EP4739655A2

EP4739655A2 - Substituted 2-phenylpiperidine compounds for use in the diagnosis, treatment and/or prevention of cancer

Info

Publication number: EP4739655A2
Application number: EP24739519.7A
Authority: EP
Inventors: Christoffer Bengtsson; Ulrika Yngve; Fabio BEGNINI; Preeti Jha; Ulrika ROSENSTRÖM; Marika NESTOR
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-07-03
Filing date: 2024-07-03
Publication date: 2026-05-13
Also published as: WO2025008409A3; CN121443582A; WO2025008409A2

Abstract

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

Description

P90727PC

SUBSTITUTED 2-PHENYLPIPERIDINE COMPOUNDS FOR USE IN THE DIAGNOSIS, TREATMENT AND/OR PREVENTION OF CANCER

Technical field

The present disclosure concerns novel substituted 2-phenylpiperidine compounds, methods for preparation thereof as well as their use in the diagnosis, treatment and/or prevention of cancer. In particular, the disclosure concerns novel substituted 2- phenylpiperidine compounds, methods for preparation thereof as well as their use in the diagnosis, treatment and/or prevention of neuroblastoma.

Background

Cancer is a generic term for a large group of diseases that can affect any part of the body. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, which can invade adjoining parts of the body and spread to other organs; the latter process is referred to as metastasis. Widespread metastases are the primary cause of death from cancer.

Approximately 1 in every 6 deaths worldwide are caused by cancer. Currently, it is the second-leading cause of death (following cardiovascular diseases) worldwide and in high- and very high Human Development Index countries. It has been estimated that by 2040 the global burden is expected to grow to 27.5 million new cancer cases and 16.3 million cancer deaths each year, due to the growth and ageing of the population.

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

After binding to the NK1R, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers a variety of functions. Antagonists against the NK1R are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects.

It has been found that the SP/NK1R system can strongly influence the microenvironment of a tumour, having implications in processes related to P90727PC oncogenesis, such as mitogenesis, angiogenesis, cell migration and metastasis. While NK1R levels typically display limited peripheral expression in normal tissues, it has been shown to be upregulated in several cancer types. Subsequently, it has been demonstrated that SP acts through the NK1R as a mitogen in several human cancer cell lines, including astrocytoma, melanoma, prostate, glioma, retinoblastoma, leukaemia and pancreatic, laryngeal, colon, gastric and breast cancers.

NK1R inhibitors have demonstrated cancer growth inhibition in a number of in vitro and in vivo models. Consequently, the NK1R/SP system is seen as a promising target for cancer diagnostics and therapeutics, including the concept of selectively imaging and targeting tumour cells overexpressing NK1R.

NK1R is highly expressed in neuroblastoma (NBL), which is the most common extracranial solid tumour in children. NBL tumours are characterised by significant biologic heterogeneity. While some tumours show very aggressive, therapy-resistant behaviour, others regress spontaneously. To account for this diversity, current treatment strategies are uniquely guided by pre-treatment risk stratification based on a large range of clinical, histological, molecular and biological markers. Thus, the prognosis and treatment for NBL are highly dependent on molecular, genetic, and pathologic tests.

Following risk stratification, NBL treatment approaches range from observation or resection for tumours considered low risk to intensive multimodal therapy for high-risk tumours including, induction chemotherapy (administered at the beginning of the cancer treatment), surgery, radiation, consolidation therapy (administered after the initial treatment to target remaining cancer cells) and immunotherapy.

Current treatments are not fully effective, and NBL remains a major therapeutic challenge in paediatric oncology. Although multimodal therapy is often able to drastically reduce the tumour burden, leading to an apparent complete remission of the disease (referred to as minimal residual disease), patients diagnosed with high- risk tumours have a survival rate of only 40-50% and, in addition to frequently suffering from long-term side effects, approximately 50% of patients who complete therapy experience disease recurrence.

Radiopharmaceuticals are pharmaceuticals comprising radioisotopes which are designed to target specific cells, organs or tissues and are being increasingly used for both the diagnosis and treatment of a number of cancers. P90727PC

Radiopharmaceuticals are administered systemically and, unlike conventional therapies (e.g., radiation therapy, chemotherapy, surgery), bind to a specific cancer cell transmembrane protein to precisely achieve the desired imaging or therapeutic effect.

Radiopharmaceuticals are often developed in 'theranostic' pairs, consisting of diagnostic and therapeutic compounds. The diagnostic compound is designed with a radioisotope that enables imaging such as Positron Emission Tomography (PET) imaging, while the therapeutic compound is designed with a radioisotope that enables radiation therapy. Using these complementary theranostic pairs, clinicians can assess patient response before treatment to tailor the subsequent radiotherapy dosing to the individual patient.

Aprepitant (commercially known as EMEND and also known as L-754,030) is a NK1R antagonist used primarily for the treatment of chemotherapy-induced nausea and vomiting and has been shown to demonstrate anti-tumoral effects. However, the poor pharmacokinetic profile of aprepitant, including low solubility and low metabolic stability, impairs its antitumoral potential. Furthermore, aprepitant crosses the bloodbrain barrier (BBB) and thus has an increased risk of side effects associated with the central nervous system (CNS). Radiohalogenation of aprepitant has not been demonstrated. Instead, it has been conjugated with a chelate, DOTA (dodecane tetraacetic acid), for radiometal labelling. The residualizing properties of DOTA- chelated radiolabelled molecules mediates a high kidney dose and dose-limiting toxicity.

Halik P. et al., Pharmaceutics 2022, 14, 607 discloses that three novel aprepitant homologues, functionalised with the DOTA chelator and labelled with ⁶⁸Ga and ¹⁷⁷Lu, P90727PC showed a high affinity and better binding capacity in a receptor binding study to the human NK1 receptor than the SP derivative currently used in glioblastoma therapy. It is stated that this confirmed assumptions about the usefulness of aprepitant as a NK1R targeting vector. Further, it is stated that some reports indicate new perspectives for the use of aprepitant and other NK1R antagonists as vectors for selective radiopharmaceutical agents for NKIR-positive tumours.

L-733,060 is an antagonist for the NK1R that has shown anticancer effects in a number of in vitro models. It is reported in Kowaluk, E. A.; Arneric, S. P., Annual Reports in

Medicinal Chemistry 1998, 33, 11-20 to overcome the bioavailability issues often associated with neurokinin antagonists and is able to cross the BBB.

L-733,060

Tattersall F. D. et al., Neuropharmacology 1996, 35, 1121-1129 discloses the pharmacological profile of the non-peptide human type neurokinin 1 (hNKl) receptor selective antagonist L-741,671, which was shown to be brain penetrant. It is stated that brain penetration is essential for the antiemetic action of systemically administered NK1 receptor antagonists.

L-741,671

WO 93/04040 Al, WO 94/19323 Al and WO 95/20575 Al disclose classes of azacyclic compounds, which are useful as tachykinin (NKl-receptor) antagonists. The compounds disclosed in WO 93/04040 Al and WO 94/19323 Al comprise an azacyclic ring system substituted by an arylmethyloxy or arylmethylthio moiety, whilst the compounds disclosed in WO 95/20575 Al comprise an azacyclic ring system P90727PC substituted by an aralkylamino moiety. Moreover, the compounds disclosed in WO 94/19323 Al and WO 95/20575 Al are stated to be of use in the treatment of pain, inflammation, migraine and emesis.

WO 95/23798 Al discloses substituted heterocycles, which are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis.

Munoz M. et al., Neuropeptides 2005, 29, 245-254 discloses 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 the growth of the cell line. NK1 receptors are demonstrated to be present in the cell line studied and, thus, it is demonstrated that the antitumoural action of L-733,060 occurs through the NK1 receptor. It is suggested that the NK1 receptor is a new and promising target in the treatment of human neuroblastoma.

Rosso M. et al., Tumor Biology 2008, 29, 245-254 discloses an in vitro study of the growth-inhibitory capacity of L-733,060 against human gastric and colon adenocarcinomas. 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 are observed in the human gastric and colon adenocarcinomas and, thus, it is demonstrated that the antitumour action of L-733,060 on both human cell lines occurs through the NK1 receptor. It is suggested that the NK1 receptor is a new and promising target in the treatment of human gastric and colon adenocarcinomas.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

A drawback of current cancer therapies is the management of the limited number of cells that escape induction and consolidation therapies. These cells are able to undergo proliferation and/or migration, giving rise to metastatic recurrence. Targeted theranostic radiopharmaceuticals may have a large impact on survival rates if administered during induction and consolidation therapies, in particular during the stage of minimal residual disease. P90727PC

Thus, there is a need for compounds for use in the diagnosis, treatment and /or prevention of cancer. Further, there is a need for a compound for use in the diagnosis, treatment and/or prevention of neuroblastoma.

Summary

It is an object of the present disclosure to provide a compound for use in the diagnosis, treatment and /or prevention of cancer. Further, it is an object of the present disclosure to provide a compound for use, or that can be transformed into a compound for use, in the diagnosis, treatment and/or prevention of neuroblastoma . A further object of the present disclosure is to provide aspects and/or advantages not provided by hitherto known technique.

The present disclosure provides a compound of Formula I:

Formula I wherein :

R¹ is H or (CH₂)_PZ;

R² is H, OH or F;

R³ is H or Ci-Csalkyl;

R⁴ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO2;

R⁵ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO2;

Q is C or N;

X is O or NH;

Y is selected from the group consisting of ¹²⁷I, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I and ²¹¹At;

Z is a five- or six-membered heterocycle comprising 1, 2 or 3 nitrogen atoms and/or an N-oxide, said heterocycle being substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, Ci-Csalkyl, oxo and (CH2)_qNHR⁶;

R⁶ is a chelating moiety or a radionuclide complex thereof; n is 0 or 1; P90727PC m is 0 or 1; p is 0, 1, 2, or 3; q is 2, 3, 4 or 5; the substituents are located cis with respect to each other; with the proviso that: n + m = l; or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Further the present disclosure also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use as a medicament in therapy.

The present disclosure also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use in the diagnosis, treatment and/or prevention of a cancer selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination(s) thereof.

The present disclosure also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for the manufacture of a medicament for the diagnosis, treatment and/or prevention of a cancer selected from the group consisting of neuroblastoma, prostate cancer, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination(s) thereof.

The present disclosure also provides a method for the diagnosis, treatment and/or prevention of a cancer selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, P90727PC colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination(s) thereof, said method comprising administering to a patient, such as a human or an animal, in need thereof, an effective amount such as a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

The present disclosure also provides a method for preparing a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, said method comprising the steps of:

- subjecting a compound of Formula IV:

Formula IV wherein

R¹ is as described herein for the compound of Formula I or a protecting group such as tert-butoxycarbonyl;

R², R³, R⁴, R⁵, X and Q are as described for the compound of Formula I herein; and the substituents are located cis with respect to each other to iodination or astatination thereby providing the compound of Formula I; and

- optionally combining the compound of Formula I with a pharmaceutically acceptable acid.

The present disclosure also provides a compound of Formula IV which is

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

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-2,4-dihydro-3/7-l,2,4-triazol-3-one.

The present disclosure also provides a compound of Formula V which is selected from the group consisting of: P90727PC tert-butyl (2S,3S)-2-phenyl-3-((3-(trifluoromethyl)-5- (trimethylstannyl)benzyl)oxy)piperidine-l -carboxy late; tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridin- 3-yl)methyl)amino)-2-phenylpiperidine-l-carboxylate; tert-butyl (2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridin-2- y I) methy l)a m i no) pi peridine-1 -carboxylate; and tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-

(trimethylstannyl)benzyl)amino)piperidine-l-carboxylate.

Brief description of the drawings

Figure 1A shows the UV-HPLC analysis of the compound of Example 1.

Figure IB shows the Radio-HPLC analysis of the compound of Example 3.

Figure 2A shows the UV HPLC analysis of the compound of Example 2.

Figure 2B shows the Radio-HPLC analysis of the compound of Example 4.

Figure 3A shows real-time binding curve of the compound of Example 4 with human NB cell line SK-N-AS as well as a 1 : 1 kinetic fit.

Figure 3B shows real-time binding curve of the compound of Example 4 with human NB cell line SK-N-AS as well as a 1:2 kinetic fit.

