Neuropeptide Y1 receptor (NPY1R) targeted therapeutic agents and uses thereof

Abstract

Described herein are radiotherapy agents that target tumor cells expressing the neuropeptide Y1 receptor (NPY1R) and their use in the treatment and / or diagnosis of cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 384,873, filed on November 23, 2022, and U.S. Provisional Patent Application No. 63 / 588,412, filed on October 6, 2023, both of which are incorporated herein by reference in their entireties. Technical Field

[0003] Described herein are radiotherapeutic agents that target tumor cells expressing the neuropeptide Y1 receptor (NPY1R) and methods of using such radiotherapeutic agents as cancer therapeutics, diagnostics, or both. Background Art

[0004] Neoplasm is the abnormal growth of cells and causes huge medical burden to mankind, including morbidity and mortality. Neoplasm includes benign or non-cancerous neoplasms, which do not show malignant characteristics and are generally unlikely to become dangerous (e.g., adenoma). Malignant neoplasms show characteristics such as: gene mutation, loss of normal function, rapid division and transfer (invasion) to the ability of other tissues, and neoplasms with uncertain or unknown behavior. Malignant neoplasms (i.e., cancerous solid tumors) are the main cause of death in industrialized countries. Non-cancerous neoplasms including benign adenomas can also cause significant morbidity and mortality. Although standard treatment can achieve significant effects in terms of tumor growth inhibition and even tumor elimination, relative to healthy tissue, the drugs administered only show minimal selectivity to malignant tissue, and their serious side effects limit their efficacy and use. Specific targeting of neoplastic cells without affecting healthy tissue is the main demand for effective solid tumor therapy.

[0005] G protein-coupled receptors (GPCRs), one of three major classes of cell surface receptors, are frequently overexpressed in tumor cells and are considered promising targets for selective tumor therapy. Specifically, NPY1R is overexpressed in multiple cancer types, including but not limited to breast cancer, adrenal and related tumors, renal cell carcinoma, and ovarian cancer, both in tumor cells and tumor-associated blood vessels. Targeted delivery of radionuclides to tumors using small molecule NPY1R-targeting ligands offers a novel approach to treating and diagnosing various cancers, including but not limited to breast cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, Wilms' tumor, or adrenal tumors. Summary of the Invention

[0006] Described herein are radiopharmaceuticals for use in diagnosing and / or treating tumors. The present disclosure provides alternative and improved methods for treating tumors by targeting tumors that overexpress the neuropeptide Y1 receptor (NPY1R). In some embodiments, the radiopharmaceuticals disclosed herein can be used to treat tumors that overexpress NPY1R. In some other embodiments, the radiopharmaceuticals disclosed herein can be used to identify tissues or organs in a subject that contain tumors that overexpress NPY1R. The radiopharmaceuticals disclosed herein can also be used to perform in vivo imaging of a subject for the presence and distribution of tumors that overexpress NPY1R.

[0007] In one aspect, described herein are compounds of formula (I), or pharmaceutically acceptable salts thereof,

[0008] R——Z——(ligand) y

[0009] Formula (I);

[0010] in:

[0011] R is -LL A -R A 、-L-(L A -R A )2 or -L-(L A -R A )3,

[0012] L is a linker or absent;

[0013] L A Is a connector or not present; R A is a chelating moiety or a radionuclide complex thereof;

[0014] Z is -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR Z -、-NR Z C(=O)-, -O-, -NR Z -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-;

[0015] R Z is H or unsubstituted C1-C4 alkyl;

[0016] The ligand is a small molecule modulator of the neuropeptide Y1 receptor (NPY1R); and

[0017] y is 1, 2, or 3.

[0018] In some embodiments, R is -LL A -R Aand L is absent. In some embodiments, the ligand is a small molecule antagonist of NPY1R. In some embodiments, the ligand comprises (2,2-diphenylacetyl)arginineamide, piperidinyl-propyl-benzimidazole, piperidinyl-propyl-indole, 2,6-dimethyl-3,5-dicarboxylate-dihydropyridine, 2,4-diaminopyridine, or 1-benzyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-keto. In some embodiments, the ligand comprises (2,2-diphenylacetyl)arginineamide. In some embodiments, the ligand comprises benzyl-(2,2-diphenylacetyl)arginineamide. In some embodiments, y is 1.

[0019] In another aspect, described herein are compounds of formula (II) or pharmaceutically acceptable salts thereof:

[0020]

[0021] in:

[0022] R 1 is H, -C1-C6 alkyl or -C(=O)NH2;

[0023] R 2 is -OH, -NH2, -C(=O)NH2 or -CH2NHCONH2;

[0024] Each R 3 Independently selected from R 3a 、R 3b 、R 3c and R 3d ;

[0025] R 3a 、R 3b 、R 3c and R 3d Each is independently selected from H, F, Cl, Br, I, -CN, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy;

[0026] R 4 is H, -C(=O)R 10 、-C(=O)NHR 10 or -C(=O)N(CH3)R 10 ;

[0027] R 10 is a substituted or unsubstituted -C1-C6 alkyl, a substituted or unsubstituted 2- to 6-membered heteroalkyl, -(CH2) t -NH2, -(CH2) t C(=O)O(CH2) uCH3, -(CH2) t NHC(=O)(CH2) u CH3 or -(CH2) t - a substituted or unsubstituted 5- to 6-membered heteroaryl ring; t is 1, 2, 3, 4, 5 or 6; and u is 1, 2, 3 or 4;

[0028] R 5 Does not exist or -Z B -L B -R B ;

[0029] Z B -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 11 -、-NR 11 C(=O)-, -O-, -NR 11 -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-;

[0030] L B is the connector; R B is a chelating moiety or a radionuclide complex thereof;

[0031] R 6 Yes-Z A -L A -R A ;

[0032] Z A -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 12 -、-NR 12 C(=O)-, -O-, -NR 12 -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-;

[0033] L A is the connector; R A is a chelating moiety or a radionuclide complex thereof;

[0034] Each R 7 Independently selected from F, Cl, Br, I, -CN, -OH, substituted or unsubstituted -C1-C6 alkyl or substituted or unsubstituted -C1-C6 alkoxy;

[0035] Each R 8 Independently selected from F, Cl, Br, I, -CN, -OH, substituted or unsubstituted -C1-C6 alkyl or substituted or unsubstituted -C1-C6 alkoxy;

[0036] R 9 is H, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted -C1-C6 alkoxy;

[0037] Each R 11 are independently H or unsubstituted C1-C4 alkyl;

[0038] Each R 12 are independently H or unsubstituted C1-C4 alkyl;

[0039] n is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and p is 0, 1, 2, or 3.

[0040] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIa):

[0041]

[0042] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIb):

[0043]

[0044] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIc):

[0045]

[0046] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IId):

[0047]

[0048] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIe):

[0049]

[0050] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the following structure: Each R 3a 、R 3b 、R 3c and R 3d Independently selected from H, F, Cl, Br, I, -CN, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy.

[0051] In some embodiments, R Aand R B If present, each is independently selected from: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A); α,α',α",α"'-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA); 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (D OTAM); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA); 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA); p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA); 6,6'-(((pyridine-2,6 -diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))-dipicolinic acid (H4pypa); H4pypa-benzyl; 6,6',6",6"'-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))-tetra(methylene))-tetrapicolinic acid (H4py4pa); H4py4pa-benzyl; 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA); 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7 ,16-diyl)bis(methylene))dipicolinic acid (macropa); 2,2',2",2"'-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown); 6,6'-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4octapa); H4octapa-benzyl; and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecandioic acid (TTHA); or their radionuclide complexes.

[0052] In some embodiments, R A and R B If present, independently selected from: or a radionuclide complex thereof.

[0053] In some embodiments, R A and RB If present, each is independently selected from: -L 2 -、-L 3 -、-L 4 -、-L 5 -、-L 6 -、-L 7 -、-L 2 -L 3 -、-L 2 -L 4 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 4 -L 6 -、-L 4 -L 7 -、-L 6 -L 7 -、-L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 5 -L 7 -、-L 2 -L 6 -L 7 -、-L 3 -L 4 -L 7 -、-L 4 -L 5 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、-L 4 -L 5 -L 6 -L 7 -、-L 2 -L 4 -L 5 -L 6 -L 7 -or-L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -;L 2Is absent, substituted or unsubstituted -C1-C 20 Alkylene, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR 16 CH2NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)CH2NR 16 -, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH2CH2O) z -、-(OCH2CH2) z -、-(CH2CH2O) w -CH2CH2-, -CH2CH2NR 16 -(CH2CH2O) w -、-(CH2CH2O) w -CH2CH2NR 16 -, -CH2CH2NHC(=O)-(CH2CH2O) w 、-(CH2CH2O) w -CH2CH2NR 16 C(=O)-, -CH2CH2C(=O)NR 16 -(CH2CH2O) w -、-CH2CH2-NR 16 C(=O)CH2-(OCH2CH2) w or -(CH2CH2O) w -CH2CH2C(=O)NR 16 -; Each R 16 is independently H or C1-C4 alkyl; each w is independently 1, 2, 3, 4, 5 or 6; each z is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L 3is absent or a natural or unnatural amino acid, or a peptide formed from two or more independently selected natural and unnatural amino acids, wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted with a -C1-C6 alkyl group; 4 is absent, substituted or unsubstituted 2- to 10-membered heteroalkylene, -CH2-(OCH2CH2) v -、-(CH2CH2O) v -CH2CH2-, -(CH2CH2O) v CH2CH2-NR 17 C(=O)(CH2CH2O) v CH2CH2-、-(CH2CH2O) v CH2CH2-C(=O)NR 17 (CH2CH2O) v CH2CH2-, -C(=O)CH2CH2, -CH2CH2C(=O)-, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 、-(CH2) v -NR 17 -(CH2) v 、-NHC(=O)NH-O-(CH2) v -, -NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v -, -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or -C1-C6 alkylene, said -C1-C6 alkylene being optionally substituted by 1 or 2 groups independently selected from the following: -OR 18 、-NR 18a R 18b 、-C(=O)OR 18 、-O(CH2CH2O) s -CH3, -NR 18 (CH2CH2O) s -CH3, -NR 18 C(=O)(CH2CH2O) s -CH3, -CH2OCH2CH2CO2R 18 or -NR 18 C(=O)CH2CH2CH-(COOH)NR 18 C(=O)-(CH2) s CH3; each R 17are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18a are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18b are independently H, -C1-C6 alkyl, -C(=O)(CH2) x -4-iodophenyl, -C(=O)(CH2) x -4-methylphenyl or sugar alcohol or its derivative; each x is independently 1, 2, 3 or 4; each v is independently an integer from 1 to 40; each s is independently an integer from 1 to 20; L 5 Is not present, -O-, -S-, -S(=O)-, -S(=O)2, -NR 13 -, -CH(=NH)-, -CH(=N-NH)-, -CCH3(=NH)-, -CCH3(=N-NH)-, -C(=O)NR 13 -、-NR 13 C(=O), -NR 13 C(=O)O-、-NR 13 C(=O)NR 13 -or-OC(=O)NR 13 -; Each R 13 Independently selected from H and C1-C4 alkyl; L 6 Is not present or -L 8 -L 9 -L 10 -;L 8 Does not exist, -(CH2) r -、-NR 14 -、-NR 14 -(CH2) r -、-(CH2) r -C(=O)-, -C(=O)-(CH2) r -、-(CH2) r -NR 14 -、-(CH2) r -NR 14 C(=O)-、-(CH2) r -C(=O)NR 14 -、-CH(NHR 14 )-(CH2) r -C(=O)-, -NR 14 C(=O)-(CH2) r - and -C(=O)NR 14 -(CH2) r-; each r is independently 0, 1, 2 or 3; L 10 Does not exist, -(CH2) q -、-NR 15 -、-NR 15 -(CH2) q -、-(CH2) q -C(=O)-, -C(=O)-(CH2) q -、-(CH2) q -NR 15 -、-NR 15 -(CH2) q -NR 15 -、-(CH2) q -NR 15 C(=O)-、-(CH2) q -C(=O)NR 15 -、-CH(NHR 15 )-(CH2) q -C(=O)-, -NR 15 C(=O)-(CH2) q -or-C(=O)NR 15 -(CH2) q -; q is 0, 1, 2, 3, 4, 5, or 6; R 14 and R 15 Each independently selected from H, -C1-C6 alkyl, -C1-C6 alkyl-C(=O)OH, -(CH2CH2O) p -CH3, -C(=O)-(CH2CH2O) p -CH3 or -(CH2CH2O) p -CH2CH2CO2H; p is 1, 2, 3, 4, 5 or 6; L 9 is a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group, a monosaccharide or k is 1, 2, 3, or 4; and L 7 is absent, -NH-, -N(CH3)-, -O-NH-, substituted or unsubstituted N-heterocycloalkylene, -O-NH=(substituted or unsubstituted N-heterocycloalkylene), or a natural or unnatural amino acid.

[0054] In some embodiments, the radionuclide of the radionuclide complex is a lanthanide or actinide. In some embodiments, the radionuclide of the radionuclide complex is actinium, bismuth, cesium, cobalt, copper, dysprosium, erbium, gold, indium, iridium, gallium, lead, lutetium, manganese, palladium, platinum, radium, rhenium, samarium, strontium, technetium, ytterbium, yttrium or zirconium. In some embodiments, the radionuclide of the radionuclide complex is a diagnostic or therapeutic radionuclide. In some embodiments, the radionuclide of the radionuclide complex is an Auger electron emitting radionuclide, an alpha emitting radionuclide, a beta emitting radionuclide or a gamma emitting radionuclide. In some embodiments, the radionuclide of the radionuclide complex is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 69-gallium ( 69 Ga), 71-gallium ( 71 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), 177-lutetium ( 177 Lu), 204-lead ( 204 Pb), 206-lead ( 206 Pb), 207-lead ( 207 Pb), 208-lead ( 208 Pb), 212-lead ( 212 Pb), 63-copper ( 63 Cu), 64-copper ( 64 Cu), 65-copper ( 65 Cu) or 67-copper ( 67 Cu).

[0055] Also described herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration.

[0056] In another aspect, described herein is a method for treating cancer comprising administering an effective amount of a compound described herein (e.g., a compound of Formula (I) or (II)) or a pharmaceutically acceptable salt thereof to a mammal having cancer. In some embodiments, the cancer comprises a tumor, and the tumor overexpresses the neuropeptide Y1 receptor (NPY1R). In some embodiments, the cancer is breast cancer, kidney cancer (e.g., renal cell carcinoma, RCC), ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, Wilms' tumor, or an adrenal tumor. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is kidney cancer (e.g., renal cell carcinoma, RCC). In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is gastrointestinal stromal tumor (GIST). In some embodiments, the cancer is Ewing's sarcoma. In some embodiments, the cancer is Wilms' tumor. In some embodiments, the cancer is an adrenal tumor.

[0057] In another aspect, described herein is a method of treating a tumor in a mammal with a radionuclide, comprising administering to the mammal a compound as described herein (e.g., a compound of Formula (I) or (II)) or a pharmaceutically acceptable salt thereof. In some embodiments, the mammal has been diagnosed with breast cancer. In some embodiments, the mammal has been diagnosed with renal cancer (e.g., renal cell carcinoma, RCC), ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, Wilms' tumor, or an adrenal tumor.

[0058] In another aspect, described herein is a method for targeted delivery of a radionuclide to a tumor in a mammal, comprising administering to a mammal having a tumor a compound described herein (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof; wherein the tumor overexpresses the neuropeptide Y1 receptor (NPY1R).

[0059] In another aspect, described herein is a method for identifying a tissue or organ in a mammal having a tumor expressing neuropeptide Y1 receptor (NPY1R), comprising administering to the mammal a compound described herein (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof; and performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); wherein R A or R B It is a chelating part-diagnostic radionuclide complex.

[0060] In yet another aspect, described herein is a method for in vivo imaging of a tissue or organ having a tumor expressing a neuropeptide Y1 receptor (NPY1R) in a mammal, comprising administering to the mammal a compound described herein (e.g., a compound of Formula (I) or (II)), or a pharmaceutically acceptable salt thereof; and performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); wherein R A or R B It is a chelating part-diagnostic radionuclide complex.

[0061] In any of the embodiments disclosed herein, the mammal is a human.

[0062] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, as various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 Depicts 111 Biodistribution of In[In]-Compound 140B in non-tumor bearing Wistar female rats. Time points were 0.5, 3.0, 6.0, 24, and 72 hours after IV treatment. Activity was measured as percent injected dose per gram of tissue (%ID / g).

[0064] Figure 2 Depicts 111 Biodistribution of In[In]-Compound 140B in female Swiss mice bearing hNPY1R-positive tumors. Time points were 0.5, 3.0, 6.0, 24, and 72 hours after IV treatment. Decay-corrected activity was measured as percent injected dose per gram of tissue (%ID / g). DETAILED DESCRIPTION

[0065] Cancer is that some cells experience genetic changes in the control of its growth and replication and cause a kind of disease of uncontrolled growth and spread, is one of the main causes of death in the world.General type of cancer includes solid tumor (usually originating from the cancer of organ), carcinoma (cancer originating from skin or lining the tissue of organ), sarcoma (cancer of connective tissue such as bone), leukemia (cancer of bone marrow) and lymphoma and myeloma (cancer of immune system).Tumor is the abnormal growth of cells that causes solid tumor, and described solid tumor can be benign (that is, do not show malignant characteristics and generally unlikely to become dangerous, such as adenoma), malignant (that is, show the feature of the ability such as gene mutation, normal function loss, rapid division and transfer (invasion) to other tissues) and have uncertain or unknown behavior.The prior art treatment of tumor is realized by the combination of surgical procedure, chemotherapy and radiotherapy.Surgical procedure can be curative under some conditions, but usually requires multiple intervention and with radiation and chemotherapy combination.In many cases, chemotherapy is proved to be a kind of powerful weapon against cancer. Chemotherapy is usually performed by systemic administration of effective cytotoxic drugs, but these compounds generally lack tumor selectivity and therefore also kill healthy cells in the body. The nonspecific toxicity produced is the cause of the serious side effects of chemotherapy, which does not specifically target cancer cells relative to other cells. Radiotherapy is the use of high-energy radiation to kill cells. The source of radiation can be external beam radiation (applied using an external source), internal radiation (placement of radioactive material near the target cells), or radiation therapy from systemic administration of radioactive material. Like chemotherapy, many radiotherapy options also lack the tumor cell discrimination properties required to achieve the ultimate goal of targeted tumor therapy using drug molecules or radionuclides.

[0066] This article describes radiopharmaceuticals that selectively deliver radionuclides to malignant cells overexpressing NPY1R for use in cancer detection, image-guided cancer surgery, and selective tumor killing.

[0067] GPCRs generally have poor antigenicity, making them difficult targets for antibody-based strategies. The large size of antibodies can affect uniform uptake and they may not penetrate deep into solid tumors. Additionally, antibodies can present difficulties during manufacturing, including batch-to-batch variability.

[0068] Peptides are inherently sensitive to proteolytic enzymes, and peptidases present in most tissues can rapidly degrade peptides into multiple fragments that no longer have significant affinity for the intended receptor. In addition, peptides may induce unwanted immunogenic responses, thereby complicating subsequent stages of development by masking therapeutic efficacy and affecting safety assessments.

[0069] When the peptide ligand is connected to the radionuclide payload, the resulting conjugate is typically rapidly degraded in plasma and produces cytotoxic or radioactive peptide fragments that can be nonspecifically bound to both tumor tissue and normal tissue. This premature decomposition of the peptide radionuclide conjugate can reduce the amount of the radionuclide payload distributed to the target tumor, thereby reducing therapeutic efficacy and possibly increasing toxicity. In addition, peptides are likely to be excreted only via the kidneys, which may limit their application. The obvious renal uptake of some peptide-based therapeutic agents limits their conventional use.

[0070] High-affinity small-molecule ligands that bind to GPCRs have been described and are cell-permeable and accessible to receptor populations in the endoplasmic reticulum and endosomes. Due to the low molecular weight of small molecules, vascular permeability and tumor penetration should be improved compared to high-molecular-weight peptide- and antibody-based conjugates. The affinities of small-molecule ligands exceed those of FDA-approved antibodies by several orders of magnitude in many cases.

[0071] Neuropeptide Y receptor (NPYR)

[0072] Neuropeptide Y (NPY) receptors belong to the class A G protein-coupled receptors (GPCRs). These receptors are involved in controlling a diverse set of behavioral processes, including appetite, circadian rhythms, and anxiety. Four functionally expressed isoforms in humans (NPY1R, NPY2R, NPY4R, and NPY5R) are distributed throughout the central nervous system and periphery. They are activated by the endogenous peptides neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP). NPY1R has been shown to be overexpressed in various cancer types, such as breast cancer. Therefore, NPY1R ligands carrying radionuclide cargo offer a novel approach for cancer imaging and treatment.

[0073] Breast cancer

[0074] Breast cancer is a type of cancer that begins in the breast. It can start in one or both breasts, and in various parts of the breast. There are many types of breast cancer, and the type of breast cancer is determined by the specific cells in the breast that become cancerous.

[0075] Types of breast cancer

[0076] Most breast cancers are carcinomas, which are tumors that begin in the epithelial cells that line organs and tissues throughout the body. When carcinomas form in the breast, they are usually a more specific type called adenocarcinoma, which begins in cells lining the ducts (milk tubes) or lobules (glands in the breast that produce milk).

[0077] The type of breast cancer may also refer to whether the cancer has spread. Breast cancer in situ (ductal carcinoma in situ or DCIS) is a precancerous condition that begins in the milk ducts and has not yet grown into the rest of the breast tissue. The term invasive (or infiltrating) breast cancer is used to describe any type of breast cancer that has spread (invaded) into surrounding breast tissue.

[0078] Breast cancer staging

[0079] The most commonly used staging system for breast cancer is the American Joint Committee on Cancer (AJCC) TNM system. The most recent AJCC system, which took effect in January 2018, has both clinical and pathological staging systems for breast cancer:

[0080] The pathologic stage (also called the surgical stage) is determined by examining the tissue removed during surgery.

[0081] Sometimes, if surgery isn't possible right away or at all, the cancer is clinically staged instead. This is based on the results of a physical examination, biopsy, and imaging tests. Clinical stage is used to help plan treatment. Sometimes, though, the cancer has spread farther than the clinical stage estimates and may not predict the patient's outlook as accurately as the pathological stage.

[0082] In both staging systems, the following seven key pieces of information are used:

[0083] i. Tumor extent (size) (T);

[0084] ii. Spread to adjacent lymph nodes (N);

[0085] iii. Spread to distant sites (metastasis) (M);

[0086] iv. Estrogen receptor (ER) status;

[0087] v. Progesterone receptor (PR) status;

[0088] vi. HER2 status; and

[0089] vii. Cancer grade (G).

[0090] In addition, in some cases, oncotype can also be considered in staging Recurrence score results. Once all of these factors have been determined, this information is combined in a process called staging to assign an overall stage.

[0091] Breast cancer treatment

[0092] Tumors can form in the breast. Current types of treatment used to treat breast tumors include surgery, radiation therapy, chemotherapy, hormone therapy, targeted drug therapy, and immunotherapy.

[0093] There are two main types of surgery to remove breast cancer: breast-conserving surgery and mastectomy. Breast-conserving surgery removes the cancer and some surrounding normal tissue. Only the part of the breast containing the cancer is removed. How much of the breast is removed depends on the location and size of the tumor, among other factors. This surgery is also called a lumpectomy, quadrantectomy, partial mastectomy, or segmental mastectomy. A mastectomy removes the entire breast, including all breast tissue and sometimes other nearby tissue. There are many different types of mastectomy. Some women also have both breasts removed in a bilateral mastectomy. Sometimes, surgery is done to remove nearby lymph nodes and other tissue to which the cancer has spread.

[0094] Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or stop them from growing. There are two types of radiation therapy: external radiation therapy uses a machine outside the body to deliver radiation toward the area with cancer; internal radiation therapy uses a radioactive substance enclosed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. Additionally, targeted radiopharmaceuticals can deliver targeted radiation to the tumor site. Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells by killing them or stopping them from dividing.

[0095] Therefore, there is a need for therapeutic options for breast tumors. This article describes a radiopharmaceutical that delivers radionuclides to breast tumors that overexpress NPY1R. Compared to chemotherapy or radiation therapy, targeted therapies generally cause less damage to normal cells.

[0096] Solid tumors: benign and / or malignant neoplasms (cancer)

[0097] In one aspect, benign and / or malignant neoplasms (solid tumors) are treated using the NPY1R radiopharmaceuticals described herein, wherein the neoplasm comprises cells that overexpress NPY1R on the cell surface.

[0098] As used herein, the term "neoplasm" refers to an abnormal growth of cells that may proliferate in an uncontrolled manner and may have the ability to metastasize (spread).

[0099] Neoplasms include solid tumors, adenomas, carcinomas, sarcomas, leukemias, and lymphomas at any stage of disease, with or without metastasis.

[0100] Solid tumors are abnormal tissue masses that usually do not contain cysts or fluid areas. Solid tumors can be benign (not cancer) or malignant (cancer). Different types of solid tumors are named after the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors.

[0101] Solid tumors are cancers that usually originate in organs such as the bladder, intestine, brain, breast, endometrium, heart, kidney, lung, liver, uterus, ovaries, pancreas or other endocrine organs (thyroid), and prostate.

[0102] In some embodiments, adenomas are treated using the NPY1R radiopharmaceuticals described herein. Adenomas are tumors that are not cancer. They begin in glandular cells of the epithelium (the thin layer of tissue that covers organs, glands, and other structures in the body). Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid gland, prostate gland, and others. Even when benign, they can cause serious health complications by compressing other structures (mass effect) and by producing large amounts of hormones in an unregulated, feedback-independent manner (leading to paraneoplastic syndromes). Over time, adenomas can transform into malignant tumors, at which point they are called adenocarcinomas.

[0103] Adenomas may be found in the colon (e.g., adenomatous polyps, which have a tendency to become malignant and lead to colon cancer), kidneys (e.g., renal adenomas can be precursors to renal cancer), adrenal glands (e.g., adrenal adenomas; some secrete hormones such as cortisol, which causes Cushing's syndrome, aldosterone, which causes Conn's syndrome, or androgens, which cause hyperandrogenism), thyroid glands (e.g., thyroid adenomas), pituitary glands (e.g., pituitary adenomas, such as prolactinomas, Cushing's disease, and acromegaly), parathyroid glands (e.g., adenomas of the parathyroid glands can secrete inappropriately high amounts of parathyroid hormone and thereby cause primary hyperparathyroidism), liver (e.g., hepatocellular adenoma), breasts (e.g., fibroadenomas), appendix (e.g., cystadenomas), bronchi (e.g., bronchial adenomas can cause carcinoid syndrome, a paraneoplastic syndrome), prostate glands (e.g., prostatic adenoma), sebaceous glands (e.g., sebaceous adenoma), and salivary glands.

[0104] Metastasis is the spread of malignant cells to new areas of the body, often via the lymphatic system or bloodstream. Metastatic tumors are tumors that have spread from their primary site of origin, or where they began, to different areas of the body. Metastatic tumors contain malignant cells that express NPY1R on their cell surfaces.

[0105] Tumors that form from cells that have spread are called secondary tumors. Tumors can spread to areas near the original site, called regional metastasis, or to more distant parts of the body, called distant metastasis.

[0106] In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, wherein the tumor is a primary or metastatic tumor. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, wherein the tumor is a primary or metastatic tumor of breast origin. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, wherein the tumor is a primary or metastatic tumor of renal origin. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, wherein the tumor is a primary or metastatic tumor of ovarian origin. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, wherein the tumor is a primary or metastatic tumor of melanoma origin. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, wherein the tumor is a primary or metastatic tumor of gastrointestinal stromal tumor origin. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, wherein the tumor is a primary or metastatic tumor of Ewing's sarcoma origin. In some embodiments, the tumor to be treated comprises tumor cells expressing NPY1R, wherein the tumor is a primary or metastatic tumor of Wilms' tumor origin. In some embodiments, the tumor to be treated comprises tumor cells expressing NPY1R, wherein the tumor is a primary or metastatic tumor of adrenal gland origin.

[0107] In some embodiments, NPY1R radiopharmaceuticals described herein are used to treat cancers, including but not limited to esophageal cancer, hepatocellular carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (of various tissues), bladder cancer including transitional cell carcinoma (a malignant neoplasm of the bladder), bronchial cancer, colon cancer, colorectal cancer, gastric cancer, lung cancer including small cell lung cancer and non-small cell lung cancer, adrenocortical carcinoma, thyroid cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, renal cell carcinoma, ductal carcinoma in situ or bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, osteoblastic cancer, epithelial cancer, and nasopharyngeal cancer.

[0108] In some embodiments, sarcomas are treated with the NPY1R radiopharmaceuticals described herein. Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0109] Solid tumors include, but are not limited to, gliomas, astrocytomas, medulloblastomas, craniopharyngiomas, ependymomas, pinealomas, hemangioblastomas, acoustic neuromas, oligodendrogliomas, meningiomas, melanomas, neuroblastomas, and retinoblastomas. Benign solid tumors include adenomas.

