX comprises the polypeptide Ala-Gly-Ser-Cys a -Tyr-Cys c -Ser-Gly-Pro-Pro-Arg-Phe-Glu-Cys d -Trp-Cys b -Tyr-Glu-Thr-Glu-Gly-Thr-Gly-Gly-Gly-Lys, where: Cys a-d are each independently a cysteine ​​residue; preferably, the residue Cys a With Cys b and Cys c With Cys dMore preferably, the carboxyl group of the terminal lysine of Formula IX is amidated; or, Formula IX has at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with the polypeptide, wherein: Cys a-d are each independently a cysteine ​​residue; preferably, the residue Cys a With Cys b and Cys c With Cys d They cyclize to form two independent disulfide bonds.

[0079] In one embodiment of the present invention, each LG in the conjugated drug prostheses as shown in Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can be independently formed by a ligand compound of Formula LG-I or an optical isomer thereof and binds to a cell surface protein PSMA; a targeting ligand formed by a ligand compound of Formula LG-II or an optical isomer thereof and binds to a cell surface protein FORL1; a targeting ligand formed by a ligand compound of Formula LG-III or an optical isomer thereof and binds to a cell surface protein TRPV6; a targeting ligand formed by a ligand compound of Formula LG-IV or an optical isomer thereof and binds to a cell surface protein A targeting ligand for the cell surface protein FAPI; a targeting ligand formed by a ligand compound of formula LG-V or an optical isomer thereof and binding to the cell surface protein CAIX; a targeting ligand formed by a ligand compound of formula LG-VI or an optical isomer thereof and binding to the cell surface protein RGD; a targeting ligand formed by a ligand compound of formula LG-VII or an optical isomer thereof and binding to the cell surface protein Hepsin; a targeting ligand formed by a ligand compound of formula LG-VIII or an optical isomer thereof and binding to the cell surface protein Sigma; or a targeting ligand formed by a ligand compound of formula LG-IX or an optical isomer thereof and binding to the cell surface protein C-MET.

[0080] In one embodiment of the present invention, each LG in the conjugated drug prostaglandins of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can be independently formed by any of the following ligand compounds.

[0081] In some embodiments of the present invention, LG in the conjugated drug progenitor (monopal conjugated drug progenitor) as shown in Formula I-1 or Formula I-2 can be formed by any one of the ligand compounds of Formula LG-I, LG-III, LG-IV, LG-V, and LG-IX (or its optical isomers); preferably, LG can be formed by any one of the ligand compounds of Formula LG-1, LG-1A, LG-1B, LG-1C, LG-1D, LG-1E, LG-1G, LG-1H, LG-1K, LG-1L, LG-3, LG-4, LG-4A, LG-4B, LG-4C, LG-4E, LG-4F, LG-11, LG-12, LG-12A, LG-12B, LG-12C, LG-12D, LG-12E, LG-14, LG-5, LG-6, LG-6A, LG-6B, and LG-6C (or its optical isomers).

[0082] In some embodiments of the present invention, each LG in the above-mentioned conjugated drug progenitor (branched bipartite conjugated drug progenitor) as shown in Formula I-3, Formula I-4 or Formula I-6 can be independently represented by Formula LG-I, LG-II, LG-III, LG-IV, LG-V, LG-VI, LG-VII, LG-VIII, LG-IX, any one of the ligand compounds (or their optical isomers); preferably, each LG can be independently represented by the formula LG-1, LG-1A, LG-1B, LG-1C, LG-1D, LG-1E, LG-1G, LG-1H, LG-1K, LG-1L, LG-2, LG-3, LG-4, LG-4A, LG-4B, LG-4C, LG-4E, LG-4F, LG-11, LG-12, LG-12A, LG-12B, LG-12C, LG-12D, LG-12E, LG-14, LG-5, LG-6, LG-6A, LG-6B, LG-6C, LG-7, LG-7A, LG-8, LG-8A, LG-8B, LG-9, LG -10 is formed by any one of the ligand compounds (or optical isomers thereof); more preferably, the two LGs can be respectively formed by the ligand compounds of formula LG-1 and LG-2, LG-1 and LG-11, LG-1B and LG-4, LG-1B and LG-7, LG-1B and LG-8A, LG-1B and LG-10, LG-1E and LG-3, LG-1L and LG-2, LG-2 and LG-3, LG-4A and LG-4B, LG-4A and LG-6C, LG-4A and LG-7A or LG-4A and LG-8B; further preferably, the two LGs can be respectively formed by the ligand compounds of formula LG-1B and LG-4, LG-1B and LG-10 or LG-4A and LG-4B (or optical isomers thereof).

[0083] In some embodiments of the present invention, each LG in the above-mentioned conjugated drug progenitor (straight-chain bipartite conjugated drug progenitor) as shown in Formula I-5 can be independently formed by any one of the ligand compounds of Formula LG-I and LG-VIII (or its optical isomers); preferably, each LG can be independently formed by any one of the ligand compounds of Formula LG-1, LG-1A, LG-1B, LG-1C, LG-1D, LG-1E, LG-1G, LG-1H, LG-1K, LG-1L, LG-9, LG-10 (or its optical isomers); more preferably, the two LGs can be respectively formed by ligand compounds of Formula LG-1 and LG-9 (or its optical isomers); further preferably, the two LGs can be respectively formed by ligand compounds of Formula LG-1 and LG-9 (or its optical isomers), and the LG formed by the ligand compound of Formula LG-9 (or its optical isomers) is connected to L.

[0084] In the present invention, the LG formed by the above-mentioned ligand compound can be various, and the present invention does not impose specific limitations thereon. For example, it can be a monovalent group obtained by losing a hydrogen atom from a primary amino group in the structure (preferably a primary amino group located at a main chain endpoint) (i.e., a secondary amino group, which can be linked to a carboxylic acid group of another structural segment in the conjugated drug precursor to form an amide group); a monovalent group obtained by losing a hydroxyl group in the structure (preferably a carboxylic acid group located at a main chain endpoint) (i.e., a carboxylic acid group, which can be linked to a secondary amino group in another structural segment in the conjugated drug precursor to form an amide group); or a monovalent group obtained by losing a hydrogen atom from a hydroxyl group in the structure (preferably a hydroxyl group located at a main chain endpoint) (e.g., an alkoxy or aryloxy group, which can be linked to a carboxylic acid group in another structural segment in the conjugated drug precursor to form an ester group).

[0085] In the present invention, the above-mentioned conjugated drug precursors shown in Formula I-3, Formula I-4, Formula I-5 or Formula I-6 are relatively preferred because the structures of these precursors contain two targeting ligands, which can act in multiple ways, improve the therapeutic effect, and reduce toxic side effects; at the same time, the two targeting molecules enhance the affinity of the conjugated compound for the target cells and reduce off-target toxicity.

[0086] Furthermore, the radionuclide chelator (i.e., C) contained in the radionuclide conjugated drug precursor of the present invention can complex with a diagnostic and / or therapeutic radioisotope, in particular a therapeutic or dual-purpose radioisotope. When the radionuclide conjugated drug precursor is chelated with the radioisotope (e.g., chelated in an equimolar ratio), a radionuclide conjugated drug can be obtained. Therefore, the radionuclide conjugated drug of the present invention comprises the radionuclide conjugated drug precursor of the present invention and the radioisotope chelated therewith.

[0087] In the present invention, examples of radioisotopes that can be used for diagnosis (imaging) include, but are not limited to, 45 Ti, 52 Fe, 59 Fe, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 63 Zn, 67 Ga, 68 Ga, 89 Zr, 99m Tc, 111 In, 117m Sn, 153 Sm, 177 Lu, 186 Re、 188 Re、 191m Pt, 193m Pt, 195m Pt, 198 Au, 199 Au et al.

[0088] In the present invention, examples of radioisotopes that can be used for treatment include, but are not limited to, 58m Co、 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 89 Sr. 90 Y. 103m Rh, 103 Pd, 111 In, 117m Sn, 119 Sb, 153 Sm, 153 Gd, 161 Tb, 161 Ho, 166 Ho, 177 Lu, 186 Re、 188 Re、 193m Pt, 195m Pt, 197 Pt, 198 Au, 199 Au, 201 Tl, 203 Pb, 212 Bi, 213 Bi, 211 At223 Ra, 224 Ra, 225 Ac, 227 Th et al.

[0089] In one embodiment of the present invention, C in the conjugated drug progenitors shown in Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can chelate any of the following radionuclides: 47 Sc, 48 Sc, 51 Cr, 55 Fe, 64 Cu, 67 Cu, 69 Zn, 67 Ga, 68 Ga, 72 Ga, 72 As、 72 Se, 89 Sr. 88 Y. 90 Y. 99 Tc, 99m Tc, 97 Such as 105 Rh, 109 Pd, 111 In, 119 Sb, 128 Ba, 139 La, 140 La, 142 Pr, 149 Pm, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Second, 175 Yb, 177 Lu, 186 Re、 188 Re、 198 Au, 199 Au, 197 Hg, 201 Tl, 202 Pb, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Th.

[0090] In one embodiment of the present invention, C in the conjugated drug progenitors shown in Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can chelate any of the following radionuclides: 64 Cu, 67 Cu, 67 Ga, 68 Ga, 89 Sr. 90 Y. 99m Tc, 111 In, 119 Sb, 153 Sm, 166 Ho, 177 Lu, 186 Re、 188 Re、 198 Au, 199 Au, 201 Tl, 203 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Th, preferably any of the following radionuclides: 64 Cu, 67 Cu, 111 In, 153 Sm, 177 Lu, 186 Re、 188 Re、 198 Au and 199 Au.

[0091] In one embodiment of the present invention, C in the conjugated drug prodrugs shown in Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can be chelated 177 Lu.

[0092] In the present invention, the chelating agent may contain a variable number of heteroatoms (typically N, O, S or P atoms, especially N, O or S atoms, preferably N or O atoms) to complex the radionuclide and may be cyclic or acyclic (especially cyclic).

[0093] Examples of cyclic chelating agents include, but are not limited to, 1,4,7-triazacyclononane; 1,4,7-triazacyclononane-triacetic acid; 1,4,7,10-tetraazacyclododecane; 1,4,7,10-tetraazacyclotridecane; 1,4,7,11-tetraazacyclotetradecane; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; 2-(1,4,7,10-tetraazacyclododec-1-yl)acetic acid; 2,2'-(1,4,7,10- acetic acid; 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 1,4,8,11-tetraazacyclotetradecane; 1,4,8,12-tetraazacyclopentadecane; 1,5,9,13-tetraazacyclohexadecane; 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid; 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid, etc.

[0094] Examples of acyclic chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (i.e., 2,2',2",2"'-(ethane-1,2-diylbis(nitrilo))tetraacetic acid); diethylenetriaminepentaacetic acid (i.e., 2,2',2",2"'-(((carboxymethyl)nitrino)bis(ethane-2,1-diyl))bis(nitrilo))tetraacetic acid); 2,2'-((2-((carboxymethyl)(2-hydroxyethyl)amino)ethyl)nitrino)diacetic acid; 2,3-bis(2-mercaptoacetamido)propionic acid ; 2,2',2",2"'-(((4'-(3-amino-4-methoxyphenyl)-[2,2':6',2"-terpyridine]-6,6"-diyl)bis(methylene))bis(nitrilo))tetraacetic acid; 2,2'-((1-carboxyethyl)nitroyl)diacetic acid; 2,2'-(ethane-1,2-diylbis(nitroyl))bis(2-(2-hydroxyphenyl)acetic acid); 2,2',2",2"'-((cyclohexane-1,2-diyl)bis(nitrilo))tetraacetic acid, etc.

[0095] In one embodiment of the present invention, C in the conjugated drug progenitor represented by Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can be formed by any of the following chelating compounds.

[0096] In one embodiment of the present invention, C in the conjugated drug prostaglandins of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5 or Formula I-6 can be formed by a chelating compound of Formula C-1.

[0097] In the present invention, C formed by the above-mentioned chelating compound can be various and is not specifically limited thereto. For example, it can be a carboxylic acid group obtained by losing a hydroxyl group from a carboxyl group in the structure (preferably a carboxyl group at the end of the main chain) (which can be connected to a secondary amino group of another structural fragment in the conjugated drug prostaglandin to form an amide group).

[0098] In one embodiment of the present invention, LG and C can be directly linked to form a radionuclide conjugated drug progenitor (i.e., a conjugated drug progenitor as shown in Formula I-2), for example, the targeting ligand is linked to the carboxylic acid group (-C(=O)-) of the chelating agent through its secondary amino group (-NH-) to form an amide group (-NH-(C=O)-).

[0099] Furthermore, the linker (i.e., L) in the radionuclide conjugated drug progenitor of the present invention can serve as an intermediate segment to connect the chelator (C) and the targeting ligand (LG); or, when a spacer (S) is present in the conjugated drug progenitor structure, L can also serve as an intermediate segment to connect C and S. In the present invention, the linker can be either cleavable (or degradable) or non-cleavable (or non-degradable), and the latter is preferred.

[0100] In one embodiment of the present invention, L in the conjugated drug prosuppressant as shown in Formula I, Formula I-1, Formula I-3, Formula I-5 or Formula I-6 can be any one of Formulas LI, L-II, L-III, L-IV, and LV.

[0101] Preferred

[0102] In formula LI (or LI'), the end marked by * is connected to LG in the conjugated drug precursor or is terminated with a hydroxyl group or an amino group, and the end marked by ** is connected to LG or C in the conjugated drug precursor or is terminated with a hydrogen group or an acetyl group; R is absent or is a divalent structural fragment formed by amino acids; preferably, R is a divalent structural fragment formed by lysine, tryptophan or valine;

[0103] Preferably, in formula LI (or LI'), the end marked by * is connected to LG in the conjugated drug progenitor or is terminated with a hydroxyl group or an amino group, the end marked by ** on the left is connected to C in the conjugated drug progenitor, and the end marked by ** on the right is connected to LG in the conjugated drug progenitor or is terminated with a hydrogen group or an acetyl group; R does not exist or is a divalent structural fragment formed by lysine (Lys);

[0104] In formula L-II, the end marked by *** is connected to S or LG in the conjugated drug precursor, and the end marked by ** is connected to C in the conjugated drug precursor; X is NH or O, preferably NH; n is any integer from 2 to 8, preferably 5;

[0105] Preferred

[0106] In formula L-III (or L-III'), the end marked by *** is connected to S or LG in the conjugated drug precursor, and the end marked by ** is connected to C in the conjugated drug precursor; X is absent or is NH or O, preferably NH; n is any integer from 1 to 4, preferably 1;

[0107] Preferred

[0108] In formula L-IV (or L-IV'), the end marked with * is connected to LG in the conjugated drug precursor or is capped with a hydroxyl group or an amino group, and the end marked with ** is connected to LG or C in the conjugated drug precursor or is capped with a hydrogen group or an acetyl group; n is any integer from 1 to 6;

[0109] Preferably, in formula L-IV (or L-IV'), the end marked by * is terminated with a hydroxyl group, the end marked by ** on the left is connected to C in the conjugated drug precursor, and the end marked by ** on the right is connected to LG in the conjugated drug precursor; n is 4;

[0110] In formula LV, the end marked by * is connected to LG in the conjugated drug precursor, and the end marked by ** is connected to C in the conjugated drug precursor; n is any integer from 1 to 5; R1 does not exist or is -NH-CH2-CH2-NH-; R2 does not exist or is Wherein, NH in the one-end connection formula LV marked by *, m is any integer from 1 to 7;

[0111] Preferably, in formula LV, the end marked by * is connected to LG in the conjugated drug precursor, and the end marked by ** is connected to C in the conjugated drug precursor; n is 2 or 3; when R1 is absent, R2 is absent or is Wherein the end marked by * is connected to NH in the formula LV, m is 5; or, when R1 is -NH-CH2-CH2-NH-, R2 does not exist.

