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

Abstract

This disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, methods for preparing the same, and their use 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 rhabdoid cancer. JPEG2026522940000099.jpg50170

Description

[Technical Field]

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

[0002] Cancer is a general term for a large group of diseases that can affect any part of the body. One defining characteristic of cancer is the rapid formation of abnormal cells that grow beyond normal boundaries, which can invade adjacent parts of the body and spread to other organs; the latter process is called metastasis. Extensive metastasis is the leading cause of death from cancer.

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

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

[0005] Peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers various functions after binding to NK1R. Antagonists of NK1R are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects.

[0006] The SP / NK1R system has been found to strongly influence the tumor microenvironment and may be involved in carcinogenesis-related processes such as mitosis induction, angiogenesis, cell migration, and metastasis. NK1R levels typically show limited peripheral expression in normal tissues but have been shown to be upregulated in several cancer types. Subsequently, SP has been demonstrated to act as a mitogenic factor through NK1R in several human cancer cell lines, including astrocytoma, melanoma, prostate, glioma, retinoblastoma, leukemia, and pancreatic, laryngeal, colon, gastric, and breast cancer.

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

[0008] NK1R is highly expressed in neuroblastoma (NBL), the most common extracranial solid tumor in children. NBL tumors are characterized by remarkable biological heterogeneity. Some tumors exhibit highly invasive and therapy-resistant behavior, while others spontaneously regress. To account for this diversity, current treatment strategies are uniquely guided by pretreatment risk stratification based on a wide range of clinical, histological, molecular, and biological markers. Thus, the prognosis and treatment of NBL are highly dependent on molecular, genetic, and pathological examinations.

[0009] Following risk stratification, NBL treatment approaches range from observation or resection of tumors considered low-risk to intensive multimodal therapy for high-risk tumors, including induction chemotherapy (administered at the start of cancer treatment), surgery, radiation, consolidation therapy (administered after initial treatment targeting residual cancer cells), and immunotherapy.

[0010] Current treatments are not entirely effective, and NBL remains a major therapeutic challenge in pediatric oncology. While multimodal therapy can often dramatically reduce tumor burden and lead to apparent complete remission of the disease (referred to as minimal residual disease), patients diagnosed with high-risk tumors have a survival rate of only 40–50%, suffer from frequent and long-lasting side effects, and approximately 50% of patients who complete treatment experience disease recurrence.

[0011] Radiopharmaceuticals are medicines containing radioisotopes that are designed to target specific cells, organs, or tissues and are increasingly being used for both the diagnosis and treatment of numerous cancers.

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

[0013] Radiopharmaceuticals are often developed in "theranostic" pairs, consisting of diagnostic and therapeutic compounds. Diagnostic compounds are designed with radioisotopes that enable imaging, such as positron emission tomography (PET) imaging, while therapeutic compounds are designed with radioisotopes that enable radiotherapy. Using these complementary theranostic pairs, clinicians can assess patient response before treatment and tailor subsequent radiotherapy doses to individual patients.

[0014] Aprepitant (commercially known as EMEND, also known as L-754,030) is an NK1R antagonist primarily used to treat chemotherapy-induced nausea and vomiting and has been shown to exhibit antitumor effects. However, aprepitant's poor pharmacokinetic profile, including low solubility and poor metabolic stability, impairs its antitumor potential. Furthermore, aprepitant crosses the blood-brain barrier (BBB) ​​and thus carries an increased risk of central nervous system (CNS) related side effects. Radiohalogenation of aprepitant has not been demonstrated. Instead, it is conjugated with the chelate DOTA (dodecanetetraacetic acid) for radiometallic labeling. The residual properties of the DOTA-chelated radiolabeled molecule mediate high renal dose and dose-limiting toxicity. [ka]

[0015] Halik P. et al., Pharmaceutics 2022, 14, 607, is functionalized with a DOTA chelating agent. 68 Ga and 177 We disclose that three novel Lu-labeled aprepitant homologs showed higher affinity and better binding ability to the human NK1 receptor in receptor binding studies than SP derivatives currently used in glioblastoma therapy. This confirmed assumption regarding the usefulness of aprepitant as an NK1R-targeting vector is stated. Furthermore, several reports state that they offer new perspectives on the use of aprepitant and other NK1R antagonists as vectors for selective radiopharmaceuticals for NK1R-positive tumors.

[0016] L-733,060 is an antagonist for NK1R that has shown anticancer effects in many in vitro models. Kowaluk,EA; Arneric,SP, Annual Reports in Medicinal Chemistry 1998,33,11-20 reported that it overcomes the bioavailability problems often associated with neurokinin antagonists and can cross the blood-brain barrier. [ka]

[0017] Tattersall FD et al., Neuropharmacology 1996, 35, 1121-1129, disclose the pharmacological profile of L-741,671, a non-peptide human neurokinin 1 (hNK1) receptor selective antagonist, which has been shown to be cerebral permeable. Cerebral permeability has been described as essential for the antiemetic effect of systemically administered NK1 receptor antagonists. [ka]

[0018] WO 93 / 04040 A1, WO 94 / 19323 A1, and WO 95 / 20575 A1 disclose a class of azacyclic compounds useful as tachykinin (NK1-receptor) antagonists. The compounds disclosed in WO 93 / 04040 A1 and WO 94 / 19323 A1 comprise azacyclic ring systems substituted with arylmethyloxy or arylmethylthio moieties, while the compounds disclosed in WO 95 / 20575 A1 comprise azacyclic ring systems substituted with aralkylamino moieties. Furthermore, the compounds disclosed in WO 94 / 19323 A1 and WO 95 / 20575 A1 are stated to be used for the treatment of pain, inflammation, migraines, and vomiting.

[0019] WO 95 / 23798A1 discloses a substituted heterocycle, a tachykinin receptor antagonist useful in the treatment of inflammatory diseases, pain or migraines, asthma, and vomiting.

[0020] Munoz M. et al., Neuropeptides 2005, 29, 245-254, disclose an in vitro study to investigate the ability of the NK1 receptor antagonist L-733,060 to inhibit cell growth in the SKN-BE(2) neuroblastoma cell line. The study shows that micromolar concentrations of L-733,060 are effective in inhibiting cell line growth. The presence of the NK1 receptor is demonstrated in the tested cell line, thus demonstrating that the antitumor effect of L-733,060 is mediated through the NK1 receptor. The NK1 receptor is suggested to be a novel and promising target in the treatment of human neuroblastoma.

[0021] Rosso M. et al., Tumor Biology 2008, 29, 245-254, disclose an in vitro study of the growth inhibitory ability of L-733,060 against human gastric and colonic adenocarcinoma. The study shows that micromolar concentrations of L-733,060 are effective in inhibiting the growth of such cell lines. The presence of several NK-1 receptor isoforms has been observed in human gastric and colonic adenocarcinoma, thus demonstrating that the antitumor effect of L-733,060 against both human cell lines is mediated through the NK-1 receptor. The NK-1 receptor is suggested to be a novel and promising target in the treatment of human gastric and colonic adenocarcinoma.

[0022] Any listing or discussion of documents that are clearly previously published in this specification should not necessarily be considered an acknowledgment that such documents are part of the latest technology or common knowledge.

[0023] A drawback of current cancer therapies is the management of a limited number of cells that evade induction and consolidation therapy. These cells are capable of proliferation and / or migration, leading to metastatic recurrence. Targeted theranostic radiopharmaceuticals, when administered during induction and consolidation therapy, particularly during the minimal residual disease (RAM) phase, can have a significant impact on survival rates.

[0024] Therefore, there is a need for compounds for use in the diagnosis, treatment, and / or prevention of cancer. Furthermore, there is a need for compounds for use in the diagnosis, treatment, and / or prevention of neuroblastoma. [Overview of the Initiative]

[0025] The object of this disclosure is to provide compounds for use in the diagnosis, treatment, and / or prevention of cancer. Furthermore, the object of this disclosure is to provide compounds for use, or compounds that can be converted into compounds for use, in the diagnosis, treatment, and / or prevention of neuroblastoma. A further object of this disclosure is to provide embodiments and / or advantages not provided by previously known techniques.

[0026] This disclosure relates to a compound of formula I, [ka] During the ceremony, R 1 However, H or (CH2) p Z is Z, R 2 However, it is H, OH, or F, R 3 However, it is H or C1-C3 alkyl, R 4 However, it is selected from the group consisting of H, CF3, OC1-C6alkyl, OCF3, CN, F, and NO2. R 5 However, it is selected from the group consisting of H, CF3, OC1-C6alkyl, OCF3, CN, F, and NO2. Q is either C or N, X is O or NH, Y is 127 I, 123 I, 124 I, 125 I, 131 I, and 211 selected from the group consisting of At, Z is a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 nitrogen atoms and / or N-oxides, the heterocyclic ring being independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C3 alkyl, oxo, and (CH2) q NHR 6 and 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, substituent

Chemical formula

[0027] The present disclosure also provides a pharmaceutical composition comprising a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0028] Furthermore, the present disclosure also provides a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use as a medicament in therapy.

[0029] This disclosure also provides compounds of Formula I as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in 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, rhabdoid cancer, and any combination thereof.

[0030] This disclosure also provides the use of compounds of Formula I described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals 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, rhabdoid cancer, and any combination thereof.

[0031] The Disclosure also provides a method for the diagnosis, treatment, and / or prevention of 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, wherein the method comprises administering to a patient, such as a human or animal, in need of it, an effective amount, for example, a therapeutically effective amount of a compound of Formula I described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0032] This disclosure also relates to a method for preparing a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, wherein the method is -A compound of formula IV, [ka] During the ceremony, R 1 However, for compounds of formula I, as described herein, or with protecting groups such as tert-butoxycarbonyl, R 2 , R 3 , R4 , R 5 X and Q are as described herein for the compound of formula I, substituent [ka] However, compounds that are in a cis position relative to each other The steps include subjecting the material to iodation or astatination to provide a compound of formula I, -The present invention provides a method comprising the optional step of combining a compound of formula I with a pharmaceutically acceptable acid.

[0033] This disclosure also, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol, or The present invention provides a compound of formula IV, which is 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one.