[0110] Primary and metastatic tumors include, for example, lung cancer (including but not limited to lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioalveolar carcinoma, non-small cell carcinoma, small cell carcinoma, and mesothelioma); breast cancer (including but not limited to ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, and mucinous carcinoma); colorectal cancer (including but not limited to colon cancer, rectal cancer); anal cancer; pancreatic cancer (including but not limited to pancreatic adenocarcinoma, islet cell carcinoma, and neuroendocrine tumors); prostate cancer; ovarian cancer (including but not limited to ovarian epithelial carcinoma or surface epithelial-stromal tumors, including serous tumors, endometrioid tumors, and mucinous cystadenocarcinomas, sex cord-stromal tumors); liver cancer and bile duct cancer (including but not limited to hepatocellular carcinoma, bile duct cancer, hemangioma); esophageal cancer (including but not limited to esophageal cancer). ductal adenocarcinoma and squamous cell carcinoma); non-Hodgkin's lymphoma; bladder cancer; uterine cancer (including but not limited to endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear cell carcinoma, uterine sarcoma and leiomyosarcoma, and mixed Müllerian tumor); glioma, glioblastoma, medulloblastoma, and other brain tumors; kidney cancer (including but not limited to renal cell carcinoma, clear cell carcinoma, and Wilms' tumor); head and neck cancer (including but not limited to squamous cell carcinoma); stomach cancer (including but not limited to gastric adenocarcinoma and gastrointestinal stromal tumor); multiple myeloma; testicular cancer; germ cell tumors; neuroendocrine tumors; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs; and signet ring cell carcinoma.

[0111] Representative neuropeptide Y receptor (NPY1R) targeting ligands

[0112] In some embodiments, the NPY1R radiopharmaceuticals described herein have an affinity for NPY1R that is at least 10-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold greater than for other non-target receptors. In some embodiments, the radiopharmaceuticals described herein are selective for NPY1R over any of the other neuropeptide Y isoforms, including NPY2R, NPY4R, and NPY5R. In some embodiments, the NPY1R radiopharmaceuticals described herein have an affinity for NPY1R that is at least 10-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, or at least 1000-fold greater than for any of NPY2R, NPY4R, and NPY5R.

[0113] In some embodiments, the NPY1R radiopharmaceuticals described herein preferentially accumulate in tumor tissues expressing the target NPY1R. In some embodiments, the NPY1R radiopharmaceuticals described herein preferentially accumulate in tissues or organs containing tumor cells expressing NPY1R compared to tissues or organs lacking tumor cells expressing NPY1R. In some embodiments, a compound of Formula (I) or Formula (II) preferentially accumulates at least 1-fold, at least 2-fold, 3-fold, at least 4-fold, at least 5-fold, or more than 5-fold more in tissues or organs containing tumor cells expressing NPY1R compared to tissues or organs lacking tumor cells expressing NPY1R. It should be understood that the compound may accumulate in certain tissues and organs involved in the metabolism and / or excretion of the therapeutic agent, including but not limited to the kidneys and liver.

[0114] In one aspect, the NPY1R radiopharmaceutical described herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0115] R——Z——(ligand) y

[0116] Formula (I);

[0117] in:

[0118] R is -LL A -R A 、-L-(L A -R A )2 or -L-(L A -R A )3,

[0119] L is a linker or absent; L A It is a joint or it is not present;

[0120] R A is a chelating moiety or a radionuclide complex thereof;

[0121] Z is -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR Z -、-NR Z C(=O)-, -O-, -NR Z -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-;

[0122] R Z is H or unsubstituted C1-C4 alkyl;

[0123] The ligand is a small molecule modulator of the neuropeptide Y1 receptor (NPY1R); and y is 1, 2, or 3.

[0124] In some embodiments, R is -LL A -R A And L does not exist.

[0125] In some embodiments, the ligand is a small molecule antagonist of NPY1R.

[0126] In some embodiments, the ligand comprises (2,2-diphenylacetyl)arginine amide, piperidinyl-propyl-benzimidazole, piperidinyl-propyl-indole, 2,6-dimethyl-3,5-dicarboxylate-dihydropyridine, 2,4-diaminopyridine, or 1-benzyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-keto. In some embodiments, the ligand comprises (2,2-diphenylacetyl)arginine amide. In some embodiments, the ligand comprises benzyl-(2,2-diphenylacetyl)arginine amide.

[0127] In some embodiments, L is a linker. In some embodiments, L is absent.

[0128] In some embodiments, Z is -C1-C6 alkylene. In some embodiments, Z is -C1-C6 alkylene-O-. In some embodiments, Z is -O-C1-C6 alkylene-. In some embodiments, Z is -C(=O)NR Z -. In some embodiments, Z is -NR Z C(=O)-. In some embodiments, Z is -O-. In some embodiments, Z is -NR z -. In some embodiments, Z is -S-. In some embodiments, Z is -S(=O)-. In some embodiments, Z is -SO2-. In some embodiments, Z is -NHC(=O)NH-.

[0129] In some embodiments, R zis H. In some embodiments, R z is an unsubstituted C1-C4 alkyl. z It is unsubstituted -CH3.

[0130] In some embodiments, y is 1.

[0131] In some embodiments, the NPY1R radiopharmaceuticals described herein have a structure of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein are of Formula (II) or a pharmaceutically acceptable salt thereof:

[0132]

[0133] in:

[0134] R 1 is H, -C1-C6 alkyl or -C(=O)NH2;

[0135] R 2 is -OH, -NH2, -C(=O)NH2 or -CH2NHCONH2;

[0136] Each R 3 Independently selected from R 3a 、R 3b 、R 3c and R 3d ;

[0137] R 3a 、R 3b 、R 3c and R 3d Each is independently selected from H, F, Cl, Br, I, -CN, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy;

[0138] R 4 is H, -C(=O)R 10 ;-C(=O)NHR 10 or -C(=O)N(CH3)R 10 ;

[0139] R 10 is a substituted or unsubstituted -C1-C6 alkyl group or an unsubstituted 2- to 6-membered heteroalkyl group;

[0140] R 5 Does not exist or -Z B -L B -R B ;

[0141] Z B-C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 11 -、-NR 11 C(=O)-, -O-, -NR 11 -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-;

[0142] L B It is a joint;

[0143] R B is a chelating moiety or a radionuclide complex thereof;

[0144] R 6 Yes-Z A -L A -R A ;

[0145] Z A -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 12 -、-NR 12 C(=O)-, -O-, -NR 12 -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-;

[0146] L A It is a joint;

[0147] R A is a chelating moiety or a radionuclide complex thereof;

[0148] Each R 7 Independently selected from F, Cl, Br, I, -CN, -OH, substituted or unsubstituted -C1-C6 alkyl or substituted or unsubstituted -C1-C6 alkoxy;

[0149] Each R 8 Independently selected from F, Cl, Br, I, -CN, -OH, substituted or unsubstituted -C1-C6 alkyl or substituted or unsubstituted -C1-C6 alkoxy;

[0150] R 9 is H, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted -C1-C6 alkoxy;

[0151] Each R 11 are independently H or unsubstituted C1-C4 alkyl;

[0152] Each R 12 are independently H or unsubstituted C1-C4 alkyl;

[0153] n is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and p is 0, 1, 2, or 3.

[0154] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIa):

[0155] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIb):

[0156] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIc):

[0157] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIf):

[0158] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIg):

[0159] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIh):

[0160] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIi):

[0161] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IId):

[0162] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIe):

[0163] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIj):

[0164] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIk):

[0165] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (III):

[0166] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIm):

[0167] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIn):

[0168] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIo):

[0169] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIp):

[0170] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIq):

[0171] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIr):

[0172] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIs):

[0173] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIt):

[0174] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIu):

[0175] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIv):

[0176] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof has the structure of Formula (IIw):

[0177] In some embodiments, R 5 In some embodiments, R 5 Yes-Z B -L B -R B .

[0178] In some embodiments, Z B Is -O-, -NH- or -N(-CH3)-. In some embodiments, Z B In some embodiments, Z B is -C1-C6 alkylene-O-. In some embodiments, Z B In some embodiments, Z B is -C(=O)NR 11 -. In some embodiments, Z B is -C(=O)NH-. In some embodiments, Z B Yes-NR 11 C(=O)-. In some embodiments, Z B is -NHC(=O)-. In some embodiments, Z B In some embodiments, Z B Yes-NR 11 -. In some embodiments, Z B is -N(-CH3)-. In some embodiments, Z B is -NH-. In some embodiments, Z B In some embodiments, Z B is -S(=O)-. In some embodiments, Z B In some embodiments, Z B It is -NHC(=O)NH-.

[0179] In some embodiments, Z A Is -O-, -NH- or -N(-CH3)-. In some embodiments, Z A In some embodiments, Z A is -C1-C6 alkylene-O-. In some embodiments, Z A In some embodiments, Z A is -C(=O)NR 12 -. In some embodiments, Z A is -C(=O)NH-. In some embodiments, Z A Yes-NR 12 C(=O)-. In some embodiments, Z A is -NHC(=O)-. In some embodiments, Z A In some embodiments, Z A Yes-NR 12-. In some embodiments, Z A is -N(-CH3)-. In some embodiments, Z A is -NH-. In some embodiments, Z A In some embodiments, Z A is -S(=O)-. In some embodiments, Z A In some embodiments, Z A It is -NHC(=O)NH-.

[0180] In some embodiments, R 1 is H. In some embodiments, R 1 In some embodiments, R 1 is -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 It is -C(=O)NH2.

[0181] In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0182] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0183] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0184] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0185] In some embodiments, each R 3 is independently H, F, Cl, Br, I, -CN, -CH3, -CF3 or OCH3. In some embodiments, each R 3 is independently F, Cl, Br, I, -CH3, -CF3 or -OCH3. In some embodiments, each R 3 are independently F, Cl, Br, I or -CH3. In some embodiments, R 3 is F. In some embodiments, R 3 Is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is 1. In some embodiments, R3 In some embodiments, R 3 is independently substituted or unsubstituted -C1-C6 alkyl. 3 is -CH3. In some embodiments, R 3 In some embodiments, R 3 is a substituted or unsubstituted -C1-C6 alkoxy group. 3 In some embodiments, R 3 It’s H.

[0186] In some embodiments, each R 7 In some embodiments, R 7 is independently F. In some embodiments, R 7 are independently Cl. In some embodiments, R 7 are independently Br. In some embodiments, R 7 is independently I. In some embodiments, R 7 is independently -CN. In some embodiments, R 7 is independently substituted or unsubstituted -C1-C6 alkyl. 7 is independently -CH3. In some embodiments, R 7 is independently substituted or unsubstituted -C1-C6 alkoxy. 7 is independently -OCH3.

[0187] In some embodiments, each R 8 In some embodiments, R 8 is independently F. In some embodiments, R 8 are independently Cl. In some embodiments, R 8 are independently Br. In some embodiments, R 8 is independently I. In some embodiments, R 8 is independently -CN. In some embodiments, R 8 is independently substituted or unsubstituted -C1-C6 alkyl. 8 is -CH3. In some embodiments, R 8 is independently substituted or unsubstituted -C1-C6 alkoxy. 8 It is -OCH3.

[0188] In some embodiments, R 9is H. In some embodiments, R 9 is a substituted or unsubstituted -C1-C4 alkyl group. 9 is -CH3. In some embodiments, R 9 is a substituted or unsubstituted -C1-C6 alkoxy group. 9 It is -OCH3.

[0189] In some embodiments, R 11 is H. In some embodiments, R 11 is -CH3. In some embodiments, R 11 It is -CH2CH3.

[0190] In some embodiments, R 12 is H. In some embodiments, R 12 is -CH3. In some embodiments, R 12 It is -CH2CH3.

[0191] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has one of the following structures:

[0192]

[0193] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0194] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has one of the following structures:

[0195]

[0196] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0197] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0198] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has one of the following structures:

[0199]

[0200] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0201] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has one of the following structures:

[0202]

[0203] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0204] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has one of the following structures:

[0205]

[0206] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0207] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0208] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has one of the following structures:

[0209]

[0210] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0211] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: Each R 3a 、R 3b 、R 3c and R 3d R is independently selected from H, F, Cl, Br, I, -CN, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy. 3a 、R 3b 、R 3c and R 3d Independently selected from H, F, Cl, Br, I, -CN, -CH3, -CF3 and -OCH3.

[0212] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0213] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0214] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0215] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0216] In some embodiments, R 3a is H, F, Cl, Br, I, -CN, -CH3, -CF3 or OCH3. In some embodiments, R 3a is H. In some embodiments, R 3a is F. In some embodiments, R 3a Is Cl. In some embodiments, R 3a is Br. In some embodiments, R 3a is 1. In some embodiments, R 3a In some embodiments, R 3a is -CH3. In some embodiments, R 3a In some embodiments, R 3a In some embodiments, R 3b is H, F, Cl, Br, I, -CN, -CH3, -CF3 or OCH3. In some embodiments, R 3b is H. In some embodiments, R 3b is F. In some embodiments, R 3b Is Cl. In some embodiments, R 3b is Br. In some embodiments, R 3b is 1. In some embodiments, R 3b In some embodiments, R 3b is -CH3. In some embodiments, R 3b In some embodiments, R 3b In some embodiments, R 3c is H, F, Cl, Br, I, -CN, -CH3, -CF3 or OCH3. In some embodiments, R 3c is H. In some embodiments, R 3c is F. In some embodiments, R 3c Is Cl. In some embodiments, R 3c is Br. In some embodiments, R 3c is 1. In some embodiments, R 3c In some embodiments, R 3c is -CH3. In some embodiments, R 3c In some embodiments, R 3c In some embodiments, R 3d is H, F, Cl, Br, I, -CN, -CH3, -CF3 or OCH3. In some embodiments, R 3d is H. In some embodiments, R3d is F. In some embodiments, R 3d Is Cl. In some embodiments, R 3d is Br. In some embodiments, R 3d is 1. In some embodiments, R 3d In some embodiments, R 3d is -CH3. In some embodiments, R 3d In some embodiments, R 3d In some embodiments, R 3a and R 3d is F or Cl and R 3b and R 3c is H. In some embodiments, R 3a and R 3d is F and R 3b and R 3c is H. In some embodiments, R 3a and R 3d is Cl and R 3b and R 3c is H. In some embodiments, R 3a is F, Cl or Br and R 3b 、R 3c and R 3d is H. In some embodiments, R 3a is F and R 3b 、R 3c and R 3d is H. In some embodiments, R 3a is Cl and R 3b 、R 3c and R 3d is H. In some embodiments, R 3a is Br and R 3b 、R 3c and R 3d It’s H.

[0217] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0218] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure:

[0219] In some embodiments, R 2 is -C(=O)NH2 or -CH2NHC(=O)NH2. In some embodiments, R 2 In some embodiments, R 2 is -NH2. In some embodiments, R 2 is -C(=O)NH2. In some embodiments, R 2 It is -CH2NHC(=O)NH2.

[0220] In some embodiments, R4 is H. In some embodiments, R 4 Yes -C(=O)R 10 In some embodiments, R 4 is -C(=O)NHR 10 In some embodiments, R 4 is -C(=O)N(CH3)R 10 .

[0221] In some embodiments, R 10 is unsubstituted -C1-C6 alkyl or unsubstituted 2- to 6-membered heteroalkyl. 10 Yes - (CH2) t CH3. In some embodiments, R 10 Yes - (CH2) t -NH2. In some embodiments, R 10 Yes - (CH2) t NHC(=O)(CH2) u CH3. In some embodiments, R 10 Yes - (CH2) t C(=O)O(CH2) u CH3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 4. In some embodiments, u is 1. In some embodiments, t is 2 and u is 1. In some embodiments, t is 4 and u is 1. In some embodiments, R 10 is -(CH2)2NHC(=O)(CH2) u CH3. In some embodiments, R 10 It is -(CH2)2NHC(=O)(CH2)CH3.

[0222] In some embodiments, R 10 is unsubstituted -C1-C6 alkyl, -(CH2) t -NH2, -(CH2) t C(=O)O(CH2) u CH3 or -(CH2) t NHC(=O)(CH2) u CH3. In some embodiments, R 10 is -CH2CH3, -(CH2)4NH2, -(CH2)4NHC(=O)CH2CH3, -CH2C(=O)OCH2CH3 or -(CH2)2C(=O)OCH2CH3. In some embodiments, R 10 is -CH2CH3. In some embodiments, R10 is -(CH2)4NH2. In some embodiments, R 10 is -(CH2)4NHC(=O)CH2CH3. In some embodiments, R 10 is -CH2C(=O)OCH2CH3. In some embodiments, R 10 It is -(CH2)2C(=O)OCH2CH3.

[0223] In some embodiments, R 10 Yes - (CH2) t -substituted or unsubstituted 5- to 6-membered heteroaryl ring. In some embodiments, R 10 is a -(CH2)-substituted or unsubstituted 5- to 6-membered heteroaryl ring. In some embodiments, the 5- to 6-membered heteroaryl ring is a pyrrolyl, thienyl, furanyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl ring, which is optionally substituted with 1 to 2 substituents selected from C1-C4 alkyl or phenyl. In some embodiments, R 10 yes In some embodiments, R 10 yes In some embodiments, R 10 yes

[0224] In some embodiments, R 4 is -C(=O)(CH2) t CH3, -C(=O)NH(CH2) t CH3-, -C(=O)(CH2) t NH2, -C(=O)NH(CH2) t NH2, -C(=O)NH(CH2) t NHC(=O)(CH2) u CH3, -C(=O)(CH2) t C(=O)O(CH2) u CH3 or -C(=O)NH(CH2) t C(=O)O(CH2) u CH3. In some embodiments, R 10 Yes - (CH2) t C(=O)O(CH2) u CH3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 4. In some embodiments, u is 1. In some embodiments, t is 2 and u is 1. In some embodiments, t is 4 and u is 1. In some embodiments, R 4It is -C(=O)NH(CH2)2NHC(=O)(CH2)CH3.

[0225] In some embodiments, R 4 is -C(=O)CH2CH3, -C(=O)NHCH2CH3-, -C(=O)NH-(CH2)4NH2, -C(=O)NH(CH2)4NHC(=O)CH2CH3, -C(=O)NH(CH2)2NHC(=O)CH2CH3, -C(=O)NHCH2C(=O)OCH2CH3 or -C(=O)NH(CH2)2C(=O)OCH2CH3. In some embodiments, R 4 is -C(=O)CH2CH3 or -C(=O)NHCH2CH3-. In some embodiments, R 4 is -C(=O)CH2CH3. In some embodiments, R 4 is -C(=O)NHCH2CH3-. In some embodiments, R 4 is -C(=O)NH-(CH2)4NH2. In some embodiments, R 4 is -C(=O)NH(CH2)4NHC(=O)CH2CH3. In some embodiments, R 4 is -C(=O)NH(CH2)2NHC(=O)CH2CH3. In some embodiments, R 4 is -C(=O)NHCH2C(=O)OCH2CH3. In some embodiments, R 4 It is -C(=O)NH(CH2)2C(=O)OCH2CH3.

[0226] In some embodiments, R 4 is -C(=O)(CH2) t CH3. In some embodiments, R 4 is -C(=O)CH2CH3. In some embodiments, R 4 is -C(=O)NH(CH2) t CH3-. In some embodiments, R 4 is -C(=O)NHCH2CH3-. In some embodiments, R 4 is -C(=O)(CH2) t NH2. In some embodiments, R 4 is -C(=O)NH(CH2) tNH2. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 4. In some embodiments, u is 1. In some embodiments, t is 2 and u is 1. In some embodiments, t is 4 and u is 1.

[0227] In some embodiments, R 4 is -C(=O)NH-(CH2)4NH2. In some embodiments, R 4 is -C(=O)NH(CH2) t NHC(=O)(CH2) u CH3. In some embodiments, R 4 is -C(=O)NH-(CH2)4NHC(=O)CH2CH3. In some embodiments, R 4 is -C(=O)NH(CH2)2NHC(=O)(CH2)CH3. In some embodiments, R 4 is -C(=O)(CH2) t C(=O)O(CH2) u CH3. In some embodiments, R 4 is -C(=O)NH(CH2) t C(=O)O(CH2) u CH3. In some embodiments, R 4 is -C(=O)NH-CH2C(=O)OCH2CH3. In some embodiments, R 4 It is -C(=O)NH(CH2)2C(=O)OCH2CH3.

[0228] In some embodiments, R 4 is -C(=O)NH-(CH2) t -substituted or unsubstituted 5- to 6-membered heteroaryl ring. In some embodiments, R 4 is a -C(=O)NH-(CH2)-substituted or unsubstituted 5- to 6-membered heteroaryl ring. In some embodiments, the 5- to 6-membered heteroaryl ring is a pyrrolyl, thienyl, furanyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl ring, which is optionally substituted with 1 to 2 substituents selected from C1-C4 alkyl or phenyl. In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes

[0229] In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. In some embodiments, t is 6.

[0230] In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4.

[0231] In some embodiments, R A and R B If present, it is independently selected from the group consisting of: cyclen, DO2A, DO3A, HP-DO3A, DO3A-Nprop, DO3AP, DO3AP PrA 、DO3AP ABn 、DO3AM nBu , BT-DO3A, DOTA, DOTAGA, DOTA(GA)2, DOTAM, DOTA-4AMP, DOTMA, DOTP, CB-DO2A, DOTPA, DOTMP, DOTAMAP, TRITA, L py , tetraazacyclotetradecane (cyclam), TETA, CB-tetraazacyclotetradecane, CB-TE2A, TE2A, NOTA, NODAGA, NODA-MPAA, TACN, TACN-TM, NOTP, Sarcophagine (Sar), DiAmSar, SarAr, AmBaSar, cis-DO2A2P, trans-DO2A2P, DOTEP, p-NO2-Bn-DOTA, BAT, DO3TMP-monoamide, CHX-A″-DTPA, c-DEPA, PCTA, p-NO2-Bn-PCTA, TRAP, TRAPH, TRAP-OH, TRAP-Ph, NOPO, AAZTA, DATAM, HEHA, PEPA, DTA, EDTMP, DTPMP, NTA, EDTA, DTPA, CyDTPA, DFO, DFO*, deferiprone, TTHA, HBED, HBED-CC, HBED-CC TFP, H4pypa, H4py4pa, CP256, THP, YM103, t-Bu-calix[4]arene-tetracarboxylic acid, CHX-A"-DTPA, H6phospha, p-NH2-Bn-CHXA"-DTPA, DEDPA, H4octox, H4octapa, H4CHXoctapa, HYNIC, macropa, crown, macropid, HOPO, bis(2-mercaptoacetamide), bis(aminothiolate), or SBTG2DAP.

[0232] In some embodiments, R A and R B If present, each is independently selected from: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A); α,α',α",α"'-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA); 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (D OTAM); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA); 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA); p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA); 6,6'-(((pyridine-2, 6-diylbis(methylene)bis((carboxymethyl)azanediyl)bis(methylene))dipicolinic acid (H4pypa); H4pypa-benzyl; 6,6',6",6"'-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))-tetra(methylene))-tetrapicolinic acid (H4py4pa); H4py4pa-benzyl; 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA); 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7 ,16-diyl)bis(methylene))dipicolinic acid (macropa); 2,2',2",2"'-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown); 6,6'-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4octapa); H4octapa-benzyl; and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecandioic acid (TTHA); or their radionuclide complexes.

[0233] In some embodiments, R A and R BIf present, each is independently selected from the group consisting of: DOTA; DO3A; DO2A; DOTMA; DOTAM; DOTPA; H4pypa; H4py4pa; macropa; crown; H4octapa; and TTHA; or a radionuclide complex thereof.

[0234] In some embodiments, R A is DOTA or a radionuclide complex thereof. In some embodiments, R A is DO3A or a radionuclide complex thereof. In some embodiments, R A is DO2A or a radionuclide complex thereof. In some embodiments, R A is DOTMA or a radionuclide complex thereof. In some embodiments, R A is DOTAM or a radionuclide complex thereof. In some embodiments, R A is DOTPA or a radionuclide complex thereof. In some embodiments, R A is 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid or a radionuclide complex thereof. In some embodiments, R A is H4pypa or a radionuclide complex thereof. In some embodiments, R A is H4py4pa or a radionuclide complex thereof. In some embodiments, R A is NOTA or a radionuclide complex thereof. In some embodiments, R A is macropa or a radionuclide complex thereof. In some embodiments, R A is a crown or a radionuclide complex thereof. In some embodiments, R A is H4octapa or a radionuclide complex thereof. In some embodiments, R A It is TTHA or a radionuclide complex thereof.

[0235] In some embodiments, R B is DOTA or a radionuclide complex thereof. In some embodiments, R B is DO3A or a radionuclide complex thereof. In some embodiments, R B is DO2A or a radionuclide complex thereof. In some embodiments, R B is DOTMA or a radionuclide complex thereof. In some embodiments, R B is DOTAM or a radionuclide complex thereof. In some embodiments, R Bis DOTPA or a radionuclide complex thereof. In some embodiments, R B is 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid or a radionuclide complex thereof. In some embodiments, R B is H4pypa or a radionuclide complex thereof. In some embodiments, R B is H4py4pa or a radionuclide complex thereof. In some embodiments, R B is NOTA or a radionuclide complex thereof. In some embodiments, R B is macropa or a radionuclide complex thereof. In some embodiments, R B is a crown or a radionuclide complex thereof. In some embodiments, R B is H4octapa or a radionuclide complex thereof. In some embodiments, R B It is TTHA or a radionuclide complex thereof.

[0236] In some embodiments, R A and R B The chelating moieties are independently selected from: DOTA and DO3A; or radionuclide complexes thereof.

[0237] In some embodiments, R A and R B The chelating moieties are independently selected from:

[0238] or a radionuclide complex thereof.

[0239] In some embodiments, R A yes or a radionuclide complex thereof. In some embodiments, R A yes or a radionuclide complex thereof. In some embodiments, R A yes or a radionuclide complex thereof. In some embodiments, R A yes or a radionuclide complex thereof. In some embodiments, R A yes or a radionuclide complex thereof.

[0240] In some embodiments, R B yes or a radionuclide complex thereof. In some embodiments, R B yes or a radionuclide complex thereof. In some embodiments, R B yes or a radionuclide complex thereof. In some embodiments, R B yes or a radionuclide complex thereof. In some embodiments, R B yes or a radionuclide complex thereof.

[0241] Radionuclide complexes

[0242] Radiopharmaceuticals are becoming an extremely useful tool for physicians in diagnosing, staging, treating and monitoring the progression of several diseases, especially cancer. The main difference between radiopharmaceuticals and other pharmaceutical drugs is that radiopharmaceuticals contain a radionuclide. The nuclear decay properties of the radionuclide determine whether the radiopharmaceutical will be used clinically as a diagnostic or therapeutic agent. Diagnostic radiopharmaceuticals require a radionuclide that emits gamma (γ) rays or positrons (β+), which then annihilate with a neighboring electron to produce two 511 keV annihilation photons emitted approximately 180° apart from each other. Gamma-emitting radionuclides (e.g. 99m Tc, 111 In, 201 Tl, etc.) can be used for single photon emission computed tomography (SPECT), while positron-emitting radionuclides (such as 18 F. 89 Zr, 68 Ga, etc.) can be used for positron emission tomography (PET).

[0243] In contrast, therapeutic radiopharmaceuticals require radionuclides that emit microparticle radiation, such as alpha (α) particles, beta (β) particles, or Auger electrons. These particles interact strongly with target tissues (e.g., cancerous tumors) and cause widespread localized ionization, which can disrupt chemical bonds in DNA molecules and potentially induce cytotoxicity.

[0244] For most nuclear medicine applications, diagnostic radiopharmaceuticals need to be paired with therapeutic radiopharmaceuticals. This concept is often referred to as "theranostics." As a first step in the theranostics concept, quantitative imaging of tumor imaging biomarkers is performed by positron emission tomography (PET) or single photon emission computed tomography (SPECT) using a target molecule labeled with a diagnostic radionuclide. Then, as a second step, it has been demonstrated that a tumor-destroying radiation absorbed dose can be delivered to tumors and metastases by administering the same or similar target molecule labeled with a therapeutic radionuclide.

[0245] In some embodiments, the chemical and pharmacokinetic behavior of both the diagnostic and therapeutic radiopharmaceuticals are matched. In some embodiments, the diagnostic and therapeutic radionuclides are chemically identical radioisotope pairs (also referred to as "matched pairs"). An example of a matched pair for theranostic radiopharmaceutical applications is 123 I / 131 I pairs, of which 123 I-labeled compounds are used for diagnostic purposes, while 131 I-labeled compounds are used for therapeutic purposes. Other theranostic matched pairs include 44 Sc / 47 Sc, 64 Cu / 67 Cu, 72 As / 77 As、 86 Y / 90 Y and 203 Pb / 212 Pb, etc. Alternatively, when the chemical properties of pairs of radionuclides from different elements are very similar (e.g. 99m Tc / 186 / 188 Re) and there is no significant difference in pharmacokinetic behavior between diagnostic and therapeutic analogs, the radionuclide pair can be used for theranostic radiopharmaceutical development. Another example is 68 Ga / 177 Lu is right, among them 68 Ga is used for diagnosis and 177 Lu is used for treatment. For example, gastrointestinal pancreatic endocrine tumors express high amounts of sst2 receptors, which can be used as 68 Ga sst2 ligand conjugate ([ 68 Ga]Ga-DOTA-TATE(NETSPOT TM )or[ 68 Ga]Ga-DOTA-TOC(DOTA-(D-Phe1,Tyr3)-Octreotide, SomaKit )) for diagnostic purposes, followed by intracavitary radiotherapy. 177 Lu sst2 ligand conjugate ([ 177 Lu]Lu-DOTA-TATE) for treatment.

