Therapeutic agents targeting the neuropeptide Y1 receptor (NPY1R) and uses thereof

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 384,873, filed November 23, 2022, and U.S. Provisional Patent Application No. 63 / 588,412, filed October 6, 2023, which applications are incorporated herein by reference in their entireties.

[0002] FIELD OF THE INVENTION Described herein are radiotherapeutic agents that target tumor cells that express the neuropeptide Y1 receptor (NPY1R), and methods of using such radiotherapeutic agents to treat, diagnose, or both cancer. [Background technology]

[0003] Neoplasms are abnormal cell growths that cause enormous medical burdens to humans, including morbidity and mortality. Neoplasms include benign or noncancerous neoplasms (e.g., adenomas) that do not exhibit malignant characteristics and generally have little potential to become dangerous. Malignant neoplasms exhibit characteristics such as gene mutations, loss of normal function, rapid division, and the ability to metastasize (invasion) to other tissues, as well as neoplasms with uncertain or unknown behavior. Malignant neoplasms (i.e., cancerous solid tumors) are the leading cause of death in industrialized countries. Noncancerous neoplasms, including benign adenomas, can also cause significant morbidity and mortality. While standard treatments can achieve remarkable results in tumor growth inhibition and even tumor elimination, the applied drugs exhibit only limited selectivity for malignant tissue over healthy tissue, and their severe side effects limit their efficacy and use. Specific targeting of neoplastic cells without affecting healthy tissue is a major goal for effective solid tumor treatment.

[0004] As one of the three major classes of cell surface receptors, G protein-coupled receptors (GPCRs) are often 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 carcinoma, adrenal and related tumors, renal cell carcinoma, and ovarian cancer, both in tumor cells and tumor-associated vasculature. Targeted delivery of radionuclides to tumors, along with 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, nephroblastoma, or adrenal tumor. Summary of the Invention

[0005] Described herein are radiopharmaceuticals for use in diagnosing and / or treating tumors. The present disclosure provides an alternative and improved method for treating tumors by targeting tumors that overexpress the neuropeptide Y1 receptor (NPY1R). In some embodiments, the radiopharmaceuticals disclosed herein are useful for treating tumors that overexpress NPY1R. In some other embodiments, the radiopharmaceuticals disclosed herein are useful for identifying tissues or organs containing tumors that overexpress NPY1R in a subject. The radiopharmaceuticals disclosed herein are also useful for in vivo imaging of a subject for the presence and distribution of tumors that overexpress NPY1R in the subject.

[0006] In one aspect of the present specification, a compound of formula (I)

[0007] [ka] or a pharmaceutically acceptable salt thereof, wherein R is -LL A -R A , -L-(L A -R A )2, or -L-(L A -RA )3, L is a linker or is absent; L A is a linker or is absent, and R A is 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), y is 1, 2, or 3; The compounds, or pharmaceutically acceptable salts thereof, are described.

[0008] In some embodiments, R is -LL A -R A and L is absent. In some embodiments, the ligand is a small molecule antagonist of NPY1R. In some embodiments, the ligand comprises (2,2-diphenylacetyl)argininamide, 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]azepin-2-one. In some embodiments, the ligand comprises (2,2-diphenylacetyl)argininamide. In some embodiments, the ligand comprises benzyl-(2,2-diphenylacetyl)argininamide. In some embodiments, y is 1.

[0009] In another aspect of the present specification, a compound of formula (II)

[0010] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H, -C1-C6 alkyl, or -C(=O)NH2, R 2 is -OH, -NH2, -C(=O)NH2, or -CH2NHCONH2, R 3 are each independently R 3a , R 3b , R 3c , and R 3d selected from the group consisting of: R 3a , R 3b , R 3c , and R 3d are each independently selected from the group consisting of 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 and 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) u CH3, -(CH2) t NHC(=O)(CH2) u CH3, or -(CH2) t - a substituted or unsubstituted 5- to 6-membered heteroaryl ring, where t is 1, 2, 3, 4, 5, or 6, and u is 1, 2, 3, or 4; R 5 does not exist or is B -L B -R B and Z Bis -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 is the linker and R B is a chelating moiety or a radionuclide complex thereof; R 6 -Z A -L A -R A and Z A is -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 is the linker and R A is a chelating moiety or a radionuclide complex thereof; R 7 are each independently selected from the group consisting of F, Cl, Br, I, —CN, —OH, substituted or unsubstituted —C1-C6 alkyl, or substituted or unsubstituted —C1-C6 alkoxy; R 8 are each independently selected from the group consisting of F, Cl, Br, I, —CN, —OH, substituted or unsubstituted —C1-C6 alkyl, or substituted or unsubstituted —C1-C6 alkoxy; R 9 is H, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted -C1-C6 alkoxy; R 11 are each independently H or unsubstituted C1-C4 alkyl; R 12 are each 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; The compounds, or pharmaceutically acceptable salts thereof, are described.

[0011] In some embodiments, the compound of formula (II) has the formula (IIa):

[0012] [ka] or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound of formula (II) has formula (IIb):

[0014] [ka] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound of Formula (II) has the formula (IIc):

[0016] [ka] or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the compound of formula (II) has the formula (IId):

[0018] [ka] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of formula (II) has the formula (IIe):

[0020] [ka] or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound has the structure:

[0022] [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , R 3c , and R 3d are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, substituted or unsubstituted —C1-C6 alkyl, and substituted or unsubstituted —C1-C6 alkoxy.

[0023] In some embodiments, R A and R Bare, when present, each 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-diacetanoic 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 Can (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 (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))-tetrakis(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-tetraoxo) 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-tetraazatetradecanedioic acid (TTHA), or a radionuclide complex thereof.

[0024] In some embodiments, R A and R B are, if present, each independently

[0025] [ka] or radionuclide complexes thereof.

[0026] In some embodiments, L A and L B are, if present, each independently -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 -L3 -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 - selected from L 2 is absent or is a 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 -C-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 - and R 16 are each independently H or C1-C4 alkyl, w is each independently 1, 2, 3, 4, 5, or 6, z is each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and L 3 is a peptide formed from a non-existent, natural or unnatural amino acid, or two or more independently selected natural and unnatural amino acids, where, when two or more amino acids are present, the N atom of the amide linking said amino acids is optionally substituted with -C1-C6 alkyl; and L 4 is absent or a 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, independently -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; and R 17 are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18 are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18a are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18b are each independently H, -C1-C6 alkyl, -C(=O)(CH2) x -4-iodophenyl, -C(=O)(CH2) x -4-methylphenyl, or a sugar alcohol or a derivative thereof, each x is independently 1, 2, 3, or 4, each v is independently an integer of 1 to 40, each s is independently an integer of 1 to 20, and L 5 is absent or -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-, -NR13 C(=O)NR 13 - or -OC(=O)NR 13 - and R 13 are each independently selected from H and C1-C4 alkyl; L 6 does not exist or -L 8 -L 9 -L 10 - and L 8 does not exist or -(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; 10 does not exist or -(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)-, -NR15 C(=O)-(CH2) q - or -C(=O)NR 15 -(CH2) q -, q is 0, 1, 2, 3, 4, 5, or 6, and R 14 and R 15 are each independently 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 9 is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, a monosaccharide, or

[0027] [ka] where 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.

[0028] 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 α-emitting radionuclide, a β-emitting radionuclide, or a γ-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).

[0029] Also described herein are pharmaceutical compositions 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.

[0030]

[0010] Another aspect of the present specification describes a method for treating cancer, the method comprising administering to a mammal having cancer an effective amount of a compound described herein (e.g., a compound of Formula (I) or (II)) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer comprises a tumor, and the tumor overexpresses 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, nephroblastoma, or 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 nephroblastoma. In some embodiments, the cancer is an adrenal tumor.

[0031] In another aspect, the present specification describes a method for treating a tumor in a mammal with a radionuclide, the method comprising administering to the mammal a compound 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 breast cancer, kidney cancer (e.g., renal cell carcinoma, RCC), ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, nephroblastoma, or adrenal tumor.

[0032] In another aspect herein, a method is described for targeted delivery of a radionuclide to a tumor in a mammal, the method comprising administering to the mammal 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).

[0033]

[0013] In another aspect herein, there is provided a method for identifying a tissue or organ in a mammal having a tumor that overexpresses 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 the R A or R B is a chelating moiety-diagnostic radionuclide complex.

[0034]

[0013] In yet another aspect herein, there is provided a method for performing in vivo diagnostic imaging of a tissue or organ in a mammal having a tumor that overexpresses the 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 the R A or R B is a chelating moiety-diagnostic radionuclide complex.

[0035] In any of the embodiments disclosed herein, the mammal is a human.

[0036] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be noted, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since 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 explanation of the drawings]

[0037] [Figure 1] Figure 1 shows the biodistribution of In[In]-Compound 140B in tumor-free female Wistar rats at 0.5, 3.0, 6.0, 24, and 72 hours after IV administration. Activity is measured as the percentage of injected dose per gram of tissue (%ID / g). [Figure 2] Figure 1 shows the biodistribution of In[In]-Compound 140B in female Swiss rats bearing hNPY1R-positive tumors. Time points are 0.5, 3.0, 6.0, 24, and 72 hours after IV administration. Decay-corrected activity is measured as the percentage of injected dose per gram of tissue (%ID / g). DETAILED DESCRIPTION OF THE INVENTION

[0038] Cancer, a disease in which some cells undergo genetic changes in the regulation of growth and replication, leading to uncontrolled growth and spread, is one of the major causes of cancer worldwide. Common types of cancer include solid tumors (cancers that typically arise in organs), carcinomas (cancers arising in the skin or tissues lining organs), sarcomas (cancers of connective tissue such as bone), leukemia (cancers of the bone marrow), and lymphomas and myelomas (cancers of the immune system). Neoplasms are abnormal cell growths that result in solid tumors that can be benign (i.e., exhibit no harmful characteristics and are unlikely to pose a risk overall, such as adenomas), malignant (i.e., exhibit characteristics such as genetic mutations, loss of normal function, rapid division, and the ability to metastasize (invasion) to other tissues), and of uncertain or unknown behavior. State-of-the-art treatment for neoplasms is accomplished through a combination of surgery, chemotherapy, and radiation therapy. While surgery can be curative under some conditions, it often requires multiple interventions, as well as the combination of radiation and chemotherapy. Chemotherapy has proven to be a powerful weapon in the fight against cancer in many cases. Chemotherapy is typically delivered by the systemic administration of potent cytotoxic drugs; however, these compounds often lack tumor selectivity, resulting in the death of healthy cells in the body. The resulting nonspecific toxicity accounts for the severe side effects of chemotherapy, as cancer cells are not specifically targeted over other cells. Radiation therapy is the use of high-energy radiation to kill cells. The radiation source can be external beam radiation (applied using an external source), internal radiation (placement of a radioactive substance near target cells), or systemic administration of radioactive substances. Like chemotherapy, many radiation therapy options lack the tumor cell signature required to achieve the ultimate goal of targeted tumor treatment using drug molecules or radionuclides.

[0039] Described herein are radiopharmaceuticals that selectively deliver radionuclides to malignant cells that overexpress NPY1R for use in cancer detection, image-guided cancer surgery, and selective tumor killing.

[0040] GPCRs are generally poorly antigenic, making them difficult to target with antibody-based strategies. The large size of antibodies can affect homogeneous uptake but may not allow for deep penetration into solid tumors. Furthermore, antibodies can present challenges during production, including batch-to-batch variability.

[0041] Peptides are inherently sensitive to proteolytic enzymes, and peptidases present in most tissues can rapidly degrade peptides into multiple fragments that lack any significant affinity for the intended receptor. Furthermore, peptides can generate unwanted immunogenic responses that complicate late-stage development by masking therapeutic efficacy and affecting safety evaluation.

[0042] When peptide ligands are linked to radionuclide payloads, the resulting conjugates often rapidly degrade in plasma, producing cytotoxic or radioactive peptide fragments that can nonspecifically bind to both tumors and normal tissues. Premature decay of such peptide-radionuclide conjugates reduces the amount of radionuclide payload distributed to targeted tumors, resulting in reduced treatment efficacy and possibly increased toxicity. Furthermore, peptides are highly likely to be excreted exclusively via the kidney, limiting their scope of application. The significant renal absorption of some peptide-based therapeutics limits their routine use.

[0043] High-affinity small molecule ligands that bind to GPCRs have been described, and they are cell-permeable, allowing them to access receptor populations in the endoplasmic reticulum and endosomes. Due to the low molecular weight of small molecules, vascular and tumor penetration should be improved compared to high molecular weight conjugates based on peptides and antibodies. In many instances, the affinity of small molecule ligands exceeds that of FDA-approved antibodies by several orders of magnitude.

[0044] Neuropeptide Y receptor (NPYR) Neuropeptide Y (NPY) receptors belong to the class A G protein-coupled receptors (GPCRs). These receptors are involved in the control of a diverse set of behavioral processes, including appetite, circadian rhythms, and anxiety. Four subtypes (NPY1R, NPY2R, NPY4R, and NPY5R) are functionally expressed in humans and distributed throughout the central nervous system and its periphery. They are activated by the endogenous peptides neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP). NPY1R has been found to be overexpressed in different types of cancer (e.g., breast cancer). Therefore, NPY1R ligands carrying radionuclide carriers offer a new modality for cancer imaging and treatment.

[0045] breast cancer Breast cancer is a type of cancer that occurs in the breast. It can occur in one or both breasts and in different parts of the breast. There are many types of breast cancer, and the type of breast cancer is determined by the particular cells in the breast that become cancerous.

[0046] Types of Breast Cancer Most breast cancers are carcinomas, tumors that begin in the epithelial cells that line organs and tissues throughout the body. When the cancer begins in the breast, it is usually a more specific type called adenocarcinoma, which begins in cells in the ducts (milk ducts) or lobules (the glands in the breast that make milk).

[0047] The type of breast cancer can also refer to whether the cancer has spread. In situ breast cancer (ductal carcinoma in situ, or DCIS) is a pre-cancer that begins in the milk ducts but does not grow into the rest of the breast tissue. The term invasive (or invasive) breast cancer is used to describe any type of breast cancer that has spread (invaded) the surrounding breast tissue.

[0048] Breast Cancer Staging The most commonly used staging system for breast cancer is the American Joint Committee on Cancer (AJCC) TNM system. The current AJCC system, valid as of January 2018, includes a clinical-pathological staging system for breast cancer.

[0049] Pathologic staging (also called surgical staging) is determined by examination of tissue removed during surgery.

[0050] Sometimes, when surgery is not immediately possible or not possible at all, the cancer will instead be given a clinical stage, which is based on the results of a physical examination, biopsy, and imaging tests. Clinical staging is used to aid in planning treatment. However, sometimes the cancer has spread further than estimated by clinical staging, and may not predict the patient's outlook as accurately as pathological staging.

[0051] Both staging systems use seven key pieces of information: i. The extent (size) of the tumor (T), ii. spread to nearby lymph nodes (N), iii. spread to distant sites (M) (metastasis), iv. estrogen receptor (ER) status, v. Progesterone receptor (PR) status, vi.HER2 status, and vii. Cancer grade (G).

[0052] Additionally, the result of the Oncotype Dx® Recurrence Score may also be considered in staging in certain circumstances. Once all of these factors have been determined, this information is combined in a process called a stage grouping to assign an overall stage.

[0053] Breast Cancer Treatment Tumors can arise in the breast. Types of treatment currently used to treat breast tumors include surgery, radiation therapy, chemotherapy, hormone therapy, targeted drug therapy, and immunotherapy.

[0054] There are two main types of surgery to remove breast cancer: breast-conserving surgery and mastectomy. Breast-conserving surgery is surgery to remove the cancer as well as some surrounding normal tissue. Only the cancerous part of the breast is removed. How much of the breast is removed depends on the location and size of the tumor, as well as other factors. This surgery is also called a lumpectomy, quadrate resection, partial mastectomy, or segmental mastectomy. A mastectomy is surgery to remove the entire breast, including all breast tissue and possibly other nearby tissue. There are seven different types of mastectomy. Some women have both breasts removed in a double mastectomy. Occasionally, surgery is performed to remove nearby lymph nodes and other tissue where the cancer has spread.

[0055] Radiation therapy uses high-energy X-rays or other types of radiation to kill cancer cells or prevent them from growing. There are two types of radiation therapy: external radiation therapy uses a machine outside the body to direct radiation toward the area of ​​the body that has cancer. Internal radiation therapy uses radioactive material sealed in needles, seeds, wires, or catheters that are placed directly on 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.

[0056] Thus, there is still a need for breast tumor treatment options.This paper describes a radiopharmaceutical that targets the delivery of radionuclides to breast tumors that overexpress NPY1R.Targeted therapy usually causes less harm to normal cells than chemotherapy or radiotherapy.

[0057] Solid tumors: benign and / or malignant neoplasms (cancer) In one aspect, the NPY1R radiopharmaceuticals described herein are used to treat benign and / or malignant neoplasms (solid tumors), which comprise cells that overexpress NPY1R on their cell surface.

[0058] As used herein, the term "neoplasm" refers to an abnormal growth of cells that can proliferate in an uncontrolled manner and have the capacity to metastasize (spread).

[0059] Neoplasms include solid tumors at any stage, with or without metastasis, adenomas, carcinomas, sarcomas, leukemias, and lymphomas.

[0060] A solid tumor is an abnormal mass of tissue that usually does not contain cysts or areas of fluid. Solid tumors can be benign (non-cancerous) or malignant (cancerous). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) do not generally form solid tumors.

[0061] Solid tumors are cancers that typically arise from organs such as the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, ovaries, pancreas or other endocrine organs (thyroid), and prostate.

[0062] In some embodiments, the NPY1R radiopharmaceuticals described herein are used to treat adenomas. Adenomas are non-cancerous tumors. They arise from gland-like cells in epithelial tissue (thin layers of tissue that cover organs, glands, and other structures in the body). Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid gland (prostate), and others. Even if benign, adenomas can cause serious health complications by compressing other structures (mass effect) and by producing large amounts of hormones in an unregulated and non-feedback-dependent manner (causing paraneoplastic syndromes). Over time, adenomas can transform and become harmful, at which point they are called adenocarcinomas.

[0063] Adenomas can occur in the colon (e.g., adenomatous polyps that tend to become harmful and result in colon cancer), kidney (e.g., renal adenomas can be precursor lesions 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 gland (e.g., goiter), pituitary gland (e.g., prolactinoma, Cushing's syndrome, and acromegaly). They may also be found in the pituitary adenomas (e.g., hypertrophy of the pituitary gland), parathyroid glands (e.g., parathyroid adenomas may secrete inappropriately high amounts of parathyroid hormone, thereby causing primary hyperparathyroidism), liver (e.g., hepatocellular adenoma), breast (e.g., fibroadenocarcinoma), appendix (e.g., cystadenoma), bronchi (e.g., bronchial adenomas may cause carcinoid syndrome, a paraneoplastic syndrome), prostate (e.g., prostatic adenoma), sebaceous glands (e.g., sebaceous adenoma), and salivary glands.

[0064] 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, i.e., where they first began, to different areas of the body. Metastatic tumors contain malignant cells that express cell surface NPY1R.

[0065] Tumors that form from spread cells are called secondary tumors. Tumors may spread to areas near the primary site (called regional metastasis) or to distant parts of the body (called distant metastasis).

[0066] In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from the breast. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from the kidney. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from the ovary. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from melanoma. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from a gastrointestinal stromal tumor. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from Ewing's sarcoma. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from a nephroblastoma. In some embodiments, the tumor to be treated comprises tumor cells that express NPY1R, and the tumor is a primary or metastatic tumor originating from the adrenal gland.

[0067] In some embodiments, the NPY1R radiopharmaceuticals described herein are used to treat carcinoma. Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma (a type of skin cancer), squamous cell carcinoma (various tissues), bladder carcinoma including transitional cell carcinoma (malignant neoplasm of the bladder), bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, renal cell carcinoma, intraductal or bile duct carcinoma, choriocarcinoma, seminoma, embryonal tumor, Wilms' tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, bone carcinoma, carcinoma of the epithelium, and nasopharyngeal carcinoma.

[0068] In some embodiments, the NPY1R radiopharmaceuticals described herein are used to treat sarcomas, including but not limited to fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0069] Solid tumors include, but are not limited to, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, medullary hemangioma, melanoma, neuroblastoma, and retinoblastoma. Benign solid tumors include adenomas.

[0070] Primary and metastatic tumors include, for example, lung cancer (including, but not limited to, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, non-small cell carcinoma, small cell carcinoma, and mesothelioma), breast cancer (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast carcinoma, clear cell carcinoma, and mucinous carcinoma), colorectal cancer (including, but not limited to, colon carcinoma, rectal carcinoma), 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, serous tumors, endometrioid tumors, and epithelial or surface epithelial-stromal tumors of the ovary, including, but not limited to, mucinous cystadenocarcinoma, sex cord-stromal tumors), liver and cholangiocarcinoma (including, but not limited to, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hemangioma), cancers of the stomach (including but not limited to gastric adenocarcinoma, gastrointestinal stromal tumor), multiple myeloma, testicular cancer, germ cell tumors, neuroendocrine tumors, cervical cancer, carcinomas of the stomach, esophageal cancer (including but not limited to esophageal adenocarcinoma and squamous cell carcinoma), non-Hodgkin's lymphoma, bladder cancer, carcinomas of the uterus (including but not limited to endometrial adenocarcinoma, uterine serous carcinoma, uterine clear cell carcinoma, uterine sarcoma, and leiomyosarcoma, mixed Mullerian tumor), gliomas, glioblastomas, medulloblastomas, and other tumors of the brain, kidney cancer (including but not limited to renal cell carcinoma, clear cell carcinoma, Wilms' tumor), cancers of the head and neck (including but not limited to squamous cell carcinoma), cancers of the stomach (including but not limited to gastric adenocarcinoma, gastrointestinal stromal tumor), multiple myeloma, testicular cancer, germ cell tumors, neuroendocrine tumors, cervical cancer, carcinoid tumors of the gastrointestinal tract, breast, and other organs, and signet ring cell carcinoma.

[0071] Representative neuropeptide Y receptor (NPY1R)-targeting ligands 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 their affinity for other non-target receptors. In some embodiments, the radiopharmaceuticals described herein are selective for NPY1R compared to any one of other neuropeptide Y subtypes, 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 their affinity for any one of NPY2R, NPY4R, and NPY5R.

[0072] In some embodiments, the NPY1R radiopharmaceuticals described herein preferentially accumulate in targeted tumor tissues expressing 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, the compounds of Formula (I) or Formula (II) preferentially accumulate at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or more than 5-fold in tissues or organs containing tumor cells expressing NPY1R, compared to tissues or organs lacking tumor cells expressing NPY1R. The compounds may accumulate in specific tissues and organs involved in the metabolism and / or excretion of therapeutic agents, including, but not limited to, the kidney and liver.

