Non-peptide targeted therapeutic agents and uses thereof

Abstract

Described herein are non-peptide drug conjugates (NPDCs) that target tumor cells expressing cell surface peptide and protein 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] Described herein are non-peptide drug conjugates (NPDCs) and methods of using such drug conjugates as cancer therapeutics, diagnostic agents, or both. [Background technology]

[0003] Neoplasms are abnormal proliferation of cells, which cause enormous medical burdens including morbidity and mortality in humans. Neoplasms include benign or non-cancerous neoplasms that do not show malignant characteristics and are generally unlikely to be dangerous (e.g., adenomas), whereas malignant neoplasms show characteristics such as gene mutations, loss of normal functions, rapid division, and the ability to metastasize (invade) to other tissues, as well as neoplasms with unclear or unknown behavior. Malignant neoplasms (i.e., cancerous solid tumors) are the leading cause of death in industrialized countries. Non-cancerous neoplasms, including benign adenomas, can also cause significant morbidity and mortality. Although standard treatments can achieve significant effects in tumor growth inhibition and even tumor elimination, the applied drugs show only a little selectivity for malignant tissues over healthy tissues, and their severe side effects limit their effectiveness and use. Specifically targeting tumor cells without affecting healthy tissues is the main hope for effective solid tumor therapy. As one of the three major classes of cell surface receptors, G protein-coupled receptors (GPCRs) are often overexpressed in tumor cells and are considered promising targets for selective tumor therapy. Despite the progress achieved with peptide-drug conjugate (PDC) therapeutics targeting cell surface receptors, there is a great need for therapeutic and diagnostic agents that overcome the limitations imposed by peptide- and protein-based targeted therapeutics, such as the inability to penetrate large solid tumors, instability to proteases and peptidases, unfavorable absorption, distribution, metabolism, and excretion (ADME) properties, and manufacturing challenges. Non-peptide ligands conjugated to suitable drug cargoes or payloads represent a novel class of selective cancer therapeutic or diagnostic agents. Summary of the Invention

[0004] Described herein are non-peptide drug conjugates and their use in the treatment of tumors. The present disclosure provides alternative and improved methods for the treatment of tumors. In some embodiments, the non-peptide drug conjugates disclosed herein provide an improved method for targeting tumor cells over conventional therapies that have narrow therapeutic indexes.

[0005] In one embodiment, a compound of formula (I)

[0006]

number

[0007] In some embodiments, the GPCR is a receptor for an endogenous peptide or protein ligand, hi 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), 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, provided that 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 a CC chemokine (β-chemokine), a CXC chemokine (α-chemokine), a C chemokine (γ-chemokine), or a C×3C 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 cholecystokinin 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 receptor, or a PACAP receptor.

[0011] In another aspect, described herein is a method for treating a tumor in a mammal, comprising administering to the mammal a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the tumor comprises tumor cells that express a GPCR. In some embodiments, the tissue comprising the tumor cells also comprises non-tumor cells that do not express the GPCR or express the GPCR at a lower expression level than the tumor cells. In some embodiments, the tumor cells overexpress the GPCR. In some embodiments, the GPCR expressed in the tumor cells of the tumor is targeted by a compound of formula (I), or a pharma- ceutically 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 neoplasm is based on the type of cellular origin and includes solid tumors, adenomas, sarcomas, carcinomas, or lymphomas. In some embodiments, the mammal having a malignant neoplasm has anal cancer, bladder cancer, intestinal cancer, brain cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, stomach 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., an endocrine tumor of 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 gland, pituitary gland, parathyroid gland, liver, breast, appendix, bronchial duct, prostate, sebaceous gland, or salivary gland.

[0015] In some embodiments, NP is a non-peptide ligand that binds to a somatostatin receptor expressed in a tumor cell, 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, NP has the structure of formula (II):

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

[0018] [ka] and Each R 1 , R 2 , R 3 and R 4 are 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 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 intermediate atom to which they are attached to form morpholine, X 1 is absent, -O-, -S-, -N(R 7 )-, -C(=O)-, -C(=O)N(R 7 )-, -C(=O)O-, -N(R 7 )C(═O)—, or a heterocycle; Each R 7 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[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 an N-{4,6-dimethoxy-pyrimidin-5-yl}-5-[3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl]oxy]-2-furamide structural motif, an N-(4,6-dimethoxypyrimidin-5-yl)-5-(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy)-2-furamide 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.

[0020] In some embodiments, NP has a structure of formula (X):

[0021] [ka] During the ceremony, V is CH or N, W is CH or N, T is absent, -CH2-, -CH(CH3)-, or -C(CH3)2-; X 2 is absent, -O-, or -N(R 7 )-and R 7 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0022] In yet another aspect, a method for targeting delivery of a chemotherapeutic agent to tumor cells in a mammal is described herein, comprising administering to a mammal a compound of formula (I):

[0023]

number

[0024] In some embodiments, the tumor cells are present in tissues and / or organs that contain non-tumor cells that do not express the target GPCR or that express the target GPCR at a level below the expression level in the tumor cells. In some embodiments, the tumor cells overexpress the GPCR. In some embodiments, the tumor cells overexpress the GPCR targeted by the 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 expressed in a tumor cell, the GPCR being a receptor for an endogenous peptide or protein hormone, the tumor cell is a neoplastic, solid tumor, adenoma, sarcoma, carcinoma, or lymphoma tumor cell, Q comprises a chemotherapeutic agent that is a cytotoxic drug, a kinase inhibitor, or both, and L is optionally a non-cleavable linker or a cleavable linker. In some embodiments, the optional cleavable linker is an acid-sensitive linker, a protease-sensitive linker, or a glutathione-sensitive linker.

[0027] In some embodiments, Q comprises a chemotherapeutic agent that is a ligand for an extracellular protein in the extracellular environment of a GPCR-expressing tumor cell. In some embodiments, Q comprises a cytotoxic drug that is an antimitotic drug, a DNA damaging agent, a transcription inhibitor, or a combination thereof. In some embodiments, Q comprises a cytotoxic drug that is an antimitotic drug, where the antimitotic drug is a maytansinoid, a taxane, an auristatin, an alkaloid, a tubulysin, or an epothilone, and the DNA damaging agent, the transcription inhibitor, or a combination thereof is a DNA polymerase inhibitor, a DNA replication inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic. In some embodiments, Q comprises a cytotoxic drug that is a DNA damaging agent, a transcription inhibitor, or a combination thereof, where the DNA damaging agent, the transcription inhibitor, or a combination thereof is a DNA polymerase inhibitor, a DNA replication inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic. In some embodiments, Q comprises a kinase inhibitor that is an inhibitor of a cytoplasmic tyrosine kinase (CTK), a serine / threonine kinase (S / T kinase), a lipid kinase (LK), or a receptor tyrosine kinase (RTK).

[0028] In another aspect, described herein is a method for the treatment of 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 an effective amount of a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0029] In another aspect, a method for treating a tumor with a chemotherapeutic agent is described herein, 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 an effective amount of a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0030] 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, stomach cancer, heart cancer, kidney cancer, lung cancer, liver cancer, melanoma, uterine cancer, lymphoma, ovarian cancer, pancreatic cancer, or prostate cancer.

[0031] In some embodiments, the mammal has an endocrine cancer, hi some embodiments, the endocrine cancer is an adrenal tumor, a neuroendocrine tumor, a parathyroid tumor, a pituitary tumor, or a thyroid tumor.

[0032] In some embodiments, the mammal has a neuroendocrine tumor.

[0033] In some embodiments, the mammal has a somatostatin receptor positive gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

[0034] 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, bronchial duct, prostate, sebaceous gland, or salivary gland.

[0035] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, or oral administration.

[0036] In any of the embodiments disclosed herein, the mammal is a human.

[0037] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description, but it should be understood that the detailed description and specific embodiments, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] 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 lining the 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 are abnormal proliferations of cells that result in solid tumors that can be benign (i.e., do not show malignant characteristics and are generally unlikely to become dangerous, such as adenomas), malignant (i.e., show characteristics such as genetic mutations, loss of normal functions, rapid division, and metastasis (infiltration) to other tissues), and of uncertain 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, as well as combinations with radiation and chemotherapy. Chemotherapy has often proven to be a powerful weapon in the fight against cancer and requires further optimization. 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 is responsible for the severe side effects of chemotherapy that does not specifically target cancer cells over other cells. Radiotherapy is the use of high-energy radiation to kill cells. The source of radiation can be external beam radiation (applied using an external source), internal radiation (placement of radioactive material near the target cells), or radiotherapy from systemic administration of radioactive material. As with chemotherapy, many radiotherapy options also lack the tumor cell-identifying properties necessary to achieve the ultimate goal of targeted tumor therapy with drug molecules or radionuclides.

[0039] Described herein is the design of NPDCs that exploit the selectively identifying properties of neoplasms, such as significantly overexpressed cell surface receptors, that are distinct from healthy cells, to achieve a therapeutic effect only in selected cells. Neoplasms that overexpress various cell surface GPCRs are actively targeted with the NPDCs described herein, thereby selectively delivering anti-cancer drugs or radionuclides to malignant cells.

[0040] GPCRs are a large and diverse group of integral membrane receptors and, as a result, are expressed in all cell types 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 to 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, making them difficult 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.

[0041] Many GPCRs, especially those that recognize endogenous peptides and endogenous proteins such as chemokines, are ideal for NPDCs with suitable drug cargo or payloads 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 significantly higher densities than other tissues. For example, gastrointestinal pancreatic (GEP) neuroendocrine tumors (NETs) overexpress somatostatin receptors, namely SSTR2, SSTR3, and SSTR5. Other peptide receptors are overexpressed in NETs, ​​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). 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 could address issues such as heterogeneity, resistance, and phenotypic changes during disease progression that hinder many current treatment options.

[0042] Most currently available drugs that target GPCRs 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 typically also peptides or proteins.

[0043] 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 mutations may result in loss of affinity and / or selectivity and may adversely affect physicochemical properties (e.g., poor solubility and tendency to aggregate). In addition, peptides may cause undesirable immunogenic responses that complicate later stages of development by masking therapeutic efficacy and affecting safety evaluation.