[0112] In one embodiment of the present invention, L in the conjugated drug progenitor as shown in Formula I, Formula I-1, Formula I-3, Formula I-5 or Formula I-6 can be any one of the following structural fragments, wherein the end marked by * is connected to LG in the conjugated drug progenitor, the end marked by ** is connected to LG or C in the conjugated drug progenitor, and the end marked by *** is connected to S or LG in the conjugated drug progenitor.

[0113] In one embodiment of the present invention, L in the conjugated drug prostaglandins as shown in Formula I, Formula I-1, Formula I-3, Formula I-5 or Formula I-6 can be one of Formulas L-1, L-2, L-3, L-10, L-11, L-12, L-13, L-14, and L-15.

[0114] In some embodiments of the present invention, L in the conjugated drug prostaglandins as shown in Formula I-1 or Formula 1-5 can be one of Formulas LI, L-III, L-IV, and LV; preferably, L can be one of Formulas L-3, L-3A, L-3B, L-10, L-11, L-12, L-13, L-14, and L-15.

[0115] In some embodiments of the present invention, L in the conjugated drug prostaglandin shown in Formula I-3 may be Formula L-II or L-III; preferably, L may be one of Formulas L-2, L-3, L-3A, and L-3B; more preferably, L may be Formula L-2.

[0116] In some embodiments of the present invention, L in the conjugated drug prostaglandin represented by Formula I-6 can be one of Formulas L-1 and L-1A.

[0117] In the present invention, the above-mentioned L can be connected with LG, C, and optionally S. For example, they can be connected to each other through a condensation reaction between an amino group and a carboxyl group; specifically, the primary amino group in the linker compound (preferably the primary amino group located at the end of the main chain) and the carboxyl group in the other compound can form an amide group through a condensation reaction, or the carboxyl group in the linker compound (preferably the carboxyl group located at the end of the main chain) and the primary amino group in the other compound can form an amide group through a condensation reaction.

[0118] In one embodiment of the present invention, when only one LG is contained, L can connect LG and C to form a radionuclide conjugated drug precursor (i.e., a conjugated drug precursor as shown in Formula I-1), for example, the targeting ligand is connected to the carboxyl group of the linker through its secondary amino group, and at the same time, the linker is connected to the carboxyl group of the chelator through its secondary amino group to form an amide group.

[0119] In another embodiment of the present invention, when two LGs are contained, L can connect one of the LGs (which is also connected to the other LG) and C to form a radionuclide-conjugated drug precursor (i.e., a conjugated drug precursor as shown in Formula I-5). For example, the first targeting ligand is connected to the carboxyl group of the second targeting ligand through its secondary amino group, and the second targeting ligand is connected to the carboxyl group of the linker through its secondary amino group. At the same time, the linker is connected to the carboxyl group of the chelator through its secondary amino group to form amide groups.

[0120] In another embodiment of the present invention, when two LGs are contained, L can simultaneously connect two LGs (which are not connected to each other) to C to form a radionuclide-conjugated drug precursor (i.e., a conjugated drug precursor as shown in Formula I-6). For example, the first targeting ligand and the second targeting ligand are each independently connected to the carboxyl group or secondary amino group of the linker through their secondary amino group or carboxyl group, and at the same time, the linker is connected to the carboxyl group of the chelator through its secondary amino group to form an amide group.

[0121] Furthermore, when the radionuclide conjugated drug progenitor of the present invention contains two targeting ligands (LG), a spacer (i.e., S) can be used as an intermediate segment to connect the chelator (C) and the targeting ligand (LG); alternatively, when a linker (L) is present in the conjugate structure, S can also be used as an intermediate segment to connect L and LG. In the present invention, the spacer can be either cleavable (or degradable) or non-cleavable (or non-degradable), with the latter being preferred.

[0122] In one embodiment of the present invention, S in the conjugated drug prosuppressant as shown in Formula I, Formula I-3 or Formula I-4 can be any one of Formula SI, S-II, and S-III.

[0123] Preferred

[0124] In formula SI (or SI'), one end marked by * is connected to one LG in the conjugated drug progenitor, one end marked by ** is connected to another LG in the conjugated drug progenitor, and the other end marked by ** is connected to L or C in the conjugated drug progenitor; A1 to A3 are each independently a divalent structural fragment formed by amino acids; preferably, A1 to A3 are each independently a divalent structural fragment formed by Asp, Lys, Glu, His or Trp; n and m are each independently any integer between 2 and 8;

[0125] Preferably, in formula SI (or SI'), the end marked by * is connected to one LG in the conjugated drug progenitor, the end marked by ** above is connected to another LG in the conjugated drug progenitor, and the end marked by ** below is connected to L or C in the conjugated drug progenitor; A1-A2-A3 is -Asp-Asp-Lys; m is 4, and n is 4;

[0126] Preferred

[0127] In formula S-II (or S-II'), one end marked by * is connected to one LG in the conjugated drug progenitor, one end marked by ** is connected to another LG in the conjugated drug progenitor, and the other end marked by ** is connected to L or C in the conjugated drug progenitor; n is any integer from 2 to 6, preferably n is 4;

[0128] Preferred

[0129] In formula S-III (or S-III'), the end marked by * is connected to LG in the conjugated drug precursor, and the end marked by ** is connected to L or C in the conjugated drug precursor; n is any integer from 1 to 5, preferably n is 1 or 2.

[0130] In one embodiment of the present invention, S in the conjugated drug progenitor as shown in Formula I, Formula I-3 or Formula I-4 can be any one of the following structural fragments, wherein the end marked by * is connected to one LG in the conjugated drug progenitor, the end marked by ** is connected to another LG in the conjugated drug progenitor, and the end marked by *** is connected to L or C in the conjugated drug progenitor.

[0131] In one embodiment of the present invention, S in the conjugated drug prostaglandins of Formula I, Formula I-3 or Formula I-4 can be one of Formulas S-6, S-9, S-13 and S-18.

[0132] In one embodiment of the present invention, S in the conjugated drug prostaglandin shown in Formula I-3 may be one of Formulas S-II and S-III; preferably, S may be one of Formulas S-13 and S-18; more preferably, S may be Formula S-13.

[0133] In one embodiment of the present invention, S in the conjugated drug prostaglandin shown in Formula I-4 can be one of Formulas SI and S-II; preferably, S can be one of Formulas S-6, S-9, and S-13.

[0134] In the present invention, the above-mentioned S can be connected with LG, C, and optionally L. For example, they can be connected to each other through a condensation reaction between an amino group and a carboxyl group; specifically, the primary amino group in the spacer compound (preferably the primary amino group located at the end of the main chain) and the carboxyl group in the other compound can form an amide group through a condensation reaction, or the carboxyl group in the spacer compound (preferably the carboxyl group located at the end of the main chain) and the primary amino group in the other compound can form an amide group through a condensation reaction.

[0135] In one embodiment of the present invention, S can simultaneously connect two LGs (which are not connected to each other) to C to form a radionuclide-conjugated drug precursor (i.e., a conjugated drug precursor as shown in Formula I-4). For example, the first targeting ligand and the second targeting ligand are each independently connected to the carboxyl group or secondary amino group of the spacer through their secondary amino group or carboxyl group, and at the same time, the spacer is connected to the carboxyl group of the chelator through its secondary amino group to form an amide group.

[0136] In another embodiment of the present invention, S can simultaneously connect two LGs (which are not connected to each other) to L, and then connect C through L to form a radionuclide-conjugated drug precursor (i.e., a conjugated drug precursor as shown in Formula I-3). For example, the first targeting ligand and the second targeting ligand are each independently connected to the carboxyl group or secondary amino group of the spacer through their secondary amino group or carboxyl group, the spacer is connected to the carboxyl group of the linker through its secondary amino group, and at the same time, the linker is connected to the carboxyl group of the chelator through its secondary amino group to form an amide group.

[0137] In one embodiment of the present invention, in Formula I-1,

[0138] LG can be formed by any one of the ligand compounds of formula LG-I, LG-IV, and LG-V (or optical isomers thereof); preferably, it can be formed by any one of the ligand compounds of formula LG-1B, LG-1D, LG-1E, LG-4, and LG-6 (or optical isomers thereof);

[0139] L can be one of formula LI, L-IV, LV (or its optical isomers); preferably, it can be one of L-10, L-11, L-12, L-13, L-14, L-15 (or its optical isomers);

[0140] C can be formed from a chelating compound of formula C-1.

[0141] In one embodiment of the present invention, in Formula I-2,

[0142] LG can be formed by any ligand compound of formula LG-I, LG-III or LG-5 (or its optical isomer); preferably, it can be formed by any ligand compound of formula LG-1D, LG-3, LG-5 (or its optical isomer);

[0143] C can be formed from a chelating compound of formula C-1.

[0144] In one embodiment of the present invention, in Formula I-3,

[0145] The two LGs can be respectively formed by any one of the ligand compounds of formula LG-I, LG-IV, LG-V, LG-VI, LG-VII, LG-VIII (or optical isomers thereof); preferably, they can be formed by the ligand compounds of formula LG-I and LG-IV, LG-I and LG-VI, LG-I and LG-VII, LG-I and LG-VIII, LG-IV and LG-IV, LG-IV and LG-V, LG-IV and LG-VI or LG-IV and LG-VII (or optical isomers thereof); more preferably, they can be formed by the ligand compounds of formula LG-1 and LG-11, LG-1B and LG-4, LG-1B and LG-7, LG-1B and LG-8A, LG-1B and LG-10, LG-4A and LG-4B, LG-4A and LG-6C, LG-4A and LG-7A, or LG-4A and LG-8B ligand compounds (or optical isomers thereof); further preferably, it can be formed by LG-1B and LG-4, LG-1B and LG-10, or LG-4A and LG-4B ligand compounds (or optical isomers thereof);

[0146] S can be one of formulas S-II and S-III (or optical isomers thereof); preferably, it can be one of formulas S-13 and S-18 (or optical isomers thereof); more preferably, it can be formula S-13 (or optical isomers thereof);

[0147] L can be one of formula L-II and L-III (or its optical isomers); preferably, it can be one of formula L-2 and L-3; more preferably, L can be formula L-2;

[0148] C can be formed from a chelating compound of formula C-1.

[0149] In one embodiment of the present invention, in formula I-4,

[0150] The two LGs can be formed by any one of the ligand compounds of formula LG-I, LG-II, and LG-III (or optical isomers thereof); preferably, they can be formed by ligand compounds of formula LG-I and LG-II, LG-I and LG-III, or LG-II and LG-III (or optical isomers thereof); more preferably, they can be formed by ligand compounds of formula LG-1 and LG-2, LG-1E and LG-3, or LG-2 and LG-3 (or optical isomers thereof);

[0151] S can be one of formula S1, S-II (or its optical isomers); preferably, it can be one of formula S-6, S-9, S-13 (or its optical isomers);

[0152] C can be formed from a chelating compound of formula C-1.

[0153] In one embodiment of the present invention, in Formula I-5,

[0154] The two LGs can be formed by ligand compounds of formula LG-I and LG-VIII (or optical isomers thereof), respectively; preferably, they can be formed by ligand compounds of formula LG-1 and LG-9 (or optical isomers thereof), and the LG formed by the ligand compound of formula LG-9 (or optical isomers thereof) is connected to L;

[0155] L may be of formula L-III (or an optical isomer thereof); preferably, may be of formula L-3 (or an optical isomer thereof);

[0156] C can be formed from a chelating compound of formula C-1.

[0157] In one embodiment of the present invention, in Formula I-6,

[0158] The two LGs can be formed by any one of the ligand compounds of formula LG-I, LG-II, and LG-III (or optical isomers thereof); preferably, they can be formed by ligand compounds of formula LG-I and LG-II, LG-I and LG-III, or LG-II and LG-III (or optical isomers thereof); more preferably, they can be formed by ligand compounds of formula LG-1E and LG-3, LG-1L and LG-2, or LG-2 and LG-3 (or optical isomers thereof);

[0159] L can be Formula LI (or an optical isomer thereof); preferably, it can be Formula L-1, L-1A (or an optical isomer thereof);

[0160] C can be formed from a chelating compound of formula C-1.

[0161] In the present invention, the different structural fragments used to construct the radionuclide conjugated drug precursor can be connected in series through an amide group, which can be formed by a condensation reaction of a primary amino group (e.g., a terminal amino group in a compound forming a linker, spacer, or targeting ligand) and a carboxyl group (e.g., multiple carboxyl groups in a compound forming a chelating agent). Generally, the above-mentioned condensation reaction can be carried out in the presence of a coupling reagent to activate the carboxylic acid into a preferred electrophilic reagent, thereby promoting the forward reaction. Exemplary coupling reagents include, but are not limited to, EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide), DCC (dicyclohexylcarbodiimide), HOBt (1-hydroxybenzotriazole), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), etc. Alternatively, amide bond formation can be achieved by activating carboxylic acids with N-hydroxysuccinimide (NHS) to form succinimide esters, which can be further reacted with amines in the absence of any other coupling reagents.

[0162] <Second Aspect>

[0163] The present invention provides the following specific presentations of radionuclide-conjugated drug progenitors.

[0164] Preferably, the present invention provides the following specific presentations of radionuclide-conjugated drug progenitors.

[0165] At the same time, the present invention also provides a dual-ligand compound, which can be directly connected or indirectly connected to a chelating agent through a connecting fragment, thereby obtaining the radionuclide-conjugated drug precursor of the present invention.

[0166] In the present invention, the biligand compound can be in the following specific forms.

[0167] <Third Aspect>

[0168] The present invention provides a radionuclide-coupled drug, which comprises the radionuclide-coupled drug precursor described in the <first aspect> or <second aspect>, and a radioactive isotope chelated therewith.

[0169] In one embodiment of the present invention, the radioactive isotope in the radionuclide-conjugated drug is selected from 47 Sc, 48 Sc, 51 Cr, 55 Fe, 64 Cu, 67 Cu, 69 Zn, 67 Ga, 68 Ga, 72 Ga, 72 As、 72 Se, 89 Sr. 88 Y. 90 Y. 99 Tc, 99m Tc, 97 Such as 105 Rh, 109 Pd, 111 In, 119 Sb, 128 Ba, 139 La, 140 La, 142 Pr, 149 Pm, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Second, 175 Yb, 177 Lu, 186 Re、 188 Re、 198 Au, 199 Au, 197 Hg, 201 Tl, 202 Pb, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Any of Th.

[0170] In one embodiment of the present invention, the radioactive isotope in the radionuclide-conjugated drug is selected from 64 Cu, 67 Cu, 67 Ga, 68Ga, 89 Sr. 90 Y. 99m Tc, 111 In, 119 Sb, 153 Sm, 166 Ho, 177 Lu, 186 Re、 188 Re、 198 Au, 199 Au, 201 Tl, 203 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Any one of Th, preferably 64 Cu, 67 Cu, 111 In, 153 Sm, 177 Lu, 186 Re、 188 Re、 198 Au and 199 Any of Au.

[0171] In one embodiment of the present invention, the radioactive isotope in the radionuclide-conjugated drug is 177 Lu.

[0172] <Fourth Aspect>

[0173] The present invention provides a pharmaceutical composition comprising the radionuclide-conjugated drug precursor described in the <first aspect> or <second aspect> or the radionuclide-conjugated drug described in the <third aspect>.

[0174] Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0175] <Fifth Aspect>

[0176] The present invention provides use of the radionuclide-conjugated drug precursor described in the <First Aspect> or <Second Aspect>, the radionuclide-conjugated drug described in the <Third Aspect>, or the pharmaceutical composition described in the <Fourth Aspect> in the preparation of a drug for preventing and / or treating a disease or condition.