Figure 3C shows real-time binding curve of the compound of Example 4 with human NB cell line IMR-32 as well as a 1: 1 kinetic fit.

Figure 3D shows real-time binding curve of the compound of Example 4 with human NB cell line IMR-32 as well as a 1 :2 kinetic fit.

Figure 4 shows the real-time binding curves of the compound of Example 4 with human NB cell lines SK-N-AS and IMR-32.

Figure 5A shows real-time binding curve of the compound of Example 4 with human colorectal cancer cell line HT55 as well as a 1 : 1 kinetic fit.

Figure 5B shows real-time binding curve of the compound of Example 4 with human colorectal cancer cell line HT55 as well as a 1 :2 kinetic fit.

Figure 6 shows the cellular uptake concentration of the compound of Example 4 per 100 000 cells for the compound of Example 4 (10 nM) alone and the compound of Example 4 (10 nM) in combination with aprepitant (1 pM).

Figures 7A and 7B show real-time binding curves of 90 nM FAM-labeled Substance P (SP) followed by binding competition of 90 nM compounds on NKIR-expressing U2OS osteosarcoma cells, (TACR1 (NK1)/U2OS cells).

Figure 8A shows the amount of the compound of Example 49 measured as pmol (i.e. picomoles) bound per 100 000 NKIR-transfected U2OS cells (U2OS-NK1R) with and without pre-blocking of NKl-receptors by aprepitant. P90727PC

Figure 8B shows the amount of the compound of Example 49 measured as pmol (i.e. picomoles) bound per 100 000 non-transfected wild-type non-transfected U2OS cells. Figure 9 shows the chemical structure of DOTA, i.e. 2,2',2",2"'-(l,4,7,10- tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid.

Figure 10 shows the chemical structure of NOTA, i.e. 2,2',2"-(l,4,7-triazonane-l,4,7- triy l)triacetic acid.

Figure 11 shows the chemical structure of TETA, i.e. 1 ,4,8,11-tetraazacyclodocedane- 1,4,8, l l-tetrayl)tetraacetic acid.

Figure 12 shows the chemical structure of DTPA, i.e. diethylenetriaminepentaacetic acid .

Figure 13 shows the chemical structure of NODAGA, i.e. 2-(4,7-bis(carboxymethyl)- 1,4,7-triazonan- 1-yl) pentanedioic acid.

Figure 14 shows the chemical structure of DOTAGA, i.e. 2-(4,7,10-tris(carboxymethyl)- 1,4, 7, 10-tetraazacyclododecan- 1-yl) pentanedioic acid.

Figure 15 shows the chemical structure of DFO, i.e. Deferoxamine.

Description

The present disclosure provides a compound of Formula I:

Formula I wherein :

R¹ is H or (CH₂)_PZ;

R² is H, OH or F;

R³ is H or Ci-Csalkyl;

R⁴ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, ON, F and

NO₂;

R⁵ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, ON, F and NO₂;

Q is C or N;

X is O or NH;

Y is selected from the group consisting of ¹²⁷I, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I and ²¹¹At; P90727PC

R⁶ 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; are located cis with respect to each other; with the proviso that: n + m = l; or a pharmaceutically acceptable salt thereof.

The following definitions apply throughout this document.

The term "Ci-Cealkyl" denotes a straight or branched, saturated alkyl group of one to six carbon atoms. Examples of "Ci-Cealkyl" include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, /so-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl and neohexyl.

The term "OCi-Ce" denotes a Ci-Cealkyl group linked to an oxygen atom. Examples of "OCi-Ce" include, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, /so-butoxy, tert-butoxy, n-pentoxy, /so-pentoxy, neo-pentoxy, n-hexoxy, /so-hexoxy, 3-methylpentoxy, 2,3-dimethylbutoxy and neohexoxy and n-hexoxy.

The term "Ci-Csalkyl" denotes a straight or branched, saturated or unsaturated alkyl group of one to three carbon atoms. Examples of "Ci-Csalkyl" include, but are not limited to, methyl, ethyl, vinyl, allyl, n-propyl and isopropyl.

The term "5-membered heterocycle" denotes a 5-membered saturated or unsaturated heterocycle. Examples of a 5-membered heterocycle include, but are not limited to pyrrolidine, tetra hydrofuran, thiolane, pyrrole, furane, thiophene, imidazolidine, P90727PC pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, imidazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole.

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

The Q substituent of the compound of Formula I may be located in the ortho, meta or para position. For instance, the Q substituent may be located in the meta position to provide the compound: Examples of the compound of Formula I wherein Q is located in the para position include the compound of Formula la and

Formula Ibl described herein.

There is also provided a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, with the further proviso that when R² is H then m is 1.

The piperidine ring of the compounds disclosed herein such as the compound of Formula I may have S configuration at carbons 2 and 3. Alternatively, the compounds disclosed herein such as the compound of Formula I may have R configuration at carbons 2 and 3. This is illustrated for the compound of Formula I provided as a compound of Formula I' and/or Formula I": P90727PC

For instance, the compound of Formula I may be a compound of Formula I'. In a further example, the compound of Formula I is provided a compound of Formula I". In still a further example, there is provided a mixture such as a 1 : 1 mixture of the compound of Formula I' and the compound of Formula I".

Q may be C, i.e. carbon, thereby providing a compound of Formula la:

Formula la

Alternatively, Q may be N, i.e., nitrogen, thereby providing a compound of Formula lb:

Formula lb

It will be appreciated that the compound of Formula lb may be provided as a compound of Formula Ibl, Formula Ib2 or Formula Ib3: P90727PC

The value for n may be 1. Thus, there is provided a compound of Formula I as described herein wherein n is 1 which may be denominated Formula II:

Formula II Examples of the compound of Formula II include compounds of Formula Ila (wherein

Q is carbon), and compounds of Formula lib, Formula lie and/or Formula lid (wherein

Formula Ila Formula lib Formula lie Formula lid In an example, the compound of Formula Ila is a compound of Formula Hal:

Further, the value of m may be 1. Thus, there is provided a compound of Formula I as described herein wherein m is 1 which may be denominated Formula III: P90727PC

Formula III

Examples of the compound of Formula III include compounds of Formula Illa (wherein

Q is carbon), and compounds of Formula Illb, Formula IIIc and/or Formula Hid (wherein Q is nitrogen).

The substituent R¹ may be H. Alternatively, R¹ may be (CHz)pZ. Z may be selected from the group consisting of Alternatively, Z may be P90727PC wherein

R⁶ is a chelating moiety or a radionuclide complex thereof; and q is 2, 3, 4, or 5. It will be appreciated that R⁶ is linked to the substituted triazole compound via a linker NH(CH2)q.

The chelating moiety may comprise a cyclic such as a macrocylic chelator or an acyclic chelator containing one or more heteroatoms such as oxygen or nitrogen atoms which may coordinate and/or entrap the radionuclide. Further, the chelating moiety R⁶ may comprises a carboxylic acid group forming an amide bond with the nitrogen atom of the linker NH(CH2)q. For instance, R⁶ may comprise one or more of the following chelating moieties: DOTA, NOTA, TETA, DTPA, NODAGA, DOTAGA, DFO, or a derivative of any one of the foregoing chelating moieties. The chemical structures of the aforementioned compounds are depicted in Figures 9-15. For instance, R⁶ may be a chelating moiety selected from the group consisting of

In a further example, R⁶ is a chelating moiety comprising or consisting of P90727PC

The value for p may be 0, 1, 2, or 3. For instance, p may be 1.

The value of q may be 2, 3, 4, or 5. For instance, q may be 4.

Further, R⁶ may be a radionuclide complex of the chelating moiety. The radionuclide complex may comprise or consist of the chelating moiety and a radionuclide. In this way, the diagnostic, therapeutic or preventive effect of the compound of Formula I may be further improved.

The radionuclide and the chelating moiety of the radionuclide complex may be provided in a ratio of 1 : 1. The radionuclide may be any radionuclide suitable for the intended purpose. For example, the radionuclide may be selected from the group consisting of ⁶⁸Ga, ¹⁸F, ⁶⁴Cu, ⁴⁴Sc, ⁸⁹Zr, ⁱⁿIn, ⁶⁷Ga, ^99mTc, Gd, ¹⁷⁷Lu, ⁸⁶/⁹⁰Y, ²²⁵Ac, 161/165-j-^^ 226/227-j- , _{a nc}| _{a n} j_on thereof. In particular, the radionuclide may be an ion such as a positive ion which may coordinate to a heteroatom such as nitrogen or oxygen atom of the chelating moiety. In an example, the radionuclide comprises or consists of ¹⁷⁷Lu such as ¹⁷⁷Lu³⁺.

In an example, R⁶ comprises DOTA and ¹⁷⁷Lu³⁺ to provide:

It will be appreciated that the choice of radionuclide for the R⁶ radionuclide complex will depend on the intended use, such as the imaging method to be used for the diagnosis, treatment and/or prevention. For example, when Positron Emission P90727PC

Tomography (PET) is the imaging method the radionuclide may be selected from the group consisting of ⁶⁸Ga, ¹⁸F, ⁶⁴Cu, ⁴⁴Sc, ⁸⁹Zr and ⁸⁶/⁹⁰Y. In a further example, when Single-Photon Emission Computed Tomography (SPECT) is the imaging method the radionuclide may be selected from the group consisting of e.g. ⁱⁿIn, ⁶⁷Ga, ^99mTc, and ¹⁷⁷Lu. Moreover, radionuclides used for treatment may be selected from the group consisting of for example ¹⁷⁷Lu, ¹⁶¹Tb, and ²²⁵Ac.

The substituent R¹ may be selected from the group consisting of

For example, the R¹ substituent may be H, or

In an example, there is provided a compound of Formula I wherein X is O, and/or R² is OH, and/or R³ is H, and/or p is 1.

The R² substituent may be H or OH. In an example R² is H. In a further example, R² is OH.

The R³ substituent may be H or CH3. For instance, R³ may be H. P90727PC

The R⁴ and R⁵ substituents may independently be selected from the group consisting of H, CF3, OCi-Cealkyl such as OCH3 or OCH(CH3)2, OCF3, F, NO2 and CN. Alternatively, R⁴ may be selected from the group consisting of CF3, OCi-Cealkyl such as OCH3 or OCH(CH3), OCF3, F, NO2 and CN, and R⁵ may be selected from the group consisting of H, CF₃, OCi-Cealkyl, OCF3 and CN.

The R⁴ and R⁵ substituents may be both CF3. Alternatively, the R⁴ and R⁵ substituents may both be CN.

Further, Y may comprise or consist of one or more of the following : ¹²³I, ¹²⁴I, ¹²⁵I. Alternatively, Y may comprise or consist of ¹³¹I. In a further example, Y may be the stable isotope ¹²⁷I. In still a further example, Y may comprise or consist of ²¹¹At.

There is also provided a compound of Formula I, which is one or more of the following : 4-((±)-c/s-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)piperidin-2-yl) phenol;

5-(((±)-c/s-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

4-((±)-c/s-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I)iodophenol; 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I)iodophenol;

4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I) iodophenol;

5-(((±)-c/s-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- (¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- (¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- (¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

(25.35)-3-((3-iodo-5-(trifluoromethyl)benzyl)oxy)-2-phenylpiperidine;

5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)oxy)-2-phenylpiperidin-l- yl)methyl)-4,5-dihydro-3/7-l,2,4-triazol-3-one;

(25.35)-3-((3-iodobenzyl)oxy)-2-phenylpiperidine;

3-(((2S,3S)-3-((3-iodobenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-lH-l,2,4-triazol- 5(4H)-one; P90727PC

5-iodo-2-methoxy-3-((((2S,3S)-2-phenylpiperidin-3-yl)oxy) methyl) pyridine;

3-(((2S,3S)-3-((5-iodo-2-methoxypyridin-3-yl)methoxy)-2-phenylpiperidin-l- yl)methyl)-lH-l,2,4-triazol-5(4H)-one;

(25.35)-N-(3-iodobenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine; or a pharmaceutically acceptable salt of any one of the foregoing compounds.

