Substituted 2-phenylpiperidine compounds for diagnosis, treatment and / or prevention of cancer

Abstract

The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, and use thereof in the treatment and / or diagnosis of cancers such as neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer and / or rhabdomyoid cancer.

Description

Technical Field

[0001] This disclosure relates to novel substituted 2-phenylpiperidine compounds, methods for their preparation, and their use in the diagnosis, treatment, and / or prevention of cancer. Specifically, this disclosure relates to novel substituted 2-phenylpiperidine compounds, methods for their preparation, and their use in the diagnosis, treatment, and / or prevention of neuroblastoma. Background Technology

[0002] Cancer is a broad term referring to a large group of diseases that can affect any part of the body. A defining characteristic of cancer is the rapid production of abnormal cells that grow beyond their normal boundaries. These cells can invade adjacent parts of the body and spread to other organs; this latter process is called metastasis. Widespread metastasis is a leading cause of cancer death.

[0003] Approximately one in six cancer deaths worldwide is caused by cancer. Currently, it is the second leading cause of death globally, and in countries with high and very high Human Development Indices (HDI), after cardiovascular disease. It is estimated that due to population growth and aging, the global burden will increase to 27.5 million new cancer cases and 16.3 million cancer deaths annually by 2040.

[0004] G protein-coupled receptors (GPCRs) belong to the largest superfamily of integrated cell membrane proteins and play multiple roles in cell signaling. The neurokinin 1 receptor (often abbreviated as NK1R, and also called the tachykinin 1 receptor) belongs to the tachykinin receptor subfamily of GPCRs. Two isoforms of NK1R have been reported: a truncated form (311 amino acids) containing a very short C-terminal sequence and a full-length form (407 amino acids).

[0005] The peptide substance P (SP), widely distributed in both the central and peripheral nervous systems, activates multiple functions upon binding to NK1R. NK1R antagonists are known to have anti-inflammatory, analgesic, anti-anxiety, antidepressant, and antiemetic effects.

[0006] The SP / NK1R system has been found to strongly influence the tumor microenvironment, affecting tumorigenesis-related processes such as mitosis, angiogenesis, cell migration, and metastasis. While NK1R levels typically exhibit limited peripheral expression in normal tissues, they have been shown to be upregulated in various cancer types. Subsequently, SP has been demonstrated to act as a mitogen in a variety of human cancer cell lines via NK1R, including astrocytoma, melanoma, prostate cancer, glioma, retinoblastoma, leukemia, as well as pancreatic cancer, laryngeal cancer, colon cancer, gastric cancer, and breast cancer.

[0007] NK1R inhibitors have demonstrated cancer growth inhibition in numerous in vitro and in vivo models. Therefore, the NK1R / SP system is considered a promising target for cancer diagnosis and treatment, including the concept of selectively imaging and targeting tumor cells overexpressing NK1R.

[0008] NK1R is highly expressed in neuroblastoma (NBL), the most common extracranial solid tumor in children. NBL tumors are characterized by significant biological heterogeneity. While some tumors exhibit highly aggressive and therapy-resistant behavior, others regress spontaneously. To address this diversity, current treatment strategies are specifically guided by pre-treatment risk stratification based on a large number of clinical, histological, molecular, and biological markers. Therefore, the prognosis and treatment of NBL are highly dependent on molecular, genetic, and pathological testing.

[0009] After risk stratification, the range of NBL treatments extends from observation or resection of tumors considered low-risk to intensified multimodal therapy for high-risk tumors, including induction chemotherapy (administered at the start of cancer treatment), surgery, radiation therapy, consolidation therapy (administered after initial treatment to target remaining cancer cells), and immunotherapy.

[0010] Current treatments are not entirely effective, and minimal residual disease (NBL) remains a major treatment challenge in pediatric oncology. Although multimodal therapies can often significantly reduce tumor burden, leading to apparent complete remission of the disease (known as minimal residual disease), survival rates for patients diagnosed with high-risk tumors are only 40-50%, and in addition to frequently suffering from long-term side effects, approximately 50% of patients who complete therapy experience disease relapse.

[0011] Radiopharmaceuticals are drugs that contain radioactive isotopes and are designed to target specific cells, organs, or tissues, and are increasingly used for both the diagnosis and treatment of a variety of cancers.

[0012] Radiopharmaceuticals are administered systemically, and unlike conventional therapies (such as radiation therapy, chemotherapy, and surgery), radiopharmaceuticals bind to specific transmembrane proteins of cancer cells to precisely achieve the desired imaging or therapeutic effect.

[0013] Radiopharmaceuticals are typically developed in a "therapeutic pair," consisting of diagnostic and therapeutic compounds. The diagnostic compound is designed to contain a radioactive isotope capable of imaging, such as positron emission tomography (PET) imaging, while the therapeutic compound is designed to contain a radioactive isotope capable of delivering radiotherapy. Using these complementary therapeutic pairs, clinicians can assess a patient's response before treatment to tailor the subsequent radiation dose to the individual patient.

[0014] Aprepitant (commercially known as EMEND, and also as L-754,030) is an NK1R antagonist primarily used to treat chemotherapy-induced nausea and vomiting, and has shown antitumor activity. However, aprepitant has poor pharmacokinetic characteristics, including low solubility and poor metabolic stability, which diminishes its antitumor potential. Furthermore, aprepitant crosses the blood-brain barrier (BBB), thus increasing the risk of central nervous system (CNS)-related side effects. Radiohalogenation of aprepitant has not been confirmed. Alternatively, it is conjugated with the chelate DOTA (dodecanetetraacetic acid) for radiolabeling of radiometals. The retention properties of DOTA in chelating radiolabeled molecules result in high renal dose and dose-limiting toxicities.

[0015]

[0016] Halik P. et al., Pharmaceutics 2022, 14, 607, disclosed three functionalized DOTA chelators and... 68 Ga and 177 New Lu-labeled aprepitant homologues have shown high affinity and better binding ability to the human NK1 receptor in receptor binding studies than SP derivatives currently used in glioblastoma therapy. This reportedly confirms the hypothesis related to the effectiveness of aprepitant as an NK1R targeting carrier. Furthermore, some reports have reportedly indicated new prospects for using aprepitant and other NK1R antagonists as carriers of selective radiopharmaceuticals for NK1R-positive tumors.

[0017] L-733,060 is an NK1R antagonist that has shown anticancer activity in various in vitro models. (According to EA; Arneric, SP,) Annual Reports in Medicinal Chemistry It was reported in 1998, 33, 11-20, that it overcomes the bioavailability problems usually associated with neurokinin antagonists and is able to cross the BBB.

[0018]

[0019] Tattersall FD et al., Neuropharmacology 1996, 35, 1121-1129, disclosed the pharmacological characteristics of the non-peptide human neurokinin 1 (hNK1) receptor selective antagonist L-741,671, showing that it is brain-penetrating. Brain penetration is reportedly crucial for the antiemetic effect of systemically administered NK1 receptor antagonists.

[0020]

[0021] WO 93 / 04040 A1, WO 94 / 19323 A1, and WO 95 / 20575 A1 disclose a class of nitrogen heterocyclic compounds that can be used as tachykinin (NK1-receptor) antagonists. The compounds disclosed in WO 93 / 04040 A1 and WO 94 / 19323 A1 comprise nitrogen heterocyclic systems partially substituted with arylmethoxy or arylmethylthio groups, while the compounds disclosed in WO 95 / 20575 A1 comprise nitrogen heterocyclic systems partially substituted with aralkylamino groups. Furthermore, the compounds disclosed in WO 94 / 19323 A1 and WO 95 / 20575 A1 are claimed to be useful in the treatment of pain, inflammation, migraines, and vomiting.

[0022] WO 95 / 23798 A1 discloses a substituted heterocyclic compound that is a tachykinin receptor antagonist that can be used to treat inflammatory diseases, pain or migraines, asthma and vomiting.

[0023] Muñoz M. et al., Neuropeptides 2005, 29, 245-254, published an in vitro study investigating the ability of the NK1 receptor antagonist L-733,060 to inhibit cell growth in the SKN-BE(2) neuroblastoma cell line. The study showed that micromolar concentrations of L-733,060 were effective in inhibiting cell line growth. The NK1 receptor was shown to be present in the studied cell line, thus demonstrating that the antitumor effect of L-733,060 occurs through the NK1 receptor. The NK1 receptor is proposed as a novel and promising target for the treatment of human neuroblastoma.

[0024] Rosso M. et al., in *Tumor Biology* 2008, 29, 245-254, published an in vitro study of the growth-inhibiting ability of L-733,060 against human gastric and colonic adenocarcinoma. The study showed that micromolar concentrations of L-733,060 were effective in inhibiting the growth of these cell lines. The presence of multiple NK-1 receptor subtypes was observed in human gastric and colonic adenocarcinoma, thus demonstrating that the antitumor effect of L-733,060 on both human cell lines occurs through the NK1 receptor. The NK1 receptor is proposed as a novel and promising target for the treatment of human gastric and colonic adenocarcinoma.

[0025] The enumeration or discussion of obviously previously disclosed documents in this specification is not necessarily an admission that such documents are part of the prior art or common general knowledge.

[0026] A drawback of current cancer therapies is the limited number of cells that can escape induction and consolidation therapy. These cells are capable of proliferating and / or migrating, leading to metastatic recurrence. Targeted therapies, if administered during induction and consolidation therapy, particularly at the minimal residual disease stage, could have a significant impact on survival.

[0027] Therefore, there is a need for compounds used in the diagnosis, treatment, and / or prevention of cancer. In addition, there is a need for compounds used in the diagnosis, treatment, and / or prevention of neuroblastoma. Summary of the Invention

[0028] One object of this disclosure is to provide a compound for the diagnosis, treatment, and / or prevention of cancer. Further, an object of this disclosure is to provide a compound for the diagnosis, treatment, and / or prevention of neuroblastoma, or a compound that can be converted into a compound for the diagnosis, treatment, and / or prevention of neuroblastoma. Yet another object of this disclosure is to provide aspects and / or advantages not provided by the techniques known to date.

[0029] This disclosure provides a compound of formula I:

[0030] in: R 1 It is H or (CH2). p Z; R 2 It can be H, OH or F; R 3 It is H or C1-C3 alkyl; R 4 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, CN, F, and NO2; R 5 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, CN, F, and NO2; Q is either C or N; X is either O or NH; Y chooses freely 127 I, 123 I, 124 I, 125 I, 131 I and 211 Groups composed of At; Z is a five- or six-membered heterocycle containing one, two, or three nitrogen atoms and / or N-oxides, wherein the heterocycle is formed by 0, 1, 2, or 3 independently selected from F, Cl, Br, I, OH, C1-C3 alkyl, oxo, and (CH2). q NHR 6 Substituents in the group constitute the group; R 6 It is a chelated portion or a radionuclide complex thereof; n is 0 or 1; m is 0 or 1; p is 0, 1, 2 or 3; q is 2, 3, 4, or 5; Substituents and Located in order of precedence relative to each other; The conditions are: n + m = 1; Or its pharmaceutically acceptable salt.

[0031] This disclosure also provides a pharmaceutical composition comprising a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0032] Furthermore, this disclosure also provides compounds of formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for use as medicaments in therapy.

[0033] This disclosure also provides compounds of formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the diagnosis, treatment and / or prevention of cancers selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdomyosarcoma, and any combination thereof.

[0034] This disclosure also provides the use of a compound of formula I as described herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for the diagnosis, treatment, and / or prevention of cancers selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdomyosarcoma, and any combination thereof.

[0035] This disclosure also provides a method for diagnosing, treating, and / or preventing cancers selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdomyosarcoma, and any combination thereof, said method comprising administering to a patient (e.g., a human or animal) an effective amount (e.g., a therapeutically effective amount) of a compound of formula I as described herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0036] This disclosure also provides a method for preparing a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: - Make compound IV:

[0037] in

[0038] R 1 As described herein for compounds of formula I, or a protecting group such as tert-butoxycarbonyl; R 2 R 3 R 4 R 5 X and Q are as described herein for compounds of formula I; and Substituents and Located in order of priority relative to each other Iodization or astatation provides a compound of formula I; and - Optionally, a compound of formula I may be combined with a pharmaceutically acceptable acid.