[0246] Chelating moieties for the production of metal (radionuclide) complexes

[0247] The compounds described herein comprise at least one R A or R B Group, where R A or R Bis a chelating moiety capable of chelating a radionuclide (Z') or a radionuclide complex thereof. In some embodiments, any suitable group or atom of a chelator is used to attach to NPY via an optional linker. 1 R targeting ligand.

[0248] In some embodiments, the chelating agent is capable of binding to a radioactive atom. In some embodiments, the binding is direct, such as when the chelating agent hydrogen bonds or electrostatically interacts with the radioactive atom. In some embodiments, the binding is indirect, such as when the chelating agent binds to a molecule containing the radioactive atom. In some embodiments, the chelating agent is or comprises a macrocycle.

[0249] In some embodiments, the chelating agent comprises one or more amine groups. In some embodiments, the metal chelating agent comprises two or more amine groups. In some embodiments, the chelating agent comprises three or more amine groups. In some embodiments, the chelating agent comprises four or more amine groups. In some embodiments, the chelating agent comprises 4 or more N atoms, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelating agent does not comprise S. In some embodiments, the chelating agent comprises a ring. In some embodiments, the ring comprises O and / or N atoms. In some embodiments, the chelating agent is a ring comprising 3 or more N atoms, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelating agent is a multidentate ligand, a bidentate ligand, or a monodentate ligand. The multidentate ligand is within the range of the number of atoms used to bond to a metal atom or ion. EDTA (a hexadentate ligand) is an example of a multidentate ligand having six donor atoms with electron pairs that can be used to bond to a central metal atom or ion. Bidentate ligands have two donor atoms, which allow them to bind to the central metal atom or ion at two points. Ethylenediamine (en) and the oxalate ion (ox) are examples of bidentate ligands.

[0250] In some embodiments, the chelators described herein comprise cyclic chelators or acyclic chelators. In some embodiments, the chelators described herein comprise cyclic chelators. In some embodiments, the chelators described herein comprise acyclic chelators.

[0251] In some embodiments, the chelating agents described herein comprise cyclamenine, DO2A, DO3A, HP-DO3A, DO3A-Nprop, DO3AP, DO3AP PrA 、DO3AP ABn 、DO3AM nBu, BT-DO3A, DOTA, PSC, DOTAGA, DOTA(GA)2, DOTAM, DOTA-4AMP, DOTMA, DOTP, CB-DO2A, DOTPA, DOTMP, DOTAMAP, TRITA, L py , tetraazacyclotetradecane, TETA, CB-tetraazacyclotetradecane, CB-TE2A, TE2A, NOTA, NODAGA, NODA-MPAA, TACN, TACN-TM, NOTP, Sarcophagine (Sar), DiAmSar, SarAr, AmBaSar, cis-DO2A2P, trans-DO2A2P, DOTEP, p-NO2-Bn-DOTA, BAT, DO3TMP-monoamide, CHX-A″-DTPA, c-DEPA, PCTA, p-NO2-Bn-PCTA, TRAP, TRAPH, TRAP-OH, TRAP-Ph, NOPO, AAZTA, DATAM, HEHA, PEPA, DTA, EDTMP, DTPMP, NTA, EDTA, DTPA, CyDTPA, DFO, DFO*, deferiprone, TTHA, HBED, HBED-CC, HBED-CC TFP, H4pypa, H4py4pa, CP256, THP, YM103, t-Bu-calix[4]arene-tetracarboxylic acid, CHX-A"-DTPA, H6phospha, p-NH2-Bn-CHXA"-DTPA, DEDPA, H4octox, H4octapa, H4CHXoctapa, HYNIC, macropa, crown, macropid, HOPO, bis(2-mercaptoacetamide), bis(aminothiolate), or SBTG2DAP.

[0252] In some embodiments, the chelating agents described herein comprise DOTA, DOTAGA, DOTA(GA)2, NOTA, NODAGA, TRITA, TETA, DOTA-MA, HP-DO3A, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, BAT, DO3TMP-monoamide, or CHX-A″-DTPA.

[0253] In some embodiments, the chelating agents described herein comprise DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, or BOPA.

[0254] In some embodiments, the chelating agents described herein comprise DOTA, PSC, DOTAGA, DOTA(GA)2, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-tetraazacyclotetradecane, CB-TE2A, DOTA-4AMP, or NOTP.

[0255] In some embodiments, the chelating agents described herein comprise DOTA, DOTAGA, DOTA(GA)2, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-tetraazacyclotetradecane, CB-TE2A, DOTA-4AMP, or NOTP.

[0256] In some embodiments, the chelating agents described herein comprise HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAMAP, DO3AM Bu , DOTMA, TCE-DOTA, DEPA, PCTA, p-NO2-Bn-PCTA, p-NO2-Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATA m , THP, HEHA, HBED or HBED-CC TFP.

[0257] In some embodiments, the chelating agents described herein comprise DOTA, NOTA, NODAGA, DOTAGA, HBED, HBED-CC TFP, H2DEPDPA, DFO-B, deferiprone, CP256, YM103, TETA, CB-TE2A, TE2A, Sar, DiAmSar, TRAPH, TRAP-Pr, TRAP-OH, TRAP-Ph, NOPO, DEADPA, PCTA, EDTA, PEPA, HEHA, DTPA, EDTMP, AAZTA, DO3AP, DO3AP PrA 、DO3AP ABn Or DOTAM.

[0258] In some embodiments, the chelating agent is or comprises DOTA, HBED-CC, DOTAGA, DOTA(GA)2, NOTA, and DOTAM. In some embodiments, the chelating agent is or comprises NODAGA, NOTA, DOTAGA, DOTA(GA)2, TRAP, NOPO, NCTA, DFO, DTPA, and HYNIC.

[0259] In some embodiments, the chelating agent comprises: a macrocycle (e.g., a macrocycle comprising O and / or N atoms), DOTA, HBED-CC, DOTAGA, DOTA(GA)2, NOTA, DOTAM, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or deferoxamine.

[0260] In some embodiments, the metal chelators described herein comprise one of the following structures:

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270] In some embodiments, R A and R B If present, each independently comprises a radionuclide and DOTA. In some embodiments, R A and R B If present, each independently comprises a radionuclide and a DOTA derivative. A and R B If present, each is independently a chelator, and at least one or both is DOTA.

[0271] In some embodiments, the chelating moiety comprises a radionuclide and a chelator configured to bind the radionuclide (Z'), wherein the chelator comprises DOTA, DOTP, DOTMA, DOTAM, DTPA, NOTA, NTA, NODAGA, EDTA, DO3A, DO2A, NOC, TETA, CB-TE2A, DiAmSar, CB-tetraazacyclotetradecane, DOTA-4AMP, H4pypa, H4octox, H4octapa, p-NO2-Bn-neunpa, or NOTP.

[0272] In some embodiments, the metal chelators described herein comprise macropa or crown. In some embodiments, the metal chelators described herein comprise macropa. In some embodiments, the metal chelators described herein comprise crown. In some embodiments, the metal chelators described herein comprise In some embodiments, the metal chelators described herein comprise

[0273] In some embodiments, R A and R BIf present, each is independently selected from: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (PSC); 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A); α,α',α",α"'-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA); 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA); 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA); p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid Acetic acid (p-OH-Bn-DOTA); 6,6'-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4pypa); H4pypa-benzyl; 6,6',6",6"'-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))-tetra(methylene))-tetrapicolinic acid (H4py4pa); H4py4pa-benzyl; 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA); 6,6'-((1,4,10,13-tetraoxacyclononane-1,4,7-triyl)triacetic acid (NOTA); -7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa); 2,2',2",2"'-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown); 6,6'-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4octapa); H4octapa-benzyl; and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecandioic acid (TTHA); or their radionuclide complexes.

[0274] In some embodiments, R A and R B If present, each is independently selected from: DOTA and DO3A; or radionuclide complexes thereof.

[0275] In some embodiments, R A and R B If present, each is independently selected from: or a radionuclide complex thereof.

[0276] In some embodiments, R A and R B If present, each is independently selected from: or a radionuclide complex thereof.

[0277] In some embodiments, R A or R B yes: or a radionuclide complex thereof.

[0278] In some embodiments, R A or R B yes: or a radionuclide complex thereof.

[0279] In some embodiments, R A or R B yes: or a radionuclide complex thereof. In some embodiments, R A or R B yes: or a radionuclide complex thereof. In some embodiments, R A or R B yes: or a radionuclide complex thereof. In some embodiments, R A or R B yes: or a radionuclide complex thereof.

[0280] In some embodiments, R A or R B yes: or a radionuclide complex thereof. In some embodiments, R A or R B yes: or a radionuclide complex thereof.

[0281] In some embodiments, R A or R B yes: where Z' is a diagnostic or therapeutic radionuclide.

[0282] In some embodiments, R Aor R B yes: where Z' is a diagnostic or therapeutic radionuclide.

[0283] In some embodiments, Z' is an Auger electron emitting radionuclide, an alpha emitting radionuclide, a beta emitting radionuclide, or a gamma emitting radionuclide. In some embodiments, Z' is an Auger electron emitting radionuclide that is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc) or 195m-platinum ( 195m In some embodiments, Z' is an alpha-emitting radionuclide that is 225-actinium ( 225 Ac), 213-bismuth ( 213 Bi), 223-radium ( 223 Ra) or 212-lead ( 212 In some embodiments, Z' is a beta-emitting radionuclide that is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), iodine-131( 131 I), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 64-copper ( 64 Cu), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Gold( 198 Au), 169-erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-technetium ( 99m Tc), 89-zirconium ( 89 Zr) or 52-manganese ( 52 In some embodiments, Z' is a gamma-emitting radionuclide that is 60-cobalt ( 60 Co), 103-palladium ( 103 Pd), 137-cesium ( 137 Cs), 169-ytterbium ( 169 Yb), 192-iridium ( 192 Ir) or 226-radium ( 226 Ra).

[0284] In some embodiments, R 6A method comprising a radionuclide (Z') and a chelating agent configured to bind the radionuclide (Z'), wherein the radionuclide is suitable for positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI). In some embodiments, the radionuclide is copper-64 ( 64 Cu), Gallium-68( 68 Ga), 111-indium ( 111 In) or technetium-99m( 99m Tc).

[0285] Metals (radionuclides)

[0286] In some embodiments, Z' is a radionuclide that emits Auger electrons. In some embodiments, Z' is a radionuclide that emits alpha. In some embodiments, Z' is a radionuclide that emits beta. In some embodiments, Z' is a radionuclide that emits gamma. In some embodiments, the type of radionuclide used in the therapeutic compound of the non-targeted peptide can be customized according to the specific type of cancer, the type of targeting moiety (e.g., non-peptide ligand), etc. Radionuclides that undergo alpha decay emit alpha particles (helium ions with a charge of +2) from their nuclei. As a result of alpha decay, the daughter nuclide has 2 fewer protons and 2 fewer neutrons than the parent nuclide. This means that in alpha decay, the number of protons decreases by 2, while the number of nucleons decreases by 4. Radionuclides that undergo beta decay emit beta particles (electrons) from their nuclei. During beta decay, one of the neutrons becomes a proton and an electron. The proton remains in the nucleus, while the electron is emitted as a beta particle. This means that in beta decay, the nucleus loses a neutron but gains a proton. In gamma decay, a nucleus in an excited (higher energy) state emits a gamma-ray photon, returning to a lower energy state. During gamma decay, the number of protons and nucleons remains unchanged. The emission of gamma rays is often accompanied by the emission of alpha and beta particles.

[0287] Auger electrons (AE) are extremely low energy electrons that are generated by radionuclides (e.g. 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I and 123 I) emission. This energy is deposited within nanometer-micrometer distances, resulting in high linear energy transfer, which effectively causes lethal damage to cancer cells. Therefore, radiotherapeutic agents that emit AE have great potential for cancer treatment.

[0288] Beta particles are electrons emitted from a nucleus. They generally have a long range in tissue (approximately 1 to 5 mm) and are the most commonly used.

[0289] Alpha particles are helium nuclei (two protons and two neutrons) emitted from the nucleus of a radioactive atom. Depending on their emission energy, they can travel 50-100 μm in tissue. They are positively charged and several orders of magnitude larger than electrons. The amount of energy deposited per path length traveled by alpha particles (called "linear energy transfer") is about 400 times higher than that of electrons. This causes substantially more damage along their path than the damage caused by electrons. Alpha particle tracks cause a large number of complex and largely unrepairable DNA double-strand breaks. The absorbed dose required to achieve cytotoxicity is related to the number of alpha particles that pass through the cell nucleus. Using this as a measure, cytotoxicity can be achieved within a range of 1 to 20 alpha particle passages of the cell nucleus. The combination of the resulting high efficacy and the short range of alpha particles (which reduces normal organ toxicity) has attracted significant attention in the development of pharmaceuticals that emit alpha particles. Commonly used alpha particle emitters include bismuth-212, lead-212, bismuth-213, actinium-225, radium-223, and thorium-227.

[0290] In some embodiments, Z' is a diagnostic or therapeutic radionuclide. Representative radionuclides

[0291] isotope <![CDATA[Radionuclide t 1 / 2 (h)]]> decay mode <![CDATA[ 60 With]]> 0.4 β+ (93%), EC (7%) <![CDATA[ 61 With]]> 3.3 β+ (62%), EC (38%) <![CDATA[ 62 With]]> 0.16 β+(98%), EC(2%) <![CDATA[ 64 With]]> 12.7 β+(19%), EC(41%), β-(40%) <![CDATA[ 67 With]]> 61.9 <![CDATA[ 66 Here]]> 9.5 β+ (56%), EC (44%) <![CDATA[ 67 Here]]> 78.2 EC (100%) <![CDATA[ 68 Here]]> 1.1 β+(90%), EC(10%) <![CDATA[ 44 Sc]]> 3.9 β+ (94%), EC (6%) <![CDATA[ 47 Sc]]> 80.2 β-(100％) <![CDATA[ 111 In]]> 67.2 EC (100%) <![CDATA[ 114m In]]> 49.5d EC (100%) <![CDATA[ 114 In(child body)]]> 73s β-(100％) <![CDATA[ 177 Monday]]> 159.4 β-(100％) <![CDATA[ 86 And]]> 14.7 β+ (33%), EC (66%) <![CDATA[ 90 And]]> 64.1 β-(100％) <![CDATA[ 89 Zr]]> 78.5 β+ (23%), EC (77%) <![CDATA[ 212 With]]> 1.1 α(36％)，β-(64％) <![CDATA[ 213 With]]> 0.76 α(2.2％)，β-(97.8％) <![CDATA[ 212 Pb(daughter is 212 Bi)]]> 10.6 β-(100％) <![CDATA[ 225 And]]> 240 α(100％) <![CDATA[ 227 Th]]> 448.8 α <![CDATA[ 211 At]]> 7.2 α

[0292] In some embodiments, Z′ is an Auger electron emitting radionuclide. In some embodiments, Z′ is an Auger electron emitting radionuclide that is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc) or 195m-platinum ( 195m Dt).

[0293] In some embodiments, Z' is an alpha-emitting radionuclide. In some embodiments, Z' is an alpha-emitting radionuclide that is 225-actinium ( 225 Ac), 213-bismuth ( 213 Bi), 223-radium ( 223 Ra) or 212-lead ( 212 Pb).

[0294] In some embodiments, Z' is a beta-emitting radionuclide. In some embodiments, Z' is a beta-emitting radionuclide that is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 64-copper ( 64 Cu), 67-copper (67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Gold( 198 Au), 169-erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-technetium ( 99m Tc), 89-zirconium ( 89 Zr) or 52-manganese ( 52 Mn).

[0295] In some embodiments, Z' is a gamma-emitting radionuclide. In some embodiments, Z' is a gamma-emitting radionuclide that is 60-cobalt ( 60 Co), 103-palladium ( 103 Pd), 137-cesium ( 137 Cs), 169-ytterbium ( 169 Yb), 192-iridium ( 192 Ir) or 226-radium ( 226 Ra).

[0296] In some embodiments, Z' is an Auger electron emitting radionuclide that is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc) or 195m-platinum ( 195m Pt); or Z' is an alpha-emitting radionuclide, the radionuclide being 225-actinium ( 225 Ac), 213-bismuth ( 213 Bi), 223-radium ( 223 Ra) or 212-lead ( 212 Pb); or Z' is a beta-emitting radionuclide, the radionuclide being 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 64-copper ( 64 Cu), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Gold( 198 Au), 169-erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-technetium ( 99m Tc), 89-zirconium (89 Zr) or 52-manganese ( 52 Mn); or Z' is a gamma-emitting radionuclide, the radionuclide being 60-cobalt ( 60 Co), 103-palladium ( 103 Pd), 137-cesium ( 137 Cs), 169-ytterbium ( 169 Yb), 192-iridium ( 192 Ir) or 226-radium ( 226 Ra).

[0297] In some embodiments, Z' is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Gold( 198 Au), 169-erbium ( 169 Er), 165-dysprosium ( 165 Dy) or 99m-technetium ( 99m Tc).

[0298] In some embodiments, Z' is 94 Tc, 90 In, 111 In, 67 Ga, 68 Ga, 86 Y. 90 Y. 177 Lu, 161 Tb, 186 Re、 188 Re、 64 Cu, 67 Cu, 55 Co、 57 Co、 43 Sc, 44 Sc, 47 Sc, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 227 Th, 153 Sm, 166 Ho, 152 Gd, 153 Gd, 157 Gd or 166 Dy.

[0299] In some embodiments, Z' is 67 Cu, 64 Cu, 90 Y. 109 Pd, 111 Ag, 149 Pm, 153 Sm, 166 Ho, 99m Tc, 67 Ga, 68 Ga, 111 In, 90 Y. 177 Lu, 186 Re、 188 Re、 197 Au, 198 Au, 199 Au, 105 Rh, 165 Ho, 161 Tb, 149 Pm, 44 Sc, 47 Sc, 70 As、 71 As、 72 As、 73 As、 74 As、 76 As、 77 As、 212 Pb, 212 Bi, 213 Bi, 225 Ac, 117m Sn, 67 Ga, 201 Tl, 160 Gd, 148 Nd or 89 Sr.

[0300] In some embodiments, Z' is 68 Ga, 43 Sc, 44 Sc, 47 Sc, 177 Lu, 161 Tb, 225 Ac, 213 Bi, 212 Bior 212 In some embodiments, Z' is 67 Ga, 99m Tc, 111 In or 201 In some embodiments, the radionuclide (Z') is 44Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y. 89 Zr, 99m Tc, 111 In or 177 In some embodiments, Z' is 44 Sc, 64 Cu, 68 Ga, 86 Y or 89 In some embodiments, Z' is 67 Ga, 99m Tc, 111 In or 177 Lu.

[0301] In some embodiments, Z' is 67 Cu, 90 Y. 111 In, 177 Lu, 225 Ac, 212 Pb or 213 Bi.

[0302] In some embodiments, Z' is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 69-gallium ( 69 Ga), 71-gallium ( 71 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), 177-lutetium ( 177 Lu), 204-lead ( 204 Pb), 206-lead ( 206 Pb), 207-lead ( 207 Pb), 208-lead ( 208 Pb), 212-lead ( 212 Pb), 63-copper ( 63 Cu), 64-copper ( 64 Cu), 65-copper ( 65 Cu) or 67-copper ( 67 Cu).

[0303] In some embodiments, Z' is 111-indium ( 111 In). In some embodiments, Z' is 115-indium ( 115In some embodiments, Z' is 67-gallium ( 67 Ga). In some embodiments, Z' is 68-gallium ( 68 Ga). In some embodiments, Z' is 69-gallium ( 69 Ga), 71-gallium ( 71 In some embodiments, Z' is 225-actinium ( 225 Ac). In some embodiments, Z' is 175-lutetium ( 175 In some embodiments, Z' is 177-lutetium ( 177 In some embodiments, Z' is 204-lead ( 204 Pb), 206-lead ( 206 Pb), 207-lead ( 207 Pb), 208-lead ( 208 Pb) or a mixture thereof. In some embodiments, Z' is 212-lead ( 212 In some embodiments, Z' is 64-copper ( 64 Cu). In some embodiments, Z' is 63-copper ( 63 Cu), 65-copper ( 65 Cu) or a mixture thereof. In some embodiments, Z' is 67-copper ( 67 Cu).

[0304] In some embodiments, Z' is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu) or 177-lutetium ( 177 Lu).

[0305] Exemplary Chelating Agents and Radionuclide Complexes

[0306] Radionuclides have useful emission properties that can be used in diagnostic imaging techniques such as single photon emission computed tomography (SPECT, e.g. 67 Ga, 99m Tc, 111 In, 177 Lu) and positron emission tomography (PET, e.g. 68 Ga, 64 Cu, 44 Sc, 86 Y. 89 Zr); and therapeutic applications (e.g.47 Sc, 114 mIn、 177 Lu, 90 Y. 212 / 213 Bi, 212 Pb, 225 Ac, 186 / 188 Re). An essential component of radiopharmaceuticals based on radiometals is a chelator, a ligand system that binds the radiometal ion in a very stable coordination complex so that the ion can be appropriately directed to the desired molecular target in vivo. The art provides guidance for selecting the best match between the chelator and the radiometal for a particular use (e.g., see Price et al., "Matching chelators to radiometals for radiopharmaceuticals", Chem. Soc. Rev., 2014, 43, 260-290).

[0307] In some embodiments, R A and R B If present, each is independently selected from: DOTA; DO3A; DO2A; DOTMA; DOTAM; DOTPA; Bn-DOTA; p-OH-Bn-DOTA; H4pypa; H4pypa-benzyl; H4py4pa; H4py4pa-benzyl; H4octapa; H4octapa-benzyl; and TTHA; or a radionuclide complex thereof.

[0308] In some embodiments, R A or R B yes: where Z' is a diagnostic or therapeutic radionuclide.

[0309] In some embodiments, the radionuclide (Z') is 44 Sc, 64 Cu, 67 Ga, 68 Ga, 86 Y. 89 Zr, 99m Tc, 111 In or 177 In some embodiments, the radionuclide (Z') is 44 Sc, 64 Cu, 68 Ga, 86 Y or 89 In some embodiments, the radionuclide (Z') is 67 Ga,99m Tc, 111 In or 177 Lu.

[0310] In some embodiments, the radionuclide (Z') is 67 Cu, 90 Y. 111 In, 177 Lu, 225 Ac, 212 Pb or 213 Bi.

[0311] In some embodiments, the radionuclide (Z') is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 69-gallium ( 69 Ga), 71-gallium ( 71 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), 177-lutetium ( 177 Lu), 204-lead ( 204 Pb), 206-lead ( 206 Pb), 207-lead ( 207 Pb), 208-lead ( 208 Pb), 212-lead ( 212 Pb), 63-copper ( 63 Cu), 64-copper ( 64 Cu), 65-copper ( 65 Cu) or 67-copper ( 67 Cu).

[0312] In some embodiments, the radionuclide (Z') is 111-indium ( 111 In). In some embodiments, the radionuclide (Z') is 115-indium ( 115 In). In some embodiments, the radionuclide (Z') is 67-gallium ( 67 Ga). In some embodiments, Z' is 68-gallium ( 68 Ga). In some embodiments, the radionuclide (Z') is 69-gallium ( 69 Ga), 71-gallium ( 71 In some embodiments, the radionuclide (Z')' is 225-actinium ( 225 Ac). In some embodiments, the radionuclide (Z') is 175-lutetium ( 175In some embodiments, the radionuclide (Z') is 177-lutetium ( 177 In some embodiments, the radionuclide (Z') is 204-lead ( 204 Pb), 206-lead ( 206 Pb), 207-lead ( 207 Pb), 208-lead ( 208 Pb) or mixtures thereof. In some embodiments, the radionuclide (Z') is 212-lead ( 212 In some embodiments, the radionuclide (Z') is 64-copper ( 64 Cu). In some embodiments, the radionuclide (Z') is 63-copper ( 63 Cu), 65-copper ( 65 Cu) or a mixture thereof. In some embodiments, the radionuclide (Z') is 67-copper ( 67 Cu).

[0313] In some embodiments, the radionuclide (Z') is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu) or 177-lutetium ( 177 Lu).

[0314] In some embodiments, the radionuclide (Z') is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Gold( 198 Au), 169-erbium ( 169 Er), 165-dysprosium ( 165 Dy) or 99m-technetium ( 99m Tc).

[0315] Emission Tomography

[0316] In some embodiments, R A or R BContains a chelated radionuclide suitable for use in positron emission tomography (PET) analysis or single photon emission computed tomography (SPECT). A or R B Contains a chelated radionuclide suitable for use in single photon emission computed tomography (SPECT). In some embodiments, R A or R B Contains a chelated radionuclide suitable for positron emission tomography (PET) analysis. In some embodiments, R A or R B Contains a chelated radionuclide suitable for use in positron emission tomography imaging, positron emission tomography combined with computed tomography imaging, or positron emission tomography combined with magnetic resonance imaging (MRI).

[0317] In some embodiments, R A or R B is a chelating moiety selected from the group consisting of: DOTA; DO3A; DO2A; DOTMA; DOTAM; DOTPA; Bn-DOTA; p-OH-Bn-DOTA; H4pypa; H4pypa-benzyl; H4py4pa; H4py4pa-benzyl; H4octapa; H4octapa-benzyl; and TTHA; or a radionuclide complex thereof. In some embodiments, the radionuclide is copper-64( 64 Cu), Gallium-68( 68 Ga) or technetium-99m( 99m Tc).

[0318] In some embodiments, the conjugates described herein are designed to have a specified elimination profile. The elimination profile can be designed by adjusting the sequence and length of the non-peptide ligand, the characteristics of the linker, the type of radionuclide, etc. In some embodiments, the conjugate has an elimination half-life of about 5 minutes to about 12 hours. In some embodiments, the conjugate has an elimination half-life of about 10 minutes to about 8 hours. In some embodiments, the conjugate has an elimination half-life of at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 8 hours. In some embodiments, the conjugate has an elimination half-life of at most about 15 minutes, at most about 30 minutes, at most about 1 hour, at most about 2 hours, at most about 3 hours, at most about 4 hours, at most about 5 hours, at most about 6 hours, or at most about 8 hours. In some embodiments, the elimination half-life is measured in rats. In some embodiments, the elimination half-life is measured in humans.

[0319] The conjugates described herein may have an elimination half-life in tumors and non-tumor tissues of a subject. The elimination half-life in a tumor may be the same as or different from (longer or shorter than) the elimination half-life in non-tumor tissue. In some embodiments, the elimination half-life of the conjugate in a tumor is from about 15 minutes to about 1 day. In some embodiments, the elimination half-life of the conjugate in a tumor is at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 4.0, or at least 5.0 times the elimination half-life of the conjugate in a non-tumor tissue of a subject.

[0320] As used herein, "elimination half-life" may refer to the time it takes for a drug to reach half its maximum concentration after administration. In some embodiments, the elimination half-life is measured after intravenous administration. In some embodiments, the elimination half-life is measured as the biological half-life, which is the half-life of the drug in a living system. In some embodiments, the elimination half-life is measured as the effective half-life, which is the half-life of the radiopharmaceutical in a living system, taking into account the half-life of the radionuclide.

[0321] Response and toxicity prediction is crucial for the rational implementation of cancer therapy. The biological effects of radionuclide therapy are mediated by a well-defined physical quantity, the absorbed dose (D), which is defined as the energy absorbed per unit mass of tissue.

[0322] Radiation dosimetry is the measurement, calculation, and assessment of the dose of ionizing radiation absorbed by an object, usually the human body, and can be considered the ability to conduct immediate pharmacodynamic studies on the treated patient. This can be applied internally, due to ingestion or inhalation of radioactive material, or externally, due to exposure to a radioactive source. Dosimetric analysis can be performed as part of a patient's treatment to calculate the absorbed dose to the tumor relative to normal organs and, therefore, the likelihood of treatment success.

[0323] The conjugates described herein can have a defined time-integrated activity coefficient (i.e., ). As used herein, It represents the cumulative number of nuclear transformations in the source tissue per unit of administered activity during the dose integration period. The value can be adjusted by modifying NPDC. The value can be determined using methods known in the art. In some embodiments, the conjugate is expressed in a tumor. The value is about 10 minutes to about 1 day. The value can be compared with the conjugate in the non-tumor tissue of the subject. The conjugates showed the same value in tumors. The values ​​are comparable to the conjugate in non-tumor tissues of the subject. In some embodiments, the conjugate is expressed in the tumor The value is the concentration of the conjugate in the non-tumor tissue of the subject. at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 4.0, or at least 5.0 times the value.

[0324] The conjugates described herein can have In some embodiments, the conjugate has a survival of up to 24 hours in the kidney of a subject. In some embodiments, the conjugate is expressed in the kidney of a subject. The value is up to 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the conjugate is in the kidney of the subject The value is about 30 minutes to about 24 hours. In some embodiments, the conjugate is in the kidney of the subject In some embodiments, the conjugate is administered to the kidney of a subject for a period of about 2 to 24 hours. In some embodiments, the conjugate is present in the liver of a subject. In some embodiments, the conjugate is present in the liver of a subject for a period of up to 24 hours. The value is up to 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the conjugate is in the liver of the subject The value is about 30 minutes to about 24 hours. In some embodiments, the conjugate is in the liver of the subject In some embodiments, the conjugate is administered to the subject's liver for a period of about 2 to 24 hours. Value exceeds 24 hours.

