Halogenated somatostatin analogs with multiple somatostatin receptor subtype selectivity.

Abstract

The present invention relates to halogenated somatostatin analogs having selectivity for multiple somatostatin receptor subtypes and pharmaceutical compositions containing the same. Furthermore, the present invention relates to the halogenated somatostatin analogs and pharmaceutical compositions for use in the treatment and / or diagnosis of diseases (e.g., neuroendocrine and other cancers) characterized by elevated (e.g., overexpression) of one or more somatostatin receptor subtypes (e.g., somatostatin receptor 2 (SST2) and / or somatostatin receptor 5 (SST5)).

Description

[Technical Field]

[0001] The present invention relates to halogenated somatostatin analogs having selectivity for multiple somatostatin receptor subtypes and pharmaceutical compositions containing the same. Furthermore, the present invention relates to the halogenated somatostatin analogs and pharmaceutical compositions for use in the diagnosis and / or treatment of diseases characterized by high expression (e.g., overexpression) of one or more somatostatin receptor subtypes, such as somatostatin receptor 2 (SST2) and / or somatostatin receptor 5 (SST5). [Background technology]

[0002] Somatostatin receptors belong to the G protein-coupled receptor family. Five somatostatin receptor subtypes (SST1-SST5) are known (Reubi JC. Endocrinology Reviews 2003;24(4):389-427; Schaer JC et al., Int. J. Cancer 1997;70(5):530-7). Somatostatin itself consists of two cyclic disulfide-containing peptide hormones, one with 14 amino acids (SS-14, Ala-Gly-c(Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys)) and one with 28 amino acids (SS-28, Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-c(Cys-Lys-Asn-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys)). Somatostatin receptors (e.g., SST2 and SST5), when activated in vivo, produce a biological effect upon binding, for example, with SS-14 or SS-28, such as inhibiting the secretion of hormones such as growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), prolactin (PRL), gastrin, insulin, and / or glucagon.

[0003] All five somatostatin receptor subtypes are expressed or overexpressed at varying frequencies in various normal and diseased tissues. For example, in neuroendocrine tumors (NETs), SST2 is often the most prominent subtype of differentiated NETs. However, although the majority of NETs express SST2, its distribution and density often vary (Reubi JC, Waser B. European Journal of Nuclear Medicine and Molecular Imaging (Eur. J. Nucl. Med. Mol. Imaging) 2003;30:781-793). Furthermore, the different somatostatin receptor subtypes SST1-SST5 exhibit distinct expression patterns in various tumors, even within the same tumor type. For example, SST2 and SST5 are highly expressed in 70-100% of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and are frequently co-expressed in growth hormone (GH)-secreting pituitary adenomas (Reubi JC, Waser B. Eur. J. Nucl. Med. Mol. Imaging 2003;30:781-793).

[0004] Due to somatostatin's ability to inhibit growth hormone secretion and overexpression of somatostatin receptors in tumors such as NETs, ​​there has been interest in using somatostatin for the treatment of proliferative diseases. However, somatostatin itself is not suitable for in vivo use given its short plasma half-life of 1-3 minutes (Benuck & Marks, Life Sciences 1976;19(8):1271-1276). As a result, numerous somatostatin analogs, which are more resistant to enzymatic degradation than somatostatin itself, have been developed over the past few decades by modifying the native molecule, including the introduction of D-amino acids, chemical modifications, especially at the N-terminus, and variations in chain length (Esther I. Van Vliet et al., "Somatostatin Analogues and Radionuclides Used in Therapy," Wiley, 2015). Unlike natural somatostatin, which binds with high affinity to all five SSTs, certain somatostatin analogs, octreotide and lanreotide, bind preferentially with high affinity to SST2.

[0005] Somatostatin analogs can also be used in diagnostic and theranostic settings, such as scintigraphy, positron emission tomography (PET) imaging, and single-photon emission computed tomography (SPECT) imaging, as well as therapeutic settings, such as peptide receptor radionuclide therapy (PRRT or PRRNT). In such settings, somatostatin analogs are labeled with various radionuclides, most often radiometals. To achieve this labeling, somatostatin analogs are usually bound to chelators capable of forming stable complexes with radiometals. The selection and use of various radionuclides depends on the specific diagnostic and therapeutic application. When bound to a somatostatin analog, the chelator immobilizes the corresponding radiometal, forming a radiolabeled somatostatin analog for diagnostic or theranostic use.

[0006] The first commercially available diagnostic somatostatin analog was a radiolabeled somatostatin analog. 111 The first imaging modality was In-DTPA-octreotide (DTPA: diethylenetriaminepentaacetic acid) (Octreoscan®). Octreoscan® has become the standard imaging modality for the management of patients with NETs, ​​has high affinity exclusively for the SST2 receptor subtype, and has shown high accuracy in diagnosing SST2-positive primary NETs and secondary lesions.

[0007] Other superior somatostatin analogs developed for diagnostic purposes are TOC (D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol)) and TATE (D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr), which show improved affinity for SST2 (Reubi JC et al., Eur J Nucl Med 2000;27(3):273-82). Furthermore, modification of octreotide by introducing the unnatural amino acid 1-naphthyl-alanine (1-Nal) at position 3 gave the analogue NOC (D-Phe-cyclo(Cys-1-Nal-D-Trp-Lys-Thr-Cys)Thr(ol)) (Antunes P et al., Eur. J. Nucl. Med. Mol. Imaging 2007;34(7):982-93), and introduction of a benzothiophene (BzThi) group at the same position gave the analogue BOC (D-Phe-cyclo(Cys-BzThi-D-Trp-Lys-Thr-Cys)Thr(ol)), both of which had affinity not only for SST2 but also for SST3 and SST5 (Ginj M et al., Chemistry and Biology 2007;34(7):982-93). Biology 2006;13:1081-1090). Further modification by introducing Thr at position 8 instead of Thr(ol) gave NOC-ATE and BOC-ATE (Ginj M et al., Chemistry and Biology 2006;13:1081-1090; Ginj M et al., Clin Cancer Res. 2005;11:1136-1145).Somatostatin analogs with affinity for SST2 are also derived from lanreotide (D-β-Nal-cyclo(Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2) (Lamberts SW et al., N Engl J Med. 1996;334:246-254) or RC-121 (D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2) (Cai et al., Proc. Natl. Acad. Sci. 1986;83:1896-1900). Furthermore, Moore et al. developed a series of somatostatin analogs with affinity for SST2 and SST5, including (4-amino-3-iodo)-D-Phe-c[Cys-(3-iodo)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (Moore SB et al., J Med Chem. 2005;48:6643-6652). However, a chelated version of this compound proved unsuitable for clinical use because chelation prevented SST5 affinity and resulted in high liver and kidney uptake (Mansi R. et al., Molecules, 2020;25:4155; Mansi R. et al., EJNMMI Research, 2020;10:90).

[0008] Somatostatin analogs are highly sensitive to structural modifications. This includes the design of somatostatin-based diagnostic and theranostic radiopharmaceuticals. The impact of introducing one or more structural modifications on the affinity, biological properties, and in vivo properties of somatostatin analogs is unpredictable, and each modification generates a unique pharmaceutical.

[0009] Despite successful development, it is of utmost interest to further develop somatostatin analogs that bind with high affinity to a broad range of SST subtypes (e.g., SST2 and / or SST5) to enhance the therapeutic efficacy of currently available analogs. Summary of the Invention

[0010] The present invention relates to halogenated somatostatin analogs that exhibit subnanomolar and low-nanomolar binding affinity to the somatostatin receptors SST2 and / or SST5. Therefore, the binding affinity of the compounds of the present invention to SST2 and SST5 is comparable to that of SS-28, one of the natural ligands of SST2 and SST5. Therefore, the compounds of the present invention are expected to exhibit high uptake and preferably high activity in tumor cells (e.g., NET cells and their metastases, preferably tumor cells expressing or overexpressing SST2 and / or SST5). Furthermore, the compounds of the present invention contain one or no iodine atoms. Therefore, the compounds of the present invention are expected to exhibit reduced regeneration in healthy organs and tissues (e.g., kidney and / or liver) in vivo. Additional features and advantages of the present technology will become apparent to those skilled in the art upon reading the detailed description below.

[0011] In one aspect, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2 is selected from the group consisting of -F, -Cl, -Br, and -I; and Y 1 -H, chelating agent, L 1 -TG, -L 1 - selected from the group consisting of a chelating agent, an amino protecting group, and a solid support;1 is a linker, TG is a terminal group, preferably said terminal group is -H; However, X 1 and X 2 are not both -I) to provide.

[0012] In one aspect, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2 is selected from the group consisting of -F, -Cl, -Br, and -I; and Y 1 -H, chelating agent, L 1 -TG, and -L 1 - selected from the group consisting of chelating agents; 1 is a linker, TG is a terminal group, preferably said terminal group is -H; However, X 1 and X 2 are not both -I) to provide.

[0013] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2 is selected from the group consisting of -F, -Cl, -Br, and -I; and Y 1 -H, chelating agent, L 1 -H, and -L 1- chelating agents; wherein L 1 is the linker; However, X 1 and X 2 are not both -I) to provide.

[0014] In some embodiments, the compound of formula I is a compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2 is selected from the group consisting of -F, -Cl, -Br, and -I; However, X 1 and X 2 are not both -I) is.

[0015] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I or Formula IA and a pharmaceutically acceptable carrier. In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula IA and a pharmaceutically acceptable carrier.