[0039] This disclosure also provides a compound of formula IV, which is, 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol, or 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one.

[0040] This disclosure also provides compounds of formula V, selected from the group consisting of: (2 S ,3 S 2-Phenylacetic-3-((3-(trifluoromethyl)-5-(trimethyltinyl)benzyl)oxy)piperidine-1-carboxylic acid tert-butyl ester; (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethyltinyl)pyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-carboxylic acid tert-butyl ester; (2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstanyl)pyridin-2-yl)methyl)amino)piperidine-1-carboxylic acid tert-butyl ester; and (2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethyltinyl)benzyl)amino)piperidine-1-carboxylic acid tert-butyl ester. Attached Figure Description

[0041] Figure 1A The UV-HPLC analysis of the compound in Example 1 is shown.

[0042] Figure 1B The radioactive HPLC analysis of the compound in Example 3 is shown.

[0043] Figure 2A The UV HPLC analysis of the compound in Example 2 is shown.

[0044] Figure 2B The radioactive HPLC analysis of the compound in Example 4 is shown.

[0045] Figure 3A The real-time binding curves of the compound in Example 4 with the human NB cell line SK-N-AS and the 1:1 kinetic fit are shown.

[0046] Figure 3B The real-time binding curves of the compound in Example 4 with the human NB cell line SK-N-AS and the 1:2 kinetic fit are shown.

[0047] Figure 3C The real-time binding curves of the compound in Example 4 with the human NB cell line IMR-32 and the 1:1 kinetic fit are shown.

[0048] Figure 3D The real-time binding curves of the compound in Example 4 with the human NB cell line IMR-32 and the 1:2 kinetic fit are shown.

[0049] Figure 4 The real-time binding curves of the compound in Example 4 with human NB cell lines SK-N-AS and IMR-32 are shown.

[0050] Figure 5A The real-time binding curves and 1:1 kinetic fits of the compound in Example 4 with the human colorectal cancer cell line HT55 are shown.

[0051] Figure 5B The real-time binding curves of the compound in Example 4 with the human colorectal cancer cell line HT55 and the 1:2 kinetic fit are shown.

[0052] Figure 6 The cellular uptake concentration of Compound 4 per 100,000 cells is shown for Compound 4 alone (10 nM) and the combination of Compound 4 (10 nM) and aprepitant (1 μM).

[0053] Figure 7A and Figure 7BReal-time binding curves showing the competition between 90 nMFAM-labeled substance P (SP) and subsequent 90 nM compounds on U2OS osteosarcoma cells expressing NK1R (TACR1(NK1) / U2OS cells).

[0054] Figure 8A The amount of compound 49 shown is measured in pmol (i.e., picomoles) per 100,000 NK1R-transfected U2OS cells (U2OS-NK1R) with and without aprepitant pre-blocking of the NK1-receptor.

[0055] Figure 8B The amount of compound 49 shown is measured in pmol (i.e., picomoles) bound per 100,000 untransfected wild-type untransfected U2OS cells.

[0056] Figure 9 The chemical structure of DOTA is shown as 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid.

[0057] Figure 10 The chemical structure of NOA is shown as 2,2',2''-(1,4,7-triazine-1,4,7-triyl)triacetic acid.

[0058] Figure 11 The chemical structure of TETA is shown as 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetramethyl)tetraacetic acid.

[0059] Figure 12 The chemical structure of DTPA is shown, namely diethylenetriaminepentaacetic acid.

[0060] Figure 13 The chemical structure of NODAGA is shown as 2-(4,7-bis(carboxymethyl)-1,4,7-triazine-1-yl)glutaric acid.

[0061] Figure 14 The chemical structure of DOTAGA is shown as 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid.

[0062] Figure 15 The chemical structure of DFO, namely deferoxamine, is shown. Detailed Implementation

[0063] This disclosure provides a compound of formula I:

[0064] in: R1 It is H or (CH2). p Z; R 2 It can be H, OH or F; R 3 It is H or C1-C3 alkyl; R 4 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, CN, F, and NO2; R 5 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, CN, F, and NO2; Q is either C or N; X is either O or NH; Y chooses freely 127 I, 123 I, 124 I, 125 I, 131 I and 211 Groups composed of At; Z is a five- or six-membered heterocycle containing one, two, or three nitrogen atoms and / or N-oxides, wherein the heterocycle is formed by 0, 1, 2, or 3 independently selected from F, Cl, Br, I, OH, C1-C3 alkyl, oxo, and (CH2). q NHR 6 Substituents in the group constitute the group; R 6 It is a chelated portion or a radionuclide complex thereof; n is 0 or 1; m is 0 or 1; p is 0, 1, 2 or 3; q is 2, 3, 4, or 5; Substituents and Located in order of precedence relative to each other; The conditions are: n + m = 1; Or its pharmaceutically acceptable salt.

[0065] The following definitions apply throughout this document.

[0066] The term "C1-C6 alkyl" refers to a straight-chain or branched saturated alkyl group with one to six carbon atoms. Examples of "C1-C6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0067] The term "OC1-C6" refers to C1-C6 alkyl groups bonded to an oxygen atom. Examples of "OC1-C6" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, 2,3-dimethylbutoxy, as well as neohexyloxy and n-hexyloxy.

[0068] The term "C1-C3 alkyl" refers to a straight-chain or branched, saturated or unsaturated alkyl group with one to three carbon atoms. Examples of "C1-C3 alkyl" include, but are not limited to, methyl, ethyl, vinyl, allyl, n-propyl, and isopropyl.

[0069] The term "5-membered heterocycle" refers to a 5-membered saturated or unsaturated heterocycle. Examples of 5-membered heterocycles include, but are not limited to, pyrrolidine, tetrahydrofuran, thiocyclopentane, pyrrole, furan, thiophene, imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazolidine, dioxopentane, dithiopentane, imidazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole.

[0070] The term "6-membered heterocycle" refers to a 6-membered saturated or unsaturated heterocycle. Examples of 6-membered heterocycles include, but are not limited to, piperidine, pyridine, piperazine, morpholine, and thiomorpholine.

[0071] The Q substituent in a compound of formula I can be located at the ortho, meta, or para position. For example, the Q substituent can be located at the meta position to provide the compound: Examples of compounds of formula I with Q at the para position include compounds of formulas Ia and Ib1 described herein.

[0072] Compounds of Formula I, as described herein, or pharmaceutically acceptable salts thereof, are also provided, further provided that when R 2 When H is used, then m is 1.

[0073] The compounds disclosed herein, such as compound I, have piperidine rings at carbons 2 and 3. S Configuration. Alternatively, the compounds disclosed herein, such as those of formula I, may have configuration at carbons 2 and 3. R Configuration. This is illustrated for compounds of formula I provided as compounds of formula I' and / or formula I'': .

[0074] For example, a compound of formula I can be a compound of formula I'. In yet another example, a compound of formula I is provided as a compound of formula I''. In still another example, a mixture is provided, such as a 1:1 mixture of a compound of formula I' and a compound of formula I''.

[0075] Q can be C, i.e., carbon, thus providing compounds of formula Ia: .

[0076] Alternatively, Q can be N, i.e., nitrogen, thus providing compounds of formula Ib: .

[0077] It should be understood that compounds of formula Ib can be provided as compounds of formula Ib1, Ib2, or Ib3: .

[0078] The value of n can be 1. Therefore, a compound of formula I, as described herein, where n is 1, is provided and can be named formula II: .

[0079] Examples of compounds of formula II include compounds of formula IIa (where Q is carbon), and compounds of formula IIb, IIc and / or IId (where Q is nitrogen).

[0080]

[0081] In one instance, a compound of formula IIa includes a compound of formula IIa1: .

[0082] Furthermore, the value of m can be 1. Therefore, a compound of formula I as described herein, where m is 1, is provided and can be named formula III: .

[0083] Examples of compounds of formula III include compounds of formula IIIa (where Q is carbon), and compounds of formula IIIb, IIIc and / or IIId (where Q is nitrogen).

[0084]

[0085] Substituent R 1 It can be H. Alternatively, R 1 It can be (CH2) p Z can be selected from the following groups: and .

[0086] For example, Z can be .

[0087] Alternatively, Z can be

[0088] in

[0089] R 6 It is a chelated portion or a radionuclide complex thereof; and

[0090] q is 2, 3, 4, or 5. It should be understood that R... 6 Via the linker NH(CH2) q Linked with substituted triazole compounds.

[0091] The chelating moiety may include a cyclic (e.g., macrocyclic) chelating agent or an acyclic chelating agent containing one or more heteroatoms, such as oxygen or nitrogen atoms, which can coordinate and / or capture radionuclides. Further, the chelating moiety R... 6 It may contain the linker group NH(CH2). q The nitrogen atom forms an amide bond in the carboxylic acid group. For example, R 6 It may contain one or more of the following chelating moieties: DOTA, NOTA, TETA, DTPA, NODAGA, DOTAGA, DFO, or derivatives of any of the aforementioned chelating moieties. The chemical structure of the aforementioned compound is described in [description of chemical structure]. Figures 9 to 15 For example, R 6 The chelate portion can be selected from the following groups: and .

[0092] In yet another instance, R 6 It is a chelate portion containing or consisting of the following: .

[0093] The value of p can be 0, 1, 2, or 3. For example, p can be 1.

[0094] The value of q can be 2, 3, 4, or 5. For example, q can be 4.

[0095] Furthermore, R 6 It can be a radionuclide complex with a chelated portion. The radionuclide complex may contain both a chelated portion and a radionuclide, or may consist of both. This could further enhance the diagnostic, therapeutic, or preventative efficacy of compounds of formula I.

[0096] The radionuclide and chelate moiety of the radionuclide complex can be provided in a 1:1 ratio. The radionuclide can be any radionuclide suitable for the intended purpose. For example, the radionuclide can be freely selected. 68 Ga、 18 F, 64 Cu、 44 Sc、 89Zr、 111 In、 67 Ga、 99m Tc, Gd, 177 Lu、 86 / 90 Y、 225 Ac、 161 / 165 Tb, 226 / 227 The group consisting of Th and its ions. Specifically, a radionuclide can be an ion that can coordinate with a heteroatom, such as a nitrogen or oxygen atom, in the chelating motif, such as a positive ion. In one instance, the radionuclide contains... 177 Lu, as 177 Lu 3+ Or it may be composed of.

[0097] In one instance, R 6 Includes DOTA and 177 Lu 3+ To provide: .

[0098] It should be understood that, for R 6 The choice of radionuclide for a radionuclide complex will depend on the intended use, such as the imaging method used for diagnosis, treatment, and / or prevention. For example, when positron emission tomography (PET) is the imaging method, the radionuclide can be selected freely... 68 Ga、 18 F, 64 Cu、 44 Sc、 89 Zr and 86 / 90 The group consists of Y. In another example, when single-photon emission computed tomography (SPECT) is the imaging method, the radionuclide can be selected from, for example... 111 In、 67 Ga、 99m Tc and 177 The group consists of Lu. Furthermore, the radionuclides used for treatment can be selected from, for example... 177 Lu、 161 Tb and 225 The group consisting of Ac.

[0099] Substituent R 1 You can choose from the following groups: and .

[0100] For example, R 1 The substituent can be H or .

[0101] In one instance, a compound of formula I is provided, where X is O and / or R. 2 It is OH, and / or R 3 H is a constant, and / or p is 1.

[0102] R 2 The substituent can be H or OH. In one example, R 2 For H. In yet another instance, R 2 It is OH.

[0103] R 3 The substituent can be H or CH3. For example, R 3 It can be H.

