Non-peptide targeted therapy and uses thereof

Abstract

Described herein are non-peptide drug conjugates (NPDCs) that target tumor cells expressing cell surface peptides and G protein-coupled receptors and their use in the treatment and / or diagnosis of cancer.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 208,923, filed June 9, 2021, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION Described herein are non-peptide drug conjugates (NPDCs) and methods of using such conjugates in the treatment, diagnosis, or both of cancer. [Background technology]

[0003] Neoplasms are abnormal proliferations of cells that cause enormous medical burdens, including morbidity and mortality, to humans. Neoplasms include benign or non-cancerous neoplasms (e.g., adenomas), which do not show malignant characteristics and are generally unlikely to be dangerous, malignant neoplasms that show characteristics such as genetic mutations, loss of normal functions, rapid division, and the ability to metastasize (invade) other tissues, as well as neoplasms that exhibit unclear or unknown behavior. Malignant neoplasms (i.e., cancerous solid tumors) are the leading cause of death in developed countries. Non-cancerous neoplasms, including benign adenomas, can also cause significant morbidity and mortality. Although standard treatments can provide significant effects in tumor growth inhibition and even tumor elimination, the applied drugs show only minor selectivity for malignant tissues over healthy tissues, and severe side effects limit their effectiveness and applications. Specific targeting of neoplasms that do not affect healthy tissues is highly desired in effective solid tumor treatment. As one of the three major classes of cell surface receptors, G protein-coupled receptors (GPCRs) are frequently overexpressed in tumor cells and are regarded as promising targets for selective tumor therapy. Despite the advantages achieved by peptide drug conjugates (PDCs) targeting cell surface receptors, there is a great need for therapies and diagnostics that overcome the limitations imposed by peptide- and protein-based targeted therapies, such as their inability to penetrate large solid tumors, instability to proteases and peptidases, unfavorable absorption, distribution, metabolism, and excretion (ADME) properties, and manufacturing difficulties. Non-peptide ligands conjugated to suitable drug cargo or payload moieties are a novel class of selective cancer therapy or diagnostics. Summary of the Invention

[0004] Non-peptide drug conjugates and their use in tumor treatment are described herein.The present disclosure provides an alternative and improved method for tumor treatment.In some embodiments, the non-peptide drug conjugates disclosed herein provide an improved method for targeting tumor cells compared to conventional treatments with narrow therapeutic index.

[0005] In one embodiment, the compound is according to formula (I) or a pharma- ceutically acceptable salt thereof:

[0006] [ka] During the ceremony, NPs are non-peptide ligands that bind to G protein-coupled receptors (GPCRs) expressed on tumor cells; Q is a payload moiety comprising a chelating moiety or its radionuclide (Z) conjugate; and L is a linker covalently connecting the non-peptide ligand NP and the payload moiety Q; Compounds according to formula (I), or pharma- ceutically acceptable salts thereof, are described herein, wherein the linker, L, is attached to NP at a position that permits attachment of NP to a peptide or protein GPCR, and upon administration to a mammal, the compounds according to formula (I), or pharma- ceutically acceptable salts thereof, target tumor cells that express the GPCR.

[0007] In some embodiments, the GPCR is a receptor for an endogenous peptide or protein ligand. In some embodiments, the GPCR is a receptor for an endogenous peptide or protein hormone or chemokine.

[0008] In some embodiments, the NP is a small molecule that binds to a GPCR that recognizes an endogenous peptide or protein hormone that is adrenocorticotropic hormone (ACTH), amylin, angiotensin, atrial natriuretic peptide (ANP), calcitonin, cholecystokinin (CCK), gastrin, ghrelin, glucagon, growth hormone (GH), follicle stimulating hormone (FSH), insulin, leptin, melanocyte stimulating hormone (MSH), neuropeptide Y, oxytocin, parathyroid hormone (PTH), prolactin, renin, somatostatin, thyroid stimulating hormone (TSH), thyrotropin releasing hormone (TRH), vasopressin, or vasoactive intestinal peptide (VIP). In some embodiments, the NP binds to a GPCR that recognizes an endogenous peptide or protein hormone only if the GPCR does not bind neurotensin.

[0009] In some embodiments, the GPCR is a chemoattractant GPCR. In some embodiments, the chemoattractant GPCR is a classical GPCR that is a formyl peptide receptor (FPR1, FPR2 or FPR3), a platelet-activating factor receptor (PAFR), an activated complement component 5a receptor (C5aR), or a chemokine GPCR that binds to a CC chemokine (β-chemokine), a CXC chemokine (α-chemokine), a C chemokine (γ-chemokine) or a CX3C chemokine (d-chemokine).

[0010] In some embodiments, the GPCR is an angiotensin receptor, an apelin receptor, a bombesin receptor, a bradykinin receptor, a calcitonin receptor, a chemokine receptor, a cholecytokinin receptor, a corticotropic releasing factor receptor, a galanin receptor, a ghrelin receptor, a glucagon receptor, a glycoprotein hormone receptor, a gonadotropin releasing hormone receptor, a kisspeptin receptor, a melanocortin receptor, a motilin receptor, a neuromedin U receptor, a neuropeptide FF / AF receptor, a neuropeptide S receptor, a neuropeptide W / B receptor, a neuropeptide Y receptor, an opioid receptor, an orexin receptor, a parathyroid hormone receptor, a prokineticin receptor, a prolactin releasing peptide receptor, a QRFP receptor, a relaxin family peptide receptor, a somatostatin receptor, a tachykinin receptor, a thyrotropin releasing hormone receptor, a urotensin receptor, a vasopressin and an oxytocin receptor, a VIP receptor, or a PACAP receptor.

[0011] In another aspect, a method for treating a tumor in a mammal is described herein, the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor comprises tumor cells expressing a GPCR. In some embodiments, the tissue comprising the tumor cells also comprises non-neoplastic cells that do not express a GPCR or express a GPCR at a lower expression level than the tumor cells. In some embodiments, the tumor cells overexpress a GPCR. In some embodiments, the GPCR expressed in the tumor cells of the tumor is targeted by a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor cells are cells of a solid tumor, an adenoma, a sarcoma, a carcinoma, or a lymphoma. In some embodiments, the tumor cells are cells of a neoplasm.

[0012] In some embodiments, the benign or malignant neoplasms include solid tumors, adenomas, sarcomas, carcinomas, or lymphomas based on the type of cellular origin. In some embodiments, the mammal having the malignant neoplasm has anal cancer, bladder cancer, intestinal cancer, brain cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, heart cancer, kidney cancer, lung cancer, liver cancer, melanoma, uterine cancer, lymphoma, ovarian cancer, pancreatic cancer, or prostate cancer.

[0013] In some embodiments, the solid tumor is an endocrine tumor (i.e., endocrine origin). In some embodiments, the endocrine tumor is an adrenal tumor, a neuroendocrine tumor, a parathyroid tumor, a pituitary tumor, or a thyroid cancer. In some embodiments, the tumor comprises a neuroendocrine tumor. In some embodiments, the tumor comprises a somatostatin receptor positive gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

[0014] In some embodiments, the mammal having a benign neoplasm has an adenoma of the colon, kidney, adrenal gland, thyroid, pituitary, parathyroid, liver, breast, appendix, bronchus, prostate, sebaceous gland, or salivary gland.

[0015] In some embodiments, NP is a non-peptide ligand that binds to a somatostatin receptor expressed in tumor cells, NP is a non-peptide ligand that includes a 4-(4-aminopiperidin-1-yl)-5-(phenyl)pyridine structural motif or a 4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(phenyl)pyridine structural motif, and -LQ is attached to NP at the 2-position of the pyridine.

[0016] In some embodiments, the NP has a structure according to formula (II) below, or a pharma- ceutically acceptable salt thereof:

[0017] [ka] During the ceremony, R A teeth,

[0018] [ka] and R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -CN, -N(R 7 )2, or -OR 7 and R 5 is hydrogen or a substituted or unsubstituted C1-C6 alkyl; R 6 is hydrogen, -OR 7 , -N(R 7 )2, -CN, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R 5 and R 6 together with the intervening atoms to which they are attached form a morpholine, and X 1 does not exist or is -O-, -S-, -N(R 7 )-, -C(=O)-, -C(=O)N(R 7 )-, -C(=O)O-, -N(R 7 )C(=O)-, or a heterocycle; R 7 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl.

[0019] In some embodiments, the NP is a non-peptide ligand that binds to a gonadotropin releasing hormone receptor (GnRHR) expressed in tumor cells, and the NP is a non-peptide ligand that includes a N-{4,6-dimethoxy-pyrimidin-5-yl}-5-[3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide structural motif, a N-(4,6-dimethoxypyrimidin-5-yl)-5-(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy)-2-furamide structural motif, or a N-(4,6-dimethoxypyrimidin-5-yl)-5-((3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy)furan-2-carboxamide structural motif.

[0020] In some embodiments, the NP has a structure according to formula (X) below, or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof:

[0021] [ka] During the ceremony, T is absent, -CH2-, -CH(CH3)-, or -C(CH3)2-; X 2 is not present or is -O- or -N(R 7 )-and V is CH or N and W is CH or N; and R 7 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl.

[0022] In yet another aspect, a method for targeted delivery of a radionuclide to a tumor in a mammal, comprising administering to a mammal having a tumor a compound according to formula (I) below, or a pharma- ceutically acceptable salt thereof:

[0023] [ka] During the ceremony, NPs are non-peptide ligands that bind to G protein-coupled receptors (GPCRs) expressed on tumor cells; Q is a payload moiety comprising a radionuclide (Z) and a chelator configured to bind to the radionuclide (Z); L is a linker that covalently connects the non-peptide small molecule ligand NP and the payload moiety Q, methods described herein.

[0024] In some embodiments, tumor cells are present in tissues and / or organs that contain non-neoplastic cells that do not express target GPCR or express target GPCR at a level below the expression level in tumor cells.In some embodiments, tumor cells overexpress GPCR.In some embodiments, tumor cells overexpress GPCR targeted by compound of formula (I).

[0025] In some embodiments, L is a non-cleavable linker or a cleavable linker.

[0026] In some embodiments, NP is a non-peptide ligand that binds to a GPCR that recognizes an endogenous peptide or protein hormone. In some embodiments, the GPCR is expressed in a tumor cell of a solid tumor, an adenoma, a sarcoma, a carcinoma, or a lymphoma, Q comprises a radionuclide (Z) and a chelator configured to bind to the radionuclide (Z), and L is an optional non-cleavable linker.

[0027] In some embodiments, Z is a diagnostic or therapeutic radionuclide. In some embodiments, Z is an Auger electron emitting radionuclide, an alpha-emitting radionuclide, a beta-emitting radionuclide, or a gamma-emitting radionuclide. In some embodiments, Q 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).

[0028] In a further aspect, there is provided a method for identifying a tissue or organ in a mammal that contains tumor cells that express a G protein-coupled receptor (GPCR), comprising: (i) A compound according to the following formula (I):

[0029] [ka] or a pharma- ceutically acceptable salt thereof to a mammal, During the ceremony, NPs are non-peptide ligands that bind to G protein-coupled receptors (GPCRs) expressed on tumor cells; Q is a payload moiety comprising a chelating moiety or its radionuclide (Z) conjugate; L is a linker covalently linking the non-peptide ligand NP and the payload moiety Q, where the linker L is attached to NP at a position that allows binding of NP to a GPCR; (ii) performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); A method is described herein, comprising:

[0030] In some embodiments, the tumor cells overexpress the GPCR. In some embodiments, the tumor cells overexpress the GPCR that is targeted by the compound of formula (I).

[0031] In another aspect, there is provided a method for in vivo imaging of a tissue or organ in a mammal having a tumor, comprising: (i) A compound according to the following formula (I):

[0032] [ka] or a pharma- ceutically acceptable salt thereof to a mammal, During the ceremony, NPs are non-peptide ligands that bind to G protein-coupled receptors (GPCRs) expressed on tumor cells; Q is a payload moiety comprising a chelating moiety or its radionuclide (Z) conjugate; L is a linker covalently linking the non-peptide ligand NP and the payload moiety Q, where the linker L is attached to NP at a position that allows binding of NP to a GPCR; (ii) performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); A method is described herein, comprising:

[0033] In some embodiments, tumor cells are present in tissues and / or organs that contain non-neoplastic cells that do not express target GPCR or express target GPCR at a level below the expression level in tumor cells.In some embodiments, tumor cells overexpress GPCR.In some embodiments, tumor cells overexpress GPCR targeted by compound of formula (I).

[0034] In some embodiments, a method for identifying a tissue or organ in a mammal that overexpresses a G protein-coupled receptor (GPCR), comprising: (i) A compound according to the following formula (I):

[0035] [ka] or a pharma- ceutically acceptable salt thereof to a mammal, During the ceremony, NPs are non-peptide ligands that bind to G protein-coupled receptors (GPCRs) expressed on tumor cells; Q is a payload moiety comprising a chelating moiety or its radionuclide (Z) conjugate; L is a linker covalently linking the non-peptide ligand NP and the payload moiety Q, where the linker L is attached to NP at a position that allows binding of NP to a GPCR; (ii) performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); A method is described herein, comprising:

[0036] In some embodiments, Z comprises a diagnostic radionuclide. In some embodiments, step (ii) is initiated following step (i) with a time sufficient for interaction between the compound described in Formula (I) and a GPCR expressed in a tumor cell in the mammal.

[0037] Also described herein is a pharmaceutical composition comprising the compound described herein, or its pharmaceutically acceptable salt or solvate, and at least one pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration.

[0038] In another aspect, described herein is a method for treating cancer comprising administering to a mammal having cancer an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0039] In another aspect, described herein is a method for treating a tumor with a radionuclide, the method comprising administering to a mammal having the tumor an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0040] In some embodiments, the mammal has anal cancer, bladder cancer, intestinal cancer, brain cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, heart cancer, kidney cancer, lung cancer, liver cancer, melanoma, uterine cancer, lymphoma, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the mammal has an endocrine cancer. In some embodiments, the endocrine cancer is an adrenal tumor, a neuroendocrine tumor, a parathyroid tumor, a pituitary tumor, or a thyroid tumor.

[0041] In some embodiments, the mammal has a neuroendocrine tumor. In some embodiments, the mammal has a somatostatin receptor positive gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

[0042] In some embodiments, the tumor comprises an adenoma, hi some embodiments, the adenoma is of the colon, kidney, adrenal gland, thyroid, pituitary, parathyroid, liver, breast, appendix, bronchus, prostate, sebaceous gland, or salivary gland.

[0043] In any of the embodiments disclosed herein, the mammal is a human.

[0044] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description, but it will be understood that the detailed description and specific examples, while indicating particular embodiments, are given by way of example 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.

[0045] Detailed Description of the Invention Cancer is a disease in which some cells undergo genetic changes in the control of their growth and replication, resulting in uncontrolled growth and spread, and is one of the leading causes of death worldwide. Common types of cancer include solid tumors (cancers that typically originate from organs), carcinomas (cancers that originate from the skin or tissues that cover organs), sarcomas (cancers of connective tissues such as bone), leukemias (cancers of the bone marrow), and lymphomas and myelomas (cancers of the immune system). Neoplasms can be benign (i.e., do not show malignant characteristics and are generally unlikely to pose a danger, such as adenomas), malignant (i.e., exhibit characteristics such as genetic mutations, loss of normal functions, rapid division, and the ability to metastasize (invade) other tissues), and are abnormal proliferations of cells that result in solid tumors with unstable or unknown behavior. State-of-the-art treatment of neoplasms is achieved by a combination of surgery, chemotherapy, and radiation therapy. Surgery can be curative under some conditions, but often requires multiple interventions and combinations with radiation therapy and chemotherapy. Chemotherapy has often proven to be a powerful weapon in the fight against cancer and further optimization is required. Chemotherapy is typically performed by systemic administration of potent cytotoxic drugs, but these compounds lack tumor selectivity and therefore also kill healthy cells in the body. The resulting non-specific toxicity does not target cancer cells more specifically than other cells and is responsible for chemotherapy's severe side effects. Radiotherapy is the use of high-energy radiation to kill cells. The source of radiation can be external beam radiation (applied using an external source), internal radiation (placement of a radioactive material near the target cells), or radiation therapy from systemic administration of a radioactive material. As with chemotherapy, many radiotherapy options also lack the tumor cell-identifying properties necessary to achieve the ultimate goal of targeted tumor treatment with drug molecules or radionuclides.

[0046] Described herein is the design of NPDCs that utilize the features that selectively identify neoplasms, such as significantly overexpressed cell surface receptors, that are different from healthy cells, to achieve therapeutic effects only in selected cells.Neoplasms that overexpress various cell surface GPCRs are actively targeted with the NPDCs described herein, thereby selectively delivering anticancer drugs or radionuclides to malignant cells.

[0047] GPCRs are a diverse group of integral membrane receptors and, as a result, are expressed in every cell type in the body. The function of GPCRs is to detect a host of extracellular signals, including but not limited to light, peptides, lipids, sugars, and proteins, and transduce the signals across the membrane to convert them into intracellular responses. Because of these important actions, the GPCR superfamily is the largest and most important family of drug targets, as highlighted by the large number of approved therapeutics that target this class. GPCRs are generally poorly antigenic and therefore challenging targets for antibody-based strategies. For many GPCRs, the majority of the protein population resides in intracellular compartments at any given time, reducing the total number of cell surface binding sites accessible to antibodies or peptides.

[0048] Many GPCRs, especially those that recognize endogenous peptides and endogenous proteins such as chemokines, are ideal in NPDCs with appropriate drug cargo or payload due to their restricted physiological expression and frequent overexpression, especially in refractory cancers (Reubi et al, The Journal Of Nuclear Medicine, Vol. 58, No. 9 (Suppl. 2), 10S-15S). Many human tumors overexpress different GPCRs, often at a significantly higher density than other tissues. For example, gastrointestinal and pancreatic (GEP) neuroendocrine tumors (NETs) overexpress somatostatin receptors, namely SSTR2, SSTR3, and SSTR5. Other peptide receptors, such as the incretin receptor glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) receptor, and cholecystokinin (CCK) receptor (CCK1 and CCK2 subtypes), are overexpressed in NETs. Medullary thyroid carcinoma (MTC) overexpresses CCK2 and GIP receptors. Breast cancer overexpresses gastrin releasing peptide (GRP) receptors, the Y1 subtype of neuropeptide Y (NPY) receptor, SSTR2, and CXCR4. Due to the complex GPCR overexpression profile in neoplasms, targeting multiple receptors simultaneously may address issues such as heterogeneity, resistance, and phenotypic changes during disease progression that have hindered many current treatment options.

[0049] Most currently available GPCR-targeting drugs act on receptors whose natural ligands are small molecules, such as histamine, adrenaline, and neurotransmitters. Drugs that target GPCRs whose natural ligands are peptides or proteins are also typically peptides or proteins.

[0050] Peptides are inherently sensitive to proteolytic enzymes and peptidases present in most tissues, and are rapidly degraded into multiple fragments that no longer have significant affinity for the intended receptor. Although there are methods to stabilize peptides (e.g., incorporating peptidomimetic structures or using more stable D-amino acids in the peptide backbone), such modifications may result in loss of affinity and / or selectivity and adversely affect physicochemical properties (e.g., low solubility and tendency to aggregate). In addition, peptides may cause undesirable immunogenic responses and complicate later stages of development by masking therapeutic effects and affecting safety evaluation.

[0051] When peptide ligands are linked to radionuclide payloads, the resulting conjugates often degrade rapidly in plasma, generating radioactive peptide fragments that can bind nonspecifically to both tumor and normal tissues. Such early degradation of peptide drug conjugates (PDCs) and antibody drug conjugates (ADCs) reduces the amount of radionuclide payload distributed to the target tumor, reducing therapeutic efficacy and, in some cases, increasing toxicity. In addition, peptides are most likely excreted exclusively via the kidney, which may limit their application. The significant renal uptake of some peptide-based therapeutics has limited their routine use.

[0052] High affinity small molecule ligands that bind to peptide GPCRs and protein GPCRs, such as chemokine GPCRs, have been described, and are cell permeable and can access receptor populations in the endoplasmic reticulum and endosomes. The low molecular weight of non-peptide small molecules should improve vascular permeability and tumor penetration compared to high molecular weight complexes based on peptides and antibodies. The binding affinity of small molecule non-peptide ligands often exceeds that of FDA-approved antibodies by orders of magnitude.