Further, there is provided a compound of Formula I which is one or more of the following :

4-((±)-c/s-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol; 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl) phenol;

4-((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl) phenol; or

(25.35)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine; or an iodine radioisotope of any one of the foregoing compounds such as any one of the foregoing compounds wherein the iodine is an iodine radioisotope, or a pharmaceutically acceptable salt of any one of the foregoing compounds or iodine radioisotope thereof.

There is also provided a compound of Formula I, which is one or more of the following : 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I)iodophenol;

4-((2/?,3/?)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I) iodophenol;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one; 5-(((2/?,3/?)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- (¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

(25.35)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine;

3-(((2S,3S)-3-((3-iodo-5-(trifluoromethy I) phenyl) meth oxy) -2-pheny 1-1- piperidyl) methyl)- 1,4-dihydro-l, 2, 4-triazol-5-one;

(25.35)-3-((3-iodophenyl)methoxy)-2-phenyl-pi peridine;

3-(((2S,3S)-3-((3-iodophenyl) methoxy) -2-pheny 1-1 -piperidyl) methyl)- 1,4-di hydro- 1,2, 4-triazol-5-one;

5-iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidyl)oxymethyl)pyridine;

3-(((2S,3S)-3-((5-iodo-2-methoxy-3-pyridy I) methoxy) -2-pheny 1-1 -piperidyl) methyl)- l,4-dihydro-l,2,4-triazol-5-one;

(25.35)-N-(3-iodobenzy I) -2-pheny lpiperidin-3-a mine; P90727PC

(25.35)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-2,4’dihydro-3/7-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- iodophenyl)pi peridin -1-yl) methyl) -2, 4-dihydro-3H-l, 2, 4-triazol-3-one;

(25.35)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpi peridine;

(25.35)-3-((3-fluoro-5-iodobenzyl)oxy)-2-pheny I pi peridine;

(25.35)-3-((3-iodo-5-nitrobenzyl)oxy)-2-pheny I piperidine;

(25.35)-3-((4-iodobenzyl)oxy)-2-phenylpiperidine;

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperid in -1-yl) methyl) -2, 4~ dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-2,4~ dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-pheny I pi peridin -1-yl) methyl) -2, 4~ dihydro-3H-l,2,4~triazol-3-one;

(25.35)-N-((5-iodopyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((4-iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3- amine;

(25.35)-2-(4-fluorophenyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)piperidin-3- amine;

(25.35)-2-(4-fluorophenyl)-N-(3-iodo-5-(trifluoromethyl)benzyl)piperidin-3-amine;

(25.35)-N-((R)-l-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine;

5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4~ dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4~ dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-l- yl)methyl)-2,4~dihydro-3H-l,2,4~triazol-3-one; P90727PC

5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4-dihydro-

3H-l,2,4-triazol-3-one;

5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-l- yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

2S,3S)-N-((5-iodo-2-methoxypy rid in -3-yl) methyl)- l-((6-methylpyrid in -2-yl) methyl)-

2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-l-(pyridin-2- ylmethyl)piperidin-3-amine;

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenyl-l-(pyrimidin-2- ylmethyl)piperidin-3-amine;

2-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-l- yl)methyl)pyrimidine 1-oxide;

5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)piperidin-

1-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

(25.35)-l-((lH-imidazol-2-yl)methyl)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2- phenylpiperidin-3-amine;

2-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-l- yl)methyl)pyrimidine 1-oxide;

(25.35)-3-((3-(¹²⁵I)iodo-5-(trifluoromethy I) phenyl) methoxy) -2-phenyl-pi peridine;

(25.35)-N-((5-(¹²⁵I)iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-(¹²⁵I)iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((4-(¹²⁵I)iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3- amine;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one

2,2',2"-(10-(2-((4-(3-(((2S,3S)-3-((3-Iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin- l-yl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l-yl)butyl)amino)-2-oxoethyl)- l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid;

[¹⁷⁷Lu ]-Lutetium(III)- -2,2',2"-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5- methoxybenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol- 1-yl) butyl)amino) -2-oxoethy I)- 1,4,7/ 10-tetraazacyclododecane- 1,4,7- triyl)triacetate; or a pharmaceutically acceptable salt of any one of the foregoing compounds.

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I)iodophenol; P90727PC

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

5-(((2/?,3/?)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

(25.35)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-piperidine;

3-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-l- piperidyl) methyl)- 1,4-dihydro-l, 2, 4-triazol-5-one;

(25.35)-3-((3-iodophenyl)methoxy)-2-phenyl-pi peridine;

3-(((2S,3S)-3-((3-iodophenyl) methoxy) -2-pheny 1-1 -piperidyl) methyl)- 1,4’di hydro- 1,2, 4-triazol-5-one;

(25.35)-N-(3-iodobenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-2,4-dihydro-3/7-l,2,4-triazol-3-one;

(25.35)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpi peridine;

(25.35)-3-((3-fluoro-5-iodobenzyl)oxy)-2-pheny I pi peridine;

(25.35)-3-((3-iodo-5-nitrobenzyl)oxy)-2-pheny I piperidine;

(25.35)-3-((4-iodobenzyl)oxy)-2-phenylpiperidine;

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-2,4- dihydro-3H-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-2,4- dihydro-3H-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-2,4- dihydro-3H-l,2,4-triazol-3-one;

(25.35)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((R)-l-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine;

5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4- dihydro-3H-l,2,4-triazol-3-one; P90727PC

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4- dihydro-3H-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-l- yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4-dihydro-

3H-l,2,4-triazol-3-one;

1-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

(25.35)-3-((3-(¹²⁵I)iodo-5-(trifluoromethyl)phenyl)methoxy)-2-pheny I- piperidine;

(25.35)-N-(5-(¹²⁵I)iodo-2-(trifluoromethoxy) benzyl) -2-phenyl pi peridi n-3-a mine;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

[¹⁷⁷Lu ]-Lutetium(III)- -2,2',2"-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5- methoxybenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol- 1-y I) butyl)a mine) -2-oxoethy I)- 1,4, 7, 10-tetraazacyclododeca ne- 1,4,7- triyl)triacetate; or a pharmaceutically acceptable salt of any one of the foregoing compounds.

There is further provided a compound of Formula I which is one or more of the following :

5-iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidyl)oxymethyl)pyridine;

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodopyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-l- yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one; P90727PC

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-l-((6-methylpyridin-2- yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((4-(¹²⁵I)iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2-phenylpiperidin-3- amine; or a pharmaceutically acceptable salt of any one of the foregoing compounds.

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

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 a large iodine atom in the compounds does not preclude interaction with the NK1R. This is a significant benefit since the iodine may be provided as different isotopes in the compounds, thereby allowing for different therapeutic uses. For example, some isotopes may be used for diagnosis, such as diagnosis involving diagnostic imaging, while other isotopes may be P90727PC used in conjunction with treatment. Thus, the same compound may be labelled with different isotopes dependent on the desired use so as to provide a theranostic pair consisting of diagnostic and therapeutic compounds.

Further, it has been found that the compounds of the present disclosure specifically bind to NK1R. This is important to ensure specific accumulation of the compound to the intended treatment site(s), and for avoiding non-specific uptake in healthy tissues/organs (i.e. tissues and/or organs not intended to be targeted by the treatment) so that associated side effects are minimised.

There is also provided a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition may be a pharmaceutical composition for intravenous administration. For example, the pharmaceutical composition for intravenous administration may be a solution such as an aqueous solution comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof.

In a further example, the pharmaceutical composition may be an oral pharmaceutical composition. In particular, the oral pharmaceutical composition may comprise a compound of Formula I wherein Y comprises or consists of ¹²⁷I or ¹²⁵I. For example, the oral pharmaceutical composition may be provided as a liquid such as a syrup, suspension or solution. Alternatively, the oral pharmaceutical composition may be provided as a solid such as a tablet, capsule or lozenge.

Further, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use as a medicament in therapy.

There is further provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for use in the diagnosis, treatment and/or prevention of cancer.

The present disclosure also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for the manufacture of a medicament for the diagnosis, treatment and/or prevention of cancer. P90727PC

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

The term "therapeutically effective amount", as used herein, refers to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect).

The cancer 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) thereof. For example, the cancer may be neuroblastoma.

As used herein, the term "treatment" (and similarly "treating") takes its normal use in the field of medicine. In particular, the term may refer to achieving the severity of one or more clinical symptoms of the disease or condition. Further, the term "prevention" (and similarly "preventing") may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the disease or condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).

The compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein may be administered to a specific patient group such as for example children up to the age of 14 years or to patients over 14 or 15 years such as adults. In particular, the diagnosis, treatment and/or prevention of neuroblastoma may involve administration to children.

It will be appreciated that the compounds of the present disclosure may contain an iodine radionuclide selected from the following : ¹²³I, ¹²⁴I, ¹²⁵I or ¹³¹I as a label to allow for diagnosis, treatment and/or prevention of one or more cancers as described herein . For instance, the radionuclide may be ¹²⁵I.

The choice of iodine radionuclide determines if the compound, or pharmaceutically acceptable salt thereof, is to be used for diagnosis or treatment so that the diagnostic P90727PC and therapeutic compounds only differ in the choice of iodine radionuclide. Thus, the same compound may be labelled with different radionuclides so as to provide a theranostic pair consisting of diagnostic and therapeutic compounds.

For example, the iodine radionuclide in the compound of Formula I may allow for use in diagnosis. For example, the iodine radionuclide may be a positron emitting radionuclide such as ¹²⁴I or a radionuclide that can be detected with a gamma camera such as ¹²³I, ¹²⁵I or ¹³¹I. In this way, the compound may serve as a diagnostic tool, radio tracer, monitoring agent or in in vivo receptor imaging.

In a further example, the iodine radioisotope in the compound of Formula I may be ¹³¹I allowing for use in radiation treatment. The treatment may comprise induction therapy, consolidation therapy and/or minimal residual disease treatment. The therapeutic compounds may be administered during induction therapy treatment, i.e., treatment during an initial stage of the cancer. In a further example, the therapeutic compounds may be administered during consolidation therapy, i.e., therapy used after initial treatment to target remaining cancer cells. In still a further example, the therapeutic compounds may be administered to address minimal residual disease, i.e., to kill a small number of cancer cells remaining in the body after cancer treatment.

Physical methods that may be used in conjunction with the present disclosure may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.

Instead of or in addition to an iodine radionuclide, the compounds of the present disclosure may contain the stable iodine isotope ¹²⁷I. Thus, Y may comprise or consist of ¹²⁷I in the compound of Formula I. It is believed that compounds of the present disclosure containing the stable iodine isotope ¹²⁷I may be used for e.g. the prevention of a disease as described herein.

The compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein may be provided in a diagnostically effective amount, i.e., an amount allowing for achieving a desired diagnostic effect. For example, the diagnostically effective amount may be adjusted to enable imaging. Further, it will be appreciated that the diagnostically effective amount may be adjusted depending on the administration route such as intravenous or oral administration. P90727PC

The compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein may be provided in a therapeutically effective amount, i.e., an amount allowing for achieving a desired therapeutic effect. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect). For example, the therapeutically effective amount may be adjusted to provide radiation therapy. Further, it will be appreciated that the therapeutically effective amount may be adjusted depending on the administration route such as intravenous or oral administration.

Further, the compound of Formula I such as a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein may be administered an appropriate number of times with a frequency suitable to achieve the desired diagnostic or therapeutic effect.

For instance, the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein may be administered daily such as once daily. Moreover, the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein may be administered during a suitable period of time such as a time sufficient to cure a cancer such as neuroblastoma.

The present disclosure also provides a compound of Formula IV, which is a compound of Formula I for which both n and m are 0. Further, the R1 substituent may include tert-butoxycarbonyl (BOC).

The compound of Formula IV may be used for preparing the compound of Formula I. Additionally or alternatively, the compound of Formula IV may be for use as a medicament in therapy. For instance, the compound of Formula IV may be used in the diagnosis, treatment and/or prevention of cancer as described for the compound of Formula I herein.

Thus, there is provided a compound of Formula IV: P90727PC

Formula IV wherein

R¹ is as described herein for the compound of Formula IV or a protecting group such as tert-butoxycarbonyl, and

R², R³, R⁴, R⁵, X, Q, p and q are as described for the compound of Formula I.