[0073] In one aspect, the NPY1R radiopharmaceuticals described herein have the formula (I):

[0074] [ka] or a pharmaceutically acceptable salt thereof, wherein R is -LL A -RA , -L-(L A -R A )2, or -L-(L A -R A )3, L is a linker or is absent, L A is a linker or is absent, R A is 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), y is 1, 2, or 3.

[0075] In some embodiments, R is -LL A -R A and L does not exist.

[0076] In some embodiments, the ligand is a small molecule antagonist of NPY1R.

[0077] In some embodiments, the ligand comprises (2,2-diphenylacetyl)argininamide, 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]azepin-2-one. In some embodiments, the ligand comprises (2,2-diphenylacetyl)argininamide. In some embodiments, the ligand comprises benzyl-(2,2-diphenylacetyl)argininamide.

[0078] In some embodiments, L is a linker. In some embodiments, L is absent.

[0079] 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 In some embodiments, Z is -C(=O)-. In some embodiments, Z is -O-. In some embodiments, Z is -NR Z In some embodiments, Z is -. 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-.

[0080] In some embodiments, R Z is H. In some embodiments, R Z is unsubstituted C1-C4 alkyl. In some embodiments, R Z is unsubstituted -CH3.

[0081] In some embodiments, y is 1.

[0082] In some embodiments, the NPY1R radiopharmaceuticals described herein have the structure of formula (II), or a pharmaceutically acceptable salt thereof.

[0083] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H, -C1-C6 alkyl, or -C(=O)NH2, R 2 is -OH, -NH2, -C(=O)NH2, or -CH2NHCONH2, R3 are each independently R 3a , R 3b , R 3c , and R 3d selected from the group consisting of: R 3a , R 3b , R 3c , and R 3d are each independently selected from the group consisting of 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 and R 10 is a substituted or unsubstituted -C1-C6 alkyl or unsubstituted 2- to 6-membered heteroalkyl; R 5 does not exist or is B -L B -R B and Z B is -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 is the linker, R B is a chelating moiety or a radionuclide complex thereof; R 6 -Z A -L A -R A and Z A is -C1-C6 alkylene, -C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 12 -, -NR 12 C(=O)-, -O-, -NR12 -, -S-, -S(=O)-, -SO2-, or -NHC(=O)NH-; L A is the linker, R A is a chelating moiety or a radionuclide complex thereof; R 7 are each independently selected from the group consisting of F, Cl, Br, I, —CN, —OH, substituted or unsubstituted —C1-C6 alkyl, or substituted or unsubstituted —C1-C6 alkoxy; R 8 are each independently selected from the group consisting of F, Cl, Br, I, —CN, —OH, substituted or unsubstituted —C1-C6 alkyl, or substituted or unsubstituted —C1-C6 alkoxy; R 9 is H, substituted or unsubstituted —C1-C4 alkyl, or substituted or unsubstituted —C1-C6 alkoxy; R 11 are each independently H or unsubstituted -C1-C4 alkyl; R 12 are each 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; The compounds, or pharmaceutically acceptable salts thereof, are described.

[0084] In some embodiments, the compound of formula (II) has the formula (IIa):

[0085] [ka] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compound of formula (II) has formula (IIb):

[0087] [ka] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound of Formula (II) has the formula (IIc):

[0089] [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound of formula (II) has the formula (IIf):

[0091] [ka] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound of formula (II) has the formula (IIg):

[0093] [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the compound of formula (II) has the formula (IIh):

[0095] [ka] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the compound of formula (II) has the formula (IIi):

[0097] [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound of formula (II) has the formula (IId):

[0099] [ka] or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the compound of formula (II) has the formula (IIe):

[0101] [ka] or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the compound of formula (II) has the formula (IIj):

[0103] [ka] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound of formula (II) has the formula (IIk):

[0105] [ka] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound of formula (II) has the formula (IIl):

[0107] [ka] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound of formula (II) has the formula (IIm):

[0109] [ka] or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound of formula (II) has the formula (IIn):

[0111] [ka] or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound of formula (II) has the formula (IIo):

[0113] [ka] or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound of formula (II) has the formula (IIp):

[0115] [ka] or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound of formula (II) has the formula (IIq):

[0117] [ka] or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound of formula (II) has the formula (IIr):

[0119] [ka] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compound of formula (II) has the formula (IIs):

[0121] [ka] or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the compound of formula (II) has the formula (IIt):

[0123] [ka] or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the compound of formula (II) has the formula (IIu):

[0125] [ka] or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the compound of formula (II) has the formula (IIv):

[0127] [ka] or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compound of formula (II) has the formula (IIw):

[0129] [ka] or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, R 5 is absent. In some embodiments, R 5-Z B -L B -R B is.

[0131] In some embodiments, Z B is -O-, -NH-, or -N(-CH)-. In some embodiments, Z B is -C1-C6 alkylene. In some embodiments, Z B is -C1-C6 alkylene-O-. In some embodiments, Z B is —O—C1-C6 alkylene-. In some embodiments, Z B is -C(=O)NR 11 In some embodiments, Z B is —C(═O)NH—. In some embodiments, Z B is -NR 11 In some embodiments, Z is C(═O)—. B is -NHC(=O)-. In some embodiments, Z B is —O—. In some embodiments, Z B is -NR 11 In some embodiments, Z B is —N(—CH)—. In some embodiments, Z B is -NH-. In some embodiments, Z B is -S-. In some embodiments, Z B is -S(=O)-. In some embodiments, Z B is -SO2-. In some embodiments, Z B is -NHC(=O)NH-.

[0132] In some embodiments, Z A is -O-, -NH-, or -N(-CH)-. In some embodiments, Z A is -C1-C6 alkylene. In some embodiments, Z A is -C1-C6 alkylene-O-. In some embodiments, Z A is —O—C1-C6 alkylene-. In some embodiments, Z Ais -C(=O)NR 12 In some embodiments, Z A is —C(═O)NH—. In some embodiments, Z A is -NR 12 In some embodiments, Z is C(═O)—. A is -NHC(=O)-. In some embodiments, Z A is —O—. In some embodiments, Z A is -NR 12 In some embodiments, Z A is —N(—CH)—. In some embodiments, Z A is -NH-. In some embodiments, Z A is -S-. In some embodiments, Z A is -S(=O)-. In some embodiments, Z A is -SO2-. In some embodiments, Z A is -NHC(=O)NH-.

[0133] In some embodiments, R 1 is H. In some embodiments, R 1 is -C1-C6 alkyl. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -C(=O)NH2.

[0134] In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0135] 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.

[0136] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0137] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0138] In some embodiments, R 3 are each independently H, F, Cl, Br, I, —CN, —CH, —CF, or OCH. 3 are each independently F, Cl, Br, I, —CN, —CH, —CF, or —OCH. 3 are each independently F, Cl, Br, I, or —CH. 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 I. In some embodiments, R 3 is -CN. In some embodiments, R 3 is independently substituted or unsubstituted -C1-C6 alkyl. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is —CF. In some embodiments, R 3 is a substituted or unsubstituted C1-C6 alkoxy. In some embodiments, R 3 is —OCH. In some embodiments, R 3 is H.

[0139] In some embodiments, R 7 are each independently selected from F, Cl, Br, I, or —CH. 7 is independently F. In some embodiments, R 7 is independently Cl. In some embodiments, R 7are 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. In some embodiments, R 7 is independently —CH. In some embodiments, R 7 is independently substituted or unsubstituted -C1-C6 alkoxy. In some embodiments, R 7 are independently -OCH3.

[0140] In some embodiments, R 8 are each independently selected from F, Cl, Br, I, or —CH. 8 is independently F. In some embodiments, R 8 is 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. In some embodiments, R 8 is -CH3. In some embodiments, R 8 is independently substituted or unsubstituted -C1-C6 alkoxy. In some embodiments, R 8 is -OCH3.

[0141] In some embodiments, R 9 is H. In some embodiments, R 9 is independently substituted or unsubstituted -C1-C4 alkyl. In some embodiments, R 9 is -CH3. In some embodiments, R 9 is a substituted or unsubstituted C1-C6 alkoxy. In some embodiments, R 9 is -OCH3.

[0142] In some embodiments, R 11 is H. In some embodiments, R 11 is -CH3. In some embodiments, R 11 is -CH2CH3.

[0143] In some embodiments, R 12 is H. In some embodiments, R 12 is -CH3. In some embodiments, R 12 is -CH2CH3.

[0144] In some embodiments, the compound of Formula (II) has the structure:

[0145] [ka] or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the compound of Formula (II) has the structure:

[0147] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0148] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0149] [ka] or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound of Formula (II) has the structure:

[0151] [ka] or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound of Formula (II) has the structure:

[0153] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0154] [ka] or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the compound of Formula (II) has the structure:

[0156] [ka] or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the compound of Formula (II) has the structure:

[0158] [ka] or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the compound of Formula (II) has the structure:

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

[0161] [ka] or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the compound of Formula (II) has the structure:

[0163] [ka] or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound of Formula (II) has the structure:

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

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

[0167] [ka] or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound of Formula (II) has the structure:

[0169] [ka] or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound of Formula (II) has the structure:

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

[0172] [ka] or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the compound of Formula (II) has the structure:

[0174] [ka] or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the compound of Formula (II) has the structure:

[0176] [ka] or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the compound of Formula (II) has the structure:

[0178] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0179] [ka] or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the compound of Formula (II) has the structure:

[0181] [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 3b , R 3c , and R 3d are each independently selected from the group consisting of 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 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, —CH 3 , —CF 3 , and —OCH 3 .

[0182] In some embodiments, the compound of Formula (II) has the structure:

[0183] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0184] [ka] or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the compound of Formula (II) has the structure:

[0186] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0187] [ka] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the compound of Formula (II) has the structure:

[0189] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0190] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0191] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0192] [ka] or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the compound of Formula (II) has the structure:

[0194] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0195] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

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

[0197] [ka] or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, R 3a is H, F, Cl, Br, I, —CN, —CH, —CF, or —OCH. 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 I. In some embodiments, R 3a is -CN. In some embodiments, R 3a is -CH3. In some embodiments, R 3a is —CF. In some embodiments, R 3a is —OCH. In some embodiments, R 3b is H, F, Cl, Br, I, —CN, —CH, —CF, or —OCH. 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 I. In some embodiments, R 3b is -CN. In some embodiments, R 3b is -CH3. In some embodiments, R 3b is —CF. In some embodiments, R 3b is —OCH. In some embodiments, R 3c is H, F, Cl, Br, I, —CN, —CH, —CF, or —OCH. In some embodiments, R3c 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 I. In some embodiments, R 3c is -CN. In some embodiments, R 3c is -CH3. In some embodiments, R 3c is —CF. In some embodiments, R 3c is —OCH. In some embodiments, R 3d is H, F, Cl, Br, I, —CN, —CH, —CF, or —OCH. In some embodiments, R 3d is H. In some embodiments, R 3d is F. In some embodiments, R 3d is Cl. In some embodiments, R 3d is Br. In some embodiments, R 3d is I. In some embodiments, R 3d is -CN. In some embodiments, R 3d is -CH3. In some embodiments, R 3d is —CF. In some embodiments, R 3d is —OCH. 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 3dis 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 is H.

[0199] In some embodiments, the compound of Formula (II) has the structure:

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

[0201] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0202] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

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

[0204] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0205] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

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

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

[0208] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0209] [ka] or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the compound of Formula (II) has the structure:

[0211] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

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

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

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

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

[0216] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

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

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

[0219] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has the structure:

[0220] [ka] or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, R 2 is —C(═O)NH or —CHNHC(═O)NH. In some embodiments, R 2 is —OH. In some embodiments, R 2 is -NH. In some embodiments, R 2 is —C(═O)NH. In some embodiments, R 2 is -CH2NHC(=O)NH2.

[0222] In some embodiments, R 4 is H. In some embodiments, R 4 is -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 is.

[0223] In some embodiments, R 10 is unsubstituted -C1-C6 alkyl or unsubstituted 2-6 membered heteroalkyl. In some embodiments, R 10 is -(CH2) t In some embodiments, R 10 is -(CH2) t In some embodiments, R 10 is -(CH2) t NHC(=O)(CH2) u In some embodiments, R 10 is -(CH2) t C(=O)O(CH2) uIn 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 In some embodiments, R 10 is -(CH2)2NHC(=O)(CH2)CH3.

[0224] 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 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, R 10 is —(CH 2 ) 4 NH 2 . In some embodiments, R 10 is —(CH)NHC(═O)CHCH. In some embodiments, R 10 is —CHC(═O)OCHCH. In some embodiments, R 10 is -(CH2)2C(=O)OCH2CH3.

[0225] In some embodiments, R 10 is -(CH2) t -substituted or unsubstituted 5-6 membered heteroaryl ring. In some embodiments, R 10is a -(CH2)-substituted or unsubstituted 5-6 membered heteroaryl ring. In some embodiments, the 5-6 membered heteroaryl ring is a pyrrolyl, thiophenyl, furanyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, or isothiazolyl ring optionally substituted with 1-2 substituents selected from C1-C4 alkyl or phenyl. In some embodiments, R 10 teeth

[0226] [ka] In some embodiments, R 10 teeth

[0227] [ka] In some embodiments, R 10 teeth

[0228] [ka] is.

[0229] 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 In some embodiments, R 10 is -(CH2) t C(=O)O(CH2) uIn 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 4 is -C(=O)NH(CH2)2NHC(=O)(CH2)CH3.

[0230] 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—(CH)NH. In some embodiments, R 4 is —C(═O)NH(CH)NHC(═O)CHCH. In some embodiments, R 4 is —C(═O)NH(CH)NHC(═O)CHCH. In some embodiments, R 4 is —C(═O)NHCHC(═O)OCHCH. In some embodiments, R 4 is -C(=O)NH(CH2)2C(=O)OCH2CH3.

[0231] In some embodiments, R 4 is -C(=O)(CH2) t In some embodiments, R 4 is —C(═O)CH2CH3. In some embodiments, R 4is -C(=O)NH(CH2) t 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) t 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.

[0232] In some embodiments, R 4 is —C(═O)NH—(CH)NH. In some embodiments, R 4 is -C(=O)NH(CH2) t NHC(=O)(CH2) u In some embodiments, R 4 is —C(═O)NH—(CH)NHC(═O)CHCH. In some embodiments, R 4 is —C(═O)NH(CH)NHC(═O)(CH)CH. In some embodiments, R 4 is -C(=O)(CH2) t C(=O)O(CH2) u In some embodiments, R 4 is -C(=O)NH(CH2) t C(=O)O(CH2) u In some embodiments, R 4 is —C(═O)NH—CHC(═O)OCHCH. In some embodiments, R 4 is -C(=O)NH(CH2)2C(=O)OCH2CH3.

[0233] In some embodiments, R 4 is -C(=O)NH-(CH2) t-substituted or unsubstituted 5-6 membered heteroaryl ring. In some embodiments, R 4 is -C(=O)NH-(CH2)-substituted or unsubstituted 5-6 membered heteroaryl ring. In some embodiments, the 5-6 membered heteroaryl ring is a pyrrolyl, thiophenyl, furanyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, or isothiazolyl ring optionally substituted with 1-2 substituents selected from C1-C4 alkyl or phenyl. In some embodiments, R 4 teeth,

[0234] [ka] In some embodiments, R 4 teeth,

[0235] [ka] In some embodiments, R 4 teeth,

[0236] [ka] is.

[0237] 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.

[0238] In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4.

[0239] In some embodiments, R A and R B If present, independently, 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 , cyclam, TETA, CB-Cyclam, 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 Selected from the group consisting of 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.

[0240] In some embodiments, R A and R Bare, when present, each 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-diacetanoic 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 Can (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 (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))-tetrakis(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-tetraoxo) 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-tetraazatetradecanedioic acid (TTHA), or a radionuclide complex thereof.

[0241] In some embodiments, R A and R B When present, each is independently selected from the group consisting of DOTA, DO3A, DO2A, DOTMA, DOTAM, DOTPA, H4pypa, H4py4pa, macropa, crown, H4octapa, and TTHA, or radionuclide complexes thereof.

[0242] 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. A is DOTMA or a radionuclide complex thereof. In some embodiments, R A is DOTAM or a radionuclide complex thereof. A is DOTPA or a radionuclide complex thereof. 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. A is H4py4pa or a radionuclide complex thereof. A is NOTA or a radionuclide complex thereof. In some embodiments, R A is a macropa or a radionuclide complex thereof. A is crown or a radionuclide complex thereof. A is H4octapa or a radionuclide complex thereof. Ais TTHA or its radionuclide complex.

[0243] 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. B is DOTMA or a radionuclide complex thereof. In some embodiments, R B is DOTAM or a radionuclide complex thereof. B is DOTPA or a radionuclide complex thereof. 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. B is H4py4pa or a radionuclide complex thereof. B is NOTA or a radionuclide complex thereof. In some embodiments, R B is a macropa or a radionuclide complex thereof. B is crown or a radionuclide complex thereof. B is H4octapa or a radionuclide complex thereof. B is TTHA or its radionuclide complex.

[0244] In some embodiments, R A and R B The chelating moieties of are independently selected from the group consisting of DOTA and DO3A, or radionuclide complexes thereof.

[0245] In some embodiments, R A and R BThe chelating moieties of

[0246] [ka] or radionuclide complexes thereof.

[0247] In some embodiments, R A teeth,

[0248] [ka] or a radionuclide complex thereof. In some embodiments, R A teeth,

[0249] [ka] or a radionuclide complex thereof. In some embodiments, R A teeth,

[0250] [ka] or a radionuclide complex thereof. In some embodiments, R A teeth,

[0251] [ka] or a radionuclide complex thereof. In some embodiments, R A teeth,

[0252] [ka] or a radionuclide complex thereof.

[0253] In some embodiments, R B teeth,

[0254] [ka] or a radionuclide complex thereof. In some embodiments, R B teeth,

[0255] [ka] or a radionuclide complex thereof. In some embodiments, R B teeth,

[0256] [ka] or a radionuclide complex thereof. In some embodiments, R B teeth,

[0257] [ka] or a radionuclide complex thereof. In some embodiments, R B teeth,

[0258] [ka] or a radionuclide complex thereof.

[0259] Radionuclide complexes Radiopharmaceuticals are becoming very useful tools for physicians to diagnose, stage, treat, and monitor 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 is used clinically as a diagnostic or therapeutic agent. Diagnostic radiopharmaceuticals require a radionuclide that emits either gamma (γ) rays or positrons (β+), which subsequently annihilate with a nearby electron to produce two 511 keV annihilation photons emitted approximately 180° apart from each other. Gamma-emitting radionuclides (e.g., 99m Tc, 111 In, 201Tl) are useful for single-photon emission computed tomography (SPECT), while positron-emitting radionuclides, e.g. 18 F, 89 Zr, 68 Ga) are useful for positron emission tomography (PET).

[0260] In contrast, therapeutic radiopharmaceuticals require radionuclides that emit particulate radiation, such as alpha (α) particles, beta (β) particles, or Auger electrons, which interact strongly with target tissue (e.g., cancerous tumors) resulting in widespread localized ionization, which can damage chemical bonds in DNA molecules and potentially induce cytotoxicity.

[0261] In most nuclear medicine applications, it is desirable to pair a diagnostic radiopharmaceutical with a therapeutic radiopharmaceutical. This concept is commonly known as "theranostics." As a first step in the theranostics concept, targeted molecules labeled with diagnostic radionuclides are used to perform quantitative imaging of tumor imaging biomarkers by either positron emission tomography (PET) or single-photon emission computed tomography (SPECT). As a second step, it has been demonstrated that tumor-destroying absorbed doses of radiation can be delivered to tumors and metastases by administering the same or similar targeted molecules labeled with therapeutic radionuclides.

[0262] In some embodiments, the chemical and pharmacokinetic behavior of diagnostic and therapeutic radiopharmaceuticals is matched. In some embodiments, the diagnostic and therapeutic radionuclides are chemically identical pairs of radioisotopes (also known as "matched pairs"). An example of a matched pair in theranostic radiopharmaceutical applications is 123 I / 131 I pair, in this case 123 I-labeled compounds are used in diagnostics, 131 I-labeled compounds are used in therapy. Other theranostic matching pairs, especially 44 Sc / 47 Sc,64 Cu / 67 Cu, 72 As / 77 As, 86 Y / 90 Y, and 203 Pb / 212 Alternatively, radionuclide pairs of different elements can be used for theranostic radiopharmaceutical development if their chemical properties are very similar (e.g., 99m Tc / 186 / 188 Re), there are no significant differences between diagnostic and therapeutic analogs in terms of pharmacokinetic behavior. Another example is 68 Ga / 177 Lu pair, in this case 68 Ga is used for diagnosis, 177 Lu is used in the treatment. For example, gastroenteropancreatic endocrine tumors express high amounts of sst2 receptors, which 68 Ga sst2 ligand conjugate ([ 68 Ga]Ga-DOTA-TATE (NETSPOT™) or [ 68 Diagnosis with ]Ga]Ga-DOTA-TOC (DOTA-(D-Phe1,Tyr3)-Octreotide, SomaKit TOC®) and subsequent internal radiotherapy 177 Lu sst2 ligand conjugate ([ 177 For purposes of treatment with [Lu]Lu-DOTA-TATE), somatostatin receptors can be targeted by somatostatin receptor scintigraphy.

[0263] Chelating moieties used in the formation of metal (radionuclide) complexes The compounds described herein comprise at least one R A or R B group, R A or R B is a chelating moiety capable of chelating a radionuclide (Z') or a radionuclide complex thereof. In some embodiments, NPY is chelating the radionuclide (Z') or a radionuclide complex thereof via an optional linker. 1 Any suitable group or atom of the chelator can be used to connect to the R targeting ligand.

[0264] In some embodiments, the chelator is capable of binding to the radioactive atom. In some embodiments, the binding is direct, e.g., the chelator undergoes hydrogen bonding or electrostatic interactions with the radioactive atom. In some embodiments, the binding is indirect, e.g., the chelator binds to a molecule that includes the radioactive atom. In some embodiments, the chelator is a macrocycle.

[0265] In some embodiments, the chelator comprises one or more amine groups. In some embodiments, the metal chelator comprises two or more amine groups. In some embodiments, the chelator comprises three or more amine groups. In some embodiments, the chelator comprises four or more amine groups. In some embodiments, the chelator comprises four or more N atoms, four or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelator does not contain S. In some embodiments, the chelator comprises a ring. In some embodiments, the ring comprises O and / or N atoms. In some embodiments, the chelator is a ring containing three or more N atoms, three or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelator is a multidentate, bidentate, or monodentate ligand. Multidentate ligands range in the number of atoms used to bind to the metal atom or ion. EDTA, a hexadentate ligand, is an example of a multidentate ligand, with six donor atoms with electron pairs available to bind to the central metal atom or ion. Bidentate ligands have two donor atoms that allow them to bond to a central metal atom or ion at two points. Ethylenediamine (en) and oxalate (ox) are examples of bidentate ligands.