[0044] When peptide ligands are linked to cytotoxic payloads, the resulting conjugates are often rapidly degraded in plasma, generating cytotoxic 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 cytotoxic payload distributed to the target tumor, reducing therapeutic efficacy and possibly increasing toxicity. In addition, peptides are most likely excreted via the kidney, which may limit their application. The significant renal uptake of some peptide-based therapeutics limits their routine use.

[0045] High affinity small molecule ligands have been described that bind to peptide GPCRs and protein GPCRs, including chemokine GPCRs, and are cell permeable, allowing access to 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. In many cases, the binding affinity of small molecule non-peptide ligands exceeds that of FDA-approved antibodies by several orders of magnitude.

[0046] 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 embeds in the extracellular loop of GPCR, leaving the conjugated drug cargo or payload moiety of NPDC facing the extracellular space. The conjugated drug cargo or payload moiety 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 moiety comprises a chemotherapeutic agent linked to the non-peptide ligand using a stable linker or a cleavable linker.

[0047] In some embodiments, slowly dissociating non-peptide ligands for GPCRs can maintain therapeutically effective concentrations long after the target tissue has been 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 the toxin conjugate in the tumor 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, non-selective release of free toxin can be avoided, and conjugates that initially "miss" the cytotoxic target can be retained in the tumor for further attempts. In some embodiments, coupling of suitable payloads (e.g., toxins) to non-peptide small molecule GPCR ligands provides an improved method for targeting of cytotoxic conjugates to cancer tissues.

[0048] In some embodiments, non-peptide ligands for internalized GPCRs are optimized to increase internalization and improve intracellular retention.

[0049] Non-peptide small molecule drug conjugates (NPDC) In one aspect, non-peptide drug conjugates (NPDCs) are described herein. In some embodiments, NPDCs are compounds having the structure of formula (I):

[0050]

number

[0051] Target Tissues and Receptors In some embodiments, the compounds of formula (I) exhibit activity against 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 against the target GPCR receptor. In some embodiments, the compounds of formula (I) exhibit binding affinity against the target GPCR receptor. In some embodiments, the compounds of formula (I) exhibit binding affinity or functional activity against 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 against 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 against 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 against 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, compounds of formula (I) exhibit 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 for measuring such binding activity. In some embodiments, compounds of formula (I) exhibit 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 for measuring such binding activity.

[0052] 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 higher 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 family of receptors, 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 higher 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.

[0053] 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 is optionally internalized in tumor cells after binding to a GPCR expressed in the tumor cells. In some embodiments, the compound of formula (I) optionally comprises a cleavable linker L, is stable in plasma and is optionally internalized in tumor cells after binding to a cancer cell surface peptide GPCR or protein GPCR, and the linker L is cleaved intracellularly to release the payload or drug cargo moiety (Q). In some embodiments, the linker L facilitates the controlled release of the payload or drug cargo moiety (Q) in the tumor cells.

[0054] 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 the GPCR, compared to tissues or organs lacking tumor cells expressing the 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 the GPCR, compared to tissues or organs lacking tumor cells expressing the 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 and liver.

[0055] In some embodiments, the GPCR targeted by a compound 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.

[0056] In some embodiments, the GPCR targeted by the compounds of formula (I) is expressed in tumor cells in tissues and / or organs that do not normally express GPCRs.

[0057] In some embodiments, the NP binds to a GPCR expressed in a tumor cell, provided that the NP does not include an unnatural amino acid residue that is 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine, or 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid.

[0058] In some embodiments, the GPCR is a receptor for an endogenous peptide or endogenous protein ligand, wherein the endogenous peptide or protein ligand is a peptide or protein hormone or a chemokine.

[0059] Peptide GPCRs Peptide hormones play a regulatory role mainly in the brain, gut and endocrine system. Although these peptides are important in biology, their receptors are becoming increasingly clinically important 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 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. Thus, a cytotoxic payload attached as part of the complex can kill tumor cells while causing minimal toxicity. This feature allows peptide hormone-ligand radionuclide complexes to perform receptor-targeted imaging and therapy.

[0060] Many 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.

[0061] Among the GPCR family members, the gonadotropin releasing hormone (GnRH) receptor is a well-established target in the clinical practice of cancer therapy. GnRH receptors are 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, choriomas, ovarian epithelial and stromal tumors. Several human tumor types, including ovarian, prostate, breast, and lung cancer, overexpress or uniquely express this receptor relative to surrounding non-malignant cells. GnRH analogs (e.g., conjugates made from doxorubicin linked to [D-Lys6]GnRH agonists) that deliver cytotoxic agents directly to cancer cells expressing the GnRH receptor have been described and shown to reduce the proliferation of breast, ovarian, and endometrial cancer cells in vitro and in xenografted nude mice.

[0062] The class of somatostatin receptors (SSTRs) consists of five members (SSTR1-5) that are widely expressed in different tissues in the body, including nerves, pituitary gland, kidney, lung, and immune cells. Their natural ligand is the neuropeptide somatostatin (SST), which occurs in two active isoforms, SST-14 and SST-28. Both isoforms, in combination with their receptors, act as inhibitory hormones. An important physiological function of the SSTR / SST axis is, for example, the inhibition of growth hormone release. SSTRs, especially SSTR subtype 2, are found to be highly expressed in many tumor 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 octreotate, octreotide, and lanreotide. For example, the DOTA chelator may be octreotide (DOTA-TATE, DOTA-(Tyr 3 By covalently linking somatostatin to 5-hydroxytryptamine (also known as somatostatin octreotide), it has become possible to target the delivery of radionuclides to tumor cells that express somatostatin receptors. 177Lu DOTA-TATE therapy is a form of peptide receptor radionuclide therapy (PRRT) that targets somatostatin receptors, a form of targeted drug delivery.

[0063] The bombesin (Bn) receptor family consists of three members, namely BB1, BB2, and BB3 receptors, which are expressed in the central nervous system (CNS) but also in the periphery, such as the gastrointestinal tract. They mediate numerous physiological functions, including autocrine growth effects on cells and potent CNS effects. The natural peptide ligand for BB1 is neuromedin B, and the natural peptide ligand for BB2 is gastrin-releasing peptide, while BB3 is considered to be an orphan receptor. Upregulation of Bn receptors has been found in various cancer subtypes, with BB2 in particular being highly overexpressed in tumors such as breast, prostate, small cell lung, and pancreatic cancer. Targeting Bn receptors for drug delivery has typically centered around the use of Bn analogs, including, for example, the peptide [d-Tyr6, β-Ala11, Phe13, Nle14]-Bn(6-14).

[0064] Vasoactive intestinal peptide (VIP) receptors 1 and 2 are overexpressed in various cancers such as colon, breast, and endocrine tumors. The natural ligand VIP and its analogs are investigated for the preparation of drug conjugates.

[0065] 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 typically involves the use of analogues of its natural peptide ligands cholecystokinin and gastrin.

[0066] Melanocortin receptor 1 (MC1R) has been found to be upregulated in malignant melanoma. For the generation of drug conjugates of this type, truncated peptide analogs of the natural MC1R ligand α-MSH, such as the agonist NAPamide, have potential as delivery agents.

[0067] The ghrelin receptor (GhrR), also known as growth hormone secretagogue receptor 1a (GHSR1a), is a class A GPCR. It is widely expressed in the brain, especially in the hypothalamus, but also in the hippocampus and pituitary gland. Furthermore, GhrR has been found to be expressed in various peripheral tissues, including the liver, heart, pancreas, thyroid, ovary, testis, 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 plays a role in 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 in astrocytomas.

[0068] 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 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 hY1R for anticancer drug delivery. Expression of hY1R and hY2R has been described in ovarian sex cord stromal tumors, nephroblastomas, gastrointestinal stromal tumors, and testicular tumors. Exclusive expression of hY1R was observed in adrenal cortical tumors and renal cell carcinoma. High expression of hY1R was also determined in Ewing sarcoma tumors, breast cancer tumors, and metastases derived from breast cancer. 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 drugs to be shuttled to breast tumors when hY1R-preferring ligands are used as delivery agents.

[0069] Orphan GPCRs have been implicated in the development and progression of cancer based on their overexpression and / or upregulation by diverse factors. For example, elevated expression of the orphan G protein-coupled receptor GPR49 has been implicated in the formation and growth of basal cell carcinoma, whereas GPR18 has been found to be associated with melanoma metastasis. High levels of GPR87 have been detected in lung, cervix, skin, bladder, testis, and head and neck squamous cell carcinomas.

[0070] As used herein, "peptide G protein-coupled receptor (GPCR)" means a GPCR that is the binding site for a peptide ligand. The natural ligand for a peptide GPCR is a peptide ligand.

[0071] As used herein, "protein G protein-coupled receptor (GPCR)" means a GPCR that is the binding site for a protein ligand. The natural ligand for a protein GPCR is a protein ligand.

[0072] In some embodiments, the NP of the compound of formula (I) binds to a GPCR that also binds to a peptide or protein hormone that is 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.

[0073] In some embodiments, the NP binds to the GPCR, provided that the GPCR does not bind to neurotensin.

[0074] 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 cholecystokinin receptor, a corticotropin 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.