For instance, there is provided a compound of Formula IV wherein

R¹ is H or (CH₂)_PZ;

R² is H, OH or F;

R³ is H or Ci-Csalkyl;

R⁴ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO2; R⁵ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO2; Q is C or N;

X is O or NH;

Z is a five- or six-membered heterocycle comprising 1, 2 or 3 nitrogen atoms and/or an N-oxide, said heterocycle being substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, Ci-Csalkyl, oxo and (CH₂)_qNHR⁶; p is 0, 1, 2, or 3;

R⁶ is a chelating moiety or a radionuclide complex thereof; q is 2, 3, 4 or 5; the substituents are located cis with respect to each other.

Further, it will be appreciated that the piperidine ring of the compound of Formula IV may have S configuration at carbons 2 and 3, or /? configuration at carbons 2 and 3. P90727PC

Examples of the compound of Formula IV include compounds of Formula IVa (wherein Q is carbon) and compounds of Formula IVb, Formula IVc and/or Formula IVd (wherein Q is nitrogen).

Formula IVb Formula IVc Formula IVd

In an example, there is provided a compound of Formula IV wherein R² is OH:

In still a further example, there is a provided a compound of Formula IV which is 4- ((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol or 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-2,4-dihydro-3/7-l,2,4-triazol-3-one.

In yet a further example, there is provided a compound of Formula IV as described herein wherein Z is substituted with (CH2)_qNHR⁶.

For instance, Z may be

H

N 'x-

R⁶NH(CH₂)_q-N / ' N

O

Combinations

The compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered alone or in combination with a further pharmaceutical drug for treating P90727PC cancer. Thus, there is provided a combination of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutical drug for treating cancer. The combination may be a single composition wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, and the further pharmaceutical drug for treating cancer are mixed together. Alternatively, the combination may be provided as a kit of parts comprising (i) the compound pf Formula I, and/or a pharmaceutically acceptable salt thereof, and/or (iii) the further pharmaceutical drug for treating cancer and (iii) optionally instructions for use.

Salts

The compounds of the present disclosure such as the compound of Formula I may be provided as a pharmaceutically acceptable salt. A suitable pharmaceutically acceptable salt of a compound of the present disclosure may be, for example, an acid addition salt.

Examples of pharmaceutically acceptable salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, and any combination thereof. Such salts may be formed by procedures well known and described in the art.

It will be appreciated that proton transfer may occur between the compound of Formula I described herein and the acid which together form the salt. The proton transfer may take place to a varying extent.

Stereoisomers

It will be appreciated that the compounds described herein are chiral. In particular, the compound of Formula I exhibits cis stereochemistry, i.e., both phenyl substituents are located cis with respect to each other as illustrated by the chemical structure depicted herein. It will be appreciated that the compound of Formula I may be provided as a single enantiomer or as a mixture of enantiomers such as a racemic mixture.

For example, the compounds described herein may be provided as the (S,S) enantiomer. Alternatively, the compounds may be provided as the (R,R) enantiomer P90727PC or as a mixture such as a racemic mixture of the (S,S) enantiomer and the (R,R) enantiomer.

For the avoidance of doubt, compounds referred to as having a specific stereochemistry at a defined position may also have stereochemistry at one or more other positions, and so may exist as mixtures of enantiomers or diastereoisomers in relation to the stereochemistry at those positions.

Solvates or hydrates

It will be appreciated that the compound of Formula I described herein may be provided as a solvate or as a solvate of a pharmaceutically acceptable salt of the compound of Formula I. It is to be understood that the present disclosure encompasses all such solvates or hydrates.

Co-crystals

In a salt, proton transfer may occur between the active pharmaceutical ingredient and the counter ion of the salt. However, in some cases there is no or only partial proton transfer and the solid is therefore not a true salt. It is accepted that the proton transfer is in fact a continuum, and can change with temperature, and therefore the point at which a salt is better described as a "co-crystal" may be subjective. The term "co-crystal" as used herein refers to multicomponent system in which there exists a host molecule or molecules (active pharmaceutical ingredient) and a guest (or coformer) molecule or molecules. The guest or co-former molecule is defined as existing as a solid at room temperature in order to distinguish the co-crystal from solvates. However, a co-crystal may itself form solvates. In a co-crystal there is generally predominance for interaction through non-ionic forces, such as hydrogen bonding. It will be appreciated that all co-crystals are included within the scope of the compounds described herein.

Polymorphs

The compounds of the present disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. Thus, it is to be understood that all polymorphs, such as mixtures of different polymorphs, are included within the scope of the claimed compounds.

Prodrugs

Compounds of the present disclosure may be administered in the form of a prodrug.

A prodrug is a compound, which may have little or no pharmacological activity itself, P90727PC but when such compound is administered into or onto the body of a patient, it is converted into a compound of Formula I.

Methods of preparation

The present disclosure provides a method for preparing a compound of Formula I, such as a compound of Formula II and/or Formula III as described herein, or a pharmaceutically acceptable salt thereof, said method comprising the steps of:

- subjecting a compound of Formula IV:

Formula IV wherein

R², R³, R⁴, R⁵, X and Q are as described herein for the compound of Formula I; and the substituents are located cis with respect to each other to iodination or astatination thereby providing the compound of Formula I; and

In an example, the compound of Formula IV in the method described herein is 4- ((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol or 5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-2,4-dihydro-3/7-l,2,4-triazol-3-one.

The iodination or astatination of the method may comprise the steps of: a) iodinating the compound of Formula IV with ¹²⁷I to provide a compound of Formula I wherein Y is ¹²⁷I; P90727PC b) substituting the ¹²⁷I with a boron or metal containing compound such as Sn(CH3)3 to provide a compound of Formula V:

(M)_n

Formula V wherein

R¹, R², R³, R⁴, R⁵, X, and Q are as defined for the compound of Formula IV,

M is the boron or metal containing compound; n is 0 or 1; m is 0 or 1; and the substituents are located cis with respect to each other; with the proviso that: n + m = l; and c) substituting the boron or metal containing compound M with an iodine radioisotope as described herein or ²¹¹At to prepare a compound of Formula I wherein Y is an iodine radioisotope as described herein or ²¹¹At.

Examples of the compound of Formula V include compounds of Formula Va (wherein Q is carbon) and compounds of Formula Vbl, Formula Vb2 and/or Formula Vb3 (wherein

Q is nitrogen). P90727PC

In particular, there is provided a compound of Formula V selected from the group consisting of tert-butyl (2S,3S)-2-phenyl-3-((3-(trifluoromethyl)-5- (trimethylstannyl)benzyl)oxy)piperidine-l -carboxy late; tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-(trimethylstannyl)pyridin- 3-yl)methyl)amino)-2-phenylpiperidine-l-carboxylate; tert-butyl (2S, 3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstanny I) pyridineyl) methyl)a mi no) pi peridi ne-1 -carboxylate; and tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-

(trimethylstannyl)benzyl)amino)piperidine-l-carboxylate. It will be appreciated that the aforementioned compounds of Formula V may be used in the method described herein.

Alternatively, the iodination of the method may comprise subjecting the compound of Formula IV to YCI, wherein Y is an iodine radioisotope as described herein. The YCI may be iodine monochloride prepared from /V-chloro-p-toluenesulfonamide or /V- chlorosuccinimide and a sodium iodide salt selected from the group consisting of Na¹²³I, Na¹²⁴I, Na¹²⁵I and Na¹³¹I.

In particular, a compound of Formula IV wherein the R² substituent is OH may be subjected to (i) iodination such as iodination involving stable iodine or a radionuclide of iodine or (ii) astatination such as astatination involving ²¹¹At.

The preparation of the compounds of the present disclosure is further exemplified below.

The iodination may take place to prepare a compound of Formula II or Formula III wherein Y is ¹²⁷I optionally followed by radiolabelling with a radioisotope of iodine via an exchange reaction. For example, the ¹²⁷I of the compound of Formula II or Formula III may be replaced with a (substituted) metal or boron containing compound M to provide an intermediate which is followed by radiolabelling with an iodine radioisotope. This is illustrated in Scheme 1 for an enantiomer of the compound of Formula II and Formula III, respectively, wherein Q is located in the meta position : P90727PC

It will be appreciated that in Scheme 1, as well as in the other schemes in this document, R¹, R², R³, R⁴, R⁵, Q and X may be as described herein unless otherwise stated, I* may be an iodine radioisotope as described herein and M may be trialkylstannyl, trialkylsilyl, B(OH)z, BF3 or B(Oalkyl)z. The starting materials of the compounds in Scheme 1 may be prepared as described herein and/or using methods described in the art.

In a further example, the iodination of a compound as described herein such as a compound of Formula IV may take place using Chloramine T or /V-chlorosuccinimide (NCS) and a salt comprising the iodine radionuclide in the presence of a solvent such as PBS. It is believed that iodine monochloride is generated in this way, which acts as an iodination agent. Chloramine T, which may be abbreviated CAT, is /V-chloro-p- toluenesulfonamide and may be purchased or prepared by reacting p- toluenesulfonamide with sodium hypochlorite. The salt comprising the iodine radionuclide may be a sodium iodide salt of the appropriate isotopically labelled iodide. For instance, the radio-iodination of the compound of Formula IV may take place using Chloramine T, and iodine-125 radionuclide solution comprising PBS having a pH of 7.4. The iodine-125 radionuclide solution may comprise or consist of the iodine-125 radionuclide and aqueous sodium hydroxide (e.g. in a concentration of 0.1 N). Further, the iodine-125 radionuclide solution may be free from reducing agents and/or have a P90727PC pH from 12 to 14. Scheme 2A illustrates iodination of an enantiomer of the compound of Formula IV, wherein Q is located in the meta position, and R¹ is as described herein but not hydrogen, using Chloramine T, and Na[¹²⁵I] to provide a compound of Formula I wherein Q is located in the meta position, Y is ¹²⁵I and R¹ is as described herein.

Scheme 2B illustrates conversion of a compound containing ¹²⁷I wherein R¹ is tertbutoxycarbonyl carbonyl group (Boc) into a compound of the present disclosure labelled with ¹²⁵I wherein R¹ is hydrogen.

P90727PC

The compounds of the present disclosure such as the compound of Formula I, II, III or IV may be prepared using methods known in the art and/or as described herein. For instance, a compound of Formula III wherein Q is in the meta position may be prepared as shown in Scheme 3. Further, a compound of Formula IV wherein Q is in the meta position may be prepared as illustrated in Scheme 4. Scheme 5A further illustrates a way of preparing the compounds of the present disclosure.

P90727PC P90727PC

The starting compound in Scheme 5A may be prepared as indicated in Scheme 5B. P90727PC

Scheme 6 illustrates a synthesis of the compounds of the present disclosure wherein X is nitrogen.

P90727PC

Scheme 7 illustrates a synthesis of compounds that may be used for preparing compounds of the present disclosure wherein X is nitrogen and R² may be fluorine.

P90727PC

In this document, unless otherwise stated, the drawing and/or naming of the chemical compounds have been made using the software package ChemDraw Ultra 12.0 or ChemDraw 21.0.28 or ChemDraw 22.2.0. In some instances, the chemical name used is a name commonly used in the art. If the drawing and naming are inconsistent, the drawing of the chemical structure shall be considered to be correct. Further, the name of an isotopically substituted compound is formed by inserting in parentheses the nuclide symbol before the name of that part of the compound that is isotopically substituted.

The present disclosure also provides the following aspects.

Aspect 1 A compound of Formula I:

Formula I P90727PC wherein:

R¹ is H or (CH₂)_PZ;

R² is H, OH or F;

R³ is H or Ci-Csalkyl;

R⁴ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3 and CN;

R⁵ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3 and CN;

Q is C or N;

X is O or NH;

Y is selected from the group consisting of ¹²⁷I, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I;

Z is a five- or six-membered heterocycle comprising 1, 2 or 3 nitrogen atoms, said heterocycle being substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, Ci-Csalkyl and oxo; n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; the substituents are located cis with respect to each other; with the proviso that: n + m = l or n + m = 0; and when R² is H then m is 1; or a pharmaceutically acceptable salt thereof.

Aspect 2

The compound according to aspect 1, or a pharmaceutically acceptable salt thereof, wherein

R⁴ is selected from the group consisting of CF3, OCi-Cealkyl, OCF3 and CN;

R⁵ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3 and CN; n + m = l or n + m= 0; and

R² is OH when n = 0.