[0325] connector

[0326] In some embodiments, the linker has a defined length, thereby connecting the neuropeptide Y1 receptor (NPY1R) targeting ligand and the chelating moiety or its radionuclide complex (R A or R B ), while allowing appropriate distance between them.

[0327] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0328] In some embodiments, the linker comprises a linear structure. In some embodiments, the linker comprises a nonlinear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure.

[0329] In some embodiments, the linker comprises one or more linear structures, one or more non-linear structures, one or more branched structures, one or more cyclic structures, one or more flexible portions, one or more rigid portions, or a combination thereof.

[0330] In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, one or more amino acids of the linker are non-natural amino acids.

[0331] In some embodiments, the linker comprises a peptide bond. The peptide bond comprises L-amino acids and / or D-amino acids. In some embodiments, D-amino acids are preferred to minimize immunogenicity and nonspecific cleavage by background peptidases or proteases. It is known that the cellular uptake of oligomeric D-arginine sequences is as good as or better than that of oligomeric L-arginine.

[0332] In some embodiments, the linker has a length of 1 to 100 atoms, 1 to 50 atoms, 1 to 30 atoms, 1 to 20 atoms, 1 to 15 atoms, 1 to 10 atoms, or 1 to 5 atoms. In some embodiments, the linker has a length of 1 to 10 atoms. In some embodiments, the linker has a length of 1 to 20 atoms.

[0333] In some embodiments, the linker may comprise flexible and / or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues ("GS" linkers), glycine residues, alkylene chains, PEG chains, and the like. Exemplary rigid linker regions include those comprising alpha-helix-forming sequences, proline-rich sequences, and regions rich in double and / or triple bonds.

[0334] In some embodiments, the cleavable linker comprises one or more of: a substituted or unsubstituted alkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, and a substituted or unsubstituted heteroarylene.

[0335] In some embodiments, the linker comprises a click chemistry residue. In some embodiments, the linker is connected to a non-peptide ligand, a metal chelator, or both via click chemistry. For example, in some embodiments, the non-peptide ligand comprises an azido group that reacts with the alkyne portion of the linker. For another example, in some embodiments, the non-peptide ligand comprises an alkyne group that reacts with the azide group of the linker. The metal chelator and the linker can be connected similarly. In some embodiments, the linker comprises an azido moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole moiety.

[0336] In some embodiments, R A and R B Independently selected from: -L 2 -、-L 3 -、-L 4 -、-L 5 -、-L 6 -、-L 7 -、-L 2 -L 3 -、-L 2 -L 4 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 4 -L 6 -、-L 4 -L 7 -、-L 6 -L 7 -、-L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 5 -L 7 -、-L 2 -L 6 -L 7 -、-L 3 -L 4 -L 7 -、-L 4 -L 5 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、-L 4 -L5 -L 6 -L 7 -、-L 2 -L 4 -L 5 -L 6 -L 7 -or-L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, or a combination thereof; L 2 Is absent, substituted or unsubstituted -C1-C 20 Alkylene, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR 16 CH2NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)CH2NR 16 -, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH2CH2O) z -、-(OCH2CH2) z -、-(CH2CH2O) w -CH2CH2-, -CH2CH2NR 16 -(CH2CH2O) w -、-(CH2CH2O) w -CH2CH2NR 16 -, -CH2CH2NHC(=O)-(CH2CH2O) w 、-(CH2CH2O) w -CH2CH2NR 16 C(=O)-, -CH2CH2C(=O)NR 16 -(CH2CH2O) w -、-CH2CH2NR16 C(=O)CH2-(OCH2CH2) w or -(CH2CH2O) w -CH2CH2C(=O)NR 16 -; Each R 16 independently selected from H or C1-C4 alkyl; w is 1, 2, 3, 4, 5 or 6; z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L 3 is absent or a natural or unnatural amino acid, or a peptide formed from two or more independently selected natural and unnatural amino acids, wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted with a -C1-C6 alkyl group; 4 is absent, substituted or unsubstituted 2- to 10-membered heteroalkylene, -CH2-(OCH2CH2) v -、-(CH2CH2O) v -CH2CH2-, -(CH2CH2O) v CH2CH2NR 17 C(=O)-(CH2CH2O) v CH2CH2-、-(CH2CH2O) v CH2CH2C(=O)NR 17 -(CH2CH2O) v CH2CH2-, -C(=O)CH2CH2, -CH2CH2C(=O)-, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 、-(CH2) v -NR 17 -(CH2) v 、-NHC(=O)NH-O-(CH2) v -, -NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v , -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or -C1-C6 alkylene, said -C1-C6 alkylene being optionally substituted by 1 or 2 groups independently selected from the following: -OR 18 、-NR 18a18b 、-C(=O)OR 18 、-O(CH2CH2O) s -CH3, -NR 18 (CH2CH2O) s -CH3, -NR 18 C(=O)(CH2CH2O)s -CH3, -CH2OCH2CH2CO2R 18 or -NR 18 C(=O)CH2CH2CH-(COOH)NR 18 C(=O)-(CH2) s CH3; R 17 is H, -C1-C6 alkyl or sugar alcohol or its derivative; each R 18 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18a are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18b are independently H, -C1-C6 alkyl, -C(=O)(CH2) x -4-iodophenyl, -C(=O)(CH2) x -4-methylphenyl or sugar alcohol or its derivative; each x is independently 1, 2, 3 or 4; each v is independently an integer from 1 to 40; each s is independently an integer from 1 to 20; L 5 Is not present, -O-, -S-, -S(=O)-, -S(=O)2, -NR 13 -, -CH(=NH)-, -CH(=N-NH)-, -CCH3(=NH)-, -CCH3(=N-NH)-, -C(=O)NR 13 -、-NR 13 C(=O), -NR 13 C(=O)O-、-NR 13 C(=O)NR 13 -or-OC(=O)NR 13 -; Each R 13 Independently selected from H and C1-C4 alkyl; L 6 Is not present or -L 8 -L 9 -L 10 -;L 8 Does not exist, -(CH2) r -、-NR 14 -、-NR 14 -(CH2) r -、-(CH2) r -C(=O)-, -C(=O)-(CH2) r -、-(CH2) r -NR 14 -、-(CH2) r -NR 14 C(=O)-、-(CH2) r -C(=O)NR 14 -、-CH(NHR14 )-(CH2) r -C(=O)-, -NR 14 C(=O)-(CH2) r - and -C(=O)NR 14 -(CH2) r -; r is 0, 1, 2, or 3; L 9 is a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group, a monosaccharide or k is 1, 2, 3, or 4; L 10 Does not exist, -(CH2) q -、-NR 15 -、-NR 15 -(CH2) q -、-(CH2) q -C(=O)-, -C(=O)-(CH2) q -、-(CH2) q -NR 15 -、-NR 15 -(CH2) q -NR 15 -、-(CH2) q -NR 15 C(=O)-、-(CH2) q -C(=O)NR 15 -、-CH(NHR 15 )-(CH2) q -C(=O)-, -NR 15 C(=O)-(CH2) q -or-C(=O)NR 15 -(CH2) q -; q is 0, 1, 2, 3, 4, 5, or 6; R 14 and R 15 Each independently selected from H, -C1-C6 alkyl, -C1-C6 alkyl-C(=O)OH, -(CH2CH2O) p -CH3, -C(=O)-(CH2CH2O) p -CH3 or -(CH2CH2O) p -CH2CH2CO2H; p is 1, 2, 3, 4, 5 or 6; and L 7 is absent, -NH-, -N(CH3)-, -O-NH-, substituted or unsubstituted N-heterocycloalkylene, -O-NH=(substituted or unsubstituted N-heterocycloalkylene), or a natural or unnatural amino acid.

[0337] In some embodiments, RA and R B Independently selected from: -L 2 -、-L 3 -、-L 4 -、-L 5 -、-L 6 -、-L 7 -、-L 2 -L 3 -、-L 2 -L 4 -、-L 2 -L 7 -、-L 4 -L 6 -、-L 4 -L 7 -、-L 6 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 5 -L 7 -、-L 2 -L 6 -L 7 -、-L 3 -L 4 -L 7 -、-L 4 -L 5 -L 7 -or-L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, or a combination thereof; L 2 Is absent, substituted or unsubstituted -C1-C 20 Alkylene, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR16 CH2NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)CH2NR 16 -, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH2CH2O) z -、-(OCH2CH2) z -、-(CH2CH2O) w -CH2CH2-, -CH2CH2NR 16 -(CH2CH2O) w -、-(CH2CH2O) w -CH2CH2NR 16 -, -CH2CH2NHC(=O)-(CH2CH2O) w 、-(CH2CH2O) w -CH2CH2NR 16 C(=O)-, -CH2CH2C(=O)NR 16 -(CH2CH2O) w -、-CH2CH2NR 16 C(=O)CH2-(OCH2CH2) w or -(CH2CH2O) w -CH2CH2C(=O)NR 16 -; Each R 16 independently selected from H and C1-C4 alkyl; w is 1, 2, 3, 4, 5 or 6; z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L 3 is absent or a natural or unnatural amino acid, or a peptide formed from two or more independently selected natural and unnatural amino acids, wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted with a -C1-C6 alkyl group; 4 is absent, substituted or unsubstituted 2- to 10-membered heteroalkylene, -CH2-(OCH2CH2) v -、-(CH2CH2O) v -CH2CH2-, -(CH2CH2O) v CH2CH2NR 17 C(=O)(CH2CH2O) v CH2CH2-、-(CH2CH2O) v CH2CH2C(=O)NR 17 (CH2CH2O) vCH2CH2-, -C(=O)CH2CH2, -CH2CH2C(=O)-, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 or -C1-C6 alkylene, wherein the -C1-C6 alkylene is optionally substituted by 1 or 2 groups independently selected from the following: -OR 18 、-NR 18 2. -C(=O)OR 18 、-O(CH2CH2O) s -CH3, -NR 18 (CH2CH2O) s -CH3, -NR 18 C(=O)(CH2CH2O) s -CH3, -CH2OCH2CH2CO2R 18 or -NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s CH3; R 17 is H, -C1-C6 alkyl or sugar alcohol or its derivative; each R 18 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each v is independently an integer from 1 to 40; each s is independently an integer from 1 to 20; L 5 Is not present, -O-, -S-, -S(=O)-, -S(=O)2, -NR 13 -, -CH(=NH)-, -CH(=N-NH)-, -CCH3(=NH)-, -CCH3(=N-NH)-, -C(=O)NR 13 -、-NR 13 C(=O), -NR 13 C(=O)O-、-NR 13 C(=O)NR 13 -or-OC(=O)NR 13 -; Each R 13 Independently selected from H and -C1-C4 alkyl; L 6 Is not present or -L 8 -L 9 -L 10 -;L 8 Does not exist, -(CH2) r -、-NR 14 -、-NR 14 -(CH2) r -、-(CH2) r -C(=O)-, -C(=O)-(CH2) r-、-(CH2) r -NR 14 -、-(CH2) r -NR 14 C(=O)-、-(CH2) r -C(=O)NR 14 -、-CH(NHR 14 )-(CH2) r -C(=O)-, -NR 14 C(=O)-(CH2) r - and -C(=O)NR 14 -(CH2) r -; r is 0, 1, 2, or 3; L 10 Does not exist, -(CH2) q -、-NR 15 -、-NR 15 -(CH2) q -、-(CH2) q -C(=O)-, -C(=O)-(CH2) q -、-(CH2) q -NR 15 -、-NR 15 -(CH2) q -NR 15 -、-(CH2) q -NR 15 C(=O)-、-(CH2) q -C(=O)NR 15 -、-CH(NHR 15 )-(CH2) q -C(=O)-, -NR 15 C(=O)-(CH2) q -or-C(=O)NR 15 -(CH2) q -; q is 0, 1, 2, or 3; R 14 and R 15 Each independently selected from H, -C1-C6 alkyl, -C1-C6 alkyl-C(=O)OH, -(CH2CH2O) p -CH3, -C(=O)-(CH2CH2O) p -CH3 or -(CH2CH2O) p -CH2CH2CO2H; p is 1, 2, 3, 4, 5 or 6; L 9 is a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group, a monosaccharide or k is 1, 2, 3, or 4; and L7 is absent, -NH-, -N(CH3)-, -O-NH-, substituted or unsubstituted N-heterocycloalkylene, -O-NH=(substituted or unsubstituted N-heterocycloalkylene), or a natural or unnatural amino acid.

[0338] In some embodiments, R A and R B Independently selected from: -L 2 -、-L 3 -、-L 4 -、-L 5 -、-L 6 -、-L 7 -、-L 2 -L 3 -、-L 2 -L 4 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 4 -L 6 -、-L 4 -L 7 -、-L 6 -L 7 -、L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 5 -L 7 -、-L 2 -L 6 -L 7 -、-L 3 -L 4 -L 7 -、-L 4 -L 5 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、-L 4 -L 5 -L 6 -L 7 -、-L 2 -L 4 -L 5 -L6 -L 7 -or-L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, or a combination thereof; L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)CH2NR 16 -、-(CH2CH2O) z -or-(CH2CH2O) w -CH2CH2-; each R 16 independently selected from H or C1-C4 alkyl; w is 1, 2, 3, 4, 5 or 6; z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L 3 is a natural or unnatural amino acid, or a peptide formed from two or more independently selected natural and unnatural amino acids, wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted with a -C1-C6 alkyl group; 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 、-(CH2) v -NR 17 -(CH2) v 、-NHC(=O)NH-O-(CH2) v -, -NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v , -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or -C1-C6 alkylene, said -C1-C6 alkylene being optionally substituted by 1 or 2 groups independently selected from the following: -OR 18 、-NR 18a R 18b、-C(=O)OR 18 、-O(CH2CH2O) s -CH3, -NR 18 (CH2CH2O) s -CH3, -NR 18 C(=O)(CH2CH2O) s -CH3, -CH2OCH2CH2CO2R 18 or -NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s CH3; each R 17 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18a are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18b are independently H, -C1-C6 alkyl, -C(=O)CH2CH2CH2-4-iodophenyl, or sugar alcohol or its derivative; v is an integer from 1 to 40; s is an integer from 1 to 20; L 5 Yes-NR 13 C(=O); R 13 is H or -C1-C4 alkyl; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist, -(CH2) r -、-(CH2) r -C(=O)NR 14 -; r is 0, 1, 2, or 3; L 9 is a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group, a monosaccharide or k is 1, 2, 3, or 4; L 10 Yes - (CH2) q -、-NR 15 -(CH2) q -or-NR 15 -(CH2) q -NR 15 -; q is 0, 1, 2, 3, 4, 5, or 6; R 14 and R 15 are each independently selected from H or -C1-C6 alkyl-C(=O)OH; and L 7 is -NH- or a natural or unnatural amino acid.

[0339] In some embodiments, R A and R B Independently selected from: -L 2 -、-L 3 -、-L 4 -、-L 5 -、-L 6 -、-L 7 -、-L 2 -L 3 -、-L 2 -L 4 -、-L 2 -L 7 -、-L 4 -L 6 -、-L 4 -L 7 -、-L 6 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 5 -L 7 -、-L 2 -L 6 -L 7 -、-L 3 -L 4 -L 7 -、-L 4 -L 5 -L 7 -or-L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -, or a combination thereof; L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)CH2NR 16 -、-(CH2CH2O) z -or-(CH2CH2O) w -CH2CH2-; each R16 independently selected from H and C1-C4 alkyl; w is 1, 2, 3, 4, 5 or 6; z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L 3 is a natural or unnatural amino acid, or a peptide formed from two or more independently selected natural and unnatural amino acids, wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted with a -C1-C6 alkyl group; 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 or -C1-C6 alkylene, wherein the -C1-C6 alkylene is optionally substituted by 1 or 2 groups independently selected from the following: -OR 18 、-NR 18 2. -C(=O)OR 18 、-O(CH2CH2O) s -CH3, -NR 18 (CH2CH2O) s -CH3, -NR 18 C(=O)(CH2CH2O) s -CH3, -CH2OCH2CH2CO2R 18 or -NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s CH3; each R 17 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; each R 18 are independently H, -C1-C6 alkyl or sugar alcohol or its derivative; v is an integer from 1 to 40; s is an integer from 1 to 20; L 5 Yes-NR 13 C(=O); R 13 is H or -C1-C4 alkyl; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist, -(CH2) r -、-(CH2) r -C(=O)NR 14 -; r is 0, 1, 2, or 3; L 10 Yes - (CH2) q -、-NR 15 -(CH2) q -or-NR 15-(CH2) q -NR 15 -; q is 0, 1, 2, or 3; R 14 and R 15 Each independently selected from H or -C1-C6 alkyl-C(=O)OH; L 9 is a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group, a monosaccharide or k is 1, 2, 3, or 4; and L 7 is -NH- or a natural or unnatural amino acid.

[0340] In some embodiments, L A Yes-L 2 -L 3 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 6 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、-L 4 -L 5 -L 6 -L 7 -or-L 2 -L 4 -L 5 -L 6 -L 7 -.

[0341] In some embodiments, L A Yes-L 2 -L 3 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 6 -L7 -、-L 2 -L 3 -L 4 -L 7 -or-L 4 -L 5 -L 6 -L 7 -. In some embodiments, L A Yes-L 2 -L 3 -. In some embodiments, L A Yes-L 2 -L 6 -. In some embodiments, L A Yes-L 2 -L 7 -. In some embodiments, L A Yes-L 2 -L 3 -L 7 -. In some embodiments, L A Yes-L 2 -L 4 -L 7 -. In some embodiments, L A Yes-L 2 -L 6 -L 7 -. In some embodiments, L A Yes-L 2 -L 3 -L 4 -L 7 -. In some embodiments, L A Yes-L 2 -L 4 -L 5 -L 7 -. In some embodiments, L A Yes-L 4 -L 5 -L 6 -L 7 -. In some embodiments, L A Yes-L 2 -L 4 -L 5 -L 6 -L 7 -.

[0342] In some embodiments, L B Yes-L 2 -L 3 -、-L 2 -L 6 -、-L2 -L 7 -、-L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 6 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、-L 4 -L 5 -L 6 -L 7 -or-L 2 -L 4 -L 5 -L 6 -L 7 -.

[0343] In some embodiments, L B Yes-L 2 -L 3 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 6 -L 7 -、-L 2 -L 3 -L 4 -L 7 -or-L 4 -L 5 -L 6 -L 7 -. In some embodiments, L B Yes-L 2 -L 3 -. In some embodiments, L B Yes-L 2 -L 6 -. In some embodiments, L B Yes-L 2 -L 7 -. In some embodiments, L B Yes-L 2-L 3 -L 7 -. In some embodiments, L B Yes-L 2 -L 4 -L 7 -. In some embodiments, L B Yes-L 2 -L 6 -L 7 -. In some embodiments, L B Yes-L 2 -L 3 -L 4 -L 7 -. In some embodiments, L B Yes-L 2 -L 4 -L 5 -L 7 -. In some embodiments, L B Yes-L 4 -L 5 -L 6 -L 7 -. In some embodiments, L B Yes-L 2 -L 4 -L 5 -L 6 -L 7 -.

[0344] In some embodiments, L 2 In some embodiments, L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-, substituted or unsubstituted-C1-C 20 Alkylene-NHC(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH- or substituted or unsubstituted-C1-C 20 Alkylene-NHC(=O)CH2NH-. In some embodiments, L 2 is substituted or unsubstituted -C1-C 20 In some embodiments, L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-. In some embodiments, L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)NR 16NH-. In some embodiments, L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)CH2NH-. In some embodiments, L 2 is -(CH2CH2O) z -. In some embodiments, L 2 Yes – (CH2CH2O) w -CH2CH2.

[0345] In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0346] In some embodiments, L 3 In some embodiments, L 3 is a natural amino acid, an unnatural amino acid, or a peptide formed from two or more independently selected amino acids selected from the group consisting of alanine (Ala), 3-(2-naphthyl)-alanine (2-Nal), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), cysteic acid, glutamine (Gln), glutamic acid (Glu), γ-carboxyglutamate (Gla), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), hydroxylysine (Hydroxy ... ), ornithine (Orn), methionine (Met), phenylalanine (Phe), p-phenylphenylalanine (Bip), proline (Pro), hydroxyproline (Hyp), serine (Ser), homoserine (Hse), sarcosine (Sar), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val), 4-benzoyl-L-phenylalanine (Bpa) and cyclohexylalanine (Cha), wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted with -CH3. In some embodiments, L 3It is a natural amino acid, a non-natural amino acid, or a peptide formed by two or more independently selected amino acids selected from the group consisting of alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), cysteic acid, glutamine (Gln), glutamic acid (Glu), glycine (Gly), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), sarcosine (Sar), tyrosine (Tyr), and valine (Val), wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted with -CH3. In some embodiments, the peptide is formed by one or more independently selected L-amino acids. In some embodiments, the peptide is formed by one or more independently selected D-amino acids. In some embodiments, the peptide is formed by one or more independently selected L-amino acids and one or more independently selected D-amino acids.

[0347] In some embodiments, L 3 is a natural amino acid. In some embodiments, L 3 is lysine. In some embodiments, L 3 is glutamic acid. In some embodiments, L 3 is glutamine. In some embodiments, L 3 is asparagine. In some embodiments, L 3 is serine. In some embodiments, L 3 is an unnatural amino acid. In some embodiments, L 3 is Bip. In some embodiments, L 3 is cysteic acid. In some embodiments, L 3 is NAL. In some embodiments, L 3 is ornithine. In some embodiments, L 3 is a dipeptide. In some embodiments, L 3 In some embodiments, L 3 It's Lys-Bip.

[0348] In some embodiments, L 4 In some embodiments, L 4 is -C(=O)CH2CH2. In some embodiments, L 4 is -(CH2CH2O) v -CH2CH2-. In some embodiments, v is 1 or 2. In some embodiments, L 4 is -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR17 In some embodiments, R 17 is a sugar alcohol or a derivative thereof. In some embodiments, R 17 is sorbitol or a derivative thereof. In some embodiments, L 4 is -C1-C6 alkylene optionally substituted by 1 or 2 groups independently selected from: -OR 18 、-NR 18 2. -NR 18a R 18b 、-C(=O)OR 18 、-O(CH2CH2O) s -CH3, -NR 18 (CH2CH2O) s -CH3, -NR 18 C(=O)(CH2CH2O) s -CH3, -CH2OCH2CH2CO2R 18 or -NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s CH3. In some embodiments, L 4 is optionally replaced by 1-NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s CH3-substituted-C1-C6 alkylene.

[0349] In some embodiments, L 4 Yes - (CH2) v -NR 17 -(CH2) v In some embodiments, L 4 is -(CH2)3-N(CH3)-(CH2)3-. In some embodiments, L 4 is -(CH2)2-N(CH3)-(CH2)2-. In some embodiments, L 4 is -NHC(=O)NH-O-(CH2) v -. In some embodiments, L 4 is -NHC(=O)NH-(CH2) v -. In some embodiments, L 4 is -NHC(=O)NH-NH-C(=O)(CH2) v -. In some embodiments, L 4 is -NHC(=O)CH2-O-NH-C(=O)(CH2)v -. In some embodiments, L 4 is unsubstituted -C1-C6 alkylene. In some embodiments, L 4 is -C1-C6 alkylene substituted by 1 or 2 groups independently selected from: -OR 18 or -NR 18a R 18b In some embodiments, L 4 is optionally replaced by 1 or 2 -NR 18a R 18b In some embodiments, R 18a is H and R 18b Is H or -CH3. In some embodiments, L 4 is a -C1-C6 alkylene substituted with one -NH2. 4 It is a -C1-C6 alkylene group substituted with one -NHC(=O)CH2CH2CH2-4-iodophenyl group.

[0350] In some embodiments, R 17 is H. In some embodiments, R 17 is -CH3. In some embodiments, R 17 is -CH2CH3. In some embodiments, R 17 It is sorbitol or its derivatives.

[0351] In some embodiments, L 5 In some embodiments, L 5 is -C(=O)NR 13 -or-NR 13 C(=O)-. In some embodiments, L 5 is -C(=O)NH- or -NHC(=O)-. In some embodiments, L 5 is -C(=O)NH-. In some embodiments, L 5 It is -NHC(=O)-.

[0352] In some embodiments, L 6 In some embodiments, wherein L 6 Yes-L 8 -L 9 -L 10 -.

[0353] In some embodiments, L 8 In some embodiments, L 8 Yes - (CH2) r In some embodiments, L8 Yes - (CH2) r -C(=O)NR 14 -. In some embodiments, R 14 In some embodiments, r is 1 or 2.

[0354] In some embodiments, L 10 In some embodiments, L 10 Yes - (CH2) q -. In some embodiments, L 10 Yes-NR 15 -(CH2) q -. In some embodiments, L 10 Yes-NR 15 -(CH2) q -NR 15 -. In some embodiments, R 15 is H. In some embodiments, q is 1 or 2. In some embodiments, L 10 is -(CH2)-. In some embodiments, L 10 is -C(=O)NR 15 -(CH2) q -.

[0355] In some embodiments, L 9 is a substituted or unsubstituted heterocycloalkylene. 9 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene group. 9 is a substituted or unsubstituted 4- to 6-membered heterocycloalkylene group. 9 L is azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl. 9 is a monosaccharide. In some embodiments, L 9 yes In some embodiments, L 9 is a substituted or unsubstituted cycloalkylene. In some embodiments, L 9 is a substituted or unsubstituted C4-C8 cycloalkylene. 9 yes In some embodiments, L 9 is a substituted or unsubstituted arylene group. In some embodiments, L 9 is substituted or unsubstituted phenylene. In some embodiments, L 9 is unsubstituted phenylene. In some embodiments, L 9 is a substituted or unsubstituted heteroarylene. In some embodiments, L9 yes In some embodiments, L 9 yes and k is 1. In some embodiments, L 9 yes and k is 2. In some embodiments, L 9 yes and k is 3. In some embodiments, L 9 yes And k is 4.

[0356] In some embodiments, L 7 In some embodiments, L 7 In some embodiments, L 7 is a natural or unnatural amino acid. In some embodiments, L 7 is 3-aminoalanine. In some embodiments, L 7 It's lysine.

[0357] In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5. In some embodiments, w is 6.

[0358] In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10.

[0359] In some embodiments, v is 1, 2, 3, 4, 5, or 6. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5. In some embodiments, v is 6. In some embodiments, v is 7. In some embodiments, v is 8. In some embodiments, v is 9. In some embodiments, v is 10. In some embodiments, v is 11. In some embodiments, v is 12. In some embodiments, v is 13. In some embodiments, v is 14. In some embodiments, v is 15. In some embodiments, v is 16. In some embodiments, v is 17. In some embodiments, v is 18. In some embodiments, v is 19. In some embodiments, v is 20. In some embodiments, v is 21. In some embodiments, v is 22. In some embodiments, v is 23. In some embodiments, v is 24. In some embodiments, v is 25. In some embodiments, v is 26. In some embodiments, v is 27. In some embodiments, v is 28. In some embodiments, v is 29. In some embodiments, v is 30. In some embodiments, v is 31. In some embodiments, v is 32. In some embodiments, v is 33. In some embodiments, v is 34. In some embodiments, v is 35. In some embodiments, v is 36. In some embodiments, v is 37. In some embodiments, v is 38. In some embodiments, v is 39. In some embodiments, v is 40.

[0360] In some embodiments, s is 1, 2, 3, 4, 5, or 6. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, s is 7. In some embodiments, s is 8. In some embodiments, s is 9. In some embodiments, s is 10. In some embodiments, s is 11. In some embodiments, s is 12. In some embodiments, s is 13. In some embodiments, s is 14. In some embodiments, s is 15. In some embodiments, s is 16. In some embodiments, s is 17. In some embodiments, s is 18. In some embodiments, s is 19. In some embodiments, s is 20.

[0361] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.

[0362] In some embodiments, q is 1 or 2. In some embodiments, q is 4, 5, or 6. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6.

[0363] In some embodiments, L A Yes-L 2 -L 3 -;L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)CH2NH-; and L 3 is a natural or non-natural amino acid or a natural or non-natural peptide, wherein the N atom of the amide connecting the amino acid is optionally substituted with -CH3. In some embodiments, the natural or non-natural amino acid is cysteic acid, lysine, glutamic acid, or asparagine. In some embodiments, the peptide is a dipeptide. In some embodiments, the peptide is a tripeptide consisting of three glycines, wherein the N atom of the amide connecting the amino acid is substituted with -CH3. In some embodiments, the dipeptide is Arg-Bip. In some embodiments, L A Yes-L 2 -L 3 -;L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)CH2NH-; and L 3 is a natural or unnatural amino acid. In some embodiments, the natural or unnatural amino acid is cysteic acid, lysine, glutamic acid, or asparagine.

[0364] In some embodiments, L A Yes-L 2 -L 6 -;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)-; and L 6 Yes-L 8 -L 9 -L 10 -.

[0365] In some embodiments, L A Yes-L 2 -L 7 -;L 2 is -(CH2CH2O) w -CH2CH2-; and L 7 It is -NH-.

[0366] In some embodiments, LA Yes-L 2 -L 3 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 is a natural or unnatural amino acid; and L 7 are natural or unnatural amino acids.