[0016] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I or Formula IA, or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use as a medicament. [Brief explanation of the drawings]

[0017] [Figure 1A] 1 is a dose-response curve showing the rate of SST2 receptor activation induced by SS-28 as a function of SS-28 concentration. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a cAMP-HTRF assay as described in Example 11. [Figure 1B] 1 is a dose-response curve showing the rate of SST2 receptor activation induced by Compound 3 as a function of the concentration of Compound 3. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a cAMP-HTRF assay as described in Example 11. [Figure 1C] 1 is a dose-response curve showing the rate of SST2 receptor activation induced by Compound 4 as a function of the concentration of Compound 4. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a cAMP-HTRF assay as described in Example 11. [Figure 1D] 1 is a dose-response curve showing the rate of SST2 receptor activation induced by Compound 5 as a function of the concentration of Compound 5. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a cAMP-HTRF assay as described in Example 11. [Figure 2A] 1 is a dose-response curve showing the results of a first competitive binding assay between [I]SS-14 and SS-28 in comparison with compounds 1 and 2. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of SS-28. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 2B] 1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 1. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of Compound 1. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 2C]1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 2. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of Compound 2. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 2D] 1 is a dose-response curve showing the results of a second competitive binding assay between [I]SS-14 and SS-28 in comparison with Compound 3. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of SS-28. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 2E] 1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 3. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of Compound 3. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 2F] 1 is a dose-response curve showing the results of a third competitive binding assay between [I]SS-14 and SS-28 in comparison with compounds 4 and 5. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of SS-28. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 2G] 1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 4. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of Compound 4. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 2H]1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 5. The binding rate of [I]SS-14 to the SST2 receptor is shown as a function of the concentration of Compound 5. The dose-response curve was measured in CHO-K1 cells (accession number NP_001041.1) in a radioligand binding competition assay as described in Example 12. [Figure 3A] 1 is a dose-response curve showing the results of a first competitive binding assay between [I]SS-14 and SS-28 in comparison with compounds 1 and 2. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of SS-28. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 3B] 1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 1. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of Compound 1. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 3C] 1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 2. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of Compound 2. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 3D] 1 is a dose-response curve showing the results of a second competitive binding assay between [I]SS-14 and SS-28 in comparison with Compound 3. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of SS-28. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 3E]1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 3. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of Compound 3. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 3F] 1 is a dose-response curve showing the results of a third competitive binding assay between [I]SS-14 and SS-28 in comparison with compounds 4 and 5. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of SS-28. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 3G] 1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 4. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of Compound 4. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 3H] 1 is a dose-response curve showing the results of a competitive binding assay between [I]SS-14 and Compound 5. The binding rate of [I]SS-14 to the SST5 receptor is shown as a function of the concentration of Compound 5. The dose-response curve was measured in CHO-K1 cells (accession number NP_001044.1) in a radioligand binding competition assay as described in Example 12. [Figure 4A] 1 is a bar graph showing the change in secreted ACTH levels from AtT-20 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 1. Changes are shown normalized to untreated (control) cells. [Figure 4B] 1 is a bar graph showing the change in secreted ACTH levels from AtT-20 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 2. Changes are shown normalized to untreated (control) cells. [Figure 4C] 1 is a bar graph showing the change in secreted ACTH levels from AtT-20 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 3. Changes are shown normalized to untreated (control) cells. [Figure 4D] 1 is a bar graph showing the change in secreted ACTH levels from AtT-20 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 4. Changes are shown normalized to untreated (control) cells. [Figure 4E] 1 is a bar graph showing the change in secreted ACTH levels from AtT-20 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 5. Changes are shown normalized to untreated (control) cells. [Figure 5A] 1 is a bar graph showing the change in secreted GH levels from GH3 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 1. Changes are shown normalized to untreated (control) cells. [Figure 5B] 1 is a bar graph showing the change in secreted GH levels from GH3 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 2. Changes are shown normalized to untreated (control) cells. [Figure 5C] 1 is a bar graph showing the change in secreted GH levels from GH3 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 3. Changes are shown normalized to untreated (control) cells. [Figure 5D] 1 is a bar graph showing the change in secreted GH levels from GH3 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 4. Changes are shown normalized to untreated (control) cells. [Figure 5E] 1 is a bar graph showing the change in secreted GH levels from GH3 cells after 72 hours of incubation with 5 nM and 10 nM of Compound 5. Changes are shown normalized to untreated (control) cells. [Figure 6A] 1 is a bar graph showing the change in insulin levels secreted from NT-3 cells after 5 days of incubation with 5 nM and 10 nM of Compound 1. Changes are shown normalized to untreated (control) cells. [Figure 6B] 1 is a bar graph showing the change in insulin levels secreted from NT-3 cells after 5 days of incubation with 5 nM and 10 nM of Compound 2. Changes are shown normalized to untreated (control) cells. [Figure 6C] 1 is a bar graph showing the change in insulin levels secreted from NT-3 cells after 5 days of incubation with 5 nM and 10 nM of Compound 3. Changes are shown normalized to untreated (control) cells. [Figure 6D] 1 is a bar graph showing the change in insulin levels secreted from NT-3 cells after 5 days of incubation with 5 nM and 10 nM of Compound 4. Changes are shown normalized to untreated (control) cells. [Figure 6E] 1 is a bar graph showing the change in insulin levels secreted from NT-3 cells after 5 days of incubation with 5 nM and 10 nM of Compound 5. Changes are shown normalized to untreated (control) cells. [Figure 7] 1 is a bar graph showing changes in proliferation of NT-3 cells after 5 days of incubation with 5 nM of compounds 1, 4, and 5. Changes are shown normalized to untreated (control; NT) cells. DETAILED DESCRIPTION OF THE INVENTION

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0019] definition As used herein, "a" or "an" means one or more, unless specifically indicated to mean only one.

[0020] Standard three-letter abbreviations identify alpha-amino acid residues. Where an amino acid residue has isomeric forms, it is the L-form of the amino acid that is represented unless expressly stated otherwise (e.g., Ser = L-serine). "L" or "D" refers to either the D- or L-isomer of a particular amino acid.

[0021] The term "halogen" (or halo) refers to fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I).

[0022] As used herein, "administration" encompasses all suitable means of providing a substance to a subject. Common routes include oral, sublingual, transmucosal, transdermal, rectal, vaginal, subcutaneous, intramuscular, intravenous, intraarterial, intrathecal, intraarticular, via catheter, via implant, and the like. Preferred routes in the context of the present invention are subcutaneous, oral, intramuscular, intravenous, and intraarterial. In some embodiments, the composition is administered near or directly to a tumor, such as by direct injection into the tumor or into the blood, such as for hematological malignancies.

[0023] As used herein, a "subject" includes any vertebrate, including horses, sheep, goats, cattle, pigs, birds, dogs, cats, and primate species. Preferably, a "subject" as used herein is a human.

[0024] As used herein, "tumor" includes solid and non-solid tumors; as well as different stages of tumor development, from precancerous lesions (hyperplasia or dysplasia) and benign tumors (adenomas) to carcinoids, malignant, and metastatic tumors. Preferably, the term "tumor" as used herein refers to any type of abnormal proliferation of cells that overexpress one or more somatostatin receptors, particularly somatostatin receptor subtypes 2 and 5 (SST2 and SST5). The term "neuroendocrine tumor" (NET) refers to neoplasms arising from cells of the endocrine and nervous systems, and can be either hormone-secreting or non-hormone-secreting.

[0025] The term "selectively binds" or "selective binding" as used herein refers to the preferential binding of a compound of the present invention to a specific somatostatin receptor subtype. For example, a compound of the present invention binds strongly to SST2 and SST5, but binds weakly or not at all to other SSTs. Typically and preferably, a "selective" compound of the present invention binds about 10-fold, preferably about 100-fold, or even more preferably about 1000-fold (or more) more strongly to the selective somatostatin receptor subtype than to other receptor subtypes, e.g., other somatostatin receptor subtypes.

[0026] As used herein, the term "effective amount" refers to the amount necessary or sufficient to achieve a desired effect.Preferably, the term "effective amount" refers to the amount of the compound of formula I or formula IA of the present invention that (i) treats or prevents a specific disease, medical condition, or disorder, (ii) attenuates, improves, or eliminates one or more symptoms of a specific disease, medical condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, medical condition, or disorder described herein.

[0027] In a preferred embodiment, a therapeutically effective amount of a compound of the present invention is administered under the guidance of a physician, and the pharmaceutical composition contains a compound of the present invention together with a conventional pharmaceutically or veterinarily acceptable carrier. A therapeutically effective amount is considered to be a predetermined amount calculated to achieve the desired effect. The required dosage will vary depending on the specific treatment and the desired duration of treatment.

[0028] The terms "reduce" and "inhibit" have the commonly understood meaning of lowering or decreasing.

[0029] The term "overexpression" is understood to mean expression of a protein that exceeds the amount of expression found in normal healthy cells.

[0030] The terms "pharmaceutically acceptable" or "therapeutically acceptable" refer to a material that does not interfere with the effectiveness or biological activity of the active ingredients and that is not toxic to the host. Representative "pharmaceutically acceptable salts" include, for example, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, and the like. Examples of suitable salts include water-soluble and water-insoluble salts such as ammonium salts of methylglucamine, ... Preferred pharmaceutically acceptable salts include hydrochlorides, hydrobromides, sulfates, phosphates, tannates, oxalates, fumarates, gluconates, alginates, maleates, acetates, citrates, benzoates, succinates, malates, ascorbates, tartrates, and the like, with acetates being preferred.

[0031] "Solvate" refers to the association or complex of one or more solvent molecules with the compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to a complex where the solvent molecule is water.

[0032] As used herein, "radionuclide" refers to an unstable form of an atomic nucleus that has excess nuclear energy. Preferably, the radionuclide used herein releases excess nuclear energy (e.g., as radiation) when it breaks down into a more stable nuclide. In some embodiments, the radionuclide is selected from the group consisting of boron-10, fluorine-18, phosphorus-32, scandium-47, copper-67, gallium-72, rubidium-82, strontium-89, yttrium-90, technetium-99, palladium-103, indium-111, iodine-125, cesium-131, iodine-131, samarium-153, gadolinium-157, gadolinium-159, Selected from the group consisting of terbium-149, samarium-153, terbium-161, dysprosium-165, holmium-166, ytterbium-175, lutetium-177, rhenium-186, rhenium-188, thallium-201, astatine-211, lead-212, bismuth-212, bismuth-213, radium-223, actinium-225, and thorium-227.

[0033] As used herein, "chelating agent" refers to a chemical moiety, preferably an organic moiety, capable of forming a coordinate bond, preferably a multidentate bond, to a metal atom (preferably a metal ion). In preferred embodiments, the chelating agent is capable of forming a stable complex (e.g., a coordinate multidentate complex) with a radionuclide.

[0034] As used herein, "linker" refers to a divalent organic residue, where one valence is attached to a compound of Formula I and the other valence is attached to a terminal group (abbreviated herein as "TG") or chelator, preferably said terminal group is -H.

[0035] As used herein, "solid support" includes, but is not limited to, a surface, a bead, a glass support, a polymer, or a resin. In a preferred embodiment, the glass is controlled pore glass, preferably having pores of 500 Å, 1000 Å, or 2000 Å. Beads include, but are not limited to, glass beads, preferably controlled pore glass, or magnetic beads. Polymers include, but are not limited to, polystyrene, including, for example, divinylbenzene, styrene, and chloromethylstyrene. In a preferred embodiment, the solid support is a highly cross-linked polystyrene bead.