[0104] R 4 and R 5 The substituents can be independently selected from the group consisting of H, CF3, OC1-C6 alkyl groups such as OCH3 or OCH(CH3)2, OCF3, F, NO2, and CN. Alternatively, R 4 The group consisting of free CF3, OC1-C6 alkyl groups such as OCH3 or OCH(CH3), OCF3, F, NO2, and CN, and R 5 The group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, and CN can be selected.

[0105] R 4 and R 5 The substituents can both be CF3. Alternatively, R 4 and R 5 Substituents can both be CN.

[0106] Furthermore, Y may include one or more of the following, or be composed of one or more of the following: 123 I, 124 I, 125 I. Alternatively, Y may contain 131 I may be composed of or composed of it. In yet another instance, Y may be a stable isotope. 127 I. In yet another instance, Y may contain 211 At or composed of.

[0107] A compound of formula I is also provided, which is one or more of the following: 4-((±)- Shun -3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol; 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol; 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol; 5-(((±)- Shun -3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 4-((±)- Shun -3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 4-((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 5-(((±)- Shun -3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; ( 2S, 3S )-3-((3-iodo-5-(trifluoromethyl)benzyl)oxy)-2-phenylpiperidine; 5-((( 2S, 3S )-3-((3-iodo-5-(trifluoromethyl)benzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-4,5-dihydro-3 H -1,2,4-triazol-3-one; ( 2S, 3S )-3-((3-iodobenzyl)oxy)-2-phenylpiperidine; 3-((( 2S, 3S )-3-((3-iodobenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-1H-1,2,4-triazol-5(4H)-one; 5-Iodo-2-methoxy-3-((((2S,3S)-2-phenylpiperidin-3-yl)oxy)methyl)pyridine; 3-((( 2S, 3S )-3-((5-iodo-2-methoxypyridin-3-yl)methoxy)-2-phenylpiperidin-1-yl)methyl)-1H-1,2,4-triazol-5(4H)-one; ( 2S, 3S )-N-(3-iodobenzyl)-2-phenylpiperidin-3-amine; ( 2S, 3S )-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine; ( 2S, 3S )-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine; ( 2S, 3S )-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; ( 2S, 3S )-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; or A pharmaceutically acceptable salt of any of the aforementioned compounds.

[0108] Furthermore, a compound of formula I is provided, which is one or more of the following: 4-((±)- Shun -3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol; 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol; 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol; or ( 2S, 3S )-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine; or The iodine radioisotope of any of the aforementioned compounds, wherein iodine is a radioisotope of any of the aforementioned compounds, or a pharmaceutically acceptable salt of any of the aforementioned compounds or a radioisotope of its iodine.

[0109] A compound of formula I is also provided, which is one or more of the following: 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 4-((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; (2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4-dihydro-1,2,4-triazol-5-one; (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4-dihydro-1,2,4-triazol-5-one; 5-Iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidinyl)oxymethyl)pyridine; 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4-dihydro-1,2,4-triazol-5-one; (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-iodophenyl)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((4-iodobenzyl)oxy)-2-phenylpiperidine; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-N-((5-iodopyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)piperidine-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-(3-iodo-5-(trifluoromethyl)benzyl)piperidine-3-amine; (2S,3S)-N-((R)-1-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine; 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-1-((6-methylpyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-1-(pyridin-2-ylmethyl)piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-1-(pyrimidin-2-ylmethyl)piperidin-3-amine; 2-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-yl)methyl)pyrimidine 1-oxide; 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-1-((1H-imidazol-2-yl)methyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-1-yl)methyl)pyrimidine 1-oxide; (2S,3S)-3-((3-( 125 I) Iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenylpiperidine; (2S,3S)-N-((5-( 125 I) Iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-(5-( 125 I) Iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-((4-( 125 I) Iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; [ 177 Lu]-lutetium(III)--2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; or A pharmaceutically acceptable salt of any of the aforementioned compounds.

[0110] Furthermore, a compound of formula I is provided, which is one or more of the following: 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 4-((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; (2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4-dihydro-1,2,4-triazol-5-one; (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4-dihydro-1,2,4-triazol-5-one; (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-iodophenyl)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((4-iodobenzyl)oxy)-2-phenylpiperidine; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-(3-iodo-5-(trifluoromethyl)benzyl)piperidine-3-amine; (2S,3S)-N-((R)-1-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine; 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-1-yl)methyl)pyrimidine 1-oxide; (2S,3S)-3-((3-( 125I) Iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenylpiperidine; (2S,3S)-N-(5-( 125 I) Iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidine-3-amine; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; [ 177 Lu]-lutetium(III)--2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; or A pharmaceutically acceptable salt of any of the aforementioned compounds.

[0111] A compound of formula I is further provided, which is one or more of the following: 5-Iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidinyl)oxymethyl)pyridine; 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4-dihydro-1,2,4-triazol-5-one; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodopyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)piperidine-3-amine; 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-1-((6-methylpyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-1-(pyridin-2-ylmethyl)piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-1-(pyrimidin-2-ylmethyl)piperidin-3-amine; 2-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-yl)methyl)pyrimidine 1-oxide; (2S,3S)-1-((1H-imidazol-2-yl)methyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-( 125 I) Iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-((4-( 125 I) Iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; or A pharmaceutically acceptable salt of any of the aforementioned compounds.

[0112] Furthermore, a compound of formula I is provided, which is one or more of the following: (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)piperidine-3-amine; 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-N-((5-( 125 I) Iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidine-3-amine; (2S,3S)-N-((4-( 125 I) Iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; or A pharmaceutically acceptable salt of any of the aforementioned compounds.

[0113] Surprisingly, the disclosed compounds have been found to bind to NK1R, the neurokinin 1 receptor, which is associated with and overexpressed in many cancers such as neuroblastoma. Therefore, the presence of a large iodine atom in the compound does not impede interaction with NK1R. This is a significant benefit because iodine can be provided in the compound as different isotopes, allowing for diverse therapeutic uses. For example, some isotopes can be used for diagnostic purposes, such as diagnostic imaging, while others can be used in combination with therapeutics. Thus, depending on the desired use, the same compound can be labeled with different isotopes to provide a therapeutic pair consisting of both diagnostic and therapeutic compounds.

[0114] Furthermore, the compounds disclosed herein have been found to bind specifically to NK1R. This is important for ensuring the specific enrichment of the compounds at one or more intended treatment sites, and for minimizing associated side effects by avoiding nonspecific uptake in healthy tissues / organs (i.e., tissues and / or organs not intended to be targeted by the treatment).

[0115] A pharmaceutical composition is also provided comprising a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0116] The pharmaceutical composition may be a pharmaceutical composition for intravenous administration. For example, a pharmaceutical composition for intravenous administration may be a solution containing a compound of formula I or a pharmaceutically acceptable salt thereof, such as an aqueous solution.

[0117] In yet another example, the pharmaceutical composition may be an oral pharmaceutical composition. Specifically, the oral pharmaceutical composition may comprise a compound of formula I, wherein Y comprises... 127 I or 125I, or components thereof. For example, oral pharmaceutical compositions may be provided as liquids, such as syrups, suspensions, or solutions. Alternatively, oral pharmaceutical compositions may be provided as solids, such as tablets, capsules, or lozenges.

[0118] Furthermore, compounds of Formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, are provided for use as medicines in therapy.

[0119] Also provided are compounds of Formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the diagnosis, treatment and / or prevention of cancer.

[0120] This disclosure also provides the use of compounds of Formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of medicaments for the diagnosis, treatment, and / or prevention of cancer.

[0121] Furthermore, this disclosure provides methods for diagnosing, treating, and / or preventing cancer, the methods comprising administering to a patient (e.g., a human or animal) an effective amount (e.g., a therapeutically effective amount) of a compound of formula I as described herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0122] As used herein, the term "therapeutic effective amount" refers to the amount of compound that imparts a therapeutic effect to the treated patient. The effect can be objective (i.e., measurable by some test or biomarker) or subjective (i.e., the subject gives indications of the effect and / or feels the effect).

[0123] The cancers described in this article can be selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdomyosarcoma, and any combination thereof. For example, cancer can be neuroblastoma.

[0124] As used herein, the term "treatment" (and similar "treating") takes its conventional usage in the medical field. Specifically, the term may refer to the severity of one or more clinical symptoms of a disease or condition. Further, the term "prevention" (and similar "preventing") may refer to achieving a reduction in the likelihood of a patient (or healthy subject) developing a disease or condition (e.g., a reduction of at least 10%, such as a reduction of at least 20%, 30%, or 40%, such as a reduction of at least 50%).

[0125] Compounds of Formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, may be administered to specific patient populations, such as children up to 14 years of age, or patients older than 14 or 15 years, such as adults. In particular, the diagnosis, treatment, and / or prevention of neuroblastoma may involve administration to children.

[0126] It should be understood that the compounds disclosed herein may contain iodine radionuclides selected from the following: 123 I, 124 I, 125 I or 131 I is used as a marker to allow for the diagnosis, treatment, and / or prevention of one or more cancers as described herein. For example, a radionuclide could be... 125 I.

[0127] The choice of iodine radionuclide determines whether a compound or its pharmaceutically acceptable salt is used for diagnosis or treatment, making diagnostic and therapeutic compounds differ only in the choice of iodine radionuclide. Therefore, the same compound can be labeled with different radionuclides to provide a therapeutic pair consisting of both diagnostic and therapeutic compounds.

[0128] For example, the iodine radionuclide in Formula I compounds may be permitted for diagnostic use. For instance, the iodine radionuclide may be a positron-emitting radionuclide such as... 124 I, or radioactive nuclides that can be detected by a gamma camera, such as 123 I, 125 I or 131 I. In this way, the compound can be used as a diagnostic tool, a radiotracer, a monitoring agent, or for in vivo receptor imaging.

[0129] In yet another example, the iodine radioactive isotope in the compound of formula I can be... 131 I. Permitted for use in radiation therapy. Treatment may include induction therapy, consolidation therapy, and / or minimal residual disease treatment. The therapeutic compound may be administered during induction therapy (i.e., treatment during the initial stages of cancer). In another example, the therapeutic compound may be administered during consolidation therapy (i.e., therapy used after initial treatment to target remaining cancer cells). In yet another example, the therapeutic compound may be administered to address minimal residual disease, which kills the small number of cancer cells remaining in the body after cancer treatment.

[0130] The physical methods that can be used in conjunction with this disclosure may be selected from positron emission tomography (PET), single-photon imaging computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed axial X-ray tomography (CAT), or combinations thereof.

[0131] The compounds disclosed herein may contain stable iodine isotopes, either as a substitute for or in addition to iodine radionuclides. 127 Therefore, Y in compound I can contain... 127 I or is composed of it. It is believed to contain stable iodine isotopes. 127 The compounds disclosed herein can be used, for example, to prevent diseases as described herein.

[0132] Compounds of Formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, may be provided in a diagnostically effective amount (i.e., an amount that allows the desired diagnostic effect to be achieved). For example, the diagnostically effective amount may be adjusted to enable imaging. Furthermore, it should be understood that the diagnostically effective amount may be adjusted according to the route of administration, such as intravenous or oral administration.

[0133] Compounds of Formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, may be provided in a therapeutically effective amount (i.e., an amount that allows the desired therapeutic effect to be achieved). The effect may be objective (i.e., measurable by some test or biomarker) or subjective (i.e., indicated and / or felt by the subject). For example, a therapeutically effective amount may be adjusted to provide radiotherapy. Furthermore, it should be understood that a therapeutically effective amount may be adjusted depending on the route of administration, such as intravenous or oral administration.

[0134] Furthermore, compounds of formula I, such as those of formula I or pharmaceutically acceptable salts or pharmaceutical compositions thereof, may be administered at a frequency appropriate to achieve the desired diagnostic or therapeutic effect.

[0135] For example, compounds of formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, may be administered daily, such as once daily. Furthermore, compounds of formula I as described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, may be administered for a suitable period of time, such as a time sufficient to cure cancer, such as neuroblastoma.