[0367] In some embodiments, L A Yes-L 2 -L 4 -L 7 ;L 2 is unsubstituted -C1-C6 alkylene-C(=O)NCH3-, unsubstituted -C1-C6 alkylene-NHC(=O)-, unsubstituted -C1-C6 alkylene-NHC(=O)NHNH- or optionally substituted by 1 -NR 18a R 18b Substituted-C1-C6 alkylene; L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2-, -(CH2) v -NR 17 -(CH2) v 、-NHC(=O)NH-O-(CH2) v -, -NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v -, -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or optionally substituted -C1-C6 alkylene; and L 7 Is -NH- or -O-NH-. In some embodiments, L A Yes-L 2 -L 4 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)- or unsubstituted -C1-C6 alkylene-NHC(=O)NHNH-; L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2 or optionally substituted -C1-C6 alkylene; and L 7 It is -NH-.

[0368] In some embodiments, L A Yes-L 2 -L 6 -L7 -;L 2 is unsubstituted -C1-C6 alkylene, unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 Is -NH-, -O-NH- or a natural or unnatural amino acid. In some embodiments, L A Yes-L 2 -L 6 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 is -NH- or a natural or unnatural amino acid.

[0369] In some embodiments, L A Yes-L 2 -L 3 -L 4 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 is glutamine or a peptide formed by two or more glycines, wherein the N atom of the amide connecting the amino acids is replaced by -CH3; L 4 is -C(=O)CH2CH2- or -(CH2) v -NR 17 -(CH2) v ; and L 7 In some embodiments, L A Yes-L 2 -L 3 -L 4 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 A peptide formed by two or more glycine residues in which the N atom of the amide connecting the amino acids is replaced by -CH3; 4 is -C(=O)CH2CH2-; and L 7 It is -NH-.

[0370] In some embodiments, L A Yes-L 2-L 4 -L 5 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is optionally replaced by 1-NR 18a18b Substituted-C1-C6 alkylene; L 5 is -NH-; and L 7 are natural or unnatural amino acids.

[0371] In some embodiments, L A Yes-L 4 -L 5 -L 6 -L 7 -;L 4 is -(CH2CH2O) v -CH2CH2-; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 It is -NH-.

[0372] In some embodiments, L A It's L 2 -L 4 -L 5 -L 6 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is optionally replaced by 1-NR 18a18b Substituted-C1-C6 alkylene; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 It is -NH-.

[0373] In some embodiments, -L A -R A Yes-L 2 -L 3 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)CH2NH-; and L 3is a natural or unnatural amino acid. In some embodiments, the natural or unnatural amino acid is cysteic acid, lysine, glutamic acid, or asparagine.

[0374] In some embodiments, -L A -R A Yes-L 2 -L 6 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)-; and L 6 Yes-L 8 -L 9 -L 10 -.

[0375] In some embodiments, -L A -R A Yes-L 2 -L 7 -R A ;L 2 is -(CH2CH2O) w -CH2CH2-; and L 7 It is -NH-.

[0376] In some embodiments, L A -R A Yes-L 2 -L 3 -L 7 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 It's Bip; and L 7 It is (R)-2,3-diaminopropionic acid.

[0377] In some embodiments, L A -R A Yes-L 2 -L 4 -L 7 -R A ;L 2 is unsubstituted -C1-C6 alkylene-C(=O)NCH3-, unsubstituted -C1-C6 alkylene-NHC(=O)-, unsubstituted -C1-C6 alkylene-NHC(=O)NHNH- or optionally substituted by 1 -NR 18a R 18b Substituted-C1-C6 alkylene; L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2-, -(CH2) v -NR17 -(CH2) v 、-NHC(=O)NH-O-(CH2) v -, -NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v -, -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or optionally substituted -C1-C6 alkylene; and L 7 Is -NH- or -O-NH-. In some embodiments, -L A -R A Yes-L 2 -L 4 -L 7 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)- or unsubstituted -C1-C6 alkylene-NHC(=O)NHNH-; L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2 or optionally substituted -C1-C6 alkylene; and L 7 It is -NH-.

[0378] In some embodiments, L A -R A Yes-L 2 -L 6 -L 7 -R A ;L 2 is unsubstituted -C1-C6 alkylene, unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 Is -NH-, -O-NH- or a natural or unnatural amino acid. In some embodiments, -L A -R A Yes-L 2 -L 6 -L 7 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10-; and L 7 is -NH- or a natural or unnatural amino acid.

[0379] In some embodiments, L A -R A Yes-L 2 -L 3 -L 4 -L 7 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 is glutamine or a peptide formed by two or more glycines, wherein the N atom of the amide connecting the amino acids is replaced by -CH3; L 4 is -C(=O)CH2CH2- or -(CH2) v -NR 17 -(CH2) v ; and L 7 In some embodiments, L A -R A Yes-L 2 -L 3 -L 4 -L 7 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 A peptide formed by two or more glycine residues in which the N atom of the amide connecting the amino acids is replaced by -CH3; 4 is -C(=O)CH2CH2-; and L 7 It is -NH-.

[0380] In some embodiments, L A -R A Yes-L 2 -L 4 -L 5 -L 7 -R A ;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is a -C1-C6 alkylene group optionally substituted by one -NH2; L 5 is -NH-; and L 7 It's Bip.

[0381] In some embodiments, L A -R A Yes-L 4 -L 5 -L 6 -L7 -R A ;L 4 is -(CH2CH2O) v -CH2CH2-; L 5 Yes -NH-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 In some embodiments, L 8 Does not exist; L 9 yes L 10 does not exist; and k is 1, 2, 3 or 4.

[0382] In some embodiments, L A -R A Yes-L 4 -L 5 -L 6 -L 7 -R A ;L 4 is -(CH2CH2O) v -CH2CH2-; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 It is -NH-.

[0383] In some embodiments, L A -R A It's L 2 -L 4 -L 5 -L 6 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is a -C1-C6 alkylene group substituted with one -NH2; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 In some embodiments, L 8 Does not exist; L 9 is unsubstituted phenylene; and L 10 Yes – (CH2) q -. In some embodiments, L 8 Yes - (CH2)r -;L 9 is an unsubstituted heterocycloalkylene group; and L 10 Does not exist.

[0384] In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 3 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-; and L 3 is an unnatural amino acid. In some embodiments, L 3 is lysine. In some embodiments, L 3 is glutamic acid. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 3 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)CH2NH-; and L 3 is an unnatural amino acid. In some embodiments, L 3 It's asparagine.

[0385] In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Yes - (CH2) t -C(=O)NR 14 -;R 14 is -CH2CO2H; t is 2; L 9 is a substituted or unsubstituted heterocycloalkylene group; and L 10 In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L10 -;L 8 Yes - (CH2) t ; t is 1; L 9 is a substituted or unsubstituted heterocycloalkylene group; and L 10 Does not exist.

[0386] In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 7 -;L 2 is -(CH2CH2O) w -CH2CH2-; and L 7 is -NH-. In some embodiments, w is 1. In some embodiments, w is =2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, Z A is -NHC(=O)-; L A Yes-L 2 -L 7 -;L 2 is -(CH2CH2O) w -CH2CH2-; L 7 is -NH-; and w is 4.

[0387] In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 3 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 is a natural or unnatural amino acid; and L 7 is a natural or unnatural amino acid. In some embodiments, L 3 is Bip. In some embodiments, L 7 It is (R)-2,3-diaminopropionic acid.

[0388] In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 4 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-C(=O)NCH3-; L 4 Yes - (CH2) v -NR 17 -(CH2) v -; and L 7is -N(CH3)-. In some embodiments, v is 3. In some embodiments, R 17 is -CH3. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 4 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is -C1-C6 alkylene-; and L 7 is -NH-. In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 4 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is a -C1-C6 alkylene substituted with one -NH2; and L 7 is -NH-. In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 4 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 Is 1-NR 18a R 18b Substituted-C1-C6 alkylene; and L 7 In some embodiments, R 18a is H and R 18b is -C(=O)CH2CH2CH2-4-iodophenyl. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 4 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is unsubstituted -C1-C6 alkylene; and L 7 is -NH-. In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 4 -L 7 -;L 2is unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is unsubstituted -C1-C6 alkylene; and L 7 is -NH-. In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 4 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-; L 4 is -NHC(=O)NH-O-(CH2)v-; and L 7 is -NH-. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 4 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-; L 4 is -NHC(=O)NH-O-(CH2)v-; and L 7 is -NH-. In some embodiments, v is 2. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-; L 4 is -NHC(=O)NH-NH-C(=O)(CH2) v -; and L 7 In some embodiments, Z is -O-; L A Yes-L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-; L 4 is -NHC(=O)CH2-O-NH-C(=O)(CH2)v-; and L 7 In some embodiments, Z is -O-; L A Yes-L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-; L 4is -NHC(=O)NH-(CH2)v-; and L 7 In some embodiments, v is 2.

[0389] In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 4 is -(CH2CH2O) v -CH2CH2-; and L 7 is -NH-. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 4 is -(CH2CH2O) v -CH2CH2-; and L 7 In some embodiments, v is 1. In some embodiments, v is 36. In some embodiments, Z A Yes-O-;L A It's L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 4 is -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 ; and L 7 In some embodiments, R 17 is a sugar alcohol or a derivative thereof. In some embodiments, R 17 is glucitol. In some embodiments, R 17 is sorbitol. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C20 Alkylene-NHC(=O)-; L 4 is a substituted or unsubstituted -C1-C6 alkylene-; and L 7 In some embodiments, L 4 It is replaced by 1 -NHC(=O)CH2CH2CH(COOH)NHC(=O)-(CH2) s -C1-C6 alkylene-substituted with CH3. In some embodiments, s is 14. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-;L 4 is -C(=O)CH2CH2-; and L 7 It is -NH-.

[0390] In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted cycloalkylene group; L 10 Yes-NR 15 -(CH2) r -; and L 7 In some embodiments, R 15 is H; in some embodiments, r is 2. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-; L 6 Yes-L 8 -L 9 -L 10 -;L8 Does not exist; L 9 is a substituted or unsubstituted cycloalkylene group; L 10 Yes-NR 15 -(CH2) q -NR 15 -; and L 7 is a natural or unnatural amino acid. In some embodiments, L 7 is 3-aminoalanine. In some embodiments, L 7 is lysine. In some embodiments, R 15 is H. In some embodiments, q is 2. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted heterocycloalkylene group; L 10 Yes - (CH2) r -; and L 7 In some embodiments, r is 1. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted arylene group; L 10 does not exist; and L 7 is -NH-. In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-; L 6It's L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted cycloalkylene group; L 10 Yes-NR 15 -(CH2) r -; and L 7 In some embodiments, R 15 is H; in some embodiments, r is 2. In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 6 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is an unsubstituted arylene group; L 10 is -C(=O)NR 15 -(CH2) q -; and L 7 is -NH-. In some embodiments, q is 4. In some embodiments, Z is -O-; L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted cycloalkylene group; L 10 Yes-NR w -(CH2) r -; and L 7 In some embodiments, r is 2. In some embodiments, R w is H. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted C1-C20 Alkylene; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted heterocycloalkylene group; L 10 is -C(=O)-(CH2) q -; and L 7 In some embodiments, q is 5.

[0391] In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted arylene group; L 10 does not exist; and L 7 is -NH-. In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 6 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted cycloalkylene group; L 10 Yes-NR 15 -(CH2) r -; and L 7 In some embodiments, R 15 is H; in some embodiments, r is 2.

[0392] In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 3 -L 4 -L7 -;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 is a natural or unnatural amino acid; L 4 Yes - (CH2) v -NR 17 -(CH2) v -; and L 7 In some embodiments, R 17 is -CH3. In some embodiments, L 3 is glutamine. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 3 -L 4 -L 7 -;L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 is a natural or unnatural amino acid; L 4 is -C(=O)CH2CH2; and L 7 In some embodiments, L 3 is serine. In some embodiments, Z A Yes-O-;L A Yes-L 2 -L 3 -L 4 -L 7 -;L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NH-; L 3 Is a natural or non-natural peptide; L 4 is -C(=O)CH2CH2-; and L 7 In some embodiments, L 3 is a natural or non-natural peptide, wherein when two or more amino acids are present, the N atom of the amide linking the amino acids is optionally substituted with a -C1-C6 alkyl group.

[0393] In some embodiments, Z A Yes -NH-; L A Yes-L 2 -L 4 -L 5 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is optionally replaced by 1-NR 18a18b Substituted-C1-C6 alkylene; L 5is -NH-; and L 7 is a natural or unnatural amino acid. In some embodiments, L 7 It's Bip.

[0394] In some embodiments, Z A is -NHC(=O)-; L A Yes-L 4 -L 5 -L 6 -L 7 -;L 4 is -(CH2CH2O) v -CH2CH2-; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;L 8 Does not exist; L 9 is a substituted or unsubstituted heterocycloalkylene group; L 10 Yes (CH2) r ; and L 7 In some embodiments, r is 1. In some embodiments, v is 1.

[0395] In some embodiments, Z A Yes-O-;L A It's L 2 -L 4 -L 5 -L 6 -L 7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is a -C1-C6 alkylene group substituted with one -NH2; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 In some embodiments, L 8 Does not exist; L 9 is an unsubstituted arylene group; and L 10 Yes - (CH2) q -. In some embodiments, q is 1. In some embodiments, Z A Yes -NH-; L A It's L 2 -L 4 -L 5 -L 6 -L7 -;L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is optionally replaced by 1-NR 18a18b Substituted-C1-C6 alkylene; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -; and L 7 In some embodiments, L 8 Yes - (CH2) r -;L 9 is an unsubstituted heterocycloalkylene group; and L 10 Does not exist.

[0396] In some embodiments, Linker-L A -or-L B -(whichever exists, choose) or -L A -and-L B - (if both are present, each independently selected from) the following linkers:

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404] In some embodiments, the linker is -L A -. In some embodiments, the linker is -L B -.

[0405] In some embodiments, Linker-L A -or-L B -(whichever exists, choose) or -L A -and-L B - (if both are present, each independently selected from) the following linkers:

[0406]

[0407]

[0408] In some embodiments, the linker is -L A -. In some embodiments, the linker is -L B -.

[0409] In some embodiments, Linker-L A -or-L B -(whichever exists, choose) or -L A -and-L B - (if both are present, each independently selected from) the following linkers:

[0410]

[0411]

[0412] In some embodiments, the linker is -L A -. In some embodiments, the linker is -L B -.

[0413] In some embodiments, Linker-L A -or-L B -(whichever exists, choose) or -L A -and-L B - (if both are present, each independently selected from) the following linkers:

[0414]

[0415] In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, -L A -yes In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-LB -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever is present) is. In some embodiments, linker -L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, -L A -yes In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A-or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-LB -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, the linker is -L A -. In some embodiments, the linker is -L B -.

[0416] In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A-or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, Linker-L A -or-L B -(whichever exists) is In some embodiments, the linker is -L A -. In some embodiments, the linker is -L B -.

[0417] Representative linkers and chelating moieties

[0418] In some embodiments, -L A -R A yes: In some embodiments, -R A yes

[0419] In some embodiments, -L A -R A yes In some embodiments, -R A yes

[0420] In some embodiments, -L A -R A -yes

[0421] In some embodiments, -R A yes

[0422] In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -LA -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -R A yes

[0423] In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -RA yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -L A-R A yes In some embodiments, -L A -R A yes In some embodiments, -L A -R A yes In some embodiments, -R A yes

[0424] In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -L A -R A -yes In some embodiments, -R A yes

[0425] In some embodiments, -L B -R B yes

[0426]

[0427] In some embodiments, -R B yes

[0428] In some embodiments, -L B -R B yes In some embodiments, -R B yes

[0429] In some embodiments, -L B -R B -yes In some embodiments, -R B yes

[0430] In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -RB yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -R B yes

[0431] In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -L B -R B yes In some embodiments, -R B yes

[0432] In some embodiments, -L B -R B -yes In some embodiments, -L B -R B -yes In some embodiments, -L B -R B -yes In some embodiments, -L B -R B -yes In some embodiments, -L B -R B -yes In some embodiments, -LB -R B -yes In some embodiments, -L B -R B -yes In some embodiments, -L B -R B -yes In some embodiments, -L B -R B -yes In some embodiments, -R B yes

[0433] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is selected from the following, or -L A -R A and -L B -R B (if both are present) and are each independently selected from the following:

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L B -R B .

[0440] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is selected from the following, or -L A -R A and -L B -RB (if both are present) and are each independently selected from the following:

[0441]

[0442]

[0443]

[0444]

[0445]

[0446] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L B -R B .

[0447] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is selected from the following, or -L A -R A and -L B -R B (if both are present) and are each independently selected from the following:

[0448] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L B -R B .

[0449] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B-R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -RA or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is

[0450] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -LB -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -LA -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -L A -R A yes In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -LB -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -L A -R A yes In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is

[0451] In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -RA or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is In some embodiments, -linker-(chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (whichever exists) and is

[0452] Representative compounds

[0453] Representative NPY1R radiopharmaceuticals described herein have one of the following structures, or a pharmaceutically acceptable salt thereof:

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473] or a radionuclide complex thereof.

[0474] Representative NPY1R radiopharmaceuticals described herein have one of the following structures, or a pharmaceutically acceptable salt thereof:

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509] or a radionuclide complex thereof.

[0510] In some embodiments, the compound of formula (II) is compound 101A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 101B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 102A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 102B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 103A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 103B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 104, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 105, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 106, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 107A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 107B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 108A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 108B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 109A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 109B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 110A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 110B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 111A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 111B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 112A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 112B, its pharmaceutically acceptable salt or its radionuclide complex.In some embodiments, the compound of formula (II) is compound 113A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 113B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 114A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 114B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 115, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 116, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 117A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 117B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 118A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 118B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 119, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 120, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 121, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 122, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 123, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 124A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 124B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 125, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 126, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 127, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 128, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of formula (II) is compound 129, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 130, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 131, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0511] In some embodiments, the compound of formula (II) is compound 115A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 115B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 116A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 116B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 120A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 120B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 121A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 121B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 132A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 132B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 133A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 133B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 134A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 134B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 135A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 135B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 136A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 136B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 137A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 137B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 138, its pharmaceutically acceptable salt or its radionuclide complex.In some embodiments, the compound of formula (II) is compound 139A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 139B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 140A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 140B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 141A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 141B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 142A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 142B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 143A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 143B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 144A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 144B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 145A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 145B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 146A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 146B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 147A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 147B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 148A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 148B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 149, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of formula (II) is compound 150, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 151, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 152, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 153, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 154, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 155, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 156, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 157, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 158, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 159, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 160, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 161A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 161B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 162A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 162B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 163A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 163B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 164A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 164B, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 165A, its pharmaceutically acceptable salt or its radionuclide complex. In some embodiments, the compound of formula (II) is compound 165B, its pharmaceutically acceptable salt or its radionuclide complex.In some embodiments, the compound of formula (II) is compound 166, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 167, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 168, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 169, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 170A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (II) is compound 170B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0512] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, one skilled in the art will select groups and substituents thereof to provide stable moieties and compounds.

[0513] Synthesis of compounds

[0514] The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0515] Conventional mass spectrometry, NMR, and HPLC methods were employed unless otherwise indicated.

[0516] The compounds are prepared using standard organic chemistry techniques, such as those described in, for example, March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed, such as varying solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions.

[0517] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0518] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, a form of the therapeutically active agent consisting of an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bigley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and CGWermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are generally more soluble and dissolve more rapidly in gastric and intestinal fluids than non-ionic species and are therefore useful in solid dosage forms. Furthermore, because their solubility often varies with pH, ​​selective solubility in one part of the digestive tract or another is possible, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Moreover, because salt-forming molecules can be equilibrated with neutral forms, delivery across biological membranes can be tailored.

[0519] In some embodiments, the pharmaceutically acceptable salt is obtained by reacting a compound of formula (I) or (II) with an acid. In some embodiments, the acid is an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); caprylic acid (decanoic acid); caprylic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclohexylaminosulfonic acid; dodecyl sulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; dapoxetine Cholic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphate; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0520] In some embodiments, the compound of formula (I) or (II) is prepared as a chloride salt, a sulfate salt, a bromide salt, a methanesulfonate salt, a maleate salt, a citrate salt, or a phosphate salt.

[0521] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of formula (I) or (II) with a base. In some cases, the compounds described herein are coordinated with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases for forming salts with compounds comprising acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

[0522] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during a crystallization process with a pharmaceutically acceptable solvent, such as water, ethanol, or the like. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0523] In some embodiments, any hydrogen atom on an organic group (eg, alkyl group, aromatic ring) of the compounds described herein is replaced with deuterium.

[0524] In some embodiments, the compound of formula (I) or formula (II) has one or more stereocenters, and each stereocenter exists independently in the R or S configuration. The compounds presented herein include all diastereoisomers, individual enantiomers, atropisomers, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis (cis), trans (trans), syn (syn), anti (anti), entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In some embodiments, the compound is a mixture of two diastereomers, wherein the diastereoisomer ratio (the ratio of the percentage of one diastereomer in the mixture to the percentage of the other diastereomer in the mixture) is about 99:1 to about 50:50. In some embodiments, the diastereoisomer ratio is about 99:1 to about 90:10. In some embodiments, the diastereoisomer ratio is about 95:5 to about 85:15. In some embodiments, the diastereoisomer ratio is from about 90:10 to about 80:20. In some embodiments, the diastereoisomer ratio is from about 85:15 to about 75:25. In some embodiments, the diastereoisomer ratio is from about 80:20 to about 70:30. In some embodiments, the diastereoisomer ratio is from about 75:25 to about 65:35. In some embodiments, the diastereoisomer ratio is from about 70:30 to about 60:40. In some embodiments, the diastereoisomer ratio is from about 65:35 to about 55:45. In some embodiments, the diastereoisomer ratio is from about 60:40 to about 50:50. In some embodiments, the diastereoisomer ratio is from about 55:45 to about 45:55.

[0525] If desired, individual stereoisomers are obtained by methods such as the following: stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by achiral or chiral chromatographic columns or crystallization and recrystallization in appropriate solvents or solvent mixtures. In certain embodiments, the compounds described herein are prepared into their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, the resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolvation techniques based on solubility differences. In other embodiments, the separation of stereoisomers is carried out by chromatography, or by forming diastereomeric salts and separating via recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0526] In some embodiments, the compounds described herein are prepared in prodrug form. A "prodrug" refers to an agent that is converted into a parent drug in vivo. Prodrugs are generally useful because, in some cases, they are easier to administer than the parent drug. They are bioavailable, for example, by oral administration, whereas the parent drug is not. Furthermore or alternatively, the prodrug also has improved solubility in pharmaceutical compositions relative to the parent drug. In some embodiments, the prodrug is designed to increase effective water solubility. See, e.g., Design of Prodrugs, Bundgaard, A., ed., Elsevier, 1985, and Method in Enzymology, Widder, K. et al., eds.; Academic, 1985, Vol. 42, pp. 309-396; Bundgaard, H. “Design and Application of Prodrugs,” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, eds., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference.

[0527] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which an organism changes a particular substance, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes. Thus, an enzyme can cause a compound to undergo a specific structural change. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds.

[0528] Pharmaceutical composition

[0529] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound for pharmaceutical use. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein is found, for example, in: Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), the disclosures of which are incorporated herein by reference.

[0530] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent to administer a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by any method capable of delivering the compound to the site of action. These methods include, but are not limited to, delivery via parenteral routes (including injection or infusion, and subcutaneous).

[0531] In some embodiments, pharmaceutical composition is formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The preparation for injection can be presented in the unit dosage form in, for example, an ampoule or a multidose container, wherein a preservative is added. The composition can take the form of a suspension, solution or emulsion such as in an oily or aqueous vehicle, and contains an optional agent such as a suspending agent, a stabilizer and / or a dispersant as an excipient. The composition can be present in unit dose or multidose container such as sealed ampoule and vial, and can be stored in powder form, or only need to add a sterile liquid carrier immediately before use, such as saline or sterile pyrogen-free water freeze drying (lyophilization) conditions to store.

[0532] Treatment

[0533] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof is administered as a pharmaceutical composition. In some embodiments, the subject suffers from cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the subject suffers from a noncancerous tumor. In some embodiments, the subject suffers from an adenoma.

[0534] In some embodiments, the treatment is sufficient to reduce or inhibit the growth of a subject's tumor, reduce the number or size of metastatic lesions, reduce tumor burden, reduce primary tumor burden, reduce invasiveness, prolong survival, or maintain or improve quality of life, or a combination thereof.

[0535] In some embodiments, provided herein are methods for killing tumor cells, comprising contacting the tumor cells with a compound of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt or solvate thereof releases a number of alpha particles through natural radioactive decay. In some embodiments, the alpha particles released are sufficient to kill the tumor cells. In some embodiments, the alpha particles released are sufficient to stop cell growth. In some embodiments, the tumor cells are malignant tumor cells. In some embodiments, the tumor cells are benign tumor cells. In some embodiments, the method comprises killing the tumor cells with a radionuclide that emits beta particles. In some embodiments, the method comprises killing the tumor cells with a radionuclide that emits alpha particles. In some embodiments, the method comprises killing the tumor cells with a radionuclide that emits gamma particles.

[0536] In one aspect, provided herein are methods and compositions for treating cancer.

[0537] In one aspect, provided herein are methods and compositions for treating adenomas.

[0538] In one aspect, provided herein are methods and compositions for treating carcinomas.

[0539] In one aspect, provided herein is a method for identifying a tissue or organ that overexpresses NPY1R in a mammal, comprising: (i) administering to the mammal an NPY1R radiopharmaceutical described herein, or a pharmaceutically acceptable salt thereof; and (ii) performing single photon emission computed tomography (SPECT) or positron emission tomography (PET) analysis on the mammal. In some embodiments, the method comprises: (i) administering to the mammal an NPY1R radiopharmaceutical described herein, or a pharmaceutically acceptable salt thereof; and (ii) performing positron emission tomography (PET) analysis on the mammal.

[0540] In some embodiments, the mammal is diagnosed with cancer. In some embodiments, the tissue overexpressing NPY1R in the mammal is a tumor.

[0541] In some embodiments, the NPY1R radiopharmaceuticals described herein, or pharmaceutically acceptable salts thereof, are used in a method for in vivo imaging of a subject. In some embodiments, the method comprises the steps of:

[0542] (i) administering to a mammal an NPY1R radiopharmaceutical described herein or a pharmaceutically acceptable salt thereof;

[0543] (ii) waiting a sufficient amount of time to allow the NPY1R radiopharmaceutical to accumulate at the tissue or cell site to be imaged; and

[0544] (iii) Imaging cells or tissues using non-invasive imaging techniques.

[0545] In some embodiments, the non-invasive imaging technique is single photon emission computed tomography (SPECT) or positron emission tomography (PET) analysis. In some embodiments, the non-invasive imaging technique is single photon emission computed tomography (SPECT). In some embodiments, the non-invasive imaging technique is selected from positron emission tomography imaging or positron emission tomography combined with computed tomography imaging, and positron emission tomography combined with magnetic resonance imaging.

[0546] Dosage and treatment regimen

[0547] In one embodiment, the NPY1R radiopharmaceuticals described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for treating a tumor in a mammal. The method for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0548] In certain embodiments, compositions containing one or more compounds described herein are administered for diagnostic and / or therapeutic treatments.

[0549] The amount of a given agent corresponding to this amount varies depending on factors such as the specific conjugate, the specific cancer or tumor to be treated (and its severity), the attributes of the subject or host in need of treatment (e.g., weight, sex), but is still determined based on the specific circumstances surrounding the situation including, for example, the specific conjugate being administered, the route of administration, the condition being treated, and the subject or host being treated. The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the subject's body mass, weight, or blood volume.

[0550] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and is expressed as LD 50 With ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or therapeutically effective unit dose amount for use in mammals, including humans.

[0551] The amount of the compound of formula (I) or (II) or its pharmaceutically acceptable salt administered is sufficient to deliver a therapeutically effective dose to a specific subject. In some embodiments, the dosage of the compound of formula (I) or (II) is between about 0.1 pg and about 50 mg per kilogram of body weight, between 1 μg and about 50 mg per kilogram of body weight, or between about 0.1 mg and about 10 mg per kilogram of body weight. The therapeutically effective dose may also be determined by a physician as appropriate. For example only, the dosage of the compound of formula (I) or (II) or its pharmaceutically acceptable salt for the method for treating a disease as described herein is about 0.001 mg to about 1 mg per dose of body weight per kilogram of object as described herein. In some embodiments, the dosage for the treated subject is about 0.001 mg to about 1000 mg per dose. In some embodiments, a compound of Formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 0.01 mg to about 500 mg, about 0.01 mg to about 100 mg, or about 0.01 mg to about 50 mg.

[0552] In some embodiments, a compound of Formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 0.01 picomolar to about 1 molar, about 0.1 picomolar to about 0.1 molar, about 1 nanomolar to about 0.1 molar, or about 0.01 micromolar to about 0.1 millimolar.

[0553] In some embodiments, a compound of Formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 0.01 Gbq to about 1000 Gbq, about 0.5 Gbq to about 100 Gbq, or about 1 Gbq to about 50 Gbq.

[0554] In some embodiments, the dosage is administered once a day, 1 to 3 times a week, 1 to 4 times a month, or 1 to 12 times a year.