[0053] Provided herein is a non-peptide drug conjugate (NPDC). When the non-peptide ligand of NPDC, which is a small molecule, binds to GPCR, it is embedded in the extracellular loop of GPCR, and the conjugated drug cargo or payload portion of NPDC points to the extracellular space. The conjugated drug cargo or payload portion is linked to the non-peptide ligand in a manner that does not affect the binding affinity of the non-peptide ligand to GPCR. The conjugated drug cargo or payload portion comprises a chelated radionuclide that is linked to the non-peptide ligand using a stable linker or a cleavable linker.

[0054] In some embodiments, slowly dissociating non-peptide ligands for GPCRs can maintain therapeutically effective concentrations in target tissues after they are cleared from the systemic circulation, resulting in improved therapeutic windows and extended duration of action compared to their circulating plasma concentrations. In some embodiments, similar optimization of receptor residence time can be used as a selective tumor targeting mechanism to increase the local concentration of radionuclide conjugates in tumors or extend tumor residence time without relying on tumor-specific intracellular trafficking. This same principle of concentration of GPCR ligands in target tissues allows PET labeling or radioligand imaging studies to visualize defined regions of receptor expression. If the conjugates are stably linked, the release of non-selective free toxins can be avoided, and conjugates that initially "lack" their cytotoxic target can be retained in the tumor for further attempts. In some embodiments, conjugation of a suitable payload (e.g., a radionuclide) to a non-peptide small molecule GPCR ligand provides an improved method for targeting radionuclide conjugates to cancerous tissues.

[0055] In some embodiments, non-peptide ligands of internalized GPCRs are optimized to increase internalization and improve intracellular retention.

[0056] Non-peptide small molecule drug conjugates (NPDCs) In one aspect, a non-peptide drug conjugate (NPDC) is described herein. In some embodiments, the NPDC is a compound according to formula (I) below, or a pharma- ceutically acceptable salt thereof:

[0057] [ka] During the ceremony, NPs are non-peptide ligands that bind to G protein-coupled receptors (GPCRs) expressed on tumor cells; Q is a payload moiety comprising a chelating moiety or its radionuclide (Z) conjugate; and L is a linker covalently linking the non-peptide ligand NP and the payload moiety Q, where the linker L is attached to NP at a position that allows binding of NP to a peptide or protein GPCR, and where, upon administration to a mammal, the compound according to formula (I), or a pharma- ceutically acceptable salt thereof, targets tumor cells that express the GPCR.

[0058] In some embodiments, NPDC is a compound having a structure according to formula (I) below, or a pharma- ceutically acceptable salt thereof:

[0059] [ka] During the ceremony, NPs are non-peptide ligands that bind to G protein-coupled receptors (GPCRs) expressed on tumor cells; Q is a payload moiety comprising a radionuclide (Z) and a chelator configured to bind to the radionuclide (Z); and L is a linker covalently linking the non-peptide small molecule ligand NP and the payload moiety Q, where the linker L is attached to NP at a position that allows binding of NP to a peptide or protein GPCR, and where, upon administration to a mammal, the compound according to formula (I), or a pharma- ceutically acceptable salt thereof, is targeted to tissues, including tumor cells that express the GPCR.

[0060] Tissues and receptors targeted In some embodiments, the compounds of formula (I) exhibit activity for the target GPCR receptor. In some embodiments, the activity is functional activity. In some embodiments, the activity is binding affinity. In some embodiments, the compounds of formula (I) exhibit functional activity for the target GPCR receptor. In some embodiments, the compounds of formula (I) exhibit binding affinity for the target GPCR receptor. In some embodiments, the compounds of formula (I) demonstrate binding affinity or functional activity for the target GPCR receptor with a binding affinity or functional activity of less than 100 nM as measured in a suitable in vitro assay for measuring such binding activity or functional activity. In some embodiments, the compounds of formula (I) demonstrate binding affinity or functional activity for the target GPCR receptor with a binding affinity or functional activity of less than 100 nM as measured in a suitable in vitro assay for measuring such binding activity or functional activity. In some embodiments, the compounds of formula (I) exhibit binding affinity or functional activity for the target GPCR receptor with a binding affinity or functional activity of less than 100 nM as measured in a suitable in vitro assay for measuring such binding activity. In some embodiments, the compounds of formula (I) exhibit binding affinity or functional activity for the target GPCR receptor with a binding affinity of less than 10 nM as measured in a suitable in vitro assay for measuring such binding activity. In some embodiments, the compounds of formula (I) demonstrate binding affinity or functional activity for a target GPCR receptor with a binding affinity or functional activity of less than 5 nM as measured in a suitable in vitro assay that measures such binding activity. In some embodiments, the compounds of formula (I) demonstrate binding affinity or functional activity for a target GPCR receptor with a binding affinity or functional activity of less than 1 nM as measured in a suitable in vitro assay that measures such binding activity or functional activity.

[0061] In some embodiments, the compound of formula (I) has a binding affinity or functional activity for a target GPCR receptor that is at least 10 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, or at least 1000 times greater than the binding affinity or functional activity for a non-target receptor. In some embodiments, the compound of formula (I) is selective for one GPCR. In some embodiments, the compound of formula (I) is selective for one family of GPCRs (e.g., the somatostatin receptor family, including SSTR1, SSTR2, SSTR3, SSTR4, SSTR5). In some embodiments, the compound of formula (I) is selective for one GPCR within a family of GPCRs. In some embodiments, the compound of formula (I) has a binding affinity or functional activity for a GPCR that is at least 10 times greater than its binding affinity or functional activity for any other GPCR. In some embodiments, the compound of formula (I) has a binding affinity or functional activity for one or more GPCRs.

[0062] In some embodiments, the compound of formula (I) is stable in the presence of liver microsomal enzymes. In some embodiments, the compound of formula (I) is stable in the presence of proteases. In some embodiments, the compound of formula (I) is stable in plasma. In some embodiments, the compound of formula (I) is stable in plasma and optionally internalized in tumor cells after binding to GPCR expressed in tumor cells. In some embodiments, the compound of formula (I) includes an optional linker L, is stable in plasma and optionally internalized in tumor cells after binding to cancer cell surface peptide GPCR or protein GPCR.

[0063] In some embodiments, the compound of formula (I) accumulates preferentially in tumor tissues expressing the target GPCR. In some embodiments, the compound of formula (I) accumulates preferentially in tissues or organs containing tumor cells expressing GPCR compared to tissues or organs lacking tumor cells expressing GPCR. In some embodiments, the compound of formula (I) accumulates preferentially at least 1-fold, at least 2-fold, 3-fold, at least 4-fold, at least 5-fold, or more than 5-fold in tissues or organs containing tumor cells expressing GPCR compared to tissues or organs lacking tumor cells expressing GPCR. It is understood that the compound may accumulate in certain tissues and organs involved in the metabolism and / or excretion of therapeutic agents, including but not limited to the kidney, liver, and interstitium.

[0064] In some embodiments, the GPCR targeted by the compounds of formula (I) is expressed at higher levels and / or higher concentrations in or by tumor cells and at substantially lower levels in or by non-tumor cells.

[0065] In some embodiments, the GPCR targeted by the compounds of formula (I) is expressed in tumor cells of tissues and / or organs that do not normally express GPCRs.

[0066] In some embodiments, the NP binds to a GPCR expressed in a tumor cell only if the NP does not contain an unnatural amino acid residue that is 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine, or 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid.

[0067] In some embodiments, the GPCR is a receptor for an endogenous peptide or endogenous protein ligand, and the endogenous peptide or protein ligand is a peptide or protein hormone or chemokine.

[0068] Peptide GPCRs Peptide hormones mainly perform regulatory functions in the brain, gut, and endocrine system. Although these peptides are important in biology, their receptors are becoming increasingly clinically relevant because they are often overexpressed in malignant tumors. Often, these peptide receptors are overexpressed in cancer cells compared to their expression in normal tissues adjacent to the neoplasm and / or in the normal tissue of its origin. Different levels of receptor expression allow high uptake of peptide hormone receptor-ligand complexes in tumor cells, whereas no or low uptake of such complexes in cells that do not express the receptor. This feature allows peptide hormone-ligand radionuclide complexes to perform receptor-targeted imaging and therapy.

[0069] Numerous hormone-activated GPCRs are overexpressed in hormone-dependent and -independent tumors and trigger multiple transduction pathways that mediate relevant biological effects in diverse cancer cells. For example, the bradykinin (BK) receptor is overexpressed in prostate cancer and mediates cell proliferation via Gαq and / or Gα13, which activate RhoA-dependent signaling.

[0070] Among the GPCR family members, the gonadotropin releasing hormone (GnRH) receptor is an established target in the clinical practice of cancer treatment. GnRH receptor is expressed not only in pituitary and normal peripheral tissues, but also in various tumor cells such as melanoma, prostate and endometrial cancer, leiomyoma, leiomyosarcoma, breast cancer, choriocarcinoma, ovarian epithelial and stromal tumors. Several human tumor types, including ovarian cancer, prostate cancer, breast cancer, endometrial cancer, and lung cancer, overexpress this receptor relative to surrounding non-malignant cells, or even express it uniquely.

[0071] The class of somatostatin receptors (SSTRs) consists of five members (SSTR1-5), which are widely expressed in different tissues in the body, including neurons, pituitary cells, kidney cells, lung cells, and immune cells. Their natural ligand is the neuropeptide somatostatin (SST), which occurs in two active isoforms, SST-14 and SST-28. In combination with their receptors, both isoforms act as inhibitory hormones. An important physiological function of the SSTR / SST axis is, for example, the suppression of growth hormone release. SSTRs, especially SSTR subtype 2, have been found to be highly expressed in many neoplastic cells and tumor vasculature. Overexpression of SSTRs, especially SSTR2, has been found in various neuroendocrine tumors, as well as other tumors such as breast, ovarian, and lung cancers. Targeting SSTR2 for drug delivery has been achieved by using stabilized cyclic somatostatin analogs, such as octreotide, octreotide, and lanreotide. For example, the DOTA chelator may be octreotide (DOTA-(Tyr 3 Covalent attachment of tetracycline to DOTA-TATE (also known as tetracycline-octreotate) allows for targeted delivery of radionuclides to tumor cells expressing somatostatin receptors. DOTA-TATE can be reacted with the radionuclides gallium-68, lutetium-177, and copper-64 to form radiopharmaceuticals for positron emission tomography (PET) imaging or radionuclide therapy. 177 LU DOTA-TATE therapy is a form of peptide receptor radionuclide therapy (PRRT) that targets somatostatin receptors and is a form of targeted drug delivery.

[0072] The bombesin (Bn) receptor family consists of three members, namely BB1, BB2, and BB3 receptors, which are expressed not only in the central nervous system (CNS) but also in the periphery, such as the gastrointestinal tract. They mediate numerous physiological functions, including autocrine proliferative effects on cells and potent CNS effects. The natural peptide ligand for BB1 is neuromedin B, and for BB2 is gastrin-releasing peptide, while BB3 is considered an orphan receptor. Upregulation of Bn receptors has been found in various cancer subtypes, and in particular, BB2 is highly overexpressed in tumors such as breast, prostate, small cell lung, and pancreatic cancers. Targeting of Bn receptors for drug delivery has typically centered on the use of Bn analogs, including, for example, the peptide [d-Tyr6,β-Ala11,Phe13,Nle14]-Bn(6-14).

[0073] Vasoactive intestinal peptide (VIP) receptors 1 and 2 are overexpressed in various cancers, such as colon cancer, breast cancer, and endocrine tumors. The natural ligand VIP and its analogs are explored for the preparation of drug conjugates.

[0074] The cholecystokinin 2 receptor (CCK2R) is overexpressed in a variety of cancers of the thyroid, lung, pancreas, liver, and gastrointestinal tract. Targeting this receptor for drug delivery has typically involved the use of analogs of its natural peptide ligands, cholecystokinin and gastrin.

[0075] Melanocortin receptor 1 (MC1R) has been found to be upregulated in malignant melanoma. For the generation of drug conjugates for this system, truncated peptide analogs of the natural MC1R ligand α-MSH, such as the agonist NAP amide, have potential as delivery agents.

[0076] The ghrelin receptor (GhrR), also called growth hormone secretagogue receptor 1a (GHSR1a), is a class A GPCR. Ghrelin receptors are widely expressed in the brain, especially in the hypothalamus, but also in the hippocampus and pituitary gland. In addition, GhrR has been found to be expressed in various peripheral tissues, including the liver, heart, pancreas, thyroid, ovaries, testes, etc. The natural ligand of GhrR is the peptide hormone ghrelin, a 28 amino acid peptide. Ligand binding to GhrR occurs quite deep in the cavity created by the TM helix of the receptor. The ghrelin / GhrR axis is responsible for numerous physiological functions, such as food intake, regulation of energy homeostasis, release of various hormones (e.g., growth hormone, prolactin, adrenocorticotropic hormone), and reward-seeking behavior. GhrR is present in a vast number of different cancer subtypes. Expression of GhrR has been described in pituitary adenomas, thyroid, breast, lung, testicular, ovarian, prostate, pancreatic, gastric, and colorectal cancers, as well as astrocytomas.

[0077] The human Y1 receptor (hY1R) is a class A GPCR from the Y receptor family in humans, which is mainly expressed in the CNS, e.g., the hypothalamus, but is also found in peripheral tissues, including the heart, lung, or smooth muscle. In addition to the hY1R, three other Y receptors are expressed in humans, namely the Y2 receptor (hY2R), the Y4 receptor (hY4R), and the Y5 receptor (hY5R). These receptors are bound and activated by the neuropeptide Y family of peptide hormones, consisting of neuropeptide Y (NPY), peptide YY (PYY), and human pancreatic polypeptide (hPP). NPY has been found to be the most abundant peptide hormone in the mammalian CNS. Endogenous NPY is a 36 amino acid peptide, consisting of a flexible N-terminus, a C-terminal amphipathic α-helix, and an amidated C-terminus. Its presence in certain tumor tissues targets the hY1R for anticancer drug delivery. Expression of hY1R along with hY2R has been described in ovarian sex cord stromal tumors, nephroblastoma, gastrointestinal stromal tumors, and testicular tumors. Only hY1R expression was observed in adrenal cortical tumors and renal cell carcinoma. High expression of hY1R was also determined in Ewing's sarcoma tumors and breast cancer tumors and breast cancer-derived metastases. In contrast, expression of hY2R was mainly observed in surrounding non-neoplastic breast tissue. Thus, this switch in Y receptor expression pattern during neoplastic transformation of breast tissue allows specific drug shuttling to breast tumors when hY1R-selective ligands are used as delivery agents.

[0078] Orphan GPCRs have been linked to cancer development and progression based on their overexpression and / or upregulation by diverse factors. For example, elevated expression of the orphan G protein-coupled receptor GPR49 was involved in the formation and growth of basal cell carcinoma, whereas GPR18 was found to be associated with melanoma metastasis. High levels of GPR87 were detected in lung, cervix, skin, bladder, testis, and head and neck squamous cell carcinomas.

[0079] As used herein, "peptide G protein-coupled receptor (GPCR)" means a GPCR that is the binding site for a peptide ligand. The natural ligand of a peptide GPCR is a peptide ligand.

[0080] As used herein, "protein G protein-coupled receptor (GPCR)" means a GPCR that is the binding site for a protein ligand. The natural ligand of a protein GPCR is a protein ligand.

[0081] In some embodiments, the NPs of the compound of formula (I) bind to GPCRs that also bind to peptide or protein hormones that are adrenocorticotropic hormone (ACTH), amylin, angiotensin, atrial natriuretic peptide (ANP), calcitonin, cholecystokinin (CCK), gastrin, ghrelin, glucagon, growth hormone, follicle stimulating hormone (FSH), insulin, leptin, melanocyte stimulating hormone (MSH), oxytocin, parathyroid hormone (PTH), prolactin, renin, somatostatin, thyroid stimulating hormone (TSH), thyrotropin releasing hormone (TRH), vasopressin, or vasoactive intestinal peptide.

[0082] In some embodiments, the NP binds to the GPCR only if the GPCR does not bind to neurotensin.

[0083] In some embodiments, the GPCR is an angiotensin receptor, an apelin receptor, a bombesin receptor, a bradykinin receptor, a calcitonin receptor, a chemokine receptor, a cholecytokinin receptor, a corticotropic releasing factor receptor, a galanin receptor, a ghrelin receptor, a glucagon receptor, a glycoprotein hormone receptor, a gonadotropin releasing hormone receptor, a kisspeptin receptor, a melanocortin receptor, a motilin receptor, a neuromedin U receptor, a neuropeptide FF / AF receptor, a neuropeptide S receptor, a neuropeptide W / B receptor, a neuropeptide Y receptor, an opioid receptor, an orexin receptor, a parathyroid hormone receptor, a prokineticin receptor, a prolactin releasing peptide receptor, a QRFP receptor, a relaxin family peptide receptor, a somatostatin receptor, a tachykinin receptor, a thyrotropin releasing hormone receptor, a urotensin receptor, a vasopressin and oxytocin receptor, a VIP and a PACAP receptor, or a combination thereof.

[0084] In some embodiments, the GPCR is a member of one of the following receptor families: angiotensin receptor (e.g., AGTR1, AGTR2), apelin receptor (APLNR), bombesin receptor (BB1 / NMBR, BB2 / GRPR, BRS3), bradykinin receptor (BDKRB1, BDKRB2), calcitonin receptor (e.g., CALCR, CALCRL), chemokine receptor (e.g., CCR1-10, CXCR1-6, etc.), cholecytokinin receptor (CCKAR, CCKBR). , corticotropin releasing factor receptors (CRHR1, CRHR2), galanin receptors (GALR1-3), ghrelin receptors (GHSR), glucagon receptor family (e.g., GHRHR, GIPR, GLP1R, GLP2R, GCGR, SCTR), glycoprotein hormone receptors (FSHR, LHCGR, TSHR), gonadotropin releasing hormone receptors (GNRHR, GNRHR2), kisspeptin receptors (KISS1R), melanocortin receptors (MC1-5R), motilin receptors (MLNR), neurometabolism receptors (MEMs), and mitochondrial receptors (MTMs). Neuropeptide U receptors (NMUR1, NMUR1-2), neuropeptide FF / AF receptors (NPFFR1, NPFFR2), neuropeptide S receptor (NPSR1), neuropeptide W / B receptors (NPBWR1, NPBWR2), neuropeptide Y receptors (NPY1-6R), opioid receptors (OPRD1, OPRK1, OPRM1), orexin receptors (HCRTR1, HCRTR2), parathyroid hormone receptors (PTH1R, PTH2R), prokineticin receptors (PROKR1, PROKR2), prolactin receptors (PROKR3, PROKR4), and prolactin receptors (PROKR5, PROKR6). These include the proline-releasing peptide receptor (PRLHR), the QRFP receptor (QRFPR), the relaxin family peptide receptors (RXFP1-4), the somatostatin receptors (SSTR1-5), the tachykinin receptors (TACR1-3), the thyrotropin-releasing hormone receptors (TRHR1, TRHR2), the urotensin receptor (UTS2R), the vasopressin and oxytocin receptors (AVPR1A, AVPR1B, AVPR2, OXTR), or the VIP and PACAP receptors (ADCYAP1R1, VIPR1, VIPR2).

[0085] In some embodiments, the GPCR is a member of one of the following receptor families: angiotensin receptor (e.g., AGTR1, AGTR2), apelin receptor (APLNR), bombesin receptor (BB1 / NMBR, BB2 / GRPR), bradykinin receptor (BDKRB1, BDKRB2), ghrelin receptor (GHSR), glycoprotein hormone receptor (FSHR, LHCGR), gonadotropin releasing hormone receptor (GNRHR), kisspeptin receptor (KISS1R), melanocortin receptor (MCR), or the like. receptor family (MC1R, MC2R, MC3R, MC4R, MC5R), neuropeptide Y receptor (NPY1), neurotensin receptor (NTSR1), parathyroid hormone receptor (PTH1R), prolactin releasing peptide receptor (PRLHR), somatostatin receptor family (SSTR1, SSTR2, SSTR2, SSTR4, SSTR5), thyrotropin releasing hormone receptor (TRHR1, TRHR2), or VIP and PACAP receptors (ADCYAP1R1, VIPR1, VIPR2).

[0086] In some embodiments, the GPCR is a chemoattractant GPCR. In some embodiments, the GPCR is a classical GPCR that is a formyl peptide receptor (FPR1, FPR2 or FPR3), a platelet activating factor receptor (PAFR), an activated complement component 5a receptor (C5aR), or a chemoattractant GPCR that binds a CC chemokine (β-chemokine), a CXC chemokine (α-chemokine), a C chemokine (γ-chemokine), or a CX3C chemokine (d-chemokine).