[0136] This disclosure also provides compounds of formula IV, which are compounds of formula I where both n and m are 0. Further, the R1 substituent may include a tert-butoxycarbonyl (BOC) group.

[0137] Compounds of formula IV can be used to prepare compounds of formula I. Alternatively or additionally, compounds of formula IV can be used as pharmaceutical ingredients in therapies. For example, compounds of formula IV can be used to diagnose, treat, and / or prevent cancer, as described herein with respect to compounds of formula I.

[0138] Therefore, compounds of formula IV are provided:

[0139] in

[0140] R1 As described herein for compounds of formula IV, or with protecting groups such as tert-butoxycarbonyl, and

[0141] R 2 R 3 R 4 R 5 X, Q, p, and q are as described for compound I.

[0142] For example, compounds of formula IV are provided, wherein

[0143] R 1 It is H or (CH2). p Z; R 2 It can be H, OH or F; R 3 It is H or C1-C3 alkyl; R 4 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, CN, F, and NO2; R 5 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, CN, F, and NO2; Q is either C or N; X is either O or NH; Z is a five- or six-membered heterocycle containing one, two, or three nitrogen atoms and / or N-oxides, wherein the heterocycle is formed by 0, 1, 2, or 3 independently selected from F, Cl, Br, I, OH, C1-C3 alkyl, oxo, and (CH2). q NHR 6 Substituents in the group constitute the group; p is 0, 1, 2 or 3; R 6 It is a chelated portion or a radionuclide complex thereof; q is 2, 3, 4, or 5; Substituents and They are in order of precedence relative to each other.

[0144] Furthermore, it should be understood that the piperidine ring of compound IV may have [missing information] at carbons 2 and 3. S Configuration, or having at carbons 2 and 3 R Configuration.

[0145] Examples of compounds of formula IV include compounds of formula IVa (where Q is carbon), and compounds of formula IVb, IVc and / or IVd (where Q is nitrogen).

[0146] .

[0147] In one example, a compound of formula IV is provided, wherein R 2 For OH: like .

[0148] In yet another example, a compound of formula IV is provided, which is 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol or

[0149] 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one.

[0150] In yet another example, a compound of formula IV as described herein is provided, wherein Z is (CH2). q NHR 6 replace.

[0151] For example, Z could be .

[0152] combination

[0153] Compounds of Formula I or pharmaceutically acceptable salts thereof may be administered alone or in combination with other drugs for the treatment of cancer. Therefore, combinations of compounds of Formula I or pharmaceutically acceptable salts thereof with drugs for the treatment of cancer are provided. This combination may be a single composition in which a compound of Formula I or a pharmaceutically acceptable salt thereof is mixed together with other drugs for the treatment of cancer. Alternatively, this combination may be provided as a multi-part kit comprising (i) a compound of Formula I and / or a pharmaceutically acceptable salt thereof, and / or (iii) other drugs for the treatment of cancer and (iii) optional instructions for use.

[0154] Salt

[0155] The compounds of Formula I disclosed herein can be provided as pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds disclosed herein may be, for example, acid addition salts.

[0156] Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic inorganic and organic acid addition salts, such as hydrochlorides, hydrobroms, borates, nitrates, perchlorates, phosphates, sulfates, formates, acetates, aconitates, ascorbic acid salts, benzenesulfonates, benzoates, cinnamates, citrates, embolates, heptanoates, fumarates, glutamates, glycolates, lactates, maleates, malonates, mandelates, methanesulfonates, naphthalene-2-sulfonates, phthalates, propionates, salicylates, sorbates, stearates, succinates, tartrates, toluene-p-sulfonates, and any combination thereof. Such salts can be formed by procedures well known and described in the art.

[0157] It should be understood that proton transfer can occur between the compound of formula I described herein and an acid, together forming a salt. Proton transfer can occur to varying degrees.

[0158] Stereoisomers

[0159] It should be understood that the compounds described herein are chiral. In particular, compounds of formula I exhibit chirality. Shun Stereochemistry, where both phenyl substituents are located relative to each other. Shun The positions are shown in the chemical structures illustrated herein. It should be understood that compounds of formula I can be provided as a single enantiomer or as a mixture of enantiomers, such as a racemic mixture.

[0160] For example, the compounds described herein can be used as ( S , S Enantiomers are provided. Alternatively, the compound can be used as ( R, R Enantiomers or mixtures, such as ( S , S Enantiomers and ( R,R The racemic mixture of enantiomers is provided.

[0161] To avoid any doubt, a compound that is said to have a specific stereochemistry at a defined position may also have stereochemistry at one or more other positions, and thus may exist as a mixture of enantiomers or diastereomers associated with the stereochemistry at those positions.

[0162] solvates or hydrates

[0163] It should be understood that the Formula I compounds described herein may be provided as solvates or as solvates of pharmaceutically acceptable salts of Formula I compounds. It should be understood that this disclosure covers all such solvates or hydrates.

[0164] Eutectic

[0165] In salts, proton transfer can occur between the active pharmaceutical ingredient and the counterion of the salt. However, in some cases, there is no or only partial proton transfer, and therefore the solid is not a true salt. It is generally accepted that proton transfer is actually a continuous process and can vary with temperature, and therefore the point at which a salt is better described as a “eutectic” may be subjective. As used herein, the term “eutectic” refers to a multicomponent system in which one or more host molecules (active pharmaceutical ingredient) and one or more guest (or co-formed) molecules are present. Guest or co-formed molecules are defined as existing as solids at room temperature to distinguish eutectics from solvates. However, eutectics can themselves form solvates. In eutectics, interactions are generally dominated by nonionic forces such as hydrogen bonding. It should be understood that all eutectics are included within the scope of the compounds described herein.

[0166] Polymorphs

[0167] The compounds disclosed herein can exist as solid continuums ranging from completely amorphous to completely crystalline. Therefore, it should be understood that all polymorphs, such as mixtures of different polymorphs, are included within the scope of the claimed compounds.

[0168] prodrug

[0169] The compounds disclosed herein can be administered in the form of prodrugs. A prodrug is a compound that may have little or no pharmacological activity on its own, but when such a compound is administered to a patient or onto the body, it is converted into a compound of formula I.

[0170] Preparation method

[0171] This disclosure provides a method for preparing compounds of formula I as described herein, compounds of formula II and / or formula III, or pharmaceutically acceptable salts thereof, the method comprising the following steps: - Make compound IV:

[0172] in

[0173] R 1 As described herein for compounds of formula I, or a protecting group such as tert-butoxycarbonyl; R 2 R 3 R 4 R 5 X and Q are as described herein for compounds of formula I; and the substituents... and Located relative to each other Shun The site undergoes iodination or astatylation to provide a compound of formula I; and - Optionally, a compound of formula I may be combined with a pharmaceutically acceptable acid.

[0174] In one instance, the compound of formula IV in the method described herein is 4-((2) S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol or

[0175] 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one.

[0176] The iodination or astatinization method may include the following steps: a) Use 127 I iodide form IV compound to provide where Y is 127 Compounds of formula I; b) Replace with boron- or metal-containing compounds, such as Sn(CH3)3 127 I provides compound of formula V:

[0177] in

[0178] R 1 R 2 R 3 R 4 R 5 X and Q are as defined for compounds of formula IV. M is a compound containing boron or metal; n is 0 or 1; m is 0 or 1; and Substituents and Located relative to each other Shun The condition is: n + m = 1; and c) Using iodine radioisotopes as described herein or 211 At is substituted with boron-containing or metal-containing compounds M to prepare compounds in which Y is a radioactive iodine isotope as described herein or 211 Compounds of formula I of At.

[0179] Examples of compounds of formula V include compounds of formula Va (where Q is carbon), and compounds of formula Vb1, formula Vb2 and / or formula Vb3 (where Q is nitrogen).

[0180]

[0181] In particular, compounds of formula V selected from the group consisting of the following are provided: (2 S ,3 S 2-Phenylacetic-3-((3-(trifluoromethyl)-5-(trimethyltinyl)benzyl)oxy)piperidine-1-carboxylic acid tert-butyl ester; (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethyltinyl)pyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-carboxylic acid tert-butyl ester; (2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstanyl)pyridin-2-yl)methyl)amino)piperidine-1-carboxylic acid tert-butyl ester; and (2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethyltinyl)benzyl)amino)piperidine-1-carboxylic acid tert-butyl ester. It should be understood that the aforementioned compound V can be used in the methods described herein.

[0182] Alternatively, the iodination of this method may include subjecting a compound of formula IV to YCl, where Y is a radioactive isotope of iodine as described herein. YCl may be iodine monochloride prepared by: N -chlorine- right Toluenesulfonamide or N -Chlorosuccinimide, and Na+ 123 I, Na 124 I, Na 125 I and Na 131 Sodium iodide salts in group I.

[0183] Specifically, R 2 Compounds of formula IV with an OH substituent can undergo (i) iodination, such as iodination involving stable iodine or radioactive nuclides of iodine, or (ii) astatinization, such as iodination involving... 211 astatification of At.

[0184] The preparation of the compounds disclosed herein is further illustrated below with examples.

[0185] Iodination can be performed to prepare a solution where Y is... 127 Compounds of formula II or III, optionally subsequently radiolabeled with a radioactive isotope of iodine via an exchange reaction. For example, compounds of formula II or III... 127 I can be replaced by a (substituted) metal- or boron-containing compound M to provide an intermediate, which is then radiolabeled with an iodine radioisotope. This is illustrated in Scheme 1 for enantiomers of compounds of formulas II and III, respectively, where Q is located at the meta position:

[0186] It should be understood that, in Scheme 1 and the other schemes in this document, unless otherwise stated, R 1 R 2 R 3 R 4 R 5 Q and X can be as described in this article, I The iodine radioisotope can be as described herein, and M can be trialkyltinyl, trialkylsilyl, B(OH)₂, BF₃, or B(Oalkyl)₂. The starting materials for the compounds in Scheme 1 can be prepared as described herein and / or using methods described in the art.

[0187] In yet another example, the iodination of compounds as described herein, such as compounds of formula IV, can be performed using chloramine-T or in the presence of a solvent, such as PBS. N 2-Chlorosuccinimide (NCS) and a salt containing a radioactive isotope of iodine are used. Iodine monochloride is believed to be generated in this manner, acting as an iodizing agent. Chloramine T (which can be abbreviated as CAT) is... N- chlorine- right Toluenesulfonamide, and can be purchased or made by... right Toluenesulfonamide is prepared by reacting it with sodium hypochlorite. The salt containing the iodine radionuclide can be a sodium iodide salt with appropriately isotopically labeled iodide ions. For example, the radioiodination of compound IV can be carried out using chloramine T and a solution of iodine-125 radionuclide containing PBS at pH 7.4. The iodine-125 radionuclide solution may contain iodine-125 radionuclide and aqueous sodium hydroxide (e.g., at a concentration of 0.1 N) or be composed thereof. Further, the iodine-125 radionuclide solution may be free of reducing agents and / or have a pH of 12 to 14. Scheme 2A illustrates the use of chloramine T and Na[ 125 I] For compounds of formula IV (where Q is in the meta position and R) 1 As described herein, but not hydrogen, the enantiomer is iodinated to provide a compound of formula I (where Q is at the meta position and Y is...). 125 I, and R 1 As described in this article).

[0188]

[0189] Scheme 2B shows that it contains 127 Compounds of I (where R) 1 for Uncle Butoxycarbonyl carbonyl group (Boc) is converted into... 125 I-labeled compounds of this disclosure (wherein R) 1 (For hydrogen).

[0190]

[0191] The compounds disclosed herein, such as those of formulas I, II, III, or IV, can be prepared using methods known in the art and / or as described herein. For example, a compound of formula III wherein Q is in the meta position can be prepared as shown in embodiment 3. Further, a compound of formula IV wherein Q is in the meta position can be prepared as shown in embodiment 4. Embodiment 5A further illustrates a method for preparing the compounds of this disclosure.

[0192]

[0193] The starting compound in Scheme 5A can be prepared as shown in Scheme 5B.