[0036] The term "amino protecting group" is well known in the art and includes those described in detail in "Protecting Groups in Organic Synthesis", T.W. Greene and P.G.M.Wuts, 3rd Edition, John Wiley & Sons, 1999, "Greene's Protective Groups in Organic Synthesis", P.G.M.Wuts, 5th Edition, John Wiley & Sons, 2014, and "Current Protocols in Nucleic Acid Chemistry", edited by S.L.B. Beaucage et al., 06 / 2012, particularly Chapter 2 herein. "Amino protecting groups" suitable for the present invention include methyl carbamate, ethyl carbamate, 9-fluorenylmethylcarbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Troc), and 2-trimethylsilylethylcarbamate (Tmoc). carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz) and 2,4,6-trimethylbenzyl carbamate; and formamide, acetamide, benzamide, typically and preferably independently selected from these at each occurrence.

[0037] Compounds of the Invention In one aspect, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2 is selected from the group consisting of -F, -Cl, -Br, and -I; and Y 1 -H, chelating agent, L 1 -TG, -L 1 - selected from the group consisting of a chelating agent, an amino protecting group, and a solid support; 1 is a linker, TG is a terminal group, preferably said terminal group is -H; However, X 1 and X 2 are not both -I) to provide.

[0038] In one aspect, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2 is selected from the group consisting of -F, -Cl, -Br, and -I; and Y 1 -H, chelating agent, L 1 -TG, and -L 1 - selected from the group consisting of chelating agents; 1 is a linker, TG is a terminal group, preferably said terminal group is -H; However, X 1 and X 2 are not both -I) to provide.

[0039] In some embodiments, the present disclosure provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2 is selected from the group consisting of -F, -Cl, -Br, and -I; and Y 1 -H, chelating agent, L 1 -H, and -L 1 - chelating agents; wherein L 1 is the linker; However, X 1 and X 2 are not both -I) to provide.

[0040] In some embodiments, Y 1 -H, chelating agent, L 1 -TG, -L 1 - selected from the group consisting of chelating agents and amino protecting groups; L 1 is a linker, TG is a terminal group, preferably said terminal group is -H;

[0041] In some embodiments, Y 1 -H, chelating agent, L 1 -TG, -L 1 - selected from the group consisting of chelating agents and solid supports; L 1 is a linker, TG is a terminal group, preferably said terminal group is -H;

[0042] In some embodiments, Y 1 -H, chelating agent, L 1 -TG, and -L 1 - selected from the group consisting of chelating agents; L 1 is a linker, TG is a terminal group, preferably said terminal group is -H;

[0043] In some embodiments, Y 1 is a chelating agent and -L 1In some embodiments, Y is selected from the group consisting of: 1 -L 1 - a chelating agent. In some embodiments, Y is a chelating agent. In some embodiments, Y 1 L 1 In some embodiments, Y is -TG. 1 L 1 In some embodiments, Y 1 is an amino protecting group. In some embodiments, Y 1 is a solid support. In some embodiments, Y 1 is -H.

[0044] In some embodiments, the chelator complexes with a radionuclide. In preferred embodiments, the radionuclide is boron-10, fluorine-18, phosphorus-32, scandium-47, copper-67, gallium-72, rubidium-82, strontium-89, yttrium-90, technetium-99, palladium-103, indium-111, iodine-125, cesium-131, iodine-131, samarium-153, gadolinium-157, gadolinium-159. , terbium-149, samarium-153, terbium-161, dysprosium-165, holmium-166, ytterbium-175, lutetium-177, rhenium-186, rhenium-188, thallium-201, astatine-211, lead-212, bismuth-212, bismuth-213, radium-223, actinium-225, and thorium-227.

[0045] In some embodiments, the compound of formula I is a compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X 1 is selected from the group consisting of -F, -Cl, -Br, and -I; X 2is selected from the group consisting of -F, -Cl, -Br, and -I; However, X 1 and X 2 are not both -I) is.

[0046] In one aspect, the invention provides a pharmaceutical composition comprising a compound of Formula I or Formula IA and a pharmaceutically acceptable carrier.

[0047] In some embodiments of Formula I or Formula IA, X 1 and X 2 are the same and both are selected from the group consisting of -F, -Cl, and -Br. In some embodiments of Formula I or Formula IA, X 1 and X 2 are the same and both are selected from the group consisting of -Cl and -Br. 1 and X 2 are the same and both are selected from the group consisting of -Cl and -F. In some embodiments, X 1 and X 2 are the same and both are selected from the group consisting of -F and -Br.

[0048] In some embodiments of Formula I or Formula IA, X 1 is -I and X 2 Is -Cl; X 1 is -Cl, and X 2 is -I or X 1 is -Cl, and X 2 Is -Cl; X 1 is -F and X 2 is -F; or X 1 is -Br and X 2 is -Br.

[0049] In some embodiments of Formula I or Formula IA, X 1 is -I and X 2 is -Cl. In some embodiments, the compound of Formula I or Formula IA is Compound 1: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0050] In some embodiments of Formula I or Formula IA, X 1 is -Cl, and X 2 is -I. In some embodiments, the compound of Formula I or Formula IA is Compound 2: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0051] In some embodiments of Formula I or Formula IA, X 1 is -Cl, and X 2 is -Cl. In some embodiments, the compound of Formula I or Formula IA is Compound 3: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0052] In some embodiments of Formula I or Formula IA, X 1 is -F and X 2 is -F. In some embodiments, the compound of Formula I or Formula IA is Compound 4: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0053] In some embodiments of Formula I or Formula IA, X 1 is -Br and X 2 is -Br. In some embodiments, the compound of Formula I or Formula IA is Compound 5: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0054] In some embodiments, the compound of formula I is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka]

[0055] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I or Formula IA and a pharmaceutically acceptable carrier. In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula IA and a pharmaceutically acceptable carrier.

[0056] Uses of the Compounds of the Invention The compounds of the present invention bind to somatostatin receptors (e.g., SST2 and / or SST5) with high affinity and selectivity and can therefore be used to treat diseases such as hormone excess, proliferative disorders, cancers (e.g., neuroendocrine cancers) and / or tumors, as described herein.

[0057] In a preferred embodiment, the compounds of the present invention bind to and activate somatostatin receptors (e.g., SST2 and / or SST5). Preferably, the compounds of the present invention selectively bind to and activate SST2 and / or SST5. In a preferred embodiment, the compounds of the present invention are internalized by cells after binding to SST2 and / or SST5 receptors.

[0058] Example 11 shows that compounds of the invention have sub-nanomolar and low nanomolar EC 50 This demonstrates that the compounds of the present invention bound to SST2 at a binding affinity of 1000 kJ / kg / day. The binding affinity of the compounds of the present invention to the SST2 receptor was comparable to that of SS-28, a natural ligand of SST2. Without wishing to be bound by theory, X 1 and X 2 Halogenation of the compounds of the invention at position 1 did not appreciably reduce the binding of the compounds of the invention to the SST2 receptor.

[0059] As described in Example 12, compounds of the present invention were assayed for the expression of SST2 or SST5 in membrane extracts from CHO-K1 cells. [125I] The compounds were tested in a radioligand binding competition assay against SS-14. To evaluate the ability of the compounds of the present invention to bind to SST2 and SST5, the assays were performed on different days using SS-28 as a standard for comparison. In the first assay, compounds 1 and 2 were [125I] Compound 3 was tested in a radioligand binding competition assay against SS-14, with SS-28 evaluated in parallel as a standard for comparison. [125I] In a third assay, compounds 4 and 5 were tested against SS-14 and SS-28 were evaluated in parallel. [125I] SS-14 was tested and SS-28 was evaluated in parallel.

[0060] As shown in Example 12, Tables 2-4, and Figures 2A-2H, the compounds of the present invention exhibited subnanomolar and low nanomolar binding affinities for the SST2 receptor in radioligand binding competition assays. The binding affinities of the compounds of the present invention were comparable to that of SS-28, a natural ligand of SST2. Without wishing to be bound by theory, X 1 and X 2 Halogenation of the compounds of the invention at position 1 did not appreciably reduce the binding of the compounds of the invention to the SST2 receptor.

[0061] As shown in Example 12, Tables 5-7, and Figures 3A-3H, the compounds of the present invention exhibited subnanomolar and low nanomolar binding affinities for the SST5 receptor in radioligand binding competition assays. The binding affinities of the compounds of the present invention were comparable to that of SS-28, a natural ligand of SST5. Without wishing to be bound by theory, X 1 and X 2 Halogenation of the compounds of the invention at position 1 did not appreciably reduce the binding of the compounds of the invention to the SST5 receptor.

[0062] As shown in Examples 13-14 and Figures 4A-4E, 5A-5E and 6A-6E, compounds of the present invention inhibited the release of hormones such as adrenocorticotropic hormone (ACTH), growth hormone (GH) and insulin.

[0063] As shown in Example 16 and Figure 7, compounds of the present invention inhibited the growth of human tumor cells.

[0064] In one aspect, the present invention provides a compound of Formula I or Formula IA, or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use as a medicament.

[0065] In one aspect, the present invention provides a compound of Formula I or Formula IA, or a pharmaceutical composition comprising a compound of Formula I or Formula IA, for use in a method for treating an SST2 or SST5 cell proliferative disorder, preferably a proliferative disorder involving cells expressing SST2 and SST5, in a subject, e.g., a subject in need of treatment, and preferably in a method for evaluating the subject after treatment with the compound or pharmaceutical composition, wherein more preferably, the cell proliferative disorder is a tumor, e.g., a primary tumor or a metastatic tumor. In a preferred embodiment, the tumor is a neuroendocrine tumor, preferably a neuroendocrine tumor of the pituitary gland, pancreas, gastrointestinal tract, lung, thymus, breast, prostate, and / or adrenal gland. In some embodiments, the proliferative disorder is thyroid cancer, melanoma, meningioma, primary brain cancer, salivary gland cancer, ovarian cancer, and / or hepatocellular carcinoma.

[0066] In a further aspect, the present invention provides a method for treating an SST2 or SST5 cell proliferative disorder, preferably a proliferative disorder involving cells expressing SST2 and SST5, in a subject in need of such treatment, the method comprising administering to the subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA; and preferably evaluating the subject after treatment with the compound or pharmaceutical composition. More preferably, the cell proliferative disorder is a tumor, such as a primary tumor or a metastatic tumor. In a preferred embodiment, the tumor is a neuroendocrine tumor, preferably a neuroendocrine tumor of the pituitary gland, pancreas, gastrointestinal tract, lung, thymus, breast, prostate, and / or adrenal gland. In some embodiments, the proliferative disorder is thyroid cancer, melanoma, meningioma, primary brain cancer, salivary gland cancer, ovarian cancer, and / or hepatocellular carcinoma. In a further aspect, the present invention provides the use of a compound of Formula I or Formula IA in the manufacture of a medicament for treating an SST2 or SST5 cell proliferative disorder, preferably a proliferative disorder involving cells expressing SST2 and SST5, and preferably evaluating a subject after treatment with the compound or pharmaceutical composition; more preferably, the cell proliferative disorder is a tumor, e.g., a primary tumor or a metastatic tumor. In preferred embodiments, the tumor is a neuroendocrine tumor, preferably a neuroendocrine tumor of the pituitary gland, pancreas, gastrointestinal tract, lung, thymus, breast, prostate, and / or adrenal gland. In some embodiments, the proliferative disorder is thyroid cancer, melanoma, meningioma, primary brain cancer, salivary gland cancer, ovarian cancer, and / or hepatocellular carcinoma.