[0075] In some embodiments, the GPCR is a member of one of the following families of receptors: angiotensin receptors (e.g., AGTR1, AGTR2), apelin receptors (APLNR), bombesin receptors (BB1 / NMBR, BB2 / GRPR, BRS3), bradykinin receptors (BDKRB1, BDKRB2), calcitonin receptors (e.g., CALCR, CALCRL), chemokine receptors (e.g., CCR1-10, CXCR1-6, etc.), cholecystokinin receptors (CCKAR, CCKB R), 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), neurotransmitter receptors (NRT1R, NRT2R, NRT3R, NRT4R, NRT5R, NRT6R, NRT7R, NRT8R, NRT9R, NRT10R, NRT11R, NRT12R, NRT13R, NRT14R, NRT15R, NRT16R, NRT17R, NRT18R, NRT19R, NRT20R, NRT21R, NRT22R, NRT23R, NRT24R, NRT25R, NRT30R, NRT31R, NRT32R, NRT40R, NRT41R, NRT52R, NRT33R, NRT42R, NRT53R, NRT64R, NRT75R, NRT86R, NRT97R, NRT108R, NRT119R, NRT129R, NRT130R, NRT140R, NRT150R, NRT161R, NRT172R, NRT182R, NRT193R, NRT204R, NRT215R, NRT325R, NRT194R, NRT225R, NRT335R, NRT426R, NRT115R, NRT236R, N Medin U receptors (NMUR1, NMUR1-2), neuropeptide FF / AF receptors (NPFFR1, NPFFR2), neuropeptide S receptors (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), promyelitis receptors (PTH1R, PTH2R), and promyelitis receptors (PROKR1, PROKR2). lolactin releasing peptide receptor (PRLRHR), QRFP receptor (QRFPR), relaxin family peptide receptor (RXFP1-4), somatostatin receptor (SSTR1-5), tachykinin receptor (TACR1-3), thyrotropin releasing hormone receptor (TRHR1, TRHR2), urotensin receptor (UTS2R), vasopressin and oxytocin receptors (AVPR1A, AVPR1B, AVPR2, OXTR), or VIP and PACAP receptors (ADCYAP1R1, VIPR1, VIPR2).

[0076] In some embodiments, the GPCR is a member of one of the following receptor families: angiotensin receptors (e.g., AGTR1, AGTR2), apelin receptors (APLNR), bombesin receptors (BB1 / NMBR, BB2 / GRPR), bradykinin receptors (BDKRB1, BDKRB2), ghrelin receptors (GHSR), glycoprotein hormone receptors (FSHR, LHCGR), gonadotropin releasing hormone receptors (GNRHR), kisspeptin receptors (KISS1R), melanocortin receptors (MCR), and the like. the thyrotropin-releasing hormone (TRHR1, TRHR2), or the VIP and PACAP receptors (ADCYAP1R1, VIPR1, VIPR2).

[0077] Chemoattractant GPCRs 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 is a chemokine GPCR that binds a CC chemokine (β-chemokine), a CXC chemokine (α-chemokine), a C chemokine (γ-chemokine), or a C×3C chemokine (d-chemokine).

[0078] Tumor cells that preferentially metastasize to specific organs via blood and lymphatic vessels present a major challenge to 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 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, as well as 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), promoting tumor cell survival, growth, and invasion and improving the cytokine-rich microenvironment. CXCR4 is a well-documented 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.

[0079] Tumor cells frequently express high levels of CXCR4, promoting cell growth, survival, and migration capabilities. For example, CXCR4 is not found in normal breast tissue, but rather overexpressed in breast cancer cells, and by inhibiting CXCR4, a significant inhibition of breast cancer metastasis is achieved. However, treatment with CXCR4 inhibitors requires caution, as CXCR4 inhibition induces mobilization of progenitor / stem cells from the bone marrow. Hypoxia-inducible factor-1 (HIF-1α), activated by hypoxia, increases CXCR4 transcription. In highly aggressive basal-like breast cancer cells, CXCR4 can also bind to Gα12 / 13 when Gα13 protein is greatly upregulated, thereby promoting spread via lymphatics and site-specific metastasis 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.

[0080] [Table 1-1]

[0081] [Table 1-2]

[0082] Solid tumors: benign and / or malignant neoplasms (cancer) In one aspect, the compounds of formula (I) are used to treat benign and / or malignant neoplasms (solid tumors), the neoplasms comprising cells that overexpress cell surface GPCRs.

[0083] 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).

[0084] Neoplasms include solid tumors, adenomas, carcinomas, sarcomas, leukemias, and lymphomas at any stage of disease, with or without metastasis.

[0085] 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 by 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.

[0086] Solid tumors are typically cancers originating from organs such as the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, ovaries, pancreas or other endocrine organs (thyroid), and prostate.

[0087] 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 can become malignant, at which point they are called adenocarcinomas. Even when benign, they can compress other structures (mass effect) and produce large amounts of hormones in an unregulated, feedback-independent manner (causing paraneoplastic syndrome), leading to serious health complications.

[0088] Adenomas are typically found in the colon (e.g., adenomatous polyps that have a tendency to become malignant and lead to colon cancer), kidney (e.g., renal adenomas can be precursor lesions to renal cancer), adrenal glands (e.g., adrenal adenomas, which secrete several hormones such as cortisol, which causes Cushing's syndrome, aldosterone, which causes Conn's syndrome, or androgens, which causes hyperandrogenism), thyroid (e.g., thyroid adenoma), pituitary gland (e.g., pituitary adenomas such as prolactinomas), parathyroid glands (e.g., adenomas of the parathyroid glands can inappropriately secrete large amounts of parathyroid hormone, thereby causing primary hyperparathyroidism), liver (e.g., hepatocellular adenoma), breast (e.g., fibrous adenoma), appendix (e.g., cystic adenoma), bronchi (e.g., bronchial adenomas can cause carcinoid syndrome, a type of paraneoplastic syndrome), prostate (e.g., prostatic adenoma), sebaceous glands (e.g., parathyroid adenoma), and salivary glands.

[0089] Metastasis is the spread of malignant cells to new areas of the body, often via the lymphatic system or bloodstream. A metastatic tumor is a tumor that has spread from its primary site, or from where it began, to different areas of the body. A metastatic tumor contains malignant cells that express cell surface GPCRs.

[0090] Tumors formed from disseminated 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.

[0091] In some embodiments, the tumor to be treated comprises tumor cells expressing a GPCR, and the tumor is a primary or metastatic tumor. In some embodiments, the tumor to be treated comprises tumor cells expressing a 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 a 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 a 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 a GPCR, and the tumor is a primary or metastatic neuroectodermal tumor, such as a pheochromocytoma or a paraganglioma. In some embodiments, the tumor to be treated comprises tumor cells expressing a GPCR, and the tumor is a primary or metastatic bronchopulmonary tumor or a 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.

[0092] In some embodiments, the compounds of formula (I) are used to treat a sarcoma, such as leiomyosarcoma or rhabdomyosarcoma.

[0093] In some embodiments, the compounds of formula (I) are used to treat adenomas.

[0094] In another aspect, described herein is a method for treating cancer in a mammal comprising administering to a mammal in need thereof a non-peptide targeted therapeutic as 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) gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

[0095] In some embodiments, a compound of formula (I) is administered to a tumor patient, hi some embodiments, the tumor 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.

[0096] 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 cancer (including transitional cell carcinoma (malignant neoplasm of the bladder)), bronchial 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, ductal carcinoma in situ or bile duct carcinoma choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.

[0097] Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovium, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0098] 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.

[0099] 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 lineage-restricted hematopoietic cells, c) chronic lymphocytic leukemia (CLL, clonal proliferation of immunologically immature and functionally incomplete 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.

[0100] Primary and metastatic tumors include, for example, lung cancer (including, but not limited to, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, non-small cell carcinoma, small cell carcinoma, and mesothelioma), breast cancer (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, and mucinous carcinoma), colorectal cancer (including, but not limited to, colon carcinoma and rectal carcinoma), anal cancer, pancreatic cancer (including, but not limited to, pancreatic adenocarcinoma, pancreatic islet cell carcinoma, and neuroendocrine tumors), prostate cancer, ovarian cancer (including, but not limited to, serous tumors, endometrioid tumors, and mucinous cystic adenocarcinomas, ovarian epithelial carcinoma or surface epithelial stromal tumors, including umbilical cord stromal tumors), liver and bile duct cancer (including, but not limited to, hepatocellular carcinoma, cholangiocarcinoma, and vascular carcinoma), cancer, including but not limited to, esophageal cancer (including but not limited to esophageal adenocarcinoma and squamous cell carcinoma), non-Hodgkin's lymphoma, bladder cancer, uterine cancer (including but not limited to endometrial adenocarcinoma, endometrial papillary serous carcinoma, endometrial clear cell carcinoma, uterine sarcoma and uterine myosinoma, mixed cartilage tumor), glioma, glioblastoma, medulloblastoma, and other brain tumors, kidney cancer (renal cell carcinoma, clear cell carcinoma, Wilm's tumor), head and neck cancer (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, carcinoids of the gastrointestinal tract, breast, and other organs, and signet ring cell carcinoma.

[0101] Cytotoxic payload / drug-containing payload moiety (Q) In some embodiments, Q comprises a chemotherapeutic agent.

[0102] 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 chemotherapeutic agent that is a cytotoxic drug, a kinase inhibitor, or both, and L is an optional non-cleavable linker or an optional cleavable linker that is cleaved near the GPCR expressed in or within the tumor cell.

[0103] In some embodiments, the optional cleavable linker is a pH-sensitive linker, a redox-sensitive linker, or an enzymatically cleavable linker, where the enzymatically cleavable linker is cleaved by an esterase, protease, or peptidase expressed in tissue that contains a GPCR expressed in a tumor cell.

[0104] In some embodiments, Q comprises a chemotherapeutic agent that is a ligand for an extracellular protein in the extracellular environment of a tumor cell that expresses a GPCR.

[0105] In some embodiments, Q comprises a cytotoxic drug that is an antimitotic drug, a DNA damaging agent, a transcription inhibitor, or a combination thereof.

[0106] In some embodiments, Q comprises a cytotoxic drug that is an antimitotic agent, wherein the antimitotic agent is a maytansinoid, a taxane, an auristatin, an alkaloid, a tubulysin, or an epothilone.

[0107] In some embodiments, Q comprises a cytotoxic drug that is a DNA damaging agent, a transcription inhibitor, or a combination thereof, wherein the DNA damaging agent, the transcription inhibitor, or a combination thereof is a DNA polymerase inhibitor, a DNA replication inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic.

[0108] In some embodiments, Q comprises a kinase inhibitor that is an inhibitor of a cytoplasmic tyrosine kinase (CTK), a serine / threonine kinase (S / T kinase), a lipid kinase (LK), or a receptor tyrosine kinase (RTK).