[0266] In some embodiments, the chelating agents described herein comprise a cyclic chelating agent or an acyclic chelating agent. In some embodiments, the chelating agents described herein comprise a cyclic chelating agent. In some embodiments, the chelating agents described herein comprise an acyclic chelating agent.

[0267] In some embodiments, the chelating agents described herein include cyclen, 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 , cyclam, TETA, CB-Cyclam, 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 Including 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.

[0268] In some embodiments, the chelating agents described herein include DOTA, DOTAGA, DOTA(GA), 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.

[0269] In some embodiments, the chelating agents described herein include DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, or BOPA.

[0270] In some embodiments, the chelating agents described herein include DOTA, PSC, DOTAGA, DOTA(GA)2, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB-TE2A, DOTA-4AMP, or NOTP.

[0271] In some embodiments, the chelating agents described herein include DOTA, DOTAGA, DOTA(GA)2, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB-TE2A, DOTA-4AMP, or NOTP.

[0272] In some embodiments, the chelating agents described herein are 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.

[0273] In some embodiments, the chelating agent described herein is selected from the group consisting of 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.

[0274] In some embodiments, the chelators described herein are or include DOTA, HBED-CC, DOTAGA, DOTA(GA)2, NOTA, and DOTAM. In some embodiments, the chelators described herein are or include NODAGA, NOTA, DOTAGA, DOTA(GA)2, TRAP, NOPO, NCTA, DFO, DTPA, and HYNIC.

[0275] In some embodiments, the chelator comprises a macrocycle, e.g., a macrocycle containing 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 desferrioxane.

[0276] In some embodiments, the metal chelators described herein have the structure:

[0277] [ka]

[0278] [ka]

[0279] [ka]

[0280] [ka]

[0281] [ka]

[0282] [ka]

[0283] [ka]

[0284] [ka]

[0285] [ka] Contains one of the following.

[0286] In some embodiments, R A and R B When present, each independently comprises a radionuclide and DOTA. A and R B When present, each independently comprises a radionuclide and a DOTA derivative. A and R B When present, each independently comprises a chelating agent, and at least one or both is DOTA.

[0287] In some embodiments, the chelating moiety comprises a radionuclide and a chelator configured to bind to the radionuclide (Z'), and the chelator comprises DOTA, DOTP, DOTMA, DOTAM, DTPA, NOTA, NTA, NODAGA, EDTA, DO3A, DO2A, NOC, TETA, CB-TE2A, DiAmSar, CB-Cyclam, DOTA-4AMP, H4pypa, H4octox, H4octapa, p-NO2-Bn-neunpa, or NOTP.

[0288] In some embodiments, the metal chelators described herein include macropa or crown. In some embodiments, the metal chelators described herein include macropa. In some embodiments, the metal chelators described herein include crown. In some embodiments, the metal chelators described herein include

[0289] [ka] In some embodiments, the metal chelators described herein include

[0290] [ka] Includes:

[0291] In some embodiments, R A and R Bare, when present, each independently 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-diacetanoic 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 (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))-tetrakis(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-tetraazatetradecanedioic acid (TTHA), or radionuclide complexes thereof.

[0292] In some embodiments, R A and R B When present, each is independently selected from the group consisting of DOTA and DO3A, or radionuclide complexes thereof.

[0293] In some embodiments, R A and R B are, if present, each independently

[0294] [ka] or radionuclide complexes thereof.

[0295] In some embodiments, R A and R B are, if present, each independently

[0296] [ka] or radionuclide complexes thereof.

[0297] In some embodiments, R A or R B teeth,

[0298] [ka] or a radionuclide complex thereof.

[0299] In some embodiments, R A or R B teeth,

[0300] [ka] or a radionuclide complex thereof.

[0301] In some embodiments, R A or R B teeth,

[0302] [ka] or a radionuclide complex thereof. In some embodiments, R A or R B teeth,

[0303] [ka] or a radionuclide complex thereof. In some embodiments, R A or R B teeth,

[0304] [ka] or a radionuclide complex thereof. In some embodiments, R A or R B teeth,

[0305] [ka] or a radionuclide complex thereof.

[0306] In some embodiments, R A or R B teeth,

[0307] [ka] or a radionuclide complex thereof. In some embodiments, R A or R B teeth,

[0308] [ka] or a radionuclide complex thereof.

[0309] In some embodiments, R A or R B teeth,

[0310] [ka] where Z' is a diagnostic or therapeutic radionuclide.

[0311] In some embodiments, R A or R B teeth,

[0312] [ka] where Z' is a diagnostic or therapeutic radionuclide.

[0313] In some embodiments, Z' is an Auger electron-emitting radionuclide, an α-emitting radionuclide, a β-emitting radionuclide, or a γ-emitting radionuclide. In some embodiments, Z' 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 Auger electron emitting radionuclide that is 225-actinium (Pt). 225 Ac), 213-Bismuth ( 213 Bi), 223-radium ( 223 Ra), or 212-lead ( 212 In some embodiments, Z' is an α-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-Kin ( 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 β-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) is a gamma-emitting radionuclide.

[0314] In some embodiments, R 6 comprises a radionuclide (Z') and a chelator configured to bind to 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).

[0315] Metals (radionuclides) In some embodiments, Z' is an Auger electron-emitting radionuclide. In some embodiments, Z' is an α-emitting radionuclide. In some embodiments, Z' is a β-emitting radionuclide. In some embodiments, Z' is a γ-emitting radionuclide. In some embodiments, the type of radionuclide used in a non-peptide targeted therapy compound can be tailored to the specific type of cancer, the type of targeting moiety (e.g., a non-peptide ligand), etc. A radionuclide undergoing α decay releases an α particle (a helium ion with a +2 charge) from its nucleus. As a result of α decay, the daughter nuclide has two fewer protons and two fewer neutrons than the parent nuclide. This means that the number of protons is reduced by two and the number of neutrons is reduced by four in α decay. A radionuclide undergoing β decay releases a β particle (an electron) from its nucleus. During β decay, one of the neutrons is transformed into a proton and an electron. The proton remains in the nucleus, while the electron is released as the β 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 changes to a lower energy state by emitting a gamma ray. The number of protons and neutrons remains the same during gamma decay. The emission of a gamma ray is often accompanied by the emission of an alpha particle and a beta particle.

[0316] Auger electrons (AE) are very low energy electrons emitted by radionuclides that decay by electron capture (EC) (e.g., 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I, and 123 I). This energy is deposited over distances of nanometers to micrometers, resulting in a high linear energy transfer that is effective in causing lethal damage to cancer cells. Therefore, AE-emitting radiotherapeutic agents have great potential for cancer treatment.

[0317] Beta particles are electrons emitted from the nucleus. These typically have a long range in tissue (about 1-5 mm) and are the most frequently used.

[0318] Alpha particles are helium nuclei (two protons and two neutrons) emitted from the nuclei of radioactive atoms. They can travel 50–100 μm in tissue, depending on the energy emitted. They are positively charged and orders of magnitude greater than electrons. The amount of energy deposited per path length of an alpha particle (termed "linear energy transfer") is approximately 400 times greater than that of an electron. This results in substantially more damage along the path than that caused by an electron. The trajectory of an alpha particle results in a large number of complex and largely irreparable DNA double-strand breaks. The absorbed dose required to achieve cytotoxicity is related to the number of alpha particles traversing the cell nucleus. On this basis, cytotoxicity can be achieved with 1–20 alpha particles traversing the cell nucleus. The resulting high potency, combined with the short range of alpha particles (which reduces normal organ toxicity), has generated significant interest in the development of alpha particle-emitting drugs. Typically used alpha particle emitters include bismuth-212, lead-212, bismuth-213, actinium-225, radium-223, and thorium-227.

[0319] In some embodiments, Z' is a diagnostic or therapeutic radionuclide.

[0320] [Table 1]

[0321] In some embodiments, Z' is an Auger electron emitting radionuclide. In some embodiments, Z' is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc), or 195m-Platinum ( 195m Pt) is an Auger electron-emitting radionuclide.

[0322] In some embodiments, Z' is an α-emitting radionuclide. In some embodiments, Z' is 225-actinium ( 225Ac), 213-Bismuth ( 213 Bi), 223-radium ( 223 Ra), or 212-lead ( 212 Pb) is an α-emitting radionuclide.

[0323] In some embodiments, Z' is a β-emitting radionuclide. In some embodiments, Z' 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-Kin ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-Technetium ( 99m Tc), 89-zirconium ( 89 Zr), or 52-manganese ( 52 Mn) is a β-emitting radionuclide.

[0324] In some embodiments, Z' is a γ-emitting radionuclide. In some embodiments, Z' 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) is a gamma-emitting radionuclide.

[0325] In some embodiments, Z' is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc), or 195m-Platinum ( 195mZ' is an Auger electron emitting radionuclide that is 225-actinium (Pt) or Z' is 225-actinium ( 225 Ac), 213-Bismuth ( 213 Bi), 223-radium ( 223 Ra), or 212-lead ( 212 Pb), or Z' 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-Kin ( 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 β-emitting radionuclide, 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) is a gamma-emitting radionuclide.

[0326] 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-Kin ( 198 Au), 169-Erbium (169 Er), 165-dysprosium ( 165 Dy), or technetium-99m ( 99m Tc).

[0327] 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.

[0328] 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, 161Tb, 149 Pm, 44 Sc, 47 Sc, 70 As, 71 As, 72 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.

[0329] In some embodiments, Z' is 68 Ga, 43 Sc, 44 Sc, 47 Sc, 177 Lu, 161 Tb, 225 Ac, 213 Bi, 212 Bi, or 212 In some embodiments, Z' is 67 Ga, 99m Tc, 111 In, or 201 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, Z' is 44Sc, 64 Cu, 68 Ga, 86 Y, or 89 In some embodiments, Z′ is 67 Ga, 99m Tc, 111 In, or 177 This is Lu.

[0330] In some embodiments, Z' is 67 Cu, 90 Y, 111 In, 177 Lu, 225 Ac, 212 Pb, or 213 I'm Bi.

[0331] 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).

[0332] In some embodiments, Z' is 111-indium ( 111 In some embodiments, Z' is 115-indium ( 115 In some embodiments, Z' is 67-gallium ( 67 In some embodiments, Z' is 68-gallium ( 68 In some embodiments, Z' is 69-gallium ( 69 Ga), 71-gallium ( 71 Ga), or a mixture thereof. In some embodiments, Z' is 225-actinium ( 225 In some embodiments, Z' is 175-lutetium ( 175In 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 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).

[0333] 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).

[0334] Exemplary Chelators and Radionuclide Complexes Radionuclides are used in 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) as well as for other diagnostic imaging techniques, as well as for therapeutic applications (e.g. 47 Sc, 114 mIn, 177 Lu, 90 Y, 212 / 213 Bi, 212 Pb,225 Ac, 186 / 188 They have useful release properties that allow them to be used for radiometals (Re). The fundamental component of radiometal-based radiopharmaceuticals is a chelator, i.e., a ligand system that binds to the radiometal ion in a tight and stable coordination complex so that it can be appropriately directed to the desired molecular target in vivo. Guidance for selecting the optimal match between chelator and radiometal for a particular application is provided in the art (see, for example, Price et al., "Matching chelators to radiometals for radiopharmaceuticals," Chem. Soc. Rev., 2014, 43, pp. 260-290).

[0335] In some embodiments, R A and R B When present, each is independently 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.

[0336] In some embodiments, R A or R B teeth,

[0337] [ka] where Z' is a diagnostic or therapeutic radionuclide.

[0338] 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') is44 Sc, 64 Cu, 68 Ga, 86 Y, or 89 In some embodiments, the radionuclide (Z') is 67 Ga, 99m Tc, 111 In, or 177 This is Lu.

[0339] In some embodiments, the radionuclide (Z') is 67 Cu, 90 Y, 111 In, 177 Lu, 225 Ac, 212 Pb, or 213 I'm Bi.

[0340] 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 ( 70 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), 177-lutetium ( 177 Lu), 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).

[0341] In some embodiments, the radionuclide (Z') is 111-indium ( 111 In some embodiments, the radionuclide (Z') is 115-indium ( 115 In some embodiments, the radionuclide (Z') is 67-gallium ( 67 In some embodiments, Z' is 68-gallium (68 In some embodiments, the radionuclide (Z') is 69-gallium ( 69 Ga), 71-gallium ( 71 In some embodiments, the radionuclide (Z') is 225-actinium ( 225 In some embodiments, the radionuclide (Z') is 175-lutetium ( 175 In 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 a mixture thereof. In some embodiments, the radionuclide (Z') is 212-lead ( 212 In some embodiments, the radionuclide (Z') is 64-copper ( 64 In some embodiments, the radionuclide (Z') is 63-copper ( 63 Cu), 65-copper ( 65 In some embodiments, the radionuclide (Z') is 67-copper ( 67 Cu).

[0342] 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).

[0343] In some embodiments, the radionuclide (Z') is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186Re), 188-rhenium ( 188 Re), 67-Copper( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Kin ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), or technetium-99m ( 99m Tc).

[0344] Emission tomography In some embodiments, R A or R B comprises a chelated radionuclide suitable for positron emission tomography (PET) analysis or single photon emission computed tomography (SPECT). A or R B comprises a chelated radionuclide suitable for single photon emission computed tomography (SPECT). A or R B comprises a chelated radionuclide suitable for positron emission tomography (PET) analysis. In some embodiments, R A or R B comprises a chelated radionuclide suitable for positron emission tomography imaging, positron emission tomography including computed tomography imaging, or positron emission tomography including magnetic resonance imaging (MRI).

[0345] 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 radionuclide complexes thereof. In some embodiments, the radionuclide is copper-64( 64 Cu), Gallium-68( 68 Ga), or technetium-99m (99m Tc).

[0346] In some embodiments, the conjugates described herein are designed to have a defined elimination profile. The elimination profile can be designed by adjusting the sequence and length of the non-peptide ligand, the properties 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, or 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 determined in mice. In some embodiments, the elimination half-life is determined in humans.

[0347] The conjugates described herein can have an elimination half-life in tumor and non-tumor tissues of a subject. The elimination half-life in a tumor can be the same as or different from (longer or shorter than) the elimination half-life in a 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 times, at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2.0 times, at least 2.5 times, at least 3.0 times, at least 4.0 times, or at least 5.0 times the elimination half-life of the conjugate in a non-tumor tissue of the subject.

[0348] As used herein, "elimination half-life" may refer to the time from maximum concentration to half maximum concentration after administration. In some embodiments, the elimination half-life is determined after intravenous administration. In some embodiments, the elimination half-life is measured as the biological half-life, which is the half-life of the pharmaceutical in a biological 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 biological system taking into account the half-life of the radionuclide.

[0349] Prediction of response and toxicity is essential for the rational implementation of cancer treatment. The biological effects of radionuclide therapy are mediated by a well-defined physical quantity, the absorbed dose (D), defined as the energy absorbed per unit mass of tissue.

[0350] Radiation dosimetry is the measurement, calculation, and assessment of the amount of ionizing radiation absorbed by an object, usually the human body, and may also be thought of as the ability to perform real-time equivalent pharmacodynamic testing on treated patients. This can be applied internally due to inhaled radioactive material or externally due to radiation from a radioactive source. Dosimetry analysis may be performed as part of a patient treatment to calculate the absorbed dose to tumor versus normal organs, and from there, the likelihood of treatment success.

[0351] The conjugates described herein have a time-integrated activity coefficient defined for tumor or non-tumor tissue of interest.

[0352] [ka] The a value of (a) can be determined using methods known in the art. In some embodiments, the a value of the conjugate in the tumor is from about 10 minutes to about 1 day. The a value of the conjugate in the tumor can be the same as the a value of the conjugate in the non-tumor tissue of the subject. The a value of the conjugate in the tumor can be longer or shorter than the a value of the conjugate in the non-tumor tissue of the subject. In some embodiments, the a value of the conjugate in the tumor is at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2.0-fold, at least 2.5-fold, at least 3.0-fold, at least 4.0-fold, or at least 5.0-fold the a value of the conjugate in the non-tumor tissue of the subject.

[0353] The conjugates described herein can have an a value in an organ of a subject. In some embodiments, the conjugate has an a value of up to 24 hours in the kidney of a subject. In some embodiments, the a value of the conjugate in the kidney of a subject is up to 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the a value of the conjugate in the kidney of a subject is from about 30 minutes to about 24 hours. In some embodiments, the a value of the conjugate in the kidney of a subject is from about 2 to 24 hours. In some embodiments, the a value of the conjugate in the kidney of a subject is longer than about 24 hours. In some embodiments, the a value of the conjugate in the liver of a subject is up to 24 hours. In some embodiments, the a value of the conjugate in the liver of a subject is up to 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the a value of the conjugate in the liver of a subject is from about 30 minutes to about 24 hours. In some embodiments, the a value of the conjugate in the liver of a subject is from about 2 to 24 hours. In some embodiments, the a value of the conjugate in the liver of the subject is greater than about 24 hours.

[0354] Linker In some embodiments, the linker has a defined length, thereby providing a link between the neuropeptide Y1 receptor (NPY1R) targeting ligand and the chelating moiety or its radionuclide complex (R A or R B ) while allowing for an appropriate distance between them.

[0355] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0356] In some embodiments, the linker comprises a linear structure. In some embodiments, the linker comprises a non-linear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure.

[0357] 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.

[0358] 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 unnatural amino acids.

[0359] In some instances, the linker comprises a peptide bond. The peptide bond may comprise an L-amino acid and / or a D-amino acid. In some embodiments, D-amino acids are preferred to minimize immune and non-specific cleavage by background peptidases or proteases. The cellular uptake of oligo-D-arginine sequences is known to be equal to or better than that of oligo-L-arginine.

[0360] In some embodiments, the linker is 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 length. In some embodiments, the linker is 1 to 10 atoms in length. In some embodiments, the linker is 1 to 20 atoms in length.

[0361] In some embodiments, a linker can 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, etc. Exemplary rigid linker regions include those comprising alpha-helix-forming sequences, proline-rich sequences, and regions rich in double and / or triple bonds.

[0362] In some embodiments, the cleavable linker comprises one or more of substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene.

[0363] In some embodiments, the linker comprises a click chemistry residue. In some embodiments, the linker is coupled to the non-peptide ligand, the metal chelator, or both via click chemistry. For example, in some embodiments, the non-peptide ligand comprises an azide group that reacts with an alkyne moiety of the linker. For another example, in some embodiments, the non-peptide ligand comprises an alkyne group that reacts with the azide of the linker. The metal chelator and the linker can be coupled in a similar manner. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole moiety.

[0364] In some embodiments, L A and L B independently, -L 2 -, -L 3 -, -L 4 -, -L5 -, -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 -, or a combination thereof; L 2 is absent or is a substituted or unsubstituted -C1-C 20 Alkylene, substituted or unsubstituted -C1-C20 Alkylene-NR 16 -, substituted or unsubstituted -C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted -C-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 - and R 16 are each 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 3is a peptide formed from a non-existent, natural or unnatural amino acid, or two or more independently selected natural and unnatural amino acids, where, when two or more amino acids are present, the N atom of the amide linking the amino acids is optionally substituted with -C1-C6 alkyl; and L 4 is absent or a 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 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) sCH3; and R 17 is H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18 are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18a are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18b are each independently H, -C1-C6 alkyl, -C(=O)(CH2) x -4-iodophenyl, -C(=O)(CH2) x -4-methylphenyl, or a sugar alcohol or a derivative thereof, each x is independently 1, 2, 3, or 4, each v is independently an integer of 1 to 40, each s is independently an integer of 1 to 20, and L 5 is absent or -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 - and R 13 are each independently selected from H or -C1-C4 alkyl; L 6 does not exist or -L 8 -L 9 -L 10 - and L 8 does not exist or -(CH2) r -, -NR 14 -, -NR 14 -(CH2) r -, -(CH2) r -C(=O)-, -C(=O)-(CH2) r -, -(CH2) r -NR 14 -, -(CH2) r -NR14 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 and r is 0, 1, 2, or 3; and L 9 is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, a monosaccharide, or

[0365] [ka] where k is 1, 2, 3, or 4, and L 10 does not exist or -(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, and R 14 and R 15are each independently 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.

[0366] In some embodiments, L A and L B independently, -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 or is a 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 -C-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 - and R 16are each 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 peptide formed from a non-existent, natural or unnatural amino acid, or two or more independently selected natural and unnatural amino acids, where, when two or more amino acids are present, the N atom of the amide linking the amino acids is optionally substituted with -C1-C6 alkyl; and L 4 is absent or a 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 , or, independently - 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; and R 17 is H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18are each independently H, -C1-C6 alkyl, or a sugar alcohol or a derivative thereof; each v is independently an integer of 1 to 40; each s is independently an integer of 1 to 20; L 5 is absent or -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 - and R 13 are each independently selected from H and -C1-C4 alkyl; L 6 does not exist or -L 8 -L 9 -L 10 - and L 8 does not exist or -(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 and r is 0, 1, 2, or 3; and L 10 does not exist or -(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, and R 14 and R 15 are each independently 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 9 is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, a monosaccharide, or

[0367] [ka] where 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.

[0368] In some embodiments, L A and L B independently, -L2 -,-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 [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​is a 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-, and R 16 are each 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 linking the amino acids is optionally substituted with -C1-C6 alkyl; and 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, independently -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; and R 17 are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18 are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18a are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18b are each independently H, -C1-C6 alkyl, -C(=O)CH2CH2CH2-4-iodophenyl, or a sugar alcohol or a derivative thereof, v is an integer of 1 to 40, s is an integer of 1 to 20, and L 5 is -NR 13 C(=O) and R 13 is H or -C1-C4 alkyl, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist or -(CH2) r - or -(CH2) r -C(=O)NR 14 and r is 0, 1, 2, or 3; and L 9 is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, a monosaccharide, or

[0369] [ka] where k is 1, 2, 3, or 4, and L 10 is -(CH2) q-, -NR 15 -(CH2) q -, or -NR 15 -(CH2) q -NR 15 -, q is 0, 1, 2, 3, 4, 5, or 6, and R 14 and R 15 are each independently selected from H or —C1-C6 alkyl-C(═O)OH; L 7 is -NH- or a natural or unnatural amino acid,

[0370] In some embodiments, L A and L B independently, -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 a substituted or unsubstituted -C1-C 20Alkylene-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-, and R 16 are each 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 linking the amino acids is optionally substituted with -C1-C6 alkyl; and L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2, -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 , or, independently - 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; and R 17are each independently H, -C1-C6 alkyl, or a sugar alcohol or derivative thereof, and R 18 are each independently H, -C1-C6 alkyl, or a sugar alcohol or a derivative thereof, v is an integer of 1 to 40, s is an integer of 1 to 20, and L 5 is -NR 13 C(=O) and R 13 is H or -C1-C4 alkyl, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist or -(CH2) r - or -(CH2) r -C(=O)NR 14 and r is 0, 1, 2, or 3; and L 10 is -(CH2) q -, -NR 15 -(CH2) q -, or -NR 15 -(CH2) q -NR 15 -, q is 0, 1, 2, or 3, and R 14 and R 15 are each independently selected from H or —C1-C6 alkyl-C(═O)OH; L 9 is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, a monosaccharide, or

[0371] [ka] where k is 1, 2, 3, or 4, and L 7 is -NH- or a natural or unnatural amino acid,

[0372] In some embodiments, L A -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 -It is.