[0067] In a further aspect, the present invention provides a compound of formula I or formula IA or a pharmaceutical composition comprising a compound of formula I or formula IA for use in a method of treating a disease characterized by overexpression of one or more somatostatin receptor subtypes, preferably overexpression of SST2 and / or SST5, more preferably overexpression of SST2 and SST5, in a subject, e.g., a subject in need of treatment.

[0068] In a further aspect, the present invention provides a method for treating a disease characterized by overexpression of one or more somatostatin receptor subtypes, preferably overexpression of SST2 and / or SST5, more preferably overexpression of SST2 and SST5, in a subject in need thereof; the method comprises administering to the subject an effective amount of a compound of formula I or formula IA or a pharmaceutical composition comprising a compound of formula I or formula IA.

[0069] In a further aspect, the present invention provides the use of a compound of formula I or formula IA in the manufacture of a medicament for treating a disease characterized by overexpression of one or more somatostatin receptor subtypes, preferably overexpression of SST2 and / or SST5, more preferably overexpression of SST2 and SST5.

[0070] In a preferred embodiment, said SST2 or SST5 cell proliferative disorder or said disease characterized by overexpression of one or more somatostatin receptor subtypes is a tumor, preferably a neuroendocrine tumor.

[0071] In a further aspect, the present disclosure provides a compound of Formula I or Formula IA, or a pharmaceutical composition comprising a compound of Formula I or Formula IA, for use in a method for treating a tumor, preferably a neuroendocrine tumor, preferably comprising administering an effective amount of the compound or the pharmaceutical composition to a subject, e.g., a subject in need of treatment. In a preferred embodiment, the method further comprises evaluating the subject after treatment with the compound or the pharmaceutical composition.

[0072] In one aspect, the present disclosure provides a method of treating a tumor, preferably a neuroendocrine tumor, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA. In a preferred embodiment, the method further comprises evaluating the subject after treatment with the compound or pharmaceutical composition.

[0073] In one aspect, the disclosure provides the use of a compound of Formula I or Formula IA in the manufacture of a medicament for treating a tumor, preferably a neuroendocrine tumor.

[0074] In a further aspect, the present invention provides a compound of formula I or formula IA, or a pharmaceutical composition comprising a compound of formula I or formula IA, for use in a method of reducing the activity and growth of a tumor, preferably a neuroendocrine tumor, in a subject, e.g., a subject in need thereof, and preferably in a method of evaluating the subject after treatment with said compound or pharmaceutical composition.

[0075] In a further aspect, the present invention provides a method of reducing the activity and growth of a tumor, preferably a neuroendocrine tumor, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or Formula IA, or a pharmaceutical composition comprising a compound of Formula I or Formula IA; and preferably a method of evaluating the subject after treatment with said compound or pharmaceutical composition.

[0076] In a further aspect, the invention provides the use of a compound of Formula I or Formula IA in the manufacture of a medicament for reducing the activity and growth of a tumor, preferably a neuroendocrine tumor.

[0077] In a further aspect, the invention provides a compound of Formula I or Formula IA, or a pharmaceutical composition comprising a compound of Formula I or Formula IA, for use in a method of decreasing the release of a hormone or neurotransmitter, preferably growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), gastrin, insulin, insulin-like growth factor 1 (IGF-1), glucagon, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide, calcitonin, somatostatin, serotonin, epinephrine, norepinephrine, or dopamine, in a subject, e.g., a subject in need thereof. Preferably, said GH, PRL, TSH and / or ACTH are released from the anterior pituitary gland of a subject, and said gastrin, insulin, insulin-like growth factor 1 (IGF-1), glucagon, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide, calcitonin, somatostatin, serotonin, epinephrine, norepinephrine, or dopamine are released by neuroendocrine cells in the pancreas, gastrointestinal tract, liver, lungs, thyroid, parathyroid, hypothalamus, adrenal glands, or sympathetic and parasympathetic ganglia of a subject, e.g., a subject in need thereof, and preferably, the subject is evaluated after treatment with said compound or pharmaceutical composition.

[0078] In a further aspect, the present invention provides a method of decreasing hormone or neurotransmitter release in a subject in need thereof, the method comprising administering to said subject a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA, preferably said hormone or neurotransmitter is growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), gastrin, insulin, insulin-like growth factor 1 (IGF-1), glucagon, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide, calcitonin, somatostatin, serotonin, epinephrine, norepinephrine, or the like. more preferably, said GH, PRL, TSH and / or ACTH are released from the anterior pituitary gland of a subject, and said gastrin, insulin, insulin-like growth factor 1 (IGF-1), glucagon, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide, calcitonin, somatostatin, serotonin, epinephrine, norepinephrine, or dopamine are released by neuroendocrine cells in the pancreas, gastrointestinal tract, liver, lungs, thyroid, parathyroid, hypothalamus, adrenal glands, or sympathetic and parasympathetic ganglia of a subject, e.g., a subject in need thereof; preferably, the subject is evaluated before and after treatment with said compound or pharmaceutical composition.

[0079] In a further aspect, the invention provides the use of a compound of Formula I or Formula IA in the manufacture of a medicament for decreasing the release of a hormone or neurotransmitter in a subject in need thereof, preferably wherein said hormone or neurotransmitter is growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), gastrin, insulin, insulin-like growth factor 1 (IGF-1), glucagon, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide, calcitonin, somatostatin, serotonin, epinephrine, norepinephrine, or dopamine, and More preferably, said GH, PRL, TSH and / or ACTH are released from the anterior pituitary gland of a subject, and said gastrin, insulin, insulin-like growth factor 1 (IGF-1), glucagon, vasoactive intestinal polypeptide (VIP), pancreatic polypeptide, calcitonin, somatostatin, serotonin, epinephrine, norepinephrine, or dopamine are released by neuroendocrine cells in the pancreas, gastrointestinal tract, liver, lungs, thyroid, parathyroid, hypothalamus, adrenal glands, or sympathetic and parasympathetic ganglia of a subject, e.g., a subject in need thereof, and preferably, the subject is further evaluated after treatment with said compound or pharmaceutical composition.

[0080] In some embodiments, compounds of the present invention inhibit growth hormone release. In some embodiments, compounds of the present invention inhibit thyroid-stimulating hormone release. In some embodiments, compounds of the present invention inhibit prolactin release. In some embodiments, compounds of the present invention inhibit adrenocorticotropic hormone release. In some embodiments, compounds of the present invention inhibit gastrin release. In some embodiments, compounds of the present invention inhibit insulin release. In some embodiments, compounds of the present invention inhibit insulin-like growth factor 1 (IGF-1) release. In some embodiments, compounds of the present invention inhibit glucagon release. In some embodiments, compounds of the present invention inhibit vasoactive intestinal polypeptide (VIP) release. In some embodiments, compounds of the present invention inhibit pancreatic polypeptide release. In some embodiments, compounds of the present invention inhibit calcitonin release. In some embodiments, compounds of the present invention inhibit somatostatin release. In some embodiments, compounds of the present invention inhibit serotonin release. In some embodiments, compounds of the present invention inhibit epinephrine release. In some embodiments, compounds of the present invention inhibit norepinephrine release. In some embodiments, compounds of the present invention inhibit dopamine release.

[0081] In some embodiments, the disease or disorder associated with hypersecretion of hormones, eg, growth hormone and / or insulin-like growth factor 1, is selected from acromegaly and pituitary gigantism.

[0082] In a further aspect, the invention provides a compound of formula I or formula IA or a pharmaceutical composition comprising a compound of formula I or formula IA for use in a method of reducing blood flow in a subject, e.g., a subject in need thereof.

[0083] In a further aspect, the present invention provides a method of reducing blood flow in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA.

[0084] In a further aspect, the invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for decreasing blood flow in a subject.

[0085] In a further aspect, the present invention provides a compound of formula I or formula IA or a pharmaceutical composition comprising a compound of formula I or formula IA for use in a method of altering, preferably decreasing, gastrointestinal motility in a subject, e.g., a subject in need thereof.

[0086] In a further aspect, the present invention provides a method of altering, preferably reducing, motility in the gastrointestinal tract of a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I or formula IA or a pharmaceutical composition comprising a compound of formula I or formula IA.

[0087] In a further aspect, the invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for altering, preferably decreasing, gastrointestinal motility in a subject.

[0088] In a further aspect, the present invention provides a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use in a method for treating a disorder of pituitary function, preferably wherein said disorder of pituitary function is a tumor, preferably a prolactinoma, an ACTH-secreting tumor, a gonadotropin-secreting tumor, a TSH-secreting and non-secreting tumor, Rathke's cyst, and a craniopharyngioma.

[0089] In a further aspect, the present invention provides a method of treating a disorder of pituitary gland function in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA, preferably said disorder of pituitary gland function is a tumor, preferably a prolactinoma, an ACTH-secreting tumor, a gonadotropin-secreting tumor, a TSH-secreting and non-secreting tumor, Rathke's cleft, and a craniopharyngioma.

[0090] In a further aspect, the present invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for treating a disorder of pituitary function, preferably wherein said disorder of pituitary function is a tumor, preferably a prolactinoma, an ACTH-secreting tumor, a gonadotropin-secreting tumor, a TSH-secreting tumor and a non-secreting tumor, Rathke's cleft, and a craniopharyngioma.

[0091] In one aspect, the present invention provides a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use in a method for treating a metabolic disease; preferably, the metabolic disease is metabolic syndrome, obesity, preferably morbid obesity, or hypothalamic obesity. In some embodiments, the metabolic disease is a disorder of carbohydrate metabolism (e.g., type I diabetes and / or type II diabetes), prediabetes, and / or hyperinsulinemia. In some embodiments, the metabolic disease is associated with a complication of diabetes mellitus; preferably, the disease associated with a complication of diabetes mellitus is nephropathy, retinopathy, vasculopathy, and / or neuropathy.

[0092] In one aspect, the present invention provides a method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA; preferably, the metabolic disease is metabolic syndrome, obesity, preferably morbid obesity, or hypothalamic obesity. In some embodiments, the metabolic disease is a disorder of carbohydrate metabolism (e.g., type I diabetes and / or type II diabetes), prediabetes, and / or hyperinsulinemia. In some embodiments, the metabolic disease is associated with a complication of diabetes mellitus; preferably, the disease associated with a complication of diabetes mellitus is nephropathy, retinopathy, vasculopathy, and / or neuropathy.