[0109] In some embodiments, Q comprises a cytotoxic drug that is an antimitotic drug, a DNA damaging agent, a transcription inhibitor, or a combination thereof. In some embodiments, Q comprises a cytotoxic drug that is an antimitotic drug, and the antimitotic drug is a maytansinoid, a taxane, an auristatin, an alkaloid, a tubulysin, or an epothilone. In some embodiments, the maytansinoid is mertansine or emtansine, the taxane is paclitaxel or docetaxel, the alkaloid is ellipticine or a vinca alkaloid, the epothilone is epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, or utiderone, and the auristatin is monomethylauristatin E or monomethylauristatin F.

[0110] In some embodiments, the vinca alkaloid is vinblastine, vincristine, vindesine, vinorelbine, or vinflunine.

[0111] In some embodiments, the DNA damaging agent, transcription inhibitor, or a combination thereof is a DNA polymerase inhibitor, a DNA replication inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic.

[0112] In some embodiments, the DNA polymerase inhibitor is amyherin, aphidicolin, cytarabine, or vernolepin; the DNA replication inhibitor is altretamine, bleomycin, cytarabine, dacarbazine, dactinomycin, ellipticine, estramastine, mitobronitol, mitomycin, mitocin, pingyangmycin, pikamycin, plicamycin, or temozolomide; the topoisomerase inhibitor is irinotecan, topotecan, camptothecin, etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, mervalone, or aclarubicin; and the cytotoxic antibiotic is an anthracycline, bleomycin, mitomycin, or actinomycin.

[0113] In some embodiments, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, or mitoxantrone, and the mitomycin is mitomycin A, mitomycin B, or mitomycin C.

[0114] In some embodiments, the cytotoxic drug is actinomycin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amsacrine, anastrozole, azacitidine, azathioprine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezomib, botulinum toxin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, chloramphenicol, chlormethine hydrochloride, cyclosporine, cidofovir, cisplatin, cladribine, clofarabine, chlorambucil, Crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, danazol, dasatinib, daunorubicin hydrochloride, decitabine, deniluikin, dienstrol, diethylstilbestrol, dinoprostone, docetaxel, doxorubicin, dutasteride, epirubicin, estradiol, estramustine sodium phosphate, estrogen-progestin combinations, complexed estrogens, estrogen esterified, estrone, estropipate, etoposide, exemestane, finasteride, flocculate Swiridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, fulvestrant, ganciclovir, gemcitabine, ibritumomab tiucetan, idarubicin, ifosfamide, imatinib mesylate, irinotecan hydrochloride, leflunomide, letrozole, leuprorelin acetate, lomustine, lymphoglobulin, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesena, methotrexate, methyltestosterone, mifepristone, mitomycin, mitotane, mitoxantrone hydrochloride, myco Phenolate mofetil, nafarelin, natalizumab, nilutamide, estrogen, oxaliplatin, oxytocin (including syntocinone and syntometrine), paclitaxel, pemetrexed disodium, pentamidine isethionate, pentostatin, perfosfamide, pipobroman, piritrexim isethionate, plicamycin, podofrillox, prednimustine, procarbazine, progesterone-containing products, progestins, raloxifene, raltitrexed, ribavirin, rituximab, sirolimus, streptozocin,Selected from tacrolimus, tamoxifen, temozolomide, teniposide, testolactone, testosterone, thalidomide, thioguanine, thiotepa, thymoglobulin, thioguanine, topotecan, toremifene citrate, tositumomab, trastuzumab, treosulfan, tretinoin, trifluridine, trimetrexate glucuronate, triptorelin, uramustine, valganciclovir, valrubicin, vidarabine, vinblastine sulfate, vincristine, vindesine, vinorelbine tartrate, and zidovudine.

[0115] In some embodiments, Q comprises:

[0116] [Table 2]

[0117] In some embodiments, Q comprises a kinase inhibitor that is an inhibitor of a cytoplasmic tyrosine kinase (CTK), a serine / threonine kinase (S / T kinase), a lipid kinase (LK), or a receptor tyrosine kinase (RTK).

[0118] In some embodiments, the cytoplasmic tyrosine kinase (CTK) is sphingosine kinase 1 (SK1), or phosphoinositide 3-kinase (PI3K).

[0119] In some embodiments, the serine / threonine kinase (S / T kinase) is protein kinase Ci (PKCi), mammalian target of rapamycin (mTOR), cyclin-dependent kinase (CDK), ataxia telangiectasia (ATM), protein kinase B (Akt), ribosomal protein S6 kinase (S6K), serine / threonine kinase 11 or liver kinase B1 (STK11 / LKB1), polo-like kinase (PLK), B-Raf proto-oncogene (b-Raf), aurora kinase A&B (Aur A&B), mitogen-activated protein (MAP) kinase kinase kinase (MAP3K), or mitogen-activated protein kinase kinase (MEK).

[0120] In some embodiments, the lipid kinase (LK) is the proto-oncogene tyrosine protein kinase Src (c-SRC), the c-Yes proto-oncogene (c-YES), Abelson murine leukemia viral oncogene homolog 1 (Abl), or Janus kinase 2 (JAK-2).

[0121] In some embodiments, the receptor tyrosine kinase (RTK) is Recepteur d'Origine Nantais (RON), fibroblast growth factor receptor (FGFR), c-MET proto-oncogene (c-Met), c-RET proto-oncogene (c-Ret), insulin-like growth factor 1 receptor (IGF-IR), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor alpha (PDGFR-α), c-Kit proto-oncogene or obesity / stem cell growth factor receptor (c-Kit), Fms-like tyrosine kinase 3, 4 (Flt3, Flt-4), platelet-derived growth factor receptor beta (PDGFR-β), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor-2 (HER-2), or Bruton's tyrosine kinase (BTK).

[0122] In some embodiments, Q comprises acalabrutinib, afatinib, alectinib, axitinib, brigatinib, bosutinib, ceritinib, crizotinib, cabozantinib, dasatinib, dabrafenib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, vemurafenib, or zanubrutinib.

[0123] Linker In some embodiments, the linker has a predetermined length, thereby linking NP and Q while allowing an appropriate distance between them.

[0124] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0125] 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.

[0126] 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 moieties, one or more rigid moieties, or a combination thereof.

[0127] In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, one or more amino acids of the linker are unnatural amino acids.

[0128] In some embodiments, the linker comprises a peptide bond. The peptide bond comprises L-amino acids and / or D-amino acids. In some embodiments, D-amino acids are preferred to minimize immunogenicity and non-specific cleavage by background peptidases or proteases. It is known that the cellular uptake of oligo-D-arginine sequences is comparable to or better than that of oligo-L-arginine.

[0129] In some embodiments, the linker has a length of 1 to 100 atoms, 1 to 50 atoms, 1 to 30 atoms, 1 to 20 atoms, 1 to 15 atoms, 1 to 10 atoms, or 1 to 5 atoms. In some embodiments, the linker has a length of 1 to 10 atoms. In some embodiments, the linker has a length of 1 to 20 atoms.

[0130] 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 double- and / or triple-bond-rich regions.

[0131] In some embodiments, the linker is cleavable. In some embodiments, the linker is designed to cleave under certain conditions or in the presence of a certain environment, such conditions or the environment near such target cells, tissues, or regions. Cleavable linkers rely on the unique properties of the cytoplasmic compartment of cells for selective release of cytotoxic drugs. Such linkers mainly include chemically cleavable linkers that respond to low pH (acid labile linkers) or reducing environments (disulfide linkers), and enzymatically cleavable linkers that are susceptible to the action of certain lysosomal enzymes (peptide linkers or β-glucuronide linkers).

[0132] 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-labile linker (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, etc.) that is hydrolyzable in the lysosome. Such linkers may be relatively stable under neutral pH conditions, such as those in blood, but are unstable below pH 7.0, such as pH 6.5-4.5, the approximate pH of lysosomes and / or endosomes.

[0133] In some embodiments, the linker comprises one or more disulfide bonds.

[0134] In some embodiments, the linker is cleaved in or near tissues suffering from hypoxia, such as cancer cells and cancerous 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 cause cancer cells to become more resistant to radiation and chemotherapy and 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 collapse when reduced to hydroquinones are used in linkers designed to cleave in hypoxic environments.

[0135] In some embodiments, the linker is cleaved by intracellular peptidases 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 after internalization, they can be recognized and rapidly hydrolyzed by certain lysosomal proteases, such as cathepsin B. 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.

[0136] In some embodiments, the linker is cleaved by a protease, a matrix metalloprotease, 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.

[0137] In some embodiments, the linker is cleaved by MMP. The hydrolytic activity of matrix metalloproteinases (MMPs) 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).

[0138] In some embodiments, the linker is cleaved by proteolytic enzymes or a reducing environment such as may be found in the vicinity of cancer cells, where such an environment or such enzymes are typically not found in the vicinity of normal cells.

[0139] 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.

[0140] 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 trigger cleavage of the linker. In some embodiments, cleavage of the linker occurs by necrotic enzymes (e.g., by calpain).

[0141] 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.

[0142] In some embodiments, the non-cleavable 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.

[0143] In some embodiments, L is absent, or is selected from 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.

[0144] 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 -L 3 -L 4 -L 5 -, or any combination thereof.

[0145] In some embodiments, each L 1 are independently absent, unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, unsubstituted or substituted alkenylene, unsubstituted or substituted alkynylene, unsubstituted or substituted cycloalkylene, unsubstituted or substituted heterocycloalkylene, unsubstituted or substituted arylene, 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-, -(CH2) p -C(=O)NH-, -C(=O)NH-(CH2) p -, -(CH2) p -C(=O)NH-(CH2) p -, and each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. 1 are independently absent, 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, -(CH) q -, -C(=O)-, -(CH2) p -C(=O)-, -C(=O)-(CH2) p -, -(CH2) p -C(=O)-(CH2) p -, -C(=O)NH-, -(CH2) p -C(=O)NH-, -C(=O)NH-(CH2) p -, -(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.