[0034] This disclosure also, tert-butyl(2S,3S)-2-phenyl-3-((3-(trifluoromethyl)-5(trimethylstannyl)benzyl)oxy)piperidine-1-carboxylate, tert-butyl(2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-carboxylate, tert-butyl(2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridine-2-yl)methyl)amino)piperidine-1-carboxylate, and The present invention provides a compound of formula V, selected from the group consisting of tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethylstannyl)benzyl)amino)piperidine-1-carboxylate. [Brief explanation of the drawing]

[0035] [Figure 1A] The UV-HPLC analysis of the compound from Example 1 is shown. [Figure 1B] The radio-HPLC analysis of the compound from Example 3 is shown. [Figure 2A] The UV HPLC analysis of the compound from Example 2 is shown. [Figure 2B] The radio-HPLC analysis of the compound from Example 4 is shown. [Figure 3A] The real-time binding curves of the compound in Example 4 with the human NB cell line SK-N-AS and 1:1 kinetic compatibility are shown. [Figure 3B] The real-time binding curves of the compound in Example 4 are shown for the human NB cell line SK-N-AS and in a 1:2 kinetic adaptation. [Figure 3C] The real-time binding curves of the compound in Example 4 are shown for human NB cell line IMR-32 and 1:1 kinetic adaptation. [Figure 3D] The real-time binding curves of the compound in Example 4 are shown for the human NB cell line IMR-32 and 1:2 kinetic adaptation. [Figure 4] The real-time binding curves of the compound in Example 4 in human NB cell lines SK-N-AS and IMR-32 are shown. [Figure 5A] The real-time binding curves of the compound in Example 4 are shown for the human colorectal cancer cell line HT55 and 1:1 kinetic adaptation. [Figure 5B] The real-time binding curves of the compound in Example 4 are shown for the human colorectal cancer cell line HT55 and 1:2 kinetic adaptation. [Figure 6]The cell uptake concentrations of the compound from Example 4 (10 nM) per 100,000 cells are shown for the compound from Example 4 alone and in combination with aprepitant (1 μM). [Figure 7A] The real-time binding curve for 90 nM FAM-labeled substance P(SP) is shown, followed by the binding competition of the 90 nM compound against NK1R-expressing U2OS osteosarcoma cells (TACR1(NK1) / U2OS cells). [Figure 7B] The real-time binding curve for 90 nM FAM-labeled substance P(SP) is shown, followed by the binding competition of the 90 nM compound against NK1R-expressing U2OS osteosarcoma cells (TACR1(NK1) / U2OS cells). [Figure 8A] The amounts of the compound in Example 49, measured as bound pmol (i.e., picomoles) per 100,000 NK1R-transfected U2OS cells (U2OS-NK1R), are shown with and without preblocking of the NK1 receptor by aprepitant. [Figure 8B] The amount of the compound in Example 49 is shown as bound pmol (i.e., picomoles) per 100,000 untransfected wild-type untransfected U2OS cells. [Figure 9] The chemical structure of DOTA, i.e., 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid, is shown. [Figure 10] The chemical structure of NOTA, i.e., 2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid, is shown. [Figure 11] The chemical structure of TETA, i.e., 1,4,8,11-tetraazacyclodosedane-1,4,8,11-tetrayl)tetraacetic acid, is shown. [Figure 12] The chemical structure of DTPA, or diethylenetriaminepentaacetic acid, is shown. [Figure 13] The chemical structure of NODAGA, i.e., 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid, is shown. [Figure 14] The chemical structure of DOTAGA, i.e., 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid, is shown. [Figure 15] The chemical structure of DFO, or deferoxamine, is shown. [Modes for carrying out the invention]

[0036] This disclosure relates to a compound of formula I, [ka] During the ceremony, R 1 However, H or (CH2) p Z is Z, R 2 However, it is H, OH, or F, R 3 However, it is H or C1-C3 alkyl, R 4 However, it is selected from the group consisting of H, CF3, OC1-C6alkyl, OCF3, CN, F, and NO2. R 5 However, it is selected from the group consisting of H, CF3, OC1-C6alkyl, OCF3, CN, F, and NO2. Q is either C or N, X is either O or NH, Y 127 I, 123 I, 124 I, 125 I, 131 I, and 211 Selected from the group consisting of At, Z is a 5-membered or 6-membered heterocycle containing 1, 2, or 3 nitrogen atoms and / or an N-oxide, and the heterocycle independently comprises F, Cl, Br, I, OH, C1-C3 alkyl, oxo, and (CH2) q NHR 6 It is substituted with 0, 1, 2, or 3 substituents selected from the group consisting of the following: R 6However, the chelate portion or its radioactive nuclide complex, n is 0 or 1, m is 0 or 1, p is 0, 1, 2, or 3, q is 2, 3, 4, or 5, substituent [ka] However, they are positioned in a cis position relative to each other. however, n+m=1 Provides a compound or a pharmaceutically acceptable salt thereof.

[0037] The following definitions apply throughout this specification.

[0038] The term "C1-C6 alkyl" refers to a linear or branched saturated alkyl group with 1 to 6 carbon atoms. Examples of "C1-C6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.

[0039] The term "OC1-C6" refers to C1-C6 alkyl groups bonded to an oxygen atom. Examples of "OC1-C6" include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, n-hexoxy, iso-hexoxy, 3-methylpentoxy, 2,3-dimethylbutoxy, and neohexoxy and n-hexoxy.

[0040] The term "C1-C3 alkyl" refers to a linear or branched, saturated or unsaturated alkyl group consisting of 1 to 3 carbon atoms. Examples of "C1-C3 alkyl" include, but are not limited to, methyl, ethyl, vinyl, allyl, n-propyl, and isopropyl alkyl groups.

[0041] The term "five-membered heterocycle" refers to a five-membered saturated or unsaturated heterocycle. Examples of five-membered heterocycles, but not limited to these, include pyrrolidine, tetrahydrofuran, thiolane, pyrrole, furan, thiophene, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidinedion, isothiazolidine, dioxolane, dithiolane, imidazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole.

[0042] The term "six-membered heterocycle" refers to a six-membered saturated or unsaturated heterocycle. Examples of six-membered heterocycles, but not limited to these, include piperidine, pyridine, piperazine, morpholine, and thiomorpholine.

[0043] The Q substituent of a compound of formula I can be located at the ortho, meta, or para position. For example, the Q substituent can be in the compound: [ka] It may be located in the meta position to provide Q. Examples of compounds of formula I in which Q is located in the para position include the compounds of formula Ia and formula Ib1 described herein.

[0044] R 2 Compounds of formula I described herein, or pharmaceutically acceptable salts thereof, are also provided, having the further condition that when is H, m is 1.

[0045] The piperidine ring of the compounds disclosed herein, such as the compound of formula I, may have an S configuration at carbon 2 and 3. Alternatively, the compounds disclosed herein, such as the compound of formula I, may have an R configuration at carbon 2 and 3. This is exemplified with respect to the compound of formula I, which is provided as a compound of formula I' and / or formula I''. [ka]

[0046] For example, a compound of formula I may be a compound of formula I'. In further examples, a compound of formula I is provided as a compound of formula I''. In even further examples, mixtures such as a 1:1 mixture of a compound of formula I' and a compound of formula I'' are provided.

[0047] Q can be C, i.e., carbon, thereby providing the compound of formula Ia. [ka]

[0048] Alternatively, Q can be N, i.e., nitrogen, thereby providing the compound of formula Ib. [ka]

[0049] It will be understood that the compound of formula Ib may be provided as the compound of formula Ib1, formula Ib2, or formula Ib3. [ka]

[0050] The value of n may be 1. Thus, a compound of formula I described herein is provided, which may be named formula II, where n is 1. [ka]

[0051] Examples of compounds of formula II include the compound of formula IIa (wherein Q is carbon), as well as the compounds of formula IIb, formula IIc, and / or formula IId (wherein Q is nitrogen). [ka]

[0052] For example, the compound of formula IIa is the same as the compound of formula IIa1. [ka]

[0053] Furthermore, the value of m may be 1. Thus, a compound of formula I described herein, which may be named formula III, is provided, where m is 1. [ka]

[0054] Examples of compounds of formula III include the compound of formula IIIa (wherein Q is carbon), as well as the compounds of formula IIIb, formula IIIc, and / or formula IIId (wherein Q is nitrogen). [ka]

[0055] Substituent R 1 It could be H. Or, R. 1 (CH2) p It could be Z. Z is [ka] A selection can be made from the group consisting of the following:

[0056] For example, Z is [ka] It is possible.

[0057] Alternatively, Z is, [ka] It could be, During the ceremony, R 6 This is the chelate portion or its radionuclide complex, q is 2, 3, 4, or 5. 6 Linker NH(CH2) q It will be understood that the substituted triazole compound is bound via this mechanism.

[0058] The chelate portion may include a cyclic chelating agent such as a macrocyclic chelating agent, or an acyclic chelating agent containing one or more heteroatoms such as oxygen or nitrogen atoms that can coordinate and / or capture radionuclides. Furthermore, the chelate portion R 6 Linker NH(CH2) q It may contain a carboxylic acid group that forms an amide bond with the nitrogen atom. For example, R 6 It may contain one or more of the following chelate moieties, namely DOTA, NOTA, TETA, DTPA, NODAGA, DOTAGA, DFO, or derivatives of any one of the aforementioned chelate moieties. The chemical structures of the aforementioned compounds are shown in Figures 9-15. For example, R 6 teeth, [ka] It may be a chelate portion selected from the group consisting of the following:

[0059] In further examples, R 6 teeth, [ka] It is a chelate moiety containing or consisting of.

[0060] The value of p can be 0, 1, 2, or 3. For example, p could be 1.

[0061] The value of q can be 2, 3, 4, or 5. For example, q could be 4.

[0062] Furthermore, R 6 This can be a radionuclide complex of the chelate portion. The radionuclide complex may contain or consist of the chelate portion and a radionuclide. In this way, the diagnostic, therapeutic, or prophylactic effects of the compound of formula I may be further improved.

[0063] The radionuclide and chelate portion of the radionuclide complex may be supplied in a 1:1 ratio. The radionuclide can be any radionuclide suitable for the intended purpose. For example, the radionuclide may be: 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 / 165 Tb, 226 / 227 The group can be selected from Th and its ions. In particular, the radionuclide may be an ion such as a cation that can coordinate to a heteroatom such as a nitrogen or oxygen atom in the chelate portion. For example, the radionuclide may be: 177 Lu 3+ etc. 177 It contains or consists of Lu.

[0064] For example, R 6 DOTA and 177 Lu 3+ Includes, [ka] To provide.

[0065] R 6It will be understood that the selection of the radionuclide for the radionuclide complex depends on the intended use, such as an 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 from the group consisting of 68 Ga, 18 F, 64 Cu, 44 Sc, 89 Zr, and 86 / 90 Y. In a further example, when single photon emission computed tomography (SPECT) is the imaging method, the radionuclide can be selected from the group consisting of, for example, 111 In, 67 Ga, 99m Tc, and 177 Lu. Also, the radionuclide used for treatment can be selected from the group consisting of, for example, 177 Lu, 161 Tb, and 225 Ac.

[0066] Substituent R 1 can be selected from the group consisting of H,

Chem.

[0067] For example, the R 1 substituent can be H, or

Chem.

[0068]

[0069] In one example, a compound of formula I is provided, wherein X is O and / or R 3 is OH and / or R 2 is H and / or p is 1. The R 2 substituent can be H or OH. In one example, R 2 is H. In a further example, R 2 is OH.

[0070] R 3 The substituent can be H or CH3. For example, R 3 can be H.