Aspect 3

The compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound of Formula I' and/or Formula I": P90727PC

Formula I' Formula I"

Aspect 4 The compound according to any one of aspects 1-3, or a pharmaceutically acceptable salt thereof, wherein : Q is C.

Aspect 5 The compound according to any one of aspects 1-4, wherein: n + m = 1; thereby providing a compound of Formula Ila or Formula lib: or a pharmaceutically acceptable salt thereof.

Aspect 6

The compound of Formula Ila according to aspect 5, which is a compound of Formula

Hal: P90727PC

Formula Hal or a pharmaceutically acceptable salt thereof.

Aspect 7

The compound of Formula I according to any one of aspects 1-4, wherein n + m = 0; and

R² is OH; thereby providing a compound of Formula III:

Formula III or a pharmaceutically acceptable salt thereof.

Aspect 8

The compound of Formula III according to aspect 7, which is a compound of Formula

Illa:

Formula Illa or a pharmaceutically acceptable salt thereof, P90727PC

9

The compound according to any one of the preceding aspects, or pharmaceutically acceptable salt thereof, wherein:

The compound according to any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, wherein:

X is O;

R² is OH;

R³ is H; and p is 1.

Aspect 11

R⁴ and R⁵ are both CF3; or

R⁴ and R⁵ are both CN.

The compound according to any one of aspects 1-6 or 9-11, or a pharmaceutically acceptable salt thereof, wherein Y comprises or consists of:

(i) ¹²³I, ¹²⁴I and/or ¹²⁵I; or

(ii) ¹³¹I.

The compound according to any one of aspects 1-6 or 9-11, or a pharmaceutically acceptable salt thereof, wherein Y comprises or consists of ¹²⁷I.

A pharmaceutical composition comprising a compound according to any one of the preceding aspects, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. P90727PC

Aspect 15

The compound according to any one of aspects 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to aspect 14 for use as a medicament in therapy.

Aspect 16

The compound according to any one of aspects 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to aspect 14 for use in the treatment and/or prevention of a 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(s) thereof.

Aspect 17

The compound according to any one of aspects 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to aspect 14 when dependent on aspect 12 for use in the diagnosis of a 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(s) thereof.

Aspect 18

The compound or pharmaceutical composition for use according to aspect 16 or 17, wherein the cancer comprises or consists of neuroblastoma.

Further aspects

The present disclosure also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein wherein m +1 =0. Thus, there is provided a compound of Formula IV, or a pharmaceutically acceptable salt thereof, as described herein.

The disclosure will be further described by reference to the following examples, which are not intended to limit the scope of the disclosure. P90727PC

Examples

General

The human neuroblastoma cell lines SKNAS and IMR-32 were obtained from 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 (Dulbecco's modified Eagle medium). Media was supplemented with 10% (SKNAS) and or 20% (IMR-32) fetal bovine serum (Sigma-Aldrich, Darmstadt, Germany), 1% antibiotics (100 IU penicillin and 100 pg/mL streptomycin) and 1% L- glutamin (Biochrom, Berlin, Germany). The media for SKNAS was further supplemented with 1% non-essential amino acids (Thermo Fisher, Waltham, MA, USA). Cells were passaged one to three times per week with 0.25% trypsin-EDTA (Life Technologies/Thermo Fisher, Waltham, MA, USA). The colorectal cell line HT-55 (colon carcinoma) was obtained from European Collection of Authenticated Cell Culture (ECACC) was cultured in Minimum Essential Medium (MEM) (Biowest, MO, USA) supplemented with 20% FBS, L-glutamine (Biochrom GmbH, 2 mM) and antibiotics (100 IU penicillin and 100 pg/ml streptomycin, Biochrom GmbH, Germany). Monolayer cultures were grown in tissue culture flasks (VWR, PA, USA) and incubated in an atmosphere containing 5% CO2 at 37°C. After reaching 70%-80% confluency, cell passaging was performed using Trypsin-EDTA (Biochrom GmbH, Germany).

HiTSeeker cell line expressing human Tachykinin receptor 1 (DNA Accession Number: GenBank: AY462098) in U2OS osteosarcoma cells, TACR1 (NK1)/U2OS (U2O2-NK1R), was purchased from Innoprot, Spain, REF: P30129-U2. Wild type (non-transfected) U2OS cells were obtained from American Type Culture Collection (ATCC). The cells were cultured in Dulbecco's modified Eagle medium (Gibco™ DMEM, high glucose, GlutaMAX™ Supplement, pyruvate, Cat. No 31966021), supplemented with 10% (v/v) fetal bovine serum (FBS) (Merck, Cat. No F7524), 100 I.U/ml penicillin-streptomycin solution (Gibco™ Cat. Nol5140-122) and 0.5 mg/ml Geneticin (Gibco, Cat. No 10131- 027). Monolayer cultures were grown in tissue culture flasks (VWR, Cat. No 734- 2313) in a humidified incubator at 37°C with 5% CO2.

Aprepitant (CAS number: 170729-80-3) was obtained from United States Pharmacopeia (1041904-150 mg). FAM-labeled substance P, FAM-SP, (Cat. No AS- 61201) was obtained from AnaSpec, USA. As used herein, substance P undecapeptide member of the tachykinin neuropeptide family. Substance P, which may be abbreviated SP, was obtained from Sigma Aldrich (Cat No S6883) and has the CAS P90727PC number 33507-63-0. The 125-radioiodine or iodine-125 radionuclide (17Ci (629GBq)/mg, 0.1M NaOH, pH 12-14, reductant free) was obtained from PerkinElmer Inc., USA, shipped at ambient temperature condition.

Abbreviations

BBB blood-brain barrier

Boc tert-butoxycarbonyl

BOC tert-butoxycarbonyl

CAS Chemical Abstracts Service

CAT Chloramine T

DCM dichloromethane

DEAD diethyl azodicarboxylate

DFO deferoxamine

DIBAL diisobutylaluminiumhydride

DIPEA /V,/V-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)-l,4,7,10-tetraazacyclododecan-l- yl)pentanedioic acid)

DTPA diethylenetriaminepentaacetic acid

EDC l-ethyl-3- [3-d i methylaminopropyl] carbodi imide

FAM-SP fluorescent (FAM)-labeled Substance P

FBS fetal bovine serum

GPCR G protein-coupled receptor hNKl human type neurokinin 1

HPLC high-performance liquid chromatography

ITLC instant thin layer chromatography (ITLC)

KD dissociation constant

L-selectride Li[(CH₃CH₂CH(CH3)))BH]

LCMS - ESI Liquid Chromatography Mass Spectroscopy Electrospray Ionization min minute(s)

MBq megabecquerel

N normality

NBL neuroblastoma

NBS sodium metabisulfite

NK1R neurokinin 1 receptor P90727PC

NOTA 2,2',2"-(l,4,7-triazonane-l,4,7-triyl)triacetic acid

NODAG A 2-(4, 7-bis(carboxy methyl)- 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-/V-butylammonium fluoride

TBS tert-butyldimethylsilyl

TBSOTf trifluoromethanesulfonic acid tert-butyldimethylsilylester

TEA triethyamine

TETA ( 1, 4,8, 11 -tetraazacyclotetradeca ne- 1,4,8, ll-tetrayl)tetraacetic acid

TEA trifluoroacetic acid

Ts para-toluenesulfonyl

THE tetra hydrofuran v/v volume per volume

Chemistry

Preparation of starting materials for Examples 1-4

Preparation of benzyl 3-hydroxy-2-methoxypiperidine-l-carboxylate

A homogeneous solution of benzyl 3,4-dihydropyridine-l(2H)-carboxylate (1 g, 4.603 mmol) dissolved in MeOH (30 mL) was added to a stirring suspension of oxone (1.681 g, 5.468 mmol) and NaHCCh (0.459 g, 5.468 mmol) in MeOH (30 mL) at room temperature (RT). The reaction was stirred for 2 h followed by further addition of oxone (1.681 g, 5.468 mmol) and NaHCOs (0.459 g, 5.468 mmol). The resulting reaction mixture was stirred for 12 h, where progress of reaction was monitored with thin layer chromatography using a 1: 1 ethyl acetate/hexane mobile system. The solids were filtered, and the filtrate was diluted with ethyl acetate (50 mL) and a saturated solution of NaHCOs (50 mL). The organic layer was extracted with ethyl acetate (2 x 50 mL), washed with brine (50 mL), dried over NaSCU and evaporated to dryness under vacuum, providing a colourless 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 %). ¹H NMR (400 MHz, Chloroform-d) 5 7.44 - 7.26 (m, 5H), 5.51 - 5.01 (m, 3H), 4.07 - 3.79 (m, 1H), 3.48 (s, 1H), 3.27 (d, J = 12.9 Hz, 3H), 3.00 - P90727PC

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 (found) : 234.275 (234.2).

Preparation of benzyl (±)-c/s-2-(4-(benzyloxy)phenyl)-3-hydroxypiperidine- 1-carboxylate

To a stirring solution of the compound of benzyl 3-hydroxy-2-methoxypiperidine-l- carboxylate (1.033 g, 3.897 mmol) and (4-(benzyloxy)phenyl)boronic acid (0.889 g, 3.897 mmol) in dry dichloromethane (10 mL), BFs-OEtz (480.95 pL, 3.897 mmol) was added at -30 °C under a sealed N2 environment. The reaction was allowed to return to RT over 4 h and further stirred for 24 h. Thereafter, it was quenched by adding a saturated solution of NH4CI (10 mL) and the organic phase was extracted with ethyl acetate (2 x 10 mL). The separated organic layers were combined, washed with brine, dried over NazSC and evaporated to dryness under vacuum. Silica gel column chromatography (ethyl acetate/hexane, 1/2 to 1/1) of the crude product provided the cis isomer title compound as a light brown liquid (0.987 g, 60.66 %). ¹H NMR (400 MHz, Chloroform-d) 5 7.47 - 7.38 (m, 4H), 7.35 (ddd, J = 7.5, 6.6, 1.4 Hz, 2H), 7.32 - 7.22 (m, 6H), 6.94 - 6.85 (m, 2H), 5.48 (d, J = 5.7 Hz, 1H), 5.11 (q, J = 12.5 Hz, 2H), 4.99 (s, 2H), 4.06 - 3.90 (m, 2H), 3.12 (s, 1H), 2.90 (td, J = 13.2, 3.7 Hz, 1H), 1.79 (td, J = 9.5, 8.0, 4.6 Hz, 2H), 1.73 - 1.46 (m, 2H). ESI-LC-MS(+) : m/z [M + H] ⁺ calculated (found): 418.51 (418.0).