[0087] Tumor cells that preferentially metastasize to specific organs via blood and lymphatic vessels present a great challenge in cancer eradication. One family of GPCRs closely related to tumor metastasis is the chemokine receptors. Chemokines enhance the motility and survival of cancer cells in the vicinity and environment of the tumor after their local release in either an autocrine or paracrine manner into the microenvironment of the peritumoral region. Among these are chemokines involved in metastatic cancer cell homing and cancer cell growth and survival, such as chemokine receptors CCR7 and CCR10. Local chemokine production in the tumor environment can recruit macrophages and leukocytes, which can then induce the release of matrix metalloproteinases (MMPs) that promote tumor cell survival, growth, and invasion, as well as improve the cytokine-rich microenvironment. CXCR4 is a well-known chemokine receptor that drives cancer metastasis. Furthermore, cells at the most frequent metastatic sites, including lung, bone marrow, lymph nodes and liver, express the chemokine ligand CXCL12 / SDF-1.

[0088] Tumor cells frequently express high levels of CXCR4, promoting cell proliferation, survival, and migration capabilities. For example, CXCR4 is not found in normal breast tissue, but rather is overexpressed in breast cancer cells, and a significant suppression of breast cancer metastatic spread is achieved by suppressing CXCR4. However, treatment with CXCR4 inhibitors should be performed with caution, as CXCR4 inhibition induces mobilization of progenitor / stem cells from the bone marrow. Hypoxia-inducible factor-1 (HIF-1α), which is activated by hypoxia, increases CXCR4 transcription. In highly aggressive basal-like breast cancer cells, CXCR4 can also couple to Gα12 / 13 when Gα13 protein is highly upregulated, thereby driving spread and site-specific metastasis via lymphatic vessels in a Gα12 / 13-RhoA-dependent manner. This molecular mechanism is similarly mediated through PAR and LPA, all of which may serve as possible targets for the prevention and treatment of metastasis.

[0089] Solid tumors: benign and / or malignant neoplasms (cancer) In one embodiment, the compounds of formula (I) are used to treat benign and / or malignant neoplasms (solid tumors), which neoplasms comprise cells that overexpress cell surface GPCRs.

[0090] The term "neoplasm" as used herein refers to an abnormal proliferation of cells that may proliferate in an uncontrolled manner and may have the capacity to metastasize (spread).

[0091] Neoplasms include solid tumors, adenomas, carcinomas, sarcomas, leukemias and lymphomas at any stage of disease with or without metastasis.

[0092] A solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors can be benign (not cancer) or malignant (cancer). 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.

[0093] Solid tumors are typically cancers originating from organs such as the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, ovary, pancreas, or other endocrine organs (thyroid) and prostate.

[0094] Adenomas are non-cancerous tumors. They begin in adenoma-like cells of epithelial tissue (a thin layer of tissue that covers organs, glands, and other structures in the body). Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid gland, prostate, and others. Over time, adenomas transform to become malignant, at which point they are called adenocarcinomas. Despite being benign, they have the potential to cause serious health complications by compressing other structures (mass effect) and by producing large amounts of hormones in an unregulated, non-feedback dependent manner (causing paraneoplastic neurological syndromes).

[0095] Adenomas typically occur in the colon (e.g., adenomatous polyps have a tendency to become malignant and lead to colon cancer), kidney (e.g., renal adenomas may be precursor lesions to renal cancer), adrenal glands (e.g., adrenal adenomas, some of which secrete hormones such as cortisol, which causes Cushing's syndrome, aldosterone, which causes Conn's syndrome, or androgens, which cause hyperandrogenism), thyroid (e.g., goiter), and pituitary gland (e.g., prolactinomas). which are found in the pituitary adenomas), parathyroid glands (e.g., adenomas of the parathyroid gland may inappropriately secrete large amounts of parathyroid hormone, thereby causing primary hyperparathyroidism), liver (e.g., hepatocellular adenomas), breasts (e.g., fibroadenomas), appendix (e.g., cystadenomas), bronchi (e.g., bronchial adenomas may cause carcinoid syndrome, a type of paraneoplastic neurological syndrome), prostate (e.g., prostatic adenomas), sebaceous glands (e.g., sebaceous adenomas), and salivary glands.

[0096] Metastasis is the spread of malignant cells to new areas of the body, often by the lymphatic system or bloodstream. A metastatic tumor is a tumor that has spread from its primary primary site, or from where it began, to a different area of ​​the body. A metastatic tumor contains malignant cells that express cell surface GPCRs.

[0097] Tumors that form from spread cells are called secondary tumors. Tumors may spread to areas near the primary site, called regional metastasis, or to more distant parts of the body, called distant metastasis.

[0098] In some embodiments, the tumor to be treated comprises tumor cells expressing GPCR, and the tumor is a primary or metastatic tumor. In some embodiments, the tumor to be treated comprises tumor cells expressing GPCR, and the tumor is a primary or metastatic tumor of gastrointestinal origin, such as colorectal cancer, gastric cancer, small intestine cancer, or esophageal cancer. In some embodiments, the tumor to be treated comprises tumor cells expressing GPCR, and the tumor is a primary or metastatic tumor of the pancreas. In some embodiments, the tumor to be treated comprises tumor cells expressing GPCR, and the tumor is a primary or metastatic tumor of the lung, such as squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma. In some embodiments, the tumor to be treated comprises tumor cells expressing GPCR, and the tumor is a primary or metastatic neuroectodermal tumor, such as a glioma or paraganglioma. In some embodiments, the tumor to be treated comprises tumor cells expressing GPCR, and the tumor is a primary or metastatic bronchopulmonary or gastrointestinal neuroendocrine tumor. In some embodiments, the tumor being treated comprises tumor cells that express a GPCR, and the tumor is a primary or metastatic tumor of the rectum or colon.

[0099] In some embodiments, the compounds of formula (I) are used to treat a sarcoma, such as a leiomyosarcoma or a rhabdomyosarcoma.

[0100] In some embodiments, the compounds of formula (I) are used to treat adenomas.

[0101] In another aspect, provided herein is a method of treating cancer in a mammal, comprising administering to a mammal in need of cancer treatment a non-peptide targeted therapy disclosed herein. In some embodiments, the cancer comprises tumor cells expressing one or more peptide hormone GPCRs. In some embodiments, the cancer comprises tumor cells overexpressing one or more GPCRs. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a sarcoma, carcinoma, or lymphoma. In some embodiments, the cancer comprises a neuroendocrine tumor. In some embodiments, the cancer comprises an insulinoma. In some embodiments, the cancer comprises a peptide hormone GPCR-positive (e.g., somatostatin receptor-positive) gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0102] In some embodiments, a compound of formula (I) is administered to a cancer patient, hi some embodiments, the cancer patient has been diagnosed with a carcinoma, a sarcoma, a primary tumor, a metastatic tumor, a solid tumor, a non-solid tumor, a hematological tumor, a leukemia, or a lymphoma.

[0103] Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma (a form 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, adrenal cortical 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 carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.

[0104] Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovium, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0105] Solid tumors include, but are not limited to, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma. Benign solid tumors include adenomas.

[0106] Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of pluripotent hematopoietic stem cells), b) acute myeloid leukemia (neoplastic transformation of pluripotent hematopoietic stem cells or hematopoietic cells of limited lineage potential, c) chronic lymphocytic leukemia (CLL; clonal proliferation of immunologically immature and dysfunctional small lymphocytes), including B-cell CLL, T-cell CLL prolymphocytic leukemia, and hairy cell leukemia, and d) acute lymphoblastic leukemia (characterized by accumulation of lymphoblasts). Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma), Hodgkin's lymphoma, and the like.

[0107] 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, mesothelioma); breast cancer (including but not limited to ductal carcinoma, lobular carcinoma, inflammatory breast carcinoma, clear cell carcinoma, mucinous carcinoma); colorectal cancer (including but not limited to colon carcinoma, rectal carcinoma); anal carcinoma; pancreatic cancer (including but not limited to adenocarcinoma of the pancreas, islet cell carcinoma, neuroendocrine tumors); prostate cancer; ovarian cancer (including but not limited to serous tumors, endometrioid tumors, and ovarian epithelial carcinoma, including mucinous cystadenocarcinoma, genital cord stromal tumor, or surface epithelial stromal tumor); liver and cholangiocarcinoma (including but not limited to hepatocellular carcinoma, intrahepatic cholangiocarcinoma, hemangioma, esophageal cancer (including but not limited to adenocarcinoma and squamous cell carcinoma of the esophagus); non-Hodgkin's lymphoma; bladder cancer; uterine cancer (including but not limited to endometrial adenocarcinoma, uterine serous adenocarcinoma, uterine clear cell carcinoma, uterine sarcoma, and leiomyosarcoma, mixed Mullerian tumor); glioma, glioblastoma, medulloblastoma, and other brain tumors; renal cancer (including but not limited to renal cell carcinoma, clear cell carcinoma, Wilms' tumor); cancer of the head and neck (including but not limited to squamous cell carcinoma); gastric cancer (including but not limited to gastric adenocarcinoma, gastrointestinal stromal tumor); multiple myeloma; testicular cancer; germ cell tumors; neuroendocrine tumors; cervical cancer; cancer of the gastrointestinal tract, breast, and other organs; and signet ring cell carcinoma.

[0108] A payload moiety (Q) containing a chelated radionuclide 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 pharmaceuticals is that radiopharmaceuticals contain a radioactive nuclide. The nuclear decay properties of the radionuclide determine whether the radioactive fan pharmaceutical is used clinically as a diagnostic or therapeutic agent. Diagnostic radiopharmaceuticals require a radionuclide that emits either a gamma (γ) ray or a positron (β+), which then annihilates with a nearby electron to produce two 511 keV annihilation photons that are emitted approximately 180° apart from each other. Gamma-ray-emitting radionuclides (e.g., 99m Tc, 111 In, 201T1) are useful for single photon emission computed tomography (SPECT), while positron-emitting radionuclides (e.g. 18 F, 89 Zr, 68 Ga) are useful in positron emission tomography (PET).

[0109] In contrast, therapeutic radiopharmaceuticals require radionuclides that emit particulate radiation, such as alpha (α) particles, beta (β-) particles, or Auger electrons. These particles, which interact strongly with target tissues (e.g., cancerous tumors) and result in extensive localized ionization, can damage chemical bonds in DNA molecules and potentially induce cytotoxicity.

[0110] 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 theranostic concept, a targeted molecule labeled with a diagnostic radionuclide is used for quantitative imaging of tumor imaging biomarkers using positron emission tomography (PET) or single photon emission computed tomography (SPECT). Once it has been demonstrated that this targeted molecule can be used to deliver tumoricidal radiation absorbed doses to tumors and metastases, the second step is the administration of the same or similar targeted molecule labeled with a therapeutic radionuclide.

[0111] In some embodiments, the chemical and pharmacokinetic behavior of both the diagnostic and therapeutic radiopharmaceuticals are consistent. In some embodiments, the diagnostic and therapeutic radionuclides are chemically identical radioisotope pairs (also known as "matched pairs"). One example of a matched pair for theranostic radiopharmaceutical applications is: 123 I / 131 I pair, 123 I-labeled compounds are used in diagnostics, 131 I-labeled compounds are used for therapy. Other theranostic match pairs include, among others: 44 Sc / 47 Sc, 64 Cu / 67 Cu, 72 AS / 77 A.S., 86 Y / 90 Y, and 203 Pb / 212 Pb. Alternatively, pairs of radionuclides from different elements may be involved because their chemistry is very similar (e.g., 99m Tc / 186 / 188 Re), when there is no significant difference in the pharmacokinetic behavior between the diagnostic and therapeutic analogs, it can be utilized in theranostic radiopharmaceutical development. Another example is 68 Ga / 177 Lu pair, 68 Ga is used for diagnosis, 177 Lu is used in the treatment of gastroenteropancreatic endocrine tumors, for example: 68 Ga sst2 ligand complex ([ 68 Ga]Ga-DOTA-TATE (NETSPOT™) or [ 68 Expressing high amounts of sst2 receptors that can be targeted for diagnostic purposes with somatostatin receptor scintigraphy using Ga]Ga-DOTA-TOC (DOTA-(D-Phel,Tyr3)-Octreotide, SomaKit TOC®)) and then for in vivo therapy. 177 Lu sst2 ligand complex ([ 177 Treat with [Lu]Lu-DOTA-TATE).

[0112] In some embodiments, NP is a non-peptide ligand that binds to a GPCR expressed in a tumor cell of a solid tumor, an adenoma, a sarcoma, a carcinoma, or a lymphoma, Q comprises a radionuclide (Z) and a chelator configured to bind to the radionuclide (Z), and L is a non-cleavable linker.

[0113] Chelating Agents for Radionuclides In some embodiments, Q is a payload moiety comprising a chelating moiety or a radionuclide (Z) conjugate thereof. In some embodiments, Q comprises a radionuclide (Z) and a chelating agent configured to bind to the radionuclide (Z). In some embodiments, the chelating agent is attached to the non-peptide ligand through any suitable group or atom of the chelating agent. In some embodiments, the chelating agent is attached to the linker through any suitable group or atom of the chelating agent.

[0114] As used herein, "chelating agent" and "chelating moiety" are used interchangeably.

[0115] In some embodiments, the chelator is capable of binding to a 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 or includes a macrocycle.

[0116] 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 that contains three or more N atoms, three or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelator is a polydentate ligand, a bidentate ligand, or a monodentate ligand. A polydentate ligand is a range of the number of atoms used to bind to a metal atom or ion. EDTA, a hexadentate ligand, is an example of a polydentate ligand with six donor atoms that have electron pairs that can be used to bind to the central metal atom or ion. A bidentate ligand has two donor atoms that allow it to bind to the central metal atom or ion at two points. Ethylenediamine (en) and oxalate (ox) are examples of bidentate ligands.

[0117] In some embodiments, the chelating agents described herein include cyclic or acyclic chelating agents. In some embodiments, the chelating agents described herein include cyclic chelating agents. In some embodiments, the chelating agents described herein include acyclic chelating agents.

[0118] In some embodiments, chelators described herein include DOTA, DOTAGA, DOTA(GA)2, NOTA, NODAGA, TRITA, TETA, DOTA-MA, DO3A-HP, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, p-NCS-DOTA, p-NCS-PADOTA, BAT, DO3TMP-monoamide, p-NCS-TRITA, and CHX-A"-DTPA. In some embodiments, chelators described herein include DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOPA.

[0119] In some embodiments, the chelators 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.

[0120] In some embodiments, the chelating agents described herein are HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAPAP, DO3AM Bu , DOTMA, TCE-DOTA, DEPA, PCTA, p-NO2-Bn-PCTA, p-NO2-Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATAT m , THP, HEHA, HBED, or HBED-CC TFP.

[0121] 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.

[0122] In some embodiments, the chelator is or includes DOTA, HBED-CC, DOTAGA, DOTA(GA)2, NOTA, and DOTAM, In some embodiments, the chelator is or includes NODAGA, NOTA, DOTAGA, DOTA(GA)2, TRAP, NOPO, NCTA, DFO, DTPA, and HYNIC.

[0123] 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 desferrioxamine.

[0124] In some embodiments, Q comprises a chelating moiety or a radionuclide (Z) conjugate thereof, the chelating moiety being 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A), α,α',α",α'"-tetramethyl-1,4,7,1 0-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)triacetate, benzyl-1,4,7,10-tetraazacyclododecane-,1,4,7,10-tetraacetate (Bn-DOTA), 6,6'-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl)azadiyl)-bis(methylene))dipicolinic acid (H4pypa), H4pypa-benzyl, 6,6',6”,6'”-(((pyridine-2,6-diylbis(methylene))bis(aza 6,6'-((ethane-1,2-diylbis((carboxymethyl)(azanediyl))bis(methylene))dipicolinic acid (H4py4pa), H4py4pa-benzyl, 6,6'-((ethane-1,2-diylbis((carboxymethyl)(azanediyl))bis(methylene))dipicolinic acid (H4octapa), H4octapa-benzyl, or 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatotetracanedioic acid (TTHA).

[0125] In some embodiments, the metal chelators described herein comprise one of the following configurations:

[0126]

change

[0127]

change

[0128]

change

[0129]

change

[0130] [ka]

[0131] [ka] aa

[0132] In some embodiments, Q comprises a chelating moiety or a radionuclide (Z) conjugate thereof, wherein the chelating moiety is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A).

[0133] In some embodiments, Q comprises a chelating moiety or a radionuclide (Z) conjugate thereof, the chelating moiety being

[0134] [ka] It is.

[0135] In some embodiments, Q comprises a radionuclide (Z) and DOTA. In some embodiments, Q comprises a radionuclide (Z) and a DOTA derivative such as p-SCN-Bn-DOTA and MeO-DOTA-NCS. In some embodiments, Q comprises two independent chelators, at least one or both of which is DOTA.

[0136] In some embodiments, Q comprises a radionuclide (Z) and a chelator configured to bind to the radionuclide (Z), wherein 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.

[0137] In some embodiments, Q is

[0138] [ka] where Z is a diagnostic or therapeutic radionuclide.

[0139] In some embodiments, Z is an Auger electron emitting radionuclide, an alpha emitting radionuclide, a beta emitting radionuclide, or a gamma emitting radionuclide. In some embodiments, Z is 111Indium ( 111 In), 67Gallium ( 67 Ga), 68 Gallium ( 68 Ga), 99mTechnetium ( 99m Tc), or 195m platinum ( 195 mPt). In some embodiments, Z is 225-actinium ( 225 Ac), 213-Bismuth ( 213 Bi), 223-Radium ( 223 Ra), or 212-lead ( 212 3,4-Dimethylpyrrolidinium (Pb). In some embodiments, Z 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 ( 153Sm), 89-strontium ( 89 Sr), 198-gold ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-Technetium ( 99m Tc), 89-zirconium ( 89 Zr), or 52-manganese ( 52 In some embodiments, Z is a β-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 It is a gamma-emitting nuclide with a molecular weight of 1.01.

[0140] In some embodiments, Q 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).

[0141] Radionuclides In some embodiments, Z is an Auger electron emitting radionuclide. In some embodiments, Z is an alpha radionuclide. In some embodiments, Z is a beta radionuclide. In some embodiments, Z is a gamma radionuclide. In some embodiments, the type of radionuclide used in the non-peptide targeted therapeutic compound can be tailored to the particular type of cancer, the type of targeting moiety (e.g., non-peptide ligand), and the like. Radionuclides that undergo alpha decay release an alpha particle (a helium ion with a +2 charge) from the nucleus. As a result of alpha decay, the daughter nuclide has two fewer protons and two fewer neutrons than the parent nuclide. This means that in alpha decay, the number of protons is reduced by two and the number of nuclei is reduced by four. Radionuclides that undergo beta decay release a beta particle (an electron) from their nucleus. During beta decay, one of the neutrons changes into a proton and an electron. The proton stays in the nucleus and the electron is released as a beta particle. This means that in beta decay, the nucleus loses a neutron but gains a proton. In gamma decay, an excited (high energy) nucleus changes to a lower energy state by emitting a gamma ray photon. The number of protons and nuclei remains the same during gamma decay. The emission of gamma rays is often accompanied by the emission of alpha and beta particles.

[0142] Auger electrons (AE) are electron capture (EC) (e.g., 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I and 123 AE is a very low energy electron released by radionuclides that decay by ionizing radiation (I). This energy is accumulated over nanometer-micrometer distances, resulting in a powerful high linear energy transfer to cause lethal damage to cancer cells. Therefore, AE radioactive radiotherapeutic agents have great potential for the treatment of cancer.

[0143] Beta particles are electrons that are emitted from the nucleus. They typically have a longer range in tissue (on the order of 1-5 mm) and are the most frequently used.

[0144] Alpha particles are helium nuclei (two protons and two neutrons) that are emitted from the nuclei of radioactive atoms. Depending on their emission energy, they can travel 50-100 μm in tissues. They are positively charged and are orders of magnitude more powerful than electrons. The amount of energy deposited per path length traveled by alpha particles (referred to as "linear energy transfer") is approximately 400 times greater than that of electrons. This results in substantially more damage along their path than is caused by electrons. Alpha particle tracks result in a preponderance of complex and largely irreparable DNA double-strand breaks. The absorbed dose required to achieve cytotoxicity is related to the number of alpha particles that traverse the cell nucleus. Using this as a measure, cytotoxicity can be achieved with 1-20 alpha particle traverses of the cell nucleus. The high potency obtained, combined with the short range of alpha particles (which reduces normal organ toxicity), has led to substantial interest in the development of alpha particle emitters. Typically used alpha particle emitters include bismuth-212, lead-212, bismuth-213, actinium-225, radium-223, and thorium-227.