[0071] R 4 and R 5 substituents can independently be selected from the group consisting of H, CF3, OC1-C6 alkyl, such as OCH3 or OCH(CH3)2, OCF3, F, NO2, and CN. Alternatively, R 4 can be selected from the group consisting of CF3, OC1-C6 alkyl, such as OCH3 or OCH(CH3), OCF3, F, NO2, and CN, and R 5 can be selected from the group consisting of H, CF3, OC1-C6 alkyl, OCF3, and CN.

[0072] R 4 and R 5 substituents can both be CF3. Alternatively, R 4 and R 5 substituents can both be CN.

[0073] Furthermore, Y can include one or more of the following, or can consist of them: 123 I, 124 I, 125 I. Alternatively, Y can 131 include I or can consist of it. In a further example, Y can be a stable isotope 127 of I. In yet a further example, Y can 211 include At or can consist of it.

[0074] The following: 4-((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol, 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol, 5-(((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 4-((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol, 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol, 5-(((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-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-phenylpiperidine-1-yl)methyl)-4,5-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-3-((3-iodobenzyl)oxy)-2-phenylpiperidine, 3-(((2S,3S)-3-((3-iodobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-1H-1,2,4-triazole-5(4H)-one, 5-Iodo-2-methoxy-3-((((2S,3S)-2-phenylpiperidine-3-yl)oxy)methyl)pyridine, 3-(((2S,3S)-3-((5-iodo-2-methoxypyridine-3-yl)methoxy)-2-phenylpiperidine-1-yl)methyl)-1H-1,2,4-triazole-5(4H)-one, (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidine-3-amine, or Also provided are compounds of formula I, which are one or more of the compounds described above, or pharmaceutically acceptable salts of any one of the aforementioned compounds.

[0075] Furthermore, the following: 4-((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-iodophenol, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol, 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol, or A compound of formula I, which is one or more of (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine, or Iodine is an iodine radioactive isotope, one of the aforementioned compounds, or one of the aforementioned compounds, or A pharmaceutically acceptable salt of any one of the aforementioned compounds or their iodine radioactive isotopes is provided.

[0076] below: 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol, 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-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-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine, 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, 5-Iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidyl)oxymethyl)pyridine, 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidine-3-amine, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-iodophenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-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-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-N-((5-iodopyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-isopropoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridine-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-phenylpiperidine-3-amine, 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-1-((6-methylpyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenyl-1-(pyridine-2-ylmethyl)piperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenyl-1-(pyrimidine-2-ylmethyl)piperidine-3-amine, 2-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)pyrimidine 1-oxide, 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-1-((1H-imidazole-2-yl)methyl)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)pyrimidine 1-oxide, (2S,3S)-3-((3-( 125 I) Iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine, (2S,3S)-N-((5-( 125 I) Iodo-2-methoxypyridine-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)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125I) Iodophenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, [ 177 One or more compounds of formula I, consisting of Lu]-lutetium(III)-2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, or A pharmaceutically acceptable salt of any one of the aforementioned compounds is also provided.

[0077] Furthermore, the following: 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol, 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-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-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine, 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidine-3-amine, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-iodophenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-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-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidine-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-phenylpiperidine-3-amine, 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)pyrimidine 1-oxide, (2S,3S)-3-((3-( 125 I) Iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine, (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)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, [ 177 One or more compounds of formula I, consisting of Lu]-lutetium(III)-2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, or A pharmaceutically acceptable salt of any one of the aforementioned compounds is provided.

[0078] below: 5-Iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidyl)oxymethyl)pyridine, 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodopyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-isopropoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)piperidine-3-amine, 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-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-phenylpiperidin-3-amine, (2S,3S)-N-((4-( 125 I)Iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine, or one or more of the compounds of formula I, or There is further provided a pharmaceutically acceptable salt of any one of the foregoing compounds.

[0079] Furthermore, 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)piperidin-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-phenylpiperidin-3-amine, (2S,3S)-N-((4-( 125 I)iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3-amine, or one or more of the compounds of formula I, or a pharmaceutically acceptable salt of any one of the foregoing compounds is provided.

[0080] Unexpectedly, the compounds of the present disclosure have been found to bind to NK1R, i.e., neurokinin 1 receptor, which is associated with and overexpressed in many cancers such as neuroblastoma. Thus, the presence of the large iodine atom in the compounds does not prevent interaction with NK1R. This is an important advantage as iodine can be provided as different isotopes in the compounds, thereby enabling different therapeutic uses. For example, some isotopes can be used for diagnosis, including diagnosis such as diagnostic imaging, and other isotopes can be used in combination with therapy. Thus, the same compound can be labeled with different isotopes depending on the desired use to provide a theranostic pair consisting of a diagnostic and a therapeutic compound.

[0081] Furthermore, the compounds of the present disclosure have been found to specifically bind to NK1R. This is important to ensure specific accumulation of the compound at the intended therapeutic site(s) and to avoid non-specific uptake in healthy tissues / organs (i.e., tissues and / or organs not intended to be targeted by the therapy) so that associated side effects are minimized.

[0082] Pharmaceutical compositions are also provided, comprising a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0083] A pharmaceutical composition may be a pharmaceutical composition for intravenous administration. For example, a pharmaceutical composition for intravenous administration may be a solution, such as an aqueous solution, containing a compound of formula I or a pharmaceutically acceptable salt thereof.

[0084] In a further example, the pharmaceutical composition may be an oral pharmaceutical composition. In particular, the oral pharmaceutical composition may contain a compound of formula I, where Y is 127 I or 125 It contains or consists of I. For example, an oral pharmaceutical composition may be provided as a liquid, such as a syrup, suspension, or solution. Alternatively, an oral pharmaceutical composition may be provided as a solid, such as a tablet, capsule, or lozenge.

[0085] Furthermore, compounds of formula I described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions are provided for use as pharmaceuticals in therapy.

[0086] Further provided are compounds of formula I described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in the diagnosis, treatment, and / or prevention of cancer.

[0087] This disclosure also provides the use of compounds of Formula I described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for the manufacture of pharmaceuticals for the diagnosis, treatment, and / or prevention of cancer.

[0088] Furthermore, the present disclosure provides a method for the diagnosis, treatment, and / or prevention of cancer, the method comprising administering to a patient, such as a human or animal, in need, an effective amount, for example, a therapeutically effective amount, of a compound of formula I described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0089] As used herein, the term “therapeutic dose” refers to the amount of a compound that produces a therapeutic effect on a treated patient. This effect may be objective (i.e., measurable by several tests or markers) or subjective (i.e., the subject gives an indicator of the effect and / or feels the effect).

[0090] The cancers described herein may 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, rhabdoid cancer, and any combination(s) of these. For example, the cancer may be neuroblastoma.

[0091] As used herein, the terms “treatment” (and similarly “to treat”) are as they are commonly used in the field of medicine. In particular, the terms may refer to achieving a degree of severity of one or more clinical symptoms of a disease or condition. Furthermore, the terms “prevention” (and similarly “to prevent”) 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%, e.g., a reduction of at least 20%, 30%, or 40%, e.g., a reduction of at least 50%).

[0092] Compounds of formula I described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions may be administered to certain patient groups, such as children up to 14 years of age, or to patients over 14 or 15 years of age, such as adults. In particular, the diagnosis, treatment, and / or prevention of neuroblastoma may include administration to children.

[0093] It will be understood that the compounds of this disclosure may include iodine radionuclides selected from: as labels enabling the diagnosis, treatment, and / or prevention of one or more cancers described herein. 123 I, 124 I, 125 I, or 131 I. For example, radioactive nuclides are, 125 It could be I.

[0094] The selection of an iodine radionuclide determines whether the compound, or a pharmaceutically acceptable salt thereof, is used for diagnosis or treatment, and consequently, diagnostic and therapeutic compounds differ only in the selection of the iodine radionuclide. Therefore, the same compound can be labeled with different radionuclides to provide a theranotic pair consisting of a diagnostic and therapeutic compound.

[0095] For example, the iodine radionuclide in the compound of formula I may be available for use in diagnostics. For example, the iodine radionuclide is 124 Positron-emitting radionuclides such as I, or 123 I, 125 I, or 131 It may be a radionuclide that can be detected by a gamma camera such as I. In this way, the compound can function as a diagnostic tool, radiotracer, monitoring agent, or in in vivo receptor imaging.

[0096] In a further example, the iodine radioactive isotope in the compound of formula I enables its use in radiotherapy. 131 I may be the case. Treatment may include induction therapy, consolidation therapy, and / or minimal residual disease (MRP) treatment. Therapeutic compounds may be administered during induction therapy, i.e., during treatment in the early stages of cancer. In further examples, therapeutic compounds may be administered during consolidation therapy, i.e., during therapy used after initial treatment that targets remaining cancer cells. In yet another example, therapeutic compounds may be administered to address minimal residual disease, i.e., to kill the small number of cancer cells remaining in the body after cancer treatment.

[0097] Physical methods that can be used in conjunction with the present disclosure can be selected from positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed tomography (CAT), or combinations thereof.

[0098] Instead of or in addition to an iodine radionuclide, the compounds of the present disclosure can contain stable iodine isotopes 127 I. Thus, Y can contain 127 I in the compound of formula I or consist of it. Compounds of the present disclosure containing stable iodine isotope 127 I are considered, for example, to be useful for the prevention of the diseases described herein.

[0099] The compounds of formula I described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, can be provided in a diagnostically effective amount, i.e., an amount that enables the desired diagnostic effect to be achieved. For example, the diagnostically effective amount can be adjusted to enable imaging. Further, it will be understood that the diagnostically effective amount can be adjusted according to the route of administration, such as intravenous or oral administration.

[0100] The compounds of formula I described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, can be provided in a therapeutically effective amount, i.e., an amount that enables the desired therapeutic effect to be achieved. The effect can be objective (i.e., measurable by some tests or markers) or subjective (i.e., the subject gives an indication of the effect and / or feels the effect). For example, the therapeutically effective amount can be adjusted to provide radiation therapy. Further, it will be understood that the therapeutically effective amount can be adjusted according to the route of administration, such as intravenous or oral administration.

[0101] Furthermore, compounds of formula I, such as the compounds of formula I described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, can be administered an appropriate number of times at a frequency suitable to achieve the desired diagnostic or therapeutic effect.

[0102] For example, the compounds of formula I described herein, or their pharmaceutically acceptable salts, or pharmaceutical compositions may be administered daily, such as once a day. Alternatively, the compounds of formula I described herein, or their pharmaceutically acceptable salts, or pharmaceutical compositions may be administered over a suitable period of time, such as enough time to cure cancer such as neuroblastoma.

[0103] This disclosure also provides compounds of formula IV, which are compounds of formula I, where both n and m are 0. Furthermore, the R1 substituent may include tert-butoxycarbonyl (BOC).