[0093] In one aspect, the present invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for treating a metabolic disease in a subject, preferably wherein the metabolic disease is metabolic syndrome, obesity, preferably morbid obesity, or hypothalamic obesity. In some embodiments, the metabolic disease is a disorder of carbohydrate metabolism (e.g., type I diabetes and / or type II diabetes), prediabetes, and / or hyperinsulinemia. In some embodiments, the metabolic disease is associated with complications of diabetes mellitus, preferably wherein the disease associated with complications of diabetes mellitus is nephropathy, retinopathy, vasculopathy, and / or neuropathy.

[0094] In one aspect, the invention provides a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use in a method for treating a disease associated with hypersecretion in the gastrointestinal system, preferably, said disease associated with hypersecretion in the gastrointestinal system is secretory diarrhea, infectious diarrhea, hormone-induced diarrhea due to increased secretion of gastrointestinal hormones (glucagon, carcinoid syndrome, VIP tumors, glucagonomas, insulinomas), pancreatic and intestinal fistulas, gastrointestinal motility disorders, and dumping syndrome.

[0095] In one aspect, the present invention provides a method of treating a disease associated with hypersecretion of the gastrointestinal system in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA, preferably said disease associated with hypersecretion of the gastrointestinal system is secretory diarrhea, infectious diarrhea, hormone-induced diarrhea due to increased secretion of gastrointestinal hormones (glucagon, carcinoid syndrome, vipoma, glucagonoma, insulinoma), pancreatic and intestinal fistula, gastrointestinal motility disorders, and dumping syndrome.

[0096] In one aspect, the invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for treating a disease associated with hypersecretion in the gastrointestinal system, preferably said disease associated with hypersecretion in the gastrointestinal system is secretory diarrhea, infectious diarrhea, hormone-induced diarrhea due to increased secretion of gastrointestinal hormones (glucagon, carcinoid syndrome, VIPomas, glucagonomas, insulinomas), pancreatic and intestinal fistulas, gastrointestinal motility disorders, and dumping syndrome.

[0097] In one aspect, the invention provides a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use in a method of treating a hyperproliferative disease, preferably wherein said hyperproliferative disease is a cyst of the kidney, liver and / or pancreas, or is due to inflammation such as acute and chronic pancreatitis.

[0098] In one aspect, the present invention provides a method of treating a hyperproliferative disease in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA, preferably wherein said hyperproliferative disease is a renal, liver and / or pancreatic cyst or is due to inflammation such as acute and chronic pancreatitis.

[0099] In one aspect, the invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for treating a disease of hyperproliferation, preferably wherein said disease of hyperproliferation is a renal, liver and / or pancreatic cyst or is due to inflammation, such as acute and chronic pancreatitis.

[0100] In one aspect, the invention provides a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use in a method of treating a disorder of abnormal bleeding or blood flow, preferably wherein said disorder of abnormal bleeding or blood flow is gastrointestinal bleeding due to esophageal varices, ulcers, anastomosis, inflammatory bowel disease and / or cirrhosis.

[0101] In one aspect, the present invention provides a method of treating an abnormal bleeding or blood flow disorder in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA, preferably wherein said disorder of abnormal bleeding or blood flow is gastrointestinal bleeding due to esophageal varices, ulcers, anastomosis, inflammatory bowel disease and / or cirrhosis.

[0102] In one aspect, the invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for treating a disorder of abnormal bleeding or blood flow, preferably wherein said disorder of abnormal bleeding or blood flow is gastrointestinal bleeding due to esophageal varices, ulcers, anastomosis, inflammatory bowel disease and / or cirrhosis.

[0103] In one aspect, the invention provides a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA for use in a method of treating a disease or disorder in a subject in need of treatment. In one aspect, the invention provides a method of treating a disease or disorder in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound of Formula I or Formula IA or a pharmaceutical composition comprising a compound of Formula I or Formula IA. In one aspect, the invention provides a compound of Formula I or Formula IA in the manufacture of a medicament for treating a disease or disorder. In some embodiments, the disease or disorder is acromegaly, pituitary gigantism, prolactinoma, ACTH-secreting tumors, gonadotropin-secreting tumors, TSH-secreting and non-secreting tumors, Rathke's cyst, craniopharyngioma, metabolic syndrome, obesity, e.g., morbid obesity or hypothalamic obesity, type I and type II diabetes, prediabetes, hyperinsulinemia, nephropathy, retinopathy, vascular disorders, neuropathy, secretory diarrhea, infectious diarrhea, gastrointestinal hormones (glucagon, carcinoma, etc.), or a combination thereof. and inflammatory bowel disease, cirrhosis, neuroendocrine tumors of the pancreas, gastrointestinal tract, lung, thymus, breast, prostate, and adrenal glands, melanoma, thyroid cancer, meningioma, primary brain cancer, salivary gland cancer, ovarian cancer, and hepatocellular carcinoma.

[0104] In another aspect, the present invention provides a method for diagnosing a tumor, preferably a neuroendocrine tumor, preferably a carcinoid tumor, in a subject, comprising the steps of: (a) administering to the subject a composition comprising a compound of the present invention, preferably the composition further comprising a pharmaceutically or veterinarily acceptable carrier; and (b) detecting the radionuclide. In a further highly preferred embodiment, the diagnosis comprises in vivo positron emission tomography (PET) imaging. In a preferred embodiment, the diagnosis comprises radionuclide imaging. In a further preferred embodiment, the tumor is selected from enteropancreatic neuroendocrine tumors, paragangliomas, pheochromocytoma, thyroid carcinoma, and neuroblastoma. In another preferred embodiment, the tumor is a neuroendocrine tumor, preferably a carcinoid tumor, selected from (i) gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs); (ii) pulmonary and mediastinal neuroendocrine neoplasms (NENs); (iii) adrenal or nervous system NENs; (iv) meningiomas and low-grade gliomas; (v) solid tumors; and (vi) hematological malignancies. In a further highly preferred embodiment, said tumor is a neuroendocrine tumor (NET), preferably said NET is selected from gastro-pancreatic neuroendocrine tumors (GEP-NET).

[0105] In a further aspect, the present invention provides a method for visualizing malignant cells in a subject, comprising administering to a subject a compound of formula I of the present invention and further a radionuclide or a pharmaceutical composition of the present invention, and visualizing said malignant cells by detecting the radionuclide.

[0106] In a further aspect, the present invention provides a method for visualizing malignant cells having SSTR2 and SSTR5 in a subject, comprising administering to a subject a compound of formula I of the present invention and further a radionuclide or a pharmaceutical composition of the present invention, and visualizing said malignant cells by detecting the radionuclide, wherein preferably said SSTR2 and SSTR5 bind to said compound.

[0107] In a further aspect, the present invention provides a method for in vivo positron emission tomography (PET) imaging of a tumor in a subject, preferably wherein the tumor is a neuroendocrine tumor (NET), more preferably wherein the NET is selected from gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the method comprising: (a) administering to the subject a composition comprising a compound of Formula I according to the present invention and comprising a radionuclide, preferably wherein the composition further comprises a pharmaceutically or veterinarily acceptable carrier; and (b) detecting the radionuclide. In a further preferred embodiment, the tumor is selected from enteropancreatic neuroendocrine tumors, paragangliomas, pheochromocytomas, thyroid carcinomas, and neuroblastomas. In another preferred embodiment, the tumor is a neuroendocrine tumor, preferably a carcinoid tumor, selected from (i) gastroenteric pancreatic neuroendocrine tumors (GEP-NETs); (ii) pulmonary and mediastinal neuroendocrine neoplasms (NENs); (iii) adrenal or nervous system NENs; (iv) meningiomas and low-grade gliomas; (v) solid tumors; and (vi) hematological malignancies. In a further preferred embodiment, the tumor is a neuroendocrine tumor, preferably a carcinoid tumor. In another preferred embodiment, the tumor is a neuroendocrine tumor (NET), preferably the NET is selected from gastro-pancreatic neuroendocrine tumors (GEP-NETs).

[0108] A therapeutically effective amount of the compound of the present invention should be administered under the supervision of a physician, and the pharmaceutical composition usually contains the compound of the present invention together with a conventional pharmaceutically or veterinarily acceptable carrier. A therapeutically effective amount is considered to be a predetermined amount calculated to achieve the desired effect. The required dosage will vary depending on the specific treatment and the desired duration of treatment.

[0109] When using the compounds of the present invention for imaging or therapeutic treatment, the short shelf life of the radiolabeled compounds and / or the short half-life of the radionuclides may require the user to perform the radionuclide labeling reaction in a hospital or laboratory. In such cases, various reaction components can be provided to the user in the form of a kit. The operations required to perform the desired reaction should be as simple as possible so that the user can prepare the radiolabeled compound from the kit using equipment normally available. Thus, a kit for preparing a radiopharmaceutical composition for detecting, localizing, or treating neuroendocrine, carcinoid, or malignant tumors and their tissue metastases may include (i) a compound of the present invention, an inert pharmaceutically acceptable carrier and / or compounding agent including an optional adjuvant, (ii) a solution of a salt or chelate of a radioactive metal isotope, and (iii) instructions for use including a recipe for reacting the components present in the kit.

[0110] Thus, in another aspect, the present invention provides a kit for diagnosing tumors, comprising: (a) a compound of Formula I in a suitable container, the compound being either (i) radionuclide-labeled; (ii) unlabeled and provided with a radionuclide in a container suitable for labeling; or (iii) unlabeled and capable of being subsequently labeled with a radionuclide; and (b) instructions. In a preferred embodiment, the diagnosis comprises radionuclide imaging. In a more highly preferred embodiment, the diagnosis comprises in vivo positron emission tomography (PET) imaging.

[0111] In a further preferred embodiment, the tumor is selected from enteropancreatic neuroendocrine tumors, paragangliomas, pheochromocytomas, thyroid carcinomas, and neuroblastomas. In another preferred embodiment, the tumor is a neuroendocrine tumor, preferably a carcinoid tumor, selected from (i) gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs); (ii) pulmonary and mediastinal neuroendocrine neoplasms (NENs); (iii) adrenal or nervous system NENs; (iv) meningiomas and low-grade gliomas; (v) solid tumors; and (vi) hematological malignancies. In a further highly preferred embodiment, the tumor is a neuroendocrine tumor (NET), preferably selected from gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs).

