Compounds and radioligands targeting neurotensin receptors and uses thereof

Abstract

The present application relates to a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof, or a radionuclide complex comprising a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof and one or more radionuclides, and to compositions thereof. The present application also includes methods of targeting neurotensin receptors using the compounds, complexes and compositions and further relates to their use in imaging, diagnosis and treatment of diseases, disorders or conditions, such as cancer. The present application relates to compounds of Formula II or pharmaceutically acceptable salts and / or solvates thereof, and to compositions and uses thereof, for example in the treatment of diseases, disorders or conditions, such as cancer. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 311,621, filed on February 18, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application generally relates to the field of radioligands targeting neurotensin receptors. In particular, it relates to compounds and complexes of said compounds containing radionuclides. The present application also relates to methods of using said compounds and complexes to target and / or kill target cells. Background Art

[0004] Neurotensin is a 13-mer peptide that functions as a neurotransmitter and hormone. It acts through the neurotensin receptor family, which consists of three receptor subtypes: neurotensin receptor 1 (NTR1 or NTSR1), NTSR2, and NTSR3 (sortilin). NTSR1 and NTSR2 are G protein-coupled receptors (GPCRs), while sortilin is a sorting receptor with a single transmembrane domain [1,2].

[0005] High expression of NTR1 has been found in many tumors, including colorectal and pancreatic cancers, as well as breast cancer, prostate cancer, small cell lung cancer, and non-small cell lung cancer [3-5]. Studies have also shown a close link between NTR1 expression levels and disease progression [6]. Such disease-related overexpression suggests that NTR1 is a viable target for cancer targeted therapy. In the case of pancreatic cancer, NTR1 was found to be present in 75%-90% of pancreatic ductal adenocarcinomas (PDAC), while normal pancreas does not express NTR.

[0006] Small molecule antagonists of NTR1 have been disclosed. For example, compound SR142948 (C-3) is one of the structures described in U.S. Patent No. 5,723,483, which exhibits high binding affinity to NTR1 as an antagonist [7]. Radioligand compounds derived from SR142948 have been reported. For example, radioligand compounds derived from SR142948 have been disclosed in WO2014086499A1 and WO2018024789A1. In addition, their ability to detect NTR1-positive tumors and inhibit their growth has been demonstrated in animals [8,9]. One of the main compounds, 3BP-227 (C-2), has also been shown to be effective in a small number of pancreatic cancer patients with its 177 The Lu-chelated form was tested, where tumor uptake of the radioligand was clearly observed

[10] .

[0007] High binding affinity is an important factor in achieving high tumor uptake of radioligands in vivo. Relatedly, high binding affinity is also important for achieving an ideal ratio of tumor uptake to normal tissue accumulation of radioligands. However, the methods disclosed in the prior art for derivatizing SR142948 into radioligands are not intended to improve their binding affinity, and in fact, such derivatization is often detrimental to their interaction with the receptor NTR1. For example, in a competitive radioligand binding assay using HT-29 cells, the potency of 3BP-227 was approximately 40% of that of SR142948. 177 In human studies of Lu-3BP-227, the kidney was identified as the dose-limiting organ

[10] . 225 Ac, 212 Pb, etc.) than β emitters ( 177 Lu, 90 Y et al.) have more stringent requirements for high ratios of tumor to kidney and tumor to other normal organs, because alpha emitters are significantly more potent than beta emitters in breaking down DNA and killing cells. In conclusion, it is still necessary to further optimize tumor uptake and the ratio of tumor to kidney and the ratio of tumor to other normal organs in order to establish NTR1-based radioligand therapy with a wide therapeutic window for clinical use. Summary of the invention

[0008] In view of the above limitations, derivatives of SR 142948 and novel radioligands derived therefrom that target the neurotensin receptor are described herein.

[0009] Therefore, the present application includes a compound or a pharmaceutically acceptable salt and / or solvate thereof,

[0010]

[0011] in

[0012] R 1 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0013] R 2 Selected from H, halogen, NO 2 , C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-3 Alkylene C 3-8 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0014] R 3Selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;

[0015] X is selected from CH 2 , O, NR 4 , S, S(O), SO 2 NR 4 and NR 4 C(O);

[0016] L is the connector;

[0017] E is a chelating group;

[0018] R 4 Selected from H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C(O)C 1-6 Alkyl, C 1-10 Alkylene NR 5 R 6 , C 1-10 Alkenylene NR 5 R 6 and C 1-10 Alkynylidene NR 5 R 6 ;and

[0019] R 5 and R 6 Independently selected from H and C 1-6 alkyl.

[0020] The present application further includes a radionuclide complex or a pharmaceutically acceptable salt and / or solvate thereof, which comprises a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof and one or more radionuclides.

[0021] The present application also includes compounds of formula II or pharmaceutically acceptable salts and / or solvates thereof

[0022]

[0023] in

[0024] R 9 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0025] R 10 Selected from H, halogen, NO 2 , C 1-6 Alkyl, C 3-8Cycloalkyl and C 1-3 Alkylene C 3-8 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0026] R 11 Selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;

[0027] Y is selected from CH 2 , O, NR 14 , S, S(O), SO 2 NR 14 and NR 14 C(O);

[0028] R 12 and R 13 Independently selected from H and C 1-6 Alkyl and

[0029] R 14 Selected from H and C 1-6 Alkyl; and

[0030] n is an integer selected from 1 to 10.

[0031] The present application includes a composition comprising one or more compounds as described above or pharmaceutically acceptable salts and / or solvates thereof, or one or more radionuclide complexes as described above or pharmaceutically acceptable salts and / or solvates thereof, and a carrier.

[0032] The present application includes a composition comprising one or more compounds as described above or pharmaceutically acceptable salts and / or solvates thereof, or one or more radionuclide complexes as described above or pharmaceutically acceptable salts and / or solvates thereof, and a pharmaceutically acceptable carrier.

[0033] Further included is a method of treating a disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds as described above or one or more radionuclide complexes as described above, or a pharmaceutically acceptable salt and / or solvate thereof.

[0034] In some embodiments, the disease or disorder is cancer.In some embodiments, the cancer is a neurotensin receptor positive cancer, optionally wherein the neurotensin receptor is neurotensin receptor 1 (NTR1).

[0035] The present application also includes a method for inhibiting proliferation activity in cells, which comprises administering to the cells an effective amount of one or more compounds as described above or one or more radionuclide complexes as described above or pharmaceutically acceptable salts and / or solvates thereof.

[0036] The present application also includes a method of imaging tissue of a subject by administering a therapeutically effective amount of one or more compounds as described above or one or more radionuclide complexes for imaging as described above or pharmaceutically acceptable salts and / or solvates thereof, and applying imaging technology to detect emitted gamma rays.

[0037] The present application also includes a method of diagnosing cancer in a subject by administering a therapeutically effective amount of one or more compounds as described above or one or more radionuclide complexes for imaging as described above or pharmaceutically acceptable salts and / or solvates thereof, and applying imaging technology to detect emitted gamma rays.

[0038] The present application also includes a theranostic treatment method, which comprises administering an effective amount of one or more complexes of the present application to a subject in need thereof and performing a medical diagnostic method on the subject.

[0039] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, although indicating embodiments of the present application, are only given as examples, and the scope of the claims should not be limited to these embodiments, but should be given the broadest interpretation consistent with the entire specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Certain embodiments of the present application will now be described in more detail with reference to the accompanying drawings, in which:

[0041] Figure 1 Illustrated example 177 Stability of Lu-labeled compounds.

[0042] Figure 2 The binding affinities of exemplary compounds of the present application in radioligand competitive binding assays are illustrated.

[0043] Figures 3A-3D Graphical comparison and exemplary complexes 177 Lu-C-2, 177 Lu-I-5, 177 Lu-I-10 and 177 Biodistribution of Lu-I-7 in different organs / tissues of ASPC-1 tumor-bearing mice.

[0044] Figure 4A-4B Graphical comparison and exemplary complexes 177 Lu-I-5 and 177 Biodistribution of Lu-I-7 in different organs / tissues of HT-29 tumor-bearing mice.

[0045] Figure 5 An exemplary embodiment of the present application is shown in Figure 72 hours.177 Lu-labeled complex 177 Lu-I-5 and 177 SPECT / CT imaging results of mice after Lu-I-7.

[0046] Figure 6 The diagram illustrates an exemplary embodiment of the present application being applied for 180 minutes. 68 Ga-labeled comparison complex and exemplary complex 68 Ga-C-5 and 68 PET / CT imaging results of mice after Ga-I-6.

[0047] Figure 7A-7B Schematic illustration of the use of an exemplary complex in ASPC-1 tumor-bearing mice 177 Lu-I-5 and 177 Lu-I-7 177 In vivo efficacy of Lu therapy.

[0048] Figures 8A-8D Schematic illustration of the use of an exemplary complex in ASPC-1 tumor-bearing mice 225 Ac-I-5 and 225 Ac-I-7 225 In vivo efficacy of Ac therapy. DETAILED DESCRIPTION

[0049] I. Definitions

[0050] Unless otherwise stated, the definitions and embodiments described in this section and other sections are intended to apply to all embodiments and aspects of the application described herein as understood by those skilled in the art to which they apply.

[0051] All features disclosed in the specification (including claims, abstract and drawings) and all steps in any disclosed method or process may be combined in any combination, unless at least some of such features and / or steps in the combination are mutually exclusive. Unless otherwise expressly stated, each feature disclosed in the specification (including claims, abstract and drawings) may be replaced by an alternative feature that performs the same, equivalent or similar function.

[0052] As used in this application and in the claims, the words "comprising" (and any form of "comprising", such as "comprise" and "comprises"), "having" (and any form of "having", such as "have" and "has"), "including" (and any form of "including", such as "include" and "includes"), or "containing" (and any form of "containing", such as "contain" and "contains") are inclusive or open-ended, and do not exclude additional, unrecited elements or process steps.

[0053] As used herein, the term "consisting of" and its derivatives are intended to serve as closed terms that specify the presence of stated features, elements, components, groups, integers and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0054] As used herein, the term "consisting essentially of" is intended to specify the presence of the basic and novel features, elements, components, groups, integers and / or steps as well as those that do not materially affect the features, elements, components, groups, integers and / or steps.