[0194]

[0195] Scheme 6 illustrates the synthesis of the compound of this disclosure in which X is nitrogen.

[0196]

[0197] Scheme 7 illustrates a method for preparing the compound disclosed herein (where X is nitrogen and R is nitrogen). 2 It can be used for the synthesis of compounds containing fluorine.

[0198]

[0199] In this document, unless otherwise stated, the diagrams and / or names of chemical compounds were created using the software packages ChemDraw Ultra 12.0, ChemDraw 21.0.28, or ChemDraw 22.2.0. In some cases, the chemical names used are those commonly used in the art. If the diagrams do not match the names, the diagrams of the chemical structures should be considered correct. Furthermore, the names of isotopically substituted compounds are formed by inserting the nuclide symbol in parentheses before the isotopically substituted portion of the compound's name.

[0200] This disclosure also provides the following aspects.

[0201] Aspect 1

[0202] A compound of formula I:

[0203] in: R 1 It is H or (CH2). p Z; R2 It can be H, OH or F; R 3 It is H or C1-C3 alkyl; R 4 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, and CN; R 5 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, and CN; Q is either C or N; X is either O or NH; Y chooses freely 127 I, 123 I, 124 I, 125 I and 131 The group consisting of I; Z is a five- or six-membered heterocycle containing 1, 2, or 3 nitrogen atoms, said heterocycle being substituted by 0, 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, C1-C3 alkyl and oxo groups; n is 0 or 1; m is 0 or 1; p is 0, 1, 2 or 3; Substituents and Located relative to each other Shun The condition is: n + m = 1 or n + m = 0; and When R 2 When m is 1, then m is 1. Or its pharmaceutically acceptable salt.

[0204] Aspect 2

[0205] According to aspect 1, the compound or a pharmaceutically acceptable salt thereof, wherein

[0206] R 4 Select from the group consisting of CF3, OC1-C6 alkyl groups, OCF3, and CN; R 5 Choose from the group consisting of H, CF3, OC1-C6 alkyl groups, OCF3, and CN; n + m = 1 or n + m = 0; and When n = 0, then R 2 It is OH.

[0207] Aspect 3

[0208] The compound or a pharmaceutically acceptable salt thereof as described in aspect 1 or 2 is a compound of formula I' and / or formula I'': .

[0209] Aspect 4

[0210] The compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 3, wherein: Q is C.

[0211] Aspect 5

[0212] The compound according to any one of aspects 1 to 4, wherein: n + m = 1; Thus, compounds of formula IIa or IIb are provided:

[0213] Or its pharmaceutically acceptable salt.

[0214] Aspect 6

[0215] According to aspect 5, the compound of formula IIa is a compound of formula IIa1:

[0216] Or its pharmaceutically acceptable salt.

[0217] Aspect 7

[0218] According to any one of aspects 1 to 4, the compound of formula I, wherein

[0219] n + m = 0; and

[0220] R 2 It is OH; Thus, compounds of formula III are provided:

[0221] Or its pharmaceutically acceptable salt.

[0222] Aspect 8

[0223] According to aspect 7, the compound of formula III is a compound of formula IIIa:

[0224] Or its pharmaceutically acceptable salt.

[0225] Aspect 9

[0226] The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing aspects, wherein: R 1 For H; or .

[0227] Aspect 10

[0228] The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing aspects, wherein: X is O; R 2 It is OH; R 3 For H; and p is 1.

[0229] Aspect 11

[0230] The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing aspects, wherein: R 4 and R 5 All are CF3; or R 4 and R 5 All are CN.

[0231] Aspect 12

[0232] The compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 6 or 9 to 11, wherein Y comprises or is composed of the following: (i) 123 I, 124 I and / or 125 I; or (ii) 131 I.

[0233] Aspect 13

[0234] The compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 6 or 9 to 11, wherein Y comprises 127 I or by 127 I is composed of.

[0235] Aspect 14

[0236] A pharmaceutical composition comprising a compound according to any one of the foregoing aspects or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, diluent or carrier.

[0237] Aspect 15

[0238] The compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 13, or

[0239] The pharmaceutical composition according to aspect 14 It is used as a drug in therapy.

[0240] Aspect 16

[0241] The compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 13, or

[0242] The pharmaceutical composition according to aspect 14 It is used to treat and / or prevent cancers selected from the group consisting of neuroblastoma, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdomyosarcoma, and any combination thereof.

[0243] Aspect 17

[0244] The compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 12, or

[0245] When subordinate to aspect 12, the pharmaceutical composition according to aspect 14 is used for the diagnosis of cancers selected from the group consisting of neuroblastoma, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdomyosarcoma, and any combination thereof.

[0246] Aspect 18

[0247] The compound or pharmaceutical composition used according to aspect 16 or 17, wherein the cancer comprises or is composed of neuroblastoma.

[0248] Further aspects

[0249] This disclosure also provides compounds of formula I as described herein, or pharmaceutically acceptable salts thereof, wherein m + 1 = 0. Therefore, compounds of formula IV as described herein, or pharmaceutically acceptable salts thereof, are provided.

[0250] This disclosure will be further described with reference to the following examples, but these examples are not intended to limit the scope of this disclosure.

[0251] Example

[0252] Basic Information

[0253] Human neuroblastoma cell lines SKNAS and IMR-32 were obtained from the American Type Culture Collection (Manassas, VA, USA). IMR-32 cells were cultured in MEM Earle medium (Biochrom, Berlin, Germany or Sigma-Aldrich, Darmstadt, Germany), while SKNAS cells were cultured in DMEM (Dulbecco modified Eagle medium). The medium was supplemented with 10% (SKNAS) and / or 20% (IMR-32) fetal bovine serum (Sigma-Aldrich, Darmstadt, Germany), 1% antibiotics (100 IU penicillin and 100 µg / mL streptomycin), and 1% L-glutamine (Biochrom, Berlin, Germany). SKNAS cells were further supplemented with 1% non-essential amino acids (Thermo Fisher, Waltham, MA, USA). Cells were passaged one to three times weekly with 0.25% trypsin-EDTA (Life Technologies / Thermo Fisher, Waltham, MA, USA). The colorectal cell line HT-55 (colon cancer) was obtained from the European Collection of Authenticated Cell Culture (ECACC) and cultured in minimum essential medium (MEM) (Biowest, MO, USA) supplemented with 20% FBS, L-glutamine (Biochrom GmbH, 2 mM), and antibiotics (100 IU penicillin and 100 µg / ml streptomycin, Biochrom GmbH, Germany). Monolayer cultures were grown in tissue culture flasks (VWR, PA, USA) and incubated at 37°C in a 5% CO2 atmosphere. After reaching 70%–80% confluence, cells were passaged using trypsin-EDTA (Biochrom GmbH, Germany).

[0254] The HiTSeeker cell line TACR1 (NK1) / U2OS (U2O2-NK1R), which expresses human tachykinin receptor 1 (DNA accession number: GenBank: AY462098) in U2OS osteosarcoma cells, was purchased from Innoprot, Spain, REF: P30129-U2. Wild-type (untransfected) U2OS cells were obtained from the American Type Culture Collection (ATCC). Cells were cultured in Dulbecco modified Eagle medium (Gibco™ DMEM, high glucose, GlutaMAX™ supplement, pyruvate, Cat. No. 31966021) supplemented with 10% (v / v) fetal bovine serum (FBS) (Merck, Cat. No. F7524), 100 IU / ml penicillin-streptomycin solution (Gibco™ Cat. No. 15140-122), and 0.5 mg / ml genimycin (Gibco, Cat. No. 10131-027). Monolayer cultures were grown in tissue culture flasks (VWR, Cat. No 734-2313) in a humidified incubator at 37°C with 5% CO2.

[0255] Aprepitant (CAS No.: 170729-80-3) was obtained from the United States Pharmacopeia (1041904-150 mg). FAM-labeled substance P, FAM-SP (Cat. No. AS-61201), was obtained from AnaSpec, USA. As used herein, substance P undecapeptide is a member of the tachykinin neuropeptide family. Substance P (which may be abbreviated as SP) was obtained from Sigma-Aldrich (Cat No. S6883) with CAS No. 33507-63-0. Radioactive iodine 125 or iodine-125 radionuclide (17Ci (629 GBq) / mg, 0.1M NaOH, pH 12-14, without reducing agent) was obtained from PerkinElmer Inc., USA, transported at ambient temperature.

[0256] abbreviation

[0257] Chemical

[0258] Preparation of starting materials for Examples 1 to 4

[0259] Preparation of 3-hydroxy-2-methoxypiperidine-1-carboxylic acid benzyl ester

[0260] At room temperature (RT), a homogeneous solution of 3,4-dihydropyridine-1(2H)-formate (1 g, 4.603 mmol) dissolved in MeOH (30 mL) was added to a stirred suspension of potassium persulfate (1.681 g, 5.468 mmol) and NaHCO3 (0.459 g, 5.468 mmol) in MeOH (30 mL). The reaction mixture was stirred for 2 h, followed by the further addition of potassium persulfate (1.681 g, 5.468 mmol) and NaHCO3 (0.459 g, 5.468 mmol). The resulting reaction mixture was stirred for 12 h, with the reaction progress monitored by thin-layer chromatography using a 1:1 ethyl acetate / hexane mobile phase. The solid was filtered off, and the filtrate was diluted with ethyl acetate (50 mL) and a saturated NaHCO3 solution (50 mL). The organic layer was extracted with ethyl acetate (2 x 50 mL), washed with brine (50 mL), dried over NaSO4, and evaporated to dryness under vacuum to provide a colorless oil. The title compound, as a mixture of diastereomers, was purified by silica gel column chromatography (1:1 ethyl acetate / hexane) (0.909 g, 74.52%). 1 H NMR (400 MHz, chloroform-) d ) δ 7.44 – 7.26 (m, 5H), 5.51 – 5.01 (m, 3H), 4.07 – 3.79 (m, 1H), 3.48 (s, 1H), 3.27 (d, J = 12.9 Hz, 3H), 3.00 – 2.72 (m,1H), 1.99 – 1.75 (m, 2H), 1.75 – 1.56 (m, 2H), 1.56 – 1.32 (m, 1H). ESI-LC-MS(+): m / z [M-OMe] + Calculated value (measured value): 234.275 (234.2).

[0261] (±)- Shun Preparation of 2-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylic acid benzyl ester

[0262] BF3·OEt2 (480.95 μL, 3.897 mmol) was added to a stirred solution of compound 3-hydroxy-2-methoxypiperidine-1-carboxylic acid benzyl ester (1.033 g, 3.897 mmol) and (4-(benzyloxy)phenyl)boronic acid (0.889 g, 3.897 mmol) in anhydrous dichloromethane (10 mL) at -30 °C and under a sealed N2 environment. The reaction was allowed to recover to RT over the entire 4 hours and the reaction was stirred for another 24 h. Subsequently, it was quenched by adding saturated NH4Cl solution (10 mL) and the organic phase was extracted with ethyl acetate (2 x 10 mL). The separated organic layers were combined, washed with brine, dried on Na2SO4, and evaporated to dryness under vacuum. Silica gel column chromatography (ethyl acetate / hexane, 1 / 2 to 1 / 1) of the crude product yielded a light brown liquid. Shun The title compound of the isomer (0.987 g, 60.66%). 1 H NMR (400 MHz, chloroform-) d ) δ 7.47 – 7.38 (m,4H), 7.35 (ddd, J = 7.5, 6.6, 1.4 Hz, 2H), 7.32 – 7.22 (m, 6H), 6.94 – 6.85(m, 2H), 5.48 (d, J = 5.7 Hz, 1H), 5.11 (q, J = 12.5 Hz, 2H), 4.99 (s, 2H), 4.06 – 3.90 (m, 2H), 3.12 (s, 1H), 2.90 (td, J = 13.2, 3.7 Hz, 1H), 1.79 (td, J = 9.5, 8.0, 4.6 Hz, 2H), 1.73 – 1.46 (m, 2H). ESI-LC-MS(+): m / z [M+H] + Calculated value (measured value): 418.51 (418.0).