Preparation of benzyl (±)-c/s-2-(4-(benzyloxy)phenyl)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)piperidine-l-carboxylate

A solution of the compound of benzyl (±)-c/s-2-(4-(benzyloxy)phenyl)-3- hydroxypiperidine-l-carboxylate (487.2 mg, 1.167 mmol) and l-(bromomethyl)-3,5- bis(trifluoromethyl)benzene (234.01 pL, 1.277 mmol) in dry DMF (2 mL) was added to a stirring solution of NaH (33.69 mg, 60 % dispersion in mineral oil, 1.404 mmol) in dry DMF (2 mL) at 0 °C. The reaction mixture was then transferred to a pre-heated block at 80 °C. After 4 h of stirring, the mixture was quenched with H2O (1 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated under vacuum . The resulting crude product was purified using silica gel column chromatography (ethyl acetate: hexane, 1 : 10), providing the cis isomer title compound as a white liquid (137.6 mg, 18.32 %). ^XH NMR (400 MHz, Chloroform-d) 5 7.70 (s, 1H), 7.62 (d, J = 1.9 Hz, 2H), 7.48 - 7.12 (m, 12H), 6.91 - 6.79 (m, 2H), 5.68 (s, 1H), 5.11 (q, J = 12.4 Hz, 2H), 4.97 (s, 2H), 4.63 (q, J = 12.4 Hz, 2H), 3.94 (dd, J = 14.0, 4.6 Hz, 1H), 3.80 (ddd, J = 8.7, 7.2, 5.5 Hz, 1H), 2.74 (td, J = 13.2, 3.5 Hz, 1H), 2.11 - 1.84 (m, 2H), 1.74 - 1.46 (m, 2H). ESI-LC-MS(+): m/z [M + H]⁺ calculated (found) : 643.6 (643.9). P90727PC

Example 1: Preparation of a racemic mixture of 4-((2S,3S)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol and 4-((2R,3R)-3- ((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol, i.e. 4-((±)-cfs-

3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)phenol

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-y I) phenol

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

The combined hydrogenolysis of the benzyl and benzyloxycarbonyl groups of the compound of benzyl (±)-c/s-2-(4-(benzyloxy)phenyl)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)piperidine-l-carboxylate was carried out in one step following the procedure outlined in H. Sajiki, Tetrahedron Lett., 1995, 36, 3465. The procedure is as follows. A mixture of the compound of benzyl (±)-c/s-2-(4- (benzyloxy)phenyl)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidine-l -carboxy late (137.6 mg, 0.214 mmol), NhUOAc (49.44 mg, 0.641 mmol) and 10 % Pd/C (10 mg) in MeOH (3 mL) was treated with Hz into a sealed reaction vial by applying two alternate vacuum/Hz cycles and stirred for 30 min at RT. The mixture was then filtered through celite, washed with MeOH (2 x 5 mL), and extracted with ethyl acetate (2 x 5 mL). The combined ethyl acetate layer was then washed with brine (5 mL), dried over NazSO4, and concentrated under vacuum. The crude product was then washed with pentane (2 x 5 ml) and evaporated to complete dryness under vacuum, providing the cis isomer title compound as white solid flakes (62.5 mg, 69.71 %). ^XH NMR (400 MHz, Methanol-ck) 5 7.84 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 1.7 Hz, 2H), 7.36 - 7.25 (m, 2H), 6.90 - 6.78 (m, 2H), 4.82 (d, J = 12.7 Hz, 1H), 4.42 (dd, J = 7.2, 5.5 Hz, 2H), 3.96 (dt, J = 3.6, 1.9 Hz, 1H), 3.51 - 3.38 (m, 1H), 3.23 (td, J = 13.1, 3.2 Hz, 1H), P90727PC

2.46 - 2.29 (m, 1H), 2.20 - 2.04 (m, 1H), 1.88 (dddd, J = 17.0, 12.6, 7.5, 2.6 Hz, 2H). ESI-LC-MS(+) : m/z [M + H]⁺ calculated (found) : 420.37 (420.0). Figure 1A shows the UV HPLC-analysis of the title compound.

Example 2: Preparation of a racemic mixture of 5-(((2S,3S)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-lH-l,2,4-triazol-3(2H)-one and 5-(((2R,3R)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl) methyl )-lH-l,2,4-triazol-3(2H)-one, i.e. 5-(((±)-cfs-3-((3,5- bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl) methyl )-lH-l,2,4-triazol-3(2H)-one

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-lH-l,2,4-triazol-3(2H)-one

5-(((2R.,3R.)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxyphenyl)piperidin-l- yl)methyl)-lH-l,2,4-triazol-3(2H)-one

A mixture of the compound of Example 1 (54.3 mg, 0.129 mmol) and 5- (chloromethyl)-l,2-dihydro-3H-l,2,4-triazol-3-one (19.02 mg, 0.142 mmol) in dry DMF (2 mL) was added to the stirring solution of NaH (3.73 mg, 0.155 mmol) in dry P90727PC

DMF (1 mL) at 0 °C. The reaction mixture was then transferred to a pre-heated block at 80 °C and stirred for 3 h. The reaction was quenched with water (2 mL) and extracted with ethyl acetate (10 mL) and brine (2 x 5 mL). The organic layer was dried over NazSC , filtered and concentrated under vacuum. Silica gel column chromatography of the crude product using dichloromethane/ethyl acetate (1/10) under Nz provided the cis isomer title compound as a white solid (44.09 mg, 65.94 %). ¹H NMR (500 MHz, Methanol-d₄) 5 7.84 (s, 1H), 7.76 (s, 2H), 7.30 (d, J = 8.2 Hz, 2H), 6.83 - 6.73 (m, 2H), 4.66 (d, J = 12.3 Hz, 1H), 4.20 (d, J = 12.3 Hz, 1H), 3.71 - 3.60 (m, 2H), 3.53 - 3.34 (m, 1H), 2.98 (d, J = 11.0 Hz, 1H), 2.95 - 2.83 (m, 1H), 2.36 - 2.20 (m, 2H), 2.01 (qt, J = 13.1, 2.7 Hz, 1H), 1.71 - 1.57 (m, 2H). ESI-LC-MS(+) : m/z [M]⁺ calculated (found): 516.44 (516.9 or 517). Figure 2A shows the HPLC analysis of the title compound.

Example 3: Preparation of a racemic mixture of 4-((2S,3S)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I)iodophenol and 4- ((2/?,3/?)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2- (¹²⁵I)iodophenol, i.e. 4-((±)-cfs-3-((3,5- bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I) iodophenol

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I)iodophenol

4-((2/?,3/?)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-(¹²⁵I) iodoph enol

Stock solutions of both chloramine-T (CAT) (2 mg/mL) and sodium metabisulfite (NBS) (2 mg/mL) were prepared in a phosphate-buffered saline (PBS, pH 7.4). The P90727PC compound of Example 1 (10.3 pg) was mixed with a solution of ([¹²⁵I]NaI, 5 MBq, dissolved in 0.1 M NaOH, pH 12-14, PerkinElmer Inc., USA) followed by the subsequent addition of the CAT (15 pL) stock solution. The radioiodination reaction was left for 60 minutes at RT, the reaction was quenched by addition of NBS (30 pL) providing the desired product in a 97.6% radiochemical yield.

The radiolabeling yield and radiochemical purity were assessed using instant thin layer chromatography (ITLC) and high-performance liquid chromatography (HPLC) with an in-built radioactivity detector channel.

HPLC analysis (5-95 % on solvent B; A: H2O/TFA, B: ACN/TFA, 1 mL/min, 254 nm) of the compounds of Example 4 and Example 6 showed clear distinct peaks in the UV and radio-channel detectors at 7.980 and 9.113 min, respectively, confirming a successful ¹²⁵I-radiolabelling of the compound of Example 6. Figure IB shows the Radio-HPLC analysis of the title compound.

Example 4: Preparation of a racemic mixture of 5-(((2S,3S)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-(¹²⁵I)iodophenyl)piperidin- l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one and 5-(((2/?,3/?)-3-((3,5- bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-(¹²⁵I)iodophenyl)piperidin- l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one, i.e. 5-(((±)-cfs-3-((3,5- bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-(¹²⁵I)iodophenyl)piperidin- l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one P90727PC

5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- (¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one

CAT (15 pL) and NBS (30 pL) stock solutions was prepared as described in Example 3. The compound of Example 2 (10.3 pg) was mixed with a solution of ([¹²⁵I]NaI, 5 MBq, dissolved in 0.1 M NaOH, pH 12-14, PerkinElmer Inc., USA) followed by the subsequent addition of the CAT (15 pL). The radioiodination reaction was left for 60 minutes at 37 °C. NBS (30 pl) was added. The desired product was obtained in a 99.6% radiochemical yield.

HPLC analysis (5-100 % on solvent B; A: H2O/TFA, B: ACN/TFA, 1 mL/min, 254 nm) of the compounds of Example 5 and Example 4 showed clear distinct peaks in the UV and radio-channel detectors at 7.010 and 7.533 min, respectively, confirming a successful ¹²⁵I-radiolabelling of the compound of Example 4. Figure 2B shows the HPLC analysis of the title compound.

Examples 5 - 54

The compounds of Examples 5 - 54 as shown in Table 1 were prepared using methods described in this document and/or using procedures known in the art. For instance, the compounds of Example(s) No. 5-10 and 16-25 were prepared as indicated in Scheme 5A. The compound(s) of Examples No. 11-15 and 26-34 were prepared from (2S, 3S)-2-phenylpiperidin-3-amine through a reductive amination with a suitable aldehyde. Example 36-47 were prepared by alkylations as in Scheme 6. Example 48- 51 were prepared according to scheme 2B and example 52 according to scheme 2A The identity of example 48-52 was confirmed by comparing the retention time from the UV-trace of a reference solution containing the [¹²⁷I]- compound with the retention time from the radiotrace of the [¹²⁵I]-compound from the labelling reaction. P90727PC

Table 1 P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC P90727PC

P90727PC

Preparation of (2S,3S)-N-((5-[¹²⁵I]Iodo-2-methoxypyridin-3-yl)methyl)-2- phenylpiperidin-3-amine, i.e. the compound of Example 49 To a vial containing [¹²⁵I]NaI (11 MBq in 0.1 M NaOH) was added tert-butyl (2S,3S)-

3-((tert-butoxyca rbonyl)((2-methoxy-5-(trimethylstannyl)pyridin-3- yl)methyl)amino)-2-phenylpiperidine-l-carboxylate (15 pl, 2 mg/ml in methanol) and P90727PC

10% acetic acid in methanol (15 pl). Chloramine-T (7.5 pl, 2 mg/ml in methanol) was added and the mixture was heated at 50°C for 35 min. The mixture was let to RT and sodium metabisulfite (15 pl, 2 mg/ml in water) was added. TEA (100 pl) was added and the mixture was heated at 65 °C for 60 min. TEA (50 pl was added) and the mixture was heated at 65 °C for 30 min. 50 pl of the mixture was diluted with water and acetonitrile and was purified by HPLC (Biphenyl coreshell column, gradients of 20-70% MeCN in 0.1% TEA (aq)). The solvents were evaporated to give the title compound (2.7 MBq). The identity of the compound was confirmed by comparing the retention time from the HPLC-UV-trace of a reference solution containing the [¹²⁷I]-compound described in Example 14 with the retention time from the radiotrace from the title compound.

Biology

Binding Affinity Measurements

NB Cell Lines

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

A total of 3 x 10⁵ cells (IMR-32) or 2.5 x 10⁵ (SK-N-AS) were seeded on a polydopamine-coated petri dish to allow cell attachment, following the manufacturer's instructions (Ridgeview Instruments, Uppsala, Sweden), and incubated for 24 h at 37 °C. CO2 independent media (3 mL, ibco/Thermo Fisher, Waltham, MA, USA) was then added to the petri dish and a baseline curve was obtained by running the LigandTracer for 10 min. The compound of Example 4 (300 nM in fresh supplemented cell medium, > 95 % radiolabeling yield) was then added and the LigandTracer was allowed to run for 3-4 h. 700 nM of the compound of Example 4 was further added to the above cell solution, resulting in a final concentration of 1 pM. After running the LigandTracer for 3-4 h, the cell media was removed and replaced with 3 mL of fresh media, and the assay was then allowed to run overnight to establish a dissociation curve. The binding curves obtained were assessed against different kinetic interaction models (1: 1 and 1:2) using the T raceDrawer 1.9 software (Ridgeview Instruments, Uppsala, Sweden).

Figures 3A-3D show the 1 : 1 and 1 :2 kinetic analysis of the real-time binding curves of the compound of Example 4 with human NB cell lines SK-N-AS and IMR-32. The solid line shows the calculated fit. It can be seen that the recorded curves are close to a P90727PC

1:2 fit indicating a 1 :2 kinetic fit. Figure 4 shows the real-time binding curves of the compound of Example 4 with human NB cell lines SK-N-AS and IMR-32. The highest signal was observed for IMR-32 followed by SK-N-AS.

Table 2 shows the equilibrium dissociation constants (KD) determined for the compound of Example 4 with human cell lines SK-N-AS and IMR-32.

Table 2

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

L-741,671 is known in the prior art to show affinity to hNKl receptors (as reported in Tattersall F. D. et al., Neuropharmacology 1996, 35, 1121-1129). The low nanomolar KDI values of the 1 :2 kinetic model analysis of the compound of Example 4 and the combined real-time binding curves show that the binding affinity of the compound of Example 4 is not altered by the attachment of a large ¹²⁵I atom.

Colorectal Cell Line HT-55

The binding characteristics of the compound of Example 4 with the human HT-55 colorectal cancer cell line, which expresses NK1 receptors, were also assessed following the same procedure outlined above.