[0104] Compounds of formula IV may be used to prepare compounds of formula I. In addition, or separately, compounds of formula IV may be for use as pharmaceuticals in therapy. For example, compounds of formula IV may be used in the diagnosis, treatment, and / or prevention of cancer, as described herein for compounds of formula I.

[0105] Therefore, the compound is of formula IV, [ka] During the ceremony, R 1 However, for compounds of formula IV, as described herein, or with protecting groups such as tert-butoxycarbonyl, R 2 , R 3 , R 4 , R 5 A compound is provided in which X, Q, p, and q are as described for the compound of formula I.

[0106] For example, a compound of formula IV, in which, R 1 However, H or (CH2) p Z is Z, R 2 However, it is H, OH, or F, R 3 However, it is H or C1-C3 alkyl, R 4 However, it is selected from the group consisting of H, CF3, OC1-C6alkyl, OCF3, CN, F, and NO2. R 5 However, it is selected from the group consisting of H, CF3, OC1-C6alkyl, OCF3, CN, F, and NO2. Q is either C or N, X is either O or NH, Z is a 5-membered or 6-membered heterocycle containing 1, 2, or 3 nitrogen atoms and / or an N-oxide, and the heterocycle independently comprises F, Cl, Br, I, OH, C1-C3 alkyl, oxo, and (CH2) q NHR 6 It is substituted with 0, 1, 2, or 3 substituents selected from the group consisting of the following: p is 0, 1, 2, or 3, R 6 However, the chelate portion or its radioactive nuclide complex, q is 2, 3, 4, or 5, substituent [ka] However, compounds are provided that are in a cis position relative to each other.

[0107] Furthermore, it will be understood that the piperidine ring of the compound of formula IV may have an S configuration at carbon 2 and 3, or an R configuration at carbon 2 and 3.

[0108] Examples of compounds of formula IV include the compound of formula IVa (wherein Q is carbon), as well as the compounds of formulas IVb, IVc, and / or IVd (wherein Q is nitrogen). [ka]

[0109] For example, R 2 But, OH: [ka] for example, [ka] A compound of formula IV is provided.

[0110] Further examples provide compounds of formula IV, which are 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol or 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one.

[0111] In a further example, Z is (CH2). q NHR 6 Compounds of formula IV described herein, which are substituted with , are provided.

[0112] For example, Z is [ka] It is possible.

[0113] combination Compounds of formula I, or pharmaceutically acceptable salts thereof, may be administered alone or in combination with further pharmaceuticals for the treatment of cancer. Thus, combinations of compounds of formula I, or pharmaceutically acceptable salts thereof, and pharmaceuticals for the treatment of cancer are provided. The combination may be a single composition in which the compound of formula I, or pharmaceutically acceptable salt thereof, and further pharmaceuticals for the treatment of cancer are mixed together. Alternatively, the combination may be provided as a kit of parts, including (i) the compound of formula I, and / or a pharmaceutically acceptable salt thereof, and / or (iii) further pharmaceuticals for the treatment of cancer, and (iii) optionally instructions for use.

[0114] salt Compounds of the present disclosure, such as the compound of formula I, may be provided as pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of the compounds of the present disclosure may be, for example, acid addition salts.

[0115] Examples of pharmaceutically acceptable salts include, without limitation, non-toxic inorganic and organic acid addition salts, such as hydrochlorides, hydrobroms, borates, nitrates, perchlorates, phosphates, sulfates, formates, acetates, aconates, ascorbicates, benzenesulfons, benzoates, cinnamates, citrates, embonates, enantates, fumarates, glutamates, glycolates, lactates, maleates, malons, mandelates, methanesulfons, naphthalene-2-sulfons, phthalates, propions, salicylates, sorbates, stearates, succinates, tartrates, toluene-p-sulfons, and any combination thereof. Such salts can be formed by procedures that are well known and described in the art.

[0116] It will be understood that proton transfer may occur between the compound of formula I described herein and the acid that forms the salt together. Proton transfer may occur to varying degrees.

[0117] stereoisomer It will be understood that the compounds described herein are chiral. In particular, the compounds of formula I exhibit cis stereochemistry, i.e., both phenyl substituents are cis relative to each other, as exemplified by the chemical structures shown herein. It will be understood that the compounds of formula I may be provided as a single enantiomer or as a mixture of enantiomers, such as a racemic mixture.

[0118] For example, the compounds described herein may be provided as (S,S) enantiomers. Alternatively, the compounds may be provided as (R,R) enantiomers, or as mixtures such as a racemic mixture of (S,S) enantiomers and (R,R) enantiomers.

[0119] To avoid any ambiguity, a compound said to have a specific stereochemistry at a defined position may also have stereochemistry at one or more other positions and therefore may exist as a mixture of enantiomers or diastereoisomers related to the stereochemistry at those positions.

[0120] Solvates or hydrates It will be understood that the compounds of formula I described herein may be provided as solvates or as solvates of pharmaceutically acceptable salts of the compounds of formula I. It should be understood that this disclosure encompasses all such solvates or hydrates.

[0121] cocrystal In salts, proton transfer can occur between the active pharmaceutical ingredient and the salt's counterion. However, in some cases, there may be no partial proton transfer, or only partial proton transfer, and therefore the solid is not a true salt. It is recognized that proton transfer is actually continuous and can change with temperature, and therefore, the point that salts are better described as “cocrystals” may be subjective. As used herein, the term “cocrystal” refers to a multicomponent system containing one or more host molecules (active pharmaceutical ingredients) and one or more guest (or co-forming) molecules. The guest or co-forming molecules are defined as existing as solids at room temperature to distinguish cocrystals from solvates. However, cocrystals themselves can form solvates. In cocrystals, interactions via nonionic forces, such as hydrogen bonds, are generally dominant. It will be understood that all cocrystals fall within the range of compounds described herein.

[0122] polymorph The compounds of this disclosure may exist in a continuous solid state ranging from completely amorphous to completely crystalline. Therefore, it should be understood that all polymorphs, including mixtures of different polymorphs, are included within the scope of the claimed compounds.

[0123] Prodrug The compounds of this disclosure may be administered in the form of prodrugs. Prodrugs are compounds that may have little or no pharmacological activity themselves, but when such compounds are administered into or onto a patient's body, they are converted to compounds of formula I.

[0124] Preparation method This disclosure relates to a method for preparing a compound of formula I described herein, for example, a compound of formula II and / or a compound of formula III, or a pharmaceutically acceptable salt thereof, wherein the method is -A compound of formula IV, [ka] During the ceremony, R 1 However, for compounds of formula I, as described herein, or with protecting groups such as tert-butoxycarbonyl, R 2 , R 3 , R 4 , R 5 X and Q are as described for the compound of formula I, substituent [ka] However, compounds that are in a cis position relative to each other The steps include subjecting the material to iodation or astatination to provide a compound of formula I, -The present invention provides a method comprising the optional step of combining a compound of formula I with a pharmaceutically acceptable acid.

[0125] For example, the compound of formula IV in the method described herein is 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol or 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one.

[0126] The iodization or astatination method is a) Compounds of formula IV 127 Iodination with I results in the compound of formula I, where Y is 127 I is the step of providing a compound, b) 127 By substituting I with a boron or metal-containing compound such as Sn(CH3)3, a compound of formula V is obtained. [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 X and Q are as defined for the compound of formula IV, M is a boron or metal-containing compound. n is 0 or 1, m is 0 or 1, substituent [ka] However, they are positioned in a cis position relative to each other. however, The step of providing a compound where n+m=1, c) Boron or metal-containing compound M is an iodine radioactive isotope or as described herein. 211 Substituting with At, the compound of formula I, where Y is an iodine radioactive isotope as described herein or 211 The process may include the step of preparing a compound, which is At.

[0127] Examples of compounds of formula V include compounds of formula Va (wherein Q is carbon), as well as compounds of formulas Vb1, Vb2, and / or Vb3 (wherein Q is nitrogen). [ka]

[0128] especially, tert-butyl(2S,3S)-2-phenyl-3-((3-(trifluoromethyl)-5-(trimethylstannyl)benzyl)oxy)piperidine-1-carboxylate, tert-butyl(2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-carboxylate, tert-butyl(2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridine-2-yl)methyl)amino)piperidine-1-carboxylate, and A compound of formula V is provided, selected from the group consisting of tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethylstannyl)benzyl)amino)piperidine-1-carboxylate. It will be understood that the aforementioned compound of formula V may be used in the manner described herein.

[0129] Alternatively, the iodination method may include providing a compound of formula IV to YCl, where Y is an iodine radioisotope as described herein. YCl is iodine monochloride prepared from N-chloro-p-toluenesulfonamide or N-chlorosuccinimide, and Na 123 I, Na 124 I, Na 125 I, and Na 131 It may be a sodium iodide salt selected from the group consisting of I.

[0130] In particular, R 2 Compounds of formula IV with an OH substituent are (i) iodinated, such as iodination with stable iodine or radioactive iodine nuclides, or (ii) 211 It can be used for astatination, including astatination involving At.

[0131] Preparation of the compounds of this disclosure is further illustrated below.

[0132] Iodination may be carried out to prepare the compound of formula II or formula III, where Y is 127 The compound is I, and optionally, radiolabeling with a radioactive isotope of iodine is then carried out via an exchange reaction. For example, the compound of formula II or III. 127 I can be replaced with a (substituted) metal or boron-containing compound M to provide an intermediate, which is then radiolabeled with an iodine radioactive isotope. This is illustrated in Scheme 1 for the enantiomers of the compounds of formulas II and III, respectively, where Q is located in the meta position. [ka]

[0133] In Scheme 1, and in other schemes herein, R 1 , R 2 , R 3 , R 4 , R 5 It will be understood that unless otherwise specified, Q and X may be as described herein, I* may be an iodine radioactive isotope as described herein, and M may be trialkylstannyl, trialkylsilyl, B(OH)2, BF3, or B(Oalkyl)2. The starting materials for the compounds in Scheme 1 may be prepared as described herein and / or using methods described in the art.