[0263] (±)- Shun Preparation of 2-(4-(benzyloxy)phenyl)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-1-carboxylic acid benzyl ester

[0264] Compound (±)- at 0℃ ShunBenzyl 2-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-carboxylate (487.2 mg, 1.167 mmol) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (234.01 μL, 1.277 mmol) in anhydrous DMF (2 mL) were added to a stirred solution of NaH (33.69 mg, in a 60% dispersion in mineral oil, 1.404 mmol) in anhydrous DMF (2 mL). The reaction mixture was then transferred to a preheated block at 80 °C. After stirring for 4 h, the mixture was quenched with H2O (1 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane, 1:10) to provide a white liquid. Shun The title compound of the isomer (137.6 mg, 18.32%). 1 H NMR (400 MHz, chloroform-) d ) δ 7.70 (s, 1H), 7.62 (d, J = 1.9 Hz, 2H), 7.48 – 7.12 (m, 12H), 6.91 – 6.79 (m, 2H), 5.68 (s, 1H), 5.11 (q, J = 12.4 Hz, 2H), 4.97 (s, 2H), 4.63 (q, J = 12.4 Hz, 2H), 3.94 (dd, J = 14.0, 4.6 Hz, 1H), 3.80 (ddd, J = 8.7, 7.2, 5.5 Hz, 1H),2.74 (td, J = 13.2, 3.5 Hz, 1H), 2.11 – 1.84 (m, 2H), 1.74 – 1.46 (m, 2H). ESI-LC-MS(+): m / z [M+H] + Calculated value (measured value): 643.6 (643.9).

[0265] Example 1: 4-((2) S ,3 S A racemic mixture of 3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol and 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol, i.e. 4-((±)- ShunPreparation of 3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol

[0266] 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol

[0267] 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol

[0268] Compound (±)- Shun The combined hydrogenolysis of the benzyl and benzyloxycarbonyl groups of 2-(4-(benzyloxy)phenyl)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-1-carboxylic acid benzyl ester was carried out one step according to the procedure outlined in H. Sajiki, Tetrahedron Lett., 1995, 36, 3465. The procedure is as follows. The compound (±)- Shun A mixture of 2-(4-(benzyloxy)phenyl)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate (137.6 mg, 0.214 mmol), NH4OAc (49.44 mg, 0.641 mmol), and 10% Pd / C (10 mg) in MeOH (3 mL) was treated with H2 introduced into a sealed reaction flask and stirred at RT for 30 min. The mixture was then filtered through diatomaceous earth, washed with MeOH (2 x 5 mL), and extracted with ethyl acetate (2 x 5 mL). The combined ethyl acetate layers were then washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was then washed with pentane (2 x 5 mL) and evaporated under vacuum until completely dry, thus providing a thin sheet of white solid. Shun The title compound isomer (62.5 mg, 69.71%). 1 H NMR (400 MHz, methanol-) d 4) δ 7.84 (d, J = 2.2 Hz, 1H), 7.80(d, J = 1.7 Hz, 2H), 7.36 – 7.25 (m, 2H), 6.90 – 6.78 (m, 2H), 4.82 (d, J =12.7 Hz, 1H), 4.42 (dd, J= 7.2, 5.5 Hz, 2H), 3.96 (dt, J = 3.6, 1.9 Hz, 1H), 3.51 – 3.38 (m, 1H), 3.23 (td, J = 13.1, 3.2 Hz, 1H), 2.46 – 2.29 (m, 1H), 2.20 – 2.04 (m, 1H), 1.88 (dddd, J = 17.0, 12.6, 7.5, 2.6 Hz, 2H). ESI-LC-MS(+): m / z [M+H] + Calculated value (measured value): 420.37 (420.0). Figure 1A The UV HPLC analysis of the title compound is shown.

[0269] Example 2: A racemic mixture of 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one and 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one, i.e. 5-(((±)- Shun Preparation of 3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one

[0270] 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one

[0271] 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one

[0272] A mixture of the compound from Example 1 (54.3 mg, 0.129 mmol) and 5-(chloromethyl)-1,2-dihydro-3H-1,2,4-triazol-3-one (19.02 mg, 0.142 mmol) in anhydrous DMF (2 mL) was added to a stirred solution of NaH (3.73 mg, 0.155 mmol) in anhydrous DMF (1 mL). The reaction mixture was then transferred to a preheated block at 80 °C and stirred for 3 h. The reaction was quenched with water (2 mL) and extracted with ethyl acetate (10 mL) and brine (2 x 5 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. Silica gel column chromatography of the crude product under N₂ with dichloromethane / ethyl acetate (1 / 10) provided a white solid. Shun The title compound of the isomer (44.09 mg, 65.94%). 1 H NMR (500 MHz, methanol-) d 4) δ 7.84 (s, 1H), 7.76 (s, 2H), 7.30 (d, J =8.2 Hz, 2H), 6.83 – 6.73 (m, 2H), 4.66 (d, J = 12.3 Hz, 1H), 4.20 (d, J =12.3 Hz, 1H), 3.71 – 3.60 (m, 2H), 3.53 – 3.34 (m, 1H), 2.98 (d, J = 11.0 Hz,1H), 2.95 – 2.83 (m, 1H), 2.36 – 2.20 (m, 2H), 2.01 (qt, J = 13.1, 2.7 Hz,1H), 1.71 – 1.57 (m, 2H). ESI-LC-MS(+): m / z [M] + Calculated value (measured value): 516.44 (516.9 or 517). Figure 2A The HPLC analysis of the title compound is shown.

[0273] Example 3: 4-((2) S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol and 4-((2) R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(125 I) A racemic mixture of iodophenol, i.e., 4-((±)- Shun -3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Preparation of Iodophenol

[0274] 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol

[0275] 4-((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol

[0276] Stock solutions of both chloramine-T (CAT) (2 mg / mL) and sodium metabisulfite (NBS) (2 mg / mL) were prepared in phosphate-buffered saline (PBS, pH 7.4). The compound from Example 1 (10.3 µg) was mixed with ([ 125 [I]NaI, 5 MBq, dissolved in 0.1 M NaOH, pH 12-14, PerkinElmer Inc., USA, was mixed, followed by the addition of CAT (15 μL) stock solution. The radioiodination reaction was incubated at RT for 60 minutes, and the reaction was quenched by the addition of NBS (30 µL), thus providing the desired product with a radiochemical yield of 97.6%.

[0277] Radiolabeled yields and radiochemical purity were evaluated using instantaneous thin-layer chromatography (ITLC) and high-performance liquid chromatography (HPLC) with built-in radiodetector channels.

[0278] HPLC analysis of the compounds in Examples 4 and 6 (5-95% solvent B; A: H2O / TFA, B: ACN / TFA, 1 mL / min, 254 nm) showed clearly distinguishable peaks at 7.980 and 9.113 min in the UV and radioactive channel detectors, respectively, thus confirming the success of the compound in Example 6. 125 I-Radioactive labeling. Figure 1B The radioactive HPLC analysis of the title compound is shown.

[0279] Example 4: 5-(((2) S ,3 S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one and 5-(((2) R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) A racemic mixture of iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one, i.e. 5-(((±)- Shun -3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 Preparation of I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one

[0280] 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one

[0281] 5-(((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one

[0282] Prepare CAT (15 μL) and NBS (30 μL) stock solutions as described in Example 3.

[0283] The compound from Example 2 (10.3 µg) was mixed with ([ 125 [I]NaI, 5 MBq, dissolved in 0.1 M NaOH, pH 12-14 (PerkinElmer Inc., USA), was mixed, followed by the addition of CAT (15 μL). The radioiodination reaction was incubated at 37°C for 60 minutes. NBS (30 µl) was then added. The desired product was obtained in 99.6% radiochemical yield.

[0284] Radiolabeled yields and radiochemical purity were evaluated using instantaneous thin-layer chromatography (ITLC) and high-performance liquid chromatography (HPLC) with built-in radiodetector channels.

[0285] HPLC analysis of the compounds in Examples 5 and 4 (5-100% solvent B; A: H2O / TFA, B: ACN / TFA, 1 mL / min, 254 nm) showed clearly distinguishable peaks at 7.010 and 7.533 min in the UV and radioactive channel detectors, respectively, thus confirming the success of the compound in Example 4. 125 I-Radioactive labeling. Figure 2B The HPLC analysis of the title compound is shown.

[0286] Examples 5 to 54

[0287] The compounds of Examples 5 to 54 shown in Table 1 are prepared using the methods described in this document and / or using procedures known in the art. For example, the compounds of Examples 5 to 10 and 16 to 25 are prepared as shown in Scheme 5A. One or more compounds of Examples 11 to 15 and 26 to 34 are prepared by ( 2S, 3S 2-Phenylopiridine-3-amine is prepared by reductive amination with a suitable aldehyde. Examples 36 to 47 are prepared by alkylation as in Scheme 6. Examples 48 to 51 are prepared according to Scheme 2B, and Example 52 is prepared according to Scheme 2A. This is achieved by reducing the aldehyde containing […]. 127 The retention time obtained from the UV trace of the reference solution of the I- compound is compared with that from the [] compound reaction. 125 The retention times obtained from the radioactive traces of the I-compound were compared to confirm the identity of Examples 48 to 52.

[0288] Table 1

[0289] (2S,3S)-N-((5-[ 125 Preparation of the compound of Example 49: I]Iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine

[0290] To contain [ 125 Add tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethyltinyl)pyridin-3-yl)methyl)amino)-2-phenylpiperidin-1-carboxylic acid (15 µl, 2 mg / ml in methanol) and 10% acetic acid in methanol (15 µl) to a vial of NaI (11 MBq in 0.1 M NaOH). Add chloramine-T (7.5 µl, 2 mg / ml in methanol) and heat the mixture at 50 °C for 35 min. Allow the mixture to return to room temperature and add sodium metabisulfite (15 µl, 2 mg / ml in water). Add TFA (100 µl) and heat the mixture at 65 °C for 60 min. Add 50 µl of TFA and the mixture and heat at 65 °C for 30 min. The mixture was diluted with water and acetonitrile and purified by HPLC (biphenyl core-shell column, gradient 20-70% MeCN in 0.1% TFA (aq)). Evaporation of the solvent gave the title compound (2.7 MBq). The compound was obtained by evaporating the solvent from the sample containing the compound described in Example 14. 127 The retention times obtained from the HPLC-UV trace of the reference solution of the I]- compound were compared with the retention times obtained from the radioactive trace of the title compound to confirm the identity of the compound.

[0291] biology

[0292] Combined with affinity measurement

[0293] NB cell line

[0294] The binding characteristics of the compound in Example 4 with different human NB cell lines, SK-N-AS and IMR-32, were evaluated using the LigandTracer Gray (Ridgeview Instruments, Uppsala, Sweden).

[0295] According to the manufacturer's instructions (Ridgeview Instruments, Uppsala, Sweden), a total of 3 x 10 5 1 cell (IMR-32) or 2.5 × 10 5 (SK-N-AS) cells were seeded on polydopamine-coated culture dishes to allow cell attachment and incubated at 37°C for 24 h. CO2-independent medium (3 mL, ibco / Thermo Fisher, Waltham, MA, USA) was then added to the dishes, and a baseline curve was obtained by running LigandTracer for 10 min. The compound from Example 4 (300 nM in freshly replenished cell culture medium, radiolabeled yield ≥ 95%) was then added, and LigandTracer was allowed to run for 3–4 h. 700 nM of the compound from Example 4 was further added to the above cell solution, resulting in a final concentration of 1 μM. After running LigandTracer for 3–4 h, the cell culture medium was removed and replaced with 3 mL of fresh medium, and then the assay was allowed to run overnight to establish dissociation curves. The obtained binding curves were evaluated using TraceDrawer 1.9 software (Ridgeview Instruments, Uppsala, Sweden) for different kinetic interaction models (1:1 and 1:2).