[0145] In some embodiments, Z is a diagnostic or therapeutic radionuclide.

[0146] [Table 1-1]

[0147] [Table 1-2]

[0148] In some embodiments, Z is an Auger electron emitting radionuclide. In some embodiments, Z is 111Indium ( 111 In), 67Gallium ( 67 Ga), 68 Gallium ( 68 Ga), 99mTechnetium ( 99m Tc), or 195m platinum ( 195m It is an Auger electron emitting radionuclide, which is Pt.

[0149] In some embodiments, Z is an alpha radionuclide. In some embodiments, Z is 225-actinium ( 225 Ac), 213-Bismuth ( 213 Bi), 223-Radium ( 223 Ra), or 212-lead ( 212 Pb) is an alpha-emitting nuclide.

[0150] In some embodiments, Z is a β-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-gold ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-Technetium ( 99mTc), 89-zirconium ( 89 Zr), or 52-manganese ( 52 It is a beta-emitting nuclide (Mn).

[0151] In some embodiments, Z is a gamma 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 It is a gamma-emitting nuclide with a molecular weight of 1.01.

[0152] In some embodiments, Z is 111 indium ( 111 In), 67Gallium ( 67 Ga), 68 Gallium ( 68 Ga), 99mTechnetium ( 99m Tc), or 195m platinum ( 195m Pt) or Z is 225-actinium ( 225 Ac), 213-Bismuth ( 213 Bi), 223-Radium ( 223 Ra), or 212-1ead( 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-gold ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-Technetium ( 99m Tc), 89-zirconium ( 89Zr), or 52-manganese ( 52 Mn), or 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 It is a gamma-emitting nuclide with a molecular weight of 1.01.

[0153] In some embodiments, Z is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 67-Copper( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-gold ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), or Technetium-99m ( 99m Tc).

[0154] 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, and 166 Dy.

[0155] In some embodiments, Z is 67 Cu, 64 Cu, 90 Y, 109 Pd, 111 Ag, 149 Pm, 153 Sm, 166 Ho, 99m Tc, 67 Ga, 68 Ga, 111 In, 90 Y, 177 Lu, 186 Re, 188 Re, 197 Au, 198 Au, 199 Au, 105 Rh, 165 Ho, 161 Tb, 149 Pm, 44 Sc, 47 Sc, 70 As, 71 As, 72 As, 73 As, 74 As, 76 As, 77 As, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 117m Sn, 67 Ga, 201 T1, 160 Gd, 148 Nd, and 89 Sr.

[0156] In some embodiments, Z is 68 Ga, 43 Sc, 42 Sc, 47 Sc, 177 Lu, 161 Tb, 225 Ac,213 Bi, 212 In some embodiments, Z is 67Ga, 99mTc, 111In, or 201T1.

[0157] Exemplary Chelators and Radionuclide Conjugates Radionuclides can be used for imaging using 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 therapeutic applications (e.g. 47 Sc, 114 mln, 177 Lu, 90 Y, 212 / 213 Bi, 212 Pb, 225 Ac, 186 / 188 Radiometal-based radiopharmaceuticals have useful luminescence properties that can be used for radioactive metals (Re). The basic component of radiometal-based radiopharmaceuticals is a chelator, which is a ligand system that binds radiometal ions into a tight and stable coordination complex so that the radiometal ions can be appropriately directed to the desired molecular target in vivo. Guidance for selecting the optimal match between chelators and radiometals 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, 260-290).

[0158] In some embodiments, Q comprises a chelated or macrocyclic complex of a radionuclide. In some embodiments, Q comprises a diethylenetriaminepentaacetic acid (DTPA) chelate, a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate, or a 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelate or a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetic acid (DOTMA) chelate of a radionuclide.

[0159] In some embodiments, Q is

[0160] [ka] where Z is a radionuclide.

[0161] In some embodiments, Q is

[0162] [ka] and Z is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 67-Copper( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-gold ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), or Technetium-99m ( 99m It is a radioactive nuclide called .Tc.

[0163] Emission Tomography In some embodiments, Q comprises a chelated radionuclide suitable for positron emission tomography (PET) analysis or single photon emission computed tomography (SPECT). In some embodiments, Q comprises a chelated radionuclide suitable for single photon emission computed tomography (SPECT). In some embodiments, Q comprises a chelated radionuclide suitable for positron emission tomography (PET) analysis. In some embodiments, Q comprises a chelated radionuclide suitable for positron emission tomography imaging, positron emission tomography with computed tomography imaging, or positron emission tomography with magnetic resonance imaging.

[0164] In some embodiments, Q comprises a diethylenetriaminepentaacetic acid (DTPA) chelate, a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelate, or a 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelate or a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetic acid (DOTMA) chelate of a radionuclide. In some embodiments, Q comprises a chelated radionuclide, and the radionuclide is copper-64 ( 64 Cu), Gallium-68( 68 Ga), or technetium-99m ( 99m Tc).

[0165] In some embodiments, Q is

[0166] [ka]

[0167] 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, at least about 8 hours. In some embodiments, the conjugate has an elimination half-life of up to about 15 minutes, up to about 30 minutes, up to about 1 hour, up to about 2 hours, up to about 3 hours, up to about 4 hours, up to about 5 hours, up to about 6 hours, or up to about 8 hours. In some embodiments, the elimination half-life is determined in rats. In some embodiments, the elimination half-life is determined in humans.

[0168] The conjugates described herein may have an elimination half-life in tumor and non-tumor tissues of a subject. The elimination half-life in a tumor may be the same or different (either 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, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 4.0, or is at least 5.0 times the elimination half-life of the conjugate in a non-tumor tissue of a subject.

[0169] As used herein, "elimination half-life" may refer to the time taken 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.

[0170] Prediction of response and toxicity is essential for the rational implementation of cancer treatment. The biological effect of radionuclide therapy is mediated by a well-defined physical quantity, namely the absorbed dose (D), defined as the energy absorbed per unit mass of tissue.

[0171] Radiation dosimetry is the measurement, calculation and evaluation of the amount of ionizing radiation absorbed by an object, usually the human body, and may be considered the ability to perform the equivalent of a pharmacodynamic study in real time in treated patients. This can be applied internally, due to ingestion or inhalation of radioactive material, or externally, due to irradiation by a radioactive source. Dosimetry analysis can be performed as part of a patient treatment to calculate tumor versus normal organ absorbed doses and therefore the likelihood of treatment success.

[0172] The conjugates described herein have a defined time-integrated activity coefficient (i.e., (a ~ As used herein, (a ~ ) is the cumulative number of nuclear transformations that occur in the source tissue over the dose integration period per unit administered activity. ~ ) values ​​can be adjusted by modifying the NPDC. ~ The (a) value can be determined using methods known in the art. In some embodiments, the (a ~ The (a) value is about 10 minutes to about 1 day. ~ ) value is the (a ~The (a ~ ) value is the (a ~ In some embodiments, the amount of the complex in the tumor may be longer or shorter than the (a ~ ) value is at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 4.0, or the (a ~ ) value is at least 5.0 times.

[0173] The conjugates described herein are capable of inhibiting the expression of ~ In some embodiments, the conjugate may have a (a) value in the kidney of a subject for up to 24 hours. ~ In some embodiments, the concentration of the complex in the kidney of the subject is (a ~ In some embodiments, the (a) value of the complex in the kidney of the subject is at most 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. ~ In some embodiments, the (a) value of the complex in the kidney of the subject is from about 30 minutes to about 24 hours. ~ In some embodiments, the (a) value of the complex in the kidney of the subject is about 2 to 24 hours. ~ In some embodiments, the (a) value of the complex in the liver of the subject is greater than 24 hours. ~ In some embodiments, the (a) value of the complex in the liver of the subject is up to 24 hours. ~ In some embodiments, the (a) value of the complex in the liver of the subject is at most 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. ~ In some embodiments, the (a) value of the complex in the liver of the subject is from about 30 minutes to about 24 hours. ~ In some embodiments, the (a) value of the complex in the liver of the subject is about 2 to 24 hours. ~ ) value is greater than 24 hours.

[0174] Linker In some embodiments, the linker has a defined length, thereby connecting NP and Q while allowing for an appropriate distance between them.

[0175] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0176] 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.

[0177] 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.

[0178] In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises 1-3, 1-5, 1-10, 5-10, or 5-20 amino acid residues. In some embodiments, one or more amino acids of the linker are unnatural amino acids.

[0179] In some embodiments, the linker comprises a peptide linkage. The peptide bond comprises L-amino acids and / or D-amino acids. 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 as good as or better than that of oligo-L-arginine.

[0180] In some embodiments, the linker has a length of 1-100 atoms, 1-50 atoms, 1-30 atoms, 1-20 atoms, 1-15 atoms, 1-10 atoms, or 1-5 atoms. In some embodiments, the linker has a length of 1-10 atoms. In some embodiments, the linker has a length of 1-20 atoms.

[0181] In some embodiments, the linker can include flexible and / or rigid regions. Exemplary flexible linker regions include those that include Gly and Ser residues ("GS" linkers), glycine residues, alkylene chains, PEG chains, etc. Exemplary rigid linker regions include those that include alpha-helix-forming sequences, proline-rich sequences, and regions rich in double and / or triple bonds.

[0182] In some embodiments, the linker is cleavable. In some embodiments, the linker is designed to be cleavable to aid in eleminization of the complex from the mammal. In some embodiments, the linker is designed for cleavage in the presence of a particular condition or in a particular environment (such conditions or the environment near such target cells, tissues or regions). Such linkers mainly include chemically cleavable linkers that respond to low pH (acid-1 labile linkers) or reducing environments (disulfide linkers), and enzymatically cleavable linkers (peptide linkers or β-glucuronide linkers) that are sensitive to the action of certain lysosomal enzymes.

[0183] In some embodiments, the linker is cleavable under physiological conditions. In some embodiments, the linker is cleavable under intracellular conditions. In some embodiments, the linker is chemically cleavable. In some embodiments, the linker is enzymatically cleavable. In some embodiments, the linker is pH sensitive, i.e., sensitive to hydrolysis at a particular pH value. For example, a pH sensitive linker may be hydrolyzable under acidic conditions. For example, the linker may be an acid-1 labile linker that is hydrolyzable in lysosomes (e.g., hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic acid amides, orthoesters, acetals, ketals, etc.). Such linkers may be relatively stable under neutral pH conditions, e.g., pH conditions in blood, but are unstable at a pH below 7.0, e.g., pH 6.5-4.5 (approximate pH of lysosomes and / or endosomes).

[0184] In some embodiments, the linker comprises one or more disulfide bonds.

[0185] In some embodiments, the linker is cleaved in or near tissues suffering from hypoxia, such as cancerous cells and tissues. In some embodiments, the linker comprises a disulfide bond. In some embodiments, linkers containing disulfide bonds are preferentially cleaved in hypoxic regions. Hypoxia is believed to make cancer cells more resistant to radiation and chemotherapy and also initiate angiogenesis. In a hypoxic environment, for example in the presence of leaky or necrotic cells, free thiols and other reducing agents become available outside the cell, but O2, which normally keeps the extracellular environment oxidized, is by definition depleted. In some embodiments, this shift in redox balance promotes the reduction and cleavage of disulfide bonds in the linker. In addition to disulfide bonds that utilize the thiol-disulfide equilibrium, bonds containing quinones that decompose when reduced to hydroquinones are used in linkers designed to cleave in hypoxic environments.

[0186] In some embodiments, the linker is cleaved by intracellular peptidase or protease enzymes, including but not limited to lysosomal or endosomal proteases. In some embodiments, the linker is cleaved by glycosidases, such as glucuronidase. Small peptide sequences, such as Val-Cit and Phe-Lys, have been developed as linkers for ADCs. These bi-peptide linkers show good stability in serum, but can be recognized and rapidly hydrolyzed by certain lysosomal proteases, such as cathepsin B, after internalization, and β-glucuronide linkers can be easily cleaved by the abundant lysosomal enzyme β-glucuronidase, facilitating easy and selective release of the active drug. In other embodiments, the linker is non-cleavable.

[0187] In some embodiments, the linker is cleaved by a protease, a matrix metalloproteinase, a serine protease, or a combination thereof. In some embodiments, the linker is cleaved by a reducing agent. In some embodiments, the linker is cleaved by an oxidizing agent or oxidative stress. In some embodiments, the linker is cleaved by an MMP. The hydrolytic activity of matrix metalloproteinase (MMP) is involved in the invasive migration of metastatic tumor cells. In some embodiments, the linker comprises the amino acid sequence PLG-C(Me)-AG, PLGLAG, which is cleaved by the metalloproteinase enzymes MMP-2, MMP-9, or MMP-7 (MMPs involved in cancer and inflammation).

[0188] In some embodiments, the linker is cleaved by proteolytic enzymes or a reducing environment, such as may be found in the vicinity of cancerous cells, where such an environment or such enzymes are not typically found in the vicinity of normal cells.

[0189] In some embodiments, the linker is cleaved by a serine protease, including but not limited to thrombin and cathepsin. In some embodiments, the linker is cleaved by cathepsin K, cathepsin S, cathepsin D, cathepsin E, cathepsin W, cathepsin F, cathepsin A, cathepsin C, cathepsin H, cathepsin Z, or any combination thereof. In some embodiments, the linker is cleaved by cathepsin K and / or cathepsin S.

[0190] In some embodiments, the linker is cleaved in a necrotic environment. Necrosis often results in the release of enzymes or other cellular contents that can be used to induce cleavage of the linker. In some embodiments, cleavage of the linker occurs by necrotic enzymes (e.g., by calpain).

[0191] For further details regarding linkers and their use in the compounds described herein, see Wu, A. M.; Senter, P. D. Arming antibodies: prospects and challenges for immunoconjugates. Nat. Biotechnol. 2005, 23(9):1137-1146; Beck, A.; et al. The next generation of antibody-drug conjugates comes of age. Discov. Med. 2010, 10(53):329-339; Nolting, B.; et al. Linker technologies for antibody-drug conjugates. Methods. Mol. Biol. 2013, 1045:71-100; Jain, N.; et al. Current ADC linker chemistry. Pharm. Res. 2015, 32:3526-3540; McCombs, JR; Owen, S. C. Antibody drug conjugates: design and selection of linker, payload and See conjugation chemistry. AAPS J. 2015, 17(2):339-351; Jun Lu, et al., Linkers Having a Crucial Role in Antibody-Drug Conjugates, Int J Mol Sci. 2016 Apr; 17(4):561, each of which is incorporated by reference for its disclosure of such linkers.

[0192] In some embodiments, the linker comprises one or more of unsubstituted or substituted alkylene, unsubstituted or substituted cycloalkylene, unsubstituted or substituted heterocycloalkylene, unsubstituted or substituted arylene, and unsubstituted or substituted heteroarylene.

[0193] In some embodiments, L is absent or is a non-cleavable linker. In some embodiments, when L is absent, the chelate is directly linked to the NP (e.g., one of the acetate groups of DOTA or DOTAGA is used to attach the chelate to the NP). In some embodiments, L is absent or is one or more amino acids, PEG groups, -L 1 -, -L 1 -L 2 -, -L 1 -L 2 -L 3 -, -L 1 -L 2 -L 3 -L 4 -, -L 1 -L 2 -L 3 -L 4 -L 5 -, -L 2 -, -L 2 -L 3 -, -L 2 -L 3 -L 4 -, -L 2 -L 3 -L 4 -L 5 -, -L 3 -, -L 3 -L 4 -, -L 3 -L 4 -L 5 -, -L 4 -, -L 4 -L 5 -, -L 5 -, -L 1 -L 2 -L 3 -L 4 -L 5 -, or any combination thereof.

[0194] In some embodiments, L is absent or is one or more amino acids, PEG groups, -L 1 -, -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 1 -L 2 -L3 -L 4 -L 5 -, or any combination thereof.

[0195] In some embodiments, L 1 each independently represents none, an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, an unsubstituted or substituted alkenylene, an unsubstituted or substituted alkynylene, an unsubstituted or substituted cycloalkylene, an unsubstituted or substituted heterocycloalkylene, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, one or more amino acids, -(CH) p -, -C(=O)-, -C(=O)-(CH2) p -, -(CH2) p -C(=O)-, -(CH2) p -C(=O)-(CH2) p -, -C(=O)NH-, -C(=O)NH-(CH2) p -, -(CH2) p -C(=O)NH-, -(CH2) p -C(=O)NH-(CH2) p -, -NHC(=O)-, -NHC(=O)-(CH2) p -, -(CH2) p -NHC(=O)-, -(CH2) p -NHC(=O)-(CH2) p -, -NHC(=O)NH-, -NHC(=O)NH-(CH2) p -, -(CH2) p -NHC(=O)NH-, -(CH2) p -NHC(=O)NH-(CH2) p -, and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. 1 each independently represents none, unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, unsubstituted or substituted monocyclic cycloalkylene, unsubstituted or substituted monocyclic heterocycloalkylene, unsubstituted or substituted phenylene, unsubstituted or substituted monocyclic heteroarylene, one or more amino acids, -(CH2) p-, -C(=O)-, -C(=O)-(CH2) p -, -(CH2) p -C(=O)-, -(CH2) p -C(=O)-(CH2) p -, -C(=O)NH-, -C(=O)NH-(CH2) p -, -(CH2) p -C(=O)NH-, -(CH2) p -C(=O)NH-(CH2) p -, and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0196] In some embodiments, L 2 are each independently absent, -O-, -S-, -S(=O)-, or -S(=O) 2- , -NH-, -CH(OH)-, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -CH(=N)-, -CH(=N-NH)-, -CCH3(=N)-, -CCH3(=N-NH)-, -OC(=O)NH-, -NHC(=O)NH-, -NHC(=O)O-, -(CH2) p -, -C(=O)-(CH2CH2X) p - or - (CH2CH2X) p -, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and each X is independently O, S, or NR X and R X is hydrogen or C1-C4 alkyl. In some embodiments, L 2 are each independently -C(=O)-, -C(=O)NH-, -C(=O)O-, -(CH2) p -, -C(=O)-(CH2CH2O) p - or -(OCH2CH2) p -, and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0197] In some embodiments, L 3each independently represents none, an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, an unsubstituted or substituted alkenylene, an unsubstituted or substituted alkynylene, an unsubstituted or substituted cycloalkylene, an unsubstituted or substituted heterocycloalkylene, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, one or more amino acids, -(CH) q -, -(CH2CH2X) q - or - (XCH2CH2) q -, each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and each X is independently O, S, or NR X and R X is hydrogen or C1-C4 alkyl. In some embodiments, L 3 each independently represents an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, -(CH2) q -, and each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0198] In some embodiments, L 4 are each independently absent, -O-, -S-, -S(O)-, or -S(O) 2- , -NH-, -CH(OH)-, -C(=O)-, -C(=O)NH-, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NH-, -NHC(=O)NH-, or -NHC(=O)O-. In some embodiments, L 4 each independently is absent or -NH-.

[0199] In some embodiments, L 5 Each is independently absent, unsubstituted or substituted alkylene, or unsubstituted or substituted heteroalkylene. 5 each independently is absent or an unsubstituted or substituted alkylene.

[0200] In some embodiments, L is absent or -L 1 -, -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 1 -L 2 -L 3 -L 4 -L 5 In some embodiments, L is a linker that is absent, -L 1 -, -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 1 -L 2 -L 3 -L 4 -L 5 -, or a combination thereof; L 1 each independently represents none, an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, an unsubstituted or substituted alkenylene, an unsubstituted or substituted alkynylene, an unsubstituted or substituted monocyclic cycloalkylene, an unsubstituted or substituted monocyclic heterocycloalkylene, an unsubstituted or substituted phenylene, an unsubstituted or substituted monocyclic heteroarylene, one or more amino acids, -(CH2) p -, -(CH2) p -, -C(=O)-, -C(=O)-(CH2) p -, -C(=O)NH-, -C(=O)NH-(CH2) p -, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 2 are each independently -C(=O)-, -C(=O)NH-, -C(=O)O-, -(CH2) p -, -C(=O)-(CH2CH2O) p - or -(CH2CH2O) p -, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 3 each independently represents an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, -(CH2)q -, each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 4 each independently is absent or -NH-; L 5 each independently is absent, unsubstituted or substituted alkylene, or unsubstituted or substituted heteroalkylene.