[0177] <Sixth Aspect>

[0178] The present invention provides the radionuclide-conjugated drug precursor described in the <First Aspect> or <Second Aspect>, the radionuclide-conjugated drug described in the <Third Aspect>, or the pharmaceutical composition described in the <Fourth Aspect>, which is used for preventing and / or treating a disease or condition.

[0179] <Seventh Aspect>

[0180] The present invention provides a method for preventing and / or treating a disease or condition, comprising:

[0181] A preventively and / or therapeutically effective amount of the radionuclide-conjugated drug precursor described in the <First Aspect> or <Second Aspect>, or the radionuclide-conjugated drug described in the <Third Aspect>, or the pharmaceutical composition described in the <Fourth Aspect> is administered to an individual in need thereof.

[0182] Preferably, in the <fifth aspect>, <sixth aspect> and / or <seventh aspect>, the disease or condition is cancer, preferably prostate cancer, breast cancer, liver cancer, pancreatic cancer, ovarian cancer, gastric cancer or lung cancer.

[0183] Effects of the Invention

[0184] The radionuclide-conjugated drug of the present invention (or a pharmaceutically acceptable derivative thereof, such as an addition salt) can specifically deliver radionuclides to target cells. When the conjugated drug contains one targeting ligand (LG), it can specifically deliver the radionuclide to target cells. When the conjugated drug contains two targeting ligands (LG), it can function in multiple ways, improving therapeutic efficacy and reducing toxic side effects. Furthermore, the presence of two targeting ligands (LG) enhances the conjugated drug's affinity for target cells and reduces off-target toxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0185] FIG1 is the HPLC spectrum of compound 1′.

[0186] FIG2 is the LC-MS spectrum of compound 1′.

[0187] FIG3 is the HPLC spectrum of compound 2′.

[0188] FIG4 is the LC-MS spectrum of compound 2′.

[0189] FIG5 is the HPLC spectrum of compound 4'.

[0190] FIG6 is the LC-MS spectrum of compound 4'.

[0191] FIG7 is the HPLC spectrum of compound 17′.

[0192] FIG8 is the LC-MS spectrum of compound 17′.

[0193] FIG9 is the HPLC spectrum of compound 21′.

[0194] FIG10 is the LC-MS spectrum of compound 21′.

[0195] FIG11 is the HPLC spectrum of compound 24′.

[0196] FIG12 is the LC-MS spectrum of compound 24′.

[0197] FIG13 is a dynamic SPECT image of the dual-radioactive nuclide-conjugated drug prepared from compound 17′.

[0198] FIG14 is a quantitative graph showing the organ accumulation of the dual-radioactive nuclide-conjugated drug prepared from compound 17′.

[0199] FIG15 is a dynamic SPECT image of the dual-radioactive nuclide-conjugated drug prepared from compound 21′.

[0200] FIG16 is a quantitative graph showing the organ accumulation of the dual-radioactive nuclide-conjugated drug prepared from compound 21′.

[0201] FIG17 is a dynamic SPECT image of a single-component radionuclide-conjugated drug prepared from compound 1′.

[0202] FIG18 is a quantitative graph showing the organ accumulation of a single-drug radionuclide-conjugated drug prepared from compound 1′.

[0203] FIG19 is a dynamic SPECT image of a single-component radionuclide-conjugated drug prepared from compound 2′.

[0204] FIG20 is a quantitative graph showing the organ accumulation of a single-drug radionuclide-conjugated drug prepared from compound 2′.

[0205] FIG21 is a dynamic SPECT image of a single-component radionuclide-conjugated drug prepared from compound 4′.

[0206] FIG22 is a quantitative graph showing the organ accumulation of a single-drug radionuclide conjugated drug prepared from compound 4′. DETAILED DESCRIPTION

[0207] General Terms and Definitions

[0208] Unless otherwise stated, the terms used in the present invention have the following meanings.

[0209] In the present invention, "target" or "drug target" refers to the binding site between the drug and the body's biological macromolecules, mainly involving receptors, enzymes, ion channels, transporters, immune system, genes, etc. Among existing drugs, more than 50% of drugs target receptors, which have become the main and most important targets; more than 20% of drugs target enzymes, especially enzyme inhibitors, which have a special status in clinical applications; about 6% of drugs target ion channels; 3% of drugs target nucleic acids; and the targets of 20% of drugs are still under further study. Specifically, when a subject undergoes certain medical treatments (such as radiotherapy), radiation is irradiated from different directions and converges on the lesion site, which is also a target.

[0210] In this application, "radionuclide" or "radioisotope" refers to an unstable element that emits radiation during its decay. This includes both naturally occurring elements and those produced primarily through nuclear fission or fusion. Radionuclides can be broadly classified into three categories: alpha, beta, and gamma, depending on the radiation emitted during their decay.

[0211] In the present invention, "drug conjugate" or "drug conjugate" refers to a pharmaceutically acceptable compound that is formed by linking fragments of different functions through optional linking fragments and can exert corresponding activities, such as antibody-drug conjugates (ADCs), polypeptide-drug conjugates (PDCs), small molecule-drug conjugates (SMDCs), radionuclide-drug conjugates (RDCs), etc.

[0212] In the present invention, "radionuclide conjugated drug" or "radionuclide drug conjugate" refers to a pharmaceutically acceptable compound that is formed by linking a chelator containing a radionuclide and a targeting ligand (ligand) for at least one target through an optional linker and a spacer, and is capable of exerting targeted radiotherapy activity, wherein the chelator portion is used to complex the radioisotope, the targeting ligand portion is used to exert targeted positioning for one or more specific targets (such as receptors), and the linker portion and the spacer portion are used to connect the chelator portion and the targeting ligand portion to form the complete structure of the radionuclide conjugated drug. In the present invention, "radionuclide conjugated drug precursor" or "radionuclide drug conjugate precursor" refers to the precursor form of the radionuclide conjugated drug before the chelator portion is complexed with the radionuclide.

[0213] In the present invention, "targeting ligand" refers to any molecule or part that can be targeted to a target site, target tissue, target organ, target cell or target cell intracellular region. In some embodiments, the targeting ligand causes the portion connected to the targeting ligand to be distributed more at the target site, target tissue, target organ, target cell or target cell intracellular region compared to non-target sites, non-target tissues, non-target organs, non-target cells or non-target cell intracellular regions, for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more. In some embodiments, the conjugate compound or agent with a targeting ligand is distributed more at the target site, target tissue, target organ, target cell or target cell intracellular region compared to the conjugate compound without a targeting ligand, for example, at least 10%, 20%, 50%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more. In some embodiments, the targeting ligand is capable of triggering or promoting the specific binding of a conjugate compound containing such a targeting ligand to a target molecule, triggering or promoting the endocytosis of the conjugate compound by target cells, and triggering or promoting the enrichment of the conjugate compound around target cells and / or entry into target cells.

[0214] In the present invention, "ligand" may include a variety of chemical molecules or polypeptides that have specific binding affinity for a selected target, and the selected target may be a cell surface protein (such as a cell surface receptor or a cell surface antigen), a specific protein, a cell, a tissue, an organ, etc. In some embodiments, the ligand may specifically bind to a cell surface receptor. In some embodiments, the ligand may specifically bind to a cell surface antigen. In some embodiments, the ligand may specifically bind to a specific protein, and the specific protein may be a disease-causing protein. In some embodiments, the overexpression of the specific protein may cause a disease or the specific protein may be a mutant protein that causes a disease. In some embodiments, the ligand of the present application may be expressed in 10 -6 ~10 -11 M(K d In some embodiments, the ligand of the present application binds to the target with an affinity of at least 10 -6 , at least 10 -7 , at least 10 -8 or at least 10 -9 M(K dIn some embodiments, the ligand of the present application binds to the target with an affinity of at least two times, three times, four times, five times, six times, eight times, ten times, twenty times, fifty times, one hundred times or more compared to the affinity of the non-target (e.g., other cell surface receptors, cell surface antigens or specific proteins, etc.). In some embodiments, the expression of the cell surface receptors, cell surface antigens, and specific proteins of the present application on the surface of target cells (e.g., cancer cells or cells with abnormal physiological functions) or in target cells is significantly higher than that in normal cells. The term "significant" as used in this application refers to a statistically significant difference, or a significant difference that can be recognized by those skilled in the art.

[0215] In this paper, "FOLR1," or folate receptor 1, is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that binds folate with nanomolar affinity, thereby promoting receptor-mediated endocytosis. Fast-growing solid malignancies, including ovarian and lung cancers, rely on folate for metabolism and nucleic acid synthesis.

[0216] In the present invention, "TRPV6" is transient receptor potential cation channel subfamily V member 6, which is a highly selective calcium ion transmembrane transport channel that mediates the active transport of calcium ions from the extracellular to the intracellular. TRPV6 is expressed in normal human kidneys, gastrointestinal tract, pancreas, mammary glands, salivary glands, etc., but is mainly expressed in intestinal epithelial cells, where it participates in the transport of calcium ions into the cells. Therefore, when the number or function of TRPV6 channels changes, changes in calcium ion regulation may be caused, further leading to structural or functional abnormalities in related tissues and organs. Compared with normal tissues, TRPV6 expression is significantly increased in malignant tumors such as breast cancer, bile duct cancer, ovarian cancer, squamous cell lung cancer, and prostate cancer, and its abnormal expression may be related to the formation and progression of tumors.

[0217] In the present invention, "PSMA" refers to prostate-specific membrane antigen, which refers to a type II transmembrane glycoprotein present in the membrane of prostate epithelial cells. It is composed of 750 amino acids, which have 19 intracellular amino acids, 24 transmembrane amino acids and 707 extracellular amino acids. Prostate-specific membrane antigen is expressed in normal prostate epithelial cells, but its expression level in prostate cancer cells is much higher. Compared with the prostate-specific antigen traditionally used for clinical detection, prostate-specific membrane antigen is a more sensitive and specific prostate cancer tumor marker, especially in hormone-refractory prostate cancer and prostate cancer metastases, which are highly expressed. It has high sensitivity and specificity in distinguishing prostate cancer from other types of malignant tumors. At the same time, in a variety of solid tumors of non-prostate origin (such as lung cancer, bladder cancer, gastric cancer, pancreatic cancer, kidney cancer and colorectal cancer, etc.), prostate-specific membrane antigen is also highly specifically expressed on tumor vascular endothelial cells.

[0218] In the present invention, "C-MET" is a protein product encoded by the C-MET proto-oncogene, a receptor for hepatocyte growth factor (HGF), with tyrosine kinase activity, associated with a variety of oncogene products and regulatory proteins, involved in the regulation of cell information transmission and cytoskeleton rearrangement, and is an important factor in cell proliferation, differentiation, and motility. C-MET is closely related to the occurrence and metastasis of various cancers. Studies have shown that many cancer patients have overexpression and gene amplification of C-MET during the occurrence and metastasis of their tumors. Because C-MET acts on different substrates in different cells and at different differentiation stages, it exhibits multiple functions under specific conditions, such as promoting the division of hepatocytes, endothelial cells, and melanocytes, causing the dispersion of epithelial cells, and inducing changes in cell morphology.

[0219] In the present invention, a "pharmaceutical composition" refers to a pharmaceutical composition comprising a small molecule drug, a polypeptide, an antibody (or an antibody-like ligand) or a conjugate thereof as an active pharmaceutical ingredient (API), and other components (e.g., pharmaceutically acceptable excipients). The pharmaceutical composition can be prepared using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding, and / or lyophilizing processes.

[0220] In the present invention, "pharmaceutically acceptable excipients" refer to auxiliary materials widely used in the field of drug production. The main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and / or has specific functionality, and also to provide a method so that after the drug is administered to a subject, the active ingredient can be dissolved at a desired rate, or to promote the effective absorption of the active ingredient in the body of the subject receiving the drug. Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function to the pharmaceutical composition (such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient in the composition). Examples of "pharmaceutically acceptable excipients" include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.

[0221] The technical solutions of the present invention will be described below in conjunction with specific embodiments. The following embodiments are provided to further illustrate the present invention, but are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0222] The starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means. The separation and purification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC) and the like. The structural identification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS) and the like.

[0223] List of abbreviations

[0224] Example 1: Preparation of Compound 1'

[0225] Step 1:

[0226] Under nitrogen, DMAP (1.8 g) and CDI (50 g) were added to a three-necked flask. The reaction temperature was maintained between -5°C and -10°C in an ice bath. DCM (300 ml) was then added to the flask and stirred to dissolve. SM1 (40 g) was weighed and dissolved in DCM (200 ml). The dissolved SM1 was added to a constant-pressure separatory funnel. The flow rate was controlled according to the reaction temperature, and SM1 was slowly added dropwise to the CDI with stirring for 5 h. After completion of the reaction, the mixture was extracted with 10% aqueous citric acid (2 L) and EA (2 L). The organic phase was mixed with silica gel (50.0 g) and passed through a column. The distillate was monitored by TLC in DCM / MeOH (30:1, v / v). The product was collected and concentrated to yield 46.7 g of the product, PSMA-001.

[0227] Step 2:

[0228] Under nitrogen, SM2 (43.81 g) and PSMA-001 (42 g) were added to a single-necked flask. DMSO (500 ml) was then added and stirred to dissolve. DIEA (46.5 g) was then added and magnetically stirred for 3 h. After the reaction was complete, the mixture was extracted with water (2 L) and EA (2 L). Silica gel (50 g) was added to the organic phase, mixed, and passed through a column. The product was eluted with ethyl acetate and collected and concentrated to yield 32.2 g of PSMA-002, with a purity of 71%.

[0229] Step 3:

[0230] PSMA-002 (6.00 g, 3.0 eq) was reacted with Wang resin (1.0 eq), HOBt (3.0 eq), DIC (3.8 eq) and DMAP (0.6 eq) in DMF (7 V) system for 1 h. The reaction was confirmed to be complete by color development with ninhydrin to obtain the product PSMA-003.

[0231] Step 4:

[0232] The Fmoc in PSMA-002 was removed using 20% ​​piperidine / DMF, and the reaction was continued for 30 min. Sampling was performed and the color was developed with ninhydrin to confirm that the reaction was complete, thereby obtaining the product PSMA-004.

[0233] Step 5:

[0234] PSMA-004 (1.0eq), Fmoc-2-Nal-OH (3.0eq), HOBt (3.0eq) and DIC (3.8eq) were reacted in DMF (7V) system for 1h, sampled, and developed with ninhydrin to confirm that the reaction was complete to obtain the product CB6-001.

[0235] Step 6:

[0236] The Fmoc residue in CB6-001 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 minutes, followed by sampling and color development with ninhydrin to confirm the completion of the reaction. The product CB6-002 was then reacted with Fmoc-tranexamic acid (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 hour. The product was then sampled and color developed with ninhydrin to confirm the completion of the reaction.

[0237] Step 7:

[0238] The Fmoc residue in CB6-002 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 minutes, followed by sampling and color development with ninhydrin to confirm the completion of the reaction. The product was then reacted with Fmoc-Cys(Trt)-OH (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 hour. The product was then sampled and color developed with ninhydrin to confirm the completion of the reaction. Finally, the product was reacted with acetic anhydride (10.0 eq) and pyridine (10.0 eq) in DMF (7 V) for 2 hours. The product was sampled and color developed with ninhydrin to confirm the completion of the reaction, yielding product CB6-003.

[0239] Step 8:

[0240] A cleavage solution (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-toluene thiophenol, 2.5% TIPS) equivalent to 7V of the crude resin (i.e., CB6-003) was prepared. The cleavage solution was pre-cooled at 0-5°C, and then the crude resin was poured into the cleavage solution. The temperature was raised to 25°C, nitrogen was protected, and the cleavage was stirred for 3 hours. After the intermediate control reaction was complete, the resin was removed by filtration to obtain a cleavage solution. The solution was slowly added dropwise to 0°C pre-cooled MTBE (MTBE volume was 10V of the cleavage solution volume), stirred to precipitate a solid, and centrifuged to obtain the crude product. The product was then purified (acetonitrile / water: 5% to 80%, v / v) to obtain 100.2 mg of pure CB6-004 as an off-white powder with a purity of 87.6%.