[0055] The terms "approximately", "substantially" and "approximately" as used herein refer to a reasonable amount of deviation of the modified term so that the end result will not be significantly changed. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified term, if such deviation does not negate the meaning of the word it modifies, or unless the context suggests otherwise to a person skilled in the art.

[0056] As used in this application, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present certain aspects with one compound or two or more additional compounds.

[0057] In embodiments comprising an "additional" or "second" component or effect, such as an additional or second compound, the second compound as used herein is different from the other compounds or the first compound. The "third" compound is different from the other, first and second compounds, and further enumerated or "additional" compounds are similarly different.

[0058] As used herein, the term "and / or" refers to the presence or use of the listed items alone or in combination. In practice, the term means the use or presence of "at least one" or "one or more" of the listed items. The term "and / or" with respect to enantiomers, prodrugs, salts and / or solvates thereof refers to the presence of the compounds of the present application as individual enantiomers, prodrugs, salts and hydrates and, for example, combinations of salts or solvates of the compounds of the present application.

[0059] The term "compound of the present application" and the like as used herein refers to compounds of Formula I, IA, Formula II, II-A and II-B or pharmaceutically acceptable salts and / or solvates thereof.

[0060] The term "complex of the present application" and the like as used herein refers to a complex comprising one or more compounds of Formula I or pharmaceutically acceptable salts and / or solvates thereof and one or more radionuclides.

[0061] The term "composition of the present application" and the like as used herein refers to a composition comprising one or more compounds or complexes of the present application.

[0062] As used herein, the term "radioligand" refers to a compound comprising a neurotensin receptor binding moiety and a radionuclide. The complex of the present application is an example of a radioligand.

[0063] As used herein, the term "radionuclide" refers to any atom that is capable of undergoing radioactive decay. The term radionuclide is used herein synonymously with radioactive nuclide, radioisotope, and radioactive isotope. Radionuclides occur naturally or can be produced artificially.

[0064] As used herein, the term "suitable" means that the selection of particular compounds or conditions will depend on the particular synthetic procedure to be performed, the nature of the molecule to be transformed, and / or the particular use of the compound, but such selection is well within the skills of one skilled in the art.

[0065] This specification refers to many chemical terms and abbreviations used by those skilled in the art. Nevertheless, for the sake of clarity and consistency, definitions of selected terms are provided.

[0066] The term "protecting group" or "PG" as used herein refers to a chemical part that protects or masks the reactive part of a molecule to prevent side reactions in these reactive parts of the molecule while manipulating or reacting different parts of the molecule. After the manipulation or reaction is completed, the protecting group is removed under conditions that do not degrade or decompose the rest of the molecule. Those skilled in the art can select a suitable protecting group. Many conventional protecting groups are known in the art, such as "Protective Groups in Organic Chemistry" McOmie, JFWEd., Plenum Press, 1973, Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd edition, 1999 and Kocienski, P. Protecting Groups, 3rd edition, 2003, described in Georg Thieme Verlag (The Americas).

[0067] As used herein, the term "alkyl", whether used alone or as part of another group, refers to a straight or branched chain saturated alkyl group. The number of carbon atoms possible in the referenced alkyl group is indicated by the prefix "C n1-n2 " means. For example, the term C 1-10 Alkyl refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Unless otherwise specified, all alkyl groups are optionally substituted by fluorine.

[0068] The term "alkylene", whether used alone or as part of another group, refers to a straight or branched saturated alkylene group, i.e. a saturated carbon chain containing substituents at both ends. The possible number of carbon atoms in the alkylene group mentioned is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 Alkylene refers to an alkylene group having 2, 3, 4, 5 or 6 carbon atoms. Unless otherwise specified, all alkylene groups are optionally substituted by fluorine.

[0069] As used herein, the term "alkenyl", whether used alone or as part of another group, refers to a straight or branched unsaturated alkyl group containing at least one double bond. The possible number of carbon atoms in the referenced alkylene group is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 Alkenyl refers to alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond. Unless otherwise specified, all alkenyl groups are optionally substituted by fluorine.

[0070] The term "alkenylene", whether used alone or as part of another group, refers to a straight or branched unsaturated alkyl group containing at least one double bond and having substituents at both ends. The possible number of carbon atoms in the mentioned alkylene group is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 Alkenylene refers to alkenylene having 2, 3, 4, 5 or 6 carbon atoms. Unless otherwise specified, all alkenylene groups are optionally substituted by fluorine.

[0071] As used herein, the term "aryl", whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing from 6 to 20 carbon atoms.

[0072] As used herein, the term "cycloalkyl", whether used alone or as part of another group, refers to a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings. The possible number of carbon atoms in the cycloalkyl group is indicated by the numerical prefix "C n1-n2 " means. For example, the term C 3-10 Cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0073] As used herein, the term "heterocycloalkyl", whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring containing 3 to 20 atoms, one or more of which is selected from O, S, SO, SO 2 , N, NH and NCH 3 heteroatom, and the remaining atoms are C. Heterocycloalkyl is saturated or unsaturated (i.e., contains one or more double bonds). n1-n2 When the prefix indicates the number of carbon atoms in the corresponding carbocyclic group, one or more, suitably 1 to 5, of the ring atoms are selected from O, S, SO, SO 2 , N, NH and NCH 3 The heterocycloalkyl radical is optionally benzo-fused. When part of another group, "heterocycloalkyl" also refers to a cyclic group containing at least one heterocycloalkyl radical fused to one or more cyclic groups (e.g., a heterocycloalkyl radical optionally fused to an aryl, heteroaryl, heterocycloalkyl, and cycloalkyl radical as defined herein).

[0074] As used herein, the term "heteroaryl", whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5 to 20 atoms, one or more of which is selected from O, S, N, NH and NCH 3 heteroatom, and the remaining atoms are C. When the heteroaryl group contains the prefix C n1-n2When , the prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1 to 5 ring atoms are replaced by heteroatoms as defined above. The heteroaryl group is optionally benzo-fused.

[0075] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl and cycloalkyl, contain one or more than one ring (ie, are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused or connected by a bond.

[0076] As used herein, the term "benzo-fused" refers to a polycyclic group in which a benzene ring is fused to another ring.

[0077] When a first ring is "fused" to a second ring, it means that the first ring and the second ring share two adjacent atoms therebetween.

[0078] A first ring is "bridged" to a second ring if the first ring and the second ring share two non-adjacent atoms therebetween.

[0079] When a first ring is "spiro-fused" to a second ring, it means that the first ring and the second ring share one atom therebetween.

[0080] The term "optionally substituted" refers to a group, structure or molecule that is unsubstituted or substituted with one or more substituents.

[0081]

[0043] As used herein, the term "halo" or "halogen", whether used with or as part of another group, refers to a halogen atom and includes fluorine, chlorine, bromine, and iodine.

[0082] As used herein, the term "neurotensin receptor binding group" refers to a moiety that is recognized by the neurotensin receptor to which it binds.

[0083] As used herein, the term "neurotensin receptor" refers to a transmembrane receptor that binds neurotensin.

[0084] The term "NTR1" (also referred to as NTR-1, NTSR1, NTSR-1 or neurotensin receptor 1) as used herein refers to the neurotensin receptor encoded by the NTSR1 gene. NTR1 belongs to a large superfamily of G protein-coupled receptors and mediates multiple functions of neurotensin. NTR1 can be native sequence NTR1 or an amino acid sequence variant thereof. In one embodiment, NTR1 is native sequence human NTR1.

[0085] As used herein, the term "chelating group" is a chelating agent capable of binding and / or complexing with a radionuclide.

[0086] As used herein, the term "linker" refers to any molecular structure that connects two or more other molecular structures together.

[0087] As used herein, the term "reacts with" generally means that there is a flow of electrons or a transfer of electrostatic charge resulting in the formation of a chemical interaction.

[0088] As used herein, the term "theranostic" refers to an agent that can be used both diagnostically and therapeutically.

[0089] As used herein, the term "theranostic application" refers to the use of a radiopharmaceutical for the diagnosis and treatment of selected conditions.

[0090] As used herein, the term "therapeutic treatment" may include treatments administered to a subject in need of imaging. A subject may require imaging to aid in diagnosis; locate a location for therapeutic intervention; assess the function of a body part; and / or assess the presence or absence of a condition. The effectiveness of a therapeutic imaging treatment may be confirmed based on image capture sufficient to achieve its intended purpose.

[0091] As used herein, the term "disease, disorder or condition associated with a neurotensin receptor" refers to any disease, disorder or condition that is affected by, regulated by, and / or has some direct or indirect biological basis that indicates that it includes, particularly increased, neurotensin receptor activity. When the activity of a neurotensin receptor (e.g., NTR1) associated with a disease, disorder or condition is inhibited by one or more of the compounds or compositions of the present application, these diseases respond favorably.

[0092] As used herein, the term "positron emission tomography (PET)" refers to a functional imaging technique used in nuclear medicine whereby three-dimensional images (e.g., of functional processes) in the body are generated. The system detects gamma-ray pairs emitted indirectly by positron-emitting radionuclides introduced into the body in the form of pharmaceutical compounds.

[0093] As used herein, the term "single photon emission computed tomography (SPECT)" refers to a three-dimensional diagnostic imaging technique that uses gamma rays emitted by radioisotopes. In contrast to PET, the tracer used in SPECT emits gamma radiation that is directly measured, whereas the PET tracer emits a positron that annihilates with a nearby electron a few millimeters away, resulting in the emission of two gamma photons in opposite directions.

[0094] As used herein and as the term "treating / treatment" as fully understood in the art refers to a method of obtaining a beneficial or desired result (including a clinical result). Beneficial or desired clinical results include, but are not limited to, alleviating or improving one or more symptoms or conditions, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, reducing the recurrence of the disease, and alleviating (whether partially or completely), whether detectable or undetectable. "Treatment" can also refer to extending the survival period compared to the expected survival period without treatment. For example, a subject with early-stage cancer can be treated to prevent progression, or a subject in remission can be treated with a compound or composition of the present application to prevent recurrence. The method of treatment includes administering to the subject a therapeutically effective amount of one or more compounds of the present application, and optionally consists of a single administration, or comprises a series of administrations.