[0112] In another aspect, the present invention provides a kit for treating tumors that overexpress somatostatin receptors, preferably neuroendocrine tumors, and more preferably carcinoid tumors, comprising: (a) a compound of Formula I in a suitable container, wherein, when the compound is labeled with a radionuclide, the compound is present in an amount therapeutically effective for tumor treatment, the compound being either (i) labeled with a radionuclide; (ii) unlabeled and provided with the radionuclide in a container suitable for labeling; or (iii) unlabeled and capable of being subsequently labeled with a radionuclide; and (b) instructions. In a further highly preferred embodiment, the tumor overexpresses somatostatin receptor subtypes 2 and / or 5.

[0113] While the present invention has been described with respect to its preferred embodiments, it should be understood that various changes and modifications, as would be apparent to one skilled in the art, can be made therein without departing from the scope of the invention as set forth in the appended claims. While the claims variously define the invention in terms of compounds of the invention, including peptide sequences, it should be understood that this is intended to include the non-toxic salts thereof, which are well known and most frequently administered as their full equivalents. [Example]

[0114] example The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate particular embodiments and are not intended to limit the scope of the disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents thereof that may suggest themselves to those skilled in the art may be resorted to without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0115] (2S)-3-(3-chloro-4-hydroxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid was purchased commercially.

[0116] Unless otherwise stated, for the cAMP HTRF assay in Example 11 and the radioligand binding competition assay in Example 12, on each day of the experiment and prior to compound testing, reference compounds were tested in duplicate (n=2) at several concentrations to generate dose-response curves and estimated EC 50 and / or IC 50 Baseline values ​​were obtained. These baseline values ​​were compared with historical values ​​from the same receptor and used to validate the experimental session. A session was considered valid only if the baseline value was found to be within a 0.5 log interval from the historical value. In the case of repeated measurements, the maximum variation allowed in the test was ±20% of the mean value of the repeated measurements.

[0117] Unless otherwise stated, HPLC was performed on an MZ Perfectsil™ column (5 μm C18 100 Å; 250 × 4.6 mm). Elution was performed using a gradient of solvent A (100% HO + 0.1% TFA) and solvent B (80% ACN, 20% HO + 0.1% TFA) with a flow rate of 1 mL / min using 30–55% solvent B. Compounds were detected at 220 nM.

[0118] material [Table 1]

[0119] [Table 2]

[0120] [Table 3]

[0121] [Table 4]

[0122] Subculture Unless otherwise specified, cells were cultured in their respective media and incubated at 37°C in an atmosphere containing 5% CO2. All cell lines were cultured under the same experimental conditions. For subculture, cells were washed with PBS and incubated with 0.05% trypsin / EDTA at 37°C for 3–5 minutes. To inhibit trypsin, cells were supplemented with FBS-containing media. Cells were split at a ratio between 1:2 and 1:10, depending on the cell line and cell confluence. After thawing, cells were used for up to 10 passages. For NT3 cells, cell culture flasks were pre-coated with collagen (type IV, human placenta) (50 μg / ml in PBS) before seeding.

[0123] Cell cryopreservation Unless otherwise stated, cell lines were cryopreserved at early passages. For this purpose, cells in logarithmic growth phase were pelleted by centrifugation at 13,400 rpm for 5 minutes. The supernatant was discarded, and the cell pellet was resuspended in medium containing 10% DMSO. The cell suspension was aliquoted into cryovials, placed in a cell freezing container, and stored at -80°C. Long-term storage was performed in liquid nitrogen.

[0124] To thaw the cells, cryovials were thawed in a 37°C water bath, and the cell suspension was immediately added to complete medium. After centrifugation at 13,400 rpm for 5 minutes, the cells were resuspended in medium and placed in a cell culture flask.

[0125] Example 1 Synthesis of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxy-3-iodo-phenyl)propanoic acid) ((2S)-Fmoc-(3-I)-Tyr-OH; Compound P1) [ka] Commercially available 3-iodo-L-tyrosine (Chemimex) (1.00 g, 3.256 mmol) was suspended in a mixture of N,N-dimethylformamide and acetone (10 mL), and the suspension was cooled to 0 °C. After stirring for 10 min, 10% sodium bicarbonate solution (7 mL, 8.141 mmol) was added dropwise, followed by 9-fluorenylmethyl N-succinimidyl carbonate (1.318 g, 3.908 mmol) and N,N-dimethylformamide (25 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, and the residue was added to water (25 mL) and washed with ethyl acetate (1 × 5 mL). The aqueous layer was cooled to 0 °C and acidified to pH 1 with 10% potassium hydrogen sulfate (11.5 mL). The mixture was extracted with ethyl acetate (15 mL, then 4 × 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over magnesium sulfate, filtered, and evaporated. The crude product was dried under vacuum overnight. Chloroform (30 mL) was added to the crude product, and the white precipitate was filtered to give the title compound (1.13 g, 2.135 mmol, 66%) as a white solid. LCMS: 97%, t R = 2.031 min, m / z = 528.0 [M−H] - .

[0126] Example 2 Synthesis of ((2R)-3-(4-amino-3-iodo-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid) (Boc-(4-amino-3-iodo)-D-Phe-OH; Compound P2) [ka] To a solution of Boc-(4-amino)-D-Phe-OH (CombiBlocks) (3.50 g, 12.485 mmol) in N,N-dimethylformamide (189 mL) was added N-iodosuccinimide (3.09 g, 13.734 mmol), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by preparative HPLC to give 2.14 g of the off-white title compound in two batches. LCMS: 100%, t R = 1.768 min, m / z = 404.9 [MH] - .

[0127] Example 3 Synthesis of ((2R)-3-(4-amino-3-chloro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid) (Boc-(4-amino-3-chloro)-D-Phe-OH; Compound P3) [ka] To a solution of Boc-(4-amino)-D-Phe-OH (2.00 g, 7.135 mmol) in N,N-dimethylformamide (108 mL) was added N-chlorosuccinimide (1.05 g, 7.848 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated, and the residue was purified by preparative HPLC to give the title compound (0.89 g, 2.828 mmol, 40%) as an off-white solid. LCMS: 100%, t R = 1.687 min, m / z = 313.0 [MH] - .

[0128] Example 4 Synthesis of (2R)-3-(4-amino-3-bromo-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid [ka] To a solution of (2R)-3-(4-aminophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (Combi-Blocks) (3.00 g, 10.702 mmol) in N,N-dimethylformamide (150 mL) was added N-bromosuccinimide (2.10 g, 11.804 mmol), and the mixture was stirred at room temperature for 1 day. The reaction mixture was evaporated, and the residue was purified by preparative HPLC to give the title compound (3.06 g, 8.518 mmol, 80%) as an off-white powder. LCMS: 97%, t R = 1.285 min, m / z = 358.9 [MH] - .

[0129] Example 5 Synthesis of (2R)-3-(4-amino-3-fluoro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid [ka] Synthesis of methyl (2R)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-4-nitro-phenyl)propanoate To a suspension of zinc (0.177 g, 2.704 mmol) in anhydrous N,N-dimethylformamide (3.8 mL) was added iodine (0.039 g, 0.152 mmol) at room temperature. The mixture was stirred at room temperature for 20 minutes, during which time the color changed from brown to gray. To the reaction mixture was added methyl (2S)-2-(tert-butoxycarbonylamino)-3-iodo-propanoate (Accelachem) (0.50 g, 1.519 mmol) along with iodine (0.039 g, 0.152 mmol). Stirring was continued at room temperature for 2 hours. To this mixture was added a solution of 4-bromo-2-fluoro-1-nitro-benzene (0.334 g, 1.519 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.037 g, 0.091 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.042 g, 0.046 mmol) in anhydrous N,N-dimethylformamide (7.5 mL). The reaction mixture was stirred at 65 °C for 17 hours. This reaction was repeated three more times. The four batches were combined and evaporated. The residue was dissolved in a mixture of ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over magnesium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (10:1→3:1) to give the title compound (0.80 g, 2.339 mmol, 22%) as a brown powder. LCMS: 94%, t R =1.561 min, m / z=243.1[M+H-tBu] + .

[0130] Synthesis of methyl (2R)-3-(4-amino-3-fluoro-phenyl)-2-(tert-butoxycarbonylamino)propanoate To a solution of methyl (2R)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-4-nitro-phenyl)propanoate (0.735 g, 2.147 mmol) in methanol (7.5 mL) was added 10% palladium on carbon (228 mg). The reaction mixture was stirred under hydrogen at room temperature for 2 hours. The mixture was filtered through a pad of Celite, and the Celite was washed with methanol (4 x 5 mL). The combined filtrate was evaporated to give the title compound (0.643 g, 2.059 mmol, 96) as a dark brown oil. LCMS: 87%, t R =1.328 min, m / z=213.2[M+H-tBu] + .

[0131] Synthesis of (2R)-3-(4-amino-3-fluoro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid Methyl (2R)-3-(4-amino-3-fluoro-phenyl)-2-(tert-butoxycarbonylamino)propanoate (2.0 g, 6.403 mmol) was suspended in a mixture of tetrahydrofuran (20 mL) and water (20 mL). To the stirred mixture was added lithium hydroxide monohydrate (0.806 g, 19.210 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated and diluted with water (30 mL) and diethyl ether (30 mL). The layers were separated, and the aqueous layer was washed with diethyl ether (1 × 30 mL). The aqueous layer was cooled to 0 °C, acidified to pH 3 with 10% aqueous potassium hydrogen sulfate, and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to give the title compound (1.42 g, 4.760 mmol, 74%) as an off-white foam. LCMS: 97%, t R =1.056 min, m / z=199.1[M+H-tBu] + .

[0132] Example 6 Synthesis of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxy-3-bromo-phenyl)propanoic acid [ka] (2S) 2-Amino-3-(3-bromo-4-hydroxyphenyl)propanoic acid (Enamine) (0.50 g, 1.922 mmol) was suspended in a mixture of 1,4-dioxane (10 mL) and water (10 mL), and the suspension was cooled to 0 °C. After stirring for 10 minutes, sodium bicarbonate (0.388 g, 4.14 mmol) was added, followed by 9-fluorenylmethyl N-succinimidyl carbonate (0.713 g, 2.115 mmol). The reaction mixture was stirred at room temperature for 2 hours and diluted with ethyl acetate (10 mL). The layers were separated. The aqueous layer was cooled to 0 °C and acidified to pH 1 with 10% aqueous potassium hydrogen sulfate. This mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by preparative HPLC to give the title compound (0.60 g, 1.244 mmol, 65%) as a brown oil. LCMS: 97%, t R = 1.617 min, m / z = 481.9 [MH] - .