[0241] Step 9:

[0242] 2-CTC resin (1.0 eq) was swollen with DMF for 2 h, then reacted with Fmoc-Lys(Dde)-OH (3.0 eq) and DIEA (4.0 eq) in DMF (7 V) system for 3 h, and finally reacted with MeOH (10.0 eq) and DIEA (10.0 eq) for 2 h to obtain intermediate 1-1.

[0243] Step 10:

[0244] The Fmoc residue in intermediate 1-1 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, followed by sampling and color development with ninhydrin to confirm the completion of the reaction. The residue was then reacted with Fmoc-Val-OH (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 h. The reaction was continued with sampling and color development with ninhydrin to confirm the completion of the reaction, yielding intermediate 1-2.

[0245] Step 11:

[0246] The Fmoc residue in intermediate 1-2 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, followed by sampling and color development with ninhydrin to confirm the completion of the reaction. The product was then reacted with Boc-Met-OH (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 h. The product was then sampled and color developed with ninhydrin to confirm the completion of the reaction, yielding intermediate 1-3.

[0247] Step 12:

[0248] The Dde in the intermediate 1-3 was removed by 2% hydrazine / DMF (7V), and the reaction was continued for 30 min. The sample was taken and the color was developed with ninhydrin to confirm that the reaction was complete, thereby obtaining the intermediate 1-4.

[0249] Step 13:

[0250] Prepare 7V of lysis buffer (formula: 30% TFE / DCM) equivalent to the weight of the crude resin (i.e., Intermediate 1-4). Pre-cool the lysis buffer at 0-5°C, add the crude resin to the lysis buffer, heat to 25°C, under nitrogen, and stir for 3 hours. After the intermediate reaction is complete, remove the resin by filtration to obtain a lysis buffer. Concentrate under reduced pressure at 30°C to remove the DCM in the lysis buffer. Pre-cool 10V of MTBE to 0°C and slowly add the lysis buffer dropwise to the lysis buffer. Stir to precipitate a solid, and centrifuge to obtain a crude Intermediate 1-5.

[0251] Step 14:

[0252] To a 100 ml single-necked jacketed bottle, add intermediate 1-5 (4.4710 mM, 1.0 eq) and saturated aqueous NaHCO3 solution (40 ml), stir evenly, protect with nitrogen, cool to 4.0 ° C in a circulating bath, add NMCM (4.4710 mM, 1.0 eq), stir and react for 2 h, and sample HPLC control shows that the reaction is complete. At 4 ° C, DCM (40 ml) is added to the reaction solution, saturated aqueous citric acid solution is added dropwise, the pH is adjusted to acidic, the liquid is separated, the aqueous phase is re-extracted with DCM, the liquid is separated, the DCM phase is combined, and the reduced pressure is concentrated to obtain 1.80 g of an off-white solid, which is purified by column purification (DCM / MeOH=10 / 1, V / V) to obtain 1.10 g of an off-white solid, namely intermediate 1-6.

[0253] Step 15:

[0254] In an ice-water bath, add 4M HCl / dioxane (11 ml) to the reaction flask, followed by Intermediate 1-6 (1.10 g, 1.9760 mM). Stir under nitrogen for 2 h. Complete reaction was confirmed by HPLC. Concentrate under reduced pressure at 30°C, add MTBE, and centrifuge to obtain crude Intermediate 1-7.

[0255] Step 16:

[0256] To a 500 mL three-necked flask was added DOTA-COOH (10.00 g, 1.01 eq), 4-aminomethyl-N-Boc-aniline (3.80 g, 1.0 eq), HATU (9.80 g, 1.5 eq), DIEA (6.60 g, 3.0 eq), and DMF (100 ml). The mixture was stirred at 25-30°C for 1-2 h. After completion of the reaction, monitored by TLC, EA (10 ml) and water (25 ml) were added, stirred for 2 min, and the layers were allowed to stand. The organic phase was separated, and the aqueous layer was extracted once with EA. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH = 10 / 1, v / v) to give 13.0 g of a white solid, Intermediate 2-1.

[0257] Step 17:

[0258] To a 500 mL three-necked flask, add Intermediate 2-1 (10.00 g, 1.0 eq), DCM (60 mL), and TES (18 mL). Cool to 0-5°C, add TFA (120 mL) dropwise, warm to room temperature, and stir for 3-5 hours. After completion of the reaction, monitor the reaction by HPLC and concentrate to remove the solvent. The concentrated oil is added to MTBE, slurried, filtered, and washed with MTBE to obtain 5.2 g of a white solid, Intermediate 2-2.

[0259] Step 18:

[0260] To a 250 mL three-necked flask, add intermediate 2-2 (4.00 g, 1.0 eq) and water (60 ml). Add a solution of CSCl2 (13.50 g, 15.0 eq) in chloroform (60 ml) dropwise with stirring. After the addition is complete, stir at room temperature for 1-2 h. HPLC control indicates that the reaction is complete. Allow the mixture to stand and separate. The aqueous phase is washed twice with dichloromethane, combined, and concentrated to yield 2.88 g of a yellow solid, intermediate 2-3.

[0261] Step 19:

[0262] To a 100 mL single-necked flask, intermediate 2-3 (1.7 g, 1.6 eq), intermediate 1-7 (1.0 g, 1.0 eq), and DMF (20 mL) were added. The mixture was cooled in an ice bath and TEA (1.2 mL) was added. The mixture was warmed to room temperature and stirred for 1.0 h. After completion of the reaction, the reaction solution was added dropwise to MTBE (200 mL) for slurrying. The mixture was filtered to yield 2.7 g of a white solid, DOTA-Met-Val-Lys(Mal)-OH, with a purity of 92%.

[0263] Step 20:

[0264] To a 25 mL jacketed vial, CB6-004 (58 mg, 1.0 eq) and DMF (2 ml) were added. After stirring until dissolved, DIEA (2 ml) was added, and the pH was controlled at 8-9. DOTA-Met-Val-Lys(Mal)-OH (218.9 mg, 3.0 eq) was then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 1 h. After completion of the reaction, the reaction solution was purified by preparative chromatography (acetonitrile / water: 5%-80%, v / v) to yield 77.8 mg of a white solid, Compound 1', with a purity of 97.07%.

[0265] LC-MS (ESI + ):m / z 1808.1[M+H] + ,904.9[M+2H] + / 2.

[0266] Example 2: Preparation of Compound 2'

[0267] A similar method to Example 1 was used, except that Fmoc-L-3,3-diphenylalanine was used instead of Fmoc-2-Nal-OH in step 5. The reaction solution was purified by preparative chromatography to obtain 172.9 mg of a white solid, compound 2', with a purity of 90.94%.

[0268] LC-MS (ESI +):m / z 1834.2[M+H] + ,918.1[M+2H] + / 2.

[0269] Example 3: Preparation of Compound 3'

[0270] Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.

[0271] Step 12:

[0272] 2-CTC-Resin (1.0 eq) was reacted with Fmoc-Cys(Trt)-OH (3.0 eq) and DIEA (4.0 eq) in DMF (7 V) system for 3 h, and then reacted with MeOH (10.0 eq) and DIEA (10.0 eq) for 2 h to obtain intermediate 3-1.

[0273] Step 13:

[0274] The Fmoc residue in intermediate 3-1 was removed using 20% ​​piperidine / DMF (7 V) for 30 min, after which sampling was performed and the reaction was confirmed to be complete. The product was then reacted with intermediate 3-2 (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 h, after which sampling was performed and the reaction was confirmed to be complete by developing the product with ninhydrin. Intermediate 3-3 was obtained.

[0275] Step 14:

[0276] Prepare 7V of lysis buffer (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-toluene thiophenol, 2.5% TIPS) equivalent to the weight of the crude resin (i.e., intermediate 3-3). Pre-cool the lysis buffer at 0-5°C, then pour the crude resin into the lysis buffer, raise the temperature to 25°C, protect with nitrogen, and stir and cleave for 3 hours. After the intermediate control reaction is complete, filter and remove the resin to obtain the lysis buffer. Slowly add dropwise to 0°C pre-cooled MTBE (MTBE volume is 10V of the lysis buffer volume), stir to precipitate solids, and centrifuge to obtain 0.9g of crude Cys-108.

[0277] Step 15 was similar to Step 20 in Example 1, except that Cys-108 was used instead of CB6-004. The reaction solution was purified by preparative chromatography to obtain 137 mg of a white solid, compound 3', with a purity of 96.62%.

[0278] LC-MS (ESI - ):m / z 1618.8[MH] -,809.7[M-2H] - / 2.

[0279] Example 4: Preparation of Compound 4'

[0280] Step 1:

[0281] Wang resin (3 g, 1.0 eq) was swollen with DMF, then reacted with Fmoc-Lys(Dde)-OH (3.0 eq), HOBt (3.0 eq), DIC (3.8 eq) and DMAP (0.6 eq) in a DMF (7 V) system for 3 h, washed with DMF, and then reacted with acetic anhydride (10.0 eq) and pyridine (10.0 eq) in a DMF (7 V) system for 2 h, washed with DMF to obtain intermediate 4-1.

[0282] Step 2:

[0283] The Fmoc residue in intermediate 4-1 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, after which sampling was performed and the reaction was confirmed complete by color development with ninhydrin. The product was then reacted with DOTA-COOH (3.0 eq), HBTU (3.0 eq), HOBt (1.5 eq), and DIEA (4.5 eq) in DMF (7 V) for 1 h. The reaction was then continued with sampling and color development with ninhydrin to confirm the completion of the reaction, yielding intermediate 4-2.

[0284] Step 3:

[0285] The Dde in intermediate 4-2 was removed using 2% hydrazine / DMF. The reaction was continued for 30 min, after which a sample was taken and the reaction was confirmed to be complete. The product was then reacted with intermediate 3-2 (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 h, after which a sample was taken and the reaction was confirmed to be complete by developing the color with ninhydrin. This afforded intermediate 4-3.

[0286] Step 4:

[0287] A cleavage solution (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-toluene thiophenol, 2.5% TIPS) equivalent to 7V of the crude resin (i.e., intermediate 4-3) was prepared. The cleavage solution was pre-cooled at 0-5°C, then the crude resin was poured into the cleavage solution, heated to 25°C, and stirred under nitrogen for 3 hours. After the reaction was complete, the resin was removed by filtration to obtain the cleavage solution. The solution was slowly added dropwise to 0°C pre-cooled MTBE (MTBE volume = 10V of the cleavage solution volume). Solids were precipitated by stirring, and the crude product was centrifuged. Purification by preparative chromatography yielded 1109.4 mg of a white solid, compound 4', with a purity of 99.38%.

[0288] LC-MS (ESI + ):m / z 1025.8[M+H] + ,513.3[M+2H] + / 2.

[0289] Example 5: Preparation of Compound 5'

[0290] Steps 1-6 were similar to those in Example 2 to obtain CB2-002.

[0291] Step 7:

[0292] The Fmoc residue in CB2-002 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, after which sampling was performed and the reaction was confirmed complete by color development with ninhydrin. The product was then reacted with DOTA-(COOH)4 (3.0 eq), HBTU (3.0 eq), HOBt (1.5 eq), and DIEA (4.5 eq) in DMF (7 V) for 1 h. The product was then sampled and the reaction was confirmed complete by color development with ninhydrin to yield CB2-003.

[0293] Step 8:

[0294] A cleavage solution (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-toluene thiophenol, 2.5% TIPS) equivalent to 7V of crude resin (i.e., CB2-003) was prepared. The cleavage solution was pre-chilled at 0-5°C. The crude resin was then poured into the cleavage solution, heated to 25°C, and cleaved under nitrogen for 3 hours with stirring. After the reaction was complete, the resin was removed by filtration to obtain the cleavage solution. The solution was then slowly added dropwise to 0°C pre-chilled MTBE (10V of the cleavage solution). Solids precipitated by stirring, and the crude product was centrifuged. Purification by preparative chromatography yielded 240.7 mg of compound 5' with a purity of 99.14%.

[0295] LC-MS (ESI + ):m / z 1068.8[M+H] + ,535.0[M+2H] + / 2.

[0296] Example 6: Preparation of Compound 7'

[0297] Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.

[0298] Step 12:

[0299] To a 25 mL jacketed vial, CB9-001 (200 mg, 1.0 eq, obtained by a method similar to the preparation of CB10-001 in Example 8) and DMF (2 mL) were added. After stirring to dissolve, DIEA (2 mL) was added, and the pH was controlled at 8-9. DOTA-Met-Val-Lys(Mal)-OH (185.19 mg, 1.4 eq) was then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 1 h. After completion of the reaction, monitored by HPLC, the reaction solution was purified by preparative chromatography to yield 128.4 mg of a yellow solid, compound 7', with a purity of 95.95%.

[0300] LC-MS (ESI + ):m / z 2529.7[M+H] + ,1265.3[M+2H] + / 2.

[0301] Example 7: Preparation of Compound 8'

[0302] Step 1:

[0303] The Fmoc residue in the TRPV6 resin (prepared by conventional peptide solid-phase synthesis by sequentially incorporating Arg, Pro, Leu, Asp, Val, Lys, Ser, Pro, His, Leu, Phe, Glu, and Lys, followed by the introduction of Fmoc at the N-terminus) was removed using 20% ​​piperidine / DMF. The reaction was allowed to proceed for 30 min, after which sampling was performed and the reaction was confirmed complete by color development with ninhydrin. The product was then reacted with DOTA-COOH (3.0 eq), HBTU (3.0 eq), HOBt (1.5 eq), and DIEA (4.5 eq) in DMF (7 V) for 1 h. The reaction was then completed by sampling and color development with ninhydrin to yield intermediate 8-1.

[0304] Step 2:

[0305] A cleavage solution (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-toluene thiophenol, 2.5% TIPS) equivalent to 7V of the crude resin (i.e., intermediate 8-1) was prepared. The cleavage solution was pre-cooled at 0-5°C, then the crude resin was poured into the cleavage solution, heated to 25°C, and stirred under nitrogen for 3 hours. After the reaction was complete, the resin was removed by filtration to obtain the cleavage solution. The solution was slowly added dropwise to 0°C pre-cooled MTBE (the volume of MTBE was 10V of the cleavage solution), stirred to precipitate a solid, and centrifuged to obtain the crude product. Purification by preparative chromatography yielded 51.6 mg of the pure product, compound 8', with a purity of 98.27%.

[0306] LC-MS (ESI +):m / z 1952.3[M+H] + ,977.2[M+2H] + / 2.

[0307] Example 8: Preparation of Compound 9'

[0308] Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.

[0309] Step 12:

[0310] The resin was loaded into a solid phase reaction column, DMF was added, and nitrogen was bubbled into the solvent to swell the resin for 30 minutes; Fmoc-Arg-OH, DCC (dicyclohexylcarbodiimide) and DMAP were added, and the reaction was carried out at 25°C for 3 hours, followed by end-capping with acetic anhydride and pyridine for 1 hour, and then washed with DMF 3 times. The Fmoc protecting group on the resin was removed with DBLK, and then washed with DMF 5 times. Fmoc-Pro-OH and HOBt were weighed and dissolved with DMF. DIC was added to the above solution in a 0°C ice-water bath, mixed to activate it for 5 minutes, and the solution was added to the above reaction column. After reacting for 3 hours, the solvent was drained and the resin in the reaction column was washed 3 times. The Fmoc protecting group was then removed using DBLK. The above procedure was repeated, sequentially coupling Fmoc-Leu-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Boc)OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-His(Trt)-OH, Fmoc-Leu-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Glu-OtBu, and Pteroic acid. The resin was cleaved with cleavage buffer and filtered. The cleavage buffer was poured into MTBE, and the precipitated solid was washed with MTBE to obtain a crude product. This crude product was then purified by pre-HPLC to yield CB10-001.