[0095] "Alleviating" a disease, disorder or condition means that the extent and / or adverse clinical manifestations of the disease, disorder or condition are reduced and / or the time course of progression is slowed or prolonged, as compared to not treating the disorder.

[0096] As used herein, the terms "preventing," "prevention," "prophylaxis," or synonyms thereof refer to reducing the risk or probability that a patient will develop a disease, disorder, or condition, or exhibit symptoms associated with a disease, disorder, or condition.

[0097] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or one or more compounds of the present application effective at dosages and for periods of time necessary to achieve the desired result.

[0098] When used in conjunction with one or more complexes of the present application, the term "imaging-effective amount" is an amount of the complex sufficient to produce a visible image when the complex is administered to a subject and radiation emitted by the complex is detected using positron emission tomography ("PET") or single photon emission tomography (SPECT) or autoradiography or an ex vivo or in vitro binding assay.

[0099] The term "diagnostically effective amount" as used herein refers to an amount of a compound or one or more compounds or a complex or one or more complexes of the present application that is effective at dosages and for periods of time necessary to achieve the desired diagnostic effect, including, for example, diagnosing a specific condition being assessed.

[0100] As used herein, the term "administering" refers to administering a therapeutically effective amount of one or more compounds, complexes or compositions of the present application to a cell, tissue, organ or subject.

[0101] As used herein, the term "cancer" refers to a cell proliferative disease state.

[0102] The term "subject" as used herein includes all members of the animal kingdom, including mammals, and appropriately refers to humans. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0103] As used herein, the term "cell" refers to a single cell or a plurality of cells, and includes cells in cell culture or in a subject.

[0104] The term "pharmaceutically acceptable" means compatible with treatment of a subject (eg, a human).

[0105] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material with which the active ingredient is mixed in order to form a pharmaceutical composition (ie, a dosage form capable of being administered to a subject).

[0106] The term "pharmaceutically acceptable salt" refers to an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of a subject.

[0107] Acid addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic acid addition salt of any basic compound.

[0108] Base addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic base addition salt of any acidic compound.

[0109] As used herein, the term "solvate" refers to a compound or salt and / or prodrug of a compound in which molecules of a suitable solvent are incorporated into a crystal lattice. Suitable solvents are physiologically tolerable at the administered dose.

[0110] When used, for example, with respect to the methods of treatment, uses, and compositions of the present application, a subject, for example, a subject "in need thereof" is a subject who will benefit from the administration of one or more compounds or complexes of the present application, or pharmaceutically acceptable salts and / or solvates thereof.

[0111] II. Compounds and complexes of the present application

[0112] Applicants have developed novel radioligands that exhibit advantageous properties such as high binding affinity to the neurotensin receptor, high uptake by tumors and low accumulation in normal organs.

[0113] Applicants have unexpectedly discovered that modification of the amide group to attach the diamine moiety directly to the rest of the structure of the known neurotensin antagonist compound SR 142948 (C-3), such as removal of the carbonyl group from the amide group, resulted in an improvement in potency of more than about 10 times (see, e.g., II-1 vs SR142948 (C-3), Tables 1 & 2). Such compounds have been further derivatized to provide a group of novel compounds comprising a neurotensin receptor binding group and a chelating group coupled via a linker. The compounds of the present application form radioligands with higher binding affinity when complexed with a radionuclide, such as an approximately 20-fold enhancement in binding affinity compared to 3BP-227 (C-2) (Table 2). Furthermore, by such derivatization, it was found that removal of the tertiary amine motif in the linker region did not impair binding affinity (see, e.g., I-10 vs 3BP-227 (C-2), Table 2). In animal studies, the radioligands of the present application have demonstrated, for example, high uptake by NTR1 -positive tumors, and an improved overall biodistribution profile, including a high ratio of tumor uptake to normal organ accumulation, including kidney, liver, and lung.

[0114] Therefore, the present application includes compounds of formula I or pharmaceutically acceptable salts and / or solvates thereof

[0115]

[0116] in

[0117] R 1 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0118] R 2 Selected from H, halogen, NO 2 , C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-3 Alkylene C 3-8 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0119] R 3 Selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;

[0120] X is selected from CH 2 , O, NR 4 , S, S(O), SO 2 NR 4 and NR 4 C(O);

[0121] L is the connector;

[0122] E is a chelating group;

[0123] R 4 Selected from H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C(O)C 1-6 Alkyl, C 1-10 Alkylene NR 5 R 6 , C 1-10 Alkenylene NR 5 R 6 and C 1-10 Alkynylidene NR 5 R 6 ;and

[0124] R 5 and R 6 Independently selected from H and C 1-6 alkyl.

[0125] In some embodiments, R 1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens. 1 Selected from H, C 1-3 Alkyl, cyclopropyl, cyclobutyl and CH 2 Cyclopropyl and CH 2 Cyclobutyl, the latter five groups are optionally substituted by one or more halogens. 1 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, CH 2 Cyclopropyl and CH 2 cyclobutyl, each of which is optionally substituted with one or more halogens. In some embodiments, halogen is selected from fluorine and chlorine. In some embodiments, R 1 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3、CH(CH 3 ) 2 , cyclopropyl and CH 2 cyclopropyl, each of which is optionally substituted with one or more fluorine. 1 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 , cyclopropyl and CH 2 Cyclopropyl, each of which is optionally substituted by 1 or 3 fluorine. 1 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 In some embodiments, R 1 Yes CH 3 .

[0126] In some embodiments, R 2 Selected from H, halogen, NO 2 , C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens. 2 Selected from halogen, NO 2 , C 1-6 Alkyl, C 3-6 Cycloalkyl and CH 2 C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens. 2 Selected from halogen, NO 2 and C 1-6 Alkyl, the latter group is optionally substituted by one or more halogens. 2 is C optionally substituted by one or more halogens 1-6 In some embodiments, halogen is selected from fluorine and chlorine. In some embodiments, R 2 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH3 、CH(CH 3 ) 2 , optionally substituted with one or more fluorine. 2 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 , optionally substituted with 1 or 3 fluorine. 2 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 In some embodiments, R 2 is CH(CH 3 ) 2 .

[0127] In some embodiments, R 3 is 2-amino-2-adamantanecarboxylic acid. In some embodiments, R 3 is cyclohexylglycine. In some embodiments, R 3 is 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid. In some embodiments, R 3 is a group having the formula

[0128]

[0129] In some embodiments, the compound of Formula I is a compound of Formula IA or a pharmaceutically acceptable salt and / or solvate thereof.

[0130]

[0131] wherein X, L and E are as defined in Formula I.

[0132] In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O). In some embodiments, X is CH 2 In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR 4 In some embodiments, X is NR 4 C(O).

[0133] In some embodiments, R 4 Selected from H, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C(O)C 1-6 Alkyl, C 1-8 Alkylene NR 5 R 6 , C 1-8 Alkenylene NR 5 R 6 and C 1-8 Alkynylidene NR 5 R 6 In some embodiments, R 4 Selected from H, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C(O)C 1-4 Alkyl, C 1-6 Alkylene NR 5 R 6 , C 1-6 Alkenylene NR 5 R 6 and C 1-6 Alkynylidene NR 5 R 6 .

[0134] In some embodiments, R 4 It is C(O)C 1-3 In some embodiments, R 4 is C(O)CH 3 .

[0135] In some embodiments, R 4 Selected from H, C 1-4 Alkyl, C(O)C 1-4 Alkyl and C 1-8 Alkylene NR 5 R 6 In some embodiments, R 4 Selected from H, C 1-4 Alkyl and C 1-6 Alkylene NR 5 R 6 .

[0136] In some embodiments, R 4 Selected from H and C 1-4 In some embodiments, R 4 Selected from H, CH 3 , CH 2 CH 3 , CH 2 CH2 CH 3 、CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 and CH(CH 3 ) 3 In some embodiments, R 4 Selected from H and CH 3 .

[0137] In some embodiments, R 4 It is C 1-8 Alkylene NR 5 R 6 In some embodiments, R 4 It is C 1-6 Alkylene NR 5 R 6 In some embodiments, R 4 It is C 1-4 Alkylene NR 5 R 6 In some embodiments, R 4 It is C 2-6 Alkylene NR 5 R 6 In some embodiments, R 4 It is C 2-4 Alkylene NR 5 R 6 In some embodiments, R 4 Yes CH 2 CH 2 CH 2 Alkylene NR 5 R 6 (For example, C 3 Alkylene NR 5 R 6 ).

[0138] In some embodiments, R 5 and R 6 Independently selected from H and C 1-4 In some embodiments, R 5 and R 6 are independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH(CH 3 )CH2 CH 3 and CH(CH 3 ) 3 In some embodiments, R 5 and R 6 Independently selected from H and CH 3 .

[0139] In some embodiments, X is NR 4 And R 4 Selected from H and C 1-4 In some embodiments, X is NR 4 And R 4 Selected from H and CH 3 .

[0140] In some embodiments, X is NR 4 C(O) and R 4 It is C 1-6 Alkylene NR 5 R 6 In some embodiments, X is NR 4 C(O) and R 4 It is C 2-6 Alkylene NR 5 R 6 In some embodiments, X is NR 4 C(O) and R 4 Yes CH 2 CH 2 CH 2 Alkylene NR 5 R 6 .

[0141] In some embodiments, X is NR 4 And R 4 It is C 1-6 Alkylene NR 5 R 6 In some embodiments, X is NR 4 And R 4 It is C 2-6 Alkylene NR 5 R 6 In some embodiments, X is NR 4 And R 4 It is C 2-4 Alkylene NR 5 R 6 In some embodiments, X is NR 4 C and R 4 Yes CH 2 CH 2 CH 2 Alkylene NR5 R 6 .