[0201] In some embodiments, -L 2 -L 3 -L 4 -L 5 -teeth,

[0202] [ka] wherein each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each X is independently O or NR X and R X is hydrogen or C1-C4 alkyl.

[0203] In some embodiments, -L 2 -L 3 -L 4 -L 5 -teeth,

[0204] [ka] wherein each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0205] In some embodiments, -L 2 -L 3 -L 4 -L 5 -teeth,

[0206] [ka] wherein each X is independently O or NR X and R X is hydrogen or C1-C4 alkyl.

[0207] In some embodiments, L is

[0208] [ka] wherein each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each X is independently O or NR X and R X is hydrogen or C1-C4 alkyl.

[0209] In some embodiments, L is

[0210] [ka] wherein each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0211] In some embodiments, L is

[0212] [ka] wherein each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0213] In some embodiments, L is absent or is one or more amino acids, a PEG group, -L 1 -, -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 1 -L 2 -, -L 1 -L 2 -L 3 -, -L 1 -L 2 -L 3 -L 4 -, -L 2 -L 3 -L 4 -L 5 -, -L 2 -L 3 -L 4 -, -L 3 -L 4 -L 5 -, -L 1 -L 2 -L 3 -L 4 -L 5 - or combinations thereof, L 1 each independently represents none, an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, an unsubstituted or substituted alkenylene, an unsubstituted or substituted alkynylene, an unsubstituted or substituted cycloalkylene, an unsubstituted or substituted heterocycloalkylene, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, one or more amino acids, -(CH) p -, -C(=O)-, -(CH2) p -C(=O)-, -C(=O)-(CH2) p -, -(CH2)p -C(=O)-(CH2) p -, -C(=O)NH-, -C(=O)NH-(CH2) p -, -(CH2) q -C(=O)NH-, -(CH2) p C(=O)NH-(CH2) p -, -NHC(=O)-, -NHC(=O)-(CH2) p -, -(CH2) q -NHC(=O)-, -(CH2) p NHC(=O)-(CH2) p -, -NHC(=O)NH-, -NHC(=O)NH-(CH2) p -, -(CH2) q -NHC(=O)NH-, -(CH2) p NHC(=O)NH-(CH2) p -, p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 2 are each independently absent, -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -CH(OH)-, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -CH(=N)-, -CH(=N-NH)-, -CCH3(=N)-, -CCH3(=N-NH)-, -OC(=O)NH-, -NHC(=O)NH-, -NHC(=O)O-, -(CH2) p -, -C(=O)-(CH2CH2X) p - or - (CH2CH2X) p -, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 3 each independently represents none, an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, an unsubstituted or substituted alkenylene, an unsubstituted or substituted alkynylene, an unsubstituted or substituted cycloalkylene, an unsubstituted or substituted heterocycloalkylene, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, one or more amino acids, -(CH) q -, -(CH2CH2X) q - or - (XCH2CH2) q-, each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 4 are each independently absent, -O-, -S-, -S(=O)-, or -S(=O) 2- , -NH-, -CH(OH)-, -C(=O)-, -C(=O)NH-, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NH-, -OC(=S)NH-, -NHC(=O)NH-, -NHC(=S)NH-, -NHC(=O)O-, or -NHC(=S)O-, and L 5 each independently represents zero, unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, or unsubstituted or substituted benzylene; each X independently represents O, S, or NR X and R X are each independently selected from hydrogen, C1-C4 alkyl, and -CH2CO2H.

[0214] In some embodiments, L 1 each independently represents none, an unsubstituted or substituted alkylene, an unsubstituted or substituted heteroalkylene, an unsubstituted or substituted alkenylene, an unsubstituted or substituted alkynylene, an unsubstituted or substituted cycloalkylene, an unsubstituted or substituted heterocycloalkylene, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, one or more amino acids, -(CH) p -, -C(=O)-, -C(=O)-(CH2) p -, -C(=O)NH-, -C(=O)NH-(CH2) p -, and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0215] In some embodiments, L is absent or -L 1 -L 2 -L 3 -L 4 -L 5 -, and L 1is absent, unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, unsubstituted or substituted alkenylene, unsubstituted or substituted alkynylene, unsubstituted or substituted monocyclic cycloalkylene, unsubstituted or substituted monocyclic heterocycloalkylene, unsubstituted or substituted phenylene, unsubstituted or substituted monocyclic heteroarylene, one or more amino acids, -(CH2) p -, -C(=O)-, -C(=O)-(CH2) p -, -C(=O)NH-, -C(=O)NH-(CH2) p -, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 2 -C(=O)-, -C(=O)NH-, -C(=O)O-, -(CH2) p -, -C(=O)-(CH2CH2O) p - or -(CH2CH2O) p -, each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 3 is unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, -(CH2) q -, each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; L 4 is absent or -NH-, and L 5 is absent, unsubstituted or substituted alkylene, or unsubstituted or substituted heteroalkylene.

[0216] In some embodiments, L is -L 4 -L 5 - Including L 4 is absent, -O-, -NH-, -C(=O)-, -NHC(=O)-, -NHC(=O)NH-, or -NHC(=S)NH-, and L 5 is absent, C1-C2 alkylene or benzylene. In some embodiments, L is -L 4 -L 5 - Including L 4is absent, -O-, -NH-, -C(=O)-, -NHC(=O)-, -NHC(=O)NH-, or -NHC(=S)NH-, and L 5 is absent, C1-C2 alkylene, or -CH2-(phen-1,4-ylene). In some embodiments, L is -L 4 -L 5 - Including L 4 is absent, -O-, -NH-, -C(=O)-, or -NHC(=O)-, and L 5 is absent or is C1-C2 alkylene. In some embodiments, L is -L 4 -L 5 - Including L 4 is absent, -O-, -NH-, -C(=O)-, or -NHC(=O)-, and L 5 is absent, -CH2- or -CH2CH2-.

[0217] In some embodiments, the linker comprises a click chemistry moiety. 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. As 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.

[0218] Representative linker and payload moieties In some embodiments, L is

[0219] [ka] wherein each X is independently O or NR X and R X is hydrogen or C1-C4 alkyl, and Q is,

[0220] [ka] It is.

[0221] In some embodiments, L is

[0222] [ka] and Q is

[0223] [ka] It is.

[0224] In some embodiments, L is

[0225] [ka] and Q is

[0226] [ka] It is.

[0227] In some embodiments, -LQ is

[0228] [ka] It is.

[0229] In some embodiments, the linker L is

[0230] [ka] and Q is

[0231] [ka] or its radionuclide (Z) complex.

[0232] In some embodiments, L is

[0233] [ka] and Q is

[0234] [ka] It is.

[0235] In some embodiments, -LQ is -(CH2) p (CH2) q NH-Q, -(CH2) p (OCH2CH2) p NH-Q, -C(=O)(CH2) p (CH2) q NH-Q, -C(=O)(CH2) p (OCH2CH2) p NH-Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NH-Q, or -(C2-C4 alkylene)(NR X CH2CH2) p (OCH2CH2) q NH-Q, where Q is

[0236] [ka] or its radionuclide (Z) complex.

[0237] In some embodiments, -LQ is -(CH2) p (CH2) q NH-Q, -(CH2) p (OCH2CH2) p NH-Q, -C(=O)(CH2) p (CH2) q NH-Q, -C(=O)(CH2) p (OCH2CH2) p NH-Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NH-Q, or -(C2-C4 alkylene)(NR X CH2CH2) p (OCH2CH2) q NH-Q, where Q is

[0238] [ka] It is.

[0239] In some embodiments, -LQ is -(CH2) p (CH2)6NH-Q, -CH2CH2(OCH2CH2)4NH-Q, -CH2CH2CH2(OCH2CH2)4NH-Q, -C(=O)(CH2) p (CH2)6NH-Q, -C(=O)CH2CH2(OCH2CH2)4NH-Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NH-Q, or -(C2-C4 alkylene)N(CH2CO2H)CH2CH2(OCH2CH2)3NH-Q, and Q is

[0240] [ka] or its radionuclide (Z) complex.

[0241] In some embodiments, -LQ is -(CH2) p (CH2)6NH-Q, -CH2CH2(OCH2CH2)4NH-Q, -CH2CH2CH2(OCH2CH2)4NH-Q, -C(=O)(CH2) p (CH2)6NH-Q, -C(=O)CH2CH2(OCH2CH2)4NH-Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NH-Q, or -(C2-C4 alkylene)N(CH2CO2H)CH2CH2(OCH2CH2)3NH-Q, and Q is

[0242] [ka] It is.

[0243] In some embodiments, the linker L is

[0244] [ka] and Q is

[0245] [ka] or its radionuclide (Z) complex.

[0246] In some embodiments, the linker L is

[0247] [ka] and Q is

[0248] [ka] It is.

[0249] In some embodiments, -LQ is -(CH2) p (CH2) q NHC(=O)CH2Q, -(CH2) p (CH2) q NHC(=O)CH2CH2Q, -(CH2) p (OCH2CH2) p NHC(=O)CH2Q, -(CH2) p (OCH2CH2)p NHC(=O)CH2CH2Q, -C(=O)(CH2) p (CH2) q NHC(=O)CH2Q, -C(=O)(CH2) p (CH2) q NHC(=O)CH2CH2Q, -C(=O)(CH2) p (OCH2CH2) p NHC(=O)CH2Q, -C(=O)(CH2) p (OCH2CH2) p NHC(=O)CH2CH2Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NHC(=O)CH2Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NHC(=O)CH2CH2Q, -(C2-C4 alkylene)(NR X CH2CH2) p (OCH2CH2) q NHC(=O)CH2Qor-(C2-C4 alkylene)(NR X CH2CH2) p (OCH2CH2) q NHC(=O)CH2CH2Q, where Q is

[0250] [ka] or its radionuclide (Z) complex.

[0251] In some embodiments, -LQ is -(CH2) p (CH2) q NHC(=O)CH2CH2Q, -(CH2) p (OCH2CH2) p NHC(=O)CH2CH2Q, -C(=O)(CH2) p (CH2) q NHC(=O)CH2CH2Q, -C(=O)(CH2)p (OCH2CH2) p NHC(=O)CH2CH2Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NHC(=O)CH2CH2Q, or -(C2-C4 alkylene)(NR X CH2CH2) p (OCH2CH2) q NHC(=O)CH2CH2Q, where Q is

[0252] [ka] It is.

[0253] In some embodiments, -LQ is -(CH2) p (CH2)6NHC(=O)CH2Q, -(CH2) p (CH2)6NHC(=O)CH2CH2Q, -CH2CH2(OCH2CH2)4NHC(=O)CH2Q, -CH2CH2(OCH2CH2)4NHC(=O)CH2CH2 Q, -CH2CH2CH2(OCH2CH2)4NHC(=O)CH2Q, -CH2CH2CH2(OCH2CH2)4NHC(=O)CH2CH2Q, -C(=O)(CH2) p (CH2)6NHC(=O)CH2Q, -C(=O)(CH2) p (CH2)6NHC(=O)CH2CH2Q, -C(=O)CH2CH2(OCH2CH2)4NHC(=O)CH2Q, -C(=O)CH2CH2(OCH2CH2)4NHC(=O)CH2CH2Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NHC(=O)CH2Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NHC(=O)CH2CH2Q, -(C2-C4 alkylene)N(CH2CO2H)CH2CH2(OCH2CH2)3NHC(=O)CH2Q, or -(C2-C4 alkylene)N(CH2CO2H)CH2CH2(OCH2CH2)3NHC(=O)CH2CH2Q, and Q is

[0254] [ka] or its radioactive nuclide (Z).

[0255] In some embodiments, -LQ is -(CH2) p (CH2)6NHC(=O)CH2CH2Q, -CH2CH2(OCH2CH2)4NHC(=O)CH2CH2Q, -CH2CH2CH2(OCH2CH2)4NHC(=O)CH2CH2Q, -C(=O)(CH2) p (CH2)6NHC(=O)CH2CH2Q, -C(=O)CH2CH2(OCH2CH2)4NHC(=O)CH2CH2Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NHC(=O)CH2CH2Q, or -(C2-C4 alkylene)N(CH2CO2H)CH2CH2(OCH2CH2)3NHC(=O)CH2CH2Q, and Q is

[0256] [ka] It is.

[0257] In some embodiments, -LQ is

[0258] [ka]

[0259] [ka]

[0260] [ka] It is.

[0261] In some embodiments, -LQ is

[0262] [ka]

[0263] [ka] It is.

[0264] Representative non-peptide small molecule drug conjugates (NPDCs) As used herein, "non-peptide ligand" refers to a compound that is a small molecule. As used herein, "non-peptide ligand" refers to a compound that is a small molecule with a molecular weight of less than 900 daltons. A non-peptide ligand is not derived from a chain of amino acids linked by peptide bonds. A non-peptide ligand is not an oligopeptide (e.g., a dipeptide, tripeptide, tetrapeptide). Larger structures such as nucleic acids, proteins, and polysaccharides are not small molecules.

[0265] In some embodiments, the NP is a non-peptide ligand that binds to tumor cells expressing somatostatin receptors.

[0266] In some embodiments, the NP is a non-peptide ligand for somatostatin receptors, where the NP is a compound described in U.S. Patent No. 10,696,689, U.S. Patent Application Publication No. US20200010453, each of which is incorporated herein by reference for such compounds. In some embodiments, the non-peptide ligand is a compound described in any one of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (Ie), (Id), (III), (IIIa), (IIIb), (IIIc), or (IIId) described in U.S. Patent No. 10,696,689. In some embodiments, the non-peptide ligand is a compound described in Table 1, Table 2, or Table 3 of U.S. Patent No. 10,696,689. In some embodiments, the non-peptide ligand is a compound described in formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI) of US20200010453. In some embodiments, the non-peptide ligand is a compound described in Table 1, Table 2, Table 3, or Table 4 of International Patent Application Publication No. WO2018 / 170284.

[0267] In some embodiments, the non-peptide ligand is a compound described in US9643951, US9630976, US20200000816, each of which is incorporated herein for such compounds.

[0268] In some embodiments, NP is a non-peptide ligand comprising a 4-(4-aminopiperidin-1-yl)-5-(phenyl)pyridine structural motif or a 4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(phenyl)pyridine structural motif. In some embodiments, NP is a non-peptide ligand comprising a 4-(4-aminopiperidin-1-yl)-5-(phenyl)pyridine structural motif or a 4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(phenyl)pyridine structural motif, where -LQ is attached to NP at the 2-position of the pyridine.

[0269] In some embodiments, the NP has a structure according to formula (II) below, or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof:

[0270] [ka] During the ceremony, R A teeth,

[0271] [ka] and R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -CN, -N(R 7 )2, or -OR 7 and R5 is hydrogen or a substituted or unsubstituted C1-C6 alkyl; R 6 is hydrogen, -OR 7 , -N(R 7 )2, -CN, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R 5 and R 6 together with the intervening atoms to which they are attached form a morpholine, and X 1 does not exist or is -O-, -S-, -N(R 7 )-, -C(=O)-, -C(=O)N(R 7 )-, -C(=O)O-, -N(R 7 )C(=O)-, or a heterocycle; R 7 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl.

[0272] In some embodiments, the NP has a structure according to formula (III) below, or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof:

[0273] [ka] During the ceremony, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -CN, -N(R 7 )2, or -OR 7 and R 5 is hydrogen or a substituted or unsubstituted C1-C6 alkyl; R 6 is hydrogen, -OR 7 , -N(R 7)2, -CN, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R 5 and R 6 together with the intervening atoms to which they are attached form a morpholine, and X 1 does not exist or is -O-, -S-, -N(R 7 )-, -C(=O)-, -C(=O)N(R 7 )-, -C(=O)O-, -N(R 7 )C(=O)-, or a heterocycle; R 7 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl.

[0274] In some embodiments, X 1 does not exist or is -O-, -S-, -N(R 7 )-, -C(=O)-, -C(=O)N(R 7 )-, -C(=O)O-, -N(R 7 )C(=O)-, azetidine, pyrrolidine, piperidine, or piperazine.

[0275] In some embodiments, X 1 is not present, -O-, -S-,

[0276] [ka] It is.

[0277] In some embodiments, the NP has a structure according to formula (III) below, or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof.

[0278] [ka]

[0279] In some embodiments, R1, R2, R3, and R4 are each independently hydrogen, F, Cl, Br, -CN, -N(R7)2, or C1-C4 alkyl. In some embodiments, R1, R2, R3, and R4 are each independently hydrogen, F, Cl, -CH3, -CH2CH3, or -OCH3. In some embodiments, R5 is hydrogen, R6 is hydrogen, -OH, or -OCH3, or R5 and R6 together with the intervening atom to which they are attached form a morpholine. In some embodiments, R7 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R7 is independently hydrogen or C1-C6 alkyl. In some embodiments, R7 is independently hydrogen, -CH3, or -CH2CH3.

[0280] In some embodiments,

[0281] [ka] teeth,

[0282] [ka] It is.

[0283] In some embodiments,

[0284] [ka] teeth,

[0285] [ka] It is.

[0286] In some embodiments,

[0287] [ka] teeth,

[0288] [ka] It is.

[0289] In some embodiments, R A teeth,

[0290] [ka] and During the ceremony, R1, R2, R3, and R4 are each independently hydrogen, F, Cl, Br, C1-C4 alkyl, -CN, -N(R7)2, or -OR7; R5 is hydrogen and R6 is hydrogen or -OR7, or R5 and R6 together with the intervening atoms to which they are attached form a morpholine; and Each R7 is independently hydrogen, -CH3, or -CH2CH3.

[0291] In some embodiments,

[0292] [ka] teeth,

[0293] [ka] and

[0294] [ka] teeth,

[0295] [ka] It is.

[0296] In some embodiments,

[0297] [ka] teeth,

[0298] [ka] and

[0299] [ka] teeth,

[0300] [ka] It is.

[0301] In some embodiments, the GPCR is somatostatin type 2 receptor (SSTR2) and the NP has the following structure:

[0302] [ka]

[0303] In some embodiments, the compound comprises the following structure:

[0304] [ka]

[0305] [ka]

[0306] In some embodiments, the compound comprises the following structure:

[0307]

change

[0308]

change

[0309]

change

[0310] [ka]

[0311] [ka]

[0312] In some embodiments, the compound comprises the following structure:

[0313] [ka]

[0314] In some embodiments, the NP is a non-peptide ligand that binds to tumor cells expressing the gonadotropin releasing hormone receptor (GnRHR).

[0315] In some embodiments, the NP is a non-peptide ligand that includes a N-{4,6-dimethoxy gamma-2-aminopyrimidin-5-yl}-5-[3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide structural motif, a N-(4,6-dimethoxypyrimidin-5-yl)-5-(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy)-2-furamide structural motif, or a N-(4,6-dimethoxypyrimidin-5-yl)-5-((3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy)furan-2-carboxamide) structural motif.

[0316] In some embodiments, the GPCR is GnRHR and the NP has the structure of formula (X) below, or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable solvate thereof:

[0317] [ka] During the ceremony, T is absent, -CH2-, -CH(CH3)-, or -C(CH3)2-; X 2 is absent, -O-, or -N(R7)-; V is CH or N and W is CH or N; R 7 is hydrogen or substituted or unsubstituted C1-C6 alkyl.

[0318] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0319] [ka] During the ceremony, V is CH or N and W is CH or N.

[0320] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0321] [ka] During the ceremony, V is CH or N and W is CH or N.

[0322] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0323] [ka] During the ceremony, V is CH or N and W is CH or N.

[0324] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0325] [ka] During the ceremony, V is CH or N and W is CH or N.

[0326] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0327] [ka] During the ceremony, V is CH or N and W is CH or N.

[0328] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0329] [ka] During the ceremony, V is CH or N and W is CH or N.

[0330] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0331] [ka] During the ceremony, V is CH or N and W is CH or N.

[0332] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0333] Synthesis of compounds The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein.

[0334] Unless otherwise specified, conventional methods of mass spectrometry, NMR, and HPLC are employed.

[0335] 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, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents or other reaction conditions.

[0336] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.In addition, the compounds described herein can exist not only in unsolvated form, but also in solvated form, including pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0337] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Drug salts are typically more soluble than the non-ionic species and are rapidly soluble in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the gastrointestinal tract, and this ability can be manipulated as an aspect of delayed- and sustained-release behavior.Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for regulated passage across biological membranes.

[0338] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with an acid. In some embodiments, the compound of formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptan-1,2-disulfonic acid, ethylhexanoic ... The acidic acids include sucrose, glycerol, glyceryl, stearate, sorbitol, sorbitolsulfonic ...