[0146] In some embodiments, each L2 are 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 -, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and each X is independently O, S, or NR X Selected from R X is hydrogen or C1-C4 alkyl. 2 are independently -C(=O)-, -C(=O)NH-, -C(=O)O-, -(CH2) p -, -C(=O)-(CH2CH2O) p - or -(CH2CH2O) p and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0147] In some embodiments, each L 3 are independently absent, unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, unsubstituted or substituted alkenylene, unsubstituted or substituted alkynylene, unsubstituted or substituted cycloalkylene, unsubstituted or substituted heterocycloalkylene, unsubstituted or substituted arylene, 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 Selected from R X is hydrogen or C1-C4 alkyl. 3are independently unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, -(CH) q and each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0148] In some embodiments, each L 4 is independently absent, -O-, -S-, -S(O)-, -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-. 4 is independently absent, -NH-.

[0149] In some embodiments, each L 5 is independently absent, unsubstituted or substituted alkylene, or unsubstituted or substituted heteroalkylene. 5 is independently absent or unsubstituted or substituted alkylene.

[0150] 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 or -L 1 -, -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 1 -L 2 -L 3 -L 4 -L 5 -, or a combination thereof, 1are independently 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, -(CH) 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; and each L 2 are 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; and each L 3 are independently unsubstituted or substituted alkylene, unsubstituted or substituted heteroalkylene, -(CH) q each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each L 4 is independently absent, -NH-, and each L 5 is independently absent, unsubstituted or substituted alkylene, or unsubstituted or substituted heteroalkylene.

[0151] In some embodiments, -L 2 -L 3 -L 4 -L 5 -teeth,

[0152] [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 Xis hydrogen or C1-C4 alkyl.

[0153] In some embodiments, -L 2 -L 3 -L 4 -L 5 -teeth,

[0154] [ka] and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0155] In some embodiments, -L 2 -L 3 -L 4 -L 5 -teeth,

[0156] [ka] and each X is independently O or NR X and R X is hydrogen or C1-C4 alkyl.

[0157] In some embodiments, L is

[0158] [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.

[0159] In some embodiments, L is

[0160] [ka] and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0161] In some embodiments, L is

[0162] [ka] and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0163] In some embodiments, L is

[0164] [ka] It is.

[0165] 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. In 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.

[0166] Representative linker and payload moieties In some embodiments, -LQ is

[0167] [ka]

[0168] [ka]

[0169] [ka]

[0170] [ka]

[0171] [ka]

[0172] [ka] It is.

[0173] 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 <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). Large structures such as nucleic acids, proteins, polysaccharides, etc. are not small molecules.

[0174] In some embodiments, the NP is a non-peptide ligand that binds to tumor cells expressing somatostatin receptors.

[0175] In some embodiments, the NP is a non-peptide ligand for the somatostatin receptor, and the NP is a compound described in U.S. Pat. No. 10,696,689, U.S. Patent Publication No. 2020 / 0010453, each of which is incorporated herein by reference. In some embodiments, the non-peptide ligand is a compound described in any one of formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IIIa), (IIIb), (IIIc) or (IIId) of U.S. Pat. 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. Pat. 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 US 2020 / 0010453. 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. WO 2018 / 170284.

[0176] In some embodiments, the non-peptide ligand is a compound described in US9643951, US9630976, US2020 / 0000816, each of which is incorporated herein by reference.

[0177] In some embodiments, 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. In some embodiments, 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.

[0178] In some embodiments, NP has the structure of formula (II):

[0179] [ka] During the ceremony, R A teeth,

[0180] [ka] and Each R 1 , R 2 , R 3 and R 4 are 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 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 R6 together with the intermediate atom to which they are attached to form morpholine, X 1 is absent, -O-, -S-, -N(R 7 )-, -C(=O)-, -C(=O)N(R 7 )-, -C(=O)O-, -N(R 7 )C(═O)—, or a heterocycle; Each R 7 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0181] In some embodiments, NP has the structure of formula (III):

[0182] [ka] During the ceremony, Each R 1 , R 2 , R 3 and R 4 are 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 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 intermediate atom to which they are attached to form morpholine, X 1 is absent, -O-, -S-, -N(R 7 )-, -C(=O)-, -C(=O)N(R 7)-, -C(=O)O-, -N(R 7 )C(═O)—, or a heterocycle; Each R 7 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0183] In some embodiments, X 1 is absent, -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.

[0184] In some embodiments, X 1 is non-existent, -O-, -S-,

[0185] [ka] It is.

[0186] In some embodiments, the NP has the structure of formula (IV), or a pharma- ceutically acceptable salt or a pharma- ceutically acceptable solvate thereof.

[0187] [ka]

[0188] In some embodiments, each R 1 , R 2 , R 3 and R 4 are independently hydrogen, F, Cl, Br, -CN, -N(R 7 )2, or C1-C4 alkyl. In some embodiments, each R 1 , R 2 , R 3 and R 4is independently hydrogen, F, Cl, —CH, —CHCH, or —OCH. In some embodiments, R 5 is hydrogen and R 6 is hydrogen, -OH, or -OCH3, or R 5 and R 6 together with the intermediate atom to which they are attached form a morpholine. 7 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In some embodiments, each R 7 is independently hydrogen or C-C alkyl. In some embodiments, each R 7 is independently hydrogen, -CH3, or -CH2CH3.

[0189] In some embodiments,

[0190] [ka] teeth

[0191] [ka] It is.

[0192] In some embodiments,

[0193] [ka] teeth,

[0194] [ka] It is.

[0195] In some embodiments,

[0196] [ka] teeth,

[0197] [ka] It is.

[0198] In some embodiments, R A teeth,

[0199] [ka] and Each R 1 , R 2 , R 3 and R 4 are independently hydrogen, F, Cl, Br, C1-C4 alkyl, -CN, -N(R 7 )2, or -OR 7 and R 5 is hydrogen and R 6 is hydrogen or -OR 7 or R 5 and R 6 together with the intermediate atom to which they are attached to form morpholine, Each R 7 is independently hydrogen, -CH3, or -CH2CH3.

[0200] In some embodiments,

[0201] [ka] teeth,

[0202] [ka] and

[0203] [ka] teeth,

[0204] [ka] It is.

[0205] In some embodiments,

[0206] [ka] teeth,

[0207] [ka] and

[0208] [ka] teeth,

[0209] [ka] It is.

[0210] In some embodiments, the GPCR is somatostatin type 2 receptor (SSTR2) and NP has the following structure:

[0211] [ka]

[0212] In some embodiments, the compound has one of the following structures:

[0213] [ka]

[0214] [ka]

[0215] [ka]

[0216] In some embodiments, the NP is a non-peptide ligand that binds to tumor cells expressing the gonadotropin releasing hormone receptor (GnRHR).

[0217] In some embodiments, the NP is a non-peptide ligand that includes a N-{4,6-dimethoxy-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.

[0218] In some embodiments, the GPCR is GnRHR and NP has a structure of formula (X):

[0219] [ka] During the ceremony, V is CH or N, W is CH or N, T is absent, -CH2-, -CH(CH3)-, or -C(CH3)2-; X 2 is absent, -O-, or -N(R 7 )-and R 7 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0220] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0221] [ka] In the formula, V is CH or N, and W is CH or N.

[0222] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0223] [ka] In the formula, V is CH or N, and W is CH or N.

[0224] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0225] [ka] In the formula, V is CH or N, and W is CH or N.

[0226] In some embodiments, the GPCR is GnRHR and the NP has one of the following structures:

[0227] [ka] In the formula, V is CH or N, and W is CH or N.

[0228] In some embodiments, the GPCR is GnRHR and the NP has the following structure:

[0229] [ka] In the formula, V is CH or N, and W is CH or N.

[0230] In some embodiments, the GPCR is GnRHR and the NP has the following structure:

[0231] [ka] In the formula, V is CH or N, and W is CH or N.

[0232] In some embodiments, the GPCR is GnRHR and the NP has the following structure:

[0233] [ka] In the formula, V is CH or N, and W is CH or N.

[0234] In some embodiments, the compound has one of the following structures:

[0235] [ka]

[0236] [ka]

[0237] [ka]

[0238] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0239] Synthesis of compounds The compounds described herein are synthesized using standard synthetic techniques, or in combination with the methods described herein, known in the art.

[0240] Conventional methods of mass spectrometry, NMR, HPLC are used unless otherwise indicated.

[0241] The compounds are described, for example, in March's Advanced Organic Chemistry, 6 th The compounds are prepared using standard organic chemistry techniques, such as those described in the "Compounds of the Organic Synthesis" series, Vol. 13, No. 1, pp. 111-115, 1999. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

[0242] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.In addition, the compounds described herein can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0243] The term "pharmaceutical acceptable salt" refers to the cationic form of a therapeutically active agent combined with a suitable anion, or in an alternative embodiment, a form of a therapeutically active agent that consists of the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J.Pharm.Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble and more rapidly soluble in gastric and intestinal fluids than non-ionic species, and are therefore useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one or other part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Also, salt-forming molecules can be in equilibrium with neutral forms, allowing for tailored passage across biological membranes.

[0244] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with an acid. In some embodiments, a compound of formula (I) (i.e., in 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 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), capric acid (hexanoic acid), capric acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and glucosides. Examples of suitable carboxylic acids include, but are not limited to, carboxylic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glyceryl folinic acid, glycolic acid, hyflic acid, isophosphoric acid, isobutyric acid, lactic acid (DL), lactic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0245] In some embodiments, the compound of formula (I) is prepared as a chloride salt, a sulfate salt, a bromide salt, a mesylate salt, a maleate salt, a citrate salt, or a phosphate salt.

[0246] 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 a 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 coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine, lysine, etc. 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, etc. In some embodiments, the compounds provided herein are prepared as a sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salt.

[0247] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent 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, and 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 and solvated forms.

[0248] In some embodiments, moieties on organic radicals (eg, alkyl groups, aromatic rings) of the compounds of Formula (I) are deuterated.

[0249] 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, entogen (E), and tusamene (Z) isomers, and the appropriate mixtures thereof.