[0311] To a 25 mL jacketed flask, CB10-001 (200 mg, 1.0 eq) and DMF (2 ml) were added. After stirring until dissolved, DIEA (2 ml) was added, and the pH was controlled at 8-9. DOTA-Met-Val-Lys(Mal)-OH (134.76 mg, 1.4 eq) was then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 1 h. After completion of the reaction, the reaction solution was purified by preparative chromatography to yield 142.2 mg of a yellow solid, compound 9', with a purity of 97.38%.

[0312] LC-MS (ESI + ):m / z 3099.5[M+H] + ,1034.4[M+3H] + / 3.

[0313] Example 9: Preparation of Compound 10'

[0314] Step 1:

[0315] The Fmoc residue in the TRPV6 resin was removed using 20% ​​piperidine / DMF. After 30 minutes of reaction, the product was sampled and visualized with ninhydrin to confirm the completion of the reaction. The product was then reacted with Cys-108 (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 hour. Samples were taken and visualized with ninhydrin to confirm the completion of the reaction, yielding intermediate 10-1.

[0316] Step 2:

[0317] Prepare a 7V lysis solution (formula: 92.5% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-toluene thiophenol, 2.5% TIPS) equivalent to the weight of the crude resin (i.e., intermediate 10-1). Pre-cool the lysis solution at 0-5°C, then pour the crude resin into the lysis solution, raise the temperature to 25°C, protect with nitrogen, and stir and cleave for 3 hours. After the intermediate control reaction is complete, filter and remove the resin to obtain the lysis solution. Slowly add dropwise to 0°C pre-cooled MTBE (the volume of MTBE is 10V of the volume of the lysis solution), stir to precipitate solids, and centrifuge to obtain the crude product. Prepare and purify to obtain CB11-001.

[0318] Steps 3-13 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.

[0319] Step 14:

[0320] To a 25 mL jacketed flask, CB11-001 (200 mg, 1.0 eq) and pH 7.4 phosphate buffer (2 ml) were added and stirred to dissolve. A 0.15 M aqueous sodium hydrogen phosphate solution was then added to control the pH to 8-9. DOTA-Met-Val-Lys(Mal)-OH (186.35 mg, 2.0 eq) was then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 1 h. After completion of the reaction, the reaction solution was purified by preparative chromatography to yield 111.5 mg of a white solid, Compound 10', with a purity of 95.00%.

[0321] LC-MS (ESI +):3168.7[M+H] + ,793.6[M+4H] + / 4.

[0322] Example 10: Preparation of Compound 11'

[0323] Step 1:

[0324] The Fmoc residue in the TRPV6 resin was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, followed by sampling and color development with ninhydrin to confirm the completion of the reaction. The product was then reacted with Fmoc-Lys(Dde)-OH (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 h. The product was then sampled and color developed with ninhydrin to confirm the completion of the reaction, yielding intermediate 11-1.

[0325] Step 2:

[0326] The Fmoc residue in intermediate 11-1 was removed using 20% ​​piperidine / DMF. After 30 minutes of reaction, a sample was taken and the reaction was confirmed to be complete by color development with ninhydrin. The product was then reacted with 108 (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (7 V) for 1 hour. The sample was taken and the reaction was confirmed to be complete by color development with ninhydrin to obtain intermediate 11-2.

[0327] Step 3:

[0328] The Dde in intermediate 11-2 was removed using 2% hydrazine / DMF. The reaction was continued for 30 min, after which sampling was performed and the reaction was confirmed to be complete. The product was then reacted with DOTA-COOH (3.0 eq), HBTU (3.0 eq), HOBt (1.5 eq), and DIEA (4.5 eq) in DMF (7 V) for 1 h. The product was then sampled and the reaction was confirmed to be complete by development with ninhydrin to yield intermediate 11-3.

[0329] Step 4:

[0330] A cleavage solution (formula: 90% TFA, 2.5% purified water, 2.5% phenol, 2.5% p-toluene thiophenol, 2.5% TIPS) equivalent to 7V of the crude resin (i.e., intermediate 11-3) was prepared. The cleavage solution was pre-cooled at 0-5°C, then the crude resin was poured into the cleavage solution. The temperature was raised to 25°C, nitrogen was applied, and the cleavage was stirred for 3 hours. After the reaction was complete, the resin was removed by filtration to obtain the cleavage solution. The solution was slowly added dropwise to 0°C pre-cooled MTBE (MTBE volume was 10V of the cleavage solution volume). Solids were precipitated by stirring, and the crude product was centrifuged. Purification by preparative chromatography yielded 222.2 mg of the pure product, compound 11', with a purity of 93.975%.

[0331] LC-MS (ESI + ):m / z 2572.91[M+H] + ,644.06[M+4H] + / 4.

[0332] Example 11: Preparation of Compound 12'

[0333] Step 1:

[0334] To a 100 mL jacketed flask, add DOTA-COOH (1 g, 1.0 eq) and acetonitrile (20 mL) and stir to dissolve. N-hydroxysuccinimide (0.3014 g, 1.5 eq) and HBTU (0.9936 g, 1.5 eq) were then added. After nitrogen replacement three times, the reaction was stirred at 25°C for 2 h. After completion of the reaction, monitored by TLC, 10% aqueous citric acid (10 mL) and water (100 mL) were added to the reaction solution, which was then extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure in a 35°C water bath to yield 1.34 g of a white solid, Intermediate 12-1.

[0335] Step 2:

[0336] To a 25 mL jacketed flask, 2-(2-(2-aminoethoxy)ethoxy)acetic acid (0.3917 g, 1.2 eq) and saturated aqueous NaHCO₃ (3.5 mL) were added. The pH was controlled at 8-9, followed by the addition of a solution of Intermediate 12-1 (1.34 g, 1.0 eq) in DME (3.5 mL) and THF (3.5 mL). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 2 h. After completion of the reaction, as monitored by TLC, the reaction solution was poured into water (50 mL) and extracted with DCM (3 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure in a 35°C water bath to afford 1.06 g of Intermediate 12-2 as an oily solid.

[0337] Step 3:

[0338] To a 25 mL jacketed vial were added Intermediate 12-2 (1.06 g, 1.0 eq), N-Boc-ethylenediamine (0.2990 g, 1.5 eq), DMF (10 mL), HATU (0.7095 g, 1.5 eq), and DIEA (0.4823 g, 3.0 eq). The atmosphere was purged with nitrogen three times and the reaction was stirred at 25°C for 2 h. After completion of the reaction, monitored by HPLC, the reaction solution was poured into water (100 mL) and extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure in a 35°C water bath, mixed, and purified by column chromatography (gradient elution, DCM:MeOH = 50:1 to 10:1) to yield 310 mg of Intermediate 12-3 as a white solid.

[0339] Step 4:

[0340] To a 100 mL single-necked flask, add Intermediate 12-3 (310 mg, 1.0 eq) and DCM (10 ml). After stirring to dissolve, TFA (20 ml), TES (3 ml), and purified water (3 ml) were added, and the reaction was stirred at 25°C for 2 h. After completion of the reaction, monitored by HPLC, the reaction solution was concentrated to near dryness under reduced pressure in a 25°C water bath, dissolved in methanol (0.5 ml), and added dropwise to MTBE (20 ml), stirred for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain 200 mg of a white solid, Intermediate 12-4.

[0341] Step 5:

[0342] To a 25 mL jacketed flask, intermediate 12-5-1 (200 mg), N-hydroxysuccinimide (155 mg), and DMF (2 mL) were added sequentially. After stirring to dissolve, EDCI (342 mg) was added. After nitrogen displacement three times, the reaction was stirred at 25°C for 2 h. After completion of the reaction, the reaction solution was poured into water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure in a 35°C water bath to obtain 400 mg of a yellow oily solid, intermediate 12-5.

[0343] To a 50 mL single-necked flask, intermediate 12-4 (200 mg, 1.0 eq) and saturated aqueous NaHCO₃ (3 mL) were added. The pH was controlled at 8-9, followed by the addition of a solution of intermediate 12-5 (275.07 mg, 1.5 eq) in DME (3 mL) and THF (3 mL). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 2 h. After completion of the reaction, monitored by HPLC, the reaction solution was purified by preparative chromatography to yield 114 mg of an oily solid, compound 12′, with a purity of 95.39%.

[0344] LC-MS (ESI + ):m / z 1019.6[M+H] + ,510.7[M+2H] + / 2.

[0345] Example 12: Preparation of Compound 13'

[0346] Steps 1-11 are similar to steps 9-19 in Example 1 to obtain DOTA-Met-Val-Lys(Mal)-OH.

[0347] Step 12:

[0348] To a 25 mL jacketed flask, S-trityl-L-cysteine ​​(200 mg, 1.0 eq) and saturated aqueous NaHCO₃ (2 mL) were added. The pH was controlled at 8-9, followed by the addition of a solution of Intermediate 12-5 (448.19 mg, 1.5 eq) in DME (2 mL) and THF (2 mL). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 2 h. After completion of the reaction, monitored by HPLC, the reaction solution was poured into water (30 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure in a 35°C water bath to yield 580 mg of crude Intermediate 13-1.

[0349] Step 13:

[0350] To a 100 mL single-necked flask, add Intermediate 13-1 (580 mg, 1.0 eq) and DCM (15 ml). After stirring to dissolve, TFA (15 ml) and TES (283.50 mg, 3.33 eq) were added and the mixture was stirred at 25°C for 2 h. After completion of the reaction, monitored by HPLC, the reaction solution was concentrated to near dryness under reduced pressure in a 25°C water bath. MTBE (20 ml) was added and stirred for 0.5 h. The precipitated solid was filtered and concentrated under reduced pressure to obtain 306 mg of crude Intermediate 13-2.

[0351] Step 14:

[0352] To a 25 mL jacketed vial, intermediate 13-2 (300 mg, 1.0 eq) and DMF (2 ml) were added. After stirring to dissolve, DIEA was added to control the pH to 8-9. DOTA-Met-Val-Lys(Mal)-OH (991 mg, 1.8 eq) was then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 25°C for 1 h. After completion of the reaction, the reaction solution was purified by preparative chromatography to yield 140.5 mg of an orange-red solid, compound 13', with a purity of 97.00%.

[0353] LC-MS (ESI + ):m / z 1554.6[M+H] + ,779.3[M+2H] + / 2.

[0354] Example 13: Preparation of Compound 14'

[0355] CR211D6 (50.0 mg, 1.0 eq, preparation method see Nature Medicine, 2015, vol. 21, pp. 955-961) was dissolved in DMF (1 ml), and DOTA-OSu-(COOH)3 (18.0 mg, 2.0 eq) was added. DIEA was then added, and the pH was adjusted to 9. The reaction was stirred at room temperature for 3 h. The reaction was complete by HPLC. Purification by preparative liquid chromatography yielded 42 mg of the product, compound 14', with a purity of 87.73%.

[0356] LC-MS (ESI + ):m / z 3167.3[M+H] + ,1584.2[M+2H] + / 2.

[0357] Example 14: Preparation of Compound 15'

[0358] Step 1:

[0359] DOTA-COOH (1000.0 mg, 1.0 eq) was added to a 100 ml single-necked flask, followed by N-hydroxysuccinimide (226.0 mg, 1.1 eq), HBTU (740.0 mg, 1.1 eq), and acetonitrile (20 ml). The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 5% aqueous citric acid, and then extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.87 g of a white waxy product, DOTA-OSu.

[0360] Step 2:

[0361] Intermediate 15-1 (100.0 mg, 1.0 eq) was added to a 100 ml single-necked flask, followed by DOTA-OSu (276.0 mg, 1.5 eq) and acetonitrile (10 ml). After stirring to dissolve, DIEA (150 μl) was added dropwise under an ice bath to control the pH to 9. The ice bath was removed and the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 5% aqueous citric acid, and then extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.272 mg of a clear oil, Intermediate 15-2.

[0362] Step 3:

[0363]

[0364] Intermediate 15-2 (100.0 mg, 1.0 eq) was added to a 100 ml single-necked flask, followed by DCM (5 ml) and TFA (5 ml), and TES (0.2 ml). The mixture was stirred overnight at room temperature. After HPLC confirmation of the reaction, the reaction solution was concentrated to near dryness under reduced pressure and added dropwise to MTBE. The supernatant was removed by centrifugation, and the solid was purified by preparative chromatography to yield 30 mg of compound 15', with a purity of 95.60%.

[0365] LC-MS (ESI + ):m / z 756.28[M+H] + .

[0366] Example 15: Preparation of Compound 16'

[0367] Steps 1-3 are similar to steps 16-18 in Example 1 to obtain intermediate 2-3.

[0368] Step 4:

[0369] To a 50 mL three-necked flask, intermediate 15-1 (1.00 g, 1.0 eq), 6-Fmoc-aminocaproic acid (0.96 g, 1.05 eq), HOBT (0.52 g, 1.5 eq), EDCI (0.74 g, 1.5 eq), DMAP (0.032 g, 0.1 eq), DIEA (1.00 g, 3.0 eq), and DMF (10 V) were added sequentially and stirred at room temperature for 2-3 h. After completion of the reaction, the reaction solution was purified by preparative chromatography to yield 1.01 g of a white solid, CB3-001.

[0370] Step 5:

[0371] To a 50 mL three-necked flask, add CB3-001 (1.00 g, 1.0 eq), DMF (3.2 ml), and piperidine (0.8 ml) and stir at room temperature for 30 min. After completion of the reaction, monitored by HPLC, the reaction solution was added dropwise to MTBE (40 ml) and centrifuged to yield 600 mg of a white solid, CB3-002.

[0372] Step 6:

[0373] To a 50 mL three-necked flask, add CB3-002 (393 mg, 1.0 eq), intermediate 2-3 (717 mg, 1.6 eq), DIEA (632 mg, 6.0 eq), and DMF (5 ml). Stir at room temperature for 2-3 h. After completion of the reaction, monitored by HPLC, the reaction solution was purified by preparative chromatography to yield 458.6 mg of a white solid, compound 16', with a purity of 95.88%.

[0374] LC-MS (ESI + ):m / z 1033.7[M+H] + .

[0375] Example 16: Preparation of Compound 17'

[0376] Steps 1-6 were similar to those in Example 1 to obtain CB6-002.

[0377] Step 7:

[0378] The Fmoc residue in CB6-002 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, followed by sampling and color development with ninhydrin to confirm the completion of the reaction. The product was then reacted with Fmoc-Lys(Boc)-OH (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (10 V) for 1 h. The product was then sampled and color developed with ninhydrin to confirm the completion of the reaction, yielding intermediate 17-1.

[0379] Step 8:

[0380] The Fmoc residue in intermediate 17-1 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, followed by sampling and color development with ninhydrin to confirm the completion of the reaction. The residue was then reacted with Fmoc-aminocaproic acid (3.0 eq), HOBt (3.0 eq), and DIC (3.8 eq) in DMF (10 V) for 1 h. The residue was then sampled and color developed with ninhydrin to confirm the completion of the reaction, yielding intermediate 17-2.

[0381] Step 9:

[0382] The Fmoc residue in intermediate 17-2 was removed using 20% ​​piperidine / DMF. The reaction was continued for 30 min, after which sampling was performed and the reaction was confirmed complete by color development with ninhydrin. The product was then reacted with DOTA-COOH (3.0 eq), HBTU (3.0 eq), HOBt (3.0 eq), and DIEA (6.0 eq) in DMF (10 V) for 2 h. The reaction was then continued with sampling and color development with ninhydrin to confirm the completion of the reaction, yielding intermediate 17-3.