[0339] In some embodiments, the compound of formula (I) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0340] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with a base. In some embodiments, a compound of formula (I) is acidic and reacts with a base. In such a situation, the acidic proton of the compound of formula (I) is replaced with a metal ion, for example, lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein cooperate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as arginine and 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.

[0341] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, solvates include either stoichiometric or non-stoichiometric solvents and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0342] In some embodiments, the organic radical (eg, alkyl group, aromatic ring) moieties of the compounds of formula (I) are deuterated.

[0343] In some embodiments, the compounds of formula (I) have one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compounds of formula (I) exist in the R configuration. In some embodiments, the compounds of formula (I) exist in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0344] Individual stereoisomers can be obtained as desired by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, the compounds of formula (I) 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 the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by a separation / resolution technique based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or by chromatography, or by any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0345] In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in some circumstances, they are easier to administer than the parent drug. Prodrugs are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally or alternatively, prodrugs have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. For the design of prodrugs, see, for example, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference.

[0346] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the sum of processes (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is altered by an organism. Thus, enzymes can result in specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of a compound disclosed herein are optionally identified either by administration of the compound to a host and analysis of tissue samples from the host, or by in vitro incubation of the compound with hepatocytes and analysis of the resulting compound.

[0347] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Appropriate formulations depend on the route of administration selected. Summary of pharmaceutical compositions described herein can be found, for example, in Remigton: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0348] In some embodiments, the compounds described herein are administered alone or in pharmaceutical compositions in combination with pharma- ceutically acceptable carriers, excipients, or diluents.The administration of the compounds and compositions described herein can be achieved by a method that allows the compound to be delivered to the site of action.These methods include, but are not limited to, delivery via enteral routes (including oral routes) and parenteral routes (including injection or infusion and subcutaneous routes).

[0349] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

[0350] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. The preparation for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, together with additional preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The composition may be presented in unit dosage or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.

[0351] Treatment In some embodiments, the method comprises administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, to a subject. In some embodiments, the compound of formula (I), or a pharma- ceutically 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 or a hematological cancer. In some embodiments, the subject has a non-cancerous tumor. In some embodiments, the subject has an adenoma.

[0352] In embodiments, treatment is sufficient to reduce or inhibit the growth of the subject's tumor, reduce the number or size of metastatic lesions, reduce tumor burden, reduce primary tumor burden, reduce invasiveness, extend survival time, or maintain or improve quality of life, or a combination thereof.

[0353] 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 a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof emits some alpha particles by natural 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 proliferation. In some embodiments, the tumor cells are malignant tumor cells. In some embodiments, the tumor cells are benign tumor cells. In some embodiments, the method comprises killing the tumor cells with a beta particle emitting radionuclide. In some embodiments, the method comprises killing the tumor cells with an alpha particle emitting radionuclide. In some embodiments, the method comprises killing the tumor cells with a gamma particle emitting radionuclide.

[0354] In one aspect, methods and compositions for treating cancer are provided herein.Cancer includes tissue and organ carcinogenesis, including metastasis, such as gastrointestinal cancer (e.g., gastric cancer, esophageal cancer, pancreatic cancer, colorectal cancer, intestinal cancer, anal cancer, liver cancer, gallbladder cancer, or colon cancer), lung cancer, thyroid cancer, skin cancer (e.g., melanoma), oral cancer, urinary tract cancer (e.g., bladder cancer or kidney cancer), blood cancer (e.g., myeloma or leukemia) or prostate cancer.In some embodiments, the present disclosure provides methods and compositions for treating gastrointestinal cancer in a subject in need thereof by administering to the subject an effective amount of the non-peptide targeted therapeutic compound disclosed herein.Non-limiting examples of gastrointestinal cancer that can be treated according to the method of the present disclosure include gastric cancer, esophageal cancer, pancreatic cancer, lung cancer (small cell lung cancer and / or non-small cell lung cancer), colorectal cancer, intestinal cancer, anal cancer, liver cancer, gallbladder cancer, or colon cancer. In some embodiments, the cancer is Hodgkin's lymphoma or B-cell lymphoma.

[0355] In one aspect, provided herein are methods and compositions for treating adenomas.

[0356] In one aspect, methods and compositions for treating peptide hormone G protein-coupled receptor expressing cancer are provided herein. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer to be treated is a primary or metastatic cancer of gastrointestinal origin, such as colorectal cancer, gastric cancer, small intestine cancer, or esophageal cancer. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer to be treated is a primary or metastatic pancreatic cancer. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer to be treated is a primary or metastatic lung cancer, such as squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer to be treated is a sarcoma, such as leiomyosarcoma or rhabdomyosarcoma. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer to be treated is a primary or metastatic neuroectodermal tumor, such as glioma cytoma or paraganglioma. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer to be treated is a primary or metastatic bronchopulmonary tumor or gastrointestinal neuroendocrine tumor. In some embodiments, the cancer is colon cancer.

[0357] In one aspect, provided herein is a method for identifying a mammalian tissue or organ that overexpresses one or more peptide hormone G protein-coupled receptors, the method comprising: (i) administering to a mammal a non-peptide targeted therapeutic compound disclosed herein; and (ii) performing a positron emission tomography (PET) analysis on the mammal. Includes.

[0358] In some embodiments, the mammal has been diagnosed with cancer.

[0359] In another aspect, provided herein is a method of treating cancer in a mammal, comprising administering to a mammal in need of cancer treatment a non-peptide targeted therapeutic compound disclosed herein. In some embodiments, the cancer expresses one or more peptide hormone G protein-coupled receptors. In some embodiments, the cancer comprises a peptide hormone G protein-coupled receptor positive cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a sarcoma, carcinoma, or lymphoma. In some embodiments, the cancer comprises a neuroendocrine tumor. In some embodiments, the cancer comprises an insulinoma. In some embodiments, the cancer comprises a peptide hormone G protein-coupled receptor positive (e.g., somatostatin receptor positive) gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0360] In some embodiments, the compounds of formula (I) disclosed herein are used in a method for in vivo imaging of a subject. In some embodiments, the method comprises: (i) administering to a mammal a compound of formula (I); (ii) waiting a sufficient time for the compound to accumulate at the tissue or cell site to be imaged; and (iii) imaging the cell or tissue using a non-invasive imaging technique. Includes.

[0361] In some embodiments, the non-invasive imaging technique is positron emission tomography (PET) analysis. In some embodiments, the non-invasive imaging technique is selected from positron emission tomography imaging, or positron emission tomography with computed tomography imaging, and positron emission tomography with magnetic resonance imaging.

[0362] Dosage and treatment regimens In one embodiment, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is used in the preparation of a medicament for the treatment of 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 a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof.

[0363] In certain embodiments, compositions containing the compounds described herein are administered for diagnostic and / or therapeutic treatments.

[0364] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular conjugate, the particular cancer or tumor (and its severity) being treated, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular 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 will vary depending on the subject's body type, weight, or blood volume.

[0365] The toxicity and therapeutic efficacy of such treatment regimens are discussed below, including but not limited to, LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dose range and / or a therapeutically effective unit dose for use in mammals, including humans.

[0366] The amount of the conjugate or its pharma- ceutically acceptable salt or solvate and / or pharmaceutical composition administered may be sufficient to deliver a therapeutically effective dose for a particular subject. In some embodiments, the dose of the conjugate is about 0.1 μg to about 50 mg / kg body weight, 1 μg to about 50 mg / kg body weight, or about 0.1 to about 10 mg / kg body weight. The therapeutically effective dose may also be determined at the discretion of the physician. By way of example only, the dose of the conjugate or its pharma- ceutically acceptable salt or solvate described herein for the methods of treating a disease described herein is about 0.001 mg / kg to about 1 mg / kg body weight of the subject per dose. In some embodiments, the dose of the conjugate or its pharma- ceutically acceptable salt or solvate described herein for the methods of treating a disease described herein is about 0.001 mg to about 1000 mg per dose for the subject to be treated. In some embodiments, a conjugate described herein, or a pharma- ceutically acceptable salt or solvate 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.

[0367] In some embodiments, a conjugate described herein or a pharma- ceutically acceptable salt or solvate thereof is administered to a subject at a dose of about 0.01 picomole to about 1 molar, about 0.1 picomole to about 0.1 molar, about 1 nanomolar to about 0.1 molar, or about 0.01 micromolar to about 0.1 millimolar.

[0368] In some embodiments, a conjugate described herein, or a pharma- ceutically acceptable salt or solvate thereof, is administered to a subject at a dosage 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.

[0369] In some embodiments, doses are administered once daily, 1-3 times per week, 1-4 times per month, or 1-12 times per year.

[0370] In any of the foregoing aspects, in further embodiments, an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal, and / or (c) administered intravenously to the mammal, and / or (d) administered by injection to the mammal.

[0371] Combination therapy In certain instances, it will be appropriate to administer at least one compound of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0372] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., an adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also includes a treatment regimen) that also has a therapeutic effect.

[0373] In any case, regardless of the disease, disorder, or condition being treated, the overall effect experienced by the patient is simply the additive of the two therapeutic agents or the patient experiences a synergistic effect.

[0374] Specific Terms Definitions of the following terms used in this application are provided below unless otherwise specified. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0375] As used herein, C1-C x is C1-C2, C1-C3... C1-Cx By way of example only, a group designated as "C1-C6" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., the group contains 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 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0376] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group can be branched or straight chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms (i.e., C1-C 10 alkyl). Whenever a number range such as "1-10" appears herein, it refers to the respective integer within the given range. For example, "1-10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, but the definition also encompasses occurrences of the term "alkyl" without a number range specified. In some embodiments, the alkyl is a C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0377] An "alkylene" group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups may be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, the alkylene is a 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-.

[0378] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0379] The term "alkenyl" refers to a type 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, R is H or alkyl. In some embodiments, an 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.

[0380] 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 an alkyl. In some embodiments, an 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, and -CH2C≡CH.

[0381] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl.

[0382] 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, the term distinguishes carbocycle from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0383] As used herein, the term "aryl" refers to an aromatic ring in which the atoms forming the ring are each carbon atoms. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6-C 10 Depending on the structure, the aryl group may be a monoradical or a diradical (i.e., an arylene group).

[0384] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic radical, where each of the atoms forming the ring (i.e., skeletal atoms) are carbon atoms. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 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.

[0385] The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0386] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with a fluorine atom. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0387] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings containing 1-4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3-10 atoms in its ring system, with the proviso that no ring contains two adjacent O or S atoms. The group of non-aromatic heterocyclic groups (also known as heterocycloalkyls) includes rings having 3-10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5-10 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, pyrrolidinyl, tetrahydropyranyl, tetrahydrothio ... 2-Pyrrinyl, 3-Pyrrolinyl, Indolinyl, 2H-Pyranyl, 4H-Pyranyl, Dioxanyl, 1,3-Dioxolanyl, Pyrazolinyl, Dithianyl, Dithiolanyl, 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, Isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-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 are C-linked (or C-linked) or N-linked where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole 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, e.g., pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0388] 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. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 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 is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0389] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the 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, the heterocycloalkyl is a C2-C 10 In another embodiment, the heterocycloalkyl is a C4-C 10 Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0390] The term "bond" or "single bond" refers to a chemical bond between two atoms or 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 single bond, the referenced group is not present, thereby allowing the formation of a bond between the remaining specified groups.

[0391] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or appended to a molecule.

[0392] 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, -COH, -COalkyl, -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, -COH, -CO(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, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. 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).

[0393] 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.

[0394] 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, interactions of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0395] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein.

[0396] Terms like "co-administration," as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include therapeutic regimens in which the therapeutic agents are administered by the same or different routes of administration or at the same or different times.

[0397] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound being administered that relieves to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to clinically significantly reduce a disease symptom. An appropriate "effective" amount in an individual case is optionally determined using techniques such as dose escalation studies.

[0398] The terms "enhance" or "enhancing," as used herein, mean 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 sufficient to enhance the effect of another therapeutic agent in a desired system.

[0399] The term "pharmaceutical combination" as used herein refers to a product resulting from the mixing or combination of more than one active ingredient, and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the active ingredients, for example, the compound of formula (I), or its pharmaceutically acceptable salt, and the auxiliary agent, both being administered to the patient at the same time in the form of a single entity or dose. The term "non-fixed combination" refers to the active ingredients, for example, the compound of formula (I), or its pharmaceutically acceptable salt, and the auxiliary agent, being administered to the patient as separate entities simultaneously, concurrently, or sequentially, without specific intervening time restrictions, where such administration provides the patient's body with effective levels of the two compounds. The latter term also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0400] The terms "article of manufacture" and "kit" are used synonymously.

[0401] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs, and the like; 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.

[0402] The terms "treat", "treating" or "treatment" as used herein include alleviating, relieving or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the progression 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 prophylactically and / or therapeutically arresting a symptom of a disease or condition. Abbreviation: Pd(DTBPF)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; TFA: Trifluoroacetic acid; TEA: Triethylamine; DIEA or DIPEA: N,N-Diisopropylethylamine; Prep-HPLC: Preparative high performance liquid chromatography; LCMS: Liquid chromatography*mass spectrometry; MS: mass spectrometry; HCl: Hydrochloric acid or hydrochloride salt; MeCN or CH3CN or ACN: Acetonitrile; H2O: water; DMSO: Dimethyl sulfoxide; DMF: Dimethylformamide; DCM: Dichloromethane; PE: Petroleum ether; rt: room temperature; hrs: time; h or hr: time; min: Min mg: Milligrams; mL: Milliliters; Eq: equivalent; mmol: millimolar; Mol: mole; Na2CO3: Sodium carbonate; K2CO3: Potassium carbonate; Na2SO4: Sodium sulfate; Brine: Saturated NaCl solution. EXAMPLES

[0403] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0404] Synthesis of compounds Example 1: 2-(4-{[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (Compound 1)

[0405] [ka] Step-1: To a solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-ol acid (91 mg, 1 Eq, 0.25 mmol) in DMF (2 mL), HATU (0.14 g, 1.5 Eq, 0.38 mmol), DIPEA (97 mg, 0.13 mL, 3 Eq, 0.75 mmol) and benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1-yl)pyridin-4-yl)piperidin-4-yl)carbamate (0.16 g, 1 Eq, 0.25 mmol) was added. The resulting mixture was stirred at ambient temperature for 0.5 hours. The reaction crude was purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-75%). Pure fractions were combined, concentrated, neutralized with saturated NaHCO3 (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (2 x 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oil)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate as a clear oil (202 mg). MS(M+H)=1001.7.

[0406] Step-2: To a solution of benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oyl)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate (202 mg, 1 Eq, 0.202 mmol) in DCM (1.0 mL) was added TFA (921 mg, 622 μL, 40 Eq, 8.08 mmol). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction crude was concentrated and MTBE (0.4 mL) and hexane (3 mL) were added to oil the desired product. The top layer was transferred to a decanter and the remaining residue was dried under vacuum to give the crude TFA salt of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid. MS (M+H)=901.5.

[0407] Step-3: To a solution of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (0.11 g, 1 Eq, 0.20 mmol) in DMF (1.0 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.11 g, 1.5 Eq, 0.30 mmol), DIPEA (0.21 g, 0.28 mL, 8 Eq, 1.6 mmol) and benzyl (1-(2-(4-(1-amino-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate-2,2,2-trifluoroacetaldehyde (1 / 1) (0.27 g, 73% Wt, 0.99 Eq, 0.20 mmol) was added. The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction crude was purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-55%). Pure fractions were combined, neutralized with saturated NaHCO3 (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give crude 2-(4-{[(15-{4-[4-(4-aminopiperidin-)1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid. MS(M+H)=1456.3. Half MS(M+H)=729.0.

[0408] Step-4: Tri-tert-butyl 2,2',2"-(10-(18-(4-(4-(4-((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,18-dioxo-6,9,12,15-tetraoxa-3-a To a solution of 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (145 mg, 1 Eq, 99.6 μmol) in TFA (4 g, 3 mL, 4e+2 Eq, 4e+1 mmol) was added thioanisole (0.2 g, 0.2 mL, 2e+1 Eq, 2 mmol). The resulting mixture was heated at 50° C. for 1 h. The reaction mixture was concentrated under vacuum to give the majority of the The TFA was removed. Hexane (4 mL) was added and the upper layer was transferred to a decanter. The remaining residue was concentrated to remove the hexane and purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-35%). Pure fractions were dried in vacuum and purified to give 2-(4-{[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzoyl)-2 ... The TFA salt of {zodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (85 mg) was obtained. MS (M+H)=1154.0.

[0409] The following compounds are prepared in a similar manner to Example 1 in different steps using appropriate substitution reagents and substrates, which may require further functional group modifications by well-known chemistry with appropriate reagents.

[0410] [Table 2]

[0411] Example 2: 2-(4-{[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl) lutetium acetate complex (compound 2)

[0412] [ka] Step-1: 1. 2,2',2"-(10-(18-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetaldehyde (1 / 2) (35 mg, 1 Eq, 51 μm To a solution of 1.5 mol) in MeCN (0.9 mL) was added water (0.5 mL), LuCl3 (15 mg), and saturated NaHCO3 solution (0.05 mL). The resulting mixture was heated at 80° C. for 1 h. LCMS showed complete conversion to the desired product. This reaction was repeated on the same scale and the reaction mixture was combined with the previous batch. The resulting mixture was purified by C18 reverse phase. Pure fractions were combined and dried under vacuum to give the title lutetium complex as a white solid (42 mg, 54%). MS (M+H)=1325.9. Half MS (M+H)=663.7.

[0413] Example 3: 2-(4-{[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)indium acetate complex (compound 3)

[0414] [ka] Step-1: To a solution of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosane-20-oleic acid (115.2 mg, 97% Wt, 1 Eq, 305.8 μmol) in DMF (1.5 mL) was added HATU (174.4 mg, 1.5 Eq, 458.7 μmol) and DIPEA (316.2 mg, 0.43 mL, 8.0 Eq, 2.446 mmol). The resulting mixture was stirred at room temperature for 10 minutes, followed by the addition of benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1-yl)pyridin-4-yl)piperidin-4-yl)carbamate-2,2,2-trifluoroacetaldehyde (1 / 2) (260.0 mg, 1 Eq, 305.8 μmol). The reaction mixture was stirred at 20° C. for 2 hours. The resulting mixture was diluted with ethyl acetate, washed with water and brine, separated and concentrated to give crude benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oyl)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate as a light brown solid. This material was used in the next step without further purification. MS(M+H)=1001.9.

[0415] Step-2: To a solution of benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-oyl)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate (306 mg, 1 Eq, 306 μmol) in DCM (1 mL), TFA (1.39 g, 941 μL, 40 Eq, 12.2 mmol) was added. The resulting mixture was stirred at ambient temperature for 0.5 hours. The reaction crude was concentrated and the remaining residue was purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA). The pure fractions were combined and dried under vacuum to give crude benzyl (1-(2-(4-(1-amino-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate (205 mg, 227 μmol, 74.4%) as a TFA salt. This material was used in the next step without further purification. MS(M+H)=901.7.

[0416] step-3: To a solution of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid in DMF (1.5 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (115.8 mg, 1.5 Eq, 304.7 μmol) and DIPEA (210.0 mg, 0.28 mL, 8 Eq, 1.625 mmol). The resulting mixture was stirred at room temperature for 10 minutes, followed by the addition of benzyl (1-(2-(4-(1-amino-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate-2,2,2-trifluoroacetaldehyde (1 / 1) (203.0 mg, 1.0 Eq, 203.1 μmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction crude was diluted with ethyl acetate, washed with water and brine, and concentrated to give crude tri-tert-butyl 2,2',2"-(10-(18-(4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate as a light brown solid. MS (M+H)=1457.5.

[0417] Step-4: To a solution of TFA (2.2 g, 1.5 mL, 97 Eq, 20 mmol) was added crude tri-tert-butyl 2,2',2"-(10-(18-(4-(4-(4-((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (295.0 mg, 1 Eq, 202.6 μmol) and the resulting mixture was heated at 60° C. for 1 h. The reaction crude was concentrated and purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA). Pure fractions were combined and dried under vacuum to give the TFA salt of 2,2',2"-(10-(18-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (160 mg, 139 μoml, 68.5%). MS (M+H)=1154.4.

[0418] Step 5: 2,2',2"-(10-(18-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid TFA salt (45 mg, 1 Eq, 33 μmol) was added to sodium bicarbonate (28 mg, Indium(III) chloride (10Eq, 0.33mmol), indium(III) chloride (22mg, 3Eq, 0.10mmol), MeCN (0.3mL), and water (0.3mL) were combined. The resulting mixture was stirred at 40°C for 3h. The reaction crude was purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA). Pure fractions were combined and dried to give the title indium complex (38.3mg, 26.2μmol, 79%) as the TFA salt. MS(M+H)=1265.9.