[0373] In some embodiments, L A -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 A -L 2 -L 3 In some embodiments, L A -L 2 -L 6 In some embodiments, L A -L 2 -L 7In some embodiments, L A -L 2 -L 3 -L 7 In some embodiments, L is -L 2 -L 4 -L 7 In some embodiments, L A -L 2 -L 6 -L 7 In some embodiments, L A -L 2 -L 3 -L 4 -L 7 In some embodiments, L A -L 2 -L 4 -L 5 -L 7 In some embodiments, L A -L 4 -L 5 -L 6 -L 7 In some embodiments, L A -L 2 -L 4 -L 5 -L 6 -L 7 -It is.

[0374] In some embodiments, L B -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 -L5 -L 7 -, -L 4 -L 5 -L 6 -L 7 -, or -L 2 -L 4 -L 5 -L 6 -L 7 -It is.

[0375] In some embodiments, L B -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 -L 2 -L 3 In some embodiments, L B -L 2 -L 6 In some embodiments, L B -L 2 -L 7 In some embodiments, L B -L 2 -L 3 -L 7 In some embodiments, L B -L 2 -L 4 -L 7 In some embodiments, L B -L 2 -L 6 -L 7 In some embodiments, L B -L2 -L 3 -L 4 -L 7 In some embodiments, L B -L 2 -L 4 -L 5 -L 7 In some embodiments, L B -L 4 -L 5 -L 6 -L 7 In some embodiments, L B -L 2 -L 4 -L 5 -L 6 -L 7 -It is.

[0376] In some embodiments, L 2 In some embodiments, L 2 is a substituted or unsubstituted -C1-C 20 Alkylene-NH-, substituted or unsubstituted -C1-C 20 Alkylene-NHC(=O)-, substituted or unsubstituted -C-C 20 Alkylene-NR 16 C(=O)NR 16 NH- or substituted or unsubstituted -C1-C 20 In some embodiments, L is alkylene -NHC(=O)CHNH-. 2 is a substituted or unsubstituted -C1-C 20 In some embodiments, L is alkylene-NH-. 2 is a substituted or unsubstituted -C1-C 20 In some embodiments, L is alkylene-NHC(=O)-. 2 is a substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)NR 16 In some embodiments, L 2 is a substituted or unsubstituted -C1-C 20 In some embodiments, L is alkylene -NHC(=O)CHNH-. 2is -(CH2CH2O) z In some embodiments, L 2 is -(CH2CH2O) w -CH2CH2-.

[0377] In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0378] In some embodiments, L 3 In some embodiments, L 3 is a natural amino acid, an unnatural amino acid, or alanine (Ala), 3-(2-naphthyl)-alanine (2-Nal), arginine (Arg), asparagine (Asn), aspartate (Asp), cysteine ​​(Cys), cysteic acid, glutamine (Gln), glutamate (Glu), gamma-carboxyglutamate (Gla), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), hydroxylysine (Hyl), ornithine (Orn), methionine (Met), phenylalanine (Phe), p- A peptide formed from two or more independently selected amino acids selected from the group consisting of 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 linking the amino acids is optionally substituted with -CH3. In some embodiments, L 3is a peptide formed from natural amino acids, unnatural amino acids, or two or more independently selected amino acids selected from the group consisting of alanine (Ala), arginine (Arg), asparagine (Asn), aspartate (Asp), cysteine ​​(Cys), cysteic acid, glutamine (Gln), glutamate (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 linking the amino acids is optionally substituted with —CH3. In some embodiments, the peptide is formed from one or more independently selected L-amino acids. In some embodiments, the peptide is formed from one or more independently selected D-amino acids. In some embodiments, the peptide is formed from one or more independently selected L-amino acids and one or more independently selected D-amino acids.

[0379] In some embodiments, L 3 is a naturally occurring amino acid. 3 is lysine. In some embodiments, L 3 is glutamic acid. 3 is glutamine. 3 is asparagine. In some embodiments, L 3 is serine. In some embodiments, L 3 is an unnatural amino acid. 3 is Bip. In some embodiments, L 3 is cysteic acid. 3 is NAL. In some embodiments, L 3 is ornithine. In some embodiments, L 3 is a dipeptide. In some embodiments, L 3 is Arg-Bip. In some embodiments, L 3is Lys-Bip.

[0380] In some embodiments, L 4 In some embodiments, L 4 is —C(═O)CH2CH2. In some embodiments, L 4 is -(CH2CH2O) v In some embodiments, v is 1 or 2. In some embodiments, L 4 is -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 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 independently -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 In some embodiments, L is -C1-C6 alkylene optionally substituted with 1 or 2 groups selected from CH3. 4 is one -NR 18 C(=O)CH2CH2CH(COOH)NR 18 C(=O)-(CH2) s is -C1-C6 alkylene optionally substituted with CH3.

[0381] In some embodiments, L 4 is -(CH2) v -NR 17 -(CH2)v In some embodiments, L 4 is —(CH)—N(CH)—(CH)—. In some embodiments, L 4 is —(CH)—N(CH)—(CH)—. 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 is -NHC(=O)CH2-O-NH-C(=O)(CH2) v In some embodiments, L 4 is an unsubstituted -C1-C6 alkylene. In some embodiments, L 4 independently -OR 18 or -NR 18a R 18b In some embodiments, L is -C1-C6 alkylene optionally substituted with one or two groups selected from 4 , 1 or 2 -NR 18a R 18b In some embodiments, R 18a is H and R 18b is H or —CH. In some embodiments, L 4 is -C1-C6 alkylene substituted with one -NH2. In some embodiments, L 4 is -C1-C6 alkylene substituted with one -NHC(=O)CH2CH2CH2-4-iodophenyl.

[0382] 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 is sorbitol or a derivative thereof.

[0383] In some embodiments, L 5 In some embodiments, L 5 is -C(=O)NR 13 -or-NR 13 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 is -NHC(=O)-.

[0384] In some embodiments, L 6 In some embodiments, L 6 -L 8 -L 9 -L 10 -That is.

[0385] In some embodiments, L 8 In some embodiments, L 8 is -(CH2) r In some embodiments, L 8 is -(CH2) r -C(=O)NR 14 In some embodiments, R 14 is —CH 2 CO 2 H. In some embodiments, r is 1 or 2.

[0386] In some embodiments, L 10 In some embodiments, L 10 is -(CH2) q In some embodiments, L 10 is -NR 15 -(CH2) q In some embodiments, L 10 is -NR 15 -(CH2) q -NR 15 In some embodiments, R 15is H. In some embodiments, q is 1 or 2. In some embodiments, L 10 is —(CH)—. In some embodiments, L 10 is -C(=O)NR 15 -(CH2) q -It is.

[0387] In some embodiments, L 9 is a substituted or unsubstituted heterocycloalkylene. 9 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 9 is a substituted or unsubstituted 4-6 membered heterocycloalkyl. In some embodiments, L 9 is azetidinylene, pyrrolidinylene, piperidinylene, or piperazinylene. 9 is a monosaccharide. 9 teeth,

[0388] [ka] In some embodiments, L 9 is a substituted or unsubstituted cycloalkylene. 9 is a substituted or unsubstituted C4-C8 cycloalkylene. 9 teeth,

[0389] [ka] In some embodiments, L 9 is a substituted or unsubstituted arylene. 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. 9 teeth,

[0390] [ka] In some embodiments, L 9 teeth,

[0391] [ka] and k is 1. In some embodiments, L 9 teeth,

[0392] [ka] and k is 2. In some embodiments, L 9 teeth,

[0393] [ka] and k is 3. In some embodiments, L 9 teeth,

[0394] [ka] and k is 4.

[0395] In some embodiments, L 7 In some embodiments, L 7 In some embodiments, L 7 is a natural or unnatural amino acid. 7 is 3-aminoalanine. In some embodiments, L 7 is lysine.

[0396] 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.

[0397] 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.

[0398] In some embodiments, v is 0, 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.

[0399] In some embodiments, s is 0, 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.

[0400] In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3.

[0401] 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.

[0402] In some embodiments, L A -L 2 -L 3 - and 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 or a natural or unnatural peptide, wherein the N atom of the amide linked to the amino acid is optionally substituted with -CH3. In some embodiments, the natural or unnatural 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 linked to the amino acid is optionally substituted with -CH3. In some embodiments, the dipeptide is Arg-BiP. In some embodiments, L A -L 2 -L 3 - and 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.

[0403] In some embodiments, L A -L 2 -L 6 - and L 2 is an unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 -It is.

[0404] In some embodiments, L A -L 2 -L 7 - and L 2 is -(CH2CH2O) w -CH2CH2-, and L 7 is -NH-,

[0405] In some embodiments, L A -L 2 -L 3 -L 7 - and L 2is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a natural or unnatural amino acid, and L 7 is a natural or unnatural amino acid.

[0406] In some embodiments, L A -L 2 -L 4 -L 7 - and L 2 is an unsubstituted C1-C6 alkylene-C(=O)NCH3-, an unsubstituted -C1-C6 alkylene-NHC(=O)-, an unsubstituted -C1-C6 alkylene-NHC(=O)NHNH-, or one -NR 18a R 18b and L is -C1-C6 alkylene optionally substituted with 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; L 7 is —NH— or —O—NH. In some embodiments, L A -L 2 -L 4 -L 7 - and L 2 is an unsubstituted —C1-C6 alkylene-NHC(═O)— or an unsubstituted —C1-C6 alkylene-NHC(═O)NHNH—, and L 4 is -(CH2CH2O) v -CH2CH2-, -C(=O)CH2CH2, or optionally substituted -C1-C6 alkylene; L 7 is -NH-,

[0407] In some embodiments, L A -L 2 -L 6 -L 7 - and L 2 is an unsubstituted —C1-C6 alkylene, an unsubstituted —C1-C6 alkylene-NH—, or an unsubstituted —C1-C6 alkylene-NHC(═O)—, and L 6 -L 8 -L 9 -L 10 - and L 7 is -NH-, -O-NH-, or a natural or unnatural amino acid. A -L 2 -L 6 -L 7 - and L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 is -NH- or a natural or unnatural amino acid.

[0408] In some embodiments, L A -L 2 -L 3 -L 4 -L 7 - and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a peptide formed from glutamine or two or more glycines, where the N atom of the amide linking the amino acid is replaced by -CH3 and L 4 is -C(=O)CH2CH2- or -(CH2) v -NR 17 -(CH2) v and L 7 In some embodiments, L A -L 2 -L 3 -L 4 -L 7 - and L 2is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a peptide formed from two or more glycines, where the N atom of the amide linking the amino acid is replaced with -CH3, and L 4 is -C(=O)CH2CH2-, and L 7 is -NH-.

[0409] In some embodiments, L A -L 2 -L 4 -L 5 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is one -NR 18a18b and L is -C1-C6 alkylene optionally substituted with 5 is -NH-, and L 7 is a natural or unnatural amino acid.

[0410] In some embodiments, L A -L 4 -L 5 -L 6 -L 7 - and L 4 is -(CH2CH2O) v -CH2CH2-, and L 5 is -NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 is -NH-.

[0411] In some embodiments, L A L 2 -L 4 -L 5 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is one -NR 18a18band L is -C1-C6 alkylene- optionally substituted with 5 is -NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 is -NH-.

[0412] In some embodiments, -L A -R A -L 2 -L 3 -R A and 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.

[0413] In some embodiments, -L A -R A -L 2 -L 6 -R A and L 2 is an unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 -It is.

[0414] In some embodiments, -L A -R A -L 2 -L 7 -R A and L 2 is -(CH2CH2O) w -CH2CH2-, and L 7 is -NH-.

[0415] In some embodiments, L A -R A -L 2 -L 3 -L7 -R A and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 3 is Bip and L 7 is (R)-2,3-diaminopropanoic acid.

[0416] In some embodiments, L A -R A -L 2 -L 4 -L 7 -R A and L 2 is an unsubstituted C1-C6 alkylene-C(=O)NCH3-, an unsubstituted -C1-C6 alkylene-NHC(=O)-, an unsubstituted -C1-C6 alkylene-NHC(=O)NHNH-, or one -NR 18a R 18b and L is -C1-C6 alkylene optionally substituted with 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; L 7 is -NH- or -O-NH. In some embodiments, -L A -R A -L 2 -L 4 -L 7 -R A and L 2 is an unsubstituted —C1-C6 alkylene-NHC(═O)— or an unsubstituted —C1-C6 alkylene-NHC(═O)NHNH—, and L 4 is -(CH2CH2O) v-CH2CH2-, -C(=O)CH2CH2, or optionally substituted -C1-C6 alkylene; L 7 is -NH-.

[0417] In some embodiments, L A -R A -L 2 -L 6 -L 7 -R A and L 2 is an unsubstituted —C1-C6 alkylene, an unsubstituted —C1-C6 alkylene-NH—, or an unsubstituted —C1-C6 alkylene-NHC(═O)—, and L 6 -L 8 -L 9 -L 10 - and L 7 is -NH-, -O-NH-, or a natural or unnatural amino acid. A -R A -L 2 -L 6 -L 7 -R A and L 2 is unsubstituted -C1-C6 alkylene-NH- or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 is -NH- or a natural or unnatural amino acid.

[0418] In some embodiments, L A -R A -L 2 -L 3 -L 4 -L 7 -R A and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a peptide formed from glutamine or two or more glycines, where the N atom of the amide linking the amino acid is replaced by -CH3 and L 4is -C(=O)CH2CH2- or -(CH2) v -NR 17 -(CH2) v and L 7 In some embodiments, L A -R A -L 2 -L 3 -L 4 -L 7 -R A and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a peptide formed from two or more glycines, where the N atom of the amide linking the amino acid is replaced with -CH3, and L 4 is -C(=O)CH2CH2-, and L 7 is -NH-.

[0419] In some embodiments, L A -R A -L 2 -L 4 -L 5 -L 7 -R A and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is -C1-C6 alkylene optionally substituted with one -NH2, and L 5 is -NH-, and L 7 is Bip.

[0420] In some embodiments, L A -R A -L 4 -L 5 -L 6 -L 7 -R A and L 4 is -(CH2CH2O) v -CH2CH2-, and L 5 is -NH-, and L 6 -L 8 -L 9 -L 10 - and L7 is absent. 8 does not exist, and L 9 teeth,

[0421] [ka] and L 10 is not present and k is 1, 2, 3, or 4.

[0422] In some embodiments, L A -R A -L 4 -L 5 -L 6 -L 7 -R A and L 4 is -(CH2CH2O) v -CH2CH2-, and L 5 is -NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 is -NH-.

[0423] In some embodiments, L A -R A L 2 -L 4 -L 5 -L 6 -L 7 - and L 2 is an unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is -C1-C6 alkylene- substituted with one -NH2, and L 5 is -NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 In some embodiments, L 8 does not exist, and L 9 is unsubstituted phenylene, and L 10 is -(CH2) qIn some embodiments, L 8 is -(CH2) r - and L 9 is unsubstituted heterocycloalkylene, and L 10 does not exist.

[0424] In some embodiments, Z A is -O- and L A -L 2 -L 3 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NH-, and L 3 is an unnatural amino acid. 3 is lysine. In some embodiments, L 3 is glutamic acid. A is -O- and L A -L 2 -L 3 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene -NHC(=O)CHNH-, and L 3 is an unnatural amino acid. 3 is asparagine.

[0425] In some embodiments, Z A is -O- and L A -L 2 -L 6 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 is -(CH2) t -C(=O)NR 14 - and R 14 is -CH2CO2H, t is 2, and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10In some embodiments, Z is absent. A is -O- and L A -L 2 -L 6 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 is -(CH2) t where t is 1 and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10 does not exist.

[0426] In some embodiments, Z A is -O- and L A -L 2 -L 7 - and 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)-, and L A -L 2 -L 7 - and L 2 is -(CH2CH2O) w -CH2CH2-, and L 7 is -NH- and w is 4.

[0427] In some embodiments, Z A is -O- and L A -L 2 -L 3 -L 7 - and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a natural or unnatural amino acid, and L 7is a natural or unnatural amino acid. 3 is Bip. In some embodiments, L 7 is (R)-2,3-diaminopropanoic acid.

[0428] In some embodiments, Z A is -NH-, and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-C(=O)NCH3-, and L 4 is -(CH2) v -NR 17 -(CH2) v and L 7 is —N(CH)—. In some embodiments, v is 3. In some embodiments, R 17 is —CH. In some embodiments, Z A is -O- and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is -C1-C6 alkylene-, and L 7 is -NH-. In some embodiments, Z A is -NH-, and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is -C1-C6 alkylene substituted with one -NH2, and L 7 is -NH-. In some embodiments, Z A is -NH-, and L A -L 2 -L 4 -L 7 - and L 2is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is one -NR 18a R 18b and L is -C1-C6 alkylene substituted with 7 is -NH-. In some embodiments, R 18a is H and R 18b is -C(=O)CH2CH2CH2-4-iodophenyl. In some embodiments, Z A is -O- and L A -L 2 -L 4 -L 7 - and L 2 is an unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is an unsubstituted -C1-C6 alkylene, and L 7 is -NH-. In some embodiments, Z A is -NH-, and L A -L 2 -L 4 -L 7 - and L 2 is an unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is an unsubstituted -C1-C6 alkylene, and L 7 is -NH-. In some embodiments, Z A is -NH-, and L A -L 2 -L 4 -L 7 - and L 2 is unsubstituted -C1-C6 alkylene-, and L 4 is -NHC(=O)NH-O-(CH2) v - and L 7 is -NH-. In some embodiments, Z A is -O- and L A -L 2 -L 4 -L 7 - and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 4 is -NHC(=O)NH-O-(CH2)v - and L 7 In some embodiments, v is 2. In some embodiments, Z A is -O- and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-, and L 4 is -NHC(=O)NH-NH-C(=O)(CH2) v - and L 7 In some embodiments, Z is -O- and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-, and L 4 is -NHC(=O)CH2-O-NH-C(=O)(CH2) v - and L 7 In some embodiments, Z is -O- and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-, and L 4 is -NHC(=O)NH-(CH2) v - and L 7 is —O—NH—. In some embodiments, v is 2.

[0429] In some embodiments, Z A is -NH-, and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 4 is -(CH2CH2O) v -CH2CH2-, and L7 is -NH-. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, Z A is -O- and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 4 is -(CH2CH2O) v -CH2CH2-, and L 7 is -NH-. In some embodiments, v is 1. In some embodiments, v is 36. In some embodiments, Z A is -O- and L A L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 4 is -CH2CH2NHC(=O)-CH-CH2CH2C(=O)NHR 17 and L 7 is -NH-. 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. A is -O- and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 4 is a substituted or unsubstituted -C1-C6 alkylene-, and L 7 In some embodiments, L 4 is one -NHC(=O)CH2CH2CH(COOH)NHC(=O)-(CH2) sIn some embodiments, s is 14. In some embodiments, Z is -C1-C6 alkylene- optionally substituted with CH3. A is -O- and L A -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 Alkylene-NR 16 C(=O)NR 16 NH- and L 4 is -C(=O)CH2CH2-, and L 7 is -NH-.

[0430] In some embodiments, Z A is -O- and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NH-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted cycloalkylene; L 10 is -NR 15 -(CH2) r - and L 7 is -NH-. In some embodiments, R 15 is H. In some embodiments, r is 2. In some embodiments, Z A is -O- and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NH-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9is a substituted or unsubstituted cycloalkylene; L 10 is -NR 15 -(CH2) q -NR 15 - and L 7 is a natural or unnatural amino acid. 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 is -O- and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10 is -(CH2) r - and L 7 is -NH-. In some embodiments, r is 1. In some embodiments, Z A is -O- and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted arylene; L 10 does not exist, and L 7 is -NH-. In some embodiments, Z A is -NH-, and L A -L2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NH-, and L 6 L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted cycloalkylene; L 10 is -NR 15 -(CH2) r - and L 7 is -NH-. In some embodiments, R 15 is H. In some embodiments, r is 2. In some embodiments, Z A is -NH-, and L A -L 2 -L 6 -L 7 - and L 2 is an unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is unsubstituted arylene, and L 10 is -C(=O)NR 15 -(CH2) q -It is. L 7 In some embodiments, q is 4. In some embodiments, Z is -O- and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NH-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted cycloalkylene; L 10 is -NRw -(CH2) r - and L 7 is O—NH—. In some embodiments, r is 2. In some embodiments, R w is H. In some embodiments, Z A is -O- and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted C1-C 20 alkylene, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10 is -C(=O)-(CH2) q - and L 7 In some embodiments, q is 5.

[0431] In some embodiments, Z A is -O- and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted arylene; L 10 does not exist, and L 7 is -NH-. In some embodiments, Z A is -NH-, and L A -L 2 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NH-, and L6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted cycloalkylene; L 10 is -NR 15 -(CH2) r - and L 7 is -NH-. In some embodiments, R 15 is H. In some embodiments, r is 2.

[0432] In some embodiments, Z A is -NH-, and L A -L 2 -L 3 -L 4 -L 7 - and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a natural or unnatural amino acid, and L 4 is -(CH2) v -NR 17 -(CH2) v and L 7 is -NH-. In some embodiments, R 17 is —CH3. In some embodiments, L 3 is glutamine. A is -O- and L A -L 2 -L 3 -L 4 -L 7 - and L 2 is unsubstituted -C1-C6 alkylene-NH-, and L 3 is a natural or unnatural amino acid, and L 4 is -C(=O)CH2CH2, and L 7 In some embodiments, L 3 is serine. A is -O- and L A -L 2 -L 3 -L4 -L 7 - and L 2 is a substituted or unsubstituted -C1-C 20 alkylene-NH-, and L 3 is a natural or non-natural peptide, and L 4 is -C(=O)CH2CH2-, and L 7 In some embodiments, L 3 is a natural or unnatural peptide, where, when two or more amino acids are present, the N atom of the amide linking the amino acids is optionally substituted with -C1-C6 alkyl.