[0134] In further examples, the iodination of compounds described herein, such as the compound of formula IV, may be carried out using a salt containing chloramine T or N-chlorosuccinimide (NCS) and an iodine radionuclide in the presence of a solvent such as PBS. Iodine monochloride is thus produced, which is thought to act as an iodinating agent. Chloramine T, which may be abbreviated as CAT, is N-chloro-p-toluenesulfonamide and can be purchased or prepared by reacting p-toluenesulfonamide with sodium hypochlorite. The salt containing the iodine radionuclide may be a sodium iodide salt of a suitable isotope-labeled iodide. For example, the radioiodination of the compound of formula IV may be carried out using an iodine-125 radionuclide solution containing chloramine T and PBS having a pH of 7.4. The iodine-125 radionuclide solution may contain or consist of the iodine-125 radionuclide and an aqueous sodium hydroxide solution (e.g., at a concentration of 0.1 N). Furthermore, the iodine-125 radionuclide solution may be free of reducing agents and / or have a pH of 12-14. Scheme 2A illustrates the iodination of the enantiomer of the compound of formula IV, where Q is located in the meta position and R 1 This is as described herein, but instead of hydrogen, chloramine T and Na[ 125 Using [I], we provide the compound of formula I, where Q is located in the meta position and Y is 125 I and R 1 This is as described herein. [ka]

[0135] Scheme 2B is R 1 This is a tert-butoxycarbonylcarbonyl group (Boc). 127 A compound containing I, R 1 That is hydrogen. 125 The conversion to the compound of this disclosure labeled with I is illustrated. [ka]

[0136] Compounds of the present disclosure, 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 with Q in the meta position can be prepared as shown in Scheme 3. Furthermore, a compound of formula IV with Q in the meta position can be prepared as illustrated in Scheme 4. Scheme 5A further illustrates a method for preparing the compounds of the present disclosure. [ka] [ka] [ka]

[0137] The starting compound in Scheme 5A can be prepared as shown in Scheme 5B. [ka]

[0138] Scheme 6 illustrates the synthesis of the compounds of this disclosure in which X is nitrogen. [ka]

[0139] In scheme 7, X is nitrogen, and R 2 Examples of the synthesis of compounds that can be used to prepare the compounds of this disclosure, wherein the compound may be fluorine, are provided. [ka]

[0140] In this specification, unless otherwise specified, drawings and / or nomenclas of chemical compounds are made 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. In the event of any discrepancy between drawings and nomenclas, the drawing of the chemical structure shall be deemed correct. Furthermore, the names of isotopically substituted compounds are formed by inserting the nuclide symbol in parentheses before the name of that part of the isotopically substituted compound.

[0141] This disclosure also provides the following aspects:

[0142] Appearance 1 A compound of formula I, [ka] During the ceremony, R 1 However, H or (CH2) p Z is Z, R 2 However, it is H, OH, or F, R 3 However, it is H or C1-C3 alkyl, R 4 However, it is selected from the group consisting of H, CF3, OC1-C6 alkyl, OCF3, and CN. R 5 However, it is selected from the group consisting of H, CF3, OC1-C6 alkyl, OCF3, and CN. Q is either C or N, X is either O or NH, Y 127 I, 123 I, 124 I, 125 I, and 131 Selected from the group consisting of I, Z is a 5-membered or 6-membered heterocycle containing 1, 2, or 3 nitrogen atoms, and the heterocycle is independently substituted with 0, 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, I, OH, C1-C3 alkyl, and oxo. n is 0 or 1, m is either 0 or 1. p is 0, 1, 2, or 3, The substituent [ka] However, they are positioned in a cis position relative to each other. however, n+m=1 or n+m=0, R 2 When is H, m is 1, compound, or a pharmaceutically acceptable salt thereof.

[0143] Appearance 2 R 4 However, it is selected from the group consisting of CF3, OC1-C6alkyl, OCF3, and CN. R 5 However, it is selected from the group consisting of H, CF3, OC1-C6 alkyl, OCF3, and CN. n+m=1 or n+m=0, When n=0, R 2 The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is an OH group.

[0144] Appearance 3 A compound according to embodiment 1 or 2, which is a compound of formula I' and / or formula I'', or a pharmaceutically acceptable salt thereof. [ka]

[0145] Pattern 4 A compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Q is C.

[0146] Appearance 5 n+m=1, The compound according to any one of embodiments 1 to 4 provides a compound of formula IIa or formula IIb. [ka] or a pharmaceutically acceptable salt thereof.

[0147] Appearance 6 The compound of formula IIa1, the compound of formula IIa described in embodiment 5, [ka] or a pharmaceutically acceptable salt thereof.

[0148] Appearance 7 n+m=0, R 2 However, it is OH, This provides a compound of formula III, as described in any one of embodiments 1 to 4, [ka] or a pharmaceutically acceptable salt thereof.

[0149] Appearance 8 The compound of formula IIIa, the compound of formula III described in embodiment 7, [ka] or a pharmaceutically acceptable salt thereof.

[0150] Appearance 9 R 1 However, H, or [ka] A compound described in any one of the prior art embodiments, or a pharmaceutically acceptable salt thereof.

[0151] Appearance 10 X is O, R 2 However, it is OH, R 3 However, H is, A compound according to any one of the prior art, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0152] Appearance 11 R 4 and R 5 However, are both CF3 or R 4 and R 5 However, both are CN, the compound described in any one of the prior art, or a pharmaceutically acceptable salt thereof.

[0153] Appearance 12 Y (i) 123 I, 124 I, and / or 125 I, or (ii) 131 A compound according to any one of embodiments 1 to 6 or 9 to 11, comprising or consisting of I, or a pharmaceutically acceptable salt thereof.

[0154] Appearance 13 Y 127 A compound comprising or consisting of I, any one of embodiments 1-6 or 9-11, or a pharmaceutically acceptable salt thereof.

[0155] Appearance 14 A pharmaceutical composition comprising a compound described in any one of the prior embodiments, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0156] Appearance 15 For use as a pharmaceutical in therapy, the compound described in any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, The pharmaceutical composition described in Embodiment 14.

[0157] Appearance 16 For use in the treatment and / or prevention of cancer selected from the group consisting of neuroblastoma, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination thereof, the compound described in any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, The pharmaceutical composition described in Embodiment 14.

[0158] Appearance 17 For use in the diagnosis of cancer selected from the group consisting of neuroblastoma, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination thereof, a compound described in any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to embodiment 14, depending on embodiment 12.

[0159] Appearance 18 The compound or pharmaceutical composition for use according to embodiment 16 or 17, wherein the cancer includes or consists of neuroblastoma.

[0160] Other embodiments This disclosure also provides compounds of formula I, as described herein, or pharmaceutically acceptable salts thereof, where m+1=0. Thus, compounds of formula IV, as described herein, or pharmaceutically acceptable salts thereof are provided.

[0161] This disclosure may be further described by reference to the following examples, which are not intended to limit the scope of this disclosure. [Examples]

[0162] overview Human neuroblastoma cell lines SKNAS and IMR-32 were obtained from the American Type Culture Collection (Manassas, VA, USA). IMR-32 was cultured in MEM Earle's (Biochrom, Berlin, Germany or Sigma Aldrich, Darmstadt, Germany), and SKNAS was cultured in DMEM (Dulbeccoo's 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). The medium for SKNAS was further supplemented with 1% non-essential amino acids (Thermo Fisher, Waltham, MA, USA). Cells were passaged 1-3 times per week 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 minimal 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, cell passage was performed using trypsin-EDTA (Biochrom GmbH, Germany).

[0163] HiTSeeker cell lines expressing human tachykinin receptor 1 in U2OS osteosarcoma cells (DNA accession number: GenBank: AY462098), TACR1(NK1) / U2OS(U2O2-NK1R), were 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's Modified Eagle Medium (Gibco® DMEM, high glucose, GlutaMAX® supplement, pyruvate, catalog no. 31966021), supplemented with 10% (v / v) fetal bovine serum (FBS) (Merck, catalog no. F7524), 100 IU / ml penicillin-streptomycin solution (Gibco® catalog no. 15140-122), and 0.5 mg / ml Geneticin (Gibco, catalog no. 10131-027). Monolayer cultures were grown in tissue culture flasks (VWR, catalog no. 734-2313) in a humidified incubator at 37°C with 5% CO2.

[0164] Aprepitant (CAS number: 170729-80-3) was obtained from the United States Pharmacopeia (1041904-150 mg). FAM-labeled substance P, FAM-SP, (catalog number AS-61201) was obtained from AnaSpec, USA. Where used herein, substance P is a member of the undecapeptide tachykinin neuropeptide family. Substance P, which may be abbreviated as SP, was obtained from Sigma Aldrich (catalog number S6883) and has CAS number 33507-63-0. 125-Radioactive iodine or iodine-125 radionuclide (17Ci(629 GBq) / mg, 0.1 M NaOH, pH 12-14, reducing agent-free) was obtained from PerkinElmer Inc., USA and shipped under ambient temperature conditions.

[0165] Abbreviation BBB (Blood-Brain Barrier) Boc tert-butoxycarbonyl BOC tert-butoxycarbonyl CAS Chemical Abstracts Service CAT Chloramine T DCM Dichloromethane DEAD Diethylazodicarboxylate DFO Deferoxamine DIBAL Diisobutylaluminum Hydrogenate DIPEA N,N-diisopropylethylamine DMEM Dulbecco's Modified Eagle Medium DMF Dimethylformamide DOTA 2,2',2'',2''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid DOTAGA 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid) DTPA (Diethylenetriaminepentaacetic acid) EDC 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide FAM-SP Fluorescent (FAM) Labeled Substance P FBS (Fetal Bovine Serum) GPCR G protein-coupled receptor hNK1 Human Neurokinin 1 HPLC (High-Performance Liquid Chromatography) ITLC (Instant Thin-Layer Chromatography) K D Dissociation constant L-Selectlid Li[(CH3CH2CH(CH3)))BH] LCMS-ESI Liquid Chromatography Mass Spectrometry Electrospray Ionization minutes (multiple minutes allowed) MBq Megabecquerel N Normality NBL neuroblastoma NBS Sodium Metabisulfite NK1R (neurokinin 1 receptor) NOTA 2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid NODAGA 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid PBS (phosphate-buffered saline) PET positron emission tomography rt room temperature RT room temperature SP Substance P TBAF Tetra-N-butylammonium fluoride TBS tert-butyldimethylsilyl TBSOTf tert-butyldimethylsilyl trifluoromethanesulfonate TEA (Triethylamine) TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrayl)tetraacetic acid TFA (Trifluoroacetic Acid) Ts-P-toluenesulfonyl THF (Tetrahydrofuran) v / v Volume per unit volume

[0166] chemistry Preparation of starting materials for Examples 1-4 Preparation of benzyl 3-hydroxy-2-methoxypiperidine-1-carboxylate A homogeneous solution of 3,4-dihydropyridine-1(2H)-carboxylate (1 g, 4.603 mmol) dissolved in MeOH (30 mL) was added at room temperature (RT) to a stirred suspension of oxone (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 hours, followed by the addition of more oxone (1.681 g, 5.468 mmol) and NaHCO3 (0.459 g, 5.468 mmol). The resulting reaction mixture was stirred for 12 hours, and the progress of the reaction was monitored by thin-layer chromatography using a 1:1 ethyl acetate / hexane transfer system. The solid was filtered, and the filtrate was diluted with a saturated solution of ethyl acetate (50 mL) and NaHCO3 (50 mL). The organic layer was extracted with ethyl acetate (2 × 50 mL), washed with brine (50 mL), dried on NaSO4, and evaporated to dryness under vacuum to provide a colorless oil. The title compound was purified using silica gel column chromatography (1:1 ethyl acetate / hexane) as a mixture of diastereomers (0.909 g, 74.52%). 1 H NMR (400MHz, 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=12.9Hz,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).