[0383] Step 10:

[0384] Prepare a 10V lysis buffer (formula: 90% TFA / DCM) equivalent to the weight of the crude resin (i.e., Intermediate 17-3). Pre-cool the lysis buffer at 0-5°C, add the crude resin to the buffer, heat to 25°C, and cleave under nitrogen for 3 hours with stirring. After the reaction is complete, filter and remove the resin to obtain a lysis buffer. Concentrate under reduced pressure at 30°C to remove the DCM. Pre-cool the lysis buffer to 0°C with 10 times the volume of MTBE, slowly add the lysis buffer dropwise, stir to precipitate a solid, and centrifuge to obtain the crude product. Purify by preparative chromatography to obtain 903 mg of the product, Intermediate 17-4.

[0385] Step 11:

[0386] Intermediate 12-5 (100 mg, 1.0 eq) and intermediate 17-4 (237 mg, 1.0 eq) were added to DIEA to adjust the pH of the reaction solution to 9. The reaction was stirred magnetically at room temperature for 2 h. After completion of the reaction, the reaction solution was purified by preparative chromatography to yield 70.9 mg of compound 17' with a purity of 98.87%.

[0387] LC-MS (ESI + ):m / z 1710.83[M+H] + ,427.3[M+4H] + / 4.

[0388] Example 17: Preparation of Compound 18'

[0389] Step 1:

[0390] Intermediate 18-1 (202.0 mg, 1.0 eq) was added to a 25 ml single-necked flask. DMF (3 ml) was added to dissolve the mixture, followed by EDCI (234.0 mg, 4.0 eq). The mixture was magnetically stirred, and N-hydroxysuccinimide (50.0 mg, 1.2 eq) was added. The reaction was allowed to react at room temperature for 2 h. After completion of the reaction as monitored by HPLC, the reaction solution was added dropwise to MTBE. After solid precipitation, the supernatant was removed by centrifugation, and the solid was filtered and dried to obtain 243.1 mg of the product, Intermediate 18-2.

[0391] Step 2:

[0392] To a 25 ml single-necked flask, add Intermediate 18-2 (100.0 mg, 1.0 eq) and Intermediate 17-4 (169.3 mg, 1.0 eq). Dissolve the mixture in DMF (5 ml). Stir magnetically at room temperature. Adjust the pH of the reaction to 9 by adding DIEA dropwise. Allow the reaction to react overnight. After HPLC monitoring of the reaction completion, add the reaction solution dropwise to MTBE. After solid precipitation, the supernatant was removed by centrifugation and the solid was dried to yield 245.3 mg of the product, Intermediate 18-3.

[0393] Step 3:

[0394] To a 25 ml single-necked vial, add intermediate 18-3 (245.3 mg) and a 50% TFA / DCM mixed solvent (5 ml). The mixture was stirred magnetically at room temperature for 1 h. After HPLC control indicated the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography to yield 130 mg of compound 18', with a purity of 98.09%.

[0395] LC-MS (ESI + ):m / z 1869.93[M+H] + ,936.0[M+2H] + / 2.

[0396] Example 18: Preparation of Compound 19'

[0397] Step 1:

[0398] Intermediate 19-1 was synthesized according to the method described in the literature (DOI: 10.1002 / cmdc.201500600) to obtain 1.23 g of a light yellow solid.

[0399] Step 2:

[0400] To a 25 ml single-necked vial, add Intermediate 19-1 (279.1 mg, 2.0 eq) and Intermediate 17-4 (169.3 mg, 1.0 eq). Dissolve in DMF (5 ml) and stir magnetically at room temperature. Adjust the pH of the reaction to 9 with DIEA dropwise. Allow to react overnight. LCMS confirmed the complete reaction. The reaction solution was then added dropwise to MTBE. After solid precipitation, the supernatant was removed by centrifugation and the solid was dried to yield 273 mg of the product, Intermediate 19-2.

[0401] Step 3:

[0402] To a 25 ml single-necked bottle, add intermediate 19-2 (273 mg) and 5 ml of TFA. The mixture was stirred magnetically at room temperature for 3 h. After the reaction was complete by HPLC, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography to obtain 140 mg of the product, compound 19', with a purity of 82.29%.

[0403] LC-MS (ESI + ):m / z 2096.10[M+H] + ,524.86[M+4H] + / 4.

[0404] Example 19: Preparation of Compound 20'

[0405] Step 1:

[0406] Cl-CTC-resin (1.09 mmol / g, 10.0 g, 1.0 eq) was added to DCM (250 ml) and mechanically stirred for 2 h to fully swell. Fmoc-Lys(Boc)-OH (16.4 g, 3.0 eq) was added, followed by DIEA (4.23 g, 3.0 eq). After reacting at room temperature for 3 h, the mixture was transferred to a solid-phase synthesis reactor. The solvent was drained and washed twice with DMF (100 ml). The solvent was drained and a 20% piperidine / DMF solution (100 ml) was added. After nitrogen bubbling for 0.5 h, ninhydrin developed color and the reaction was complete. DMF (100 ml) was added and washed 5 times. Then, the next amino acid (2.0 eq), HATU (3.0 eq) and DIEA (3.0 eq) were added. After nitrogen bubbling for 1 h at room temperature, ninhydrin developed color and the reaction was complete. According to the above method, Fmoc-Lys(Dde)-OH, Fmoc-aminocaproic acid, DOTA-COOH and Fmoc-tranexamic acid were sequentially added to Fmoc-Lys(Boc)-OH.

[0407] After the amino acid condensation and docking were complete, the resin was washed three times with DCM (100 ml) to remove residual DMF, then washed twice with methanol (100 ml) and dried. The dried resin was soaked in 20% trifluoroethanol / DCM solution (200 ml) and reacted at room temperature with magnetic stirring for 3 hours to remove the condensed amino acid fragments from the resin. HPLC monitoring of the reaction was performed to monitor the completion of the reaction. The reaction solution was filtered to remove the resin, and the organic phase was concentrated to near dryness under reduced pressure. Purification by preparative chromatography yielded 7.47 g of a white solid, Intermediate 20-1.

[0408] Step 2:

[0409] To a 50 ml single-necked flask, Intermediate 20-1 (445 mg, 1.0 eq) and HBTU (455 mg, 1.2 eq) were added. The mixture was dissolved in DMF (10 ml) and then DIEA (388 mg, 3.0 eq) was added. The mixture was stirred magnetically at room temperature for 0.5 h. Intermediate 12-5-1 (1182 mg, 1.0 eq) was then added and stirred for 2 h. The reaction was complete by HPLC. The reaction was quenched by the addition of 5% aqueous citric acid (10 ml), extracted with DCM (100 ml), and washed twice with 5% aqueous citric acid (100 ml). The organic phase was then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.63 g of an oil, Intermediate 20-2.

[0410] Step 3:

[0411] To a 50 ml single-necked flask, add Intermediate 20-2 (1.63 g), an equal volume of a mixed TFA / DCM solution (20 ml), and TES (0.2 ml). The mixture was allowed to react at room temperature for 2 h. After completion of the reaction as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure and added dropwise to MTBE. After precipitation of a solid, the supernatant was removed and the solid was purified by preparative chromatography to yield 545 mg of the product, Intermediate 20-3.

[0412] Step 4:

[0413] Intermediate 20-4 (202.0 mg, 1.0 eq) was added to a 25 ml single-necked flask. DMF (3 ml) was added to dissolve the mixture, followed by EDCI (234.0 mg, 4.0 eq). The mixture was magnetically stirred, and N-hydroxysuccinimide (50.0 mg, 1.2 eq) was added. The reaction was allowed to react at room temperature for 2 h. After completion of the reaction as monitored by HPLC, the reaction solution was added dropwise to MTBE. After solid precipitation, the supernatant was removed by centrifugation, the solid was filtered, and dried to yield 243.1 mg of the product, Intermediate 20-5.

[0414] Step 5:

[0415] To a 25 ml single-necked flask, add Intermediate 20-5 (100.0 mg, 1.0 eq) and Intermediate 20-4 (134.0 mg, 1.0 eq). Dissolve the mixture in DMF (5 ml). Stir magnetically at room temperature. Adjust the pH of the reaction to 9 by adding DIEA dropwise. Allow the reaction to react overnight. After HPLC monitoring, the reaction mixture was added dropwise to MTBE. After solid precipitation, the supernatant was removed by centrifugation and the solid was dried to yield 206.7 mg of the product, Intermediate 20-6.

[0416] Step 6:

[0417] To a 25 ml single-necked vial, add intermediate 20-6 (206.7 mg) and a 50% TFA / DCM mixed solvent (5 ml). The mixture was stirred magnetically at room temperature for 1 h. After the reaction was complete by HPLC, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography to yield 9.6 mg of compound 20', with a purity of 86.49%.

[0418] LC-MS (ESI + ):m / z 1926.96[M+H] + ,643.4[M+3H] + / 3.

[0419] Example 20: Preparation of Compound 21'

[0420] Step 1-3 was similar to Step 1-3 in Example 19 to obtain 545 mg of a white solid, Intermediate 20-3.

[0421] Step 4:

[0422] To a 25 ml single-necked flask, add Intermediate 20-3 (100.0 mg, 1.0 eq) and Intermediate 12-5 (134.1 mg, 1.0 eq). Dissolve the mixture in DMF (5 ml). Stir magnetically at room temperature. Adjust the pH of the reaction to 9 by dropwise addition of DIEA. Allow the reaction to react overnight. After HPLC control of the reaction, add the reaction solution dropwise to MTBE. After a solid precipitates, centrifuge and remove the supernatant. The solid is purified by preparative chromatography to yield 6.4 mg of compound 21', with a purity of 90.78%.

[0423] LC-MS (ESI + ):m / z 1767.86[M+H] + ,884.6[M+2H] + / 2.

[0424] Example 21: Preparation of Compound 22'

[0425] Step 1:

[0426] To a 25 ml single-necked flask, add Intermediate 19-1 (279.1 mg, 2.0 eq) and Intermediate 20-3 (134.0 mg, 1.0 eq). Dissolve the mixture in DMF (5 ml). Stir magnetically at room temperature. Adjust the pH of the reaction to 9 by adding DIEA dropwise. Allow the reaction to react overnight. After LC-MS monitoring of the reaction completion, add the reaction solution dropwise to MTBE. After solid precipitation, the supernatant was removed by centrifugation and the solid was dried to yield 216 mg of the product, Intermediate 22-1.

[0427] Step 2:

[0428] To a 25 ml single-necked bottle, add intermediate 22-1 (216 mg) and TFA (5 ml). The mixture was stirred magnetically at room temperature for 3 h. After completion of the reaction under HPLC monitoring, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography to obtain 105 mg of the product, compound 22', with a purity of 83.66%.

[0429] LC-MS (ESI + ):m / z 2153.21[M+H] + ,539.17[M+4H] + / 4.

[0430] Example 22: Preparation of Compound 23'

[0431] Step 1:

[0432] Intermediate 23-1 (200 mg, 1.0 eq) and EDCI (114 mg, 1.5 eq) were added to a 25 ml single-necked flask, and DCM (5 ml) was added to dissolve the mixture. After magnetic stirring for 5 min, N-hydroxysuccinimide (92 mg, 2.0 eq) was added and the mixture was stirred at room temperature for 2 h. After completion of the reaction as monitored by HPLC, the mixture was diluted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 235 mg of a yellow solid, Intermediate 23-2.

[0433] Step 2:

[0434] Intermediate 23-3 (580 mg, 1.0 eq) was dissolved in DMF (5 ml) and magnetically stirred. DBU (153 mg, 1.0 eq) was then added and allowed to react at room temperature for 1 h. After completion of the reaction as monitored by HPLC, the reaction solution was added dropwise to MTBE. An oily substance precipitated. The supernatant was removed and the oil was transferred to a single-necked flask and concentrated under reduced pressure to yield 281 mg of a solid, Intermediate 23-4.

[0435] Intermediate 23-2 (213 mg, 1.0 eq) and intermediate 23-4 (140 mg, 1.0 eq) were added to a 25 ml single-necked vial. THF (5 ml) was then added to dissolve the mixture. The mixture was stirred magnetically for 5 min. DIEA (138 mg, 3.0 eq) was added and the mixture was stirred at room temperature for 2 h. The reaction was monitored for completion by HPLC. The reaction solution was purified by preparative chromatography to yield 79 mg of the product, intermediate 23-5.

[0436] Step 3:

[0437] Intermediate 23-5 (78 mg, 1.0 eq) was added to a 25 ml single-necked vial and dissolved in DCM (5 ml). TFA (2 ml) was then added with magnetic stirring and the reaction was stirred at room temperature for 2 h. The reaction was monitored for completion by HPLC. The reaction solution was concentrated under reduced pressure to yield 53 mg of a glassy solid, Intermediate 23-6.

[0438] Step 4 and Step 5:

[0439] Intermediate 23-7 (300 mg, 1.0 eq) was added to a 25 ml single-necked flask, followed by DCC (174 mg, 2.0 eq) and dissolution in DMF (5 ml). The mixture was stirred magnetically for 5 min. N-hydroxysuccinimide (146 mg, 3.0 eq) was then added and the mixture was allowed to react at room temperature for 2 h. LC-MS monitored the reaction completion. The reaction was quenched by the addition of 5% aqueous citric acid (100 ml), extracted with DCM (100 ml), and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 473 mg of a white solid, Intermediate 23-8.

[0440] Intermediate 23-6 (53 mg, 1.0 eq) was added to a 25 ml single-necked vial and dissolved in DMF (3 ml). Intermediate 23-8 (120 mg, 2.0 eq) was then added and magnetically stirred. DIEA (29 mg, 3.0 eq) was added dropwise and the mixture was stirred at room temperature for 2 h. The reaction was monitored for completion by HPLC. The reaction solution was then added dropwise to MTBE. After solid precipitation, the supernatant was removed by centrifugation. The solid (i.e., crude Intermediate 23-9) was transferred to a 25 ml single-necked vial and TFA (5 ml) was added. The mixture was stirred overnight. The reaction was monitored for completion by LC-MS. The mixture was concentrated under reduced pressure and purified by preparative chromatography to yield 18.3 mg of compound 23' with a purity of 99.71%.

[0441] LC-MS (ESI + ):m / z 1230.64[M+H] + ,616.03[M+2H] + / 2.

[0442] Example 23: Preparation of Compound 24'

[0443] Intermediate 24-1 (50 mg, 1.0 eq) was added to a 25 mL single-necked flask. DMF (2 ml) was added to dissolve the mixture. HBTU (65 mg, 1.5 eq) and EDCI (22 mg, 1.0 eq) were then added. After stirring for 5 min, N-hydroxysuccinimide (29 mg, 2.0 eq) was added and magnetic stirring was continued at room temperature for 1 h. After HPLC monitoring of the reaction completion, the reaction solution was added dropwise to MTBE. A white solid precipitated, and the supernatant was removed by centrifugation, filtered, and dried to yield 63 mg of a solid, Intermediate 24-2.

[0444] 63 mg (1.0 eq) of Intermediate 24-2 and 226 mg (1.5 eq) of Intermediate 17-4 were added with TEA (36 mg, 3.0 eq). The pH of the reaction solution was adjusted to alkaline and the reaction was stirred magnetically at room temperature for 2 h. The reaction was monitored for completion by HPLC. The reaction solution was then purified by preparative chromatography to yield 20.6 mg of the product, Compound 24', with a purity of 91.60%.

[0445] LC-MS (ESI + ):m / z 1703.89[M+H] + ,852.28[M+2H] + / 2.