[0250] If necessary, the individual stereoisomers are obtained 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 an appropriate 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 diastereomeric 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 the stereoisomers is carried out by chromatography, or by forming diastereomeric salts and separating them by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0251] 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 cases, they are easier to administer than the parent drug. They are, for example, more bioavailable by oral administration, whereas the parent is not. Additionally or alternatively, prodrugs also have improved solubility in pharmaceutical compositions than the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Design of Prodrugs, 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.

[0252] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes can produce specific structural changes to a compound. For example, uridine diphosphate glucuronyl transferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups, while cytochrome P450 catalyzes various oxidation and reduction reactions. Metabolites of a compound disclosed herein are optionally identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound.

[0253] 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 selected route of administration. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: 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 disclosures.

[0254] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent. The administration of the compounds and compositions described herein can be performed by any method that allows the compound to be delivered to the site of action. These methods include, but are not limited to, delivery by enteral routes (including oral) and parenteral routes (including injection or infusion, and subcutaneous).

[0255] 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 non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

[0256] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. The formulation for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. The composition may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The composition may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a lyophilized (lyophilized) state, requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.

[0257] Treatment method In some embodiments, the method includes administering a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof to the 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.

[0258] In embodiments, treatment is sufficient to reduce or inhibit the growth of a subject's tumor, reduce the number or size of metastatic lesions, reduce tumor burden, reduce primary tumor burden, reduce invasiveness, prolong survival time, or maintain or improve quality of life, or a combination thereof.

[0259] 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.

[0260] In one aspect, methods and compositions for treating cancer are provided herein. Cancer includes tissue and organ cancer development, including metastasis, such as, for example, 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 of such treatment by administering to the subject an effective amount of a non-peptide targeted therapeutic compound disclosed herein. Non-limiting examples of gastrointestinal cancer that can be treated according to the methods 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.

[0261] In one aspect, provided herein are methods and compositions for treating adenoma.

[0262] In one aspect, methods and compositions are provided herein for treating peptide hormone G protein-coupled receptor expressing cancer. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer 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 treated is a primary or metastatic pancreatic cancer. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer 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 treated is a sarcoma, such as leiomyosarcoma or rhabdomyosarcoma. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer treated is a primary or metastatic neuroectodermal tumor, such as pheochromocytoma or paraganglioma. In some embodiments, the peptide hormone G protein-coupled receptor expressing cancer treated is a primary or metastatic bronchopulmonary tumor or gastrointestinal neuroendocrine tumor. In some embodiments, the cancer is colorectal cancer.

[0263] In another aspect, described herein is a method for treating cancer in a mammal comprising administering a non-peptide targeted therapeutic compound disclosed herein to a mammal in need thereof. 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) gastrointestinal pancreatic neuroendocrine tumor (GEP-NET).

[0264] Methods of Administration and Treatment Regimen 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 said 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.

[0265] In certain embodiments, compositions containing the compounds described herein are administered for diagnostic and / or therapeutic treatments.

[0266] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the specific conjugate, the specific cancer or tumor being treated (and its severity), the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the specific conjugate being administered, the route of administration, the condition being treated, and the subject or host being treated. Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses depend on the subject's weight, body weight, or blood volume.

[0267] The toxicity and therapeutic efficacy of such treatment regimens are 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and is known as the LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies is used in formulating a therapeutically effective daily dose range and / or therapeutically effective unit dosage form for use in mammals, including humans.

[0268] The amount of the complex or its pharma- ceutically acceptable salt or solvate and / or pharmaceutical composition administered may be sufficient to deliver a therapeutically effective amount to a particular subject. In some embodiments, the complex dosage is about 0.1 pg to about 50 mg per kg of body weight, 1 μg to about 50 mg per kg of body weight, or about 0.1 to about 10 mg per kg of body weight. The therapeutically effective dosage may also be determined at the discretion of the physician. By way of example only, the dose of the complex 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 of body weight of the subject per dose. In some embodiments, the dose of the complex or its pharma- ceutically acceptable salt or solvate described herein for the methods described herein is about 0.001 mg to about 1000 mg per dose to the subject to be treated. In some embodiments, the 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.

[0269] In some embodiments, the 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 mole, about 0.1 picomole to about 0.1 mole, about 1 nanomolar to about 0.1 mole, or about 0.01 micromolar to about 0.1 millimolar.

[0270] In some embodiments, doses are administered once a day, 1-3 times a week, 1-4 times a month, or 1-12 times a year.

[0271] In any of the foregoing aspects, there are further embodiments in which 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.

[0272] Combination treatment In certain cases, 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.

[0273] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced), or, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (including a treatment regimen) that also has therapeutic benefit.

[0274] In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[0275] Specific Terms Unless otherwise stated, the following terms used in this application have the definitions set forth below. The term "including" and other forms of "include," "includes," and "included" are non-exclusive. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0276] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated "C1-C6" indicates that there is from 1 to 6 carbon atoms in the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms in the group. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0277] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group is branched or straight chain. In some embodiments, an "alkyl" group is an alkyl group having 1 to 10 carbon atoms, i.e., C1-C 10 It has an alkyl. Whenever it appears in this specification, a numerical range such as "1-10" refers to each 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 and including 10 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is a C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 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.

[0278] An "alkylene" group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstracting 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-.

[0279] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0280] 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.

[0281] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3-C≡CCH2CH3, -CH2C≡CH.

[0282] 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.

[0283] The term "carbocyclic" or "carbocyclic" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocycles 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.

[0284] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, an aryl is phenyl or naphthyl. In some embodiments, an aryl is phenyl. In some embodiments, an aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C 10 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0285] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl.

[0286] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0287] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0288] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (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, with the proviso that each heterocyclic group has 3-10 atoms in its ring system and no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include 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, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiamine ... oranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.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 either C-linked (or C-linked) or N-linked where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Additionally, 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, such as 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.

[0289] 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.

[0290] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused to an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is C4-C 10 Heterocycloalkyl. In some embodiments, heterocycloalkyl is monocyclic or bicyclic. In some embodiments, heterocycloalkyl is monocyclic and has 3, 4, 5, 6, 7, or 8 ring members. In some embodiments, heterocycloalkyl is monocyclic and has 3, 4, 5, or 6 ring members. In some embodiments, heterocycloalkyl is monocyclic and has 3 or 4 ring members. In some embodiments, heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0291] 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 bond, the reference group is not present, thereby allowing a bond to be formed between the remaining identified groups.

[0292] 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.

[0293] 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, a substituent is substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0294] The term "modulate," as used herein, means to directly or indirectly interact with the activity of a target so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0295] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. The interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0296] The terms "administer", "administering", "administration" and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion). Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein.

[0297] Terms such as "concomitant 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 agents are administered by the same or different routes of administration or at the same or different times.

[0298] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered that relieves to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to bring about a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0299] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration of 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.

[0300] The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient as separate entities simultaneously, concurrently, or sequentially, without any specific intervening time restriction, such administration providing an effective level of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0301] The terms "article of manufacture" and "kit" are used synonymously.

[0302] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, humans, non-human primates such as chimpanzees, and other ape and monkey species, farm animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0303] The terms "treat", "treating" or "treatment" as used herein include improving, alleviating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the onset of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating symptoms caused by the disease or condition, or halting the symptoms of the disease or condition, either prophylactically and / or therapeutically. EXAMPLES

[0304] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0305] Compound synthesis Example 1. N-[3-({3-[(4,6-dimethoxy-5-{5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-amido}pyrimidin-2-yl)amino]propyl}(methyl)amino)propyl]-5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxamide (Compound 1)

[0306] [ka] Step 1-1, Preparation of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid: To 5-fluoroindolin-2-one (151 mg, 1.0 eq, 1.0 mmol) in EtOH (3.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (167 mg, 1.0 eq, 1.0 mmol) and pyrrolidine (0.50 mL, 6.0 eq, 6.1 mmol) were added. The resulting mixture was heated at 65° C. for 3 hours. The reaction crude was acidified and diluted with water. The resulting suspension was filtered and the filtrate was washed with water and hexane. The remaining solid was collected and dried under vacuum to give crude 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (213 mg, 71%), which was used in the next step without further purification.

[0307] Step 1-2, Preparation of N-[2-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide: To a solution of N-(2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide (229 mg, 1.0 equiv, 0.50 mml) in MeCN (1.0 mL) was added N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (289 mg, 4.0 equiv, 2.0 mmol). The resulting mixture was heated at 115° C. for 3 h. The reaction crude was concentrated, diluted with ethyl acetate, washed with water, dried and concentrated to give crude N-[2-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide (272 mg, 98%) as a colorless oil. This material was used in the next step without further purification.

[0308] Step 1-3, Preparation of N-[3-({3-[(4,6-dimethoxy-5-{5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-amido}pyrimidin-2-yl)amino]propyl}(methyl)amino)propyl]-5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxamide: 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (30 mg, 1.0 equiv., 0.10 To a solution of 1.0 mmol of 1H-benzotriazol-1-yl (1H-benzotriazol-1-yl)uronium hexofulvophosphate (HBTU) (76 mg, 2.0 equiv., 0.20 mmol) and N-[2-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide (56 mg, 1.0 equiv., 0.10 mmol) were added. The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The remaining residue was purified by preparative TLC eluting with DCM / MeOH / NH4OH (20 / 1 / 0.5) to give N-[3-({3-[(4,6-dimethoxy-5-{5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-amido}pyrimidin-2-yl)amino]propyl}(methyl)amino)propyl]-5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxamide (12 mg, 14%). MS (M+H) + =849.5.

[0309] The following conjugates were prepared similarly to Example 1 using appropriate substitution reagents and substrates at different steps, which may require additional functional group modifications via well-known chemistry with appropriate reagents.