[0167] Preparation of benzyl(±)-cis-2-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate To a stirred solution of benzyl 3-hydroxy-2-methoxypiperidine-1-carboxylate (1.033 g, 3.897 mmol) and (4-(benzyloxy)phenyl)boronic acid (0.889 g, 3.897 mmol) in anhydrous dichloromethane (10 mL), BF3·OEt2 (480.95 μL, 3.897 mmol) was added at -30°C under a sealed N2 environment. The reaction mixture was returned to RT over 4 hours and stirred for a further 24 hours. The mixture was then quenched by adding a saturated solution of NH4Cl (10 mL), and the organic phase was extracted with ethyl acetate (2 × 10 mL). The separated organic layers were combined, washed with brine, dried over Na2SO4, and evaporated to dryness under vacuum. Silica gel column chromatography (ethyl acetate / hexane, 1 / 2 to 1 / 1) of the crude product yielded the cis isomer of the title compound as a light brown liquid (0.987 g, 60.66%). 1 H NMR (400MHz, chloroform-d)δ 7.47-7.38(m,4H),7.35(ddd,J=7.5,6.6,1.4Hz,2H),7.32-7.22(m,6H), 6.94-6.85(m,2H),5.48(d,J=5.7Hz,1H),5.11(q,J=12.5Hz,2H),4.99(s ,2H),4.06-3.90(m,2H),3.12(s,1H),2.90(td,J=13.2,3.7Hz,1H),1.79 (td,J=9.5,8.0,4.6Hz,2H),1.73-1.46(m,2H).ESI-LC-MS(+):m / z[M+H] + Calculated value (measured value): 418.51 (418.0).

[0168] Preparation of benzyl(±)-cis-2-(4-(benzyloxy)phenyl)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate A solution of (±)-cis-2-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (487.2 mg, 1.167 mmol) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (234.01 μL, 1.277 mmol) compounds in anhydrous DMF (2 mL) was added at 0°C to a stirred solution of NaH (33.69 mg, 60% dispersion in mineral oil, 1.404 mmol) in anhydrous DMF (2 mL). The reaction mixture was then transferred to a block preheated at 80°C. After stirring for 4 hours, 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 obtained was purified using silica gel column chromatography (ethyl acetate:hexane, 1:10) to provide the cis isomer of the title compound as a white liquid (137.6 mg, 18.32%). 1 1H NMR (400 MHz, chloroform-d)δ 7.70(s,1H),7.62(d,J=1.9Hz,2H),7.48-7.12(m,12H),6.91-6.79(m,2H),5 .68(s,1H),5.11(q,J=12.4Hz,2H),4.97(s,2H),4.63(q,J=12.4Hz,2H),3.9 4(dd,J=14.0,4.6Hz,1H),3.80(ddd,J=8.7,7.2,5.5Hz,1H),2.74(td,J=13. 2,3.5Hz,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).

[0169] Example 1: Preparation of a racemic mixture of 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol and 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol, i.e., 4-((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol [ka] 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol [ka] 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)phenol

[0170] The combined hydrogenolysis of the benzyl and benzyloxycarbonyl groups of the compound benzyl(±)-cis-2-(4-(benzyloxy)phenyl)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-1-carboxylate was carried out in a single step according to the procedure outlined in H. Sajiki, Tetrahedron Lett., 1995, 36, 3465. The procedure is as follows: A mixture of the compounds benzyl(±)-cis-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 in a sealed reaction vial by applying two alternative vacuum / H2 cycles and stirred at RT for 30 minutes. The mixture was then filtered through Celite, washed with MeOH (2 × 5 mL), and extracted with ethyl acetate (2 × 5 mL). The combined ethyl acetate layer was then washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. Next, the crude product was washed with pentane (2 × 5 ml) and completely evaporated to dryness under vacuum, providing the cis-isomer title compound as white solid flakes (62.5 mg, 69.71%). 11H NMR (400 MHz, methanol-d4) δ 7.84(d,J=2.2Hz,1H),7.80(d,J=1.7Hz,2H),7.36-7.25(m,2H),6.90-6.78(m,2 H),4.82(d,J=12.7Hz,1H),4.42(dd,J=7.2,5.5Hz,2H),3.96(dt,J=3.6,1.9Hz, 1H),3.51-3.38(m,1H),3.23(td,J=13.1,3.2Hz,1H),2.46-2.29(m,1H),2.20-2 .04(m,1H),1.88(dddd,J=17.0,12.6,7.5,2.6Hz,2H).ESI-LC-MS(+):m / z[M+H] + Calculated value (measured value): 420.37 (420.0). Figure 1A shows the UV HPLC analysis of the title compound.

[0171] Example 2: Preparation of a racemic mixture of 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one and 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, i.e., 5-(((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one [ka] 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one [ka] 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one A mixture of the compound from Example 1 (54.3 mg, 0.129 mmol) and 5-(chloromethyl)-1,2-dihydro-3H-1,2,4-triazole-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) at 0°C. The reaction mixture was then transferred to a preheated block at 80°C and stirred for 3 hours. The reaction product was quenched with water (2 mL) and extracted with ethyl acetate (10 mL) and brine (2 × 5 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. Silica gel column chromatography of the crude product using dichloromethane / ethyl acetate (1 / 10) under N₂ provided the cis-isomer of the title compound as a white solid (44.09 mg, 65.94%). 1 H NMR (500MHz, methanol-d4)δ 7.84(s,1H),7.76(s,2H),7.30(d,J=8.2Hz,2H),6.83-6.73(m,2H),4.6 6(d,J=12.3Hz,1H),4.20(d,J=12.3Hz,1H),3.71-3.60(m,2H),3.53-3. 34(m,1H),2.98(d,J=11.0Hz,1H),2.95-2.83(m,1H),2.36-2.20(m,2H) ,2.01(qt,J=13.1,2.7Hz,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 shows the HPLC analysis of the title compound.

[0172] Example 3: 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol and 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-(125 I) A racemic mixture of iodophenols, i.e., 4-((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Preparation of iodophenol [ka] 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol [ka] 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( 125 I) Iodophenol 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 added to ([ 125 [I]NaI, 5 MBq, was dissolved in 0.1 M NaOH, pH 12-14, mixed with a solution from PerkinElmer Inc., USA, and then CAT (15 μL) stock solution was added. The radioactive iodine reaction product was left at room temperature for 60 minutes, and the reaction product was quenched by adding NBS (30 μL), providing the desired product in a radiochemical yield of 97.6%.

[0173] Radiolabeling yield and radiochemical purity were evaluated using instant thin-layer chromatography (ITLC) and high-performance liquid chromatography (HPLC) with a built-in radioactivity detector channel.

[0174] HPLC analysis of the compounds from Example 4 and Example 6 (5-95% on solvent B, A: H2O / TFA, B: ACN / TFA, 1 mL / min, 254 nm) showed distinctly different peaks in the UV detector and radio-channel detector at 7.980 and 9.113 mins, respectively, indicating the compound of Example 6. 125 I confirmed the success of radiolabeling. Figure 1B shows the radio-HPLC analysis of the title compound.

[0175] Example 4: 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one and 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) A racemic mixture of iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, i.e., 5-(((±)-cis-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Preparation of iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one [ka] 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one [ka] 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( 125 I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one CAT (15 μL) and NBS (30 μL) stock solutions were prepared as described in Example 3.

[0176] The compound from Example 2 (10.3 μg) was used, ([ 125 [I]NaI, 5 MBq, was dissolved in 0.1 M NaOH, pH 12-14, and mixed with a solution from PerkinElmer Inc., USA. Subsequently, CAT (15 μL) was added. The radioactive iodination reaction product was left to stand at 37°C for 60 minutes. NBS (30 μL) was added. The desired product was obtained in a radiochemical yield of 99.6%.

[0177] Radiolabeling yield and radiochemical purity were evaluated using instant thin-layer chromatography (ITLC) and high-performance liquid chromatography (HPLC) with a built-in radioactivity detector channel.

[0178] HPLC analysis of the compounds from Example 5 and Example 4 (5-100% on solvent B, A: H2O / TFA, B: ACN / TFA, 1 mL / min, 254 nm) showed distinctly different peaks in the UV detector and radio-channel detector at 7.010 and 7.533 mins, respectively, indicating the absence of the compound from Example 4. 125 The success of radioactive labeling was confirmed. Figure 2B shows the HPLC analysis of the title compound.

[0179] Examples 5-54: The compounds of Examples 5-54 shown in Table 1 were prepared using the methods described herein and / or procedures known in the art. For example, the compounds of Examples 5-10 and 16-25 were prepared as shown in Scheme 5A. The compounds of Examples 11-15 and 26-34 were prepared from (2S,3S)-2-phenylpiperidine-3-amine by reductive amination with a suitable aldehyde. Examples 36-47 were prepared by alkylation as shown in Scheme 6. Examples 48-51 were prepared according to Scheme 2B, and Example 52 was prepared according to Scheme 2A. The identification of Examples 48-52 was done from the labeling reaction. 127The retention time from UV trace of a reference solution containing compound I is [ 125 This was confirmed by comparing it with the retention time from the radioactive trace of the compound. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

[0180] (2S,3S)-N-((5-[ 125 I) Preparation of the compound of Example 49, i.e., i.e., i.e., i.e. [ka] [ 125 To a vial containing [I]NaI (11 MBq in 0.1 M NaOH), tert-butyl(2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-carboxylate (15 μl, 2 mg / ml in methanol) and 10% acetic acid were added in methanol (15 μl). Chloramine-T (7.5 μl, 2 mg / ml in methanol) was added, and the mixture was heated at 50°C for 35 minutes. The mixture was allowed to stand until RT, and sodium metabisulfite (15 μl, 2 mg / ml in water) was added. TFA (100 μl) was added, and the mixture was heated at 65°C for 60 minutes. TFA (50 μl added) and the mixture were heated at 65°C for 30 minutes. 50 μl of the mixture was diluted with water and acetonitrile and purified by HPLC (biphenyl core-shell column, gradient of 20-70% MeCN in 0.1% TFA (aqueous solution)). The solvent was evaporated to obtain the title compound (2.7 MBq). The identity of the compound was confirmed as described in Example 14. 127 The retention time from the HPLC-UV trace of a reference solution containing compound I was confirmed by comparing it with the retention time from the radioactive trace of the title compound.

[0181] biology Binding affinity measurement NB cell line The binding characteristics of the compound from Example 4 in different human NB cell lines, SK-N-AS, and IMR-32 were evaluated using LigandTracer Grey (Ridgeview Instruments, Uppsala, Sweden).