[0446] Example 24: Preparation of Compound 26'

[0447] Step 1:

[0448] Intermediate 26-1 (400 mg, 1.0 eq) was added to a 25 ml single-necked flask and dissolved in DCM (10 ml). TFA (2 ml) was then added and stirred magnetically at room temperature for 2 h. The reaction was monitored for completion by HPLC, and the reaction solution was concentrated under reduced pressure to yield 313 mg of a pale yellow solid. This solid (313 mg, 1.0 eq) was added to a 25 ml single-necked flask and dissolved in DMF (5 ml). Fmoc-Asp-OtBu (451 mg, 1.2 eq) and HATU (497 mg, 1.5 eq) were then added. Magnetic stirring was then performed, followed by the addition of DIEA (338 mg, 3.0 eq) and the mixture was stirred overnight. The reaction was monitored for completion by HPLC, and the mixture was diluted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 670 mg of an orange-red oil, Intermediate 26-2.

[0449] Step 2:

[0450] Intermediate 26-2 (670 mg, 1.0 eq) was added to a 50 ml single-necked flask and dissolved in DCM (10 ml). TFA (2 ml) was then added and stirred with magnetic stirring at room temperature for 2 h. The reaction was monitored for completion by HPLC. The reaction solution was concentrated under reduced pressure and purified by preparative chromatography to yield 436 mg of a yellow solid, Intermediate 26-3.

[0451] Step 3:

[0452] Intermediate 26-3 (200 mg, 1.0 eq) was added to a 25 ml single-necked flask and dissolved in DMF (5 ml). EDCI (111 mg, 2.0 eq) and N-hydroxysuccinimide (100 mg, 3.0 eq) were then added. The mixture was stirred magnetically at room temperature for 3 h. The reaction was monitored for completion by HPLC. The mixture was diluted with DCM and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 231 mg of a yellow solid, Intermediate 26-4.

[0453] Step 4:

[0454] Intermediate 26-4 (200 mg, 1.0 eq) and Intermediate 23-4 (181 mg, 2.0 eq) were added to a 25 ml single-necked vial. DMF (5 ml) was added to dissolve the mixture. The mixture was magnetically stirred for 5 min, followed by the addition of DIEA (98 mg, 3.0 eq). The mixture was stirred at room temperature for 2 h. The reaction was monitored for completion by HPLC, and the reaction solution was purified by preparative chromatography to yield 162 mg of the product, Intermediate 26-5.

[0455] Step 5 and Step 6:

[0456] Intermediate 26-5 (100 mg, 1.0 eq) was dissolved in DMF (5 ml) and magnetically stirred. DBU (16 mg, 1.0 eq) was then added and allowed to react at room temperature for 1 h. The reaction was monitored for completion by HPLC (intermediate 26-6 was generated). Intermediate 23-8 (162 mg, 2.0 eq) was added, and DIEA was added to adjust the pH to above 9. The reaction was stirred at room temperature for 3 h. The reaction was monitored for completion by HPLC, diluted with DCM, and then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 121 mg of a yellow solid, intermediate 26-7.

[0457] Step 7:

[0458] Intermediate 26-7 (121 mg) was added to a 25 ml single-necked bottle, and TFA (5 ml) was added. The mixture was stirred at room temperature overnight. LC-MS monitored the reaction completion. The reaction solution was concentrated under reduced pressure and purified by preparative chromatography to obtain 29.6 mg of the product, compound 26', with a purity of 98.71%.

[0459] LC-MS (ESI + ):m / z 1301.43[M+H] + .

[0460] Example 25: Preparation of Compound 27'

[0461] Steps 1-3 were similar to those in Example 19 to obtain 545 mg of the product, intermediate 20-3.

[0462] Step 4:

[0463] Intermediate 15-1 (369 mg, 1.0 eq) was added to a 25 ml single-necked flask and dissolved in DMF (2 ml). Succinic anhydride (120 mg, 1.2 eq) was then added, followed by DIEA (388 mg, 3.0 eq), and the mixture was allowed to react at room temperature for 2 h. LC-MS confirmed the reaction was complete, and the reaction solution was added dropwise to MTBE. After the solid precipitated, it was filtered and dried to yield 470 mg of a white solid, Intermediate 27-1. Intermediate 27-1 (470 mg, 1.0 eq) was added to a 25 ml single-necked flask and dissolved in DMF (2 ml). EDCI (287 mg, 1.5 eq) and N-hydroxysuccinimide (230 mg, 2.0 eq) were added and the mixture was stirred at room temperature for 2 h. LC-MS confirmed the reaction was complete, and the reaction solution was added dropwise to MTBE. After the solid precipitated, the supernatant was removed and the solid was dried to yield 435 mg of the product, Intermediate 27-2.

[0464] Step 5:

[0465] To a 25 ml single-necked flask, add Intermediate 27-2 (57 mg, 1.0 eq) and Intermediate 20-3 (134.1 mg, 1.0 eq). Dissolve in DMF (5 ml) and stir magnetically at room temperature. DIEA was then added dropwise to adjust the pH of the reaction mixture to 9. The reaction was allowed to react overnight. The reaction was monitored for completion by HPLC. The reaction mixture was then added dropwise to MTBE. After precipitation of a solid, the supernatant was removed by centrifugation and purified by preparative chromatography to yield 11.3 mg of compound 27' (93.78% purity).

[0466] LC-MS (ESI + ):m / z 1791.81[M+H] + .

[0467] Experimental Example 1: Imaging Study of Radionuclide-Conjugated Drugs in CDX Model

[0468] 1. Sample Preparation

[0469] Take the radionuclide conjugated drug precursor of the present invention (the actual amount of the precursor is about one thousandth of its theoretical molecular weight), add it to physiological saline (1 ml), take 100 μl and add it to 900 μl acetic acid solution (pH = 4.5, 0.4 M) for dilution, take 10 μl and add 0.5 mCi of 177 LuCl3 solution, then add 30μl acetic acid solution, heat at 60℃ for 30min, cool to room temperature after the reaction is completed, and obtain radionuclide conjugated drug. Taking compound 7' as an example, its actual dosage is 2.5mg. 177 After the chelation is completed in LuCl3 solution, the corresponding 177 Lu-conjugated drug.

[0470] 2. Construction of CDX Mouse Model

[0471] Preparation of 293T-F / P cells (overexpressing FOLR1 and PSMA receptors): 293T cells were transfected with FOLR and PSMA receptor plasmids to generate 293T cells that overexpress FOLR1 and PSMA receptors, namely 293T-F / P cells. Related testing has shown that these cells also overexpress the FAPI receptor, making them suitable for screening radionuclide-conjugated drugs targeting the FAPI receptor. Compound activity was tested using these 293T-F / P cells.

[0472] Model construction: The prepared 293T-F / P cells were inoculated subcutaneously into the right leg of BALB / c nude mice (5 weeks old, 18-20 g, female) and the tumor was allowed to grow to 300-500 mm. 3 When , the model construction is completed.

[0473] 3. Grouping and Observation

[0474] Group: The average tumor size is about 300-500 mm 3 The mice were then divided into groups, including a model control group (BALB / c nude mice inoculated with 293T cells) and different drug administration groups.

[0475] Experimental observation and measurement: The Micro-SPECT / CT machine was turned on and the scanning software was opened according to the operating procedures. Tumor-bearing mice were anesthetized with isoflurane and the imaging agent was injected into the tail vein at a dose of 1 nmol / 500 μCi / 0.2 mL / mouse. Data were collected at 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 ​​hours, and 72 hours after administration using static 5-minute SPECT and medium-resolution whole-body CT.

[0476] 4. Experimental Results and Analysis

[0477] As shown in Figures 13 and 14 , the conjugate prepared from precursor 17' is highly and rapidly enriched in tumors, with a long retention time (drug still accumulated in tumors after 72 hours). It is rapidly metabolized in the kidneys (basic metabolism is completed in 8 hours), while accumulation in other organs is low. These results demonstrate that the conjugate and its precursor bind to PSMA / FAP with good specificity, low toxicity to the kidneys and other organs, and a high safety profile, making it suitable for the treatment or diagnosis of tumors.

[0478] As shown in Figures 15 and 16 , the conjugate prepared from precursor 21' exhibits high and rapid tumor accumulation, a long retention time (some drug accumulation in the tumor persists after 72 hours), and rapid renal metabolism (substantially complete within 2 hours). Concentration in other organs is low, and metabolism is rapid. These results demonstrate that the conjugate and its precursor bind to FAP / FAP with good specificity, low toxicity in other organs, and a high safety profile, making them suitable for tumor treatment or diagnosis.

[0479] As shown in Figures 17 and 18 , the conjugate prepared from precursor 1' is highly and rapidly enriched in tumors, has a long retention time (some drug is still accumulated in the tumor after 72 hours), is rapidly metabolized in the kidneys (basic metabolism is completed within 24 hours), and has low accumulation and rapid metabolism in other organs. These results demonstrate that the conjugate and its precursor bind to PSMA with good specificity, low toxicity, and high safety, making them suitable for the treatment or diagnosis of tumors.

[0480] As shown in Figures 19 and 20, the conjugate prepared from precursor 2' is highly and rapidly enriched in tumors, has a long retention time (over 8 hours), is rapidly metabolized in the kidneys (basic metabolism is completed within 8 hours), and has low accumulation in other organs. These results demonstrate that the conjugate and its precursor bind to PSMA with good specificity, low nephrotoxicity, and high safety, making them suitable for the treatment or diagnosis of tumors.

[0481] As shown in Figures 21 and 22, the conjugate prepared from precursor 4' is highly and rapidly enriched in tumors, has a long retention time (over 8 hours), is rapidly metabolized in the kidneys (basic metabolism is completed within 8 hours), and has low accumulation in other organs. These results demonstrate that the conjugate and its precursor bind to PSMA with good specificity, low nephrotoxicity, and high safety, making them suitable for the treatment or diagnosis of tumors.

[0482] The above results show that the precursor of the present invention has good tumor targeting, and the radionuclide-coupled drug prepared therefrom is rapidly enriched in tumors and has a long treatment time, while it is less enriched in other organs (especially the kidneys), has rapid metabolism, and has low toxicity, and can be used for the treatment or diagnosis of tumors.

[0483] Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are illustrative and should not be construed as limiting the present invention. Without departing from the principles and purpose of the present invention, those skilled in the art may make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention, and such changes, modifications, substitutions, and variations are intended to be within the scope of the present invention.

Claims

1. A radionuclide-conjugated drug precursor having a structure as shown in Formula I, in, LG indicates targeting ligand; S represents a spacer; L represents a linker; C represents a chelating agent; m is 1 or 2; n is 0 or 1; p is 0 or 1; and When p is 0, C is directly connected to S or LG; When n is 0, LG is directly connected to L or C; When m is 2, the two LGs are the same as or different from each other, and the two LGs are connected to S, L or C at the same time, or the two LGs are connected to each other and then to S, L or C.

2. The radionuclide-conjugated drug precursor according to claim 1, characterized in that: It has a structure as shown in formula I-1, LG-LC I-1 wherein LG, L and C are as defined in claim 1.

3. The radionuclide-conjugated drug precursor according to claim 1, characterized in that: It has a structure as shown in formula I-2, LG-C I-2 wherein LG and C are as defined in claim 1.

4. The radionuclide-conjugated drug precursor according to claim 1, characterized in that: It has a structure as shown in Formula I-3, wherein LG, S, L and C are as defined in claim 1.

5. The radionuclide-conjugated drug precursor according to claim 1, characterized in that: It has a structure as shown in Formula I-4, wherein LG, S and C are as defined in claim 1.

6. The radionuclide-conjugated drug precursor according to claim 1, characterized in that: It has a structure as shown in Formula I-5, wherein LG, L and C are as defined in claim 1.

7. The radionuclide-conjugated drug precursor according to claim 1, characterized in that: It has a structure as shown in Formula I-6, wherein LG, L and C are as defined in claim 1.

8. The radionuclide-conjugated drug precursor according to any one of claims 1 to 7, characterized in that: The targeting ligands bind to the following cell surface proteins: PSMA, FORL1, TRPV6, FAPI, C-MET, CAIX, RGD, Hepsin, or Sigma.

9. The radionuclide-conjugated drug precursor according to claim 2 or 3, characterized in that: The targeting ligand binds to the following cell surface proteins: PSMA, TRPV6, FAPI, C-MET or CAIX.

10. The radionuclide-conjugated drug precursor according to any one of claims 4 to 7, characterized in that: The targeting ligand binds to the following cell surface proteins: PSMA / FORL1, FORL1 / TRPV6, PSMA / TRPV6, PSMA / FAPI, PSMA / RGD, PSMA / Hepsin, FAPI / RGD, FAPI / FAPI, FAPI / Hespin, PSMA / Sigma, or FAPI / CAIX.

11. The radionuclide-conjugated drug precursor according to any one of claims 1 to 10, characterized in that: The targeting ligand is formed by a polypeptide, an antibody or a small molecule.

12. The radionuclide-conjugated drug precursor according to any one of claims 1 to 7, characterized in that: Each of the targeting ligands is independently formed by any one of the ligand compounds of formula LG-I, LG-II, LG-III, LG-IV, LG-V, LG-VI, LG-VII, LG-VIII, and LG-IX, In formula LG-I, R LG1 For amino, in R1 is hydrogen or optionally substituted cycloalkylformyl; R2 and R3 are each independently hydrogen or an optionally substituted C6-C 10 aryl; R4 is a hydroxyl group, an optionally substituted C1-C6 alkylamino group, an amino acid derivative group, or an oligopeptide derivative group consisting of 2-6 amino acids; R5 is an optionally substituted C1-C6 alkyl group; when substituted, the substituent is an amino-substituted C1-C6 alkanoyl group, an amino-substituted C6-C 10 Aroyl or an acyl group obtained by amidation reaction of the two; Formula LG-II is pteroic acid or folic acid or an analog thereof; Preferably, the folic acid analog is selected from 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 10-formylfolate, methotrexate, 5,10-methylenetetrahydrofolate, aminopterin and raltitrexed; Formula LG-III comprises all or part of the amino acids in the polypeptide EGKLSSNDTEGGLCKEFLHPSKVDLPR; Preferably, formula LG-III comprises 9 to 27 amino acids in said polypeptide; Alternatively, formula LG-III has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the polypeptide KEFLHPSKVDLPR; In formula LG-IV, R LG2 For halogen, amino, in R8 is hydrogen, in R 8’ is a carboxyl-substituted C1-C6 alkylamino group, a carboxyl-substituted C3-C8 cycloalkylmethylamino group, or a carboxyl-substituted C1-C2 alkoxy group; R 8” is hydrogen, amino-substituted C1-C6 alkanoyl, amino-substituted C1-C2 alkoxy C1-C2 alkoxy C1-C2 alkanoyl, carboxyl-substituted C1-C6 alkanoyl or carboxyl substituted C1-C2 alkoxy C1-C2 alkoxy C1-C2 alkanoyl; R9 is in R 9’ is a carbonyl group or a methylene group; In the LG-V model, X is a single bond or -(CH2CH2O) n CH2CONH-, where n is 0, 1, 2, or 3; R LG3 For hydrogen or in R 10 A C1-C6 alkylamino group substituted with a hydroxyl group or a carboxyl group; In formula LG-VI, B1 to B5 are each independently an amino acid fragment formed by any one of the following amino acids: phenylalanine, glutamic acid, arginine, glycine and aspartic acid; and optionally introducing an optionally substituted alkanoyl group and / or an optionally substituted amino group into at least one of the residues of B1 to B5; In formula LG-VII, C1 to C4 each independently represent an amino acid fragment, wherein the C-terminus of C1 is connected to a benzothiazolyl group, the N-terminus of C4 is connected to an acetyl group, and optionally introducing an optionally substituted alkanoyl group into at least one of the C1 to C4 residues; In formula LG-VIII, Y is One end marked by * is connected to the carboxyl group, and the other end is connected to the ring Z; Ring Z is C6-C 10 Aromatic ring or 5-9 membered heteroaromatic ring; R LG4 is hydrogen, C1-C6 alkyl or C1-C6 alkoxy; Formula LG-IX comprises a polypeptide Cys a -X1-Cys c -X2-Gly-Pro-Pro-X3-Phe-Glu-Cys d -Trp-Cys b -Tyr-X4-X5-X6, wherein: X1 is Asn, His or Tyr; X2 is Gly, Ser, Thr or Asn; X3 is Thr or Arg; X4 is Ala, Asp, Glu, Gly or Ser; X5 is Ser or Thr; X6 is Asp or Glu; Cys a-d are each independently a cysteine ​​residue; preferably, the residue Cys a With Cys b and Cys c With Cys d They cyclize to form two independent disulfide bonds; Furthermore, formula LG-IX comprises the polypeptide Ala-Gly-Ser-Cys a -Tyr-Cys c -Ser-Gly-Pro-Pro-Arg-Phe-Glu-Cys d -Trp-Cys b -Tyr-Glu-Thr-Glu-Gly-Thr-Gly-Gly-Gly-Lys, where: Cys a-d are each independently a cysteine ​​residue; preferably, the residue Cys a With Cys b and Cys c With Cys d More preferably, the carboxyl group of the terminal lysine of Formula IX is amidated; or, Formula IX has at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with the polypeptide, wherein: Cys a-d are each independently a cysteine ​​residue; preferably, the residue Cys a With Cys b and Cys c With Cys d They cyclize to form two independent disulfide bonds.