[0142] Those skilled in the art will recognize that the linker forms a covalent bond with both X and E. Thus, in some embodiments, L is any chemical moiety capable of forming a covalent bond with both X and E. In some embodiments, L comprises a linker moiety selected from an amine, an ether, a thioether, a carbonyl, a thiocarbonyl, a sulfone, a sulfoxide, a urea, a thiourea, and an amide. In some embodiments, L comprises a group at the terminal end that is capable of forming a covalent bond with E. For example, in some embodiments, L comprises an amine at the terminal end that reacts with the carboxylic acid group of the chelating group.

[0143] In some embodiments, L comprises C 1-20 Alkylene, C 1-20 Alkenylene and C 1-20 In some embodiments, C 1-20 Alkylene, C 1-20 Alkenylene and C 1-6 One or more of the alkynylene groups are optionally selected from amine, ether, thioether, carbonyl, thiocarbonyl, sulfone, sulfoxide, urea, thiourea, amide, C 4-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 The heteroarylene group is interrupted by one or more linker moieties. 1-20 Alkylene, C 1-20 Alkenylene, C 1-6 Alkynylidene, C 4-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 One or more of the heteroarylene groups are optionally substituted with one or more of hydroxy, halogen, alkyl, and alkyl substituted with one or more of hydroxy, halogen, and amino.

[0144] Thus, in some embodiments, L comprises 1 to 20 independently selected from R a –W a , W a –R b , R a –W a –R b and W a –R b –W b Groups;

[0145] in

[0146] W a and W b Independently selected from O, S, S(O), S(O)2 NR 7 、C(Q)、C(Q)N、NR 7 C(Q), NR 7 C(Q')NR 8 ;

[0147] R a and R b Independently selected from C 1-20 Alkylene, C 1-20 Alkenylene and C 1-20 Alkynylidene;

[0148] Each Q is independently selected from O and S;

[0149] Each Q' is independently selected from O, S, NH and N(C 1-6 alkyl);

[0150] R 7 and R 8 Independently selected from H and C 1-6 Alkyl, and

[0151] R a and R b Each alkylene, alkenylene, alkynylene group in 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene is independently and optionally selected from halogen, CO 2 H, OH, SH, NH 2 、NHC 1-4 Alkyl, N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-6 Alkyl, OC 1-6 Alkyl and SC 1-6 The alkyl group is substituted with one or more substituents, wherein all alkyl groups are optionally further substituted with halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 alkyl) is substituted with one or more substituents.

[0152] One skilled in the art will recognize that two adjacent groups in L should be selected to avoid direct bonding between the two groups which would result in a partial structure that is unstable, for example, in aqueous media at room temperature, such as about 18°C ​​to about 25°C.

[0153] In some embodiments, R a and R b Independently selected from C 1-15 Alkylene, C 1-15 Alkenylene and C 1-15 Alkynylidene, R a and R b Each alkylene group and each alkenylene group and alkynylene group in 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene is independently and optionally selected from halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl, N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-6 Alkyl and OC 1-6 The alkyl group is substituted with one or more substituents, wherein all alkyl groups are optionally further substituted with halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 In some embodiments, R a and R b Independently and optionally selected from C 1-10 Alkylene, C 1-10 Alkenylene and C 1-10 Alkyne, and R a and R b Each alkylene, alkenylene and alkynylene in is independently and optionally substituted by C 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 and one or more interruptions of the heteroarylene group, and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene group is independently and optionally selected from halogen, CO 2 H, OH, C 1-6 Alkyl and OC 1-6 The alkyl group is substituted with one or more substituents, wherein all alkyl groups are optionally further substituted with halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C1-4 In some embodiments, R a and R b Independently and optionally selected from C 1-10 Alkylene, C 1-10 Alkenylene and C 1-10 Alkynylidene, R a and R b Each alkylene, alkenylene and alkynylene in is independently and optionally substituted by C 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 One or two of the heteroarylene groups are interrupted, and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene group is independently and optionally selected from halogen, CO 2 H, OH, C 1-6 Alkyl and OC 1-6 alkyl, wherein all alkyl groups are optionally further substituted by halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 In some embodiments, R a and R b Independently selected from C 1-10 Alkylene, C 1-10 Alkenylene and C 1-10 In some embodiments, R a and R b Independently for C 1-10 In some embodiments, R a and R b Independently for C 1-6 Alkylene.

[0154] In some embodiments, C 3-10 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0155] In some embodiments, C 4-10The heterocycloalkyl group is selected from the group consisting of azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, dioxidothiomorpholino, tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl and thiepanyl.

[0156] In some embodiments, C 6-10 Aryl is selected from phenyl, indanyl or naphthyl.

[0157] In some embodiments, C 5-10 The heteroaryl group is selected from the group consisting of triazolyl, pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.

[0158] In some embodiments, each Q is independently S. In some embodiments, each Q is independently O.

[0159] In some embodiments, each Q' is independently selected from O, S, NH and N(C 1-4 alkyl).

[0160] In some embodiments, each Q is independently selected from O and S, and W a and W b Independently selected from O, S, S(O), S(O) 2 NR 7 、C(O)、C(O)NR 7 NR 7 C(O),NR 7 C(O)NR 8 and NR 7 C(S)NR 8 In some embodiments, W a and W b Independently selected from O, S, S(O), S(O) 2 NR 7 、C(O)、C(O)NR 7 NR 7 C(O),NR 7 C(O)NR 8 and NR 7 C(S)NR 8 In some embodiments, W a and W bIndependently selected from O, S, S(O), S(O) 2 and NR 7 In some embodiments, W a and W b Independently selected from O, NR 7 and C(O).

[0161] In some embodiments, W a and W b Independently selected from O, S, S(O), S(O) 2 NR 7 、C(O)、C(O)NR 7 NR 7 C(O),NR 7 C(O)NR 8 and NR 7 C(S)NR 8 , and R a and R b Independently for C 1-10 In some embodiments, L comprises 1 to 20 independently selected C 1-10 Alkylene O, C 1-10 Alkylene NR 7 , OC 1-10 Alkylene, NR 7 C 1-10 Alkylene, C 1-10 Alkylene NR 7 C(S)NR 8 NR 7 C(S)NR 8 C 1-10 Alkylene, C(O)C 1-10 Alkylene O, C(O)C 1-10 Alkylene NR 7 , OC 1-10 Alkylene C(O) and NR 7 C 1-10 alkylene C(O), and each alkylene, alkenylene and alkynylene is independently and optionally substituted by C 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 and one or more interruptions of the heteroarylene group, and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene group is independently and optionally selected from halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl, N(C 1-4 Alkyl)(C 1-4 Alkyl), C1-6 Alkyl and OC 1-6 The alkyl group is substituted with one or more substituents, wherein all alkyl groups are optionally further substituted with halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 In some embodiments, W a and W b Independently selected from O, NR 7 and C(O), and R a and R b Independently for C 1-10 In some embodiments, L comprises 1 to 20 independently selected C 1-10 Alkylene O, C 1-10 Alkylene NR 7 , OC 1-6 Alkylene, NR 7 C 1-10 Alkylene, C(O)C 1-10 Alkylene O, C(O)C 1-10 Alkylene NR 7 , OC 1-10 Alkylene C(O) and NR 7 C 1-10 alkylene C(O), and each alkylene, alkenylene and alkynylene is independently and optionally substituted by C 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 One or two of the heteroarylene groups are interrupted, and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene group is independently and optionally selected from halogen, CO 2 H, OH, C 1-6 Alkyl and OC 1-6 alkyl, wherein all alkyl groups are optionally further substituted with 1 to 4 substituents selected from halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 In some embodiments, L comprises 1 to 20 independently selected C 1-10 Alkylene O, C 1-10 Alkylene NR 7 , OC 1-6 Alkylene, NR 7 C 1-10Alkylene, C(O)C 1-10 Alkylene O, C(O)C 1-10 Alkylene NR 7 , OC 1-10 Alkylene C(O) and NR 7 C 1-10 alkylene C(O), and each alkylene, alkenylene and alkynylene is independently and optionally substituted by C 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 One or two of the heteroarylene groups are interrupted, and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene group is independently and optionally selected from halogen, CO 2 H, OH, C 1-4 Alkyl and OC 1-4 alkyl, wherein all alkyl groups are optionally further substituted by halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 In some embodiments, L comprises 1 to 20 independently selected C 1-10 Alkylene O, C 1-10 Alkylene NR 7 , OC 1-6 Alkylene, NR 7 C 1-10 Alkylene, C(O)C 1-10 Alkylene O, C(O)C 1-10 Alkylene NR 7 , OC 1-10 Alkylene C(O) and NR 7 C 1-10 alkylene C(O), and each alkylene, alkenylene and alkynylene is independently and optionally substituted by C 3-10 Cycloalkylene and C 4-10 One or two of the heterocycloalkylene groups are interrupted, and each alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene group is independently and optionally selected from F, Cl, CO 2 H, OH, C 1-4 Alkyl and OC 1-4 alkyl, wherein all alkyl groups are optionally further substituted by halogen, CO 2 H, OH, NH 2 、NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4In some embodiments, L comprises 1 to 20 independently selected C 1-10 Alkylene O, C 1-10 Alkylene NR 7 , OC 1-10 Alkylene, NR 7 C 1-10 Alkylene, C(O)C 1-10 Alkylene O, C(O)C 1-10 Alkylene NR 7 , OC 1-10 Alkylene C(O) and NR 7 C 1-10 In some embodiments, L comprises 1 to 20 independently selected C 1-10 Alkylene O, C 1-10 Alkylene NR 7 、C(O)C 1-10 Alkylene O and C(O)C 1-10 Alkylene NR 7 In some embodiments, L comprises 1 to 20 independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 In some embodiments, L comprises 1 to 15 independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 In some embodiments, L comprises 1 to 10 independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 In some embodiments, L comprises 2 to 10 independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 In some embodiments, L comprises 2 to 7 independently selected from C 1-6 Alkylene O, C 1-6Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 In some embodiments, L comprises 2 to 5 independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 The group.