[0296] Figures 3A to 3D This image shows 1:1 and 1:2 kinetic analyses of the real-time binding curves of the compound in Example 4 with human NB cell lines SK-N-AS and IMR-32. The solid lines represent the calculated fits. It can be seen that the recorded curves approximate a 1:2 fit, indicating a 1:2 kinetic fit. Figure 4 The real-time binding curves of the compound from Example 4 with the human NB cell lines SK-N-AS and IMR-32 are shown. The highest signal was observed for IMR-32, followed by SK-N-AS.

[0297] Table 2 shows the equilibrium dissociation constants (K0) determined for the compounds in Example 4 with human cell lines SK-N-AS and IMR-32. D ).

[0298] Table 2

[0299] The real-time binding curves of the compound in Example 4 with the combination of IMR-32 and SK-N-AS clearly show different binding modes, demonstrating the affinity of the compound in Example 4 for human cell lines.

[0300] In the prior art, L-741 and 671 are known to exhibit affinity for the hNK1 receptor (as reported by Tattersall FD et al., Neuropharmacology 1996, 35, 1121-1129). Example 4: Low nanomolar Ka analysis of the compound using a 1:2 kinetic model. D1 The values ​​and combinations are combined in real time, and the curve shows the connection of large values. 125 The I atom does not change the binding affinity of the compound in Example 4.

[0301] HT-55 colorectal cell line

[0302] The binding characteristics of the compound in Example 4 to the human HT-55 colorectal cancer cell line expressing the NK1 receptor were also evaluated according to the same procedure outlined above.

[0303] 1.5 × 10 6 HT-55 cells were seeded on tilted, cell culture-treated Nunc dishes (Cat. No. 150350, Thermo Fisher Scientific) and incubated at 37°C in a 5% CO2 atmosphere. After 48 h of incubation, real-time binding measurements were performed. Before starting the binding measurements, the cell culture medium was replaced with 3 ml of fresh medium. The binding of the compound of Example 4 to HT-55 cells was measured at room temperature using a Ligand Tracer Gray (Ridgeview Instruments AB, Uppsala, Sweden). Baseline signals were collected for approximately 10 min, after which the compound of Example 4 was gradually added to final concentrations of 300 nM and 1 uM. Dissociation was initiated by replacing the medium with 3 ml of fresh medium when the binding curves achieved sufficient curvature at at least one concentration. The cell-free plastic surface of the same culture dish was used as a reference background region to study off-target binding of the radiolabeled molecule. The reference background signal was automatically subtracted from the decay-corrected target region signal, resulting in a specific real-time binding curve of the compound of Example 4 to the target cells. Dynamic interaction assessment was performed using TraceDrawer 1.9.2 (RidgeviewInstruments AB, Uppsala, Sweden).

[0304] Figure 5AFigure 5D shows the 1:1 and 1:2 kinetic analyses of the real-time binding curves of the compound from Example 4 with the human colorectal cancer cell line HT-55. The solid lines represent the calculated fits. It can be seen that the recorded curves are close to a 1:2 fit, indicating a 1:2 kinetic fit.

[0305] Table 3

[0306] Table 3 shows the equilibrium dissociation constants (K0) determined for the compounds in Example 4 and the human colorectal cancer cell line HT-55. D Therefore, compounds of formula I can be used for the diagnosis, treatment, and / or prevention of colorectal cancer expressing elevated levels of the NK1 receptor.

[0307] Specificity assay

[0308] In a specificity assay, the cellular uptake of the compound in Example 4 in the human NB cell line IMR-32 was investigated.

[0309] Total 2 × 10 5 Cells / well were seeded into 24-well plates and incubated at 37°C for 48 h. The old medium was removed and replaced with either the compound of Example 4 (10 nM) or a combination of the compound of Example 4 (10 nM) and aprepitant (1 μM). The treated cells were then incubated for 1 h. The medium was removed, the cells were trypsinized (i.e., dissociated using trypsin), and the fractions were collected in fraction tubes. Radioactive uptake in each fraction tube was measured using a gamma counter (1480 Wizard 3”, Wallace). Differences in the amount of bound radioactivity between the treated groups were calculated using an unpaired t-test.

[0310] Figure 6 The cellular uptake concentration of Compound 4 per 100,000 cells is shown for Compound 4 alone (10 nM) and the combination of Compound 4 (10 nM) and aprepitant (1 μM).

[0311] Specificity assays showed NK1R-targeted uptake of the Example 4 compound at a concentration of 10 nM, which was blocked by aprepitant at a concentration of 1 μM (100 times stronger than the concentration of the Example 4 compound).

[0312] This demonstrates the specific binding of the compound in Example 4 to NK1R, which is important for ensuring the specific enrichment of the compound at the intended treatment site and for avoiding nonspecific uptake in healthy tissues / organs to minimize associated side effects.

[0313] Further specificity assays

[0314] NK1R-transfected U2OS cells (TACR1 (NK1) / U2OS, “U2OS-NK1R”) were seeded into ten wells of a 48-well plate, with each well containing 500 µL of DMEM medium supplemented with 10% FBS and 1% penicillin-streptomycin. Wild-type untransfected U2OS cells were seeded into another ten wells of the 48-well plate, with each well containing 500 µL of DMEM medium supplemented with 10% FBS and 1% penicillin-streptomycin. The cells were then incubated at 37°C for 48 hours in a 5% CO2 atmosphere. After incubation, the medium was aspirated and the wells were washed twice with PBS.

[0315] To prepare the "blocking" wells, five wells containing U2OS-NK1R cells and five wells containing wild-type U2OS cells were pretreated with 500 nM aprepitant in 100 µL of DMEM medium containing 1% penicillin-streptomycin. In the remaining five U2OS and five U2OS-NK1R wells, 100 µL of DMEM medium containing 1% penicillin-streptomycin was added to each well. After incubation at 37°C for 10 minutes, 10 nM of compound 49 (containing 1% penicillin-streptomycin) was added to 100 μL of DMEM medium containing 1% penicillin-streptomycin. 125 I) Add to each well and incubate at 37°C for another 30 minutes.

[0316] After incubation with the compound of Example 49, the radioactive medium was aspirated and the cells were washed with PBS. Subsequently, the cells were trypsinized (i.e., dissociated using trypsin), counted using a TC20™ automated cell counter (BioRad, Sweden), and cell-related radioactivity was measured using a gamma counter (1480 Wizard 3′, Wallace, Finland). Statistical significance was assessed using Student's t-test, and data were analyzed to determine the pmol of the compound of Example 49 per 100,000 cells. Results are shown in... Figure 8A and Figure 8B The error bars in the figure represent the 95% confidence interval.

[0317] Figure 8A The amount of compound 49 shown is measured in pmol (i.e., picomoles) bound per 100,000 NK1R-transfected U2OS cells. Figure 8A It is clear that NK1R-targeted uptake exists in compound 49 at a concentration of 5 nM, which is blocked by aprepitant at a concentration of 250 nM. Figure 8B The amount of compound 49 shown is measured in pmol (i.e., picomoles) bound per 100,000 untransfected wild-type U2OS cells. Figure 8BNo NK1R-targeted uptake was observed in compound 49 of this invention. The conclusion is that compounds of formula I specifically bind to NKR1. This specific binding is important for ensuring specific enrichment of the compound at the intended therapeutic site and for minimizing associated side effects by avoiding nonspecific uptake in normal tissues / organs.

[0318] Competition Measurement

[0319] To conduct a real-time competitive binding assay on U2OS osteosarcoma cells expressing NK1R (TACR1 (NK1) / U2OS), 1.5–2.0 × 10⁻⁶ μg / mL of urea nitrogen was used. 6 Cells were seeded into tilted culture dishes (Nunc™ Cell Culture / Petri Dishes, Cat. No. 150350, ThermoFisherScientific) and incubated overnight at 37°C and 5% CO2. The next day, the medium was replaced with 10 mL of fresh medium (supplemented with Dulbecco modified Eagle medium, as described in the Basic Information section), and the dishes were incubated horizontally overnight.

[0320] Kinetic measurements were performed at ambient temperature using a blue (488 nm)-green (535 nm) detector on a LigandTracer Green (Ridgeview Instruments AB, Uppsala, Sweden).

[0321] Before binding measurements, the cell culture medium was replaced with 3 ml of CO2-independent medium (Gibco, Cat. No. 18045-054) supplied with 10% (v / v) fetal bovine serum (FBS), and the culture dishes were placed on the tilting rotating stand of the instrument. Baseline signals were recorded for 30 min, after which 90 nM FAM-labeled substance P, FAM-SP, was added to the cells, and signals from the cellular target and background reference regions were recorded over time. After obtaining sufficient binding curve curvature (typically about 60 min), 90 nM competing compounds (Examples 7, 8, 9, 10, 11, 13, 14, and 15) were subsequently added. Fluorescence signals were recorded for at least 60 min.

[0322] Dynamics evaluation was performed using a one-to-one competition model with TraceDrawer 1.9.2 software (Ridgeview Instruments AB, Uppsala, Sweden).

[0323] Figure 7A and Figure 7BThe background-corrected binding signal of FAM-SP is shown, followed by the competition phase, in which the evaluated compounds ( Figure 7A The compounds in Examples 7 to 10, and Figure 7B The compounds of Examples 11 and 13 through 15 compete with FAM-SP for binding, resulting in a compound-dependent decrease in FAM-SP signal levels. Positive controls aprepitant and SP are shown for comparison. It is concluded that the compounds of this disclosure exhibit NK1R-specific binding to epitopes overlapping with FAM-SP. The percentage of FAM-SP displacement 60 minutes after the addition of the competing compound is reported in Table 4 below.

[0324] Further competition determination

[0325] (i) FAM-SP and (ii) were tested using the example compounds described herein. 125 I-SP (i.e., use) 125 Further competitive testing will be conducted by replacing the SP with the I-label.

[0326] The FAM-SP was replaced using the competition assay described above. The results are shown in Table 4.

[0327] Compounds from Examples 5, 14, 15, 18, 27, and 32 were sent to Eurofins Cerep SA in Celle-Lévescault, France, for testing in the NK1 human tachykinin GPCR binding agonist radioligand LeadHunter assay. This assay used a membrane formulation derived from U373MG cells and 0.05 nM of [unclear - likely a specific reagent or solution]. 125 IP material LYS3 was used as a ligand. The compound was tested in dual-well configurations at eight concentrations ranging from 30 pM to 100 nM. IC 50 Calculations provided by Eurofins Cerep. For comparison, the reference compound [Sar9,Met(O2)11]-SP was given an IC50 of 167 pM. 50 .

[0328] The results are shown in Table 5.

[0329] Table 4

[0330] Therefore, the compounds disclosed herein allow for the substitution of FAM-SP.

[0331] Table 5

[0332] Table 5 shows that the compounds of this disclosure are permissible to bind to NK1R. In particular, the compounds of this disclosure, where Q is nitrogen, such as those in Examples 14 and 32, have a high affinity for NK1R.

[0333] References

[0334] 1. Halik P. et al., Pharmaceutics 2022, 14, 607

[0335] 2. Kowaluk, EA; Arneric, SP, Annual Reports in MedicinalChemistry 1998, 33, 11-20

[0336] 3. Tattersall FD et al., Neuropharmacology 1996, 35, 1121-1129

[0337] 4.WO 95 / 20575 A1.