[0555] Within any of the aforementioned aspects are further embodiments, wherein an effective amount of an NPY1R radiopharmaceutical described herein, or a pharmaceutically acceptable salt thereof, is: (a) administered systemically to the mammal; and / or (b) administered intravenously to the mammal; and / or (c) administered to the mammal by injection.

[0556] In certain circumstances, it may be appropriate to administer at least one NPY1R radiopharmaceutical described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0557] Certain terms

[0558] Unless otherwise indicated, the following terms used in this application have the definitions given below. The use of the term "including" as well as other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0559] Unless otherwise indicated herein or clearly contradicted by context, as used herein and in the appended claims, in the context of describing various elements (especially in the context of the following claims), singular articles such as "a" and "an" and "the" and similar references should be construed to cover both the single and the plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0560] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there is a use of the term that is unclear to one of ordinary skill in the art, "about" will mean up to ±10% of the particular term, given the context in which the term is used.

[0561] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C6" indicates that there are from one to six carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0562] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group is a branched or straight chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms, i.e., C1-C 10Alkyl. Whenever it appears in this article, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 10 carbon atoms, but this definition also covers the existence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group is -C1-C6 alkyl. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl or hexyl. In some embodiments, the alkyl group is an "alkenyl" or "alkynyl" group.

[0563] An "alkylene" group refers to a divalent alkyl group. Any of the above monovalent alkyl groups can be converted to an alkylene group by extracting a second hydrogen atom from the alkyl group. In some embodiments, the alkylene group is a -C1-C6 alkylene group. In other embodiments, the alkylene group is a C1-C4 alkylene group. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene group is -CH2-. In some embodiments, the alkylene group is -CH2CH2-.

[0564] An "alkoxy" group refers to an (alkyl)O- group where alkyl is as defined herein.

[0565] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula: -C(R)=CR2, wherein R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, each R is independently H or an alkyl group. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl (vinyl)), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0566] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or an alkyl group. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, or -CH2C≡CH.

[0567] The term "heteroalkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. In some embodiments, a "heteroalkyl" group has 2 to 10 atoms in the backbone, comprising a combination of carbon atoms and heteroatoms (e.g., N, O, S), i.e., a 2- to 10-membered heteroalkyl group. In some embodiments, the heteroalkyl group is connected to the rest of the molecule at a carbon atom of the heteroalkyl group. In one embodiment, the heteroalkyl group is a 2- to 8-membered heteroalkyl group.

[0568] A "heteroalkylene" group refers to a divalent alkyl group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2-CH2- and -CH2-O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, the direction in which the chemical formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(=O)O- represents both -C(=O)O- and -OC(=O)-. Additionally, the formula -C(=O)NH- represents both -C(=O)NH- and -NHC(=O)-.

[0569] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the ring backbone are all carbon atoms. Thus, the term distinguishes carbocycles from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom that is not carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl groups.

[0570] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, dihydroindenyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6-C 10 Depending on the structure, an aryl group is a monoradical or a diradical (ie, an arylene group).

[0571] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic group, wherein each of the atoms (i.e., skeleton atoms) forming the ring is a carbon atom. In some embodiments, cycloalkyl is a spirocyclic or bridged cycloalkyl. In some embodiments, cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl includes groups with 3 to 12 ring atoms. In some embodiments, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro [2.2] pentyl, norbornyl and bicyclo [1.1.1] pentyl. In some embodiments, cycloalkyl is C3-C6 cycloalkyl. In some embodiments, cycloalkyl is C3-C4 cycloalkyl. In some embodiments, cycloalkyl is C5-C6 cycloalkyl.

[0572] The term "halo," or alternatively, "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0573] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, the fluoroalkyl group is a -C1-C6 fluoroalkyl group.

[0574] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in one or more rings, wherein each heteroatom in the one or more rings is selected from O, S, and N, wherein each heterocyclyl has 3 to 12 atoms in its ring system, and with the proviso that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclyls (also known as heterocycloalkyls) include rings having 3 to 12 atoms in their ring systems, and aromatic heterocyclyls include rings having 5 to 10 atoms in their ring systems. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinone, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, oxazepanyl, oxe ... oxazepinyl, diazepine thiazolinone thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4. 1.0] heptyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dione, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-disulfinyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl and quinolizinyl. The example of aromatic heterocyclic group is pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridyl. Where possible, the aforementioned groups are C-connected (or C-bonded) or N-connected. For example, the group derived from pyrrole includes both pyrrol-1-yl (N-connected) or pyrrol-3-yl (C-connected). In addition, the group derived from imidazole includes imidazole-1-yl or imidazole-3-yl (both are N-connected) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (all are C-connected). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is an aromatic ring. In some embodiments, both rings of the bicyclic heterocycle are aromatic rings.

[0575] The term "heteroaryl", or alternatively, "heteroaromatic" refers to an aryl group comprising one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryl and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryl groups include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl groups contain 0-4 N atoms in the ring. In some embodiments, heteroaryl groups contain 1-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1 O atom. In some embodiments, the heteroaryl group contains 1 S atom in the ring. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5-membered heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a 10-membered heteroaryl group.

[0576] A "heterocycloalkyl" group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group is fused to an aryl or heteroaryl group. In some embodiments, the heterocycloalkyl group is oxazolidinone, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-one, pyrrolidine-2,5-disulfinyl, pyrrolidine-2,5-dione, pyrrolidinone, imidazolidinyl, imidazolidin-2-one, or thiazolidin-2-one. In one aspect, the heterocycloalkyl group is a 3- to 12-membered heterocycloalkyl group. In another aspect, the heterocycloalkyl group is a 5- to 10-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 5-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 6-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, heterocycloalkyl contains 1-4 nitrogen (N) atoms in the ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms, 0-2 oxygen (O) atoms, and 0-1 sulfur (S) atoms in the ring.

[0577] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms joined by the bond are considered part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing bonds to form between the remaining identified groups.

[0578] The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is a generally recognized chemical entity embedded in or attached to a molecule.

[0579] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted by one or more other groups individually and independently selected from the group consisting of halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -C(=O)OH, -C(=O)O-alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, the substituted groups are substituted with one or both of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0580] As used herein, the term "modulate" means interacting directly or indirectly with a target so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.

[0581] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions with agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0582] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion). Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein.

[0583] As used herein, the terms "co-administer," "co-administer," and the like are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0584] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an administered agent or compound that will alleviate to some extent one or more symptoms of the disease or condition being treated. Results include alleviation and / or relief of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is optionally determined using techniques such as dose escalation studies.

[0585] As used herein, the terms "enhance" or "enhancing" mean to increase or prolong either in potency or duration a desired effect. Thus, with respect to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0586] The terms "article of manufacture" and "kit" are used synonymously.

[0587] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, etc. In one aspect, the mammal is a human.

[0588] As used herein, the terms "treat," "treating," or "treatment" encompass alleviating, alleviating, or ameliorating at least one symptom of a disease or condition; preventing additional symptoms; inhibiting the disease or condition, such as arresting the development of the disease or condition; relieving the disease or condition; causing regression of the disease or condition; relieving the condition caused by the disease or condition; or halting the symptoms of the disease or condition.

[0589] Example

[0590] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0591] abbreviation

[0592] ACN or MeCN or CH3CN: acetonitrile;

[0593] BBr3: Boron tribromide;

[0594] Brine: saturated NaCl solution;

[0595] BSA: bovine serum albumin;

[0596] CaCl2: calcium chloride;

[0597] CDI: 1,1′-carbonyldiimidazole;

[0598] Cs2CO3: cesium carbonate;

[0599] DavePhos: 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl;

[0600] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0601] DCC: N,N'-dicyclohexylcarbodiimide;

[0602] DCM: dichloromethane;

[0603] DIEA or DIPEA: N,N-diisopropylethylamine;

[0604] DMAP: 4-dimethylaminopyridine;

[0605] DMF: dimethylformamide;

[0606] DMSO: dimethyl sulfoxide;

[0607] DOTA: 2,2′,2″,2″′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid;

[0608] DOTA-tris(t-Bu) ester NHS ester: 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;

[0609] EDC: (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride);

[0610] EGTA: ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid;

[0611] EtOAc or EA: ethyl acetate;

[0612] FA: formic acid;

[0613] FBS: fetal bovine serum;

[0614] FDPP: pentafluorophenyl diphenylphosphite or perfluorophenyl diphenylphosphite or pentafluorophenyl diphenylphosphinate;

[0615] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0616] HSTU: N,N,N,N-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate;

[0617] HCl: hydrochloric acid or hydrochloride;

[0618] HEPES: N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid;

[0619] HgCl2: mercury(II) chloride or mercuric chloride;

[0620] H2O: water;

[0621] HOBt: 1-hydroxybenzotriazole;

[0622] InCl3: indium trichloride;

[0623] IPA: i-PrOH or isopropyl alcohol;

[0624] K2CO3: potassium carbonate;

[0625] LCMS: liquid chromatography-mass spectrometry;

[0626] LiHMDS: lithium hexamethyldisilazane or lithium bis(trimethylsilyl)amide;

[0627] LiOH: lithium hydroxide;

[0628] LuCl3: lutetium(III) chloride;

[0629] MeOH: methanol;

[0630] MgCl2: magnesium chloride;

[0631] MPLC: medium pressure liquid chromatography;

[0632] MS: mass spectrometry;

[0633] MsCl: methanesulfonyl chloride;

[0634] NaCl: sodium chloride;

[0635] NaH: sodium hydride;

[0636] NaHCO3: sodium bicarbonate;

[0637] NaHSO4: sodium bisulfate;

[0638] NaI: sodium iodide;

[0639] NMM: 4-methylmorpholine;

[0640] Na2SO4: sodium sulfate;

[0641] NHS: N-hydroxysuccinimide;

[0642] NMM: N-methylmorpholine or 4-methylmorpholine;

[0643] PA: phosphoric acid;

[0644] PACM: 4,4'-diaminodicyclohexylmethane;

[0645] PBS: phosphate-buffered saline;

[0646] Pd / C: palladium supported on activated carbon; PdCl2: palladium(II) chloride;

[0647] Pd(OAc)2: palladium(II) acetate;

[0648] PE: petroleum ether;

[0649] Preparative HPLC: Preparative high performance liquid chromatography;

[0650] TBTU: O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate;

[0651] TEA or Et3N: triethylamine;

[0652] TFA: trifluoroacetic acid;

[0653] THF: tetrahydrofuran;

[0654] XPhos: dicyclohexyl[2′,4′,6′-tri(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane;

[0655] rt: room temperature;

[0656] hrs: hours; h or hr: hours; min: minutes;

[0657] mg: milligram; kg: kilogram;

[0658] mL or ml: milliliter;

[0659] Eq: equivalent;

[0660] mmol: millimole; mol: mole;

[0661] UV: ultraviolet light.

[0662] General analytical methods:

[0663] Preparative HPLC using DAC: The crude product was purified by DAC-HPLC: column, YMC-C18, 150-250 nm, 10 μm; mobile phase, water (0.05% TFA) and ACN (25% ACN to 65% in 8 minutes); total flow rate, 120 mL / min; detector, UV 220 nm.

[0664] LC-MS analysis was performed on a Shimadzu LCMS-2020 series equipped with a binary pump LC-20ADXR, a micro vacuum degasser, a standard autosampler SIL-20AC XR, a thermostatted column oven CTO-20AC, and a variable wavelength detector SPD-M20A. Data were analyzed using Shimadzu LabSolutions standalone workstation software. The HPLC solvents consisted of H2O containing 0.05% ammonia (mobile phase A) and acetonitrile (mobile phase B). An Ascentis Express C18 column (2.6 μm, 3.0 × 50 mm) was used at a flow rate of 1.2 mL / min.

[0665] Recorded using AVANCE III HD 300MHz1 H NMR spectroscopy. Unless otherwise indicated, chemical shifts are reported in δ (ppm) relative to TMS4Si (in DMSO-d6) as internal standard using the instrument model (Bruker TopSpin).

[0666] Synthesis of compounds

[0667] Example

[0668] Example 101: 2,2′,2″-(10-(17-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecanyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (Compounds 101A and 101B)

[0669]

[0670] Synthesis of intermediate B:

[0671] Step 1: A mixture of methyl thiocarbamide (30.0 g, 1 equivalent, 333 mmol), sodium bicarbonate (41 g, 19 mL, 1.5 equivalents, 0.49 mol), THF (300 mL) and H2O (300 mL) was placed in a 1 L round-bottom flask, and a solution of di-tert-butyl dicarbonate (87 g, 1.2 equivalents, 0.40 mol) in THF (100 mL) was added dropwise thereto at 0 ° C. The reaction mixture was stirred for 4 hours at 25 ° C. The mixture was quenched with water (300 mL), extracted with DCM (500 mL×2), and the combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide intermediate A (30.6 g, 161 mmol, 48.3%) as a white solid, which was used directly in the next step without any purification. MS: C7H 14 Calculated value of N2O2S: 190.08, found [M+H] + :191.1.

[0672] Step 2: A mixture of tert-butyl (2-aminoethyl)carbamate (20.0 g, 1 eq., 125 mmol), TEA (37.9 g, 52.2 mL, 3.00 eq., 375 mmol) and THF (300 mL) was placed in a 500 mL round-bottom flask, to which propionyl chloride (13.9 g, 1.20 eq., 150 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred for 1 hour at 25 ° C. The mixture was quenched with water (100 mL), extracted with DCM (300 mL×2), and the combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to provide tert-butyl (2-propionamidoethyl)carbamate (27.6 g, 0.11 mol, 92%, 90% purity) as a light yellow solid, which was used directly in the next step without any purification. MS: C 10 H 20 Calculated value for N2O3: 216.15, found [M+H] + :217.3.

[0673] Step 3: Into a 500 mL round-bottom flask was placed a mixture of tert-butyl (2-propionamidoethyl)carbamate (27.6 g, 1 equivalent, 128 mmol) and 4M HCl in dioxane (14.0 g, 96.0 mL, 4 mol, 3.01 equivalents, 384 mmol), to which was added MeOH (100 mL). The reaction mixture was stirred at 25 ° C for 4 hours. The mixture was concentrated under reduced pressure to provide N- (2-aminoethyl) propionamide (22 g, 0.13 mol, 100%, 70% purity) as a yellow solid, which was stored at -78 ° C. MS: C5H 12 N2O calculated: 116.09, found [M+H] + :117.2.

[0674] Step 4: Into a 500 mL round-bottom flask was placed a mixture of Intermediate A (from Step 1, 30.6 g, 1 eq, 161 mmol), DIEA (104 g, 140 mL, 5.00 eq, 805 mmol), CDI (53 g, 2.0 eq, 0.33 mol) and THF (300 mL). The reaction mixture was stirred at 0°C for 1 hour, followed by the addition of N-(2-aminoethyl)propionamide (28 g, 1.5 eq, 0.24 mol) and the reaction mixture was stirred for an additional 2 hours at 25°C. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: 330 g silica gel column, PE / EtOAc system, EtOAc ratio from 0% to 85% in 25 minutes, flow rate: 90 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to provide Intermediate B (25 g, 75 mmol, 47%) as a white solid. MS: C 13 H 24 Calculated value of N4O4S: 332.15, found [M+H] + :333.1.

[0675]

[0676] Synthesis of intermediate C:

[0677] Step 1: Into a 500 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere were placed 4-(tert-butoxy)benzonitrile (23 g, 1 eq., 0.13 mol), IPA (400 mL) and NH 3 · H 2 O (15 mL), to which nickel (15 g, 2.0 mL, 1.9 eq., 0.26 mol) was carefully added. The flask was evacuated and flushed with hydrogen three times. Under H 2 , the mixture was stirred at 25 ° C. for 3 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to provide (4-(tert-butoxy)phenyl)methanamine (20 g, 0.11 mol, 85%) as a white solid.

[0678]

[0146] Step 2: Into a 40 mL vial was placed a mixture of (R)-5-(((benzyloxy)carbonyl)-amino)-2-((tert-butoxycarbonyl)amino)pentanoic acid (5 g, 1 eq, 0.01 mol), 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (6 g, 1 eq, 0.02 mol), DIEA (5 g, 7 mL, 3 eq, 0.04 mol), and THF (2 mL). The reaction mixture was stirred at 30°C for 1 hour, followed by the addition of (4-(tert-butoxy)phenyl)methanamine (3.3 g, 1 eq, 18 mmol) and KCO (1.1 g, 2.9 eq, 8.0 mmol) in additional THF (2 mL):HO (1.9 mL) and the reaction mixture was stirred for an additional 10 minutes. Then, the reaction solution was mixed and the reaction was continued at 30° C. for 1 hour. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 330 g, Spherical 20-40 μm; mobile phase, water (0.05% TFA) and ACN (5% ACN to 5% ACN in 1 minute, 30% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to provide (5-((4-(tert-butoxy)benzyl)amino)-5-oxopentane-1,4-diyl)(R)-dicarbamic acid benzyl tert-butyl ester (4.1 g, 7.8 mmol, 60%) as a yellow oil. MS: C 29 H 41 Calculated value for N3O6: 527.30, found [M+H] + :528.3.

[0679] Step 3.: Into a 500 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere were placed benzyl (5-((4-(tert-butoxy)benzyl)amino)-5-oxopentan-1,4-diyl)(R)-dicarbamic acid tert-butyl ester (4.1 g, 1 eq., 7.8 mmol) and CF3CH2OH (300 mL), to which Pd / C (4.1 g, 5.0 eq., 39 mmol) was carefully added. The flask was evacuated and flushed with hydrogen three times. Under H2, the mixture was stirred at 30°C for 1 hour. The reaction mixture was filtered through a pad of celite. The collected fractions were concentrated under reduced pressure and dried to give tert-butyl (R)-(5-amino-1-((4-(tert-butoxy)benzyl)amino)-1-oxopentan-2-yl)carbamate (3.1 g, 7.9 mmol, 100%) as a liquid. MS: C 21 H 35 Calculated value for N3O4: 393.26, found [M+H]+ :394.2.

[0680] Step 4.: Into a 40 mL vial was placed a mixture of tert-butyl (R)-(5-amino-1-((4-(tert-butoxy)benzyl)amino)-1-oxopentan-2-yl)carbamate (360 mg, 70% Wt, 1 eq, 640 μmol), HgCl (273 mg, 1.57 eq, 1.01 mmol), DIEA (355 mg, 4.29 eq, 2.75 mmol) and DCM (4 mL). The mixture was cooled to 0° C., and a solution of Intermediate B (335 mg, 1.57 eq, 1.01 mmol) in DCM (1 mL) was added dropwise. The reaction mixture was stirred at 20° C. for 2 hours. The mixture was concentrated and the crude product was purified by MPLC using the following conditions: column, WelFlash™, C18 330 g, Spherical 20-40 μm; mobile phase, water (0.05% TFA) and ACN (5% ACN to 5% ACN in 1 minute, 30% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 100 mL / min; detector, UV 220 nm. Purification afforded the product (350 mg, 516 μmol, 80.6%) as a yellow oil. MS: C 33 H 55 Calculated value for N7O8: 677.41, found [M+H] + :678.4.

[0681] Step 5.: Into an 8 mL vial was placed a mixture of the product from step 3 (350 mg, 1 eq, 516 μmol) and DCM (3 mL), to which was added TFA (1 mL). The reaction mixture was stirred at 20 ° C for 1 hour. The mixture was concentrated under reduced pressure. The crude product (R, Z)-2-amino-N-(4-hydroxybenzyl)-5-(2-((2-propionamidoethyl)carbamoyl)guanidino)-pentanamide (Intermediate C, 350 mg, 0.46 mmol, 88%, 55% purity) was used directly in the next step without purification. MS: C 19 H 31 Calculated value for N7O4: 421.24, found [M+H] + :422.2.

[0682]

[0683] Synthesis of compounds 101A and 101B:

[0684] Step 1: Into a 250 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was placed a mixture of Pd(OAc)2 (0.33 g, 0.030 eq, 1.6 mmol), DavePhos (2.3 g, 0.061 eq, 3.3 mmol) and toluene (100 mL). The reaction mixture was stirred at -10°C for 15 minutes, followed by the addition of LiHMDS (22 g, 0.13 L, 1 mol, 2.4 eq, 0.13 mol) and ethyl 2-phenylacetate (13 g, 1.5 eq, 79 mmol) and the mixture was stirred for 15 minutes. 1-Bromo-3-methoxybenzene (10 g, 1 eq, 53 mmol) in 10 mL of toluene was added and the reaction mixture was stirred at 80°C for 1 hour. The mixture was diluted with water (250 mL), extracted with EtOAc (100 mL×3), and the combined organic layers were washed with water (100 mL×2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 330 g, PE / EtOAc system, EtOAc ratio from 0% to 10% in 30 minutes, flow rate: 100 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to provide ethyl 2-(3-methoxyphenyl)-2-phenylacetate (16.0 g, 47 mmol, 89%, 80% purity) as a yellow oil. MS: C 17 H 18 O3 calculated value: 270.13, found value [MH]: 269.0.

[0685] Step 2: At 0 ° C, a mixture of ethyl 2-(3-methoxyphenyl)-2-phenylacetate (3.0 g, 1 equivalent, 11 mmol) and DCM (130 mL) was placed in a flask purged and maintained with an inert nitrogen atmosphere, followed by the addition of tribromoborane (19.3 g, 2.00 equivalents, 77.0 mmol). The reaction mixture was stirred for 10 minutes at 25 ° C. The mixture was quenched with EtOH (250 mL) and concentrated, and the crude product was then passed through MPLC and purified using the following conditions: silica gel column 330 g, PE / EtOAc system, EtOAc ratio from 0% to 10% in 20 minutes, flow rate: 80 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to provide ethyl 2-(3-methoxyphenyl)-2-phenylacetate (13.0 g, 80% Wt, 1 equivalent, 38.5 mmol) as a yellow oil. MS: C 16 H 16 O3 calculated value: 256.11, found value [MH]: 255.0.

[0686] Step 3: Into a 50 mL round-bottom flask was placed a mixture of ethyl 2-(3-hydroxyphenyl)-2-phenylacetate (2.0 g, 1.1 eq, 7.8 mmol), CsCO (7.1 g, 3.0 eq, 22 mmol), sodium iodide (2.2 g, 2.0 eq, 15 mmol), and DMF (25 mL). The reaction mixture was stirred at 20°C for 30 minutes, followed by the addition of 8-ethyl-2,2-dimethyl-4-oxo-3,813,9,12,15-pentaoxa-5-azaheptadecan-17-yl methanesulfonate (3.0 g, 1 eq, 7.2 mmol). The reaction mixture was stirred at 80°C for 3 hours. The mixture was diluted with water (150 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: 80 g silica gel column, PE / EtOAc system, EtOAc ratio from 0% to 85% over 25 minutes, flow rate: 70 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to provide ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)phenyl)-2-phenylacetate (3.6 g, 6.3 mmol, 87%) as a yellow oil. MS: C 31 H 45 NO9 calculated value: 575.31, found value [M+H] + :576.2.

[0687] Step 4: Into a 40 mL vial was placed a mixture of ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)phenyl)-2-phenylacetate (1.5 g, 1 eq, 2.6 mmol), LiOH (0.62 g, 9.9 eq, 26 mmol), MeOH (12 mL) and H2O (4 mL). The reaction mixture was stirred at 25°C for an additional 3 hours. The mixture was diluted with water (40 mL), and the pH was adjusted to approximately 5-6 by adding NaHSO4 solution, followed by extraction with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)phenyl)-2-phenylacetic acid (1.4 g, 2.2 mmol, 83%, 85% purity) as a yellow oil. MS: C 29 H 41NO9 calculated value: 547.28, found value [M+H] + :548.2.

[0688] Step 5: Into a 40 mL vial under N2 was placed 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)phenyl)-2-phenylacetic acid (550 mg, 1 eq, 1.00 mmol), NHS (175 mg, 1.51 eq, 1.52 mmol) and THF (6 mL). To the mixture was added DCC (310 mg, 1.50 eq, 1.50 mmol) and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated with slight heating below 35° C. to provide 2,5-dioxopyrrolidin-1-yl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)phenyl)-2-phenylacetate (660 mg) as a crude white oil. Into a 40 mL vial was placed a mixture of (R,Z)-2-amino-N-(4-hydroxybenzyl)-5-(2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (440 mg, 1.04 equiv, 1.04 mmol), KCO (280 mg, 2.02 equiv, 2.03 mmol), H0 (5 mL) and 1,4-dioxane (2 mL). At 25 ° C, a solution of crude 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)phenyl)-2-phenylacetic acid 2,5-dioxopyrrolidin-1-yl ester in 1,4-dioxane (4 mL) was added dropwise to the mixture. The reaction mixture was stirred at 50 ° C for 1 hour, and then the crude product was purified by preparative HPLC using the following conditions: column: SunFire prep OBD 19*150mm 5μm; mobile phase A: water (0.05% TFA); mobile phase B: ACN; gradient: 25% B to 65% B in 8 minutes; flow rate: 50 mL / min; wavelength: 220 nm. The collected fractions were dried by lyophilization to a yellow oil. MS: C 48 H 70 N8O 12 Calculated value: 950.51, found [M+H] + :951.7.

[0689] Step 6: Into an 8 mL vial was placed a mixture of tert-butyl (14-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-3,6,9,12-tetraoxatetradecyl)carbamate (400 mg, 1 eq, 421 μmol) and DCM (4.5 mL) and TFA (1.5 mL) was added. The reaction mixture was stirred at 20° C. for 1 hour. The mixture was concentrated under reduced pressure to provide the crude product (2R)-2-(2-(3-((14-amino-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (320 mg, 376 μmol, 89.4%), which was used directly in the next step without further purification. MS: C 43 H 62 N8O 10 Calculated value: 850.46, found [M+H] + :851.7

[0690] Step 7: Into an 8 mL vial was placed a mixture of (2R)-2-(2-(3-((14-amino-3,6,9,12-tetraoxatetradecyl)oxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (320 mg, 1 eq, 376 μmol) in DMF (4 mL), followed by the addition of 2,2′,2″-(10-(2-((2,5 To the mixture were added triacetic acid (283 mg, 1.50 equiv., 564 μmol) and N-ethyl-N-isopropylpropan-2-amine (146 mg, 3.00 equiv., 1.13 mmol). The resulting mixture was stirred at 20° C. for 2 hours. The crude product was purified by preparative HPLC using the following conditions: column: Xselect-C18 5 μm; mobile phase A: water (0.05% TFA); mobile phase B: ACN; gradient: 12% B to 30% in 8 minutes. B; flow rate: 20 mL / min; wavelength: 220 nm. The top peak fraction was dried by lyophilization to provide a single diastereomer of 2,2′,2″-(10-(17-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecanyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) as a white solid (Compound 101A, 69 mg, 51 μmol, 14%). The latter peak fractions were dried by lyophilization to afford a single diastereomer of 2,2′,2″-(10-(17-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecanyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) as a white solid (Compound 101B, 64 mg, 47 μmol, 13%). Compound 101A: MS: C 61 H 89 F3N 12 O 19 Calculated value: 1350.63, found value [M+H-TFA]: 1237.7; Compound 101B: MS: C61 H 89 F3N 12 O 19 Calculated: 1350.63, found [M+H-TFA]: 1237.9.

[0691] Example 102: 2,2′,2″-(10-(17-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecanyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (Compounds 102A and 102B)

[0692]

[0693] Step 1.: At 0 ° C, a mixture of sodium hydride (6.8 g, 4.0 equivalents, 0.28 mol) and DMF (100 mL) was placed in a 250 mL three-necked flask. 2-phenylacetic acid ethyl ester (35 g, 3.0 equivalents, 0.21 mol) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at 0 ° C for 1 hour, followed by the dropwise addition of 1-fluoro-4-nitrobenzene (10 g, 1 equivalent, 71 mmol) over a period of 30 minutes. The mixture was stirred at 0 ° C for 1 hour. The mixture was quenched with aqueous NaHSO4 (50 mL) at 0 ° C and then extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: 330 g silica gel column, PE / EtOAc system, EtOAc ratio from 0% to 85% in 15 minutes, flow rate: 90 mL / min; wavelength: 254 nm. The collected fractions were concentrated to provide ethyl 2-(4-nitrophenyl)-2-phenylacetate (8.5 g, 30 mmol, 42%) as a light yellow oil.

[0694] Step 2.: Into a 50 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere were placed ethyl 2-(4-nitrophenyl)-2-phenylacetate (600 mg, 1 equivalent, 2.10 mmol) and i-PrOH (10 mL), to which Pd / C (60 mg, 0.27 equivalent, 0.56 mmol) was carefully added. The flask was evacuated and flushed with hydrogen three times. Under an H2 atmosphere, the mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered through a pad of celite, and the filtrate was then concentrated to provide ethyl 2-(4-aminophenyl)-2-phenylacetate (500 mg, 1.8 mmol, 84%, 90% purity) as a colorless oil. MS: C 16 H 17 NO3 calculated value: 255.13, found value [M+H] + :256.3.