1.5 x 10⁶ HT-55 cells were seeded on tilted cell culture-treated Nunc dishes (Cat. Nol50350, Thermo Fisher Scientific) and incubated in an atmosphere containing 5% CO2 at 37°C. After 48 h of incubation, the real-time binding measurement was performed, the cell medium was switched to 3 ml of fresh medium prior to the start of the binding measurement. The binding of compound of Example 4 to HT-55 cells was measured with LigandTracer Grey (Ridgeview Instruments AB, Uppsala, Sweden) at room temperature. A baseline signal was collected for around 10 min before stepwise adding compound of Example 4 to final concentrations of 300 nM and 1 uM. Dissociation was initiated when the binding curve got sufficient curvature at least in one concentration by replacing the media with 3 ml fresh media. Plastic surface of an area with no cells on the same dish was used as the reference background area to P90727PC investigate off-target binding of radiolabeled molecule. The reference background signal was automatically subtracted from the decay-corrected target area signal that resulted in a specific real-time binding curve of compound of Example 4 to the target cells. Kinetic interaction evaluation was performed with TraceDrawer 1.9.2 (Ridgeview Instruments AB, Uppsala, Sweden).

Figures 5A-5D show the 1 : 1 and 1 :2 kinetic analysis of the real-time binding curves of the compound of Example 4 with human colorectal cancer cell line HT-55. The solid line shows the calculated fit. It can be seen that the recorded curves are close to a 1:2 fit indicating a 1:2 kinetic fit.

Table 3

Table 3 shows the equilibrium dissociation constants ( KD) determined for the compound of Example 4 with human colorectal cancer cell line HT-55. Thus, the compounds of Formula I can be used in the diagnosis, treatment and/or prevention of colorectal cancers, which express elevated levels of NK1 receptors.

Specificity assay

The cellular uptake of the compound of Example 4 in the human NB cell line IMR-32 was investigated in a specificity assay.

A total of 2 x 10⁵ cells/well were seeded in a 24-well plate and incubated for 48 h at 37 °C. The old media was removed and replaced with either the compound of Example 4 (10 nM) or a combination of the compound of Example 4 (10 nM) and aprepitant (1 pM). The treated cells were then incubated for 1 h. The mediate was removed, the cells were trypsinized, i.e., dissociated using trypsin, and fractions were collected in fraction tubes. The radioactive uptake in each fraction tube was measured using a gamma counter (1480 Wizard 3", Wallace). The difference in the amount of bound radioactivity between the treatment groups was calculated using an unpaired t-test.

The specificity assay shows the NK1R targeted uptake of the compound of Example 4 at a concentration of 10 nM, which was blocked by aprepitant at a concentration of 1 pM, 100 times stronger than that of the compound of Example 4. P90727PC

This demonstrates the specific binding of the compound of Example 4 for NK1R, which is important to ensure specific accumulation of the compound to the intended treatment sites, and for avoiding non-specific uptake in healthy tissues/organs so that associated side effects are minimised.

Further

NKIR-transfected U2OS cells (TACR1 (NK1)/U2OS, "U2OS-NK1R") were seeded into ten wells in a 48-well plate with 500 pL of DMEM media supplemented with 10% FBS and 1% Penicillin-Streptomycin per well. Wild-type non -transfected U2OS cells were seeded into an additional ten wells in a 48-well plate with 500 pL of DMEM media supplemented with 10% FBS and 1% Penicillin-Streptomycin per well. The cells were then incubated for 48 hours at 37°C in a 5% CO2 atmosphere. Following the incubation period, the media was aspirated, and the wells were washed twice with PBS.

For preparing "blocked" wells, five of wells containing the U2OS-NK1R cells and five of the wells containing the wild-type U2OS cells were pre-treated with 500 nM aprepitant in 100 pL of DMEM media containing 1% Penicillin-Streptomycin per well. In the remaining five U2OS and five U2OS-NK1R wells, 100 pL of DMEM media with 1% Penicillin-Streptomycin was added per well. After a 10-minute incubation at 37°C, 100 pL of 10 nM of the compound of Example 49, said compound containing ¹²⁵I, in DMEM media with 1% Penicillin-Streptomycin was added to each well and incubated for an additional 30 minutes at 37°C.

Following the incubation with the compound of Example 49, the radioactive media was aspirated, and the cells were washed with PBS. Subsequently, the cells were trypsinized, i.e dissociated using trypsin, counted using a TC20™ Automated Cell Counter (BioRad, Sweden), and cell-associated radioactivity was measured using a gamma counter (1480 Wizard 3', Wallace, Finland). Statistical significance was assessed using a Student's t-test, and the data were analyzed to determine pmol of the compound of Example 49 per 100000 cells. The results are shown in Figures 8A and 8B. The error bars in the figures denote a 95% confidence interval.

Figure 8A shows the amount of the compound of Example 49 measured as pmol (i.e. picomoles) bound per 100 000 NKIR-transfected U2OS cells. It is clear from Figure 8A that there is NK1R targeted uptake of the compound of 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 of Example 49 measured as pmol (i.e. picomoles) bound per 100 000 non-transfected wild-type U2OS cells. Figure 8B shows no NK1R targeted uptake of the compound of Example 49. It was concluded that the P90727PC compounds of the present disclosure such as the compound of Formula I specifically bind to NKR1. This specific binding is important to ensure specific accumulation of the compound to the intended treatment sites, and for avoiding non-specific uptake in normal tissues/organs so that associated side effects are minimised.

For real-time competition binding experiments on the NKIR-expressing U2OS osteosarcoma cells (TACR1 (NK1)/U2OS), 1.5-2.0 x 10⁶ cells were seeded into tilted dishes (Nunc™ Cell Culture/Petri Dishes, Cat. No. 150350, ThermoFisherScientific) and incubated at 37°C and 5% CO2 overnight. The next day the medium (supplemented Dulbecco's modified Eagle medium, as described in General section) was replaced with 10 mL of fresh medium and the dishes were incubated overnight horizontally.

The kinetic measurements were done on LigandTracer Green (Ridgeview Instruments AB, Uppsala, Sweden) using a blue (488 nm)-green (535 nm) detector at ambient temperature.

Before the binding measurement, the cell medium was switched to 3 ml of CO2- Independent medium (Gibco, Cat. Nol8045-054), supplied with 10% (v/v) fetal bovine serum (FBS), and the dish was placed on inclined rotating support of the instrument. A baseline signal was recorded for 30 min before 90 nM of the FAM- labeled substance P, FAM-SP, was added to the cells and signals from cell target and background reference areas were recorded over time. After sufficient curvature of the binding curve was obtained (usually c.a. 60 min), 90 nM of the competing compound (Example 7 Example 8, Example 9, Example 10, Example 11, Example 13, Example 14, Example 15) was consequently added. The fluorescent signal was recorded for at least 60 min.

Kinetic evaluation was performed with TraceDrawer 1.9.2 software (Ridgeview Instruments AB, Uppsala, Sweden) using One-to-One Competiton model.

Figures 7A and 7B show the background corrected binding signal of the FAM-SP, followed by the competition phase in which the assessed compounds (the compounds of Examples 7-10 in Figure 7A, and the compounds of Examples 11 and 13-15 in Figure 7B) compete with FAM-SP for binding, resulting in compound-dependent levels of reduced FAM-SP signal. The positive controls Aprepitant and SP are shown for comparison. It was concluded that the compounds of the present disclosure demonstrate NK1R specific binding to an epitope overlapping with FAM-SP. The % of displacement of FAM-SP at 60 minutes after addition of the competing compound is reported in Table 4 below. P90727PC

Further competition assay

Further competition tests were performed by testing displacement of (i) FAM-SP and (ii) ¹²⁵I-SP, i.e. SP labelled with ¹²⁵I, using the compounds of the Examples described herein. The displacement of FAM-SP was performed using the competition assay described above. The results are shown in Table 4.

Compounds of Example 5, 14, 15, 18, 27, 32 were sent to Eurofins Cerep SA in Celle- Levescault, France to be tested in the NK1 Human Tachykinin GPCR Binding Agonist Radioligand LeadHunter Assay. The assay use membrane preparations from U373MG cells and ¹²⁵I-Substance P LYS3 as a ligand at 0.05 nM. Compounds were tested in duplicate at 8 concentrations ranging from 30 pM to 100 nM. The ICso calculations were provided by Eurofins Cerep. For comparison, the reference compound [Sar9,Met(O2)ll]-SP gave an IC50 of 167 pM.

The results are shown in Table 5. Table 4« P90727PC

Thus, the compounds of the present disclosure allow for displacement of FAM-SP.

Table 5 Table 5 shows that the compounds of the present disclosure allow for binding to

NK1R. In particular, compounds of the present disclosure wherein Q is nitrogen such as the compounds of Examples 14 and 32 have high affinity for NK1R. P90727PC

References

1. Halik P. et al., Pharmaceutics 2022, 14, 607

2. Kowaluk, E. A.; Arneric, S. P., Annual Reports in Medicinal Chemistry 1998, 33,

11-20 3. Tattersall F. D. et al., Neuropharmacology 1996, 35, 1121-1129

4. WO 95/20575 Al.

5. WO 94/19323 Al

6. WO 93/04040 Al

7. Munoz M. et al., Neuropeptides 2005, 29, 245-254 8. WO 95/23798 Al

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

Claims

P90727PC Claims

1. A compound of Formula I:

Formula I wherein :

R¹ is H or (CH₂)_PZ;

R² is H, OH or F;

R³ is H or Ci-Csalkyl;

R⁴ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO₂;

R⁵ is selected from the group consisting of H, CF3, OCi-Cealkyl, OCF3, CN, F and NO₂;

Q is C or N;

X is O or NH;

R⁶ 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; the substituents are located cis with respect to each other; with the proviso that: n + m = l; P90727PC or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, with the further proviso that when R² is H then m is 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is C thereby providing a compound of Formula la:

Formula la

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is N thereby providing a compound of Formula lb:

Formula lb

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula lb is a compound of Formula Ibl, Formula Ib2 or Formula Ib3 : P90727PC

6. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the piperidine ring has

S configuration at carbons 2 and 3, or

/? configuration at carbons 2 and 3.

7. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R¹ is H.

8. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R¹ is (CH2)_PZ.

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

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

11. The compound according to any one of claims 1-6 or 8-10, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a chelating moiety selected from the group consisting of

P90727PC

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a chelating moiety comprising or consisting of

13. The compound according to any one of claims 1-6 or 8-12, or a pharmaceutically acceptable salt thereof, wherein q is 4.

14. The compound according to any one of claims 1-6 or 8-13, or a pharmaceutically acceptable salt thereof, wherein R⁶ is a radionuclide complex comprising the chelating moiety and a radionuclide.

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is selected from the group consisting of ⁶⁸Ga, ¹⁸F, ⁶⁴Cu, 4⁴Sc, ⁸⁹Zr, ⁱⁿIn, ⁶⁷Ga, ^99mTc, Gd, ¹⁷⁷Lu, ⁸⁶/⁹⁰Y, ²²⁵Ac, ^161/155Tb, ^226/227Th, and an ion thereof. P90727PC

16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is ¹⁷⁷Lu such as ¹⁷⁷Lu³⁺.

17. The compound according to any one of claims 1-6 or 8-16, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of

18. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R¹ is

19. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R² is H or OH.

20. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R³ is H or CH3.

21. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein P90727PC

R⁴ is selected from the group consisting of H, CF3, OCH3, OCH(CH3)2, OCF3, F, NO2 and CN; and/or

R⁵ is selected from the group consisting of H, CF3, OCH3, OCH(CH3)2, OCF3, F, NO2 and CN.

22. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein :

R⁴ and R⁵ are both CF3; or

R⁴ and R⁵ are both CN.