[0338] 5. WO 94 / 19323 A1

[0339] 6. WO 93 / 04040 A1

[0340] 7. Muñoz M. et al., Neuropeptides 2005, 29, 245-254

[0341] 8. WO 95 / 23798 A1

[0342] 9. Rosso M. et al., Tumor Biology 2008, 29, 245-254

Claims

1. A compound of Formula I: wherein: R 1 is H or (CH2) p Z; R 2 is H, OH or F; R 3 R is H or C1-C3 alkyl; R 4 is selected from the group consisting of H, CF3, OC1-C6 alkyl, OCF3, CN, F and NO2; R 5 selected from the group consisting of H, CF3, OC1-C6 alkyl, OCF3, CN, F, and NO2; Q is C or N; X is O or NH; Y is selected from the group consisting of 127 I, 123 I, 124 I, 125 I, 131 I and 211 At consisting of Z is a five- or six-membered heterocycle comprising 1, 2 or 3 nitrogen atoms and / or N-oxides, which heterocycle is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of F, CI, Br, I, OH, C1-C3 alkyl, oxo and (CH2) q NHR 6 substituents selected from the group consisting of F, CI, Br, I, OH, C1-C3 alkyl, oxo and (CH2) R 6 is a chelating moiety or a radionuclide complex thereof; n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; q is 2, 3, 4, or 5; substituents and are located in an order relative to each other; provided that: n + m = 1; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, further provided that when R 2 is H then m is 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is C, thereby providing a compound of Formula la: 。 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is N, thereby providing a compound of Formula lb: 。 5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula lb is a compound of Formula lb1, Formula lb2, or Formula lb3: 。 6. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the piperidine ring having the configuration of S configuration, or having a configuration at carbon 2 and carbon 3 R configuration.

7. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R 1 is H.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is (CH2) p Z.

9. The compound according to any one of claims 1 to 6 or 8, or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of: and .

10. The compound according to any one of claims 1 to 6, 8, or 9, or a pharmaceutically acceptable salt thereof, wherein p is 1.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 6 or 8 to 10, wherein R 6 is a chelating moiety selected from the group consisting of: and .

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R 6 is a chelating moiety comprising or consisting of: 。 13. The compound according to any one of claims 1 to 6 or 8 to 12, or a pharmaceutically acceptable salt thereof, wherein q is 4.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 6 or 8 to 13, wherein R 6 is a radionuclide complex comprising the chelating moiety and a radionuclide.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is selected from the group consisting of 68 Ga, 18 F, 64 Cu, 44 Sc, 89 Zr, 111 In, 67 Ga, 99m Tc, Gd, 177 Lu, 86 / 90 Y, 225 Ac, 161 / 155 Tb, 226 / 227 Th and ions thereof.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is 177 Lu, as 177 Lu 3+ .

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 6 or 8 to 16, wherein R 1 is selected from the group consisting of: and .

18. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R 1 is H; or 。 19. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R 2 is H or OH.

20. The compound or pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein R 3 is H or CH3.

21. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of H, CF3, OCH3, OCH(CH3)2, OCF3, F, NO2, and CN; and / or R 5 is selected from the group consisting of H, CF3, OCH3, OCH(CH3)2, OCF3, F, NO2, and CN.

22. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R 4 and R 5 are each CF3; or R 4 and R 5 are each CN.

23. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1.

24. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein m is 1.

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 4-((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; (2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4- dihydro-1,2,4-triazol-5-one; (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4-dihydro-1,2,4-triazol-5- one; 5-iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidinyl)oxymethyl)pyridine; 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridinyl)methoxy)-2-phenyl-1-piperidinyl)methyl)-1,4- dihydro-1,2,4-triazol-5-one; (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2- iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- iodophenyl)piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((4-iodobenzyl)oxy)-2-phenylpiperidine; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidin-1-yl)methyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-N-((5-iodopyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3- amine; (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin- 3-amine; (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)piperidin- 3-amine; (2S,3S)-2-(4-fluorophenyl)-N-(3-iodo-5-(trifluoromethyl)benzyl)piperidin-3- amine; (2S,3S)-N-((R)-1-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine; 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-l- yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4-dihydro- 3H-l,2,4-triazol-3-one; 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin- 1-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-l-((6-methylpyridin-2-yl)methyl)- 2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-l-(pyridin-2-ylmethyl)- piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-l-(pyrimidin-2-ylmethyl)- piperidin-3-amine; 2-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-l- yl)methyl)pyrimidine 1-oxide; 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidin- 1-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one; (2S,3S)-l-((lH-imidazol-2-yl)methyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2- phenylpiperidin-3-amine; 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-l-yl)- methyl)pyrimidine 1-oxide; (2S,3S)-3-((3-((2,4-difluorophenoxy)carbonyl)pyrrolidin-l- yl)methyl)-5-(trifluoromethyl)-oxazolidine; 125 I) 2-(iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine; (2S,3S)-N-((5- 125 I)iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-(5- 125 I) Iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((4- 125 I)iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- 125 I)iodophenyl)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one; 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin- 1-yl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)butyl)amino)-2-oxoethyl)-l,4,7,10- tetraazacyclododecane-l,4,7-trisyl)triacetic acid; and [ 177 Lu] lutetium (III) -2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2- phenylpiperidin-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)butyl)amino)-2- oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-trilyl)triacetate.

26. The compound or pharmaceutically acceptable salt thereof of claim 1, selected from the group consisting of: 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 4-((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( 125 I) Iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; 5-(((2 R ,3 R )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidin-1-yl)methyl)-1H-1,2,4-triazol-3(2H)-one; (2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidin-1- yl)methyl)-1,4-dihydro-1,2,4-triazol-5-one; (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine; 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidin-1-yl)methyl)-1,4-dihydro- 1,2,4-triazol-5-one; (2S,3S)-N-(3-iodobenzyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenyl-piperidin-3-amine; 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol; 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-iodophenyl)- piperidin-1 -yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenyl-piperidine; (2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenyl-piperidine; (2 S ,3 S )-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine; (2S,3S)-3-((4-iodobenzyl)oxy)-2-phenyl-piperidine; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenyl-piperidin-1-yl)methyl)-2,4- dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenyl-piperidin-1-yl)methyl)-2,4- dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenyl-piperidin-1-yl)methyl)-2,4- dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenyl-piperidin-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-(3-iodo-5-(trifluoromethyl)benzyl)piperidin-3-amine; (2S,3S)-N-((R)-1-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine; 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)methyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-1-yl)methyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-1-yl)methyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one; 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-1-yl)methyl)-2,4-dihydro- 3H-1,2,4-triazol-3-one; 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidin- 1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-1-yl)methyl) pyrimidine 1-oxide; (2S,3S)-3-((3-((2,2-dimethyl- 1,3-benzodioxol-5-yl)methyl)- 1,1-dioxothiomoφholin-4-yl)methyl)-5-( 1,1-dioxothiomoφholin-4-ylmethyl)-piperidine-2-carboxylic acid; 125 I) 5-(trifluorom (2S,3S)-N-(5- 125 I) Iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine; 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- 125 I)iodophenyl)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one; 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-1- yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane-1,4,7-trilyl)triacetic acid; and [ 177 Lu] lutetium (III) -2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2- phenylpiperidin-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)butyl)amino)-2- oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-trilyl)triacetate.

27. The compound or pharmaceutically acceptable salt thereof of claim 1, selected from the group consisting of: 5-iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidinyl)oxymethyl)pyridine; 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridyl)methoxy)-2-phenyl-1-piperidinyl)methyl)- 1,4-dihydro-1,2,4-triazol-5-one; (2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodopyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)piperidin-3-amine; 5-(((2S,3S)-3-(((5-iodo-2-methoxy-pyridin-3-yl)methyl)amino)-2- phenyl-piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; 2-(((2S,3S)-3-(((5-iodo-2-methoxy-pyridin-3-yl)methyl)amino)-2-phenyl- piperidin-1-yl)methyl)pyrimidine 1-oxide; (2S,3S)-N-((5- 125 I)iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; and (2S,3S)-N-((4- 125 I)iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine. (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; 28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; (2S,3S)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)-2-phenyl-piperidin-3-amine; (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxy-pyridin-3-yl)methyl)piperidin- 3-amine; (2S,3S)-N-((5- 125 I)iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; and (2S,3S)-N-((4- 125 I)iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine. 5-(((2S,3S)-3-(((5-iodo-2-methoxy-pyridin-3-yl)methyl)amino)-2-phenyl- piperidin-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; (i) 123 I, 124 I and / or 125 I; or (ii) 131 I.

30. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 24, wherein Y comprises 127 I or consists of 127 I.

31. The compound according to any one of claims 1 to 24, wherein Y comprises 211 At or by 211 At consists of.

29. The compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein Y comprises or consists of:

32. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

33. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32, for use as a medicament in therapy.

34. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 32, for use in the diagnosis, treatment and / or prevention of a cancer selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer and any combination thereof.

35. The compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or The pharmaceutical composition of claim 32 The use for the manufacture of a medicament for the diagnosis, treatment and / or prevention of a cancer selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination thereof.

36. A method for the diagnosis, treatment and / or prevention of a cancer selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination thereof, the method comprising administering to a patient, such as a human or animal, in need thereof, a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32.

37. The compound or pharmaceutical composition for use according to claim 34, or The use according to claim 35, or The method according to claim 36 wherein the cancer comprises or consists of neuroblastoma.

38. A method for preparing a compound of Formula I as defined in any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, the method comprising the steps of: - subjecting a compound of Formula IV: wherein R 1 as defined in any one of claims 1 to 31 or is a protecting group, such as tert-butyloxycarbonyl; R 2 , R 3 , R 4 , R 5 , X and Q are as defined in any one of claims 1 to 31 ; and the substituents and are located in an order relative to each other; to iodination or astatination, thereby providing the compound of Formula I; and - optionally combining the compound of Formula I with a pharmaceutically acceptable acid.

39. The method of claim 38, wherein the compound of Formula IV is 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol, or 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one.

40. The method of claim 38 or 39, wherein the iodination or astatination comprises the steps of: a) treating a compound of formula IV 127 I iodinating said compound of formula IV to provide a compound of formula I wherein Y is 127 I of formula I; b) substituting said compound with a boron or metal containing compound such as Sn(CH3)3 127 I to provide a compound of formula V: wherein R 1 , R 2 , R 3 , R 4 , R 5 , X and Q are as defined in claim 38 or 39, M is a boron-containing or metal compound; n is 0 or 1 ; m is 0 or 1 ; and the substituents and are located in an order relative to each other; with the proviso that: n + m = 1 ; and c) with an iodine radioisotope as defined in claim 29 or 211 At substituting the boron or metal containing compound.

41. The method of claim 40, wherein the compound of Formula V is selected from the group consisting of: (2 S ,3 S )-2-phenyl-3-((3-(trifluoromethyl)-5-(trimethylstannyl)benzyl)oxy)piperidine-1 - carboxylic acid tert-butyl ester; tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridin-3- yl)methyl)amino)-2-phenylpiperidine-1 -carboxylate; tert-butyl (2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridin-2- yl)methyl)amino)piperidine-1 -carboxylate; and tert-butyl (2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethylstannyl)benzyl)amino)piperidine- 1 -carboxylate.

42. The method of claim 38, wherein the iodination comprises subjecting the compound of Formula IV to YCI, wherein Y is an iodine radioisotope as defined in claim 29.

43. The method of claim 42, wherein the YCI is prepared from N - chloro- to toluenesulfonamide or N - chlorosuccinimide and a sodium iodide salt selected from the group consisting of Na 123 I, Na 124 I, Na 125 I and Na 131 I.

44. A compound of Formula IV, which is: 4-((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol, or 5-(((2 S ,3 S )-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-1-yl)methyl)-2,4-dihydro-3 H -1,2,4-triazol-3-one.

45. A compound of Formula V, which is selected from the group consisting of: (2 S ,3 S )-2-phenyl-3-((3-(trifluoromethyl)-5-(trimethylstannyl)benzyl)oxy)piperidine-1 - carboxylic acid tert-butyl ester; (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridin-3- yl)methyl)amino)-2-phenylpiperidine-l-carboxylic acid tert-butyl ester; (2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridin-2- yl)methyl)amino)piperidine-l-carboxylic acid tert-butyl ester; and (2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethylstannyl)benzyl)amino)piperidine- 1 -carboxylic acid tert-butyl ester.

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