[0419] Example 4: 2-(4-{[(21-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-21-oxo-3,6,9,12,15,18-hexaoxaheneicosan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)indium acetate complex (compound 5)

[0420] [ka] Step-1: In an 8 mL flask, add 2,2',2"-(10-(24-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate. Acid (40 mg, 1 Eq, 32 μmol), indium trichloride (20 mg, 5.8 μL, 2.8 Eq, 90 μmol), sodium bicarbonate (15 mg, 6.9 μL, 5.5 Eq, 0.18 mmol), water (0.25 mL), and acetonitrile (0.5 mL) were added. The resulting mixture was stirred at 80° C. for 1 h. The reaction mixture was diluted with DMSO (4 mL) and filtered. The filtrate was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water (0.05% TFA) and ACN (30% ACN to 75% in 15 min); total flow rate 20mL / min; detector, UV 220nm. This gave the TFA salt of the title indium complex (24.6mg, 15.6μmol, 48%) as a white solid. MS(M+H)=1354.7, 1356.7.

[0421] Example 5: 2-(4-{[(21-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-21-oxo-3,6,9,12,15,18-hexaoxaheneicosan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)gallium acetate complex (compound 6)

[0422] [ka] Step-1: In an 8 mL flask, add 2,2',2"-(10-(24-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (10 mg, 1Eq, 8.1μmol), gallium chloride (4mg, 2μL, 3Eq, 0.02mmol), sodium bicarbonate (4mg, 6Eq, 0.05mmol), water (0.15mL), and acetonitrile (0.3mL) were added. The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with DMSO (4mL) and filtered. The filtrate was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water (0.05% TFA) and ACN (from 30% ACN to 75% in 15min); total flow, 20mL / min; detector, UV 220nm. This gave the TFA salt of the title gallium complex (6mg, 4μmol, 50%) as a white solid. MS(M+H)=1309.3,1311.3.

[0423] Example 6: 2-(4-{[(21-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-21-oxo-3,6,9,12,15,18-hexaoxaheneicosan-1-yl)carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl) lutetium acetate complex (compound 7)

[0424] [ka] Step-1: In an 8 mL flask, add 2,2',2"-(10-(24-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,24-dioxo-6,9),12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tetramethylphenyl)pyridin-2-yl. A mixture of lutetium(III)triacetate (10 mg, 1 Eq, 8.1 μmol), lutetium(III) chloride (7 mg, 3 Eq, 0.02 mmol), sodium bicarbonate (5 mg, 7 Eq, 0.06 mmol), acetonitrile (0.3 mL), and water (0.15 mL) was added. The mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with DMSO (4 mL), filtered, and the filtrate was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water (0.05% TFA) and ACN (30% ACN to 75% in 15 min); total flow rate 20mL / min; detector, UV 220nm. This gave the title lutetium complex (2.5mg, 1.5μmol, 19%) as a white solid. MS(M+H)=1414.8, 1416.8.

[0425] Example 7: 2-(7-{[(27-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-27-oxo-3,6,9,12,15,18,21,24-octaoxaheptacosan-1-yl)carbamoyl]methyl}-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (compound 8)

[0426] [ka] Step-1: A 500 mL round bottom flask was charged with 2,4-dichloronicotinaldehyde (19 g, 1 Eq, 0.11 mol), tert-butyl piperidin-4-ylcarbamate (22 g, 1.0 Eq, 0.11 mol), DIEA (14 g, 19 mL, 1.0 Eq, 0.11 mol), and MeCN (200 mL). The resulting mixture was stirred at 25° C. for 1 h. The reaction crude was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (2×100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography eluted with ethyl acetate / petroleum ether (1:2). This gave tert-butyl (1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (20 g, 59 mmol, 55%) as a yellow solid. MS (M+H)=340.1, 342.1.

[0427] Step-2: A 100 mL round bottom flask was charged with tert-butyl (1-(5-bromo-2-chloro-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (4 g, 1 Eq, 0.01 mol) and HCl in dioxane (45 g, 30 mL, 4 M, le+2 Eq, 1.2 mol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under vacuum to give crude 4-(4-aminopiperidin-1-yl)-5-bromo-2-chloronicotinaldehyde hydrochloride (2.8 g, 7.9 mmol, 80%) as a pale yellow solid. This material was used in the next step without further purification. MS (M+H)=318.0, 320.0.

[0428] Step-3: A 100 mL round bottom flask was charged with 4-(4-aminopiperidin-1-yl)-5-bromo-2-chloronicotinaldehyde hydrochloride (2.8 g, 1 Eq, 7.9 mmol), K2CO3 (5.4 g, 5.0 Eq, 39 mmol), and THE (30 mL). The resulting mixture was stirred at 25° C., followed by the addition of Cbz-Cl (2.0 g, 1.7 mL, 1.5 Eq, 12 mmol). The reaction solution was stirred at 25° C. for another 2 h. The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (1×50 mL), dried over anhydrous sodium sulfate, and concentrated. The remaining residue was purified by silica gel chromatography eluting with PE / EA (1:1). This gave benzyl (1-(5-bromo-2-chloro-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (3.5 g, 7.0 mmol, 88%, 90% purity) as a yellow solid. MS (M+H)=452.1, 454.1.

[0429] Step-4: A 100 mL round bottom flask was charged with a mixture of benzyl (1-(5-bromo-2-chloro-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (3.5 g, 1 Eq, 7.7 mmol), (3-fluoro-5-methylphenyl)boronic acid (1.1 g, 0.92 Eq, 7.1 mmol), 1,-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (280 mg, 0.049 Eq, 383 μmol), K3PO4 (4.9 g, 3.0 Eq, 23 mmol), toluene (175 mL), and water (17.5 mL). The resulting mixture was stirred at 50° C. under N2 for 2.5 hours. The reaction mixture was concentrated and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The remaining residue was purified by silica gel chromatography eluting with PE / EA (1:1). This gave benzyl (1-(2-chloro-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (2.8 g, 4.6 mmol, 60%, 80% purity) as a yellow solid. MS (M+H)=482.4, 484.4.

[0430] Step 5: A 40 mL vial was charged with benzyl (1-(2-chloro-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (600 mg, 1 Eq, 1.24 mmol), tert-butyl piperazine-1-carboxylate (350 mg, 1.51 Eq, 1.88 mmol), DIEA (483 mg, 651 μL, 3.00 Eq, 3.74 mmol), and DMSO (6 mL). The resulting mixture was stirred at 100° C. for 3 h. The reaction crude was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated. The remaining residue was purified by silica gel chromatography eluting with PE / EA (1:1). This gave tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-2-yl)piperazine-1-carboxylate (400 mg, 0.57 mmol, 46%, 90% purity) as a yellow solid. MS (M+H)=632.4.

[0431] step-6: A 40 mL vial was charged with tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-2-yl)piperazine-1-carboxylate (400 mg, 1 Eq, 633 μmol), 4-chlorobenzene-1,2-diamine (180 mg, 1.99 Eq, 1.26 mmol), NaSO (360 mg, 2.99 Eq, 1.89 mmol), and DMSO (4 mL). The resulting mixture was stirred at 80° C. for 1 h. The reaction crude was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated. The remaining residue was purified by silica gel chromatography eluting with PE / EA (1:1). This gave tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate) (500 mg, 0.60 mmol, 94%, 90% purity) as a yellow solid. MS (M+H)=754.5, 756.5.

[0432] Step-7: To a solution of tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-)1-yl)-3-(6-chloro-)1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate) (500 mg, 1 Eq, 663 μmol) in DCM (9 mL) was added TFA (3 mL). The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under vacuum. The remaining residue was diluted with ethyl acetate (10 mL) and saturated NaHCO3 was added until pH=8. The resulting mixture was extracted with ethyl acetate (50 mL) and the organic layer was concentrated under vacuum. This gave crude benzyl (1-(3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-)1-yl)pyridin-4-yl)piperidin-4-yl)carbamate) (390 mg, 0.54 mmol, 81%, 90% purity) as a yellow oil. MS (M+H)=654.2, 656.2.

[0433] step-8: A 40 mL vial was charged with 2,2-dimethyl-4-oxo-3,81,1,14,17,20,23,26,29-nonaoxa-5-azadotriacontan-32-oic acid (323 mg, 1.00 Eq, 596 μmol), 4-methylmorpholine (181 mg, 3.00 Eq, 1.79 mmol), perfluorophenyl diphenylphosphinate (275 mg, 1.20 Eq, 716 μmol), and DMF (4 mL). Crude benzyl (1-(3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1-yl)pyridin-4-yl)piperidin-4-yl)carbamate (390 mg, 1 Eq, 596 μmol) was added and the resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (50 mL), separated and concentrated under vacuum. The remaining residue was purified by flash preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (0.1% TFA) and CH3CN (10% CH3CN to 90% in 10 min); detector, UV254 and 220 nm. This gave benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3),8,11,14,17,20,23,26,29-nonaoxa-5-azadotriacontan-32-oyl)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate) (500 mg, 0.40 mmol, 68%, 95% purity) as a pale yellow oil. MS (M+H)=1177.9.

[0434] Step-9: To a solution of benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23,26,29-nonaoxa-5-azadotriacontan-32-oyl)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate (500 mg, 1 Eq, 425 μmol) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo to give crude benzyl (1-(2-(4-(1-amino-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oil)piperazin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate 2,2,2-trifluoroacetate (500 mg, 420 μmol, 98.8%) as a yellow oil. This material was used in the next step without further purification. MS(M+H)=1077.5.

[0435] step-10: A 40 mL vial was charged with 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (240 mg, 0.999 Eq, 419 μmol), HATU (191 mg, 1.20 Eq, 502 μmol), DIEA (271 mg, 365 μL, 5.00 Eq, 2.10 mmol), and DMF (5 mL). Crude benzyl (1-(2-(4-(1-amino-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-)oyl)piperazin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate 2,2,2-trifluoroacetate) (500 mg, 1 Eq, 420 μmol) was added and the resulting solution was stirred at 25° C. for 2 hours. The reaction mixture was purified by flash preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (0.1% TFA) and CH3CN (10% CH3CN to 90% in 10 min); detector, UV254 and 220 nm. This gave tri-tert-butyl 2,2',2"-(10-(30-(4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,30-dioxo-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (510 mg, 0.30 mmol, 71%, 95% purity) as an off-white solid. MS (M+H) = 632.0.

[0436] Step-11: A 40 mL vial was charged with a mixture of tri-tert-butyl 2,2',2"-(10-(30-(4-(4-(4-((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl) (350 mg, 1 Eq, 214 μmol) and TFA (4 mL). The resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated and the remaining residue was purified by preparative HPLC using the following conditions: Column, SunFire Prep C18 OBD column, 19*150 mm 5um; mobile phase, water (0.05% TFA) and ACN (from 30.0% ACN to 50.0% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. This resulted in the determination of 2,2',2"-(10-(30-(4-(4-(4-aminopiperidin-1-yl)-3-(5- Chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,30-dioxo-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (170 mg, 117 μmol, 54.4%, purity 99.0%) was obtained as an off-white solid. MS (M+H)=1329.6.

[0437] Example 8: 2-(7-{[(27-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-27-oxo-3,6,9,12,15,18,21,24-octaoxaheptacosan-1-yl)carbamoyl]methyl}-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)indium acetate complex (compound 9)

[0438] [ka] Step-1: 2,2',2"-(10-(30-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,30-dioxo-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontyl)-1,4,7,10-tetraazacyclododecane-1,4,7-trimethylphenyl)pyridin-2-yl)piperazin-1-yl Indium(III)triacetic acid (50 mg, 1 Eq, 38 μmol) was combined with sodium bicarbonate (30 mg, 9.5 Eq, 0.36 mmol), indium(III) chloride (25 mg, 3.0 Eq, 0.11 mmol), water (0.25 mL), and acetonitrile (0.5 mL). The resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under vacuum and the remaining residue was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water (0.1% FA) and ACN (30% ACN to 80% in 16 min); total flow rate 20mL / min; detector, UV 220nm. This gave the title indium complex (28.4mg, 19.1μmol, 51%) as a white solid. MS(M+H)=1441.7, 1443.7.

[0439] Example 9: 2-(7-{[(27-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-27-oxo-3,6,9,12,15,18,21,24-octaoxaheptacosan-1-yl)carbamoyl]methyl}-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl) lutetium acetate complex (compound 10)

[0440] [ka] Step-1: 2,2',2"-(10-(30-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,30-dioxo-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontyl)-1,4,7,10-tetraazacyclododecane-1,4,7- Lutetium(III) triacetate (10 mg, 1 Eq, 7.5 μmol) was combined with sodium bicarbonate (6 mg, 9 Eq, 0.07 mmol), lutetium(III) chloride (7 mg, 3 Eq, 0.02 mmol), water (0.25 mL), and acetonitrile (0.5 mL). The resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under vacuum and the remaining residue was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150 mm 5 um 10 nm; mobile phase, water (0.1% FA) and ACN (30% ACN to 70% in 15 min); total flow rate 20 mL / min; detector, UV 220 nm. This afforded the title lutetium complex (7.2 mg, 4.7 pmol, 62%) as a white solid. MS (M+H)=502.9, 1504.9.

[0441] Example 10: 2-(7-{[(27-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-27-oxo-3,6,9,12,15,18,21,24-octaoxaheptacosan-1-yl)carbamoyl]methyl}-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)gallium acetate complex (compound 11)

[0442] [ka] Step-1: 2,2',2"-(10-(30-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,30-dioxo-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tetramethylphenyl)pyridin-2-yl)piperazin-1-yl Gallium trichloride (5mg, 4Eq, 0.03mmol), water (0.25mL), and acetonitrile (0.5mL) were combined with sodium bicarbonate (5mg, 8Eq, 0.06mmol), gallium trichloride (5mg, 4Eq, 0.03mmol), water (0.25mL), and acetonitrile (0.5mL). The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with DMSO (4mL), filtered, and the filtrate was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water and ACN (30% ACN to 80% in 15min); total flow rate 20mL / min; detector, UV 220nm. The resulting product was partially decomposed to acid during lyophilization, therefore, the material was purified under neutral conditions and lyophilized. This gave the title gallium complex. MS(M+H)=398.6,1440.6.

[0443] Example 11: 4-[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]butanoic acid (compound 12)

[0444] [ka] Step-1: Benzyl (1-(2-chloro-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (400 mg, 1 Eq, 830 μmol) was combined with tert-butyl piperazine-1-carboxylate (309 mg, 2.00 Eq, 1.66 mmol), N-ethyl-N-isopropylpropan-2-amine (322 mg, 3.00 Eq, 2.49 mmol), and DMSO (2 mL). The resulting mixture was stirred at 100° C. for 1 hour. The reaction crude was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were combined, washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The remaining residue was purified by silica gel chromatography and eluted with ethyl acetate / petroleum ether (1:3). This gave tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-2-yl)piperazine-1-carboxylate (367 mg, 581 μmol, 70.0%) as a yellow solid. MS (M+H)=632.3.

[0445] Step-2: To a solution of tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-2-yl)piperazine-1-carboxylate) (367 mg, 1 Eq, 581 μmol) in DMSO (2 mL) was added 4-chlorobenzene-1,2-diamine (166 mg, 2.00 Eq, 1.16 mmol) and Na2S2O3 (331 mg, 3.00 Eq, 1.74 mmol). The resulting mixture was stirred at 80° C. for 1 h. The reaction mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and then concentrated. The remaining residue was purified by silica gel chromatography eluting with PE / EA (1:1). This gave tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-)1-yl)-3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate) (365 mg, 484 μmol, 83.3%) as a yellow solid. MS (M+H)=754.2.

[0446] Step-3: To a solution of tert-butyl 4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(6-chloro-)1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazine-1-carboxylate) (249 mg, 1 Eq, 330 μmol) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under vacuum. This gave crude benzyl (1-(3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1-crude-yl)pyridin-4-yl)piperidin-4-yl)carbamate (200 mg, 306 μmol, 92.6%) as a brown solid. This material was used in the next step without further purification. MS (M+H)=654.2.

[0447] Step-4: 2,2-Dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-acid (72.1 mg, 1.00 Eq, 197 μmol), 4-methylmorpholine (120 mg, 6.02 Eq, 1.19 mmol) were combined with perfluorophenyl diphenylphosphinate (182 mg, 2.40 Eq, 474 μmol) and DMF (1 mL). The resulting mixture was stirred at 25° C. for 10 minutes, followed by the addition of crude benzyl (1-(3-(H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazine-16-chloro-1-yl)pyridin-4-yl)piperidin-4-yl)carbamate (258 mg, 2 Eq, 394 μmol). The reaction mixture was stirred at ambient temperature for an additional hour. The reaction crude was purified by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (0.1% TFA) and ACN (50.0% ACN to 85.0% in 12 min); total flow rate 70 mL / min; detector, UV 220 nm. This gave tert-butyl (15-(4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate (300 mg, 300 μmol, 152%) as a white solid. MS (M+H)=1001.2.

[0448] Step 5: To a solution of tert-butyl (15-(4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate)) (298 mg, 1 Eq, 298 μmol) in DCM (3 mL), TFA (1 mL) was added. The resulting solution was stirred at 25° C. for 1 h. The reaction mixture was concentrated under vacuum and the remaining residue was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um; mobile phase, water (0.05% TFA) and ACN (from 30.0% ACN to 50.0% in 7 min); total flow rate 20mL / min; detector, UV 220nm. This gave benzyl (1-(2-(4-(1-amino-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate) (250mg, 277μmol, 93.2%) as a yellow solid. MS(M+H)=901.4.

[0449] Step-6: Into a 8 mL vial was placed a mixture of 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanoic acid (97.2 mg, 1.00 Eq, 139 μmol), perfluorophenyl diphenylphosphinate (63.9 mg, 1.20 Eq, 166 μmol), 4-methylmorpholine (42.1 mg, 3.00 Eq, 416 μmol), and DMF (2 mL). The mixture was stirred at 25° C. for 1 hour, followed by the addition of benzyl (1-(3-(6-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1,-yl)pyridin-4-yl)piperidin-4-yl)carbamate (258 mg, 2 Eq, 394 μmol). The reaction mixture was stirred at 25° C. for 1 hour. The reaction crude was purified by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (0.1% TFA) and ACN (50.0% ACN to 85.0% in 12 minutes); total flow rate 70 mL / min; detector, UV 220 nm. This gave tert-butyl (15-(4-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-)1-yl)-3-(5-chloro-)1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-)1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate (230 mg, 139 μmol, 105%) as a white solid. MS(M+H)=1585.0.

[0450] Step-7: Tri-tert-butyl 2,2',2"-(10-(24-(4-(4-(4-((benzyloxy)carbonyl)amino)piperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-2,2-dimethyl-4,8,24-trioxo-3,12,15,18,21-pentaoxa-9-azatetracosan-5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (230 mg, 1 Eq, 145 μmol) was combined with TFA (1 mL). The resulting The mixture was stirred at 60 °C for 2 h and lyophilized with water (5 mL) and ACN (1 mL) to give 4-[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-,benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]-2-[4,7,10-tris(carboxymethyl)-,1,4,7,10-tetraazacyclododecan-1-yl]butanoic acid (48 mg, 39 μmol, 27%) as a white solid. MS (M+H) = 1226.6.

[0451] Example 12: 4-[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]butanoic acid indium complex (compound 13)

[0452] [ka] Step-1: In an 8 mL flask, add 2,2',2"-(10-(1-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-20-carboxy-1,17-dioxo-4,7,10,13-tetraoxa-16-azaicosan-20-yl)-1,4,7,10-tetraazacyclododecane-1,4 A mixture of (10 mg, 1 Eq, 8.2 μmol), indium trichloride (5 mg, 3 Eq, 0.02 mmol), sodium bicarbonate (3 mg, 1 μL, 4 Eq, 0.04 mmol), water (0.1 mL), and ACN (0.2 mL) was added. The resulting mixture was stirred at 80° C. for 2 h. The reaction crude was diluted with DMSO (4 mL), filtered, and the filtrate was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water (0.05% TFA) and ACN (30% ACN to 75% in 15 min); total flow rate 20mL / min; detector, UV 220nm. This gave the TFA salt of the title indium complex (6.6mg, 4.2μmol, 52%) as a white solid. MS(M+H)=1337.3, 1339.3.