[0695] Step 3.: Into a 40 mL vial was placed a mixture of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaeicosane-20-oic acid (572 mg, 1 eq, 1.57 mmol) and DMF (5 mL), followed by the addition of HATU (714 mg, 1.20 eq, 1.88 mmol) and DIEA (607 mg, 818 μL, 3.00 eq, 4.70 mmol). The mixture was stirred at 25° C. for 10 minutes. Ethyl 2-(4-aminophenyl)-2-phenylacetate (400 mg, 1.00 eq, 1.57 mmol) was then added and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, Spheri 20-40 μm; mobile phase, water (0.05% TFA) and ACN (5% ACN to 5% ACN in 1 minute, 5% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were dried by lyophilization to provide ethyl 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaeicosane-20-amido)phenyl)-2-phenylacetate (710 mg, 1.1 mmol, 68%, 90% purity) as a light yellow oil. MS: C 32 H 46 Calculated value of N2O9: 602.32, found [M+H] + :603.6.

[0696] Step 4.: Into a 40 mL vial was placed a mixture of ethyl 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaeicosane-20-amido)phenyl)-2-phenylacetate (400 mg, 1 eq, 664 μmol), LiOH (80 mg, 5.0 eq, 3.3 mmol), MeOH (4 mL) and water (0.8 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, the residue was diluted with water (50 mL), and the pH was adjusted to 6.0 by adding saturated NaHSO4 solution. The reaction mixture was extracted with DCM (50 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaeicosane-20-amido)phenyl)-2-phenylacetic acid (260 mg, 452 μmol, 68.2%) as a light yellow oil, which was used directly in the next step without any purification. MS: C 30 H 42 Calculated value of N2O9: 574.29, found [M+H] + :575.3.

[0697] Step 5.: In a manner similar to that of compound 101, step 5, 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaeicosane-20-amido)phenyl)-2-phenylacetic acid was combined with intermediate C to provide tert-butyl (15-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate (150 mg, 153 μmol, 33.9%) as a light yellow oil. MS: C 49 H 71 N9O 12 Calculated: 977.52, found [M+H] + :978.8.

[0698] Step 6.: In a similar manner to that of compound 101, step 6, tert-butyl (15-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate was treated with TFA. The ester was added to provide 1-amino-N-(4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)-3,6,9,12-tetraoxapentadecan-15-amide (150 mg, 0.15 mmol, 100%, 90% pure) as a light yellow oil. MS: C 44 H 63 N9O 10 Calculated value: 877.47, found [M+H] + :878.5.

[0699] Step 7.: 1-Amino-N-(4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentacyclopentyl)-1-nitropropane was treated with 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid in a manner similar to that of step 7 of compound 101. and purified by HPLC to provide 2,2′,2″-(10-(18-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadecan-9-en-1-yl)phenyl)amino)-2,18-dioxo-6,9,12,15- A single diastereomer of tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (compound 102A, 19.6 mg, 14 μmol, 7.9%, 95% purity, front peak) and 2,2′,2″-(10-(18-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl) The other diastereomer of triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (Compound 102B, 19.8 mg, 14 μmol, 8.0%, 95% purity, latter peak) was obtained from 1,4,7,10-tetraazacyclododec-1,4,7-triyl)-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (Compound 102B, 19.8 mg, 14 μmol, 8.0%, 95% purity, latter peak). Compound 102A: MS: C 62 H 90 F3N 13 O 19 Calculated: 1377.64, found [M+H-TFA] + :1264.7. Compound 102B: MS: C 62 H 90 F3N 13 O 19 Calculated: 1377.64, found [M+H-TFA] + :1264.7.

[0700] Example 103: 2,2′,2″-(10-(16-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)-2,12-dioxo-6,9-dioxa-3,13-diazahexadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 2) (Compounds 103A and 103B)

[0701]

[0702] Step 1.: Into a 40 mL vial was placed a mixture of ethyl 2-(4-aminophenyl)-2-phenylacetate (800 mg, 1 eq., 3.13 mmol), 3-bromopropan-1-amine hydrobromide (1.03 g, 1.50 eq., 4.70 mmol), and toluene (10 mL). The reaction mixture was stirred at 110°C for 16 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150mm 5μm; Mobile phase A: Water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B over 8 minutes; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were dried by lyophilization to afford ethyl 2-(4-((3-aminopropyl)amino)phenyl)-2-phenylacetate (620 mg, 1.8 mmol, 57%, 90% purity) as a white solid. MS: C 19 H 24 Calculated value of N2O2: 312.18, found [M+H] + :313.1.

[0703] Step 2.: Into a 40 mL vial was placed a mixture of 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecane-14-oic acid (222 mg, 1 eq, 801 μmol) and DMF (3 mL), followed by the addition of DIEA (310 mg, 418 μL, 3.00 eq, 2.40 mmol) and HATU (365 mg, 1.20 eq, 960 μmol). The mixture was stirred at 25°C for 10 minutes, followed by the addition of ethyl 2-(4-((3-aminopropyl)amino)phenyl)-2-phenylacetate (300 mg, 1.20 eq, 960 μmol). The resulting mixture was stirred at 25°C for 2 hours. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, Spheri 20-40 μm; mobile phase, water (0.05% TFA) and ACN (15% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were dried by lyophilization to provide ethyl 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadec-18-yl)amino)phenyl)-2-phenylacetate (400 mg, 0.54 mmol, 67%, 77% purity) as a light yellow oil. MS: C 31 H 45 Calculated value for N3O7: 571.33, found [M+H] + :572.5.

[0704] Step 3.: Into a 40 mL vial was placed a mixture of ethyl 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadec-18-yl)amino)phenyl)-2-phenylacetate (400 mg, 1 eq, 700 μmol), MeOH (5 mL) and water (1 mL). The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, and the residue was then diluted with water (50 mL) and the pH was adjusted to 6.0 by adding saturated NaHSO4 solution. The reaction mixture was extracted with DCM (50 mL x 3), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to provide 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadec-18-yl)amino)phenyl)-2-phenylacetic acid (330 mg, 607 μmol, 86.8%) as a light yellow oil, which was used directly in the next step without any purification. MS: C 29 H 41Calculated value for N3O7: 543.29, found [M+H] + :544.4.

[0705] Step 4.: In a manner analogous to compound 101, step 5, 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadec-18-yl)amino)phenyl)-2-phenylacetic acid (330 mg, 1 equiv, 607 μmol) was combined with Intermediate C to afford tert-butyl (2-(2-(3-((3-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)carbamate (150 mg, 0.13 mmol, 21%, 80% purity) as a light yellow oil. MS:C 48 H 70 N 10 O 10 Calculated: 946.53, found [M / 2+H] + :474.5.

[0706] Step 5.: Tert-butyl (2-(2-(3-((3-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)carbamate ( The reaction mixture was stirred at 40 ℃ for 1 hr at 40 ℃ for 2 h (150 mg, 1 eq, 158 μmol) to provide (2R)-2-(2-(4-((3-(3-(2-(2-aminoethoxy)ethoxy)propionamido)propyl)amino)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (150 mg, 0.14 mmol, 89%, 80% purity) as a light yellow oil. MS: C 43 H 62 N 10 O8 calculated value: 846.48, found value [M+H] + :847.4.

[0707] Step 6.: (2R)-2-(2-(4-((3-(3-(2-(2-aminoethoxy)ethoxy)propionamido)propyl)amino)phenyl)-2-phenylacetamido)-N-(4 ... hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)-guanidino)pentanamide (140 mg, 1 eq, 165 μmol) was used to provide 2,2′,2″-(10-(16-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)-2,12- A single diastereomer of dioxo-6,9-dioxa-3,13-diazahexadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 2) (compound 103A, 3.7 mg, 2.4 μmol, 1.5%, 86.6% purity, front peak) and 2,2′,2″-(10-(16-((4-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,1 Another diastereomer of triacetic acid (1 / 2) (Compound 103B, 11.9 mg, 9.3 μmol, 5.63%, latter peak) of 6-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenyl)amino)-2,12-dioxo-6,9-dioxa-3,13-diazahexadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 2) (Compound 103B, 11.9 mg, 9.3 μmol, 5.63%, latter peak). Compound 103A: MS: C 61 H 92 N 14 O 19 Calculated value: 1324.66, found value [M+H-2FA]: 1233.7. Compound 103B: MS: C 61 H 92 N 14 O 19 Calculated value: 1324.66, found [M+H-2FA]: 1233.7.

[0708] Example 104: 2,2′,2″-(10-(14-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-2-oxo-6,9,12-trioxa-3-azatetradecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 104)

[0709]

[0710] Step 1.: Into a 40 mL vial was placed a mixture of 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadec-16-yl methanesulfonate (960 mg, 1.20 eq, 2.58 mmol), Cs2CO3 (1400 mg, 2.00 eq, 4.297 mmol), ethyl 2-(3-hydroxyphenyl)-2-phenylacetate (550 mg, 1 eq, 2.15 mmol), sodium iodide (480 mg, 1.49 eq, 3.20 mmol) and DMF (6 mL). The reaction mixture was stirred at 80°C for 3 hours. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, Spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 minute, 30% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to provide ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadec-16-yl)oxy)phenyl)-2-phenylacetate (690 mg, 1.2 mmol, 54%, 90% purity) as a yellow oil. MS: C 29 H 41 NO8 calculated value: 531.28, found value [M+H] + :532.2.

[0711] Step 2.: Into a 40 mL vial was placed a mixture of ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadec-16-yl)oxy)phenyl)-2-phenylacetate (690 mg, 1 eq, 1.30 mmol), LiOH (310 mg, 9.97 eq, 12.9 mmol), H2O (0.7 mL) and MeOH (7 mL). The reaction mixture was stirred at 25°C for 3 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with water (10 mL×2) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: 40 g silica gel column, PE / EtOAc system, EtOAc ratio from 0% to 85% in 15 minutes, flow rate: 40 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to provide 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadec-16-yl)oxy)phenyl)-2-phenylacetic acid (670 mg, 1.2 mmol, 90%, 88% purity) as an off-white solid. MS: C 27 H 37 NO8 calculated value: 503.25, found value [M+H] + :504.1.

[0712] Step 3.: In a manner similar to that of Compound 101, Step 5, 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadec-16-yl)oxy)phenyl)-2-phenylacetic acid (600 mg, 1 eq, 1.19 mmol) was combined with Intermediate C to afford tert-butyl (2-(2-(2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (100 mg, 0.10 mmol, 8.6%, 93% purity) as an off-white solid. MS: C 46 H 66 N8O 11 Calculated value: 906.49, found [M+H] + :907.3.

[0713] Step 4.: Tert-butyl (2-(2-(2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethoxy)-ethoxy)ethyl)carbamate (100 mg) was treated with TFA in a manner similar to that of compound 101, step 6. , 1 equiv, 110 μmol) to provide (2R)-2-(2-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide, trifluoroacetic acid (90 mg, 88 μmol, 91%, 90% purity) as a light yellow oil. MS: C 41 H 58 Calculated value for O9·C2HF3O2: 806.43, found [M+H] + :807.4.

[0714] Step 5.: (2R)-2-(2-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)-guanidino)pentanamide (90 mg, 1 eq, 0.11 mm Hg) was treated with 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid in a manner analogous to that of step 7 of compound 101. ol) to afford 2,2′,2″-(10-(14-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-2-oxo-6,9,12-trioxa-3-azatetradecyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (compound 104, 45.1 mg, 37.8 μmol, 34%, 99.9% purity) as an off-white solid diastereomeric mixture. MS: C 57 H 84 N 12 O 16 Calculated value: 1192.61, found [M+H] + :1193.8.

[0715] Example 105: 2,2′,2″-(10-(2-((2-(2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 105)

[0716]

[0717] Step 1.: Into a 40 mL vial was placed a mixture of tert-butyl (2-(2-(2-hydroxyethoxy)-ethoxy)ethyl)carbamate (1.0 g, 1 eq, 4.0 mmol), methanesulfonyl chloride (0.7 g, 0.5 mL, 2 eq, 6 mmol), TEA (1.2 g, 1.7 mL, 3.0 eq, 12 mmol) and DCM (10 mL). The reaction mixture was stirred at 25°C for one hour. The mixture was diluted with 6 mL of water (6 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were then washed with water (6 mL x 2) and brine (12 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: a 40 g silica gel column, a PE / EtOAc system, an EtOAc ratio from 0% to 85% over 15 minutes, a flow rate of 40 mL / min, and a wavelength of 254 nm. The collected fractions were concentrated under reduced pressure to provide 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl methanesulfonate (1.2 g, 3.1 mmol, 78%, 85% purity) as a yellow oil. MS: C 12 H 25 NO7S calculated value: 327.14, found [M+H] + :328.2.

[0718] Step 2.: Into a 40 mL vial was placed a mixture of 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl methanesulfonate (500 mg, 1 eq, 1.53 mmol), Cs2CO3 (990 mg, 1.99 eq, 3.04 mmol), ethyl 2-(3-hydroxyphenyl)-2-phenylacetate (470 mg, 1.20 eq, 1.83 mmol), sodium iodide (270 mg, 1.18 eq, 1.80 mmol) and DMF (12 mL). The reaction mixture was stirred at 80°C for 3 hours. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, Spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 minute, 30% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to provide ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)phenyl)-2-phenylacetate (650 mg, 1.2 mmol, 79%, 90% purity) as a yellow oil. MS: C 27 H 37 NO7 calculated value: 487.26, found value [M+H] + :488.1.

[0719] Step 3.: Into a 40 mL vial was placed a mixture of ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)phenyl)-2-phenylacetate (650 mg, 1 eq, 1.33 mmol), LiOH (320 mg, 10.0 eq, 13.4 mmol), H2O (0.65 mL) and MeOH (6.5 mL). The reaction mixture was stirred at 25°C for 3 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL×3), and the combined organic layers were washed with water (10 mL×2) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: a 40 g silica gel column, a PE / EtOAc system, an EtOAc ratio from 0% to 85% over 15 minutes, a flow rate of 40 mL / min, and a wavelength of 254 nm. The collected fractions were concentrated under reduced pressure to provide 2-(3-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)phenyl)-2-phenylacetic acid (630 mg, 0.96 mmol, 72%, 70% purity) as an off-white solid. MS: C 25 H 33 NO7 calculated value: 459.23, found value [M+H] + :460.1.

[0720] Step 4.: In a manner similar to that of Compound 101, Step 5, 2-(3-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)phenyl)-2-phenylacetic acid was combined with Intermediate C to provide tert-butyl (2-(2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamate as an off-white solid (180 mg, 0.19 mmol, 14%, 90% purity). MS: C 44 H 62 N8O 10 Calculated value: 862.46, found [M+H] + :863.5.

[0721] Step 5.: In a manner similar to that of compound 101, step 6, tert-butyl (2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)-carbamate (180 mg, 1 eq, 209 μmol) to provide (2R)-2-(2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)-pentanamide (200 mg, 0.16 mmol, 75%, 60% purity) as a yellow oil. MS: C 25 H 33 NO7 calculated value: 762.41, found value [M+H] + :763.5.

[0722] Step 6.: (2R)-2-(2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)-pentanamide (200 mg, 1 eq, 262 μmol) was treated with 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid in a manner analogous to that of step 7 of compound 101. l) to afford 2,2′,2″-(10-(2-((2-(2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, formic acid (74.7 mg, 62.5 μmol, 23.8%) as a mixture of diastereomers of off-white solid. MS: C 55 H 80 N 12 O 15 Calculated for CH2O2: 1148.59, found [M+H] + :1149.8.

[0723] Example 106: 2,2′,2″-(10-(2-((2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 106)

[0724]

[0725] Step 1.: Into a 40 mL vial was placed a mixture of tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate (1.0 g, 1 eq, 4.9 mmol), TEA (1.6 g, 2.2 mL, 3.2 eq, 16 mmol), MsCl (1.1 g, 0.76 mL, 2.0 eq, 9.7 mmol) and DCM (10 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (6 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were then washed with water (6 mL x 2) and brine (12 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: a 40 g silica gel column, a PE / EtOAc system, an EtOAc ratio from 0% to 85% in 15 minutes, a flow rate of 40 mL / min, and a wavelength of 254 nm. The collected fractions were concentrated under reduced pressure to provide 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (1.2 g, 4.2 mmol, 87%) as a yellow oil. MS: C 10 H 21 NO6S calculated value: 283.11, found value [M+H]: 284.0

[0726] Step 2.: Into a 40 mL vial was placed a mixture of 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (500 mg, 1 eq, 1.76 mmol), CsCO (1.72 g, 2.99 eq, 5.28 mmol), ethyl 2-(3-hydroxyphenyl)-2-phenylacetate (679 mg, 1.50 eq, 2.65 mmol), sodium iodide (530 mg, 145 μL, 2.00 eq, 3.54 mmol) and DMF (5.0 mL). The reaction mixture was stirred at 80° C. for 2 h. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, Spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 minute, 30% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to provide ethyl 2-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)-2-phenylacetate (650 mg, 1.47 mmol, 83.0%) as a yellow oil. MS: C 25 H 33 NO6 calculated value: 443.23, found value [M+H] + :444.2.

[0727] Step 3.: Into a 40 mL vial was placed a mixture of ethyl 2-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)-2-phenylacetate (650 mg, 1 eq, 1.47 mmol), LiOH (35.1 mg, 1 eq, 1.47 mmol), H2O (1.0 mL) and MeOH (5.0 mL). The reaction mixture was stirred at 25°C for 3 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with water (10 mL×2) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 40 g, PE / EtOAc system, EtOAc ratio from 0% to 85% in 15 minutes, flow rate: 40 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to provide 2-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)-2-phenylacetic acid (670 mg, 1.61 mmol, 110%) as an off-white solid. MS: C 23 H 29 NO6 calculated value: 415.20, found [M+H]+ :416.1.

[0728] Step 4.: In a manner similar to that of Compound 101, Step 5, 2-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)-2-phenylacetic acid (300 mg, 1 eq, 722 μmol) was combined with Intermediate C to provide tert-butyl (2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)-carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethyl)carbamate (150 mg, 183 μmol, 25.4%) as an off-white solid. MS: C 42 H 58 Calculated value for N8O9: 818.43, found [M+H] + :819.5.

[0729] Step 5.: Tert-butyl (2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethyl)carbamate (150 mg, 1 eq, 183 μmol) was treated with TFA in a manner analogous to that of compound 101, step 6 to afford (2R)-2-(2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (105 mg, 146 μmol, 79.7%) as a yellow oil. MS: C 37 H 50 Calculated value for N8O7: 718.38, found [M+H] + :719.4.

[0730] Step 6.: (2R)-2-(2-(3-(2-(2-aminoethoxy)ethoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (105 mg, 1 eq, 146 μm) was treated with 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid in a manner analogous to that of step 7 of compound 101. ol) to afford 2,2′,2″-(10-(2-((2-(2-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (70.9 mg, 64.1 μmol, 43.9%) as an off-white solid diastereomeric mixture. MS: C 53 H 76 N 12 O 14 Calculated value: 1104.56, found [M+H] + :1105.8.

[0731] Example 107: 2,2′,2″-(10-(2-(((2R)-1-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)-carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-butyl)amino)-1-oxo-3-sulfopropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (Compounds 107A and 107B)

[0732]

[0733] Step 1.: Into a 100 mL round-bottom flask was placed a mixture of ethyl 2-(3-hydroxyphenyl)-2-phenylacetate (4.5 g, 1 eq., 18 mmol), tert-butyl (4-bromobutyl)carbamate (6.6 g, 1.5 eq., 26 mmol), CsCO (17 g, 3.0 eq., 52 mmol), sodium iodide (5.3 g, 1.4 mL, 2.0 eq., 35 mmol) and DMF (50 mL). The reaction mixture was stirred at 80° C. for 3 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were then washed with water (200 mL×2), brine (200 mL), dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: a 120 g silica gel column, a PE / EtOAc system, an EtOAc ratio from 0% to 85% over 25 minutes, a flow rate of 90 mL / min, and a wavelength of 254 nm. The collected fractions were concentrated under reduced pressure to provide ethyl 2-(3-(4-((tert-butoxycarbonyl)amino)-butoxy)phenyl)-2-phenylacetate (4.2 g, 9.8 mmol, 56%) as a yellow oil. 25 H 33 NO5 calculated value: 427.24, found value [M+Na] + :450.3.

[0734] Step 2.: Into a 50 mL vial was placed a mixture of ethyl 2-(3-(4-((tert-butoxycarbonyl)amino)butoxy)phenyl)-2-phenylacetate (3.0 g, 1 eq, 7.0 mmol), LiOH (1.7 g, 10 eq, 71 mmol), MeOH (30 mL) and H2O (10 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, then the residue was diluted with water (50 mL), and the pH was adjusted to 6.0 by adding saturated NaHSO4 solution. The reaction mixture was extracted with DCM (50 mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide 2-(3-(4-((tert-butoxycarbonyl)amino)butoxy)phenyl)-2-phenylacetic acid (2.3 g, 5.8 mmol, 82%) as a light yellow solid, which was used directly in the next step without any purification. MS: C 23 H 29 NO5 calculated value: 399.20, found value [M+Na] + :422.1.

[0735] Step 3.: In a manner similar to that of Compound 101, Step 5, 2-(3-(4-((tert-butoxycarbonyl)amino)butoxy)phenyl)-2-phenylacetic acid (2.5 g, 1.2 equiv, 6.3 mmol) was combined with Intermediate C to afford tert-butyl (4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)-carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)-butyl)carbamate (2.1 g, 2.6 mmol, 50%) as a yellow oil. 42 H 58 Calculated value for N8O8: 802.44, found [M+H] + :803.5.

[0736] Step 4.: Tert-butyl (4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)carbamate (600 mg, 1 eq, 747 μmol) was treated with TFA in a manner similar to that of compound 101, step 6 to provide (2R)-2-(2-(3-(4-aminobutyloxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (Intermediate H) (550 mg, 0.63 mmol, 84%, 80% purity) which was used directly in the next step without purification. MS: C 37 H 50 Calculated value for N8O6: 702.39, found [M+H] + :703.4.

[0737] Step 5.: Into an 8 mL vial was placed a mixture of (((9H-fluoren-9-yl)methoxy)carbonyl)(sulfo)-D-alanine (170 mg, 0.872 eq, 434 μmol), FDPP (280 mg, 1.46 eq, 729 μmol), 4-methylmorpholine (160 mg, 0.17 mL, 3.18 eq, 1.58 mmol), and DMF (0.35 mL). The reaction mixture was stirred at 26° C. for 15 minutes, followed by the addition of (2R)-2-(2-(3-(4-aminobutoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (350 mg, 1 eq, 498 μmol). The reaction mixture was stirred at 26° C. for 2 hours. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, Spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 minute, 30% ACN to 98% in 6 minutes, 98% ACN to 98% in 3 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated to afford (2R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropane-1-sulfonic acid (85 mg, 79 μmol, 16%) as a yellow solid. MS: C 55 H 65 N9O 12 S calculated: 1075.44, found [M+H] + :1076.4.

[0738] Step 6.: To an 8 mL flask was added a mixture of (2R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropane-1-sulfonic acid (85 mg, 1 eq, 79 μmol), DMF (1 mL) and DBU (35 mg, 35 μL, 2.9 eq, 0.23 mmol). The mixture was stirred at 26° C. for 1 hour. This gave (2R)-2-amino-3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropane-1-sulfonic acid (85 mg, 83 μmol, 100%, 83% purity) which was used directly in the next step without any purification. MS: C 40 H 55 N9O 10 S calculated: 853.38, found [M+H] + :854.4.

[0739] Step 7.: (2R)-2-amino-3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropane-1-sulfonic acid (85 mg, 83%) was treated with 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid in a manner analogous to that of compound 101, step 7. Wt, 1 equiv, 83 μmol) to provide a single diastereomer of 2,2′,2″-(10-(2-(((2R)-1-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-1-oxo-3-sulfopropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) as a white solid (Compound 107A, 15.1 mg, 11.1 μmol, 13%, previous Peak) and the other diastereomer of 2,2′,2″-(10-(2-(((2R)-1-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-1-oxo-3-sulfopropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) as a white solid (Compound 107B, 16.7 mg, 12.3 μmol, 15%, latter peak). Compound 107A: MS: C 58 H 82 F3N 13 O 19 S calculated: 1353.55, found [M+H-TFA] + :1240.7. Compound 107B: MS: C 58 H 82 F3N 13 O 19 S calculated: 1353.55, found [M+H-TFA] + :1240.7.

[0740] Example 108: 2,2′,2″-(10-(2-((2-(3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (Compounds 108A and 108B)

[0741]

[0742] Step 1: Into an 8 mL vial was placed a mixture of 3-(2-((tert-butoxycarbonyl)amino)-ethoxy)propanoic acid (45 mg, 0.85 equiv, 0.19 mmol) and DMF (2 mL), to which were added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (100 mg, 1.16 equiv, 263 μmol) and N-ethyl-N-isopropylpropan-2-amine (90 mg, 3.1 equiv, 0.70 mmol). The reaction mixture was stirred at 25° C. for 15 minutes, followed by the addition of (2R)-2-(2-(3-(4-amino-butoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamido-ethyl)carbamoyl)guanidino)pentanamide (Intermediate H from Example 107, Step 4, 200 mg, 80% Wt, 1 eq, 228 μmol). The reaction mixture was stirred at 25° C. for 2 hours. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, Spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 minute, 30% ACN to 98% in 9 minutes, 98% ACN to 98% in 2 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated to give tert-butyl (2-(3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropoxy)ethyl)carbamate (87 mg, 95 μmol, 42%) as a yellow solid. MS: C 47 H 67 N9O 10Calculated: 917.50, found [M+H] + :918.5.

[0743] Step 2.: Tert-butyl (2-(3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropoxy)ethyl)carbamate (87 mg, 1 mmol) was treated with TFA in a manner similar to that of compound 101, step 6. 4-[4-(4-(2-aminoethoxy)propionamido)-butoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)-carbamoyl)guanidino)pentanamide (90 mg, 77 μmol, 81%, 70% purity) was added to provide (2R)-2-(2-(3-(4-(3-(2-aminoethoxy)propionamido)-butoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)-carbamoyl)guanidino)pentanamide as a brown solid, which was used directly in the next step without any purification. MS: C 42 H 59 Calculated for N9O8: 817.45, found [M+H-TFA] + :818.3.

[0744] Step 3.: (2R)-2-(2-(3-(4-(3-(2-aminoethoxy)propionamido)butoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)-pentanamide (90 mg, 70% yield) was treated with 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid in a manner analogous to that of step 7 of compound 101. Wt, 1 equiv, 77 μmol) to provide a single diastereomer of 2,2′,2″-(10-(2-((2-(3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropoxy)ethyl)-amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) as a white solid (Compound 108A, 24.4 mg, 19.5 μmol, 25%, The first peak) and the other diastereomer of 2,2',2"-(10-(2-((2-(3-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-3-oxopropoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) as a white solid (Compound 108B, 21.6 mg, 17.3 μmol, 22%, second peak). Compound 108A: MS: C 62 H 90 F3N 13 O 19 Calculated: 1249.63, found [M+H-FA] + :1204.8. Compound 108B:MS:C 62 H 90 F3N 13 O 19 Calculated: 1249.63, found [M+H-FA] + :1204.8.

[0745] Example 109: 2,2′,2″-(10-(2-(((5R)-5-amino-6-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-6-oxohexyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compounds 109A and 109B)

[0746]

[0747] Step 1.: Into an 8 mL vial was placed a mixture of N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-D-lysine (100 mg, 0.750 equiv, 213 μmol) and DMF (2 mL). DIEA (110 mg, 148 μL, 2.99 equiv, 851 μmol) and HATU (100 mg, 0.924 equiv, 263 μmol) were added. The reaction mixture was stirred at 25°C for 15 minutes, followed by the addition of (2R)-2-(2-(3-(4-aminobutoxy)phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (200 mg, 1 equiv, 285 μmol). The reaction mixture was stirred at 25°C for 1 hour. The crude product was purified by preparative HPLC using the following conditions: column: SunFire prep OBD 19*150mm 5μm; mobile phase A: water (0.05% FA); mobile phase B: ACN; gradient: 25% B to 65% B in 10 minutes; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were dried by lyophilization to afford (9H-fluoren-9-yl)methyl ((5R)-6-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-6-oxohexane-1,5-diyl)dicarbamate tert-butyl ester (55 mg, 48 μmol, 17%) as a yellow solid. MS: C 63 H 80 N 10 O 11 Calculated value: 1152.60, found [M+H] + :1153.6.

[0748] Step 2.: In a similar manner to that of compound 101, step 6, (9H-fluoren-9-yl)methyl ((5R)-6-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-6-oxohexane-1,5-diyl)dicarbamate tert-butyl ester was treated with TFA to afford tert-butyl ((5R)-6-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-6-oxohexane-1,5-diyl)dicarbamate as a brown solid. (9H-fluoren-9-yl)methyl ((2R)-6-amino-1-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-1-oxohexan-2-yl)carbamate (55 mg, 42 μmol, 88%, 80% purity) was used directly in the next step without any purification. MS: C 58 H 72 N 10 O9 calculated value: 1052.55, found value [M+H] + :1053.5.