[0162] In some embodiments, L comprises 1 to 18 groups, 1 to 15 groups, 1 to 10 groups, 1 to 8 groups, 1 to 6 groups, 1 to 5 groups, 1 to 4 groups, 1 to 3 groups, 2 to 10 groups, 2 to 7 groups, 2 to 5 groups, 2 to 4 groups, or 2 to 3 groups. In some embodiments, L comprises 1 to 18 groups, 1 to 15 groups, 1 to 10 groups, 1 to 8 groups, 1 to 6 groups, 1 to 5 groups, 1 to 4 groups, or 1 to 3 groups. In some embodiments, L comprises 1 to 10 groups, 1 to 8 groups, 1 to 6 groups, 1 to 5 groups, 1 to 4 groups, or 1 to 3 groups. In some embodiments, L contains 1 to 8 groups, 1 to 7 groups, 1 to 6 groups, 1 to 5 groups, 1 to 4 groups, 1 to 3 groups, 2 to 8 groups, 2 to 7 groups, 2 to 5 groups, 2 to 4 groups, or 2 to 3 groups. In some embodiments, L contains 2 to 7 groups or 2 to 5 groups.

[0163] In some embodiments, L comprises 1 to 6 C 1-6 Alkylene NR 7 group, and each C 1-6 Alkylene NR 7 In some embodiments, L comprises 1 to 6 C 2-6 Alkylene NR 7 group, and each C 2-6 Alkylene NR 7 The groups are the same or different. In some embodiments, L is C 2-6 Alkylene NR 7 –C 2-6 Alkylene NR 7 In some embodiments, L comprises 2 to 6 C 2-5 Alkylene NR 7 group, and each C 2-5 Alkylene NR 7 In some embodiments, L comprises 2 to 4 C2-5 Alkylene NR 7 group, and each C 2-5 Alkylene NR 7 The groups are the same or different. In some embodiments, L is C 2-5 Alkylene NR 7 –C 2-5 Alkylene NR 7 In some embodiments, L comprises 2 to 4 C 3 Alkylene NR 7 group, and each C 3 Alkylene NR 7 In some embodiments, L comprises 2 C 3 Alkylene NR 7 group, and each C 3 Alkylene NR 7 The groups are the same or different. In some embodiments, L is C 3 Alkylene NR 7 –C 3 Alkylene NR 7 .

[0164] In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O), R 4 Selected from H and C 1-4 alkyl, and L is (C 3 Alkylene NR 7 ) n , and n is an integer selected from 2 to 4. In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O), R 4 Selected from H and CH 3 , and L contains 2 to 4 C 3 Alkylene NR 7 group, and each C 3 Alkylene NR 7 In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O), R 4 Selected from H and CH 3 , and L is C 3 Alkylene NR 7 –C 3 Alkylene NR 7 In some embodiments, X is selected from CH 2, O, S, NR 4 and NR 4 C(O), and L is C 3 Alkylene NR 7 –C 3 Alkylene NR 7 .

[0165] In some embodiments, L comprises 3 to 10 independently selected from C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C 1-6 In some embodiments, L contains 1 to 4 C 1-6 Alkylene NR 7 group and each C 1-6 Alkylene NR 7 The groups are the same or different, 1 or 2 C(O)C 1-6 Alkylene O group and each C(O)C 1-6 The alkylene O groups are the same or different and have 1 to 4 C 1-6 Alkylene O, and each C 1-6 The alkylene O groups are the same or different. In some embodiments, L comprises 3 C 1-6 Alkylene NR 7 group and each C 1-6 Alkylene NR 7 The groups are the same or different, 1 C(O)C 1-6 Alkylene O and 1 C 1-6 In some embodiments, L is (C 1-6 Alkylene NR 7 ) 2 –C(O)C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, L is (C 3 Alkylene NR 7 ) 2 –C(O)C 1 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 .

[0166] In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O), and L contains 1 to 4 C 1-6 Alkylene NR 7 group and each C1-6 Alkylene NR 7 The groups are the same or different, 1 or 2 C(O)C 1-6 Alkylene O group and each C(O)C 1-6 The alkylene groups are the same or different and have 1 to 4 C 1-6 Alkylene O and each C 1-6 The alkylene O groups are the same or different. In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O), R 4 Selected from H and C 1-4 Alkyl, and L is C 1-6 Alkylene NR 7 –C 1-6 Alkylene NR 7 –C(O)C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, X is selected from CH 2 , O, S and NR 4 , R 4 Selected from H and CH 3 , and L is C 1-6 Alkylene NR 7 –C 1-6 Alkylene NR 7 –C(O)C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, X is NR 4 , R 4 Selected from H and CH 3 , and L is (C 3 Alkylene NR 7 ) 2 –C(O)C 1 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 .

[0167] In some embodiments, L comprises 3 to 8 independently selected from C(O)C 1-6 Alkylene O, C 1-6 Alkylene O and C 1-6 Alkylene NR 7 In some embodiments, L comprises 1 or 2 C(O)C 1-6 Alkylene O group and each C(O)C 1-6The alkylene O groups are the same or different, 1 or 2 C 1-6 Alkylene O group and each C 1-6 The alkylene O groups are the same or different and 1 or 2 C 1-6 Alkylene NR 7 group and each C 1-6 Alkylene NR 7 In some embodiments, L comprises 1 C(O)C 1-6 Alkylene O, 1 C 1-6 Alkylene O and 1 C 1-6 Alkylene NR 7 In some embodiments, L is C(O)C 1-6 Alkylene O–C 1-6 Alkylene OC 1-6 Alkylene NR 7 .

[0168] In some embodiments, X is NR 4 C(O), R 4 It is C 1-6 Alkylene NR 5 R 6 , and L is C(O)C 1-6 Alkylene O–C 1-6 Alkylene OC 1-6 Alkylene NR 7 In some embodiments, X is NR 4 , R 4 It is C 1-6 Alkylene NR 5 R 6 , and L is C(O)C 1-6 Alkylene O–C 1-6 Alkylene OC 1-6 Alkylene NR 7 .

[0169] In some embodiments, L comprises 3 to 10 independently selected from C 1-6 Alkylene O and C 1-6 Alkylene NR 7 In some embodiments, L contains 1 to 8 C 1-6 Alkylene O group and each C 1-6 The alkylene O groups are the same or different and 1 or 2 C 1-6 Alkylene NR 7 group and each C 1-6 Alkylene NR 7 In some embodiments, L comprises 2 to 6 C 1-6 Alkylene O group and each C 1-6The alkylene O groups are the same or different and 1 or 2 C 1-6 Alkylene NR 7 group and each C 1-6 Alkylene NR 7 The groups are the same or different. In some embodiments, L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, L is C 2 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 In some embodiments, L is C 1 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 .

[0170] In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O), R 4 Selected from H, C 1-4 Alkyl and C 1-6 Alkylene NR 5 R 6 , and L contains 2 to 6 C 1-6 Alkylene O group and each C 1-6 The alkylene O groups are the same or different and 1 or 2 C 1-6 Alkylene NR 7 group and each C 1-6 Alkylene NR 7 The groups may be the same or different.

[0171] In some embodiments, X is selected from CH 2 , O, S, NR 4 and NR 4 C(O), R 4 Selected from H and C 1-4 Alkyl, and L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, X is NR 4 , R 4 Selected from H and C 1-4 Alkyl, and L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, X is NR 4 or NR 4 C(O), R 4 Selected from H and CH 3 , and L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 or C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, X is NR 4 or NR 4 C(O), R 4 Selected from H and CH 3 , and L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, X is NR 4 , R 4 Selected from H and CH 3 , and L is C 2 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 In some embodiments, X is NR 4 C(O), R 4 Selected from H and CH 3 , and L is C 1 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 .

[0172] In some embodiments, X is selected from NR 4 and NR 4 C(O), R 4 It is C 1-6 Alkylene NR 5 R 6 , and L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 In some embodiments, X is NR 4 , R 4 It is C 1-6 Alkylene NR 5 R 6 , and L is C 2 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 In some embodiments, X is NR 4 C(O), R 4 It is C 1-6 Alkylene NR 5 R 6 , and L is C 1 Alkylene O–C 2 Alkylene O–C 2 Alkylene NR 7 .

[0173] In some embodiments, R 7 and R 8 Independently selected from H and C 1-4 In some embodiments, R 7 and R 8 Independently selected from H and CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 In some embodiments, R 7 and R 8 Independently selected from H and CH 3 .

[0174] In some embodiments, E is any chelating group capable of binding and / or complexing with metal ions. In some embodiments, E is any chelating group capable of binding and / or complexing with metal ions to form a heterocyclic ring comprising metal ions. In some embodiments, E is any chelating group derived from a chelating agent known in the art, for example, as disclosed in Banerjee et al., Nucl. Med. Biol., 2005, 32, 1-20, Wadas et al., Chem. Rev., 2010, 110, 2858-2902, U.S. Patent Nos. 5,367,080, 5,364,613, 5,021,556, 5,075,099 and 5,886,142.

[0175] Thus, in some embodiments, E is a chelating group derived from a chelating agent. In some embodiments, the chelating agent is selected from a cyclic or acyclic bifunctional chelating agent capable of binding and / or complexing with one or more radionuclides. In some embodiments, the chelating agent is selected from 1,4,7-triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic acid-N',N"-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic acid-N',N"-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N',N"-tri(methylenephosphonic) acid (NOTP); 1,4,7,10-tetraazacyclododecane (

[12] aneN4) (cyclen); 1,4,7,10-tetraazacyclotridecane (

[13] aneN4) ; 1,4,7,11-tetraazacyclotetradecane (isocyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecane-1-yl) acetate (DO1A); 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid (DO2A); 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP); 1,4,7,1 0-Tetraazacyclododecane-1,7-di(methylphosphonic acid) (DO2P); 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methylphosphonic acid) (DO3P); 1,4,7,10-tetraazacyclodecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-tetraazacyclotetradecane (

[14] aneN4) (cyclam); 1,4,8,12-tetraazacyclopentadecane (

[15] aneN4); 1,5,9,13-tetraazacyclohexadecane ([ 16]aneN4); 1,4-ethano-1,4,8,11-tetraazacyclotetradecane (et-cyclam); 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A); 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A); 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexaazabicyclo[6.6.6] Eicosane (Sar); 1,4,7,10-tetrakis-(2-carbamoyl-methyl)-cyclododecane (TCMC); N,N′-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine and its derivatives; porphyrin and its derivatives. In some embodiments, the chelating agent is selected from DOTA, DOTAGA and NOTA. In some embodiments, the chelating agent is NOTA. In some embodiments, the chelating agent is selected from DOTA and DOTAGA. In some embodiments, the chelating agent is DOTA. .