[0133] Example 7 Synthesis of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxy-3-fluoro-phenyl)propanoic acid [ka] (2S)2-Amino-3-(3-fluoro-4-hydroxyphenyl)propanoic acid (Ambeed) (1.50 g, 7.531 mmol) was suspended in a mixture of 1,4-dioxane (40 mL) and water (40 mL), and the suspension was cooled to 0 °C. After stirring for 10 minutes, sodium bicarbonate (1.581 g, 18.827 mmol) was added, followed by 9-fluorenylmethyl N-succinimidyl carbonate (3.048 g, 9.037 mmol). The reaction mixture was stirred at room temperature for 2 hours and diluted with diethyl ether (10 mL). The layers were separated. The aqueous layer was cooled to 0 °C and acidified to pH 1 with 10% aqueous potassium hydrogen sulfate. This mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound (3.00 g, 7.119 mmol, 94%) as an off-white solid. LCMS: 93%, t R = 1.517 min, m / z = 420.0 [MH] - .

[0134] Example 8 Synthesis of (2R)-3-(4-amino-3-chloro-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid [ka] Synthesis of (2R)-2-amino-3-(4-amino-3-chloro-phenyl)propanoic acid dihydrochloride To a solution of (2R)-3-(4-amino-3-chloro-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid (2.0 g, 5.568 mmol) in 1,4-dioxane (10 mL) was added 7.06 M hydrochloric acid in 1,4-dioxane (15.7 mL, 111.35 mmol). The reaction mixture was stirred at room temperature for 16 hours and evaporated to give the title compound (2.12 g, 7.372 mmol, crude) as a light brown crystalline solid. LCMS: 96%, t R =0.193 min, m / z=215.1[M+H] + .

[0135] Synthesis of (2R)-3-(4-amino-3-chloro-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (2R)2-Amino-3-(4-amino-3-chlorophenyl)propanoic acid dihydrochloride (2.11 g, 7.337 mmol, crude) was dissolved in 9% aqueous sodium carbonate (16.8 mL), and the suspension was cooled to 0 °C. To the reaction mixture was added a mixture of 9-fluorenylmethyl N-succinimidyl carbonate (2.475 g, 7.337 mmol) and 1,4-dioxane (24 mL). The reaction was allowed to warm to room temperature and stirred for 1 h. The pH of the reaction mixture was adjusted to 5-6 by the addition of 10% aqueous citric acid. The layers were separated, and the aqueous layer was extracted with chloroform (4 × 40 mL), followed by a mixture of chloroform:2-propanol (3:1, 2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by preparative HPLC to give the title compound (1.434 g, 3.282 mmol, 59% over two steps) as an off-white crystalline solid. LCMS: 100%, t R =1.643min, m / z=437.1[M+H] + .

[0136] Example 9 Synthesis of (2R)-3-(4-amino-3-bromo-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid [ka] Synthesis of (2R)-2-amino-3-(4-amino-3-bromo-phenyl)propanoic acid dihydrochloride To a solution of (2R)-3-(4-amino-3-bromo-phenyl)-2-(tert-butoxycarbonylamino)propanoic acid (1.44 g, 4.009 mmol) in 1,4-dioxane (6 mL) was added 7.06 M hydrochloric acid in 1,4-dioxane (11.3 mL, 80.17 mmol). The reaction mixture was stirred at room temperature for 2 hours and evaporated to give the title compound (1.66 g, 4.999 mmol, crude) as an off-white crystalline solid. LCMS: 100%, t R=0.214 min, m / z=261.1[M+H] + .

[0137] Synthesis of (2R)-3-(4-amino-3-bromo-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (2R)2-Amino-3-(4-amino-3-bromo-phenyl)propanoic acid dihydrochloride (1.55 g, 4.668 mmol, crude) was dissolved in 9% aqueous sodium carbonate (10.7 mL) and the suspension was cooled to 0 °C. To the reaction mixture was added a mixture of 9-fluorenylmethyl N-succinimidyl carbonate (1.575 g, 4.668 mmol) and 1,4-dioxane (15.2 mL). The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was combined with a batch starting with 100 mg of the dihydrochloride salt. The pH of the reaction mixture was adjusted to 5-6 by the addition of 10% aqueous citric acid. The layers were separated, and the aqueous layer was extracted with chloroform (4 × 40 mL), followed by a 3:1 mixture of chloroform:2-propanol (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The crude product was purified by preparative HPLC to give the title compound (1.447 g, 3.005 mmol, 75% over two steps) as a white crystalline solid. LCMS: 100%, t R =1.662 min, m / z=483.1[M+H] + .

[0138] Example 10 Synthesis of cyclic peptide analogues The peptide was synthesized manually using Fmoc-Rink-Amide MBHA resin, 0.71 mmol / g, 0.33 mmol, 0.464 g of resin. Cyclization proceeded in the presence of potassium hexacyanoferrate(III) in water for 24 h.

[0139] (4-Amino-3-I)-D-Phe-c[Cys-(3-Cl)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (Compound 1): Cyclization afforded 305 mg of crude product, of which 14.5 mg of pure peptide was obtained for an overall yield of 4.75%. Purification was achieved by RP HPLC. The purity and identity of the peptide were established by analytical HPLC and LCMS, respectively: ESI-MS (m / z): [MH] + , C 50 H 66 ClIN 12 O 10 S2; Predicted: 1221.62; Measured: 1221.21.

[0140] (4-Amino-3-Cl)-D-Phe-c[Cys-(3-I)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (compound 2): Cyclization afforded 293 mg of crude product, of which 13.76 mg of pure peptide was obtained for an overall yield of 4.7%. Purification was achieved by RP HPLC. The purity and identity of the peptide were established by analytical HPLC and LCMS, respectively: ESI-MS (m / z): [MH] + , C 50 H 66 ClIN 12 O 10 S2; Predicted: 1221.62; Measured: 1221.26.

[0141] (4-Amino-3-Cl)-D-Phe-c[Cys-(3-Cl)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (compound 3): Cyclization afforded 313 mg of crude product, of which 19.1 mg of pure peptide was obtained for an overall yield of 6.1%. Purification was achieved by RP HPLC. The purity and identity of the peptide were established by analytical HPLC and LCMS, respectively: ESI-MS (m / z): [MH] + , C 50 H 66 Cl2N 12 O 10 S2; Predicted: 1130.16; Measured: 1131.21.

[0142] (4-Amino-3-F)-D-Phe-c[Cys-(3-F)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (compound 4) was synthesized manually using Fmoc-Rink-Amide MBHA resin, 0.71 mmol / g, 0.5 mmol, 0.705 g of resin, as described in General Experimental Procedures. Cyclization proceeded for 24 h in water in the presence of potassium hexacyanoferrate(III). The crude yield was 285 mg, of which 9.45 mg of pure peptide was obtained, for an overall yield of 3.15%. Purification was performed with 10% solvent B for 10 min, followed by 40% solvent B for 70 min (4 mL / min, λ = 220 nM), and finally with an isocratic elution. The purity of the compound was confirmed by analytical HPLC using a gradient of 35% solvent B at 0 min and isocratic elution at 50% solvent B at 15 min. ESI-MS (m / z): [M−H] + C 50 H 67 F2N 12 O 10 S2 predicted value 1098.32, measured value 1099.18.

[0143] (4-Amino-3-Br)-D-Phe-c[Cys-(3-Br)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2 (compound 5) was synthesized manually using Fmoc-Rink-Amide MBHA resin, 0.71 mmol / g, 0.5 mmol, 0.705 g of resin, as described in General Experimental Procedures. Cyclization proceeded for 24 h in water in the presence of potassium hexacyanoferrate(III). The crude yield was 262 mg, of which 6.3 mg of pure peptide was obtained, for an overall yield of 2.40%. Purification was performed with 15% solvent B for 15 min, followed by 45% solvent B for 75 min (4 mL / min, λ = 220 nM), and finally with an isocratic elution. The purity of the compound was confirmed by analytical HPLC using a gradient of 40% solvent B at 0 min and isocratic elution at 55% solvent B at 15 min. ESI-MS (m / z): [M−H] + C 50 H 67 Br2N 12 O 10S2 predicted value 1221.06, measured value 1222.01.

[0144] Example 11 cAMP HTRF assay CHO-K1 cells (accession number NP_001041.1) expressing the human recombinant receptor SST2 were grown in antibiotic-free medium and gently washed with PBS-EDTA (5 mM EDTA) before testing. Cells were harvested by centrifugation and resuspended in assay buffer (KRH: supplemented with 5 mM KCl, 1.25 mM MgSO, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KHPO, 1.45 mM CaCl, 0.5 g / L BSA, and 1 mM IBMX).

[0145] Dose-response curves for compounds of the present invention were generated in parallel with the reference compound SS-28 (collectively, "test compounds"). In a 96-well plate, 12 μl of cells were mixed with 6 μl of increasing concentrations of test compound and 6 μl of forskolin, then incubated at room temperature for 30 minutes. The final concentrations of test compound were 0.003 nM; 0.01 nM; 0.03 nM; 0.1 nM; 0.3 nM; 1 nM; 3 nM; 10 nM; 30 nM; and 100 nM. After adding lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagent, the plate was incubated at room temperature for 1 hour, and the fluorescence ratio was measured using an HTRF kit according to the manufacturer's specifications. The results are shown in Table 1 below and Figures 1A-1D.

[0146] [Table 5]

[0147] Example 12 Radioligand binding competition assay Competitive binding was performed using binding buffer, membrane extracts from CHO cells, radioactive tracer ( [125I]The SST2 assay was performed in duplicate in wells of a 96-well Masterblock® plate (Greiner, 786201) containing a test compound (i.e., a compound of the invention or SS-28 as a reference). For the SST2 assay, membrane extracts from CHO-K1 cells (accession number NP_001041.1) were used. For the SST5 assay, membrane extracts from CHO-K1 cells (accession number NP_001044.1) were used.

[0148] Nonspecific binding was suppressed by 200-fold excess of cold competitor. [125I] The activity was determined by co-incubation with SS-14. Samples were incubated in a final volume of 0.1 mL at a temperature and duration optimized for each receptor, then filtered through a filter plate. The filters were washed six times with 0.5 mL of ice-cold wash buffer (optimized for each receptor), and 50 μL of Microscint™ 20 (Packard) was added to each well. The plates were incubated on an orbital shaker for 15 minutes and then counted for 1 minute per well using a TopCount™. Experiments were performed on different days and compared with SS-28 for each experiment (Day 1: Compounds 1 and 2; Day 2: Compound 3; Day 3: Compounds 4 and 5).

[0149] Dose-response data for test compounds were analyzed with XLfit (IDBS) software (XLfit model 203 4-parameter logistic model) using nonlinear regression applied to a sigmoidal dose-response model and the following equations 1-3: A: Bottom B: Top C:Log EC 50 D: Hill fit=(A+((BA) / (1+(((10^C) / x)^D))))Equation 1 inv=((10^C) / ((((BA) / (yA))-1)^(1 / D)))Equation 2 res=(y-fit) Equation 3

[0150] The results are shown in Tables 2-7 below and in Figures 2A-2H and 3A-3H.