[0310] [Table 3-1]

[0311] [Table 3-2]

[0312] Example 2. N-[2-({2-[4-(2-{[(E)-{[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0 2 , 11 .0 4 , 9 .0 15 , 20 ]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-10-yl]methylidene}amino]oxy}acetyl)piperazin-1-yl]ethyl}amino)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide (compound 9)

[0313] [ka] Step 2-1, preparation of tert-butyl 4-{2-[(4,6-dimethoxy-5-{5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-amido}pyrimidin-2-yl)amino]ethyl}piperazine-1-carboxylate: N-(2-chloro-4,6-dimethoxypyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-amido}pyrimidin-2-yl)amino]ethyl}piperazine-1-carboxylate To a solution of 457 mg, 1.0 eq, 1.0 mmol of d-1H-inden-5-yl)oxy]furan-2-carboxamide in 2.0 mL of DMSO was added tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (230 mg, 1.0 eq, 1.0 mmol) and N,N-diisopropylethylamine (DIPEA) (1.74 mL, 10 eq, 10 mmol). The resulting mixture was stirred at 120° C. for 8 hours. The reaction crude was diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated. The remaining residue was purified by silica gel chromatography eluting with MeOH / DCM (0-5%) to give tert-butyl 4-{2-[(4,6-dimethoxy-5-{5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-amido}pyrimidin-2-yl)amino]ethyl}piperazine-1-carboxylate (560 mg, 86%).

[0314] Step 2-2, Preparation of N-(4,6-dimethoxy-2-{[2-(piperazin-1-yl)ethyl]amino}pyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide: To a solution of tert-butyl 4-{2-[(4,6-dimethoxy-5-{5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-amide}pyrimidin-2-yl)amino]ethyl}piperazine-1-carboxylate (560 mg, 1.0 equiv, 0.86 mmol) in DCM (3.0 mL) was added TFA (1.5 mL, 23.0 equiv, 19.7 mmol). The resulting mixture was stirred at ambient temperature for 24 hours. The reaction crude was concentrated, diluted with ethyl acetate, washed with saturated KCO, dried and concentrated to give crude N-(4,6-dimethoxy-2-{[2-(piperazin-1-yl)ethyl]amino}pyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide (300 mg, 63%). This material was used in the next step without further purification.

[0315] Step 2-3, 2-{[(E)-{[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0 2 , 11 .0 4 , 9 .0 15 , 20 Preparation of ]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-10-yl]methylidene}amino]oxy}acetic acid: (19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0 2 , 11 ,0 4 , 9 .0 15 , 20To a solution of 188 mg, 1.0 equiv, 0.50 mmol) of henicosa-1(21),2(11),3,5,7,9,15(20)-heptaene-10-carbaldehyde in 15 mL of MeOH was added 2-(aminoxy)acetic acid (55 mg, 1.0 equiv, 0.50 mmol) and the HCl salt of acetic acid (1.0 mmL). The resulting mixture was stirred at ambient temperature for 1 h. The resulting suspension was filtered and the filtrate was washed several times with ethyl acetate / hexane (1:9). The remaining solid was dried under vacuum to give crude 2-{[(E)-{[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0 2 , 11 .0 4 , 9 .0 15 , 20 ]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-10-yl]methylidene}amino]oxy}acetic acid (43 mg, 20%) was obtained, which was used in the next step without further purification.

[0316] Step 2-4, N-[2-({2-[4-(2-{[(E)-{[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0 2 , 11 .0 4 , 9 .0 15 , 20 Preparation of 2-{[(E)-{[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[1(21),2(11),3,5,7,9,15(20)-heptaen-10-yl]methylidene}amino]oxy}acetyl)piperazin-1-yl]ethyl}amino)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide: crude 2-{[(E)-{[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[1(21),2(11),3,5,7,9,15(20)-heptaen-10-yl]methylidene}amino]oxy}acetyl)piperazin-1-yl]ethyl}amino)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide 2 , 11 .0 4 , 9 .015 , 20 To a solution of 22 mg, 1.0 equiv., 0.050 mmol) of 1(21),2(11),3,5,7,9,15(20)-heptaen-10-yl]methylidene}amino]oxy}acetic acid in 1.0 mL of DMF was added N,N-diisopropylethylamine (DIPEA) (18 μL, 2.0 equiv., 0.10 mmol), N,N,N',N'-tetramethyl-O(1H-benzotriazol-1-yl) Uronium hexofluorophosphate (HBTU) (38 mg, 2.0 equiv., 0.10 mmol) and crude N-(4,6-dimethoxy-2-{[2-(piperazin-1-yl)ethyl]amino}pyrimidin-5-yl)-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide (27 mg, 1.0 equiv., 0.050 mmol) were added. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The remaining residue was purified by preparative TLC eluting with DCM / MeOH (20 / 1) to give N-[2-({2-[4-(2-{[(E)-{[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0 2 , 11 .0 4 , 9 .0 15 , 20 ]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-10-yl]methylidene}amino]oxy}acetyl)piperazin-1-yl]ethyl}amino)-4,6-dimethoxypyrimidin-5-yl]-5-[(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yl)oxy]furan-2-carboxamide (22 mg, 44%) was obtained. MS (M+H) + =982.6.

[0317] The following compounds were prepared analogously to Example 2 using appropriate substitution reagents and substrates at different steps, which may require additional functional group modifications via well-known chemistry with appropriate reagents.

[0318] [Table 4]

[0319] Example 3. 2-{[6-(16-{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}-16-oxo-4,7,10,13-tetraoxa-1-azahexadecan-1-yl)-2-methylpyrimidin-4-yl]amino}-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (compound 11)

[0320] [ka] Step 3-1, Preparation of tert-butyl 1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecan-15-oate: 2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(2-chloro-6-methylphenyl) To a solution of 1,3-thiazole-5-carboxamide (78 mg, 1.0 equiv., 0.2 mmol) in DMSO (1.0 mL) was added tert-butyl 1-amino-3,6,9,12-tetraoxapentadecan-15-ol (96 mg, 1.5 equiv., 0.30 mmol) and N,N-diisopropylethylamine (DIPEA) (0.30 mL, 8.6 equiv., 1.73 mmol). The resulting mixture was heated at 130 °C for 8 h. The reaction crude was purified by C18 reverse phase eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-50%). Pure fractions were combined, neutralized with saturated NaHCO3 (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give tert-butyl 1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecan-15-oate (120 mg, 88%).

[0321] Step 3-2, Preparation of 1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecan-15-oic acid: To a solution of tert-butyl 1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecan-15-oic acid (120 mg, 1.0 equiv., 0.17 mmol) in DCM (2.0 mL) was added triethylsilane (0.25 mL, 10 equiv., 1.7 mmol) and TFA (0.48 mL, 40 equiv., 0.8 mL). The resulting mixture was stirred at ambient temperature for 1 h. The reaction crude was concentrated and MTBE was added. The top ether layer was decanted and the remaining residue was dried under vacuum to give the crude TFA salt of 1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecan-15-oic acid (90 mg, 72%). MS (M+H) + =623.4.

[0322] Step 3-3, benzyl N-{1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-2-[4-(1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecanoyl)piperazin-1-yl]-5-(3-fluoro-5-methylphenyl)pyridine-4- Preparation of 1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecan-15-oic acid (40 mg, 1.0 equiv., 0.064 mmol) in DMF (1.0 mL) was diluted with N,N-diisopropylethylamine (DIPEA) ( 67 μL, 6.0 equiv., 0.38 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (49 mg, 2.0 equiv., 0.128 mmol) and (benzyl N-{1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1-yl)pyridinium 3-oxide hexafluorophosphate (HATU) {Zin-4-yl}piperidin-4-yl}carbamate (50 mg, 1.1 equiv., 0.077 mmol) was added. The resulting mixture was stirred at ambient temperature for 1 h. The reaction crude was purified by C18 reverse phase eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-50%). Pure fractions were combined, neutralized with saturated NaHCO3 (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (2 x 10 mL).The organic layers were combined, dried over MgSO4, filtered, and concentrated to give benzyl N-{1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-2-[4-(1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecanoyl)piperazin-1-yl]-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate (45 mg, 56%). MS (1 / 2M+H). + =630.7.

[0323] Step 3-4, Preparation of 2-{[6-(16-{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}-16-oxo-4,7,10,13-tetraoxa-1-azahexadecan-1-yl)-2-methylpyrimidin-4-yl]amino}-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide: benzyl N-{1-[3-(5-chloro-1H- To a solution of 1,3-benzodiazol-2-yl)-2-[4-(1-{[6-({5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}amino)-2-methylpyrimidin-4-yl]amino}-3,6,9,12-tetraoxapentadecanoyl)piperazin-1-yl]-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl}carbamate (45 mg, 1.0 equiv., 0.036 mmol) in TFA (1.0 mL) was added thioanisole (60 μL). The resulting mixture was heated at 60 °C for 1 h. The reaction crude was purified by C18 reverse phase eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-50%). The pure fractions were combined, neutralized with saturated NaHCO3 (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated with HCl in ethyl ether (0.1 mL, 2.0 N) to give the HCl salt of 2-{[6-(16-{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}-16-oxo-4,7,10,13-tetraoxa-1-azahexadecan-1-yl)-2-methylpyrimidin-4-yl]amino}-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (15 mg, 28%). MS(1 / 2M+H) + =563.0.

[0324] The following compounds were prepared analogously to Example 3 using appropriate substitution reagents and substrates at different steps, which may require additional functional group modifications via well-known chemistry with appropriate reagents.