[0433] In some embodiments, Z A is -NH-, and L A -L 2 -L 4 -L 5 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is one -NR 18a18b and L is -C1-C6 alkylene optionally substituted with 5 is -NH-, and L 7 is a natural or unnatural amino acid. 7 is Bip.

[0434] In some embodiments, Z A is -NHC(=O)-, and L A -L 4 -L 5 -L 6 -L 7 - and L 4 is -(CH2CH2O) v -CH2CH2-, and L 5 is -NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted heterocycloalkylene; L10 (CH2) r and L 7 is —NH—. In some embodiments, r is 1. In some embodiments, v is 1.

[0435] In some embodiments, Z A is -O- and L A L 2 -L 4 -L 5 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is -C1-C6 alkylene- substituted with one -NH2, and L 5 is -NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 In some embodiments, L 8 does not exist, and L 9 is unsubstituted arylene, and L 10 is -(CH2) q In some embodiments, q is 1. In some embodiments, Z A is -NH-, and L A L 2 -L 4 -L 5 -L 6 -L 7 - and L 2 is a substituted or unsubstituted -C1-C6 alkylene-NHC(=O)-, and L 4 is one -NR 18a18b and L is -C1-C6 alkylene- optionally substituted with 5 is -NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 7 In some embodiments, L 8 is -(CH2) r - and L9 is unsubstituted heterocycloalkylene, and L 10 does not exist.

[0436] In some embodiments, the linker-L A -or-L B - (if either exists), or -L A - and -L B - (independently, if both are present) a linker:

[0437] [ka]

[0438] [ka]

[0439] [ka]

[0440] [ka]

[0441] [ka]

[0442] [ka]

[0443] [ka] In some embodiments, the linker is selected from: -L A In some embodiments, the linker is -L B -It is.

[0444] In some embodiments, the linker-L A -or-L B - (if either exists), or -L A - and -L B - (independently, if both are present) a linker:

[0445] [ka]

[0446] [ka] In some embodiments, the linker is selected from: -L A In some embodiments, the linker is -L B -It is.

[0447] In some embodiments, the linker-L A -or-L B - (if either exists), or -L A - and -L B - (independently, if both are present) a linker:

[0448] [ka]

[0449] [ka]

[0450] [ka] In some embodiments, the linker is selected from: -L A In some embodiments, the linker is -L B -It is.

[0451] In some embodiments, the linker-L A-or-L B - (if either exists), or -L A - and -L B - (independently, if both are present) a linker:

[0452] [ka] is selected from.

[0453] In some embodiments, the linker-L A -or-L B - (if any)

[0454] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0455] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0456] [ka] In some embodiments, -L A -teeth,

[0457] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0458] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0459] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0460] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0461] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0462] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0463] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0464] [ka] In some embodiments, the linker-L A -or-L B - (if any are present). In some embodiments, the linker -L A -or-L B - (if any)

[0465] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0466] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0467] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0468] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0469] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0470] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0471] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0472] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0473] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0474] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0475] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0476] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0477] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0478] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0479] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0480] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0481] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0482] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0483] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0484] [ka] In some embodiments, -L A -teeth,

[0485] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0486] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0487] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0488] [ka] In some embodiments, the linker-L A -or-L B- (if any)

[0489] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0490] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0491] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0492] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0493] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0494] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0495] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0496] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0497] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0498] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0499] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0500] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0501] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0502] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0503] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0504] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0505] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0506] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0507] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0508] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0509] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0510] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0511] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0512] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0513] [ka] In some embodiments, the linker is -L A In some embodiments, the linker is -L B In some embodiments, the linker -L A -or-L B - (if any)

[0514] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0515] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0516] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0517] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0518] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0519] [ka] In some embodiments, the linker-L A -or-L B - (if any)

[0520] [ka] In some embodiments, the linker is -L A In some embodiments, the linker is -L B -It is.

[0521] Representative Linkers and Chelating Moieties In some embodiments, -L A -R A teeth,

[0522] [ka]

[0523] [ka] In some embodiments, -R in the previous embodiment is A teeth,

[0524] [ka] is.

[0525] In some embodiments, -L A -R A teeth,

[0526] [ka]

[0527] [ka]

[0528] [ka] In some embodiments, -R in the previous embodiment is A teeth,

[0529] [ka] is.

[0530] In some embodiments, -L A -R A teeth,

[0531] [ka] In some embodiments, -R in the previous embodiment is A teeth,

[0532] [ka] is.

[0533] In some embodiments, -L A -R A teeth,

[0534] [ka] In some embodiments, -L A -R A teeth,

[0535] [ka] In some embodiments, -L A -R A teeth,

[0536] [ka] In some embodiments, -L A -R A teeth,

[0537] [ka] In some embodiments, -L A -R A teeth,

[0538] [ka] In some embodiments, -L A -R A teeth,

[0539] [ka] In some embodiments, -L A -R A teeth,

[0540] [ka] In some embodiments, -L A -R A teeth,

[0541] [ka] In some embodiments, -L A -R A teeth,

[0542] [ka] In some embodiments, -L A -R A teeth,

[0543] [ka] In some embodiments, -LA -R A teeth,

[0544] [ka] In some embodiments, -L A -R A teeth,

[0545] [ka] In some embodiments, -L A -R A teeth,

[0546] [ka] In some embodiments, -L A -R A teeth,

[0547] [ka] In some embodiments, -L A -R A teeth,

[0548] [ka] In some embodiments, -L A -R A teeth,

[0549] [ka] In some embodiments, -L A -R A teeth,

[0550] [ka] In some embodiments, -L A -RA teeth,

[0551] [ka] In some embodiments, -L A -R A teeth,

[0552] [ka] In some embodiments, -L A -R A teeth,

[0553] [ka] In some embodiments, -L A -R A teeth,

[0554] [ka] In some embodiments, -L A -R A teeth,

[0555] [ka] In some embodiments, -L A -R A teeth,

[0556] [ka] In some embodiments, -L A -R A teeth,

[0557] [ka] In some embodiments, -L A -R A teeth,

[0558] [ka] In some embodiments, -L A -R A teeth,

[0559] [ka] In some embodiments, -R in the previous embodiment is A teeth,

[0560] [ka] is.

[0561] In some embodiments, -L A -R A teeth,

[0562] [ka] In some embodiments, -L A -R A teeth,

[0563] [ka] In some embodiments, -L A -R A teeth,

[0564] [ka] In some embodiments, -L A -R A teeth,

[0565] [ka] In some embodiments, -L A -RA teeth,

[0566] [ka] In some embodiments, -L A -R A teeth,

[0567] [ka] In some embodiments, -L A -R A teeth,

[0568] [ka] In some embodiments, -L A -R A teeth,

[0569] [ka] In some embodiments, -L A -R A teeth,

[0570] [ka] In some embodiments, -L A -R A teeth,

[0571] [ka] In some embodiments, -L A -R A teeth,

[0572] [ka] In some embodiments, -L A -R A teeth,

[0573] [ka] In some embodiments, -L A -R A teeth,

[0574] [ka] In some embodiments, -L A -R A teeth,

[0575] [ka] In some embodiments, -L A -R A teeth,

[0576] [ka] In some embodiments, -L A -R A teeth,

[0577] [ka] In some embodiments, -L A -R A teeth,

[0578] [ka] In some embodiments, -L A -R A teeth,

[0579] [ka] In some embodiments, -L A -R A teeth,

[0580] [ka] In some embodiments, -L A -R A teeth,

[0581] [ka] In some embodiments, -L A -R A teeth,

[0582] [ka] In some embodiments, -L A -R A teeth,

[0583] [ka] In some embodiments, -L A -R A teeth,

[0584] [ka] In some embodiments, -L A -R A teeth,

[0585] [ka] In some embodiments, -L A -R A teeth,

[0586] [ka] In some embodiments, -L A -R A teeth,

[0587] [ka] In some embodiments, -L A -R A teeth,

[0588] [ka] In some embodiments, -L A -R A teeth,

[0589] [ka] In some embodiments, -L A -R A teeth,

[0590] [ka] In some embodiments, -L A -R A teeth,

[0591] [ka] In some embodiments, -L A -R A teeth,

[0592] [ka] In some embodiments, -L A -R A teeth,

[0593] [ka] In some embodiments, -L A -R A teeth,

[0594] [ka] In some embodiments, -L A -R A teeth,

[0595] [ka] In some embodiments, -L A -R A teeth,

[0596] [ka] In some embodiments, -R in the previous embodiment is A teeth,

[0597] [ka] is.

[0598] In some embodiments, -L A -R A -teeth,

[0599] [ka] In some embodiments, -L A -R A -teeth,

[0600] [ka] In some embodiments, -L A -R A -teeth,

[0601] [ka] In some embodiments, -L A -R A -teeth,

[0602] [ka] In some embodiments, -L A -R A -teeth,

[0603] [ka] In some embodiments, -L A -R A -teeth,

[0604] [ka] In some embodiments, -L A -R A -teeth,

[0605] [ka] In some embodiments, -L A -R A -teeth,

[0606] [ka] In some embodiments, -L A -R A -teeth,

[0607] [ka] In some embodiments, -R in the previous embodiment is A teeth,

[0608] [ka] is.

[0609] In some embodiments, -L B -R B teeth,

[0610] [ka]

[0611] [ka] In some embodiments, -R in the previous embodiment is B teeth,

[0612] [ka] is.

[0613] In some embodiments, -L B -R B teeth,

[0614] [ka]

[0615] [ka]

[0616] [ka] In some embodiments, -R in the previous embodiment is B teeth,

[0617] [ka] is.

[0618] In some embodiments, -L B -R B teeth,

[0619] [ka] In some embodiments, -R in the previous embodiment is B teeth,

[0620] [ka] is.

[0621] In some embodiments, -L B -R B teeth,

[0622] [ka] In some embodiments, -L B -R B teeth,

[0623] [ka] In some embodiments, -L B -R B teeth,

[0624] [ka] In some embodiments, -L B -R B teeth,

[0625] [ka] In some embodiments, -L B -R B teeth,

[0626] [ka] In some embodiments, -L B -R B teeth,

[0627] [ka] In some embodiments, -L B -R B teeth,

[0628] [ka] In some embodiments, -L B -R B teeth,

[0629] [ka] In some embodiments, -L B -R B teeth,

[0630] [ka] In some embodiments, -L B -R B teeth,

[0631] [ka] In some embodiments, -L B -R B teeth,

[0632] [ka] In some embodiments, -L B -R B teeth,

[0633] [ka] In some embodiments, -L B -R B teeth,

[0634] [ka] In some embodiments, -L B -R B teeth,

[0635] [ka] In some embodiments, -L B -R B teeth,

[0636] [ka] In some embodiments, -L B -R B teeth,

[0637] [ka] In some embodiments, -L B -R B teeth,

[0638] [ka] In some embodiments, -L B -R B teeth,

[0639] [ka] In some embodiments, -L B -R B teeth,

[0640] [ka] In some embodiments, -L B -R B teeth,

[0641] [ka] In some embodiments, -LB -R B teeth,

[0642] [ka] In some embodiments, -L B -R B teeth,

[0643] [ka] In some embodiments, -L B -R B teeth,

[0644] [ka] In some embodiments, -L B -R B teeth,

[0645] [ka] In some embodiments, -L B -R B teeth,

[0646] [ka] In some embodiments, -L B -R B teeth,

[0647] [ka] In some embodiments, -R in the previous embodiment is B teeth,

[0648] [ka] is.

[0649] In some embodiments, -L B -R B teeth,

[0650] [ka] In some embodiments, -L B -R B teeth,

[0651] [ka] In some embodiments, -L B -R B teeth,

[0652] [ka] In some embodiments, -L B -R B teeth,

[0653] [ka] In some embodiments, -L B -R B teeth,

[0654] [ka] In some embodiments, -L B -R B teeth,

[0655] [ka] In some embodiments, -L B -R B teeth,

[0656] [ka] In some embodiments, -LB -R B teeth,

[0657] [ka] In some embodiments, -L B -R B teeth,

[0658] [ka] In some embodiments, -L B -R B teeth,

[0659] [ka] In some embodiments, -L B -R B teeth,

[0660] [ka] In some embodiments, -L B -R B teeth,

[0661] [ka] In some embodiments, -L B -R B teeth,

[0662] [ka] In some embodiments, -L B -R B teeth,

[0663] [ka] In some embodiments, -L B -RB teeth,

[0664] [ka] In some embodiments, -L B -R B teeth,

[0665] [ka] In some embodiments, -L B -R B teeth,

[0666] [ka] In some embodiments, -L B -R B teeth,

[0667] [ka] In some embodiments, -L B -R B teeth,

[0668] [ka] In some embodiments, -L B -R B teeth,

[0669] [ka] In some embodiments, -L B -R B teeth,

[0670] [ka] In some embodiments, -L B -R B teeth,

[0671] [ka] In some embodiments, -L B -R B teeth,

[0672] [ka] In some embodiments, -L B -R B teeth,

[0673] [ka] In some embodiments, -L B -R B teeth,

[0674] [ka] In some embodiments, -L B -R B teeth,

[0675] [ka] In some embodiments, -L B -R B teeth,

[0676] [ka] In some embodiments, -L B -R B teeth,

[0677] [ka] In some embodiments, -L B -R B teeth,

[0678] [ka] In some embodiments, -L B -R B teeth,

[0679] [ka] In some embodiments, -L B -R B teeth,

[0680] [ka] In some embodiments, -L B -R B teeth,

[0681] [ka] In some embodiments, -L B -R B teeth,

[0682] [ka] In some embodiments, -L B -R B teeth,

[0683] [ka] In some embodiments, -L B -R B teeth,

[0684] [ka] In some embodiments, -R in the previous embodiment is B teeth,

[0685] [ka] is.

[0686] In some embodiments, -L B -R B -teeth,

[0687] [ka] In some embodiments, -L B -R B -teeth,

[0688] [ka] In some embodiments, -L B -R B -teeth,

[0689] [ka] In some embodiments, -L B -R B -teeth,

[0690] [ka] In some embodiments, -L B -R B -teeth,

[0691] [ka] In some embodiments, -L B -R B -teeth,

[0692] [ka] In some embodiments, -L B -R B -teeth,

[0693] [ka] In some embodiments, -L B -R B -teeth,

[0694] [ka] In some embodiments, -L B -R B -teeth,

[0695] [ka] In some embodiments, -R in the previous embodiment is B teeth,

[0696] [ka] is.

[0697] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A Or -L B -R B (if any are present) and is selected from: A -R A and -L B -R B (if both are present), and independently,

[0698] [ka]

[0699] [ka]

[0700] [ka]

[0701] [ka]

[0702] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is selected from: -L A -R A In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L B -R B is.

[0703] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A Or -L B -R B and (if any) is selected from: A -R A and -L B -R B (if both are present), and independently,

[0704] [ka]

[0705] [ka]

[0706] [ka]

[0707] [ka]

[0708] [ka]

[0709] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is selected from: -L A -R A In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L B -R B is.

[0710] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A Or -L B -R B and (if any) is selected from: A -R A and -L B -R B (when both are present) and independently,

[0711] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is selected from: -L A -R A In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L B -R B is.

[0712] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -RB (if any exists), and

[0713] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0714] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0715] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0716] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0717] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0718] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0719] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0720] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0721] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0722] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0723] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0724] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0725] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0726] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0727] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0728] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0729] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0730] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0731] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0732] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0733] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0734] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0735] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0736] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0737] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0738] [ka] is.

[0739] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0740] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -LB -R B (if any exists), and

[0741] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0742] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0743] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0744] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0745] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0746] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0747] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0748] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0749] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B(if any exists), and

[0750] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0751] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0752] [ka] In some embodiments, -L A -R A teeth,

[0753] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0754] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B-R B (if any exists), and

[0755] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0756] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0757] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0758] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0759] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0760] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0761] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0762] [ka] In some embodiments, -L A -R A teeth,

[0763] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0764] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0765] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0766] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0767] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0768] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -RB (if any exists), and

[0769] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0770] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0771] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0772] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0773] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0774] [ka] is.

[0775] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0776] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0777] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0778] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -LB -R B (if any exists), and

[0779] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0780] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0781] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0782] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0783] [ka] In some embodiments, the -linker- (chelating moiety or radionuclide complex thereof) is -L A -R A or -L B -R B (if any exists), and

[0784] [ka] is.

[0785] Representative compounds Representative NPY1R radiopharmaceuticals described herein have the following structure:

[0786] [ka]

[0787] [ka]

[0788] [ka]

[0789] [ka]

[0790] [ka]

[0791] [ka]

[0792] [ka]

[0793]

change

[0794]

change

[0795]

change

[0796]

change

[0797]

change

[0798]

change

[0799]

change

[0800]

change

[0801]

change

[0802]

change

[0803]

change

[0804] [ka] or a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0805] Representative NPY1R radiopharmaceuticals described herein have the following structure:

[0806] [ka]

[0807] [ka]

[0808] [ka]

[0809] [ka]

[0810] [ka]

[0811] [ka]

[0812] [ka]

[0813] [ka]

[0814]

change

[0815]

change

[0816]

change

[0817]

change

[0818]

change

[0819]

change

[0820]

change

[0821]

change

[0822]

change

[0823]

change

[0824]

change

[0825]

change

[0826]

change

[0827]

change

[0828]

change

[0829]

change

[0830]

change

[0831]

change

[0832]

change

[0833]

change

[0834]

change

[0835] [ka]

[0836] [ka]

[0837] [ka]

[0838] [ka]

[0839] [ka] or a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0840] In some embodiments, the compound of Formula (II) is Compound 101A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 101B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 102A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 102B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 103A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 103B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 104, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 105, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. 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, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of Formula (II) is Compound 111A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 111B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 112A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 112B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 113A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 113B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 114A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 114B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 115, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 116, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 117A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 117B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. 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.

[0841] In some embodiments, the compound of Formula (II) is Compound 115A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 115B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 116A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 116B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 120A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 120B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 121A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 121B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. 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, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of Formula (II) is Compound 136B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 137A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 137B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 138, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. 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, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 164A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 164B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 165A, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (II) is Compound 165B, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. 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.

[0842] All combinations of the groups described above for the various variables are contemplated herein. Throughout this specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0843] Compound synthesis The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein.

[0844] Unless otherwise specified, conventional mass spectroscopy, NMR, and HPLC are utilized.

[0845] The compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be utilized, including variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

[0846] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.In addition, the compounds described herein can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water and ethanol.The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0847] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are useful in solid dosage forms because they are typically more soluble than non-ionic species and dissolve rapidly in gastric and intestinal fluids. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Furthermore, salt-forming molecules can be in equilibrium with neutral forms, thereby modulating passage through biological membranes.

[0848] 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 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 (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and glutamic acid. These include, but are not limited to, conic 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.

[0849] In some embodiments, the compound of formula (I) or (II) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

[0850] 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 combined with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, or tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine or lysine. Acceptable inorganic bases used to form salts with compounds containing 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, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0851] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are formed during the crystallization process using a pharmaceutically acceptable solvent, such as water or ethanol. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein are advantageously prepared or formed during the processes described herein. Furthermore, the compounds provided herein optionally exist in solvated as well as unsolvated forms.

[0852] In some embodiments, any one of the hydrogen atoms on an organic radical (eg, alkyl group, aromatic ring) of the compounds described herein is replaced with deuterium.

[0853] In some embodiments, compounds of Formula (I) or Formula (II) contain one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. The compounds provided herein include all enantiomeric, atropisomeric, and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In some embodiments, the compound is a mixture of two diastereoisomers, and the diastereomeric ratio (the ratio of one diastereoisomer in the mixture to the other diastereoisomer in the mixture) is from about 99:1 to about 50:50. In some embodiments, the diastereomeric ratio is from about 99:1 to about 90:10. In some embodiments, the diastereomeric ratio is from about 95:5 to about 85:15. In some embodiments, the diastereomeric ratio is from about 90:10 to about 80:20. In some embodiments, the diastereomeric ratio is about 85:15 to about 75:25. In some embodiments, the diastereomeric ratio is about 80:20 to about 70:30. In some embodiments, the diastereomeric ratio is about 75:25 to about 65:35. In some embodiments, the diastereomeric ratio is about 70:30 to about 60:40. In some embodiments, the diastereomeric ratio is about 65:35 to about 55:45. In some embodiments, the diastereomeric ratio is about 60:40 to about 50:50. In some embodiments, the diastereomeric ratio is about 55:45 to about 45:55.

[0854] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers on chiral chromatographic columns, or separation of diastereomers on either non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or solvent mixture. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or diastereomeric salts and separation by recrystallization or chromatography, or any combination thereof. "Enantiomers, Racemates and Resolutions" by Jean Jacques, Andre Collet, and Samuel H. Wilen, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0855] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful in some situations because they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally, or alternatively, prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of the prodrug improves effective water solubility. See, for example, Design of Prodrugs, edited by Bundgaard, A., Elsevier, 1985 and Method in Enzymology, edited by Widder, K. et al., Academic, 1985, Vol. 42, pp. 309-396; "Design and Application of Prodrugs" by Bundgaard, H., A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, 1991, Chapter 5, pp. 113-191; and "Advanced Drug Delivery Review" by Bundgaard, H., 1992, 8, pp. 1-38, each of which is incorporated herein by reference.

[0856] 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 totality of processes (including, but not limited to, hydrolysis and enzyme-catalyzed reactions) by which a particular substance is transformed by an organism. Thus, enzymes may induce specific structural changes in a compound. For example, cytochrome P450 catalyzes various 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 either administering the compound to a host and analyzing multiple tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0857] Pharmaceutical Composition In some embodiments, the compound described herein is formulated into pharmaceutical compositions. Pharmaceutical compositions are conventionally formulated with one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the selected route of administration. Summary information on pharmaceutical compositions described herein can be 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, New York, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), which are incorporated herein by reference for disclosure.

[0858] In some embodiments, the compound described herein is administered alone or in pharmaceutical compositions with pharmaceutically acceptable carriers, excipients or diluents.The administration of the compound and composition described herein can be achieved by any method that allows compound to be delivered to the site of action.These methods include but are not limited to parenteral delivery (including injection or infusion and subcutaneous).

[0859] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage form, e.g., in ampoules or multi-dose containers with added preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain optional agents as excipients, such as suspending, stabilizing, and / or dispersing agents. The composition may be provided in unit-dose or multi-dose containers, e.g., sealed ampoules or vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., saline or pyrogen-free distilled water, immediately prior to use.