[0176] One skilled in the art will recognize that "chelating group derived from a chelating agent" as used herein refers to the chelating agent derivative formed after the chelating agent is attached to a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, e.g., to L. For example, a "chelating group derived from a chelating agent" can be a chelating agent without an "-OH" (or an ester thereof) available carboxyl group (or an ester thereof) on the chelating agent, a chelating agent without an "H" moiety available amino group on the chelating agent, a chelating agent without an "NCS" moiety available isothiocyanate group on the chelating agent, a chelating agent without an "H" moiety available maleimide group on the chelating agent, a chelating agent after an available acetylene group on the chelating agent has been reacted to attach to a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, or a chelating agent after an available tetrazole group on the chelating agent has been reacted to attach to a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof. For example, one skilled in the art will recognize that when E is a chelating group derived from DOTA, one "-OH" is removed from one of the four available carboxyl groups on DOTA to form a connection, such as an amide bond, to L in the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, to leave three available carboxyl groups.

[0177] In some embodiments, the one or more radionuclides are radioisotopes of C, N, F, S, Br, Ru, Pd, Tc, Ga, In, Zn, Gd, Bi, At, Cu, Pb, Fe, Ti, F, I, Y, Sr, Ra, P, Re, Sc, Zr, Rh, Pt, Rb, Au, Sn, Tl, Co, Pm, lanthanides, or actinides.

[0178] In some embodiments, the lanthanide is Lu, Sm, Pm, Ho, or Tb.

[0179] In some embodiments, the actinide is Ac or Th.

[0180] In some embodiments, the one or more radionuclides are selected from 14 C. 15 N. 18 F.75 Br、 76 Br、 77 Br、 123 OF, 124 OF, 125 OF, 131 OF, 35 S、 99 Tc、 99m Tc、 188 Re、 186 Re、 153 Sm、 67 Ga、 68 Ga、 111 Through, 59 Fe、 63 Zn、 52 Fe、 45 Water, 60 Cu、 61 Cu、 67 Cu、 64 Cu、 62 Cu、 82 Rb、 195m Pt、 191m Pt、 193m Pt、 117m Sn、 89 Zr、 177 Head, 18 F、 123 OF, 188 Re、 186 Re、 153 Sm、 66 You、 86 Y、 87 Y、 90 Y、 89 Sr、 111 Through, 153 Gd、 225 Ac、 212 Bi、 213 Bi、 211 And、 198 Shout, 199 Shout, 193m Pt、 197 Pt、 103 Pd、 109 Pd、 105 Rh、 103m Rh、 223 Ra、 224 Ra、 97 Ru、 227 Th、 229 Th、 32 P、 161 Tb、33 P. 149 Tb, 125 I. 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co. 55 Co. 47 Sc, 149 Pm and 161 Ho.

[0181] In some embodiments, the one or more radionuclides are used for imaging or for therapy.

[0182] In some embodiments, the one or more radionuclides used for imaging are selected from 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F and 123 I.

[0183] In some embodiments, the one or more radionuclides used for treatment are selected from 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 60 Cu, 61Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 161 Tb, 32 P. 33 P. 125 I. 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co. 47 Sc, 149 Pm and 161 Ho.

[0184] In some embodiments, the one or more radionuclides used for treatment are selected from 177 Lu, 212 Pb and 225 Ac. In some embodiments, the one or more radionuclides used for treatment are 177 Lu.

[0185] In some embodiments, the compound of Formula I is selected from the following list of compounds:

[0186]

[0187]

[0188]

[0189]

[0190] or a pharmaceutically acceptable salt and / or solvate thereof.

[0191] The chelate binding group is capable of binding and / or complexing with a radionuclide. Thus, in some embodiments, the compound of Formula I further comprises a radionuclide complexed with a chelate binding group.

[0192] Therefore, the present application also includes radionuclide complexes (radioligands) or pharmaceutically acceptable salts and / or solvates thereof, which contain the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof, and one or more radionuclides.

[0193] In some embodiments, the radionuclide is selected from transition metals, rare earth metals, lanthanides, actinides, and metalloids.

[0194] In some embodiments, the one or more radionuclides are radioisotopes of C, N, F, S, Br, Ru, Tc, Ga, In, Zn, Gd, Bi, At, Cu, Pb, Fe, Ti, F, I, Y, Sr, Ra, P, Re, Sc, Zr, Rh, Pt, Rb, Au, Sn, Tl, Co, Pm, lanthanides, or actinides.

[0195] In some embodiments, the lanthanide is Lu, Sm, Ho, or Tb.

[0196] In some embodiments, the actinide is Ac or Th.

[0197] In some embodiments, the radionuclide is selected from 225 Ac, 226 Ac, 228 Ac, 105 Ag, 106 mAg, 110 mAg, 111 Ag, 112 Ag, 113 Ag, 239 Am, 240 Am, 242 Am, 244 Am, 37 Ar, 71 As, 72 As, 73 As, 74 As, 76 As, 77 As, 209 At 210 At 191 Au, 192 Au, 193 Au, 194 Au, 195 Au, 196 Au, 196 m 2 Au, 198 Au, 198 mAu, 199 Au, 200 mAu, 128 8.131 Well, 133 mBa, 135 mBa, 140 Well, 7 Be、 203 Yes, 204 Yes, 205 Yes, 206 Yes, 210 Yes, 212 Yes, 243 Bk、 244 Bk、 245 Bk、 246 Bk、 248 mBk、 250 Bk、 76 Br、 77 Br、 80 mBr、 82 Br、 11 C、 14 C、 45 That, 47 That, 107 CD, 115 CD, 115 mCd、 117 mCd、 132 What, 133 What? 134 What, 135 What, 137 What, 137 What? 139 What, 141 What, 143 What, 144 What, 246 See, 247 See, 253 See, 254 See, 240 Cm、 241 Cm、 242 Cm、 252 Cm、 55 Who, 56 Who, 57 Who, 58 Who, 58 mCo, 60 Who, 48 Cr、 51 Cr、 127 Cs, 129 Cs, 131 Cs, 132 Cs, 136 Cs, 137 Cs, 61 With,62 With, 64 With, 67 With, 153 Dy, 155 Dy, 157 Dy, 159 Dy, 165 Dy, 166 Dy, 160 Err, 161 Err, 165 Err, 169 Err, 171 Err, 172 Err, 250 Yes, 251 Yes, 253 Yes, 254 Yes, 254 mEs, 255 Yes, 256 mEs, 145 I, 146 I, 147 I, 148 I, 149 I, 150 my, 152 my, 156 I, 157 I, 52 Fe、 59 Fe、 251 Fm, 252 Fm, 253 Fm, 254 Fm, 255 Fm, 257 Fm, 66 Ga、 67 Ga、 68 Ga、 72 Ga、 73 Ga、 146 Gd、 147 Gd、 149 Gd、 151 Gd、 153 Gd、 159 Gd、 68 Ge、 69 Ge、 71 Ge、 77 Ge、 170 Hf、 171 Hf、 173 Hf、 175 Hf、 179m2 Hf、 180m Hf、 181 Hf、 184 Hf、192 Hg、 193 Hg、 193 mHg、 195 Hg、 195 mHg、 197 Hg、 197 mHg、 203 Hg、 160m You、 166 You、 167 You、 123 OF, 124 OF, 126 OF, 130 OF, 132 OF, 133 OF, 135 OF, 109 Through, 110 Through, 111 Through, 114m Through, 115m Through, 184 They、 185 They、 186 They、 187 They、 188 They、 189 They、 190 They、 190 m 2 They、 192 They、 193 mIr、 194 They、 194 m 2 They、 195 mIr、 42 K、 43 K、 76 Kr、 79 Kr、 81 mKr、 85 mKr、 132 Get, 133 Get, 135 Get, 140 Get, 141 Get, 262 Lr、 169 Head, 170 Head, 171 Head, 172 Head, 174 mLu、 176 mLu、 177 Head, 177 mLu、 179 Head, 257 Md、 258 Md、 260 Md、 28Mg、 52 Mn、 90 Mold, 93 mMo、Mo、 13 N、 24 And、 90 Nb、 91 mNb、 92 mNb、 95 Nb、 95 mNb、 96 Nb、 138 Nd、 139 mNd、 140 Nd、 147 Nd、 56 Nor, 57 Nor, 66 Nor, 234 Np、 236 mNp、 238 Np、 239 Np、 15 O、 182 Os、 183 Os、 183 mOs、 185 Os、 189 mOs、 191 Os、 191 mOs、 193 Os、 32 P、 33 P、 228 Pa、 229 Pa、 230 Pa、 232 Pa、 233 Pa、 234 Pa、 200 Pb、 201 Pb、 202 mPb、 203 Pb、 209 Pb、 212 Pb、 100 Pd、 101 Pd、 103 Pd、 109 Pd、 111 mPd、 112 Pd、 143 Pm、 148 Pm、 148 mPm、 149 Pm、 151 Pm、 204 Month, 206 Month, 207 Month, 210 Month, 139 Pr、 142Pr、 143 Pr、 145 Pr、 188 Pt、 189 Pt、 191 Pt、 193 mPt、 195 mPt、 197 Pt、 200 Pt、 202 Pt、 234 Pu、 237 Pu、 243 Pu、 245 Pu、 246 Pu、 247 Pu、 223 Ra、 224 Ra、 225 Ra、 81 Rb、 82 Rb、 82 mRb、 83 Rb、 84 Rb、 86 Rb、 181 Re、 182 Re、 182 mRe、 183 Re、 184 Re、 184 mRe、 186 Re、 188 Re、 189 Re、 190 mRe、 99 Rh、 99 mRh、 100 Rh、 101 mRh、 102 Rh、 103 mRh、 105 Rh、 211 Rn、 222 Rn、 97 Ru、 103 Ru、 105 Ru、 35 S、 118 mSb、 119 Sb、 120 Sb、 120 mSb、 122 Sb、 124 Sb、 126 Sb、 127 Sb、 128 Sb、 129 Sb、 43 Sc、 44 Sc、 44 mSc、 46Sc、 47 Sc、 48 Sc、 72 Se、 Se、 73 Se、 Se、 75 Se、 Se、 153 Sm、 156 Sm、 110 Sn、 113 Sn、 117 mSn、 119 mSn、 121 Sn、 123 Sn、 125 Sn、 82 Sr、 83 Sr、 85 Sr、 89 Sr、 91 Sr、 173 Belong, 175 Belong, 176 Belong, 177 Belong, 180 Belong, 182 Belong, 183 Belong, 184 Belong, 149 Tb、 150 Tb、 151 Tb、 152 Tb、 153 Tb、 154 Tb、 154 mTb、 154 m 2 Tb、 155 Tb、 156 Tb、 156 mTb、 156 m 2 Tb、 160 Tb、 161 Tb、 94 Tc、 95 Tc、 95 mTc、 96 Tc、 97 mTc、 99 mTc、 118 Little, 119 Little, 119 mTe、 121 Little, 121 mTe、 123 mTe、 125 mTe、 127 Little, 127 mTe、 129 mTe、 131 mTe、 132 Little, 227Th, 231 Th, 234Th , 45 Ti, 198 TI, 199 TI, 200 TI, 201 TI, 202 TI, 204 TI, 165 Tm, 166 Tm, 167 Tm, 168 Tm, 170 Tm, 172 Tm, 173 Tm, 230 U. 231 U. 237 U. 240 U. 48 V. 178 W. 181 W. 185 W. 187 W. 188 W. 122 Xe, 125 Xe, 127 Xe, 129 mXe, 131 mXe, 133 Xe, 133 mXe, 135 Xe, 85 mY, 86 Y. 87 Y. 87 mY, 88 Y. 90 Y. 90 mY, 91 Y. 92 Y. 93 Y. 166 Yb, 169 Yb, 175 Yb, 62 Zn, 65 Zn, 69 mZn, 71 mZn, 72 Zn, 86 Zr, 88 Zr, 89 Zr, 95 Zr and 97 Zr.