[0151] [Table 6]

[0152] [Table 7]

[0153] [Table 8]

[0154] [Table 9]

[0155] [Table 10]

[0156] [Table 11]

[0157] Example 13 Inhibition of hormone release from mouse pituitary corticotrophic adenoma (AtT-20) cells Corticotropin-producing cells are cells in the anterior pituitary gland that secrete the hormone adrenocorticotropic hormone (ACTH). Corticotropin tumors cause excessive secretion of ACTH, which stimulates the adrenal glands to produce high levels of cortisol; this pituitary disorder is called Cushing's disease. The mouse AtT-20 cell line is the standard model for studying ACTH secretion by pituitary corticotropin tumors.

[0158] AtT-20 cells were seeded in 24-well plates (20,000 cells / well) in complete medium and incubated overnight in standard incubator conditions (37°C, 5% CO2) to promote adhesion. The supernatant was then discarded and the cells were incubated with the following compounds: Compound 1; Compound 2; Compound 3; Compound 4; Compound 5.

[0159] All compounds were investigated at concentrations of 5 nM and 10 nM; untreated cell controls were also investigated. Biological replicates were performed for each drug concentration. The treatment exposure period was 72 h. At the 72-h time point, cell supernatants were collected, placed in 1.5 mL tubes, and centrifuged at 13,400 rpm for 5 min to remove cellular debris. Samples were stored at -80°C until analysis.

[0160] ACTH levels were quantified using a sandwich ELISA technique (Abcam Mouse / Rat ACTH ELISA Kit #ab263880) according to the manufacturer's instructions. Samples and standards were added individually to wells, followed by the antibody mixture. After incubation, the wells were washed to remove unbound material, and a developing solution was added to catalyze and then stop the reaction. A signal was generated proportional to the amount of bound analyte, and the intensity was measured at 450 nM. The results are shown in Table 8 and Figure 4A-4E.

[0161] [Table 12]

[0162] Example 14 Inhibition of hormone release from rat pituitary somatotroph (GH3) cells Somatotroph cells in the anterior pituitary gland produce growth hormone (GH). Pituitary tumors of these cells, called somatotrophomas, result in excessive GH secretion, causing either pituitary gigantism in children and adolescents or acromegaly in adults. GH3 cells are derived from rat somatotroph tumors and are the standard model used to study somatotroph tumors and GH secretion. GH3 cells express multiple SSTRs, making them a suitable model for studying somatostatin analog properties.

[0163] GH3 cells were seeded at a density of 100,000 cells / well in 24-well plates in serum-free medium supplemented with the following drugs: Compound 1; Compound 2; Compound 3; Compound 4; Compound 5.

[0164] All compounds were investigated at concentrations of 5 nM and 10 nM; untreated cell controls were also investigated. Biological replicates were performed for each drug concentration. The treatment exposure period was 72 h. At the 72-h time point, cell supernatants were collected, placed in 1.5 mL tubes, and centrifuged at 13,400 rpm for 5 min to remove cellular debris. Samples were stored at -80°C until analysis.

[0165] GH levels in the supernatants were quantified using a sandwich ELISA assay (Millipore Rat / Mouse Growth Hormone ELISA Kit #EZRMGH-45K) according to the manufacturer's instructions. In this method, rat GH supernatants were first captured in wells of a microtiter plate coated with a pre-titered amount of anti-growth hormone polyclonal antibody. After washing away unbound GH, a second biotinylated anti-GH polyclonal antibody was allowed to bind to the captured GH molecules. Unbound GH was again washed away, followed by a step of binding horseradish peroxidase to the immobilized biotinylated antibody. After a final wash step, the immobilized antibody-enzyme complex was quantified using horseradish peroxidase activity in the presence of the substrate 3,3',5,5'-tetramethylbenzidine. Enzyme activity was measured spectrophotometrically. Rat GH concentrations were derived by interpolation from a reference curve generated in the same assay using reference standards of known concentrations of rat GH. The results are shown in Table 9 and Figures 5A–5E.

[0166] [Table 13]

[0167] Example 15 Inhibition of hormone release from human neuroendocrine tumor (NT-3) cells NT-3 is a human neuroendocrine cell line derived from an advanced, insulin-secreting pancreatic neuroendocrine tumor (insulinoma). NT-3 recapitulates many of the key characteristics of human neuroendocrine tumors, such as well-differentiation, slow growth, and expression of multiple somatostatin receptors (Benten et al., 2018). Therefore, we chose to investigate the effects of compounds on relevant measures of neuroendocrine cell function, such as hormone secretion and proliferation.

[0168] For the study, 24-well plates were coated with 1 mg / ml human placenta-derived type IV collagen in 950 μL of PBS and allowed to dry completely. NT3 cells were seeded at a density of 20,000 cells / well in complete medium (0.5 ml) containing growth factors and incubated overnight at 37°C with 5% CO2. After 24 hours, the medium was aspirated and fresh complete medium (1 ml / well) supplemented with the following drugs was added: Compound 1; Compound 2; Compound 3; Compound 4; Compound 5.

[0169] All drugs were administered at 5 nM and 10 nM, and biological replicates were run. The treatment exposure period was 5 days. An untreated cell control was also run. After 5 days, the supernatant was collected and placed in a 1.5 ml tube, which was then centrifuged at 13,400 rpm for 5 minutes to remove cellular debris. Samples were stored at -80°C until analysis.

[0170] Secreted insulin levels in the supernatants were investigated using a sandwich ELISA method (Elabscience® Human Insulin ELISA Kit #E-EL-H2665) according to the manufacturer's instructions. Micro-ELISA plates were precoated with an antibody specific to human insulin. Samples or standards were added to the micro-ELISA plate wells and combined with the specific antibody. Next, a biotinylated detection antibody specific to human insulin and an avidin-horseradish peroxidase (HRP) conjugate were added sequentially to each microplate well, incubated, and then washed. Substrate solution was added to each well. Only wells containing human insulin, biotinylated detection antibody, and avidin-HRP conjugate appeared blue. The enzyme-substrate reaction was stopped by adding stop solution. Optical density (OD) was measured spectrophotometrically at a wavelength of 450 nM ± 2 nM, and human insulin concentrations were derived from a standard curve. The results are shown in Table 10 and Figures 6A–6E.

[0171] [Table 14]

[0172] Example 16 Inhibition of proliferation of human neuroendocrine tumor (NT-3) cells The water-soluble tetrazolium-1 (WST-1) assay is a standard method for assessing cell viability and proliferation in vitro. The WST-1 assay is based on the cleavage of tetrazolium salt in the culture medium into the dye formazan by active mitochondrial enzymes. As the number of viable cells changes, so does the activity of mitochondrial dehydrogenases and the cleavage of the tetrazolium salt. The formation of formazan in the cell culture medium can be assayed spectrophotometrically as a measure of the number of viable cells in the sample well. The effects of various compounds on cell viability or proliferation can be measured relative to a control or standard.

[0173] The compounds investigated were: Compound 1; Compound 4; Compound 5.

[0174] All compounds were investigated at a dose of 5 nM and appropriate untreated controls were included.

[0175] NT-3 cells were seeded in RPMI-1640 complete medium (100 μl) and placed in a 96-well microplate (20,000 cells / well). This was incubated at 37°C in 5% CO2 to allow cell attachment. The cells were treated with test compounds at a concentration of 5 nM for 5 days without changing the medium or adding fresh compound. To achieve a 1:10 ratio, a total of 10 μl of WST-1 reagent was added to each well, and the plate was incubated in the dark at 37°C for 3 hours. The absorbance of the formazan dye was measured at 450 nM and 690 nM using a microplate reader. Cell culture medium was used as a blank control. The average absorbance values ​​for each group were calculated at wavelengths of 450 nM and 690 nM and corrected for the blank value. All values ​​were compared to those of the untreated cell group control. The results are shown in Table 11 and Figure 7A.

[0176] [Table 15]

[0177] Although several embodiments of the present invention have been described, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

1. Compounds of formula I, or pharmaceutically acceptable salts or solvates thereof: 【Chemistry 1】 (In the formula, X １ is selected from the group consisting of -F, -Cl, -Br, and -I; X ２ is selected from the group consisting of -F, -Cl, -Br, and -I; and Y １ is -H, chelating agent, L １ -H, -L １ - Selected from the group consisting of chelating agents, amino protecting groups, and solid support structures; where L １ It is a linker; However, X １ and X ２ (Neither of them is -I).

2. Y １ is selected from the group consisting of a chelating agent and -L １ - a chelating agent, the compound according to claim 1.

3. The chelating agent forms a complex with a radionuclide, preferably the radionuclide is boron-10, fluorine-18, phosphorus-32, scandium-47, copper-67, gallium-72, rubidium-82, strontium-89, yttrium-90, technetium-99, palladium-103, indium-111, iodine-125, cesium-131, iodine-131, samarium-153, gadolinium-157, gadolinium- A compound according to claim 1, selected from the group consisting of 159, terbium-149, samarium-153, terbium-161, dysprosium-165, holmium-166, ytterbium-175, lutetium-177, rhenium-186, rhenium-188, thallium-201, astatine-211, lead-212, bismuth-212, bismuth-213, radium-223, actinium-225, and thorium-227.

4. The compound is the compound of formula I-A, or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 2】 (In the formula, X １ is selected from the group consisting of -F, -Cl, -Br, and -I; X ２ is selected from the group consisting of -F, -Cl, -Br, and -I; However, X １ and X ２ (Neither of them is -I) The compound according to claim 1.

5. X １ and X ２ The compound according to claim 1, wherein the two are the same and both are selected from the group consisting of -F, -Cl, and -Br.

6. The aforementioned compound, 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 A compound according to claim 1, selected from the group consisting of the following.

7. X １ is -I, X ２ The compound according to claim 1, wherein is -Cl.

8. X １ is -Cl, X ２ The compound according to claim 1, wherein is -I.

9. X １ is -Cl, X ２ The compound according to claim 1, wherein is -Cl.

10. X １ is -F, X ２ The compound according to claim 1, wherein is -F.

11. X １ is -Br, X ２ The compound according to claim 1, wherein is -Br.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. A compound according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12, for use as a pharmaceutical.

14. A compound according to any one of claims 1 to 11, for use as a pharmaceutical product.

15. A compound according to any one of claims 1 to 11, for use in a method of treating SST2 or SST5 cell proliferation disorder, preferably a proliferation disorder involving cells expressing SST2 and SST5.

Images