13. The radionuclide-conjugated drug precursor according to claim 2 or 3, characterized in that: The targeting ligand is formed by any one of the ligand compounds of formula LG-I, LG-III, LG-IV, LG-V, LG-IX or an optical isomer thereof.

14. The radionuclide-conjugated drug precursor according to any one of claims 4 to 7, characterized in that: Each of the targeting ligands is independently formed by any one of the ligand compounds of formula LG-I, LG-II, LG-III, LG-IV, LG-V, LG-VI, LG-VII, LG-VIII or an optical isomer thereof; Preferably, the two targeting ligands are respectively formed by LG-I / LG-II, LG-I / LG-IV, LG-I / LG-VI, LG-I / LG-VII, LG-I / LG-VIII, LG-I / LG-III, LG-II / LG-III, LG-IV / LG-IV, LG-IV / LG-V, LG-IV / LG-VI or LG-IV / LG-VII ligand compounds or their optical isomers.

15. The radioactive conjugate drug precursor according to claim 8, characterized in that The targeting ligand is any one of the following: A targeting ligand formed from a ligand compound of formula LG-I or an optical isomer thereof and binding to the cell surface protein PSMA; A targeting ligand formed from a ligand compound of formula LG-II or an optical isomer thereof and binding to the cell surface protein FORL1; A targeting ligand formed from a ligand compound of formula LG-III or an optical isomer thereof and binding to the cell surface protein TRPV6; A targeting ligand formed from a ligand compound of formula LG-IV or an optical isomer thereof and binding to a cell surface protein FAPI; A targeting ligand formed from a ligand compound of formula LG-V or an optical isomer thereof and binding to the cell surface protein CAIX; A targeting ligand formed from a ligand compound of formula LG-VI or an optical isomer thereof and binding to a cell surface protein RGD; A targeting ligand formed from a ligand compound of formula LG-VII or an optical isomer thereof and binding to the cell surface protein Hepsin; A targeting ligand formed from a ligand compound of formula LG-VIII or an optical isomer thereof and binding to a cell surface protein Sigma; and A targeting ligand formed from a ligand compound of formula LG-IX or an optical isomer thereof and binding to a cell surface protein C-MET.

16. The radionuclide-conjugated drug precursor according to any one of claims 1 to 7, characterized in that: Each of the targeting ligands is independently formed by any one of the following ligand compounds:

17. The radionuclide-conjugated drug precursor according to any one of claims 1 to 3, characterized in that: The targeting ligand is formed by any one of the following ligand compounds:

18. The radionuclide-conjugated drug precursor according to any one of claims 1 and 4-7, characterized in that: Each of the targeting ligands is independently formed by any one of the following ligand compounds:

19. The radionuclide-conjugated drug precursor according to any one of claims 1 to 18, characterized in that: The chelating agent contains a variable number of heteroatoms to complex the radionuclide and is cyclic or acyclic, wherein: the heteroatom is N, O, S or P atom, preferably N, O or S atom, more preferably N or O atom; Preferably, the cyclic chelating agent is 1,4,7-triazacyclononane, 1,4,7-triazacyclononane-triacetic acid, 1,4,7,10-tetraazacyclododecane, 1,4,7,10-tetraazacyclotridecane, 1,4,7,11-tetraazacyclotetradecane, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, 2-(1,4,7,10-tetraazacyclododec-1-yl)acetic acid, 2,2'-(1,4,7,10-tetraazacyclododecane-1-yl)acetic acid, acetic acid, 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, 1,4,8,11-tetraazacyclotetradecane, 1,4,8,12-tetraazacyclopentadecane, 1,5,9,13-tetraazacyclohexadecane, 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid or 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid; Preferably, the acyclic chelating agent is 2,2',2",2"'-(ethane-1,2-diylbis(nitrilo))tetraacetic acid, 2,2',2",2"'-(((carboxymethyl)nitryl)bis(ethane-2,1-diyl))bis(nitrilo))tetraacetic acid, 2,2'-((2-((carboxymethyl)(2-hydroxyethyl)amino)ethyl)nitryl)diacetic acid, 2,3-bis(2-mercaptoacetamido)propionic acid, 2,2',2",2" '-(((4'-(3-amino-4-methoxyphenyl)-[2,2':6',2"-terpyridine]-6,6"-diyl)bis(methylene))bis(nitrilo))tetraacetic acid, 2,2'-((1-carboxyethyl)nitrilo)diacetic acid, 2,2'-(ethane-1,2-diylbis(nitrilo))bis(2-(2-hydroxyphenyl)acetic acid) or 2,2',2",2"'-((cyclohexane-1,2-diyl)bis(nitrilo))tetraacetic acid.

20. The radionuclide-conjugated drug precursor according to any one of claims 1 to 18, characterized in that: The chelating agent is formed by any one of the following chelating agent compounds:

21. The radionuclide-conjugated drug precursor according to any one of claims 1 to 20, characterized in that: The linker is cleavable or non-cleavable, preferably non-cleavable.

22. The radionuclide-conjugated drug precursor according to any one of claims 1 to 20, characterized in that: The linker is any one of formula LI, L-II, L-III, L-IV, and LV, In Formula LI, the end marked by * is connected to the targeting ligand in the conjugated drug progenitor or is terminated with a hydroxyl group or an amino group, and the end marked by ** is connected to the targeting ligand or chelating agent in the conjugated drug progenitor or is terminated with a hydrogen or acetyl group; R is absent or is a divalent structural fragment formed by amino acids; preferably, R is a divalent structural fragment formed by lysine, tryptophan or valine; In Formula L-II, the end marked by *** is connected to the spacer or targeting ligand in the conjugated drug precursor, and the end marked by ** is connected to the chelating agent in the conjugated drug precursor; X is NH or O; n is any integer from 2 to 8; In Formula L-III, the end marked with *** is connected to the spacer or targeting ligand in the conjugated drug precursor, and the end marked with ** is connected to the chelating agent in the conjugated drug precursor; X is absent or is NH or O; n is any integer from 1 to 4; In formula L-IV, the end marked with * is connected to the targeting ligand in the conjugated drug prodrug or is capped with a hydroxyl group or an amino group, and the end marked with ** is connected to the targeting ligand or chelating agent in the conjugated drug prodrug or is capped with a hydrogen or acetyl group; n is any integer from 1 to 6; In formula LV, the end marked by * is connected to the targeting ligand in the conjugated drug precursor, and the end marked by ** is connected to the chelating agent in the conjugated drug precursor; n is any integer from 1 to 5; R1 does not exist or is -NH-CH2-CH2-NH-; R2 does not exist or is Wherein one end marked by * is connected to NH in the formula LV, and m is any integer from 1 to 7.

23. The radionuclide-conjugated drug precursor according to any one of claims 1 to 20, characterized in that: The linker is any one of Formula LI, L-III, L-IV or LV.

24. The radionuclide-conjugated drug precursor according to any one of claims 1 to 20, characterized in that: The linker is of formula L-II or L-III.

25. The radionuclide-conjugated drug precursor according to any one of claims 1 to 20, characterized in that: The linker is of formula LI.

26. The radionuclide-conjugated drug precursor according to any one of claims 1 to 22, characterized in that: The linker is any one of the following structural fragments, wherein the end marked with * is connected to the targeting ligand in the conjugated drug prodrug, the end marked with ** is connected to the targeting ligand or chelator in the conjugated drug prodrug, and the end marked with *** is connected to the spacer or targeting ligand in the conjugated drug prodrug:

27. The radionuclide-conjugated drug precursor according to claim 1, 2 or 6, characterized in that: The linker is any one of the following structural fragments, wherein the end marked with * is connected to the targeting ligand in the conjugated drug prodrug, the end marked with ** is connected to the chelating agent in the conjugated drug prodrug, and the end marked with *** is connected to the targeting ligand in the conjugated drug prodrug:

28. The radionuclide-conjugated drug precursor according to claim 1 or 4, characterized in that: The linker is any one of the following structural fragments, wherein the end marked with ** is connected to the chelator in the conjugated drug precursor, and the end marked with *** is connected to the spacer in the conjugated drug precursor:

29. The radionuclide-conjugated drug precursor according to claim 1 or 7, characterized in that: The linker is any one of the following structural fragments, wherein the end marked with * is connected to the targeting ligand in the conjugated drug prodrug, and the end marked with ** is connected to the targeting ligand or chelator in the conjugated drug prodrug:

30. The radionuclide-conjugated drug precursor according to any one of claims 1 to 29, characterized in that: The spacer is cleavable or non-cleavable, preferably non-cleavable.

31. The radionuclide-conjugated drug precursor according to any one of claims 1 to 29, characterized in that: The spacer is any one of formula S1, S-II, and S-III, In Formula S1, one end marked by * is connected to a targeting ligand in the conjugated drug progenitor, one end marked by ** is connected to another targeting ligand in the conjugated drug progenitor, and the other end marked by ** is connected to a linker or chelator in the conjugated drug progenitor; A1 to A3 are each independently a bivalent structural fragment formed by amino acids; preferably, A1 to A3 are each independently a bivalent structural fragment formed by Asp, Lys, Glu, His or Trp; n and m are each independently any integer between 2 and 8; In Formula S-II, one end marked with * is connected to a targeting ligand in the conjugated drug prodrug, one end marked with ** is connected to another targeting ligand in the conjugated drug prodrug, and the other end marked with ** is connected to a linker or chelator in the conjugated drug prodrug; n is any integer from 2 to 6; In formula S-III, the end marked with * is connected to the targeting ligand in the conjugated drug precursor, and the end marked with ** is connected to the linker or chelator in the conjugated drug precursor; n is any integer from 1 to 5.

32. The radionuclide-conjugated drug precursor according to any one of claims 1 to 29, characterized in that: The spacer is of formula S-II or S-III.

33. The radionuclide-conjugated drug precursor according to any one of claims 1 to 29, characterized in that: The spacer is of formula SI or S-II.

34. The radionuclide-conjugated drug precursor according to any one of claims 1 to 31, characterized in that: The spacer is any one of the following structural fragments, wherein the end marked with * is connected to a targeting ligand in the conjugated drug prodrug, the end marked with ** is connected to another targeting ligand in the conjugated drug prodrug, and the end marked with *** is connected to a linker or chelator in the conjugated drug prodrug:

35. The radionuclide-conjugated drug precursor according to claim 1 or 4, characterized in that: The spacer is any one of the following structural fragments, wherein the end marked with * is connected to a targeting ligand in the conjugated drug prodrug, the end marked with ** is connected to another targeting ligand in the conjugated drug prodrug, and the end marked with *** is connected to a linker or chelator in the conjugated drug prodrug:

36. The radionuclide-conjugated drug precursor according to claim 1 or 5, characterized in that: The spacer is any one of the following structural fragments, wherein the end marked with * is connected to a targeting ligand in the conjugated drug prodrug, the end marked with ** is connected to another targeting ligand in the conjugated drug prodrug, and the end marked with *** is connected to a chelating agent in the conjugated drug prodrug:

37. The following radionuclide-conjugated drug precursors:

38. A radionuclide-conjugated drug comprising the radionuclide-conjugated drug precursor according to any one of claims 1 to 37, and a radioactive isotope chelated thereto.

39. The radionuclide-conjugated drug according to claim 38, characterized in that The radioisotope is selected from 47 Sc, 48 Sc, 51 Cr, 55 Fe, 64 Cu, 67 Cu, 69 Zn, 67 Ga, 68 Ga, 72 Ga, 72 As、 72 Se, 89 Sr. 88 Y. 90 Y. 99 Tc, 99m Tc, 97 Such as 105 Rh, 109 Pd, 111 In, 119 Sb, 128 Ba, 139 La, 140 La, 142 Pr, 149 Pm, 153 Sm, 159 Gd, 165 Dy, 166 Ho, 169 Second, 175 Yb, 177 Lu, 186 Re、 188 Re、 198 Au, 199 Au, 197 Hg, 201 Tl, 202 Pb, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Any of Th; Preferably, the radioisotope is selected from 64 Cu, 67 Cu, 67 Ga, 68 Ga, 89 Sr. 90 Y. 99m Tc, 111 In, 119 Sb, 153 Sm, 166 Ho, 177 Lu, 186 Re、 188 Re、 198 Au, 199 Au, 201 Tl, 203 Pb, 212 Bi, 213 Bi, 225 Ac and 227 Any of Th; More preferably, the radioisotope is selected from 64 Cu, 67 Cu, 111 In, 153 Sm, 177 Lu, 186 Re、 188 Re、 198 Au and 199 Any of Au; More preferably, the radioisotope is 177 Lu.

40. A pharmaceutical composition comprising the radionuclide-conjugated drug precursor according to any one of claims 1 to 37 or the radionuclide-conjugated drug according to claim 38 or 39; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

41. Use of the radionuclide-conjugated drug precursor according to any one of claims 1 to 37, the radionuclide-conjugated drug according to claim 38 or 39, or the pharmaceutical composition according to claim 40 in the preparation of a medicament for preventing and / or treating a disease or condition; Preferably, the disease or disorder is cancer, preferably prostate cancer, breast cancer, liver cancer, pancreatic cancer, ovarian cancer, gastric cancer or lung cancer.

42. The radionuclide-conjugated drug precursor according to any one of claims 1 to 37, the radionuclide-conjugated drug according to claim 38 or 39, or the pharmaceutical composition according to claim 40, for use in preventing and / or treating a disease or condition; Preferably, the disease or disorder is cancer, preferably prostate cancer, breast cancer, liver cancer, pancreatic cancer, ovarian cancer, gastric cancer or lung cancer.

43. A method for preventing and / or treating a disease or condition, comprising: administering a preventively and / or therapeutically effective amount of the radionuclide-conjugated drug precursor according to any one of claims 1 to 37, the radionuclide-conjugated drug according to claim 38 or 39, or the pharmaceutical composition according to claim 40 to an individual in need thereof; Preferably, the disease or disorder is cancer, preferably prostate cancer, breast cancer, liver cancer, pancreatic cancer, ovarian cancer, gastric cancer or lung cancer.

44. The following biligand compounds:

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