[0198] In some embodiments, the one or more radionuclides are selected from 14 C. 15 N. 18 F.75 Br、 76 Br、 77 Br、 123 OF, 124 OF, 125 OF, 131 OF, 35 S、 99 Tc、 99m Tc、 188 Re、 186 Re、 153 Sm、 67 Ga、 68 Ga、 111 Through, 59 Fe、 63 Zn、 52 Fe、 45 Water, 60 Cu、 61 Cu、 67 Cu、 64 Cu、 62 Cu、 82 Rb、 195m Pt、 191m Pt、 193m Pt、 117m Sn、 89 Zr、 177 Head, 18 F、 123 OF, 188 Re、 186 Re、 153 Sm、 66 You、 86 Y、 87 Y、 90 Y、 89 Sr、 111 Through, 153 Gd、 225 Ac、 212 Bi、 213 Bi、 211 And、 198 Shout, 199 Shout, 193m Pt、 197 Pt、 103 Pd、 109 Pd、 105 Rh、 103m Rh、 223 Ra、 224 Ra、 97 Ru、 227 Th、 229 Th、 32 P、 161 Tb、33 P. 149 Tb, 125 I. 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co. 55 Co. 47 Sc, 149 Pm and 161 Ho.

[0199] In some embodiments, the one or more radionuclides are used for imaging or diagnosis, or for therapy.

[0200] In some embodiments, the one or more radionuclides used for imaging or diagnosis are selected from 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F. 203 Pb and 123 I. In some embodiments, the one or more radionuclides used for imaging or diagnosis are selected from 68 Ga, 111 In and 89 Zr.

[0201] In some embodiments, the one or more radionuclides used for treatment are selected from 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y. 89 Sr. 111 In,153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 161 Tb, 32 P. 33 P. 125 I. 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co. 47 Sc, 149 Pm and 161 Ho.

[0202] In some embodiments, the radionuclide used for treatment is selected from 177 Lu, 153 Sm, 212 Pb, 90 Y and 225 Ac. In some embodiments, the one or more radionuclides used for treatment are 177 In some embodiments, the one or more radionuclides used for treatment are 225 Ac.

[0203] Applicants have surprisingly discovered that modification of the amide group, such as removal of the carbonyl group from the amide group to attach the diamine moiety directly to the remainder of the structure of the known neurotensin antagonist compound SR 142948 (C-3), results in improved potency of the antagonist. For example, Applicants have shown that structurally very similar derivatives of SR142948 having an amino bond instead of an amide bond (e.g., without a carbonyl group) exhibited greater than a 10-fold improvement in activity, see Table 1. Thus, derivatives of compound SR142948 that do not contain a directly attached carbonyl group are useful as neurotensin receptor antagonists with improved inhibition of neurotensin receptors (e.g., NTR1) compared to SR142948. Such derivatives of compound SR 142948 are also useful as intermediates in the process for preparing compounds of Formula I.

[0204] Therefore, the present application further includes compounds of formula II or pharmaceutically acceptable salts and / or solvates thereof

[0205]

[0206] in

[0207] R 9 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0208] R 10 Selected from H, halogen, NO 2 , C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-3 Alkylene C 3-8 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens;

[0209] R 11 Selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;

[0210] Y is selected from CH 2 , O, NR 14 , S, S(O), SO 2 NR 14 and NR 14 C(O);

[0211] R 12 and R 13 Independently selected from H and C 1-6 alkyl;

[0212] R14 Selected from H and C 1-6 Alkyl; and

[0213] n is an integer selected from 1 to 10.

[0214] In some embodiments, R 9 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens. 9 Selected from H, C 1-3 Alkyl, cyclopropyl, cyclobutyl and CH 2 Cyclopropyl and CH 2 Cyclobutyl, the latter five groups are optionally substituted by one or more halogens. 1 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, CH 2 Cyclopropyl and CH 2 cyclobutyl, each of which is optionally substituted with one or more halogens. 9 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 , cyclopropyl and CH 2 cyclopropyl, each of which is optionally substituted with one or more fluorine. 9 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 In some embodiments, R 1 Yes CH 3 .

[0215] In some embodiments, R 10 Selected from H, halogen, NO 2 , C 1-6Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens. 10 Selected from halogen, NO 2 , C 1-6 Alkyl, C 3-6 Cycloalkyl and CH 2 C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens. 10 Selected from halogen, NO 2 and C 1-6 Alkyl, the latter group is optionally substituted by one or more halogens. 10 is C optionally substituted by one or more halogens 1-6 In some embodiments, R 10 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 , optionally substituted with one or more fluorine. 10 Selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 、CH(CH 3 ) 2 In some embodiments, R 10 is CH(CH 3 ) 2 .

[0216] In some embodiments, R 11 is 2-amino-2-adamantanecarboxylic acid. In some embodiments, R 11 is cyclohexylglycine. In some embodiments, R 11 is 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid. In some embodiments, R 11 is a group having the formula

[0217]

[0218] In some embodiments, the compound of Formula II is a compound of Formula II-A or a pharmaceutically acceptable salt and / or solvate thereof

[0219]

[0220] Among them, Y, R 12 , R 13 and n are as defined in Formula II.

[0221] In some embodiments, Y is selected from CH 2 , O, S, NR 14 and NR 14 C(O). In some embodiments, Y is CH 2 In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is NR 14 In some embodiments, Y is NR 14 C(O). In some embodiments, R 14 Selected from H and C 1-4 In some embodiments, R 14 Selected from H and CH 3 .

[0222] In some embodiments, Y is S and the compound of Formula II is a compound of Formula II-B or a pharmaceutically acceptable salt and / or solvate thereof

[0223]

[0224] Where R 9 , R 10 , R 11 , R 12 , R 13 and n are as defined in Formula II.

[0225] In some embodiments, R 12 and R 13 Independently selected from H and C 1-4 In some embodiments, R 12 and R 13 Selected from H and CH 3 In some embodiments, R 12 and R 13 are all H. In some embodiments, R 12 and R 13 One is H and the other is CH 3 In some embodiments, R 12 and R 13 All CH 3 .

[0226] In some embodiments, n is an integer selected from 2 to 10. In some embodiments, n is an integer selected from 2 to 9. In some embodiments, n is an integer selected from 2 to 8. In some embodiments, n is an integer selected from 2 to 7. In some embodiments, n is an integer selected from 2 to 6. In some embodiments, n is an integer selected from 2 to 5. In some embodiments, n is an integer selected from 2 to 4. In some embodiments, n is an integer selected from 2 to 3. In some embodiments, n is an integer selected from 1 to 5. In some embodiments, n is an integer selected from 2 to 5. In some embodiments, n is an integer selected from 1 to 4. In some embodiments, n is 3. In some embodiments, n is 4.

[0227] In some embodiments, the compound of Formula II is selected from the following list of compounds:

[0228]

[0229]

[0230] or a pharmaceutically acceptable salt and / or solvate thereof.

[0231] In one embodiment, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of suitable salts can be made by one skilled in the art (see, for example, SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19).

[0232] III. Methods and Uses of the Present Application

[0233] The present application also includes a method for treating a disease, disorder or condition, comprising administering a therapeutically effective amount of one or more compounds or complexes of the present application to a subject in need thereof. The present application also includes the use of one or more compounds or complexes of the present application for treating a disease, disorder or condition, and the use of one or more compounds or complexes of the present application for preparing a therapeutic agent for a disease, disorder or condition. The present application further includes one or more compounds or complexes of the present application for treating a disease, disorder or condition.

[0234] Applicants have shown that the compounds of the present application have high binding affinity for neurotensin receptors, such as neurotensin receptor 1 (NTR1). Therefore, the compounds of the present application that interact with neurotensin receptors can be used as neurotensin receptor targeting compounds. NTR1 has been found to be highly expressed in several tumor cells and tumor indications.

[0235] Therefore, the present application includes a method of treating a disease, disorder or condition associated with a neurotensin receptor in a cell, comprising administering to the cell an effective amount of one or more compounds or complexes of the present application or a pharmaceutically acceptable salt and / or solvate thereof.