[0453] Example 13: 4-[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12-tetraoxapentadecan-1-yl)carbamoyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]butanoic acid lutetium complex (compound 14)

[0454] [ka] Step-1: In an 8 mL flask, add 2,2',2"-(10-(1-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-20-carboxy-1,17-dioxo-4,7,10,13-tetraoxa-16-azaicosan-20-yl)-1,4,7,10-tetraazacyclododecane-1,4,7 A mixture of 1-triyl)triacetic acid (10 mg, 1 Eq, 8.2 μmol), lutetium(III) chloride (7 mg, 3 Eq, 0.02 mmol), sodium bicarbonate (4 mg, 2 μL, 6 Eq, 0.05 mmol), water (0.1 mL), and ACN (0.2 mL) was added. The resulting mixture was stirred at 80° C. for 2 h. The reaction crude was diluted with DMSO (4 mL), filtered, and the filtrate was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150mm 5um 10nm; mobile phase, water (0.05% TFA) and ACN (30% ACN to 75% in 15 min); total flow rate 20mL / min; detector, UV 220nm. This gave the title lutetium complex (8.2mg, 5.0μmol, 62%) as a white solid. MS(M+H)=1398.0,1400.0.

[0455] Example 14: 4-[(15-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-15-oxo-3,6,9,12 tetraoxapentadecan-1-yl)carbamoyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]butanoic acid gallium complex (compound 15)

[0456] [ka] Step-1: In an 8 mL flask, add 2,2',2"-(10-(1-(4-(4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl)piperazin-1-yl)-20-carboxy-1,17-dioxo-4,7,10,13-tetraoxa-16-azaicosan-20-yl)-1,4,7,10-tetraazanilide. A mixture of cyclododecane-1,4,7-triyl)triacetic acid (10 mg, 1 Eq, 8.2 μmol), gallium chloride (5 mg, 3 Eq, 0.03 mmol), sodium bicarbonate (4 mg, 2 μL, 6 Eq, 0.05 mmol), water (0.1 mL), and ACN (0.2 mL) was added. The reaction crude was diluted with DMSO (4 mL), filtered, and the filtrate was purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150 mm 5 um 10 nm; mobile phase, water and ACN (30% ACN to 80% in 15 min); total flow rate 20 mL / min; detector, UV 220 nm. This gave the title gallium complex (7.2 mg, 5.6 μmol, 68%) as a white solid. MS (M+H)=1292.5, 1294.5.

[0457] Example 15: 1-amino-27-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-one (compound 16)

[0458] [ka] Step-1: 2,2-dimethyl-4-oxo-3,8,11,14,17,20,23,26,29-nonaoxa-5-azadotriacontan-32-acid (51 mg, 97% Wt, 1.5 Eq, 92 μmol) was added to a solution of HATU (35 mg, 1.5 Eq, 92 μmol) and DIPEA (40 mg, 53 μL, 5 Eq, 0.31 mmol) in DMF (1.5 mL). The resulting mixture was stirred at room temperature for 10 minutes, followed by the addition of benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1-yl)pyridin-4-yl)piperidin-4-yl)carbamate (46 mg, 1 Eq, 61 μmol). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and concentrated. The remaining residue was purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA). Pure fractions were combined and dried to give benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23,26,29-nonaoxa-5-azadotriacontan-32-oyl)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate (31.3 mg, 26.6 μmol, 43%) as an off-white solid. MS(M+H)=1177.9.

[0459] Step-2: To a solution of benzyl (1-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)-2-(4-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23,26,29-nonaoxa-5-azadotriacontan-32-oyl)piperazin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-yl)carbamate (31.3 mg, 1 Eq, 26.6 μmol) in DCM (1 mL), TFA (1 g, 1 mL, 5e+2Eq, 0.01 mol) was added. The resulting mixture was stirred at 60° C. for 2 hours. The reaction crude was concentrated and purified by C18 reverse phase chromatography eluting with MeCN (0.1% TFA) / water (0.1% TFA). The pure fractions were combined and dried to give the TFA salt of 1-amino-27-{4-[4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-one (15.1 mg, 16.0 μmol, 60.2%). MS (M+H)=943.6.

[0460] Example 16: Compound 1 111 Radiochemical synthesis of In[In]-conjugates [ 111 In]InCl3 (20.7 MBq, 40.0 μL, 0.1 M HCl) and compound 1 (2.9 nmol, 2.9 μL, 1.0 mM in deionized (DI) water) were added to NHOAc solution (4.0 μL, 1.0 M). The resulting mixture was heated at 85 °C for 30 min in a thermal mixer. At the end of labeling, Ca-DTPA (4.0 μL, 4 mM) was added. The radiochemical purity was determined by RP-HPLC and was 97.1%. The radiotracer solution for in vivo studies was prepared by dilution with 0.9% saline.

[0461] [Table 3]

[0462] [Table 4]

[0463] Example A-1: ​​Parenteral pharmaceutical composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. An appropriate buffer is optionally added, along with an optional acid or base, to adjust the pH. The mixture is incorporated into a unit dosage form suitable for administration by injection.

[0464] Biology Examples Example B-1: Functional assay for SSTR2 agonists General overview: All five SSTR subtypes are Gi-coupled G protein-coupled receptors (GPCRs) that reduce intracellular cyclic AMP (cAMP) when activated by agonists. Therefore, measuring intracellular cAMP levels can be used to evaluate whether the compounds of the present invention are agonists of SSTR subtypes (John Kelly, Troy Stevens, W. Joseph Thompson, and Roland Seifert, Current Protocols in Pharmacology, 2005, 2.2.1-2.2). One example of intracellular cAMP assay is described below.

[0465] cAMP Assay Protocol Four days prior to the assay, 5000 Chinese hamster ovary cells (CHO-K1, ATCC#CCL-61) stably expressing human somatostatin receptor subtype 2 were seeded into each well of a 96-well tissue culture treated plate in Ham's F12 growth medium (ThermoFisher #10-080-CM) supplemented with 10% donor bovine serum (Gemini Bio-Products #100-506), 100U / mL penicillin, 100ug / mL streptomycin, 2mM L-glutamine (Gemini Bio-Products #400-110), and 0.2mg / mL hygromycin B (GoldBio #31282-04-9). Cells are cultured at 37°C, 5% CO2, and 95% humidity. On the day of the assay, the medium is aspirated and the cells are treated with 50 μL of 1.6 μM NKH477 (Sigma #N3290) and various dilutions of the compounds of the invention in assay buffer [1x Hank's Balanced Salt Solution (ThermoFisher #SH3058802), 0.5 mM HEPES pH 7.4, 0.1% bovine serum albumin, 0.2 mM 3-isobutyl-1-methylxanthine (IBMX, VWR #200002-790)]. The cells are incubated for 20 min at 37 °C (final concentrations of the compounds of the invention are typically 0-10,000 nM). The cells are treated with 50 μL of lysis buffer (HRTF cAMP kit, Cisbio). The lysates are transferred to 384-well plates, antibodies for cAMP detection and visualization are added, and the cells are incubated for 1-24 h at room temperature. The time-resolved fluorescent signal is read using a Tecan M1000Pro multiplate reader. The intracellular cAMP concentration is calculated by regression to a standard curve and plotted against the concentration of the compounds of the invention to obtain the EC 50 is calculated using standard methods. All data manipulations were performed using GraphPad Prism v8 (GraphPad, San Diego, CA).

[0466] Example B-2: GnRHR Assay Functional assay of GnRHR General Overview: The GnRHR mediates the action of the GnRH hormone by activating the phosphatidylinositol-calcium second messenger system. q / 11 GnRHR is a receptor-coupled receptor. Activation of GnRHR induces the accumulation of inositol monophosphate, a stable metabolite of IP-3, which can be characterized as a measure of agonist activity (increase in IP-1) or antagonist activity (blocking the accumulation of IP-1) by the compounds of the present invention. An example of the intracellular IP-One assay used to characterize GnRHR antagonists is described below. IP-one Assay Protocol 24 hours prior to the assay, 30000 Flpin T-Rex 293 cells (ThermoFisher #R78007), stably expressing functional human GnRH receptor upon tetracycline induction, were seeded into 96-well tissue culture treated plates in Flpin T-Rex 293 growth medium [DMEM (Coming #10-013-CM)] supplemented with 10% fetal bovine serum (Gemini Bio-Products #900-208), 100 U / mL penicillin, 100 μg / mL streptomycin, 2 mM L-glutamine (Gemini Bio-Products #400-110), and 50 ng / mL tetracycline hydrochloride (Sigma, T7660). Cells were cultured at 37°C, 5% CO2 and 95% humidity. On the day of the assay, growth medium was discarded and cells were treated with a dose-response curve of 50 μL of GnRH (Bachem #4033013) in the presence of various concentrations of fixed compound in assay buffer [10 mM HEPES (Biopioneer Cat. No. C0113) pH 7.4, 1 mM CaCl2 (Fisher Scientific BP510-100), 0.5 mM MgCh (Sigma M8266-100G), 4.2 mM KCl (Fisher Scientific P330-500), 146 mM NaCl (Spectrum Chemical #SO155), 5.5 mM glucose (Sigma G7528), 50 mM LiCl (Fisher Scientific L121-100)]. 0.1% bovine serum albumin (Fisher Scientific catalogue no. BP1600)] and incubated for 1 h at 37 °C (final concentrations of GnRH ranged from 0 to 250 nM, and final concentrations of compounds ranged from 0 to 10000 nM). 50 μL of lysis buffer (HRTF IP-one kit, Cisbio) was added in addition to the above treatment to lyse the cells. Lysates were transferred to 384-well plates, IP-one detection and visualization antibodies were added, and incubated for 1 to 24 h at room temperature. Time-resolved fluorescent signals were read on a Tecan MIOOOPro (Tecan) multiplate reader.Intracellular IP-one concentrations were calculated by regression to a standard curve and plotted against the concentration of GnRH agonist in the presence of various concentrations of antagonist, and the KB of the compound was calculated using standard curve fitting methods. All data manipulations were performed using GraphPad Prism v8 (GraphPad, San Diego, CA).

[0467] Exemplary biological activities of the compounds are demonstrated in the table below.

[0468] [Table 5]

[0469] The examples and embodiments described herein are for illustrative purposes only, and various modifications and changes suggested to those skilled in the art are intended to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A compound according to formula (I) below, or a pharmaceutically acceptable salt thereof, 【Chemical Formula 1】 wherein, NP is a non-peptide ligand that binds to a G protein-coupled receptor (GPCR) expressed in tumor cells, Q is a payload moiety comprising a chelating moiety or a radionuclide (Z) complex thereof, and L is a linker that covalently attaches the non-peptide ligand NP and the payload moiety Q, wherein the linker L is attached to the NP at a position that permits binding of the NP to the GPCR, and the compound according to formula (I) or a pharmaceutically acceptable salt thereof targets tumor cells expressing the GPCR upon administration to a mammal, the GPCR is a gonadotropin-releasing hormone receptor or a somatostatin receptor, the chelating moiety is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), the Z is an Auger electron-emitting radionuclide, an α-emitting radionuclide, a β-emitting radionuclide, or a γ-emitting radionuclide, a compound, or a pharmaceutically acceptable salt thereof.

2. The NP is a non-peptide ligand that binds to a somatostatin receptor expressed in tumor cells, and the NP is a non-peptide ligand comprising a 4-(4-aminopiperidin-1-yl)-5-(phenyl)pyridine structural motif or a 4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-5-(phenyl)pyridine structural motif, wherein -L-Q is attached to the NP at the 2-position of the pyridine, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The NP has a structure according to formula (II) below, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, [Chemical Formula 2] wherein RA is [Chemical Formula 3] and R1, R2, R3, and R4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted C1-C4 heteroalkyl, -CN, -N(R7)2, or -OR7, R5 is hydrogen, or substituted or unsubstituted C1-C6 alkyl, R6 is hydrogen, -OR7, -N(R7)2, -CN, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, or R5 and R6 together with the intervening atoms to which they are attached form morpholine, X1 is absent, -O-, -S-, -N(R7)-, -C(=O)-, -C(=O)N(R7)-, -C(=O)O-, -N(R7)C(=O)-, or a heterocycle, each R7 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, optionally, said X1 is absent, -O-, -S-, [Chemical Formula 4] The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. Said RA is [Chemical Formula 5] and said R1, said R2, said R3, and said R4 are each independently hydrogen, F, Cl, Br, C1-C4 alkyl, -CN, -N(R7)2, or -OR7, R5 is hydrogen, R6 is hydrogen or -OR7, or R5 and R6 together with the intervening atom to which they are attached form morpholine, and each R7 is independently hydrogen, -CH3, or -CH2CH3, and / or 【Chemical Formula 6】 is 【Chemical Formula 7】 and 【Chemical Formula 8】 is 【Chemical Formula 9】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. The NP is a non-peptide ligand that binds to the gonadotropin-releasing hormone receptor (GnRHR) expressed in tumor cells, and the NP is an N-{4,6-dimethoxy-pyrimidin-5-yl}-5-[3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-framide structural motif, an N-(4,6-dimethoxypyrimidin-5-yl)-5-(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy)-2-framide structural motif, or an N-(4,6-dimethoxypyrimidin-5-yl)-5-((3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy)furan-2-carboxamide structural motif-containing non-peptide ligand, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The NP has the structure described by the following formula (X), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, 【Chemical Formula 10】 In the formula, T is absent or -CH2-, -CH(CH3)-, or -C(CH3)2-, X2 is absent or is -O- or -N(R7)-, V is CH or N, and W is CH or N, and each R7 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, the compound according to claim 5, or a pharmaceutically acceptable salt thereof.

7. The GPCR is GnRHR, and the NP has the following structure 【Chemical Formula 11】 one of the following, the compound according to claim 6, or a pharmaceutically acceptable salt thereof.

8. Q contains a chelating moiety or a radionuclide (Z) complex thereof, and the chelating moiety is 【Chemical Formula 12】 and / or L is absent or is a linker of -L1-L2-L3-L4-L5-, L1 is absent or is unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, unsubstituted or substituted alkenylene, unsubstituted or substituted alkynylene, unsubstituted or substituted monocyclic cycloalkylene, unsubstituted or substituted monocyclic heterocycloalkylene, unsubstituted or substituted phenylene, unsubstituted or substituted monocyclic heteroarylene, one or more amino acids, -(CH2)p-, -C(=O)-, -C(=O)-(CH2)p-, -C(=O)NH-, -C(=O)NH-(CH2)p-, where p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, L2 is -C(=O)-, -C(=O)NH-, -C(=O)O-, -(CH2)p-, -C(=O)-(CH2CH2O)p-, or -(CH2CH2O)p-, where p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, L3 is unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, or -(CH2)q-, where q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. L4 is absent or is -NH-. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L5 is absent, unsubstituted or substituted alkylene, or unsubstituted or substituted heteroalkylene.

9. The linker L is 【Chemical Formula 13】 and Q is 【Chemical Formula 14】 or a radionuclide (Z) complex thereof, being the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. -L-Q is -(CH2)p(CH2)qNH-Q, -(CH2)p(OCH2CH2)pNH-Q, -C(=O)(CH2)p(CH2)qNH-Q, -C(=O)(CH2)p(OCH2CH2)pNH-Q, -C(=O)CH(NH2)CH2C(=O)NHCH2CH2OCH2CH2NH-Q, or -(C2-C4 alkylene)(NRXCH2CH2)p(OCH2CH2)qNH-Q, and Q is 【Chemical Formula 15】 or a radionuclide (Z) complex thereof, or said -L-Q is -(CH₂)p(CH₂)qNHC(=O)CH₂Q, -(CH₂)p(CH₂)qNHC(=O)CH₂CH₂Q, -(CH₂)p(OCH₂CH₂)pNHC(=O)CH₂Q, -(CH₂)p(OCH₂CH₂)pNHC(=O)CH₂CH₂Q, -C(=O)(CH₂)p(CH₂)qNHC(=O)CH₂Q, -C(=O)(CH₂)p(CH₂)qNHC(=O)CH₂CH₂Q, -C(=O)(CH₂)p(OCH₂CH₂)pNHC(=O)CH₂Q, -C(=O)(CH₂)p(OCH₂CH₂)pNHC(=O)CH₂CH₂Q, -C(=O)CH(NH₂)CH₂C(=O)NHCH₂CH₂OCH₂CH₂NHC(=O)CH₂Q, -C(=O)CH(NH₂)CH₂C(=O)NHCH₂CH₂OCH₂CH₂NHC(=O)CH₂CH₂Q, -(C₂-C₄ alkylene)(NRXCH₂CH₂)p(OCH₂CH₂)qNHC(=O)CH₂Q, or -(C₂-C₄ alkylene)(NRXCH₂CH₂)p(OCH₂CH₂)qNHC(=O)CH₂CH₂Q, and said Q is [Chemical Formula 16] or its radionuclide (Z) complex, or said -L-Q is -(CH₂)p(CH₂)₆NH C(=O)CH₂Q, -(CH₂)p(CH₂)₆NH C(=O)CH₂CH₂Q, -CH₂CH₂(OCH₂CH₂)₄NH C(=O)CH₂Q, -CH₂CH₂(OCH₂CH₂)₄NH C(=O)CH₂CH₂Q, -CH₂CH₂CH₂(OCH₂CH₂)₄NH C(=O)CH₂Q, -CH₂CH₂CH₂(OCH₂CH₂)₄NH C(=O)CH₂CH₂Q, -C(=O)(CH₂)p(CH₂)₆NH C(=O)CH₂Q, -C(=O)(CH₂)p(CH₂)₆NH C(=O)CH₂CH₂Q, -C(=O)CH₂CH₂(OCH₂CH₂)₄NH C(=O)CH₂Q, -C(=O)CH₂CH₂(OCH₂CH₂)₄NH C(=O)CH₂CH₂Q, -C(=O)CH(NH₂)CH₂C(=O)NHCH₂CH₂OCH₂CH₂NH C(=O)CH₂Q, -C(=O)CH(NH₂)CH₂C(=O)NHCH₂CH₂OCH₂CH₂NH C(=O)CH₂CH₂Q, -(C₂-C₄ alkylene)N(CH₂CO₂H)CH₂CH₂(OCH₂CH₂)₃NH C(=O)CH₂Q, or -(C₂-C₄ alkylene)N(CH₂CO₂H)CH₂CH₂(OCH₂CH₂)₃NH C(=O)CH₂CH₂Q, and said Q is [Chemical Formula 17] or a radionuclide (Z) complex thereof, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. Said linker L is [Chemical Formula 18] and said Q is [Chemical Formula 19] The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is or a radionuclide (Z) complex thereof.

12. The -L-Q is 【Chemical formula 20-1】 【Chemical formula 20-2】 【Chemical formula 20-3】 【Chemical formula 20-4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is or a radionuclide (Z) complex thereof.

13. The Z is 111-indium (111In), 115-indium (115In), 67-gallium (67Ga), 68-gallium (68Ga), 70-gallium (70Ga), 225-actinium (225Ac), 175-lutetium (175Lu), or 177-lutetium (177Lu), the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

15. Administering an effective amount of the pharmaceutical composition to a mammal having cancer, Optionally, the mammal has anal cancer, bladder cancer, intestinal cancer, brain tumor, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, heart cancer, kidney cancer, lung cancer, liver cancer, melanoma, uterine cancer, lymphoma, ovarian cancer, pancreatic cancer, or prostate cancer, the pharmaceutical composition according to claim 14 for use in the treatment of cancer.

16. A pharmaceutical composition comprising a compound of the following formula (I) or a pharmaceutically acceptable salt thereof for use in the identification of a tissue or organ of a mammal having tumor cells expressing a G protein-coupled receptor (GPCR), (i) A compound of the following formula (I) 【Chemical formula 21】 administering to the mammal the compound or a pharmaceutically acceptable salt thereof, wherein, NP is a non-peptide ligand that binds to a G protein-coupled receptor (GPCR) expressed in tumor cells, Q is a payload moiety comprising a chelate moiety or a radionuclide (Z) complex thereof, L is a linker that covalently attaches the non-peptide ligand NP and the payload moiety Q, wherein the linker L is attached to the NP at a position that permits binding of the NP to the GPCR, the administering step; (ii) performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); comprising wherein Z is a diagnostic radionuclide, the GPCR is a gonadotropin-releasing hormone receptor or a somatostatin receptor, the chelate moiety is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), Step (ii) is initiated after step (i) after a time sufficient for the interaction between the compound of formula (I) and the GPCR expressed in the tumor cells of the mammal, a pharmaceutical composition.

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