[0325] [Table 5]

[0326] Example 4: (2S)-30-{4-[4-(4-aminopiperidin-1-yl)-3-(6-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-N-[(1S)-1-{[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl ethyl-2-{[2-(pyridin-2-yl)ethyl]carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl}-2-methylpropyl]-3-methyl-30-oxo-2-(propan-2-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontanamide (compound 17)

[0327] [ka] Step 4-1, benzyl N-{1-[3-(6-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-{4-[(1S)-1-{[(1S)-1-{[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[2-(pyridin-2-yl)ethyl]carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl}-2-methylpropyl]carbamoyl Preparation of (29S)-29{[(1S)-1-{[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[2-(pyridin-2-yl)ethyl]carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl} A solution of {2-methylpropyl}-28,30-dimethyl-4,7,10,13,16,19,22,25-octaoxa-28-azahentriacontanoic acid (12 mg, 1.0 equiv., 0.010 mmol) in DMF (0.5 mL) was diluted with N,N-diisopropylethylamine (DIPEA) (10 μL, 5 equiv., 0.050 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HAT) (1.0 mg, 1.0 equiv., 0.010 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HAT) (1.0 mg, 1.0 equiv., 0.010 mmol). U) (8.0 mg, 2.0 equiv., 0.020 mmol) and (benzyl N-{1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-(piperazin-1-yl)pyridin-4-yl]piperidin-4-yl}carbamate (12 mg, 2.0 equiv., 0.020 mmol) were added. The resulting mixture was stirred at ambient temperature for 1 h. The reaction crude was purified by C18 reverse phase eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-50%).The pure fractions were combined, neutralized with saturated NaHCO3 (3 mL), solid NaCl (5 g) was added, and extracted with ethyl acetate (2 x 10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to give benzyl N-{1-[3-(6-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-{4-[(1S)-1-{[(1S)-1-{[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[2-(pyridin-2-yl)ethyl] Carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl}-2-methylpropyl]carbamoyl}-2-methyl-1-(propan-2-yl)-5,8,11,14,17,20,23,26-octaoxa-2-azanonacosanoyl]piperazin-1-yl}pyridin-4-yl]piperidin-4-yl}carbamate (10 mg, 57%) was obtained. MS (1 / 2M+H). + =876.1.

[0328] Step 4-2, (2S)-30-{4-[4-(4-aminopiperidin-1-yl)-3-(6-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-N-[(1S)-1-{[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[2-(pi Preparation of benzyl N-{1-[3-(6-chloro-1H-lysine-2-yl)ethyl]carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl}-2-methylpropyl]-3-methyl-30-oxo-2-(propan-2-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontanamide: Preparation of benzyl N-{1-[3-(6-chloro-1H-lysine-2-yl)ethyl]carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl}-2-methylpropyl]-3-methyl-30-oxo-2-(propan-2-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontanamide 5-(3-fluoro-5-methylphenyl)-2-{4-[(1S)-1-{[(1S)-1-{[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[2-(pyridin-2-yl)ethyl]carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl To a solution of {5,8,11,14,17,20,23,26-octaoxa-2-azanonacosanoyl}piperazin-1-yl}pyridin-4-yl}piperidin-4-yl}carbamate (10 mg, 1.0 equiv., 0.0057 mmol) in TFA (0.50 mL) was added thioanisole (20 μL). The resulting mixture was heated at 60 °C for 1 h. The reaction crude was purified by C18 reverse phase eluting with MeCN (0.1% TFA) / water (0.1% TFA) (5-50%).Pure fractions were combined and lyophilized to give (2S)-30-{4-[4-(4-aminopiperidin-1-yl)-3-(6-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-yl]piperazin-1-yl}-N-[(1S)-1-{[(3R,4S,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl]pyridin-1-yl] The TFA salt of ethyl-2-{[2-(pyridin-2-yl)ethyl]carbamoyl}ethyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl}-2-methylpropyl]-3-methyl-30-oxo-2-(propan-2-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontanamide (6.6 mg, 72%) was obtained. MS (1 / 2M+H). + =808.4.

[0329] The following compounds were prepared similarly to Example 4 using appropriate substitution reagents and substrates at different steps, as well as additional functional group modifications, as necessary, with appropriate reagents, via well-known chemistry.

[0330] [Table 6]

[0331] Example A-1: ​​Parenteral Pharmaceutical Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 0.001-500 mg of the compound of formula (I), 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. Optionally, a suitable buffer is added to adjust the pH, as well as optionally a suitable acid or base. The mixture is incorporated into a unit dosage form suitable for administration by injection.

[0332] Biology examples Example B-1: SSTR assay Functional assay for SSTR2 agonists General overview: All five SSTR subtypes are Gi-coupled G protein-coupled receptors (GPCRs) that, when activated by agonists, result in a decrease in intracellular cyclic AMP (cAMP). 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). An example of intracellular cAMP assay is described below.

[0333] cAMP Assay Protocol Four days prior to the assay, 5,000 Chinese hamster ovary cells (CHO-K1, ATCC#CCL-61) stably expressing human somatostatin receptor subtype 2 are placed 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), 100 U / mL penicillin, 100 ug / mL streptomycin, 2 mM L-glutamine (Gemini Bio-Products#400-110), and 0.2 mg / 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) along with 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 minutes 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 a 384-well plate, cAMP detection and visualization antibodies are added, and incubated at room temperature for 1-24 hours. The time-resolved fluorescent signal is read on 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 are in GraphPad Prism v8 (GraphPad, San Diego, CA).

[0334] Example B-2: GnRHR Assay Functional assay for GnRHR General Overview: GnRHR mediates the action of GnRH phopulmones by activating the phosphatidylinositol-calcium second messenger system. q / 11 GnRHR is a receptor-coupled receptor. Activation of GnRHR induces accumulation of inositol monophosphate, a stable metabolite of IP-3, which can be characterized as a measure of agonist activity (increase in IP-one) or antagonist activity (blocking accumulation of IP-One) by the compounds of the present invention. An example of intracellular IP-One assay used to characterize GnRHR antagonists is described below.

[0335] IP-one Assay Protocol 24 hours prior to the assay, 30,000 FlpIn T-Rex293 cells (ThermoFisher #R78007), which stably express functional human GnRH receptors when induced with tetracycline, were placed in 96-well tissue culture-treated plates in FlpIn T-Rex293 growth medium [DMEM (Corning #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 hydrocortisone (Sigma, T7660). Cells were cultured at 37°C, 5% CO2, and 95% humidity. On the day of the assay, the growth medium was discarded and the cells were incubated in 50 μL of a dose-response curve of GnRH (Bachem Biosciences) in the presence of various concentrations of fixative compound [10 mM HEPES (Biopioneer Cat. No. C0113) pH 7.4, 1 mM CaCl2 (Fisher Scientific BP510-100), 0.5 mM MgCl2 (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 Cat. No. BP1600)] in assay buffer. #4033013) and incubated at 37 °C for 1 h (final GnRH concentrations were 0-250 nM, and final compound concentrations ranged from 0-10,000 nM). To lyse the cells, 50 μL of lysis buffer (HRTF IP-one kit, Cisbio) was added on top of the treatment. The lysates were transferred to a 384-well plate, IP-one detection and visualization antibodies were added, and incubated at room temperature for 1-24 h. Time-resolved fluorescent signals were read on a Tecan M1000Pro (Tecan) multiplate reader.Intracellular IP-one concentrations were calculated by regression to the standard curve and plotted relative to the concentration of GnRH agonist in the presence of various concentrations of antagonist, giving the K of the compound. B was calculated using standard curve fitting methods. All data manipulations were performed using GraphPad Prism v8 (GraphPad, San Diego, CA).

[0336] Exemplary biological activities of the compounds are shown in the table below.

[0337] [Table 7-1]

[0338] [Table 7-2]

[0339] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art should be included within the spirit and scope of this application and the appended claims.

Claims

Compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: [Number 1] In the formula: (a) NP is a non-peptide ligand that binds to the gonadotropin-releasing hormone receptor (GnRHR) expressed in tumor cells; (b) a payload portion (Q) containing a chemotherapeutic agent; and (c) a linker (L) that covalently links the non-peptide ligand NP and the payload portion Q, NP has the structure of formula (X), wherein: [Number] In the formula: V is CH or N, W is CH or N; T is absent, -CH₂-, -CH(CH₃)-, or -C(CH₃)₂-; X₂ is absent, -O-, or -N(R₇)-; R₇ is hydrogen, or substituted or unsubstituted C₁-C₆ alkyl, having the structure of formula (X), or a pharmaceutically acceptable salt thereof; When administered to a mammal, the compound of formula (I), or a pharmaceutically acceptable salt thereof, targets tumor cells expressing the GnRHR. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein NP has one of the following structures: [Chemical formula 2] Compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Q contains a chemotherapeutic agent that is a cytotoxic drug, a kinase inhibitor, or both, and L is a non-cleavable linker or a cleavable linker. **Claim 4**: The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the cleavable linker is an acid-sensitive linker, a protease-sensitive linker, or a glutathione-sensitive linker. **Claim 5**: The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Q comprises a cytotoxic drug that is an anti-mitotic agent, a DNA-damaging agent, a transcription inhibitor, or a combination thereof. **Claim 6**: The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Q comprises a cytotoxic drug that is an anti-mitotic agent, and the anti-mitotic agent is a maytansinoid, a taxane, an auristatin, an alkaloid, a tubulysin, or an epothilone. **Claim 7**: The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein Q comprises a kinase inhibitor that is an inhibitor of cytoplasmic tyrosine kinase (CTK), serine / threonine kinase (S / T kinase), lipid kinase (LK), or receptor tyrosine kinase (RTK). **Claim 8**: Q is 【Chemical formula 3-1】 【Chemical formula 3-2】 【Chemical formula 3-3】 and the compound according to claim 3, or a pharmaceutically acceptable salt thereof. **Claim 9**: L is 【Chemical formula 4】 and each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, each X is independently selected from O and NR_X, and each R_X is independently selected from hydrogen, C1-C4 alkyl, and -CH2CO2H, and the compound according to claim 3, or a pharmaceutically acceptable salt thereof. **Claim 10**: L is 【Chemical formula 5】 and The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein each p is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

11. L is 【Chemical Formula 6】 and The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein each X is independently selected from O and NR X, and each R X is independently selected from hydrogen, C 1 -C 4 alkyl, and -CH 2 CO 2 H.

12. L is 【Chemical Formula 7-1】 【Chemical Formula 7-2】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof, which is

13. -L-Q is 【Chemical Formula 8-1】 【Chemical Formula 8-2】 【Chemical Formula 8-3】 【Chemical Formula 8-4】 【Chemical Formula 8-5】 【Chemical Formula 8-6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

14. The compound has one of the following structures: 【Chemical Formula 9-1】 【Chemical Formula 9-2】 【Chemical Formula 9-3】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof, which has one of the pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in mammals.

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