[0182] Total 3 x 10 5Individual cells (IMR-32) or 2.5 × 10⁶ 5 Cells (SK-N-AS) were seeded on polydopamine-coated petri dishes according to the manufacturer's instructions (Ridgeview Instruments, Uppsala, Sweden) to allow cell adhesion, and incubated at 37°C for 24 hours. A baseline curve was then obtained by adding CO2-bound medium (3 mL, ibco / Thermo Fisher, Waltham, MA, USA) to the petri dish and running LigandTracer for 10 minutes. The compound from Example 4 (300 nM in fresh supplemental cell medium, ≥95% radiolabeling yield) was then added, and LigandTracer was run for 3-4 hours. A further 700 nM of the compound from Example 4 was added to the cell solution to obtain a final concentration of 1 μM. After running LigandTracer for 3-4 hours, the cell medium was removed and replaced with 3 mL of fresh medium, and the assay was run overnight to establish the dissociation curve. The resulting coupling curves were evaluated for different dynamic interaction models (1:1 and 1:2) using TraceDrawer 1.9 software (Ridgeview Instruments, Uppsala, Sweden).

[0183] Figures 3A–3D show the 1:1 and 1:2 kinetic analyses of the real-time binding curves of the compounds from Example 4 in human NB cell lines SK-N-AS and IMR-32. The solid lines represent the calculated fit. The recorded curves can be seen as being close to a 1:2 fit, indicating a 1:2 kinetic fit. Figure 4 shows the real-time binding curves of the compounds from Example 4 in human NB cell lines SK-N-AS and IMR-32. The highest signals were observed for IMR-32, followed by SK-N-AS.

[0184] Table 2 shows the equilibrium dissociation constants (K) determined for the compounds of Example 4 in human cell lines SK-N-AS and IMR-32. D ) indicates. [Table 2]

[0185] The real-time binding curves of the combined compound from Example 4 in IMR-32 and SK-N-AS clearly show a distinct binding pattern, demonstrating the affinity of the compound from Example 4 for human cell lines.

[0186] L-741,671 is known in the prior art to exhibit affinity for the hNK1 receptor (as reported in Tattersall FD et al., Neuropharmacology 1996, 35, 1121-1129). Low nanomolar K of the compound in Example 4 1:2 kinetic model analysis D1 The values ​​and combined real-time binding curves show that the binding affinity of the compound in Example 4 is large. 125 This demonstrates that the material is not altered by the attachment of an I atom.

[0187] Colorectal cell line HT-55 The binding characteristics of the compound in Example 4 in a human HT-55 colorectal cancer cell line expressing the NK1 receptor were evaluated according to the same procedure outlined above.

[0188] 1.5 × 10 6HT-55 cells were seeded on a gradient cell culture Nunc dish (catalog number 150350, Thermo Fisher Scientific) and incubated at 37°C in an atmosphere containing 5% CO2. After 48 hours of incubation, real-time binding measurements were performed. The cell medium was switched to 3 ml of fresh medium before the start of the binding measurements. Binding of the compound of Example 4 to HT-55 cells was measured at room temperature using a LigandTracer Grey (Ridgeview Instruments AB, Uppsala, Sweden). After collecting the baseline signal for approximately 10 minutes, the compound of Example 4 was added stepwise 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 curve obtained sufficient curvature at at least one concentration. Off-target binding of the radiolabeled molecule was investigated by using a plastic surface in a cell-free area on the same dish as a reference background region. The reference background signal was automatically subtracted from the attenuated target region signal, which yielded a specific real-time binding curve of the compound of Example 4 to target cells. Dynamic interaction evaluation was performed using TraceDrawer 1.9.2 (Ridgeview Instruments AB, Uppsala, Sweden).

[0189] Figures 5A–5D show the 1:1 and 1:2 kinetic analyses of the real-time binding curves of the compound in Example 4 in the human colorectal cancer cell line HT-55. The solid line represents the calculated fit. The recorded curve can be seen to be close to the 1:2 fit, indicating a 1:2 kinetic fit. [Table 3]

[0190] Table 3 shows the equilibrium dissociation constants (K) determined for the compounds of Example 4 in the human colorectal cancer cell line HT-55. D This indicates that the compounds of formula I can be used in the diagnosis, treatment, and / or prevention of colorectal cancer that express elevated levels of NK1 receptors.

[0191] chromosome assay The cellular uptake of the compound from Example 4 in the human NB cell line IMR-32 was investigated using a specificity assay.

[0192] Total 2 x 10 5 Cells / well were seeded in 24-well plates and incubated at 37°C for 48 hours. The old medium was removed and replaced with either the compound from Example 4 (10 nM) or a combination of the compound from Example 4 (10 nM) and aprepitant (1 μM). The treated cells were then incubated for 1 hour. 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 treatment groups were calculated using an unpaired t-test.

[0193] Figure 6 shows the cellular uptake concentration of the compound from Example 4 (10 nM) per 100,000 cells, both for the compound from Example 4 alone and in combination with aprepitant (1 μM).

[0194] The specificity assay showed NK1R-targeted uptake of the compound from Example 4 at a concentration of 10 nM, blocked by aprepitant at a concentration of 1 μM, which was 100 times stronger than that of the compound from Example 4.

[0195] This demonstrates the specific binding of the compound in Example 4 to NK1R, which is important to ensure the specific accumulation of the compound at the intended therapeutic site and to avoid nonspecific uptake in healthy tissues / organs, thus minimizing associated side effects.

[0196] Further Specific Assays NK1R-transfected U2OS cells (TACR1(NK1) / U2OS, "U2OS-NK1R") were seeded in 10 wells of a 48-well plate containing 500 μL of DMEM medium supplemented with 10% FBS and 1% penicillin-streptomycin per well. Wild-type, untransfected U2OS cells were seeded in an additional 10 wells of a 48-well plate containing 500 μL of DMEM medium supplemented with 10% FBS and 1% penicillin-streptomycin per well. The cells were then incubated at 37°C for 48 hours in a 5% CO2 atmosphere. After the incubation period, the medium was aspirated and the wells were washed twice with PBS.

[0197] To prepare the "blocked" wells, five of the wells containing U2OS-NK1R cells and five of the wells containing wild-type U2OS cells were pretreated with 500 nM aprepitant in 100 μL of DMEM medium containing 1% penicillin-streptomycin per well. The remaining five U2OS wells and five U2OS-NK1R wells were then treated with 100 μL of DMEM medium containing 1% penicillin-streptomycin per well. After incubation of 100 μL of 10 nM of the compound from Example 49 at 37°C for 10 minutes, the cells were treated in DMEM medium containing 1% penicillin-streptomycin. 125 The compound containing I was added to each well and incubated at 37°C for an additional 30 minutes.

[0198] After incubation with the compound of Example 49, the radioactive medium was aspirated and the cells were washed with PBS. The cells were then trypsinized, i.e., dissociated using trypsin, counted using a TC20® automated cell counter (BioRad, Sweden), and cell-associated radioactivity was measured using a gamma counter (1480 Wizard 3', Wallace, Finland). Statistical significance was assessed using Student's t-test, and the data were analyzed to determine the pmol of the compound of Example 49 per 100,000 cells. The results are shown in Figures 8A and 8B. Error bars in the figures indicate 95% confidence intervals.

[0199] Figure 8A shows the amount of the compound from Example 49, measured as bound pmol (i.e., picomoles) per 100,000 NK1R-transfected U2OS cells. It is evident from Figure 8A that there was NK1R-targeted uptake of the compound from Example 49 at a concentration of 5 nM, which was blocked by aprepitant at a concentration of 250 nM. Figure 8B shows the amount of the compound from Example 49, measured as bound pmol (i.e., picomoles) per 100,000 untransfected wild-type U2OS cells. Figure 8B does not show NK1R-targeted uptake of the compound from Example 49. It was concluded that the compounds of this disclosure, such as the compound of Formula I, specifically bind to NKR1. This specific binding is important to ensure specific accumulation of the compound at the intended therapeutic site and to avoid nonspecific uptake in normal tissues / organs, minimizing associated side effects.

[0200] Competitive assay For real-time competitive binding experiments on NK1R-expressing U2OS osteosarcoma cells (TACR1(NK1) / U2OS), 1.5–2.0 × 10⁶ 6 The cells were seeded in an inclined dish (Nunc® cell culture / Petri dish, catalog no. 150350, ThermoFisherScientific) and incubated overnight at 37°C and 5% CO2. The following day, the culture medium (Dulbecc's Modified Eagle Medium Supplement, as described in the summary section) was replaced with 10 mL of fresh medium, and the dish was incubated horizontally overnight.

[0201] Dynamic measurements were performed using a LigandTracer Green (Ridgeview Instruments AB, Uppsala, Sweden) with a blue (488nm) to green (535nm) detector at ambient temperature.

[0202] Before binding measurement, the cell medium was switched to 3 ml of CO2-independent medium (Gibco, catalog no. 18045-054), supplemented with 10% (v / v) fetal bovine serum (FBS), and the dish was placed on the instrument's inclined rotating support. After recording the baseline signal for 30 minutes, 90 nM FAM-labeled substance P, FAM-SP, was added to the cells, and signals from the cell target and background reference region were recorded over time. After sufficient curvature of the binding curve was obtained (usually about 60 minutes), 90 nM competing compounds (Examples 7, 8, 9, 10, 11, 13, 14, and 15) were consequently added. The fluorescence signal was recorded for at least 60 minutes.

[0203] Dynamic evaluation was performed using TraceDrawer 1.9.2 software (Ridgeview Instruments AB, Uppsala, Sweden) with a one-to-one competition model.

[0204] Figures 7A and 7B show the background-corrected binding signal of FAM-SP, followed by the competition phase in which the evaluated compounds (compounds from Examples 7–10 in Figure 7A, and compounds from Examples 11 and 13–15 in Figure 7B) compete with FAM-SP for binding, resulting in a FAM-SP signal with reduced compound-dependent levels. Positive control aprepitant and SP are shown for comparison. It was concluded that the compounds of this disclosure demonstrate NK1R-specific binding to epitopes overlapping with FAM-SP. The percentage of FAM-SP substitution 60 minutes after the addition of competing compounds is reported in Table 4 below.

[0205] Further competitive assays Further competitive testing was conducted using the compounds of the examples described herein, (i) FAM-SP and (ii) 125 I-SP, that is, 125 This was carried out by testing the substitution of SP labeled with I.

[0206] FAM-SP substitution was performed using the competitive assay described above. The results are shown in Table 4.

[0207] The compounds from Examples 5, 14, 15, 18, 27, and 32 were sent to Eurofins Cerep SA in Celle-Levescault, France, and tested using the LeadHunter assay for NK1 human tachykinin GPCR-binding agonist radioligands. The assay was performed on membrane preparations derived from U373MG cells and 125 I-substance P LYS3 was used as the ligand at 0.05 nM. The compound was tested in two ways at eight concentrations ranging from 30 pM to 100 nM. IC 50 The calculations were provided by Eurofins Cerep. For comparison, the reference compound [Sar9,Met(O2)11]-SP was measured at 167 pM IC2. 50 He gave it.