[0860] Treatment method In some embodiments, the method comprises administering to a 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 in a pharmaceutical composition. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the subject has a non-cancerous tumor. In some embodiments, the subject has an adenoma.

[0861] In some embodiments, treatment is sufficient to reduce or inhibit tumor growth, 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 in a subject, or a combination thereof.

[0862] In some embodiments, provided herein is a method for killing tumor cells, the method comprising contacting 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, emits many alpha particles by spontaneous radioactive decay. In some embodiments, the emitted alpha particles are sufficient to kill the tumor cells. In some embodiments, the emitted alpha particles 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 tumor cells with a beta particle-emitting radionuclide. In some embodiments, the method comprises killing tumor cells with an alpha particle-emitting radionuclide. In some embodiments, the method comprises killing tumor cells with a gamma particle-emitting radionuclide.

[0863] In one aspect herein, methods and compositions for treating cancer are provided.

[0864] In one aspect herein, methods and compositions for treating adenoma are provided.

[0865] In one aspect herein, methods and compositions for treating carcinoma are provided.

[0866] In one aspect herein, there is provided a method for identifying tissues or organs in a mammal that overexpress NPY1R, the method comprising: (i) administering to the mammal an NPY1R radiopharmaceutical or a pharmaceutically acceptable salt thereof described herein; 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 or a pharmaceutically acceptable salt thereof described herein; and (ii) performing positron emission tomography (PET) analysis on the mammal.

[0867] In some embodiments, the mammal is diagnosed with ovarian cancer. In some embodiments, the tissue that overexpresses NPY1R in the mammal is a tumor.

[0868] In some embodiments, the NPY1R radiopharmaceuticals described herein, or pharmaceutically acceptable salts thereof, are used in a method for performing in vivo diagnostic imaging on a subject. (i) administering to a mammal an NPY1R radiopharmaceutical or a pharmaceutically acceptable salt thereof described herein; (ii) waiting a sufficient time for the NPY1R radiopharmaceutical to accumulate in the tissue or cell site being imaged; (iii) imaging the cells or tissue with a non-invasive imaging technique.

[0869] 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 including computed tomography imaging, and positron emission tomography including magnetic resonance imaging (MRI).

[0870] Dosage and Treatment Regimen 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. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises 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.

[0871] In certain embodiments, compositions containing the compounds described herein are administered for diagnostic and / or therapeutic treatments.

[0872] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the specific conjugate, the specific cancer or tumor being treated (and its severity), the identity (e.g., weight, sex) of the subject or host requiring treatment, and the like, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the specific conjugate being administered, the route of administration, the disease being treated, and the subject or host being treated. Optimal dosages are generally determined using experimental models and / or clinical trials. Optimal dosages depend on the subject's body type, weight, or blood volume.

[0873] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies is used to formulate a therapeutically effective daily dose range and / or therapeutically effective unit dose for use in mammals, including humans.

[0874] The dosage of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is sufficient to deliver a therapeutically effective dose to a particular 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 and about 10 mg per kg of body weight. Therapeutically effective dosages can also be determined at the discretion of a physician. By way of example only, the dosage of the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, described herein in the methods for treating a disease described herein is between about 0.001 mg and about 1 mg per kg of subject body weight per administration. In some embodiments, the dosage is between about 0.001 mg and about 1000 mg per administration in the subject being treated. 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.

[0875] 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 picomole to about 1 mole, about 0.1 picomole to about 0.1 mole, about 1 nanomolar to about 0.1 mole, or about 0.01 micromolar to about 0.1 millimolar.

[0876] 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.

[0877] In some embodiments, the dose is administered once daily, 1 to 3 times weekly, 1 to 4 times monthly, or 1 to 12 times yearly.

[0878] In further embodiments of any of the foregoing aspects, an effective amount of the NPY1R radiopharmaceutical or pharmaceutically acceptable salt thereof described herein is (a) administered systemically to the mammal, and / or (b) administered intravenously to the mammal, and / or (c) administered by injection to the mammal.

[0879] In certain instances, it will be appropriate to administer the NPY1R radiopharmaceuticals described herein, or pharmaceutically acceptable salts thereof, in combination with one or more other therapeutic agents.

[0880] Specific Terms Unless otherwise specified, the following terms used in this application have the definitions provided below. 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.

[0881] As used herein and in the appended claims, singular forms such as "a," "an," and "the," and similar referents, where an element is described (particularly in the context of the claims below), should be construed to encompass both the singular and the plural, unless otherwise stated herein or clearly contradicted by context. The listing of ranges of values ​​herein is intended to serve merely as a shorthand method for referring to each separate value falling within the range, unless otherwise stated herein, and each separate value is incorporated herein as if it were individually listed herein. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context.

[0882] As used herein, "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to those of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which it is used.

[0883] As used herein, C1-C x is C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C6" indicates that there are from 1 to 6 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 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0884] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group may be branched or straight-chain. In some embodiments, an "alkyl" group may contain 1 to 10 carbon atoms, i.e., C1-C6. 10The term "alkyl" includes alkyl. Whenever it appears herein, 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 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" without any numerical range specified. In some embodiments, alkyl is -C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. In some embodiments, the alkyl group is an "alkenyl" or "alkynyl" group.

[0885] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above can be an alkylene by abstraction of another hydrogen atom from the alkyl. In some embodiments, the alkylene is -C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-.

[0886] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0887] The term "alkenyl" refers to a species of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where 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 alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0888] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl 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.

[0889] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. In some embodiments, "heteroalkyl" groups have 2 to 10 atoms in their backbone, which includes a combination of carbon atoms and heteroatoms (e.g., N, O, S), i.e., 2-10 membered heteroalkyls. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a 2-8 membered heteroalkyl.

[0890] A "heteroalkylene" group refers to a divalent alkyl radical derived from heteroalkyl, including, but not limited to, -CH-CH-O-CH-CH- and -CH-O-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(=O)O- represents both -C(=O)O- and -OC(=O)-. Furthermore, the formula -C(=O)NH- represents both -C(=O)NH- and -NHC(=O)-.

[0891] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocycle from "heterocyclic" or "heterocycle" rings, which have at least one atom other than carbon in the backbone of the ring. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0892] 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, an aryl is phenyl or naphthyl. In some embodiments, an aryl is phenyl. In some embodiments, an aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C 10 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0893] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the atoms forming the ring (i.e., the skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged cycloalkyl. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is to a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 12 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl. In some embodiments, the cycloalkyl is a C5-C6 cycloalkyl.

[0894] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0895] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl is -C1-C6 fluoroalkyl.

[0896] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 12 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 12 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be C-bonded (i.e., C-linked) or N-bonded, where possible. For example, pyrrole-derived groups include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, imidazole-derived groups include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). 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 a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0897] The term "heteroaryl," or alternatively "heteroaromatic," refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1 O atom. In some embodiments, the heteroaryl contains 1 S atom in the ring. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5 membered heteroaryl. In some embodiments, the monocyclic heteroaryl is a 6 membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a 10 membered heteroaryl.

[0898] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a 3- to 12-membered heterocycloalkyl. In another aspect, a heterocycloalkyl is a 5- to 10-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, a heterocycloalkyl contains 1-4 nitrogen (N) atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 oxygen (O) atoms, and 0-1 sulfur (S) atoms in the ring.

[0899] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing a bond to be formed between the remaining specified groups.

[0900] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or attached to a molecule.

[0901] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -C(=O)OH, -C(=O)O-alkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —C(═O)OH, —C(═O)O(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0902] The term "modulate," as used herein, means to interact with a target directly or indirectly 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 expanding the activity of the target.

[0903] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0904] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological effect. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion). Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein.

[0905] Terms such as "co-administration," as used herein, are intended to encompass the administration of selected therapeutic agents to a single patient and include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0906] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound administered such that one or more of the symptoms of the disease or disorder being treated are alleviated to some extent. This result may include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount," in therapeutic applications, is the quantity of a composition comprising a compound disclosed herein that is required to result in a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0907] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in regard 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. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0908] The terms "article of manufacture" and "kit" are used synonymously.

[0909] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of any of the following mammalian classes: humans, non-human primates such as chimpanzees, other apes, and monkey species; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0910] "Treat," "treating," or "treatment," as used herein, includes alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition. [Example]

[0911] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. Abbreviation ACN or MeCN or CH3CN: acetonitrile, BBr3: boron tribromide, Brine: saturated NaCl solution, BSA: bovine serum albumin; CaCl2: calcium chloride, CDI: 1,1′-carbonyldiimidazole; Cs2CO3: Cesium carbonate, DavePhos: 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC: N,N'-dicyclohexylcarbodiimide; DCM: dichloromethane, DIEA or DIPEA: N,N-diisopropylethylamine, DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide, DMSO: dimethyl sulfoxide; DOTA: 2,2',2'',2''''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; 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, EDC: (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), EGTA: ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid; EtOAc or EA: ethyl acetate, FA: formic acid; FBS: fetal bovine serum FDPP: pentafluorophenyl diphenyl phosphinate or perfluorophenyl diphenyl phosphinate or diphenylphosphinic acid pentafluorophenyl ester, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HSTU: N,N,N,N-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate; HCl: Hydrochloric acid or hydrochloride, HEPES: N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid; HgCl2: mercury(II) chloride or mercuric chloride H2O: water, HOBt: 1-hydroxybenzotriazole; InCl3: indium trichloride; IPA: i-PrOH or isopropanol, K2CO3: Potassium carbonate, LCMS: liquid chromatography mass spectrometry; LiHMDS: lithium hexamethyldisilazane salt or lithium bis(trimethylsilyl)amide; LiOH: lithium hydroxide; LuCl3: ruthenium(III) chloride, MeOH: methanol, MgCl2: magnesium chloride, MPLC: Medium pressure liquid chromatography MS: mass spectrometry; MsCl: methanesulfonyl chloride NaCl: sodium chloride; NaH: sodium hydride; NaHCO3: sodium bicarbonate, NaHSO4: sodium hydrogen sulfate, NaI: sodium iodide; NMM: 4-methylmorpholine; Na2SO4: sodium sulfate, NHS: N-hydroxysuccinimide; NMM: N-methylmorpholine or 4-methylmorpholine; PA: Phosphoric acid; PACM: 4,4'-diaminodicyclohexylmethane; PBS: phosphate buffered saline; Pd / C: palladium on activated carbon, PdCl2: palladium(II) chloride, Pd(OAc)2: Palladium(II) acetate, PE: Petroleum ether Prep-HPLC: preparative high performance liquid chromatography; TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, TEA or Et3N: triethylamine, TFA: trifluoroacetic acid; THF: tetrahydrofuran; XPhos: dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane; rt: room temperature, h or hr: hour, hrs: hour, min: minute, mg: milligram, kg: kilogram, mL or ml: milliliter, Eq: equivalent, mmol: millimole, mol: mole, UV: Ultraviolet light

[0912] Basic analysis methods: 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, up to 65% in 8 min); total flow rate, 120 mL / min; detector, UV 220 nm.

[0913] LC-MS analysis was performed on a Shimadzu LCMS-2020 series instrument equipped with a binary pump LC-20ADXR, a micro vacuum degasser, a standard autosampler SIL-20AC XR, a thermostatic column compartment CTO-20AC, and a variable wavelength detector SPD-M20A. Data were analyzed using Shimadzu LabSolutions stand-alone workstation software. The HPLC solvent consisted of 0.05% ammonia in HO (mobile phase A) and acetonitrile (mobile phase B). Conditions: An Ascentis Express C18 (2.6 μm, 3.0 × 50 mm) column was used at a flow rate of 1.2 mL / min.

[0914] 1 H NMR spectra were recorded using an AVANCE III HD 300 MHz. Unless otherwise specified, chemical shifts are reported as δ (ppm) relative to TMS4Si (in DMSO-d6) as an internal standard using an Instrument model (Bruker TopSpin).

[0915] Compound synthesis Example 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-azaheptadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compounds 101A and 101B)

[0916] [ka]

[0917] Synthesis of intermediate B:

[0918] Step 1: A 1 L round-bottom flask was charged with a mixture of methyl carbamimidothioate (30.0 g, 1 Eq, 333 mmol), sodium bicarbonate (41 g, 19 mL, 1.5 Eq, 0.49 mol), THF (300 mL), and HO (300 mL), to which a solution of di-tert-butyl dicarbonate (87 g, 1.2 Eq, 0.40 mol) in THF (100 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 4 h. The mixture was quenched with water (300 mL) and extracted with DCM (2 x 500 mL), and the combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give Intermediate A (30.6 g, 161 mmol, 48.3%) as a white solid, which was used directly in the next step without further purification. MS:Calc'd for C7H 14 N2O2S:190.08,found[M+H] + :191.1.

[0919] Step 2: A 500 mL round-bottom flask was charged with 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), to which propionyl chloride (13.9 g, 1.20 Eq, 150 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was quenched with water (100 mL) and extracted with DCM (2 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, and then concentrated under reduced pressure to give tert-butyl (2-propionamidoethyl)carbamate (27.6 g, 0.11 mol, 92%, 90% purity) as a pale yellow solid, which was used directly in the next step without further purification. MS: Calculated for C 10 H 20 N2O3:216.15,found[M+H] + :217.3.

[0920] Step 3: A 500 mL round-bottom flask was charged with a mixture of tert-butyl (2-propionamidoethyl)carbamate (27.6 g, 1 Eq, 128 mmol) and 4 M HCl in dioxane (14.0 g, 96.0 mL, 4 mol, 3.01 Eq, 384 mmol), and MeOH (100 mL) was added. The reaction mixture was stirred at 25 °C for 4 h. The mixture was concentrated under reduced pressure to give N-(2-aminoethyl)propionamide (22 g, 0.13 mol, 100%, 70% purity) as a yellow solid, which was stored at -78 °C. MS: Calculated for CH 12 NO: 116.09, found [M+H] + :117.2.

[0921] Step 4: A 500 mL round-bottom flask was charged with 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 h, then N-(2-aminoethyl)propionamide (28 g, 1.5 Eq, 0.24 mol) was added, and the reaction mixture was stirred at 25° C. for an additional 2 h. The mixture was diluted with water (100 mL) and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC under the following conditions: silica gel column 330 g, PE / EtOAc system, 0% to 85% EtOAc in 25 min, flow rate: 90 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give intermediate B (25 g, 75 mmol, 47%) as a white solid. MS: Calculated for C 13 H 24 N4O4S:332.15,found[M+H] + :333.1.

[0922] [ka]

[0923] Synthesis of intermediate C:

[0924] Step 1: To a 500 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged 4-(tert-butoxy)benzonitrile (23 g, 1 Eq, 0.13 mol), IPA (400 mL), and NH3·HO (15 mL), 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. The mixture was stirred under H2 at 25 °C for 3 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to give (4-(tert-butoxy)phenyl)methanamine (20 g, 0.11 mol, 85%) as a white solid.

[0925] Step 2: A 40 mL vial was charged with 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 h, then (4-(tert-butoxy)phenyl)methanamine (3.3 g, 1 eq, 18 mmol) and K2CO3 (1.1 g, 2.9 eq, 8.0 mmol) were added in additional THF (2 mL):HO (1.9 mL), and the reaction mixture was stirred for an additional 10 min. The reaction solution was then mixed, and the reaction continued at 30 °C for 1 h. 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 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to give benzyl tert-butyl (5-((4-(tert-butoxy)benzyl)amino)-5-oxopentane-1,4-diyl)(R)-dicarbamate (4.1 g, 7.8 mmol, 60%) as a yellow oil. MS: Calculated for C 29 H 41 N3O6:527.30,found[M+H] + :528.3.

[0926] Step 3.: A 500 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere was charged with benzyl tert-butyl (5-((4-(tert-butoxy)benzyl)amino)-5-oxopentane-1,4-diyl)(R)-dicarbamate (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. The mixture was stirred under H2 at 30 °C for 1 h. 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: Calculated for C 21 H 35 N3O4:393.26,found[M+H] + :394.2.

[0927] Step 4: A 40 mL vial was charged with 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 then 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 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); 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: Calculated for C 33 H55 N7O8:677.41,found[M+H] + :678.4.

[0928] Step 5.: An 8 mL vial was charged with a mixture of the product from Step 3 (350 mg, 1 Eq, 516 μmol) and DCM (3 mL), to which TFA (1 mL) was added. The reaction mixture was stirred at 20° C. for 1 h. 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: Calculated for C 19 H 31 N7O4:421.24,found[M+H] + :422.2.

[0929] [ka]

[0930] Synthesis of compounds 101A and 101B:

[0931] Step 1: A 250 mL round-bottom flask purged with an inert nitrogen atmosphere was charged with 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, and then 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) were added, 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) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 330 g, PE / EtOAc system, 0% to 10% EtOAc in 30 min, flow rate: 100 mL / min, wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give ethyl 2-(3-methoxyphenyl)-2-phenylacetate (16.0 g, 47 mmol, 89%, 80% purity) as a yellow oil. MS: Calculated for C 17 H 18 O3:270.13,found[MH]:269.0.

[0932] Step 2: A mixture of ethyl 2-(3-methoxyphenyl)-2-phenylacetate (3.0 g, 1 Eq, 11 mmol) and DCM (130 mL) was charged to a flask purged with an inert nitrogen atmosphere at 0 °C, followed by the addition of boron tribromide (19.3 g, 2.00 Eq, 77.0 mmol). The reaction mixture was stirred at 25 °C for 10 min. The mixture was quenched with EtOH (250 mL) and concentrated. The crude product was purified by MPLC using the following conditions: a 330 g silica gel column, PE / EtOAc system, 0% to 10% EtOAc in 20 min, flow rate: 80 mL / min, wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give ethyl 2-(3-methoxyphenyl)-2-phenylacetate (13.0 g, 80% Wt, 1 Eq, 38.5 mmol) as a yellow oil. MS:Calc'd for C 16 H 16 O3:256.11,found[MH]:255.0.

[0933] Step 3: A 50 mL round-bottom flask was charged with 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 min, and then 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) was added. The reaction mixture was stirred at 80 °C for 3 h. The mixture was diluted with water (150 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were then washed with water (2×50 mL), 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, 0% to 85% EtOAc in 25 min, flow rate: 70 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-19-yl)oxy)phenyl)-2-phenylacetate (3.6 g, 6.3 mmol, 87%) as a yellow oil. MS: Calculated for C 31 H 45 NO9:575.31,found[M+H] + :576.2.

[0934] Step 4: A 40 mL vial was charged with a mixture of ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-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 HO (4 mL). The mixture was stirred at 25 °C for an additional 3 h. The mixture was diluted with water (40 mL), the pH was adjusted to about 5-6 by the addition of NaHSO solution, and then the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-19-yl)oxy)phenyl)-2-phenylacetic acid (1.4 g, 2.2 mmol, 83%, 85% purity) as a yellow oil. MS: Calculated for C 29 H 41 NO9:547.28,found[M+H] + :548.2.

[0935] Step 5: A 40 mL vial under N was charged with 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-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 h. The reaction mixture was filtered and the cake was washed with THF. The filtrate was concentrated by slight heating below 35 °C to give 2,5-dioxopyrrolidin-1-yl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-19-yl)oxy)phenyl)-2-phenylacetate as a crude white oil (660 mg). A 40 mL vial was charged with a mixture of (R,Z)-2-amino-N-(4-hydroxybenzyl)-5-(2-((2-propionamidoethyl)carbamoyl)guanidino)pentanamide (440 mg, 1.04 Eq, 1.04 mmol), KCO (280 mg, 2.02 Eq, 2.03 mmol), HO (5 mL), and 1,4-dioxane (2 mL). A solution of crude 2,5-dioxopyrrolidin-1-yl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecane-19-yl)oxy)phenyl)-2-phenylacetate in 1,4-dioxane (4 mL) was added dropwise to the mixture at 25° C. The reaction mixture was stirred at 50° C. for 1 hour, then the crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150 mm 5 um; Mobile phase A: water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 50 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized as a yellow oil. MS: Calc'd for C 48 H 70 N8O 12 :950.51,found[M+H] + :951.7.

[0936] Step 6: An 8 mL vial was charged with 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 give 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: Calculated for C 43 H 62 N8O 10 :850.46,found[M+H] + :851.7

[0937] Step 7: In an 8 mL vial, add 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). The mixture was stirred at 20°C for 2 hours. The crude product was purified by preparative HPLC using the following conditions: Column: Xselect-C18 5um; Mobile phase A: Water (0.05% TFA); Mobile phase B: ACN; Gradient: 12% B to 30% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The front peak fraction was lyophilized to give 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-azaheptadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (Compound 101A, 69 mg, 51 μmol, 14%) as a white solid.The back peak fractions were lyophilized to give 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-azaheptadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (Compound 101B, 64 mg, 47 μmol, 13%) as a white solid. Compound 101A: MS: Calculated for C. 61 H 89 F3N 12 O 19 :1350.63,found[M+H-TFA]:1237.7 Compound 101B:MS:Calc'd for C 61 H 89 F3N 12 O 19 :1350.63,found M+H-TFA]:1237.9.

[0938] 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-azaheptadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compounds 102A and 102B)

[0939] [ka]

[0940] Step 1: A 250 mL three-neck flask was charged with a mixture of sodium hydride (6.8 g, 4.0 Eq, 0.28 mol) and DMF (100 mL) at 0 °C, to which ethyl 2-phenylacetate (35 g, 3.0 Eq, 0.21 mol) was added dropwise over 20 minutes. The reaction mixture was stirred at 0 °C for 1 hour, and then 1-fluoro-4-nitrobenzene (10 g, 1 Eq, 71 mmol) was added dropwise over 30 minutes. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with aqueous NaHSO (50 mL) at 0 °C and then extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 330 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 90 mL / min, wavelength: 254 nm. The collected fractions were concentrated to give ethyl 2-(4-nitrophenyl)-2-phenylacetate (8.5 g, 30 mmol, 42%) as a pale yellow oil.

[0941] Step 2: A 50 mL round-bottom flask, purged and maintained with an inert nitrogen atmosphere, was charged with ethyl 2-(4-nitrophenyl)-2-phenylacetate (600 mg, 1 Eq, 2.10 mmol) and i-PrOH (10 mL), to which Pd / C (60 mg, 0.27 Eq, 0.56 mmol) was carefully added. The flask was evacuated and flushed with hydrogen three times. The mixture was stirred under an H atmosphere at 25 °C for 1 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to give ethyl 2-(4-aminophenyl)-2-phenylacetate (500 mg, 1.8 mmol, 84%, 90% pure) as a colorless oil. MS: Calculated for C 16 H 17 NO3:255.13,found[M+H] + :256.3.