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

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

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2- (¹²⁵I)iodophenol;

4-((2/?,3/?)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-

(¹²⁵I)iodophenol;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

5-(((2/?,3/?)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4-triazol-3(2H)-one;

(25.35)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-pi peridine;

3-(((2S,3S)-3-((3-iodo-5-(trifluoromethy I) phenyl) methoxy) -2-pheny 1-1- piperidyl) methyl)- 1,4-dihydro-l, 2, 4-triazol-5-one;

(25.35)-3-((3-iodophenyl)methoxy)-2-phenyl-pi peridine;

3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-l-piperidyl)methyl)-l,4- dihydro-l,2,4-triazol-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-pheny 1-1- piperidyl) methyl)- 1,4-dihydro-l, 2, 4-triazol-5-one;

(25.35)-N-(3-iodobenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine; P90727PC

(25.35)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4- hydroxyphenyl)piperidin-l-yl)methyl)-2,4~dihydro-3/7-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- iodophenyl)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4’triazol-3-one;

(25.35)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpi peridine;

(25.35)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine;

(25.35)-3-((3-iodo-5-nitrobenzyl)oxy)-2-pheny I piperidine;

(25.35)-3-((4-iodobenzyl)oxy)-2-phenylpiperidine;

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpiperid in -1-yl) methyl)-

2,4~dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-nitrobenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-2,4~ dihydro-3H-l,2,4~triazol-3-one;

(25.35)-N-((5-iodopyrid in -3-yl) methyl)-2-phenylpiperidin-3-a mine;

(25.35)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((4-iodo-6-(trifluoromethy I) pyridin -2-yl) methyl) -2-phenylpi peridin -3- amine;

(25.35)-2-(4-fluoropheny I) -N-((5-iodo-2-methoxypy rid in -3-yl) methyl) pi peridin -3- amine;

(25.35)-2-(4-fluorophenyl)-N-(3-iodo-5-(trifluoromethyl)benzyl)piperidin-3- amine;

(25.35)-N-((R)-l-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine;

5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-

2,4~dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-

2,4~dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)benzyl)amino)-2-phenylpiperidin-l- yl)methyl)-2,4~dihydro-3H-l,2,4~triazol-3-one;

5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4~ dihydro-3H-l,2,4~triazol-3-one; P90727PC

5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-

1-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

2S,3S)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-l-((6-methylpyridin-2- yl)methyl)-2-phenylpiperidin-3-amine;

2-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-

1-yl)methyl)pyrimidine 1-oxide;

5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-

(trifluoromethyl)benzyl)amino)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4- triazol-3-one;

(25.35)-l-((lH-imidazol-2-yl)methyl)-N-((5-iodo-2-methoxypy rid in -3-yl) methyl)-

2-phenylpiperidin-3-amine;

(25.35)-3-((3-(¹²⁵I)iodo-5-(trifluoromethyl) phenyl) methoxy) -2-phenyl-pi peridine;

(25.35)-N-((5-(¹²⁵I)iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3- amine;

(25.35)-N-((4-(¹²⁵I)iodo-6-(trifluoromethyl)pyridin-2-yl)methyl)-2- phenylpiperidin-3-amine;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one; 2,2',2"-(10-(2-((4-(3-(((2S,3S)-3-((3-Iodo-5-methoxybenzyl)oxy)-2- phenylpiperidin-l-yl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)butyl)amino)-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid; and

[¹⁷⁷Lu ]-Lutetium(III)- -2,2',2"-(10-(2-((4-(3-(((2S,3S)-3-((3-iodo-5- methoxybenzyl)oxy)-2-phenylpiperidin-l-yl)methyl)-5-oxo-4,5-dihydro-lH- 1,2,4- triazol-l-yl)butyl)amino)-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7- triyl)triacetate.

26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2- (¹²⁵I)iodophenol; P90727PC

4-((2/?,3/?)-3-((3,5-bis(trifl uoromethy I) benzy l)oxy) pi perid i n -2-yl)-2- (¹²⁵I)iodophenol;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4~triazol-3(2H)-one;

5-(((2R,3R)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3-

(¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-lH-l,2,4~triazol-3(2H)-one;

(25.35)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-pi peridine;

3-(((2S,3S)-3-((3-iodo-5-(trifluoromethyl)phenyl)methoxy)-2-phenyl-l- piperidyl) methyl)- 1,4-dihydro-l, 2, 4~triazol-5-one;

(25.35)-3-((3-iodophenyl)methoxy)-2-phenyl-pi peridine;

3-(((2S,3S)-3-((3-iodophenyl)methoxy)-2-phenyl-l-piperidyl)methyl)-l,4~ dihydro-l,2,4~triazol-5-one;

(25.35)-N-(3-iodobenzyl)-2-phenylpi perid in -3-a mine;

(25.35)-N-(3-iodo-5-methoxybenzyl)-2-phenylpiperidin -3-a mine;

(25.35)-N-(5-iodo-2-methoxybenzyl)-2-phenylpiperidin -3-a mine;

(25.35)-N-(3-iodo-5-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

4-((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)piperidin-2-yl)-2-iodophenol;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4- hydroxyphenyl)piperidin-l-yl)methyl)-2,4~dihydro-3/7-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- iodophenyl)piperidin-l-yl)methyl)-2,4~dihydro-3H-l,2,4-triazol-3-one;

(25.35)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpi peridine;

(25.35)-3-((3-fluoro-5-iodobenzyl)oxy)-2-phenylpiperidine;

(25.35)-3-((3-Iodo-5-nitrobenzyl)oxy)-2-phenylpiperidine;

(25.35)-3-((4-iodobenzyl)oxy)-2-phenylpiperidine;

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)oxy)-2-phenylpi perid in -1-yl) methyl)-

2,4~dihydro-3H-l,2,4~triazol-3-one;

(25.35)-N-(5-iodo-2-(trifluoromethoxy)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-isopropoxybenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(2-fluoro-5-iodobenzyl)-2-phenylpiperidin-3-amine;

(25.35)-N-(5-iodo-2-(trifluoromethyl)benzyl)-2-phenylpiperidin-3-amine;

(25.35)-2-(4-fluoropheny I) -N-(3-iodo-5-(trifl uoromethy I) benzyl) piperid in -3- amine;

(25.35)-N-((R)-l-(3-iodophenyl)ethyl)-2-phenylpiperidin-3-amine; P90727PC

5-(((2S,3S)-3-((5-iodo-2-methoxybenzyl)a mi no) -2-phenylpi peridin -1-yl) methyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3-iodo-5-methoxybenzyl)amino)-2-phenylpiperidin-l-yl)methyl)- 2,4-dihydro-3H-l,2,4-triazol-3-one;

5-(((2S,3S)-3-((3-iodobenzyl)amino)-2-phenylpiperidin-l-yl)methyl)-2,4- dihydro-3H-l,2,4-triazol-3-one;

5-(((2S,3S)-2-(4-fluorophenyl)-3-((3-iodo-5-

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4-hydroxy-3- (¹²⁵I)iodophenyl)piperidin-l-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

2,2',2"-(10-(2-((4-(3-(((2S,3S)-3-((3-Iodo-5-methoxybenzyl)oxy)-2- phenylpiperidin-l-yl)methyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-l- yl)butyl)amino)-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid; and

27. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 5-iodo-2-methoxy-3-(((2S,3S)-2-phenyl-3-piperidyl)oxymethyl)pyridine;

3-(((2S,3S) -3-((5-iodo-2-methoxy-3-py ridy I) methoxy) -2-pheny 1-1- piperidyl) methyl)- 1,4-dihydro-l, 2, 4-triazol-5-one;

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodopyrid in -3-yl) methyl)-2-phenylpiperidin-3-a mine;

(25.35)-N-((5-iodo-2-isopropoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-2-(4-fluoropheny I) -N-((5-iodo-2-methoxypy rid in -3-yl) methyl) pi peridin -3- amine; P90727PC

5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin-

1-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

2-(((2S,3S)-3-(((5-iodo-2-methoxy pyridin -3-yl) methyl)amino) -2-pheny I piperidin-

1-yl)methyl)pyrimidine 1-oxide;

(25.35)-l-((lH-imidazol-2-yl)methyl)-N-((5-iodo-2-methoxy pyridin -3-yl) methyl)-

2-phenylpiperidin-3-amine;

(25.35)-N-((5-(¹²⁵I)iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3- amine; and

(25.35)-N-((4-(¹²⁵I)iodo-6-(trifluoromethyl) pyridin -2-yl) methyl)-2- phenylpiperidin-3-amine.

28. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

(25.35)-N-((5-iodo-2-methoxypyridin-3-yl)methyl)-2-phenylpiperidin-3-amine;

(25.35)-N-((5-iodo-2-isopropoxy pyridin -3-yl) methyl) -2-pheny Ipiperid in -3-a mine;

5-(((2S,3S)-3-(((5-iodo-2-methoxypyridin-3-yl)methyl)amino)-2-phenylpiperidin- l-yl)methyl)-2,4-dihydro-3H-l,2,4-triazol-3-one;

(25.35)-N-((5-(¹²⁵I)iodo-2-methoxy pyridin -3-yl) methyl)-2-phenylpiperid in -3- amine; and

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

(i) ¹²³I, ¹²⁴I and/or ¹²⁵I; or

(ii) ¹³¹I.

30. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein Y comprises or consists of ¹²⁷I. P90727PC

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

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

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

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

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

36. A method for the diagnosis, treatment and/or prevention of a cancer selected from the group consisting of neuroblastoma, prostate cancer, pancreatic cancer, leukemia, osteosarcoma, hepatoblastoma, lung cancer, colon cancer, breast cancer, skin cancer, thyroid cancer, rhabdoid cancer, and any combination(s) thereof, said method comprising administering to a patient, such as a human or an animal, in need thereof, a therapeutically effective amount of a compound of Formula I according to any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32. P90727PC

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

38. A method for preparing a compound of Formula I as defined in any one of claims 1-31, or a pharmaceutically acceptable salt thereof, said method comprising the steps of: subjecting a compound of Formula IV:

Formula IV wherein

R¹ is as defined in any one of claims 1-31 or a protecting group such as tert- butoxyca rbonyl;

R², R³, R⁴, R⁵, X and Q are as defined in any one of claims 1-31; and the substituents are located cis with respect to each other; to iodination or astatination thereby providing the compound of Formula I; and

39. The method according to claim 38, wherein the compound of Formula IV is

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

5-(((2S,3S)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)-2-(4- hydroxyphenyl)piperidin-l-yl)methyl)-2,4-dihydro-3/7-l,2,4-triazol-3-one.

40. The method according to claim 38 or 39, wherein the iodination or astatination comprises the steps of: P90727PC a) iodinating the compound of Formula IV with ¹²⁷I to provide a compound of Formula I wherein Y is ¹²⁷I; b) substituting the ¹²⁷I with a boron or metal containing compound such as Sn(CH3)3 to provide a compound of Formula V:

Formula V wherein

R¹, R², R³, R⁴, R⁵, 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; and the substituents are located cis with respect to each other; with the proviso that: n + m = l; and c) substituting the boron or metal containing compound with an iodine radioisotope as defined in claim 29 or ²¹¹At.

41. The method according to claim 40, wherein the compound of Formula V is selected from the group consisting of tert-butyl (2S,3S)-2-phenyl-3-((3-(trifluoromethyl)-5-

(trimethylstannyl)benzyl)oxy)piperidine-l -carboxy late; tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-

(trimethy Istanny I) pyridin -3-yl) methyl)amino)-2-phenylpiperidine-l -carboxy late; tert-butyl (2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridin-

2-yl)methyl)amino) pi peridine-1 -carboxylate; and tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-

(trimethy Istanny I) benzyl)amino)piperidine-l-carboxy late. P90727PC

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

43. The method according to claim 42, wherein the YCI is prepared from /V-chloro-p- toluenesulfonamide or /V-chlorosuccinimide, and a sodium iodide salt selected from the group consisting of Na¹²³I, Na¹²⁴I, Na¹²⁵I and Na¹³¹I.

44. A compound of Formula IV which is

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

45. A compound of Formula V which is selected from the group consisting of tert-butyl (2S,3S)-2-phenyl-3-((3-(trifluoromethyl)-5- (trimethylstannyl)benzyl)oxy)piperidine-l -carboxy late; tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)((2-methoxy-5-

(trimethy Istanny I) pyridin -3-yl) methyl)amino)-2-phenylpiperidine-l -carboxy late; tert-butyl (2S,3S)-2-phenyl-3-(((6-(trifluoromethyl)-4-(trimethylstannyl)pyridin- 2-yl)methyl)amino) pi peridine-1 -carboxylate; and tert-butyl-(2S,3S)-2-phenyl-3-((2-(trifluoromethoxy)-5-

(trimethy Istanny I) benzyl)amino)piperidine-l-carboxy late.