[0208] The results are shown in Table 5. [Table 4-1] [Table 4-2]

[0209] Therefore, the compounds of this disclosure enable substitution of FAM-SP. [Table 5]

[0210] Table 5 shows that the compounds of this disclosure enable binding to NK1R. In particular, the compounds of this disclosure in which Q is nitrogen, for example, the compounds of Examples 14 and 32, have high affinity for NK1R.

[0211] References 1.Halik P.et al.,Pharmaceutics 2022,14,607 2.Kowaluk,EA;Arneric,SP,Annual Reports in Medicinal Chemistry 1998,33,11-20 3.Tattersall F.D.et al.,Neuropharmacology 1996,35,1121-1129 4.WO 95 / 20575 A1. 5.WO 94 / 19323 A1 6.WO 93 / 04040 A1 7.Munoz M.et al.,Neuropeptides 2005,29,245-254 8.WO 95 / 23798 A1 9.Rosso M.et al.,Tumor Biology 2008,29,245-254

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, R １ However, H or (CH ２ ) ｐ It is Z, R ２ However, it is H, OH, or F, R ３ However, H or C １ ~C ３ It is alkyl, R ４ is selected from the group consisting of H, CF ３ , OC １ -C ６ alkyl, OCF ３ , CN, F, and NO ２ and is selected from the group consisting of: R ５ However, H, CF ３ , OC １ ~C ６ Alkyl, OCF ３ , CN, F, and NO ２ Selected from the group consisting of, Q is either C or N, X is O or NH, Y, １２７ I, １２３ I, １２４ I, １２５ I, １３１ I, and ２１１ Selected from the group consisting of At, Z is a five- or six-membered heterocycle containing one, two, or three nitrogen atoms and / or an N-oxide, wherein the heterocycle independently comprises F, Cl, Br, I, OH, and C. １ ~C ３ Alkyl, oxo, and (CH ２ ) ｑ NHR ６ It is substituted with 0, 1, 2, or 3 substituents selected from the group consisting of the following: R ６ However, the chelate portion or its radioactive nuclide complex, n is 0 or 1, m is 0 or 1, p is 0, 1, 2, or 3, q is 2, 3, 4, or 5, The substituent 【Chemistry 2】 However, they are positioned in a cis position relative to each other. however, n + m = 1, A compound, or a pharmaceutically acceptable salt thereof.

2. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the further condition that when is H, 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 Ia. 【Transformation 3】

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 Ib. 【Chemistry 4】

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound of formula Ib is a compound of formula Ib1, formula Ib2, or formula Ib3. 【Transformation 5】

6. The piperidine ring, Carbon 2 and 3 have an S configuration, or A compound according to any one of the prior claims, having R configurations at carbon 2 and 3, or a pharmaceutically acceptable salt thereof.

7. R １ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, wherein H is present.

8. R １ However, (CH ２ ) ｐ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Z.

9. Z is 【Transformation 6】 A compound according to any one of claims 1 to 6 or 8, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

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

11. R ６ but, 【Transformation 7】 A compound according to any one of claims 1 to 6 or 8 to 10, or a pharmaceutically acceptable salt thereof, which is a chelate portion selected from the group consisting of the above.

12. R ６ but, 【Transformation 8】 The compound according to claim 11, or a pharmaceutically acceptable salt thereof, comprising a chelate portion containing or consisting thereof.

13. A 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. R ６ The compound according to any one of claims 1 to 6 or 8 to 13, or a pharmaceutically acceptable salt thereof, which is a radionuclide complex containing the chelate portion and a radionuclide.

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

16. The aforementioned radioactive nuclide is １７７ Lu, for example, １７７ Lu ３＋ The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

17. R １ However, H, 【Chemistry 9】 A compound according to any one of claims 1 to 6 or 8 to 16, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

18. R １ but, H, or 【Chemistry 10】 A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof.

19. R ２ The compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, wherein the compound is H or OH.

20. R ３ However, H or CH ３ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof.

21. R ４ However, H, CF ３ , OCH ３ , OCH(CH ３ ) ２ OCF ３ , F, NO ２ Selected from the group consisting of , and CN, and / or R ５ However, H, CF ３ , OCH ３ , OCH(CH ３ ) ２ OCF ３ , F, NO ２ A compound according to any one of the prior claims, selected from the group consisting of , and CN, or a pharmaceutically acceptable salt thereof.

22. R ４ and R ５ However, both are CF ３ is, or R ４ and R ５ The compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, wherein both are CN.

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

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

25. 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( １２５ I) Iodophenol, 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( １２５ I) Iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( １２５ I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( １２５ I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-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-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine, 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, 5-iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidyl)oxymethyl)pyridine, 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidine-3-amine, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-iodophenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-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-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-N-((5-iodopyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-isopropoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridine-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-phenylpiperidine-3-amine, 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-1-((6-methylpyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenyl-1-(pyridine-2-ylmethyl)piperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenyl-1-(pyrimidine-2-ylmethyl)piperidine-3-amine, 2-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)pyrimidine 1-oxide, 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-1-((1H-imidazole-2-yl)methyl)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)pyrimidine 1-oxide, (2S,3S)-3-((3-( １２５ I) Iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine, (2S,3S)-N-((5-( １２５ I) Iodo-2-methoxypyridine-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)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( １２５ I) Iodophenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, and [ １７７ A compound according to claim 1, selected from the group consisting of Lu]-Lutetium(III)-2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, or a pharmaceutically acceptable salt thereof.

26. 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-( １２５ I) iodophenol, 4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-( １２５ I) Iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( １２５ I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-3(2H)-one, 5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-( １２５ I) Iodophenyl)piperidine-1-yl)methyl)-1H-1,2,4-triazole-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-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-piperidine, 3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-N-(3-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidine-3-amine, 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-2-yl)-2-iodophenol, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-iodophenyl)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-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-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidine-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-phenylpiperidine-3-amine, 5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidine-1-yl)methyl)pyrimidine 1-oxide, (2S,3S)-3-((3-( １２５ I) Iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine, (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)piperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2,2',2''-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidine-1-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, and １７７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of [[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.​

27. 5-iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidyl)oxymethyl)pyridine, 3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridyl)methoxy)-2-phenyl-1-piperidyl)methyl)-1,4-dihydro-1,2,4-triazole-5-one, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodopyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-isopropoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)piperidine-3-amine, 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, 2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-1-((6-methylpyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenyl-1-(pyridine-2-ylmethyl)piperidine-3-amine, (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenyl-1-(pyrimidine-2-ylmethyl)piperidine-3-amine, 2-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)pyrimidine 1-oxide, (2S,3S)-1-((1H-imidazole-2-yl)methyl)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-( １２５ I) Iodo-2-methoxypyridine-3-yl)methyl)2-phenylpiperidine-3-amine, and (2S,3S)-N-((4-( １２５ I) A compound according to claim 1, selected from the group consisting of iodo-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, or a pharmaceutically acceptable salt thereof.

28. (2S,3S)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((5-iodo-2-isopropoxypyridine-3-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-N-((4-iodo-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, (2S,3S)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridine-3-yl)methyl)piperidine-3-amine, 5-(((2S,3S)-3-(((5-iodo-2-methoxypyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-yl)methyl)-2,4-dihydro-3H-1,2,4-triazole-3-one, (2S,3S)-N-((5-( １２５ I) Iodo-2-methoxypyridine-3-yl)methyl)2-phenylpiperidine-3-amine, and (2S,3S)-N-((4-( １２５ I) A compound according to claim 1, selected from the group consisting of iodo-6-(trifluoromethyl)pyridine-2-yl)methyl)-2-phenylpiperidine-3-amine, or a pharmaceutically acceptable salt thereof.

29. Y, (i) １２３ I, １２４ I, and / or １２５ I, or (ii) １３１ A compound according to any one of claims 1 to 24, comprising or consisting of I, or a pharmaceutically acceptable salt thereof.

30. Y, １２７ A compound according to any one of claims 1 to 24, comprising or consisting of I, or a pharmaceutically acceptable salt thereof.

31. Y, ２１１ A compound according to any one of claims 1 to 24, comprising or consisting of At.

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

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

34. For use in 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, rhabdoid cancer, and any combination thereof, the compound described in any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to claim 32.

35. For the manufacture of a pharmaceutical product for the diagnosis, treatment, and / or prevention of 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, a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition according to claim 32.

36. A method for the diagnosis, treatment, and / or prevention of 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, wherein the method comprises 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 aforementioned cancer includes or comprises neuroblastoma, or the compound or pharmaceutical composition for use according to claim 34, or The use described in claim 35, or The method according to claim 36.

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, - A compound of formula IV, 【Chemistry 11】 During the ceremony, R １ However, as defined in any one of claims 1 to 31, or a protecting group such as tert-butoxycarbonyl, R ２ , R ３ , R ４ , R ５ X and Q are as defined in any one of claims 1 to 31, The substituent 【Chemistry 12】 However, compounds that are in a cis position relative to each other, The steps include subjecting the material to iodine or astatination to provide a compound of formula I, A method comprising the step of optionally combining the compound of formula I with a pharmaceutically acceptable acid.

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

40. The aforementioned iodization or astatination is a) The compound of formula IV １２７ Iodinate with I to form a compound of formula I, where Y is １２７ The step of providing compound I, b) The above １２７ I, Sn(CH ３ ) ３ Substituted with boron or metal-containing compounds such as, a compound of formula V, 【Chemistry 13】 During the ceremony, 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 or metal-containing compound. n is 0 or 1, m is 0 or 1, The substituent 【Chemistry 14】 However, they are positioned in a cis position relative to each other. however, The steps include providing a compound where n + m = 1, c) The boron or metal-containing compound is an iodine radioactive isotope as defined in claim 29 or ２１１ The method according to claim 38 or 39, comprising the step of replacing with At.

41. The compound of formula V is, tert-butyl(2S,3S)-2-phenyl-3-((3(trifluoromethyl)-5-(trimethylstannyl)benzyl)oxy)piperidine-1-carboxylate, tert-butyl(2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-carboxylate, tert-butyl(2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridine-2-yl)methyl)amino)piperidine-1-carboxylate, and The method according to claim 40, selected from the group consisting of tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethylstannyl)benzyl)amino)piperidine-1-carboxylate.

42. The iodination includes providing the compound of formula IV to YCl, The method according to claim 38, wherein Y is an iodine radioactive isotope as defined in claim 29.

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

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

45. tert-butyl(2S,3S)-2-phenyl-3-((3(trifluoromethyl)-5-(trimethylstannyl)benzyl)oxy)piperidine-1-carboxylate, tert-butyl(2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridine-3-yl)methyl)amino)-2-phenylpiperidine-1-carboxylate, tert-butyl(2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridine-2-yl)methyl)amino)piperidine-1-carboxylate, and A compound of formula V, selected from the group consisting of tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-(trimethylstannyl)benzyl)amino)piperidine-1-carboxylate.

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