[0942] Step 3: A 40 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-onic acid (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 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Collected fractions were lyophilized to give ethyl 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosane-20-amido)phenyl)-2-phenylacetate (710 mg, 1.1 mmol, 68%, 90% purity) as a pale yellow oil. MS: Calculated for C 32 H 46 N2O9:602.32,found[M+H] + :603.6.

[0943] Step 4.: A 40 mL vial was charged with a mixture of ethyl 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-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 h. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, and the residue was diluted with water (50 mL), and the pH was adjusted to 6.0 by adding saturated NaHSO solution. The reaction mixture was extracted with DCM (3 x 50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-amido)phenyl)-2-phenylacetic acid (260 mg, 452 µmol, 68.2%) as a pale yellow oil, which was used directly in the next step without further purification. MS: Calculated for C 30 H 42 N2O9:574.29,found[M+H] + :575.3.

[0944] Step 5.: 2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaeicosan-20-amido)phenyl)-2-phenylacetic acid was combined with intermediate C in the same manner as in Step 5 of compound 101 to give 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 pale yellow oil. MS: Calculated for C 49 H 71 N9O 12 :977.52,found[M+H] + :978.8.

[0945] 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 in the same manner as in Step 6 of Compound 101. Elution with 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% purity) was obtained as a pale yellow oil. MS: Calculated for C 44 H 63 N9O 10 :877.47,found[M+H] + :878.5.

[0946] 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-pentaazaoctadec-9-en-1-yl)phenyl)-3,6,9,12-tetraoxapentadecan-15-amide was reacted 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 and purified by HPLC to give 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-pentaazaoctadec-9-en-1-yl)phenyl)amino)-2,18-dioxo-6,9,12,1 A single diastereomer of 5-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-trifluoroacetic acid) The other diastereomer of (1,18-dioxo-1-phenyl-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-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) was obtained (compound 102B, 19.8 mg, 14 μmol, 8.0%, 95% purity, back peak). Compound 102A: MS: Calculated for C 62 H 90 F3N 13 O 19 :1377.64,found[M+H-TFA] + :1264.7. Compound 101B:MS:Calc'd for C 62 H 90F3N 13 O 19 :1377.64,found[M+H-TFA] + :1264.7.

[0947] 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)

[0948] [ka]

[0949] Step 1: A 40 mL vial was charged with 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 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give ethyl 2-(4-((3-aminopropyl)amino)phenyl)-2-phenylacetate (620 mg, 1.8 mmol, 57%, 90% purity) as a white solid. MS: Calculated for C 19 H 24 N2O2:312.18,found[M+H] + :313.1.

[0950] Step 2: A 40 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecan-14-onic 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, and ethyl 2-(4-((3-aminopropyl)amino)phenyl)-2-phenylacetate (300 mg, 1.20 eq, 960 μmol) was added. 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 98% in 16 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Collected fractions were lyophilized to give ethyl 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadecan-18-yl)amino)phenyl)-2-phenylacetate (400 mg, 0.54 mmol, 67%, 77% purity) as a pale yellow oil. MS: Calculated for C 31 H 45 N3O7:571.33,found[M+H] + :572.5.

[0951] Step 3.: A 40 mL vial was charged with a mixture of ethyl 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadecan-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 h. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, and then the residue was diluted with water (50 mL), and the pH value was adjusted to 6.0 by adding saturated NaHSO solution. The reaction mixture was extracted with DCM (3 x 50 mL), dried over anhydrous NaSO, and then concentrated under reduced pressure to give 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadecan-18-yl)amino)phenyl)-2-phenylacetic acid (330 mg, 607 µmol, 86.8%) as a pale yellow oil, which was used directly in the next step without further purification. MS: Calculated for C 29 H 41 N3O7:543.29,found[M+H] + :544.4.

[0952] Step 4. 2-(4-((2,2-dimethyl-4,14-dioxo-3,8,11-trioxa-5,15-diazaoctadecan-18-yl)amino)phenyl)-2-phenylacetic acid (330 mg, 1 Eq, 607 μmol) was combined with intermediate C in the same manner as in Step 5 of compound 101 to give tert-butyl (2-(2-(3-((3-((4-((4R,Z)-9 150 mg, 0.13 mmol, 21%, 80% purity) of 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 as a pale yellow oil. MS: Calculated for C 48 H 70 N 10 O 10 :946.53,found[M / 2+H] +:474.5.

[0953] 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 (150 mg, 1 Eq, 158 μmol) was added to Compound 101 in Step 5. Treatment with TFA in the same manner as for 6 gave (2R)-2-(2-(4-((3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)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 pale yellow oil. MS: Calculated for C 43 H 62 N 10 O8:846.48,found[M+H] + :847.4.

[0954] Step 6.: (2R)-2-(2-(4-((3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)-propyl)amino)-phenyl)-2-phenylacetamido)-N-(4-hydroxybenzyl)-5-((Z)-2-((2-propionamidoethyl)carbamoyl)-guanidino)pentanamide (140 mg, 1 Eq, 165 μmol) was reacted with 2,2′,2″-(10-( Treatment with 2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid afforded 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) A single diastereomer of (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 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)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) were obtained (compound 103A, 3.7 mg, 2.4 μmol, 1.5%, 86.6% purity, front peak). Compound 103A: MS: Calculated for C 61 H 92 N 14 O 19 :1324.66,found[M+H-2FA]:1233.7. Compound 101B:MS:Calc'd for C 61 H 92 N 14 O 19:1324.66,found[M+H-2FA]:1233.7.

[0955] 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)

[0956] [ka]

[0957] Step 1: A 40 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl methanesulfonate (960 mg, 1.20 Eq, 2.58 mmol), CsCO (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 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 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Collected fractions were concentrated under reduced pressure to give ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)phenyl)-2-phenylacetate (690 mg, 1.2 mmol, 54%, 90% purity) as a yellow oil. MS: Calculated for C 29 H 41NO8:531.28,found[M+H] + :532.2.

[0958] Step 2.: A 40 mL vial was charged with a mixture of ethyl 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)phenyl)-2-phenylacetate (690 mg, 1 Eq, 1.30 mmol), LiOH (310 mg, 9.97 Eq, 12.9 mmol), HO (0.7 mL), and MeOH (7 mL). The reaction mixture was stirred at 25 °C for 3 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL), and the combined organic layers were washed with water (2 x 10 mL) and brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 40 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 2-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)phenyl)-2-phenylacetic acid (670 mg, 1.2 mmol, 90%, 88% purity) as an off-white solid. MS: Calculated for C 27 H 37 NO8:503.25,found[M+H] + :504.1.

[0959] Step 3: 2-(3-((2,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)phenyl)-2-phenylacetic acid (600 mg, 1 Eq, 1.19 mmol) was combined with intermediate C in the same manner as in Step 5 of compound 101 to provide 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:Calc'd for C 46 H 66 N8O 11 :906.49,found[M+H] + :907.3.

[0960] 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, 1 Eq, 110 μmol) was reacted with 100 mg of Compound 101 in the same manner as in Step 6. Treatment of this with TFA gave (2R)-2-(2-(3-(2-(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 pale yellow oil. MS: Calculated for C 41 H 58 O9·C2HF3O2:806.43,found[M+H] + :807.4.

[0961] Step 5.: (2R)-2-(2-(3-(2-(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 mmol) was reacted 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 the same manner as in Step 7 of Example 101. Treatment with HCl afforded 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 as a diastereomeric mixture (compound 104, 45.1 mg, 37.8 μmol, 34%, 99.9% purity) as an off-white solid. MS: Calculated for C 57 H 84 N 12 O 16 :1192.61,found[M+H] + :1193.8.

[0962] 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)

[0963] [ka]

[0964] Step 1.: A 40 mL vial was charged with 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 1 h. The mixture was diluted with 6 mL of water (6 mL) and extracted with EtOAc (3 x 10 mL), then the combined organic layers were washed with water (2 x 6 mL) and brine (12 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 40 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min, wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 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: Calculated for C 12 H 25 NO7S:327.14,found[M+H] + :328.2.

[0965] Step 2: A 40 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl methanesulfonate (500 mg, 1 Eq, 1.53 mmol), CsCO (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 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 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Collected fractions were concentrated under reduced pressure to give 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: Calculated for C 27 H 37 NO7:487.26,found[M+H] + :488.1.

[0966] Step 3.: A 40 mL vial was charged with 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), HO (0.65 mL), and MeOH (6.5 mL). The reaction mixture was stirred at 25 °C for 3 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL), then the combined organic layers were washed with water (2 x 10 mL) and brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 40 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 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: Calculated for C 25 H 33 NO7:459.23,found[M+H] + :460.1.

[0967] Step 4. 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 in a manner similar to that in step 5 of compound 101 to afford 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 (180 mg, 0.19 mmol, 14%, 90% purity) as an off-white solid. MS: Calc'd for C 44 H 62 N8O 10 :862.46,found[M+H]+ :863.5.

[0968] Step 5.: 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 (180 mg, 1 Eq, 209 μmol) was added to the same as in Step 6 of Compound 101. Treatment with TFA as in Example 1 gave (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: Calculated for C 25 H 33 NO7:762.41,found[M+H] + :763.5.

[0969] 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 similar to that described in Step 7 of Example 101. Treatment gave 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, formate as a diastereomeric mixture (74.7 mg, 62.5 μmol, 23.8%) as an off-white solid. MS: Calculated for C 55 H 80 N 12 O 15 CH2O2:1148.59,found[M+H] + :1149.8.

[0970] 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)

[0971] [ka]

[0972] Step 1: A 40 mL vial was charged with 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 h. The mixture was diluted with water (6 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were then washed with water (2 x 6 mL) and brine (12 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: a 40 g silica gel column, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min, wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl methanesulfonate (1.2 g, 4.2 mmol, 87%) as a yellow oil. MS: Calculated for C 10 H 21 NO6S:283.11,found[M+H]:284.0

[0973] Step 2. A 40 mL vial was charged with 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 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Collected fractions were concentrated under reduced pressure to give 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: Calculated for C 25 H 33 NO6:443.23,found[M+H] + :444.2.

[0974] Step 3: A 40 mL vial was charged with 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), HO (1.0 mL), and MeOH (5.0 mL). The reaction mixture was stirred at 25 °C for 3 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: 40 g silica gel column, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min, wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 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: Calculated for C 23 H 29 NO6:415.20,found[M+H] + :416.1.

[0975] Step 4. 2-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethoxy)phenyl)-2-phenylacetic acid (300 mg, 1 Eq, 722 μmol) was combined with intermediate C in a manner similar to that in step 5 of compound 101 to afford 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: Calc'd for C 42 H 58 N8O9:818.43,found[M+H] + :819.5.

[0976] 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 the same manner as in Step 6 of Compound 101 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:Calc'd for C 37 H 50 N8O7:718.38,found[M+H] + :719.4.

[0977] 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 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 the same manner as in Step 7 of Example 101. Work-up afforded 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 as a diastereomeric mixture (70.9 mg, 64.1 μmol, 43.9%) as an off-white solid. MS: Calculated for C 53 H 76 N 12O 14 :1104.56,found[M+H] + :1105.8.

[0978] 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)

[0979] [ka]

[0980] Step 1. A 100 mL round-bottom flask was charged with 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 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were then washed with water (2 x 200 mL), brine (200 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: silica gel column 120 g, PE / EtOAc system, 0% to 85% EtOAc in 25 min, flow rate: 90 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give ethyl 2-(3-(4-((tert-butoxycarbonyl)amino)-butoxy)phenyl)-2-phenylacetate (4.2 g, 9.8 mmol, 56%) as a yellow oil. Calc'd for C25 H 33 NO5: 427.24, found [M+Na] + :450.3.

[0981] Step 2.: A 50 mL vial was charged with 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 HO (10 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, and then the residue was diluted with water (50 mL), and the pH was adjusted to 6.0 by adding saturated NaHSO solution. The reaction mixture was extracted with DCM (3 x 50 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give 2-(3-(4-((tert-butoxycarbonyl)amino)butoxy)phenyl)-2-phenylacetic acid (2.3 g, 5.8 mmol, 82%) as a pale yellow solid, which was used directly in the next step without further purification. MS: Calculated for C 23 H 29 NO5: 399.20, found [M+Na] + :422.1.

[0982] Step 3.: 2-(3-(4-((tert-butoxycarbonyl)amino)butoxy)phenyl)-2-phenylacetic acid (2.5 g, 1.2 Eq, 6.3 mmol) was combined with intermediate C in the same manner as in step 5 of compound 101 to give 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. Calc'd for C 42 H 58 N8O8:802.44,found[M+H] + :803.5.

[0983] 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 the same manner as in Step 6 of Compound 101 to give (2R)-2-(2-(3-(4-aminobutoxy)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:Calc'd for C 37 H 50 N8O6:702.39,found[M+H] + :703.4.

[0984] Step 5.: An 8 mL vial was charged with 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 (from 350 mg, 1 Eq, 498 μmol). The reaction mixture was stirred for 2 h at 26 °C. The mixture was directly purified by MPLC under 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 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Concentration of the collected fractions gave (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: Calculated for C 55 H 65 N9O 12 S:1075.44,found[M+H] + :1076.4.

[0985] 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 resulted in (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 further purification. MS: Calculated for C 40 H 55 N9O 10 S:853.38,found[M+H] + :854.4.

[0986] 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% Wt, 1 Eq, 83 μmol) was reacted with 2,2′,2″-(10-(2-((2,5-dioxo- pyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid to give 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- A single diastereomer of sulfopropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (compound 107A, 15.1 mg, 11.1 μmol, 13%, front peak) was obtained as a white solid, and 2,2',2''-(10-(2-(((2R)-1-((4-(3-((4R,Z)-9-amino-4-((4-hydroxybenzyl)carbamoyl)-2,1 The other diastereomer of 1,16-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) (compound 107B, 16.7 mg, 12.3 μmol, 15%, back peak) was obtained as a white solid. Compound 107A: MS: Calculated for C 58 H 82 F3N 13 O 19 S: 1353.55, found [M+H-TFA] +:1240.7. Compound 107B:MS:Calc'd for C 58 H 82 F3N 13 O 19 S: 1353.55, found [M+H-TFA] + :1240.7.

[0987] 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)phenox...

Claims

1. Formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein R is -LL Ａ -R Ａ , -L-(L Ａ -R Ａ ) ２ , or -L-(L Ａ -R Ａ ) ３ and L is a linker or is absent; L Ａ are each independently a linker or absent, R Ａ are each independently a chelating moiety or a radionuclide complex thereof; Z is -C １ -C ６ Alkylene, -C １ -C ６ Alkylene-O-, -O-C １ -C ６ Alkylene-, —C(═O)NR Ｚ -, -NR Ｚ C(=O)-, -O-, -NR Ｚ -, -S-, -S(=O)-, -SO ２ - or -NHC(=O)NH-, R Ｚ is H or unsubstituted C １ -C ４ is alkyl, The ligand is neuropeptide Y １ Receptor (NPY １ R), y is 1, 2, or 3; The compound, or a pharmaceutically acceptable salt thereof.

2. R is -LL Ａ -R Ａ and L is absent, or a pharmaceutically acceptable salt thereof.

3. The ligand is NPY １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a small molecule antagonist of R.

4. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the ligand comprises (2,2-diphenylacetyl)argininamide, 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]azepin-2-one.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the ligand comprises (2,2-diphenylacetyl)argininamide.

6. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the ligand is benzyl-(2,2-diphenylacetyl)argininamide.

7. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein y is 1.

8. Formula (II) 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein R １ is H, -C １ -C ６ Alkyl, or —C(═O)NH ２ and R ２ is -OH, -NH ２ , —C(═O)NH ２ , or -CH ２ NHC(=O)NH ２ and R ３ are each independently R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ is selected from the group consisting of R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ are each independently H, F, Cl, Br, I, —CN, substituted or unsubstituted —C １ -C ６ Alkyl, and substituted or unsubstituted -C １ -C ６ alkoxy; R ４ is H, -C(=O)R １０ , -C(=O)NHR １０ , or -C(=O)N(CH ３ ) R １０ and R １０ is a substituted or unsubstituted -C １ -C ６ Alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —(CH ２ ) ｔ -NH ２ , -(CH ２ ) ｔ C(=O)O(CH ２ ) ｕ CH ３ , -(CH ２ ) ｔ NHC(=O)(CH ２ ) ｕ CH ３ , or -(CH ２ ) ｔ - a substituted or unsubstituted 5- or 6-membered heteroaryl ring, t is 1, 2, 3, 4, 5, or 6; u is 1, 2, 3, or 4; R ５ is not present or -Z Ｂ -L Ｂ -R Ｂ and Z Ｂ is -C １ -C ６ Alkylene, -C １ -C ６ Alkylene-O-, -O-C １ -C ６ Alkylene-, —C(═O)NR １１ -, -NR １１ C(=O)-, -O-, -NR １１ -, -S-, -S(=O)-, -SO ２ - or -NHC(=O)NH-, L Ｂ is the linker, R Ｂ is a chelating moiety or a radionuclide complex thereof; R ６ Is, -Z Ａ -L Ａ -R Ａ and Z Ａ is -C １ -C ６ Alkylene, -C １ -C ６ Alkylene-O-, -O-C １ -C ６ Alkylene-, —C(═O)NR １２ -, -NR １２ C(=O)-, -O-, -NR １２ -, -S-, -S(=O)-, -SO ２ - or -NHC(=O)NH-, L Ａ is the linker, R Ａ is a chelating moiety or a radionuclide complex thereof; R ７ are each independently F, Cl, Br, I, —CN, —OH, substituted or unsubstituted —C １ -C ６ Alkyl, and substituted or unsubstituted -C １ -C ６ alkoxy; R ８ are each independently F, Cl, Br, I, —CN, —OH, substituted or unsubstituted —C １ -C ６ Alkyl, and substituted or unsubstituted -C １ -C ６ alkoxy; R ９ is H, substituted or unsubstituted —C １ -C ４ Alkyl, or substituted or unsubstituted -C １ -C ６ is an alkoxy, R １１ are each independently H or unsubstituted —C １ -C ４ is alkyl, R １２ are each independently H or unsubstituted —C １ -C ４ is alkyl, n is 0, 1, 2, 3, or 4; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; The compound, or a pharmaceutically acceptable salt thereof.

9. The compound has the formula (IIa) 【Transformation 3】 9. The compound of claim 8 having the structure: or a pharmaceutically acceptable salt thereof.

10. The compound is represented by formula (IIb) 【Chemistry 4】 9. The compound of claim 8 having the structure: or a pharmaceutically acceptable salt thereof.

11. The compound is represented by formula (IIc) 【Transformation 5】 9. The compound of claim 8 having the structure: or a pharmaceutically acceptable salt thereof.

12. The compound has the formula (IId) 【Transformation 6】 9. The compound of claim 8 having the structure: or a pharmaceutically acceptable salt thereof.

13. The compound is represented by formula (IIe) 【Transformation 7】 9. The compound of claim 8 having the structure: or a pharmaceutically acceptable salt thereof.

14. R ５ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein:

15. R ５ Ga-Z Ｂ -L Ｂ -R Ｂ 9. The compound of claim 8, wherein:

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

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

18. R １ Ga-CH ３ 17. The compound according to any one of claims 8 to 16, wherein:

19. R １ -C(=O)NH ２ 17. The compound of any one of claims 8 to 16, wherein:

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

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

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

23. R ３ are each independently R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ is selected from the group consisting of R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ are each independently H, F, Cl, Br, I, —CN, or —CH ３ , -CF ３ , and -OCH ３ 23. The compound of any one of claims 8 to 22, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

24. The compound has the following structure: 【Transformation 8】 or a pharmaceutically acceptable salt thereof, wherein R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ are each independently H, F, Cl, Br, I, —CN, substituted or unsubstituted —C １ -C ６ Alkyl, and substituted or unsubstituted -C １ -C ６ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkoxy.

25. R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ are each independently H, F, Cl, Br, I, —CN, or —CH ３ , -CF ３ , or -OCH ３ 25. The compound of claim 24, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

26. R ３ａ and R ３ｄ is F or Cl, and R ３ｂ and R ３ｃ 25. The compound of claim 24, wherein is H, or a pharmaceutically acceptable salt thereof.

27. R ３ａ is F, Cl, or Br, and R ３ｂ , R ３ｃ , and R ３ｄ 25. The compound of claim 24, wherein is H, or a pharmaceutically acceptable salt thereof.

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

29. R ２ is -C(=O)NH ２ or -CH ２ NHC(=O)NH ２ 28. The compound according to any one of claims 8 to 27, wherein:

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

31. R ４ -C(=O)NHR １０ 30. The compound of any one of claims 8 to 29, wherein:

32. R ４ is -C(=O)NH(CH ２ ) ｔ NHC(=O)(CH ２ ) ｕ CH ３ 30. The compound of any one of claims 8 to 29, wherein:

33. R １０ is unsubstituted -C １ -C ６ Alkyl, -(CH ２ ) ｔ -NH ２ , -(CH ２ ) ｔ C(=O)O(CH ２ ) ｕ CH ３ , -(CH ２ ) ｔ NHC(=O)(CH ２ ) ｕ CH ３ , or -(CH ２ ) ｔ - a substituted or unsubstituted 5-6 membered heteroaryl ring, t is 1, 2, 3, 4, 5, or 6, and u is 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

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

35. Z Ａ is —O—, —NH—, or —N(—CH ３ 35. The compound of any one of claims 8 to 34, or a pharmaceutically acceptable salt thereof, wherein:

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

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

38. R Ａ and R Ｂ When present, each independently represents 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-diacetanoic 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-tetraazasilic acid Chlododecane (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 (p-OH-Bn-DOTA), 6,6'-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H ４ pypa), H ４ pypa-benzyl, 6,6',6'',6'''-(((pyridine-2,6-diylbis(methylene))-bis(azanetriyl))-tetrakis(methylene))-tetrapicolinic acid (H ４ py4pa), H ４ Py4pa-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 (H ４ octapa), H ４ 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, selected from the group consisting of octapa-benzyl, and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA), or a radionuclide complex thereof.

39. R Ａ and R Ｂ 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein, if present, is independently selected from the group consisting of 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 radionuclide complexes thereof.

40. R Ａ and R Ｂ , if present, independently 【Chemistry 9】 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or a radionuclide complex thereof.

41. R Ａ and R Ｂ But if it exists, 【Chemistry 10】 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or a radionuclide complex thereof.