[0749] Step 3.: (9H-fluoren-9-yl)methyl ((2R)-6-amino-1-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,11,16-trioxo-1-phenyl-3,8,10,12,15-pentaazaoctadec-9-en-1-yl)phenoxy)butyl)amino)-1-oxohexan-2-yl)carbamate (55 mg, 80%) was treated with 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid. Wt, 1 equiv, 42 μmol) to afford 2,2′,2″-(10-(2-(((5R)-5-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, R——Z——(ligand) y Formula (I); in: R is -LL A -R A 、-L-(L A -R A )2 or -L-(L A -R A )3, L is a linker or absent; Each L A independently a linker or absent; Each R A independently a chelating moiety or a radionuclide complex thereof; Z is -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR Z -、-NR Z C(=O)-, -O-, -NR Z -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-; R Z is H or unsubstituted C1-C4 alkyl; The ligand is a small molecule modulator of the neuropeptide Y1 receptor (NPY1R); and y is 1, 2, or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is -LL A -R A And L does not exist. 3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ligand is a small molecule antagonist of NPY1R.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the ligand comprises (2,2-diphenylacetyl)arginine amide, piperidinyl-propyl-benzimidazole, piperidinyl-propyl-indole, 2,6-dimethyl-3,5-dicarboxylate-dihydropyridine, 2,4-diaminopyridine or 1-benzyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine -2-ketone. 5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ligand comprises (2,2-diphenylacetyl)arginine amide. 6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ligand comprises benzyl-(2,2-diphenylacetyl)arginine amide.

7. The compound according to any one of claims 1 to 6, wherein y is 1.

8. A compound of formula (II) or a pharmaceutically acceptable salt thereof: in: R 1 is H, -C1-C6 alkyl or -C(=O)NH2; R 2 is -OH, -NH2, -C(=O)NH2 or -CH2NHC(=O)NH2; Each R 3 Independently selected from R 3a 、R 3b 、R 3c and R 3d ; R 3a 、R 3b 、R 3c and R 3d Each is independently selected from H, F, Cl, Br, I, -CN, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy; R 4 is H, -C(=O)R 10 、-C(=O)NHR 10 or -C(=O)N(CH3)R 10 ; R 10 is substituted or unsubstituted -C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, -(CH2) t -NH2, -(CH2) t C(=O)O(CH2) u CH3, -(CH2) t NHC(=O)(CH2) u CH3 or -(CH2) t - a substituted or unsubstituted 5- to 6-membered heteroaryl ring; t is 1, 2, 3, 4, 5, or 6; u is 1, 2, 3, or 4; R 5 Does not exist or -Z B -L B -R B ; Z B -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 11 -、-NR 11 C(=O)-, -O-, -NR 11 -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-; L B It is a joint; R B is a chelating moiety or a radionuclide complex thereof; R 6 Yes-Z A -L A -R A ; Z A -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, - C(=O)NR 12 -、-NR 12 C(=O)-, -O-, -NR 12 -, -S-, -S(=O)-, -SO2- or -NHC(=O)NH-; L A It is a joint; R A is a chelating moiety or a radionuclide complex thereof; Each R 7 Independently selected from F, Cl, Br, I, -CN, -OH, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy; Each R 8 Independently selected from F, Cl, Br, I, -CN, -OH, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy; R 9 is H, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted -C1-C6 alkoxy; Each R 11 are independently H or unsubstituted C1-C4 alkyl; Each R 12 are independently H or unsubstituted C1-C4 alkyl; n is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; and p is 0, 1, 2, or 3.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IIa):

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IIb):

11. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IIc):

12. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IId):

13. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IIe):

14. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 5 Does not exist.

15. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 5 Yes-Z B -L B -R B .

16. The compound according to claim 8 or 15, or a pharmaceutically acceptable salt thereof, wherein Z B It is -O-, -NH- or -NMe-.

17. The compound according to any one of claims 8 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 It’s H.

18. The compound according to any one of claims 8 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH3.

19. The compound according to any one of claims 8 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -C(=O)NH2.

20. The compound according to any one of claims 8 to 19, or a pharmaceutically acceptable salt thereof, wherein n is 0.

21. The compound according to any one of claims 8-11 or 14-20, or a pharmaceutically acceptable salt thereof, wherein m is 0.

22. The compound according to any one of claims 8-11 or 14-21, or a pharmaceutically acceptable salt thereof, wherein p is 0.

23. The compound according to any one of claims 8 to 22, or a pharmaceutically acceptable salt thereof, wherein each R 3 Independently selected from R 3a 、R 3b 、R 3c and R 3d ; R 3a 、R 3b 、R 3c and R 3d Each is independently selected from H, F, Cl, Br, I, -CN, -CH3, -CF3 and -OCH3.

24. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: Each R 3a 、R 3b 、R 3c and R 3d Independently selected from H, F, Cl, Br, I, -CN, substituted or unsubstituted -C1-C6 alkyl and substituted or unsubstituted -C1-C6 alkoxy.

25. The compound of claim 24, wherein each R 3a 、R 3b 、R 3c and R 3d Independently selected from H, F, Cl, Br, I, -CN, -CH3, -CF3 or -OCH3.

26. The compound according to claim 24, wherein R 3a and R 3d is F or Cl and R 3b and R 3c It’s H.

27. The compound according to claim 24, wherein R 3a is F, Cl or Br and R 3b 、R 3c and R 3d It’s H.

28. The compound according to any one of claims 8 to 27, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -OH.

29. The compound according to any one of claims 8 to 27, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -C(=O)NH2 or -CH2NHC(=O)NH2.

30. The compound according to any one of claims 8 to 29, or a pharmaceutically acceptable salt thereof, wherein R 4 It’s H.

31. A compound according to any one of claims 8 to 29, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C(=O)NHR 10 .

32. A compound according to any one of claims 8 to 29, or a pharmaceutically acceptable salt thereof, wherein R 4 is -C(=O)NH(CH2) t NHC(=O)(CH2) u CH3.

33. A compound according to any one of claims 8 to 29, or a pharmaceutically acceptable salt thereof, wherein R 10 is unsubstituted -C1-C6 alkyl, -(CH2) t -NH2,- (CH2) t C(=O)O(CH2) u CH3, -(CH2) t NHC(=O)(CH2) u CH3 or -(CH2) t - a substituted or unsubstituted 5- to 6-membered heteroaryl ring; t is 1, 2, 3, 4, 5, or 6; and u is 1, 2, 3, or 4.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein t is 2 and u is 1.

35. A compound according to any one of claims 8 to 34, or a pharmaceutically acceptable salt thereof, wherein Z A It is -O-, -NH- or -N(-CH3)-.

36. A compound according to any one of claims 8 to 34, or a pharmaceutically acceptable salt thereof, wherein Z A Yes -O-.

37. A compound according to any one of claims 8 to 34, or a pharmaceutically acceptable salt thereof, wherein Z A It is -NH-.

38. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R A and R B If present, independently selected from: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (PSC); 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A); α, α', α", α"' -tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA); 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA); 2,2',2"-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) Benzyl)triacetic acid; benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA); p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA); 6,6'-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4pypa); H4pypa-benzyl; 6,6',6 ”,6”'-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))-tetra(methylene))-tetrapicolinic acid (H4py4pa); H4py4pa-benzyl; 2,2′,2”-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA); 6,6′-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa); 2,2',2",2"'-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown); 6,6'-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4octapa); H4octapa-benzyl; and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecandioic acid (TTHA); or their radionuclide complexes.

39. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R A and R B If present, independently selected from: 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A); or their radionuclide complexes.

40. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R A and R B If present, independently selected from: or a radionuclide complex thereof.

41. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R A and R B If it exists, then or a radionuclide complex thereof.

42. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R A and R B If present, independently selected from: or a radionuclide complex thereof.

43. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R A and R B If present, independently selected from: -L 2 -、-L 3 -、-L 4 -、-L 5 -、-L 6 -、-L 7 -、-L 2 -L 3 -、-L 2 -L 4 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 4 -L 6 -、-L 4 -L 7 -、-L 6 -L 7 -、-L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 5 -L 7 -、-L 2 -L 6 -L 7 -、-L 3 -L 4 -L 7 -、-L 4 -L 5 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、-L 4 -L 5 -L 6 -L 7 -、-L 2 -L 4 -L 5 -L 6 -L 7 -or-L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -; L 2 Is absent, substituted or unsubstituted -C1-C 20 Alkylene, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NR 16 CH2NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)CH2NR 16 -, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH2CH2O) z -、-(OCH2CH2) z -、-(CH2CH2O) w -CH2CH2-, -CH2CH2NR 16 -(CH2CH2O) w -、-(CH2CH2O) w -CH2CH2NR 16 -, -CH2CH2NHC(=O)-(CH2CH2O) w 、-(CH2CH2O) w -CH2CH2NR 16 C(=O)-, -CH2CH2C(=O)NR 16 -(CH2CH2O) w -、-CH2CH2NR 16 C(=O)CH2-(OCH2CH2) w or -(CH2CH2O) w -CH2CH2C(=O)NR 16 -; Each R 16 Independently selected from H and C1-C4 alkyl; w is 1, 2, 3, 4, 5, or 6; z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; L 3 is absent or a natural or unnatural amino acid, or a peptide formed from two or more independently selected natural and unnatural amino acids, wherein when two or more amino acids are present, the N atom to which the amino acids are attached is optionally substituted with a -C1-C6 alkyl group; L 4 is absent, substituted or unsubstituted 2- to 10-membered heteroalkylene, -CH2-(OCH2CH2) v -、-(CH2CH2O) v -CH2CH2-, -(CH2CH2O) v CH2CH2NR 17 C(=O)(CH2CH2O) v CH2CH2-、-(CH2CH2O) v CH2CH2C(=O)NR 17 (CH2CH2O) v CH2CH2-, -C(=O)CH2CH2-, -CH2CH2C(=O)-, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 、-(CH2) v -NR 17 -(CH2) v 、-NHC(=O)NH-O-(CH2) v -、-NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v -, -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or -C1-C6 alkylene, said -C1-C6 alkylene being optionally substituted by 1 or 2 groups independently selected from the following: -OR 18 、-NR 18a R 18b 、-C(=O)OR 18 、-O(CH2CH2O) s -CH3, -NR 18 (CH2CH2O) s -CH3, -NR 18 C(=O)(CH2CH2O) s -CH3, -CH2OCH2CH2CO2R 18 or -NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s CH3; Each R 17 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; Each R 18 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; Each R 18a are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; Each R 18b are independently H, -C1-C6 alkyl, -C(=O)(CH2) x -4-iodophenyl, C(=O)(CH2) x -4-methylphenyl or sugar alcohol or its derivatives; Each x is independently 1, 2, 3, or 4; v is an integer from 1 to 40; s is an integer from 1 to 20; L 5 Is absent, -O-, -S-, -S(=O)-, -S(=O)2, -NR 13 -, -CH(=NH)-, -CH(=N-NH)-, -CCH3(=NH)-, -CCH3(=N-NH)-, -C(=O)NR 13 -、-NR 13 C(=O), -NR 13 C(=O)O-、-NR 13 C(=O)NR 13 -or-OC(=O)NR 13 -; Each R 13 Independently selected from H and C1-C4 alkyl; L 6 Is not present or -L 8 -L 9 -L 10 -; L 8 Does not exist, -(CH2) r -、-NR 14 -、-NR 14 -(CH2) r -、-(CH2) r -C(=O)-, -C(=O)-(CH2) r -、-(CH2) r -NR 14 -、-(CH2) r -NR 14 C(=O)-、-(CH2) r -C(=O)NR 14 -、-CH(NHR 14 )-(CH2) r -C(=O)-, -NR 14 C(=O)-(CH2) r - and -C(=O)NR 14 -(CH2) r -; r is 0, 1, 2, or 3; L 9 is a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or Unsubstituted arylene, substituted or unsubstituted heteroarylene, monosaccharide or k is 1, 2, 3, or 4; L 10 Does not exist, -(CH2) q -、-NR 15 -、-NR 15 -(CH2) q -、-(CH2) q -C(=O)-, -C(=O)-(CH2) q -、-(CH2) q -NR 15 -、-NR 15 -(CH2) q -NR 15 -、-(CH2) q -NR 15 C(=O)-、-(CH2) q -C(=O)NR 15 -、-CH(NHR 15 )-(CH2) q -C(=O)-, -NR 15 C(=O)-(CH2) q -or-C(=O)NR 15 -(CH2) q -; q is 0, 1, 2, 3, 4, 5, or 6; R 14 and R 15 Each independently selected from H, -C1-C6 alkyl, -C1-C6 alkyl-C(=O)OH, -(CH2CH2O) p -CH3, -C(=O)-(CH2CH2O) p -CH3 or -(CH2CH2O) p -CH2CH2C(=O)OH; p is 1, 2, 3, 4, 5, or 6; and L 7 is absent, -NH-, -N(CH3)-, -O-NH-, substituted or unsubstituted N-heterocycloalkylene or -O-NH=(substituted or unsubstituted N-heterocycloalkylene) or a natural or unnatural amino acid.

44. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R A and R B If present, independently selected from: -L 2 -、-L 3 -、-L 4 -、-L 5 -、-L 6 -、-L 7 -、-L 2 -L 3 -、-L 2 -L 4 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 4 -L 6 -、-L 4 -L 7 -、-L 6 -L 7 -、L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 5 -L 7 -、-L 2 -L 6 -L 7 -、-L 3 -L 4 -L 7 -、-L 4 -L 5 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、L 4 -L 5 -L 6 -L 7 -、-L 2 -L 4 -L 5 -L 6 -L 7 -or-L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -; L 2 is substituted or unsubstituted -C1-C 20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH-, substituted or unsubstituted-C1-C 20 Alkylene-NR 16 C(=O)CH2NR 16 -、-(CH2CH2O) z -or-(CH2CH2O) w -CH2CH2-; Each R 16 Independently selected from H and C1-C4 alkyl; w is 1, 2, 3, 4, 5, or 6; z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; L 3 is a natural or unnatural amino acid or a combination of two or more independently selected natural and unnatural amino acids wherein when there are two or more amino acids, the N atom of the amide connecting the amino acids is optionally substituted with a -C1-C6 alkyl group; L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 、-(CH2) v -NR 17 -(CH2) v 、-NHC(=O)NH-O- (CH2) v -、-NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v , -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or -C1-C6 alkylene, said -C1-C6 alkylene is optionally substituted by 1 or 2 independently selected from -NR 18a R 18b or -NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s Group substitution of CH3; Each R 17 is independently H or a sugar alcohol or a derivative thereof; Each R 18 are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; Each R 18a are independently H, -C1-C6 alkyl or sugar alcohol or its derivatives; Each R 18b independently H, -C1-C6 alkyl, -C(=O)CH2CH2CH2-4-iodophenyl, or sugar alcohol or its derivatives; v is an integer from 1 to 40; s is an integer from 1 to 20; L 5 Yes-NR 13 C(=O); R 13 is H or C1-C4 alkyl; L 6 Yes-L 8 -L 9 -L 10 -; L 8 Does not exist, -(CH2) r -or-(CH2) r -C(=O)NR 14 -; r is 0, 1, 2, or 3; L 9 is a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or unsubstituted arylene group, a monosaccharide or k is 1, 2, 3, or 4; L 10 Does not exist, -(CH2) q -、-NR 15 -(CH2) q -or-NR 15 -(CH2) q -NR 15 -; q is 0, 1, 2, 3, 4, 5, or 6; R 14 and R 15 Each is independently selected from H or -C1-C6 alkyl-C(=O)OH; p is 1, 2, 3, 4, 5, or 6; and L 7 is -NH- or a natural or unnatural amino acid.

45. The compound according to claim 43 or 44, or a pharmaceutically acceptable salt thereof, wherein L A Yes-L 2 -L 3 -、-L 2 -L 6 -、-L 2 -L 7 -、-L 2 -L 3 -L 7 -、-L 2 -L 4 -L 7 -、-L 2 -L 6 -L 7 -、-L 2 -L 3 -L 4 -L 7 -、-L 2 -L 4 -L 5 -L 7 -、-L 4 -L 5 -L 6 -L 7 -or-L 2 -L 4 -L 5 -L 6 -L 7 -.

46. ​​A compound according to any one of claims 43 to 45, or a pharmaceutically acceptable salt thereof, wherein L 2 Does not exist.

47. A compound according to any one of claims 43 to 45, or a pharmaceutically acceptable salt thereof, wherein L 2 is substituted or unsubstituted -C1-C 20 Alkylene, substituted or unsubstituted -C1-C 20 Alkylene-NH-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NH-, substituted or unsubstituted-C1-C 20 Alkylene-C(=O)NCH3-, substituted or unsubstituted-C1-C 20 Alkylene-NHC(=O)-, substituted or unsubstituted-C1-C 20 Alkylene-NHC(=O)NHNH- or substituted or unsubstituted-C1-C 20 Alkylene-NHC(=O)CH2NH-.

48. A compound according to any one of claims 43 to 45, or a pharmaceutically acceptable salt thereof, wherein L 2 Yes – (CH2CH2O) w -CH2CH2-.

49. The compound of any one of claims 43-48, or a pharmaceutically acceptable salt thereof, wherein w is 1, 2, 3 or 4.

50. The compound according to any one of claims 43-48, or a pharmaceutically acceptable salt thereof, wherein w is 4.

51. A compound according to any one of claims 43 to 50, or a pharmaceutically acceptable salt thereof, wherein L 3 Does not exist.

52. A compound according to any one of claims 43 to 50, or a pharmaceutically acceptable salt thereof, wherein L 3 is a natural amino acid, an unnatural amino acid, or a peptide formed from two or more independently selected amino acids selected from the group consisting of alanine (Ala), 3-(2-naphthyl)-alanine (2-Nal), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), cysteic acid, glutamine (Gln), glutamic acid (Glu), γ-carboxyglutamate (Gla), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), hydroxylysine (Hyl), ornithine (Orn), methionine (Met), phenylalanine (Phe), p-phenylphenylalanine (Bip), proline (Pro), hydroxyproline (Hyp), serine (Ser), homoserine (Hse), sarcosine (Sar), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val), wherein when two or more amino acids are present, the N atom of the amide connecting the amino acids is optionally substituted by -CH3.

53. A compound according to any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein L 4 Does not exist.

54. A compound according to any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein L 4 It is -C(=O)CH2CH2-.

55. A compound according to any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein L 4 is -(CH2CH2O) v -CH2CH2-.

56. A compound according to any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein L 4 Yes – (CH2) v -NR 17 -(CH2) v -.

57. A compound according to any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein L 4 is –NH(C=O)NH-O-(CH2) v -、-NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v -or-NHC(=O)CH2-O-NH-C(=O)(CH2) v -.

58. The compound of any one of claims 43-57, or a pharmaceutically acceptable salt thereof, wherein v is 1, 2, 3, 4, 5, or 6.

59. A compound according to any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein L 4 is -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 .

60. A compound according to any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein L 4 is optionally 1 or 2 independently selected from -OR 18 or -NR 18a R 18b C1-C6 alkylene substituted with a group.

61. The compound according to claim 56 or 59, wherein R 17 It is CH3.

62. The compound according to claim 56 or 59, wherein R 17 It is sorbitol or its derivatives.

63. A compound according to any one of claims 43 to 62, or a pharmaceutically acceptable salt thereof, wherein R 18a is H and R 18b It is H or CH3.

64. A compound according to any one of claims 43-63 or a pharmaceutically acceptable salt thereof, wherein L 5 Does not exist.

65. A compound according to any one of claims 43-63 or a pharmaceutically acceptable salt thereof, wherein L 5 It is -C(=O)NH- or -NHC(=O)-.

66. A compound according to any one of claims 43 to 65, or a pharmaceutically acceptable salt thereof, wherein L 6 Yes-L 8 -L 9 -L 10 -.

67. A compound according to any one of claims 43 to 65, or a pharmaceutically acceptable salt thereof, wherein L 6 Does not exist.

68. A compound according to any one of claims 43 to 67, or a pharmaceutically acceptable salt thereof, wherein L 8 Does not exist.

69. A compound according to any one of claims 43 to 67, or a pharmaceutically acceptable salt thereof, wherein L 8 Yes - (CH2) r -.

70. A compound according to any one of claims 43-67 or a pharmaceutically acceptable salt thereof, wherein L 8 Yes - (CH2) r -C(=O)NR 14 -.

71. The compound according to claim 70 or a pharmaceutically acceptable salt thereof, wherein R 14 It is -CH2CO2H.

72. The compound of any one of claims 43-67, 69 or 70, or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2.

73. A compound according to any one of claims 43-72, or a pharmaceutically acceptable salt thereof, wherein L 10 Does not exist.

74. A compound according to any one of claims 43 to 72, or a pharmaceutically acceptable salt thereof, wherein L 10 Yes - (CH2) q -.

75. A compound according to any one of claims 43 to 72, or a pharmaceutically acceptable salt thereof, wherein L 10 Yes-NR 15 -(CH2) q -or-NR 15 -(CH2) q -NR 15 -.

76. A compound according to any one of claims 43-72, or a pharmaceutically acceptable salt thereof, wherein L 10 is -C(=O)NR 15 -(CH2) q -.

77. The compound according to claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein R 15 It’s H.

78. The compound of any one of claims 43-77, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

79. The compound of any one of claims 43-77, or a pharmaceutically acceptable salt thereof, wherein q is 4, 5 or 6.

80. A compound according to any one of claims 43-79 or a pharmaceutically acceptable salt thereof, wherein L 9 It is a substituted or unsubstituted 4- to 6-membered heterocycloalkylene group.

81. A compound according to any one of claims 43-79 or a pharmaceutically acceptable salt thereof, wherein L 9 is azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl.

82. A compound according to any one of claims 43-79 or a pharmaceutically acceptable salt thereof, wherein L 9 It is a monosaccharide.

83. A compound according to any one of claims 43-79 or a pharmaceutically acceptable salt thereof, wherein L 9 yes 84. A compound according to any one of claims 43-79 or a pharmaceutically acceptable salt thereof, wherein L 9 It is an unsubstituted or substituted C4-C8 cycloalkylene group.

85. A compound according to any one of claims 43-79 or a pharmaceutically acceptable salt thereof, wherein L 9 yes 86. A compound according to any one of claims 43-79 or a pharmaceutically acceptable salt thereof, wherein L 9 is an unsubstituted phenylene group.

87. A compound according to any one of claims 43 to 86, or a pharmaceutically acceptable salt thereof, wherein L 7 Does not exist.

88. A compound according to any one of claims 43-86 or a pharmaceutically acceptable salt thereof, wherein L 7 is -NH- or a natural or unnatural amino acid.

89. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 2 -L 3 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)CH2NH-; and L 3 are natural or unnatural amino acids.

90. The compound of claim 89, wherein the natural or unnatural amino acid is cysteic acid, lysine, glutamic acid, or asparagine.

91. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 2 -L 6 -R A ;L 2 is unsubstituted -C1-C6 alkylene-NHC(=O)-; and L 6 Yes-L 8 -L 9 -L 10 .

92. A compound according to any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 2 -L 7 -R A ;L 2 is -(CH2CH2O) w -CH2CH2-; and L 7 It is -NH-.

93. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 2 -L 4 -L 7 -R A ; L 2 is unsubstituted -C1-C6 alkylene-C(=O)NCH3-, unsubstituted -C1-C6 alkylene-NHC(=O)-, unsubstituted -C1-C6 alkylene-NHC(=O)NHNH- or optionally substituted by 1 -NR 18a R 18b Substituted-C1-C6 alkylene; L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2, -(CH2) v -NR 17 -(CH2) v 、-NHC(=O)NH-O-(CH2) v -、-NHC(=O)NH-(CH2) v -, -NHC(=O)NH-NH-C(=O)(CH2) v -, -NHC(=O)CH2-O-NH-C(=O)(CH2) v - or optionally substituted -C1-C6 alkylene; and L 7 It is -NH- or -O-NH-.

94. A compound according to any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 2 -L 6 -L 7 -R A ; L 2 is unsubstituted -C1-C6 alkylene, unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;and L 7 It is -NH-, -O-NH-, or a natural or unnatural amino acid.

95. A compound according to any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 2 -L 3 -L 4 -L 7 -R A ; L 2 is unsubstituted -C1-C6 alkylene-NH-; L 3 is glutamine or a peptide formed from two or more glycines in which the N atom of the amide linking the amino acids is replaced by -CH3; L 4 is -C(=O)CH2CH2- or -(CH2) v -NR 17 -(CH2) v ;and L 7 It is -NH-.

96. A compound according to any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 2 -L 4 -L 5 -L 7 -R A ; L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-; L 4 is -C1-C6 alkylene optionally substituted by -NH2; L 5 is -NH-; and L 7 It's Bip.

97. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A Yes-L 4 -L 5 -L 6 -L 7 -R A ; L 4 is -(CH2CH2O) v -CH2CH2-; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;and L 7 It is -NH-.

98. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A It's L 2 -L 4 -L 5 -L 6 -L 7 -; L 2 is unsubstituted -C1-C6alkylene-NHC(=O)-; L 4 is -C1-C6 alkylene- substituted by -NH2; L 5 is -NHC(=O)-; L 6 Yes-L 8 -L 9 -L 10 -;and L 7 It is -NH-.

99. A compound according to any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein -L A -and-L B - if present, each independently:

100. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein -L A -R A and -L B -R B If present, each independently is:

101. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof has one of the following structures: or a radionuclide complex thereof.

102. The compound according to any one of claims 1-101, or a pharmaceutically acceptable salt thereof, wherein: The radionuclide of the radionuclide complex is a lanthanide or an actinide.

103. The compound according to any one of claims 1-101, or a pharmaceutically acceptable salt thereof, wherein: The radionuclide of the radionuclide complex is actinium, bismuth, cesium, cobalt, copper, dysprosium, erbium, gold, indium, iridium, gallium, lead, lutetium, manganese, palladium, platinum, radium, rhenium, samarium, strontium, technetium, ytterbium, yttrium or zirconium.

104. The compound according to any one of claims 1-101, or a pharmaceutically acceptable salt thereof, wherein: The radionuclide of the radionuclide complex is a diagnostic or therapeutic radionuclide.

105. The compound according to any one of claims 1-101, or a pharmaceutically acceptable salt thereof, wherein: The radionuclide of the radionuclide complex is an Auger electron emitting radionuclide, an alpha emitting radionuclide, a beta emitting radionuclide or a gamma emitting radionuclide.

106. The compound according to any one of claims 1-101, or a pharmaceutically acceptable salt thereof, wherein: The radionuclide of the radionuclide complex is a radionuclide that emits Auger electrons, and the radionuclide is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc) or 195m-platinum ( 195m Pt); or an alpha-emitting radionuclide, said radionuclide being 225-actinium ( 225 Ac), 213-bismuth ( 213 Bi), 223-radium ( 223 Ra) or 212-lead ( 212 Pb); or a beta-emitting radionuclide, said radionuclide being 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 64-copper ( 64 Cu), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Gold( 198 Au), 169-erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-technetium ( 99m Tc), 89-zirconium ( 89 Zr) or 52-manganese ( 52 Mn); or a gamma-emitting radionuclide, said radionuclide being 60-cobalt ( 60 Co), 103-palladium ( 103 Pd), 137-Cesium ( 137 Cs), 169-ytterbium ( 169 Yb), 192-iridium ( 192 Ir) or 226-radium ( 226 Ra).

107. A compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of the radionuclide complex is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 69-gallium ( 69 Ga), 71-gallium ( 71 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), 177-lutetium ( 177 Lu), 204-lead ( 204 Pb), 206-lead ( 206 Pb), 207-lead ( 207 Pb), 208-lead ( 208 Pb), 212-lead ( 212 Pb), 63-copper ( 63 Cu), 64-copper ( 64 Cu), 65-copper ( 65 Cu) or 67-copper ( 67 Cu).

108. A compound according to any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of the radionuclide complex is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu) or 177-lutetium ( 177 Lu).

109. A pharmaceutical composition comprising a compound according to any one of claims 1-108 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

110. The pharmaceutical composition of claim 109, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration.

111. A method for treating cancer, comprising administering an effective amount of a compound according to any one of claims 1-108 or a pharmaceutically acceptable salt thereof to a mammal suffering from cancer.

112. The method of claim 111, wherein the cancer comprises a tumor and the tumor overexpresses neuropeptide Y1 receptor (NPY1R).

113. The method of claim 111 or claim 112, wherein the cancer is breast cancer, kidney cancer, ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, Wilms' tumor, or an adrenal tumor.

114. The method of claim 111 or claim 112, wherein the cancer is breast cancer.

115. A method of killing a tumor that overexpresses neuropeptide Y1 receptor (NPY1R) in a mammal, the method comprising administering to the mammal a compound according to any one of claims 1-108 or a pharmaceutically acceptable salt thereof, wherein the compound according to any one of claims 1-108 or a pharmaceutically acceptable salt thereof comprises a therapeutic radionuclide.

116. The method of claim 115, wherein the mammal has been diagnosed with breast cancer, renal cancer, ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, Wilms' tumor, or an adrenal tumor.

117. The method of claim 115, wherein the mammal has been diagnosed with breast cancer.

118. A method for identifying a tumor expressing neuropeptide Y1 receptor (NPY1R) in a mammal, the method comprising administering to the mammal a compound according to any one of claims 1-108, or a pharmaceutically acceptable salt thereof; and performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); wherein the compound according to any one of claims 1-108, or a pharmaceutically acceptable salt thereof, comprises a diagnostic radionuclide.

119. A method for in vivo imaging of a tissue or organ having a tumor expressing neuropeptide Y1 receptor (NPY1R) in a mammal, the method comprising administering to the mammal a compound according to any one of claims 1-108, or a pharmaceutically acceptable salt thereof; and performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); wherein the compound according to any one of claims 1-108, or a pharmaceutically acceptable salt thereof, comprises a diagnostic radionuclide.

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