42. R Ａ and R Ｂ , if present, independently 【Chemistry 11】 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, selected from:

43. L Ａ and L Ｂ if present, independently, -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 ]END]]-L ４ -L ７ -, -L ４ -L<000026]]-L ７ -, -L ２ -L ３ -L ４ -L ７ -, -L ２ -L ４ -L ５ -L<]]-, -L<]]-L ５ -L<]][[ID=]] 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 - is selected from, L ２ is absent or is a substituted or unsubstituted -C １ -C ２０ Alkylene, substituted or unsubstituted -C １ -C ２０ Alkylene -NR １６ -, substituted or unsubstituted -C １ -C ２０ Alkylene-C(=O)-, substituted or unsubstituted -C １ -C ２０ Alkylene -C(=O)NR １６ -, substituted or unsubstituted -C １ -C ２０ Alkylene -NR １６ C(=O)-, substituted or unsubstituted -C １ -C ２０ Alkylene -NR １６ C(=O)NR １６ NH—, substituted or unsubstituted —C １ -C ２０ Alkylene -C(=O)NR １６ CH ２ NR １６ -, substituted or unsubstituted -C １ -C ２０ Alkylene -NR １６ C(=O)CH ２ NR １６ -, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH ２ CH ２ O) ｚ -, -(OCH ２ CH ２ ) ｚ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ -, -CH ２ CH ２ NR １６ - (CH ２ CH ２ O) ｗ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NR １６ -, -CH ２ CH ２ NHC(=O)-(CH ２ CH ２ O) ｗ 、-(CH ２ CH ２ O) ｗ -CH ２ CH ２ NR １６ C(=O)-、-CH ２ CH ２ C(=O)NR １６ -(CH ２ CH ２ O) ｗ -、-CH ２ CH ２ NR １６ C(=O)CH ２ -(OCH ２ CH ２ ) ｗ 、または-(CH ２ CH ２ O) ｗ -CH ２ CH ２ C(=O)NR １６ -であり、 R １６ are each independently H and C １ -C ４ 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 peptide formed from a non-existent, natural or unnatural amino acid, or two or more independently selected natural and unnatural amino acids, and when two or more amino acids are present, the N atom of the amide linking said amino acids is -C １ -C ６ optionally substituted with alkyl; L ４ is absent, substituted or unsubstituted 2- to 10-membered heteroalkylene, —CH ２ -(OCH ２ CH ２ ) ｖ -, -(CH ２ CH ２ O) ｖ -CH ２ CH ２ -, -(CH ２ CH ２ O) ｖ CH ２ CH ２ NR １７ C(=O)(CH ２ CH ２ O) ｖ CH ２ CH ２ -, -(CH ２ CH ２ O) ｖ CH ２ CH ２ C(=O)NR １７ (CH ２ CH ２ O) ｖ CH ２ CH ２ -, -C(=O)CH ２ CH ２ -, -CH ２ CH ２ C(=O)-, -CH ２ CH ２ NHC(=O)-CH-CH ２ CH ２ C(=O)NHR １７ , -(CH ２ ) ｖ -NR １７ - (CH ２ ) ｖ , -NHC(=O)NH-O-(CH ２ ) ｖ -, -NHC(=O)NH-(CH ２ ) ｖ -, -NHC(=O)NH-NH-C(=O)(CH ２ ) ｖ -, -NHC(=O)CH ２ -O-NH-C(=O)(CH ２ ) ｖ -, or independently -OR １８ , -NR １８ａ R １８ｂ , -C(=O)OR １８ , -O(CH ２ CH ２ O) ｓ -CH ３ , -NR １８ (CH ２ CH ２ O) ｓ -CH ３ , -NR １８ C(=O)(CH ２ CH ２ O) ｓ -CH ３ , -CH ２ OCH ２ CH ２ CO ２ R １８ , or -NR １８ C(=O)CH ２ CH ２ CH(COOH)NR １８ C(=O)-(CH ２ ) ｓ CH ３ -C optionally substituted with one or two groups selected from １ -C ６ is alkylene, R １７ are each independently H, —C １ -C ６ alkyl or sugar alcohol or derivative thereof, R １８ are each independently H, —C １ -C ６ alkyl or sugar alcohol or derivative thereof, R １８ａ are each independently H, —C １ -C ６ alkyl or sugar alcohol or derivative thereof, R １８ｂ are each independently H, —C １ -C ６ Alkyl, —C(═O)(CH ２ ) ｘ -4-iodophenyl, -C(=O)(CH ２ ) ｘ -4-methylphenyl, or a sugar alcohol or a derivative thereof, 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 not present or is -O-, -S-, -S(=O)-, -S(=O) ２ , -NR １３ -, -CH(=NH)-, -CH(=N-NH)-, -CCH ３ (=NH)-,-CCH ３ (=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 - and R １３ are each independently H and —C １ -C ４ alkyl, L ６ is not present or -L ８ -L ９ -L １０ - and L ８ does not exist or is -(CH ２ ) ｒ -, -NR １４ -, -NR １４ - (CH ２ ) ｒ -, -(CH ２ ) ｒ -C(=O)-, -C(=O)-(CH ２ ) ｒ -, -(CH ２ ) ｒ -NR １４ -, -(CH ２ ) ｒ -NR １４ C(=O)-,-(CH ２ ) ｒ -C(=O)NR １４ -, -CH(NHR １４ )-(CH ２ ) ｒ -C(=O)-, -NR １４ C(=O)-(CH ２ ) ｒ -, and -C(=O)NR １４ - (CH ２ ) ｒ - and r is 0, 1, 2, or 3; L ９ is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene, a monosaccharide, or 【Chemistry 12】 and k is 1, 2, 3, or 4; L １０ does not exist or is -(CH ２ ) ｑ -, -NR １５ -, -NR １５ - (CH ２ ) ｑ -, -(CH ２ ) ｑ -C(=O)-, -C(=O)-(CH ２ ) ｑ -, -(CH ２ ) ｑ -NR １５ -, -NR １５ - (CH ２ ) ｑ -NR １５ -, -(CH ２ ) ｑ -NR １５ C(=O)-,-(CH ２ ) ｑ -C(=O)NR １５ -, -CH(NHR １５ )-(CH ２ ) ｑ -C(=O)-, -NR １５ C(=O)-(CH ２ ) ｑ - or -C(=O)NR １５ - (CH ２ ) ｑ - and q is 0, 1, 2, 3, 4, 5, or 6; R １４ and R １５ are each independently H, —C １ -C ６ Alkyl, —C １ -C ６ Alkyl-C(=O)OH, -(CH ２ CH ２ O) ｐ -CH ３ , -C(=O)-(CH ２ CH ２ O) ｐ -CH ３ , or -(CH ２ CH ２ O) ｐ -CH ２ CH ２ C(═O)OH, p is 1, 2, 3, 4, 5, or 6; L ７ does not exist or is -NH-, -N(CH ３ )-, —O—NH-, substituted or unsubstituted N-heterocycloalkylene, or —O—NH=(substituted or unsubstituted N-heterocycloalkylene), or a natural or unnatural amino acid; 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

44. L Ａ and L Ｂ if present, independently, -L ２ -, -L ３ -, -L ４ -, -L ５ -, -L ６ [[ID=I4]]-, -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<00OO601>-, -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[[ID=M]] ６ -L ７ -, -L ３ -L ４ -L ７ -, -L ４ -L ５ -L<000062]>-, -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 - is selected from, L ２ is a substituted or unsubstituted -C １ -C ２０ Alkylene -NR １６ -, substituted or unsubstituted -C １ -C ２０ Alkylene -NR １６ C(=O)-, substituted or unsubstituted -C １ -C ２０ Alkylene -NR １６ C(=O)NR １６ NH—, substituted or unsubstituted —C １ -C ２０ Alkylene -NR １６ C(=O)CH ２ NR １６ , -(CH ２ CH ２ O) ｚ , or -(CH ２ CH ２ O) ｗ -CH ２ CH ２ - and R １６ are each independently H and C １ -C ４ 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 linking said amino acids is -C １ -C ６ optionally substituted with alkyl; L ４ is -(CH ２ CH ２ O) ｖ -CH ２ CH ２ -, -C(=O)CH ２ CH ２ , -CH ２ CH ２ NHC(=O)-CH-CH ２ CH ２ C(=O)NHR １７ , -(CH ２ ) ｖ -NR １７ - (CH ２ ) ｖ , -NHC(=O)NH-O-(CH ２ ) ｖ -, -NHC(=O)NH-(CH ２ ) ｖ -, -NHC(=O)NH-NH-C(=O)(CH ２ ) ｖ -, -NHC(=O)CH ２ -O-NH-C(=O)(CH ２ ) ｖ -, or independently -NR １８ａ R １８ｂ Or -NR １８ C(=O)CH ２ CH ２ CH(COOH)NR １８ C(=O)-(CH ２ ) ｓ CH ３ -C optionally substituted with one or two groups selected from １ -C ６ is alkylene, R １７ are each independently H or a sugar alcohol or a derivative thereof, R １８ are each independently H, —C １ -C ６ alkyl or sugar alcohol or derivative thereof, R １８ａ are each independently H, —C １ -C ６ alkyl or sugar alcohol or derivative thereof, R １８ｂ are each independently H, —C １ -C ６ Alkyl, —C(═O)CH ２ CH ２ CH ２ -4-iodophenyl, or a sugar alcohol or a derivative thereof, v is an integer from 1 to 40, s is an integer from 1 to 20, L ５ is -NR １３ C(=O) and R １３ is H or C １ -C ４ is alkyl, L ６ Is, -L ８ -L ９ -L １０ - and L ８ does not exist or is -(CH ２ ) ｒ - or -(CH ２ ) ｒ -C(=O)NR １４ - and r is 0, 1, 2, or 3; L ９ is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, a monosaccharide, or 【Chemistry 13】 and k is 1, 2, 3, or 4; L １０ does not exist or is -(CH ２ ) ｑ -, -NR １５ - (CH ２ ) ｑ - or -NR １５ - (CH ２ ) ｑ -NR １５ - and q is 0, 1, 2, 3, 4, 5, or 6; R １４ and R １５ are each independently H or —C １ -C ６ alkyl-C(=O)OH; p is 1, 2, 3, 4, 5, or 6; L ７ is —NH— or a natural or unnatural amino acid, 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof.

45. L Ａ But, -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 45. The compound of claim 43 or 44, wherein: -, or a pharmaceutically acceptable salt thereof.

46. L ２ 46. ​​The compound of any one of claims 43 to 45, or a pharmaceutically acceptable salt thereof, wherein is absent.

47. L ２ is a substituted or unsubstituted -C １ -C ２０ Alkylene, substituted or unsubstituted -C １ -C ２０ Alkylene-NH-, substituted or unsubstituted -C １ -C ２０ Alkylene -C(=O)NH-, substituted or unsubstituted -C １ -C ２０ Alkylene -C(=O)NCH ３ -, substituted or unsubstituted -C １ -C ２０ Alkylene-NHC(=O)-, substituted or unsubstituted -C １ -C ２０ Alkylene -NHC(=O)NHNH-, or substituted or unsubstituted -C １ -C ２０ Alkylene -NHC(=O)CH ２ 46. ​​The compound of any one of claims 43 to 45, or a pharmaceutically acceptable salt thereof, which is NH-.

48. L ２ But -(CH ２ CH ２ O) ｗ -CH ２ CH ２ 46. ​​The compound of any one of claims 43 to 45, or a pharmaceutically acceptable salt thereof, wherein:

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

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

51. L ３ 51. The compound of any one of claims 43 to 50, or a pharmaceutically acceptable salt thereof, wherein is absent.

52. L ３ is a natural amino acid, an unnatural amino acid, or alanine (Ala), 3-(2-naphthyl)-alanine (2-Nal), arginine (Arg), asparagine (Asn), aspartate (Asp), cysteine ​​(Cys), cysteic acid, glutamine (Gln), glutamate (Glu), gamma-carboxyglutamate (Gla), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), hydroxylysine (Hyl), ornithine (Orn), A peptide formed from two or more independently selected amino acids selected from the group consisting of 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 linked to said amino acids is -CH ３ 51. The compound of any one of claims 43 to 50, or a pharmaceutically acceptable salt thereof, optionally substituted with:

53. L ４ 53. The compound of any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein is absent.

54. L ４ -C(=O)CH ２ CH ２ 53. The compound of any one of claims 43 to 52, or a pharmaceutically acceptable salt or solvate thereof, wherein

55. L ４ But -(CH ２ CH ２ O) ｖ -CH ２ CH ２ 53. The compound of any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein:

56. L ４ But -(CH ２ ) ｖ -NR １７ - (CH ２ ) ｖ 53. The compound of any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein:

57. L ４ is -NH(C=O)NH-O-(CH ２ ) ｖ -, -NHC(=O)NH-(CH ２ ) ｖ -, -NHC(=O)NH-NH-C(=O)(CH ２ ) ｖ -, or -NHC(=O)CH ２ -O-NH-C(=O)(CH ２ ) ｖ 53. The compound of any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, wherein:

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

59. L ４ But -CH ２ CH ２ NHC(=O)-CH-CH ２ CH ２ C(=O)NHR １７ 58. The compound of any one of claims 43 to 57, wherein:

60. L ４ But independently -OR １８ or -NR １８ａ R １８ｂ -C optionally substituted with one or two groups selected from １ -C ６ 53. The compound of any one of claims 43 to 52, or a pharmaceutically acceptable salt thereof, which is alkylene.

61. R １７ is CH ３ 60. The compound of claim 56 or 59, wherein:

62. R １７ 60. The compound of claim 56 or 59, or a pharmaceutically acceptable salt thereof, wherein is sorbitol or a derivative thereof.

63. R １８ａ is H and R １８ｂ is H or CH ３ 63. The compound of any one of claims 43 to 62, wherein:

64. L ５ 64. The compound of any one of claims 43 to 63, or a pharmaceutically acceptable salt thereof, wherein is absent.

65. L ５ 64. The compound of any one of claims 43 to 63, or a pharmaceutically acceptable salt thereof, wherein is -C(=O)NH- or -NHC(=O)-.

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

67. L ６ 66. The compound of any one of claims 43 to 65, or a pharmaceutically acceptable salt thereof, wherein is absent.

68. L ８ 68. The compound of any one of claims 43 to 67, or a pharmaceutically acceptable salt thereof, wherein is absent.

69. L ８ Ga-(CH ２ ) ｒ 68. The compound of any one of claims 43 to 67, or a pharmaceutically acceptable salt thereof, wherein:

70. L ８ Ga-(CH ２ ) ｒ -C(=O)NR １４ 68. The compound of any one of claims 43 to 67, or a pharmaceutically acceptable salt or solvate thereof, wherein

71. R １４ Ga-CH ２ CO ２ H, or a pharmaceutically acceptable salt thereof.

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

73. L １０ 73. The compound of any one of claims 43 to 72, or a pharmaceutically acceptable salt thereof, wherein is absent.

74. L １０ Ga-(CH ２ ) ｑ 73. The compound of any one of claims 43 to 72, or a pharmaceutically acceptable salt thereof, wherein:

75. L １０ But, -NR １５ - (CH ２ ) ｑ -or-NR １５ - (CH ２ ) ｑ -NR １５ 73. The compound of any one of claims 43 to 72, or a pharmaceutically acceptable salt thereof, wherein:

76. L １０ -C(=O)NR １５ - (CH ２ ) ｑ 73. The compound of any one of claims 43 to 72, or a pharmaceutically acceptable salt or solvate thereof, wherein

77. R １５ 77. The compound of claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein

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

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

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

81. L ９ 80. The compound of any one of claims 43 to 79, or a pharmaceutically acceptable salt thereof, wherein is azetidinylene, pyrrolidinylene, piperidinylene, or piperazinylene.

82. L ９ 80. The compound of any one of claims 43 to 79, or a pharmaceutically acceptable salt thereof, wherein is a monosaccharide.

83. L ９ but, 【Chemistry 14】 80. The compound of any one of claims 43 to 79, wherein:

84. L ９ is unsubstituted or substituted C ４ -C ８ 80. The compound of any one of claims 43 to 79, or a pharmaceutically acceptable salt thereof, which is cycloalkylene.

85. L ９ but, 【Chemistry 15】 80. The compound of any one of claims 43 to 79, wherein:

86. L ９ 80. The compound of any one of claims 43 to 79, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted phenylene.

87. L ７ 87. The compound of any one of claims 43 to 86, or a pharmaceutically acceptable salt thereof, wherein is absent.

88. L ７ 87. The compound of any one of claims 43 to 86, or a pharmaceutically acceptable salt thereof, wherein is -NH- or a natural or unnatural amino acid.

89. -L Ａ -R Ａ Ga-L ２ -L ３ -R Ａ and L ２ is unsubstituted -C １ -C ６ Alkylene-NH- or unsubstituted -C １ -C ６ Alkylene -NHC(=O)CH ２ NH- and L ３ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein is a natural or unnatural amino acid.

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

91. -L Ａ -R Ａ Ga-L ２ -L ６ -R Ａ and L ２ is unsubstituted -C １ -C ６ alkylene -NHC(=O)-, and L ６ Ga-L ８ -L ９ -L １０ 43. The compound of any one of claims 1 to 42, wherein:

92. -L Ａ -R Ａ Ga-L ２ -L ７ -R Ａ and L ２ Ga-(CH ２ CH ２ O) ｗ -CH ２ CH ２ - and L ７ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein is -NH-.

93. -L Ａ -R Ａ But, -L ２ -L ４ -L ７ -R Ａ and L ２ is unsubstituted C １ -C ６ Alkylene -C(=O)NCH ３ -, unsubstituted -C １ -C ６ Alkylene-NHC(=O)-, unsubstituted -C １ -C ６ Alkylene -NHC(=O)NHNH- or one -NR １８ａ R １８ｂ -C optionally substituted with １ -C ６ is alkylene, L ４ But -(CH ２ CH ２ O) ｖ -CH ２ CH ２ -, -C(=O)CH ２ CH ２ , -(CH ２ ) ｖ -NR １７ - (CH ２ ) ｖ , -NHC(=O)NH-O-(CH ２ ) ｖ -,-NHC(=O)NH-(CH ２ ) ｖ -, -NHC(=O)NH-NH-C(=O)(CH ２ ) ｖ -, -NHC(=O)CH ２ -O-NH-C(=O)(CH ２ ) ｖ - or optionally substituted -C １ -C ６ is alkylene, L ７ is —NH— or —O—NH; 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

94. -L Ａ -R Ａ But, -L ２ -L ６ -L ７ -R Ａ and L ２ is unsubstituted -C １ -C ６ Alkylene, unsubstituted -C １ -C ６ Alkylene -NH- or unsubstituted -C １ -C ６ alkylene-NHC(═O)—, L ６ But, -L ８ -L ９ -L １０ - and L ７ is -NH-, -O-NH-, or a natural or unnatural amino acid; 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

95. -L Ａ -R Ａ But, -L ２ -L ３ -L ４ -L ７ -R Ａ and L ２ is unsubstituted -C １ -C ６ alkylene-NH-; L ３ is a peptide formed from glutamine or two or more glycines, in which the N atom of the amide linked to said amino acid is -CH ３ is replaced by L ４ is -C(=O)CH ２ CH ２ - or - (CH ２ ) ｖ -NR １７ - (CH ２ ) ｖ and L ７ is —NH—; 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

96. -L Ａ -R Ａ But, -L ２ -L ４ -L ５ -L ７ -R Ａ and L ２ is a substituted or unsubstituted -C １ -C ６ alkylene-NHC(═O)—, L ４ But -NH ２ -C optionally substituted with １ -C ６ is alkylene, L ５ is —NH—, L ７ But it is Bip, 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

97. -L Ａ -R Ａ But, -L ４ -L ５ -L ６ -L ７ -R Ａ and L ４ But -(CH ２ CH ２ O) ｖ -CH ２ CH ２ - and L ５ is —NHC(═O)—, L ６ But, -L ８ -L ９ -L １０ - and L ７ is —NH—; 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

98. -L Ａ -R Ａ But, -L ２ -L ４ -L ５ -L ６ -L ７ - and L ２ is unsubstituted -C １ -C ６ alkylene-NHC(═O)—, L ４ But -NH ２ -C substituted with １ -C ６ alkylene-, L ５ is —NHC(═O)—, L ６ But, -L ８ -L ９ -L １０ - and L ７ is —NH—; 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

99. -L Ａ - and -L Ｂ -, when present, are each independently 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 43. The compound of any one of claims 1 to 42, wherein:

100. -L Ａ -R Ａ and -L Ｂ -R Ｂ are present, each independently 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 43. The compound of any one of claims 1 to 42, wherein:

101. The compound of formula (II) has the following structure: 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 or a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

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

103. 102. The compound of any one of claims 1 to 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. 102. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of the radionuclide complex is a diagnostic or therapeutic radionuclide.

105. 102. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of the radionuclide complex is an Auger electron-emitting radionuclide, an α-emitting radionuclide, a β-emitting radionuclide, or a γ-emitting radionuclide.

106. the radionuclide of the radionuclide complex is 111-Indium ( １１１ In), 67-gallium ( ６７ Ga), 68-gallium ( ６８ Ga), 99m-technetium ( ９９ｍ Tc), or 195m-Platinum ( １９５ｍ an Auger electron emitting radionuclide, which is 225-Actinium ( ２２５ Ac), 213-bismuth ( ２１３ Bi), 223-radium ( ２２３ Ra), or 212-lead ( ２１２ α-emitting radionuclide, which 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-Fri ( １９８ Au), 169-erbium ( １６９ Er), 165-dysprosium ( １６５ Dy), 99m-technetium ( ９９ｍ Tc), 89-zirconium ( ８９ Zr), or 52-manganese ( ５２ Mn), or 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) a gamma-emitting radionuclide 102. The compound of any one of claims 1 to 101, wherein:

107. 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 ( ６７ 102. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, wherein:

108. 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 ( １７７ 102. The compound of any one of claims 1 to 101, or a pharmaceutically acceptable salt thereof, wherein:

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

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

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

112. the cancer comprises a tumor, and the tumor is １ Receptor (NPY １ 112. The method of claim 111, wherein the vector is overexpressing a gene encoding the vector R.

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

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

115. Neuropeptide Y in mammals １ Receptor (NPY １ 109. A method of killing tumors overexpressing a nucleotide analog of ribonucleotide 1 (RI) comprising administering to said mammal a compound of any one of claims 1 to 108, or a pharmaceutically acceptable salt thereof, wherein the compound of any one of claims 1 to 108, or a pharmaceutically acceptable salt thereof, comprises a therapeutic radionuclide.

116. 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, nephroblastoma, or adrenal tumor.

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

118. Neuropeptide Y in mammals １ Receptor (NPY １ 109. A method of identifying tumors expressing a diagnostic radionuclide (RAR), comprising administering to the mammal a compound of any one of claims 1-108, or a pharmaceutically acceptable salt thereof, and performing positron emission tomography (PET) analysis, single photon emission tomography (SPECT), or magnetic resonance imaging (MRI), wherein the compound of any one of claims 1-108, or a pharmaceutically acceptable salt thereof, comprises a diagnostic radionuclide.

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

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