[0236] The present application also includes the use of one or more compounds or complexes of the present application or pharmaceutically acceptable salts and / or solvates thereof for treating diseases, disorders or conditions associated with neurotensin receptors in cells, and the use of one or more compounds or complexes of the present application or pharmaceutically acceptable salts and / or solvates thereof for preparing therapeutic agents for diseases, disorders or conditions associated with neurotensin receptors in cells. The present application further includes one or more compounds or complexes of the present application or pharmaceutically acceptable salts and / or solvates thereof for treating diseases, disorders or conditions associated with neurotensin receptors in cells.

[0237] In some embodiments, the neurotensin receptor is neurotensin receptor-1 (NTR1).

[0238] In one embodiment, the neurotensin receptor target of the neurotensin receptor binding group of the compound or complex is present on diseased cells. Indeed, the presence and / or overexpression of neurotensin receptors on the cell surface is a hallmark of many disease-associated cells, including cancer cells. Thus, in another embodiment, the neurotensin receptor target of the neurotensin receptor binding group is present on cancer cells, and the disease or disorder is cancer.

[0239] In one embodiment, the disease, disorder or condition associated with the neurotensin receptor is cancer.

[0240] In one embodiment, the cancer is selected from, but is not limited to, acute lymphoblastic leukemia in adults; acute lymphoblastic leukemia in children; acute myeloid leukemia in adults; adrenocortical carcinoma; adrenocortical carcinoma in children; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; cerebellar astrocytoma in children; cerebral astrocytoma in children; extrahepatic bile duct cancer; bladder cancer; bladder cancer in children; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma in children; brain tumors in adults; brain tumors, brain stem glioma, children; brain tumors, cerebellar astrocytoma, children; brain tumors, brain astrocytoma / malignant glioma, children; brain tumors, ependymoma, children; brain tumors, medulloblastoma, children; brain tumors, supratentorial primitive neuroectodermal tumors, children; brain tumors, visual pathway and hypothalamic gliomas, children; brain tumors, children (other); breast cancer; breast cancer and Pregnancy); breast cancer in children; breast cancer in men; bronchial adenoma / carcinoid in children; carcinoid tumor in children; carcinoid tumor in the gastrointestinal tract; adrenocortical carcinoma; islet cell carcinoma; carcinoma of unknown primary site; primary central nervous system lymphoma; cerebellar astrocytoma in children; cerebral astrocytoma / malignant glioma in children; cervical cancer; cancer in children; chronic lymphocytic leukemia; chronic myeloid leukemia; chronic myeloproliferative disease; clear cell sarcoma of the tenosynovium; colon cancer; colorectal cancer in children; skin T-cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Ovarian Epithelial Cancer; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic cell tumors; glioma, brainstem, children; glioma, visual pathway and hypothalamus, children; hairy cell leukemia; head and neck cancer; hepatocellular (liver) cancer, adult (primary); hepatocellular (liver) cancer, child (primary); Hodgkin lymphoma, adult; Hodgkin lymphoma, child; Hodgkin lymphoma, pregnancy; hypopharyngeal cancer; glioma, hypothalamus and visual pathway, children; intraocular melanoma; islet cell carcinoma (endocrine pancreas); Kaposi's sarcoma; kidney cancer; laryngeal cancer; laryngeal cancer, child; acute lymphoblastic leukemia, adult; acute Lymphocytic leukemia; acute myeloid leukemia, adult; acute myeloid leukemia, childhood; chronic lymphocytic leukemia; chronic myeloid leukemia; hairy cell leukemia; cancer of the lip and oral cavity; liver cancer, adult (primary); liver cancer, childhood (primary); non-small cell lung cancer; small cell lung cancer; lymphocytic leukemia, adult acute; lymphocytic leukemia, childhood acute; lymphocytic leukemia, chronic; AIDS-related lymphoma; lymphoma of the central nervous system (primary); cutaneous T-cell lymphoma;Hodgkin's lymphoma, adult; Hodgkin's lymphoma, childhood; Hodgkin's lymphoma; Hodgkin's lymphoma, pregnancy; Non-Hodgkin's lymphoma, adult; Non-Hodgkin's lymphoma, childhood; Non-Hodgkin's lymphoma, pregnancy; Primary central nervous system lymphoma; Waldenstrom's macroglobulinemia; Male breast cancer; Malignant mesothelioma, adult; Malignant mesothelioma, childhood; Malignant thymoma; Medulloblastoma, childhood; Melanoma; Melanoma, intraocular; Merkel cell carcinoma; Malignant mesothelioma; Squamous neck carcinoma with occult metastatic primary; Multiple endocrine neoplasia syndrome, childhood; Multiple myeloma / plasma cell neoplasms; Mycosis fungoides; Myelodysplastic syndrome; Myeloid leukemia, chronic; Myeloid leukemia, childhood Acute, childhood; Multiple myeloma; Chronic myeloproliferative disorders; Nasal and paranasal sinus cancer; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, childhood; Neuroblastoma; Non-Hodgkin lymphoma, adult; Non-Hodgkin lymphoma, childhood; Non-Hodgkin lymphoma, pregnancy; Non-small cell lung cancer; Oral cancer, childhood; Oral and lip cancer; Oropharyngeal cancer; Osteosarcoma / malignant fibrous histiocytoma of bone; Ovarian cancer, childhood; Ovarian epithelial cancer; Ovarian germ cell tumor; Ovarian tumor of low malignant potential; Pancreatic cancer; Pancreatic cancer, childhood; Islet cell pancreatic cancer; Paranasal sinus and nasal cavity cancer; Parathyroid cancer; Penile cancer; Pheochromocytoma; Pineal and supratentorial primitive neuroectodermal tumors, childhood; Pituitary tumors; Plasmacytoma / multiple myeloma; Pleuropulmonary blastoma; Pregnancy Breast cancer, stage II; Hodgkin lymphoma, pregnancy; Non-Hodgkin lymphoma, pregnancy; Primary central nervous system lymphoma; Primary liver cancer, adults; Primary liver cancer, children; Prostate cancer; Rectal cancer; Renal cell (kidney) cancer; Renal cell cancer, children; Transitional cell carcinoma of the renal pelvis and ureter; Retinoblastoma; Rhabdomyosarcoma, children; Salivary gland cancer; Salivary gland cancer, children; Sarcoma, Ewing family of tumors; Kaposi's sarcoma; Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; Sarcoma, rhabdomyosarcoma, children; Sarcoma, soft tissue, adults; Sarcoma, soft tissue, children; Sezary syndrome; Skin cancer; Skin cancer, children; Skin cancer (melanoma); Skin cancer, Merkel cell; Small cell lung cancer; Small intestine cancer; Soft tissue sarcoma, adult; Soft tissue sarcoma, child; Squamous neck cancer, occult primary, metastatic; Stomach (Gastric) Cancer; Gastric cancer, child; Supratentorial primitive neuroectodermal tumor, child; Cutaneous T-cell lymphoma; Testicular cancer; Thymoma, child; Malignant thymoma; Thyroid cancer; Thyroid cancer, child; Transitional cell carcinoma of the renal pelvis and ureter; Gestational trophoblastic tumor; Cancer of unknown primary, child; Rare cancers of childhood; Ureter and renal pelvis, transitional cell carcinoma; Urethra cancer; Uterine sarcoma; Vaginal cancer; Visual pathway and hypothalamic glioma, child; Vulvar cancer; Waldenstrom's macroglobulinemia; Wilms tumor and neuroendocrine tumors. Metastases of the above cancers can also be treated according to the methods described herein. ;

[0241] In some embodiments, the cancer is a cancer associated with a neurotensin receptor. In some embodiments, the cancer is a neurotensin receptor-positive cancer. "Neurotensin receptor-positive cancer" includes cancer cells that have a higher expression of a neurotensin receptor protein or gene compared to non-cancerous cells of the same tissue type. In some embodiments, the neurotensin receptor is neurotensin receptor 1 (NTR1).

[0242] In some embodiments, the cancer, optionally a neurotensin receptor-positive cancer, is selected from colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, meningioma, Ewing's sarcoma, head and neck cancer, pleural mesothelioma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, and non-small cell lung cancer.

[0243] In some embodiments, the cancer is colorectal cancer.

[0244] In some embodiments, the cancer is pancreatic cancer.

[0245] As used herein, "treating cancer" includes, but is not limited to, reversing, alleviating or inhibiting the progression of cancer or symptoms or conditions associated with cancer. "Treating cancer" also includes extending the survival of a subject. The survival period is optionally extended by at least 1, 2, 3, 6 or 12 months, or at least 2, 3, 4, 5 or 10 years compared to the expected survival period without treatment with a compound, compound or composition as described herein. "Treating cancer" also includes reducing tumor mass and / or reducing tumors. Optionally, after treatment with a compound, compound or composition as described herein, tumor mass and / or tumor burden is reduced by at least 5%, 10%, 25%, 50%, 75% or 100%. "Treating cancer" also includes reducing the infiltrativeness, grade and / or invasiveness of a tumor.

[0246] The present application also includes a method for inhibiting proliferation activity in cells, which comprises administering an effective amount of one or more compounds or complexes of the present application to cells. The present application also includes the use of one or more compounds or complexes of the present application for inhibiting proliferation activity in cells, and the use of one or more compounds or complexes of the present application for preparing a medicament for inhibiting proliferation activity in cells. The present application further includes one or more compounds or complexes of the present application for inhibiting proliferation activity in cells. In one embodiment, the one or more compounds or complexes contain a radionuclide for treatment, optionally 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac,212 Bi, 213 Bi, 211 At 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 32 P. 147 Tb, 161 Tb, 33 P. 125 I. 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co or 161 Ho.

[0247] The present application also includes a method of imaging a subject's tissue by administering an imaging effective amount of one or more compounds or complexes of the present application for imaging to a subject in need, and applying imaging technology to detect the emitted gamma rays. The present application also includes the use of one or more compounds or complexes of the present application for imaging tissues, and the use of one or more compounds or complexes of the present application containing radionuclides for imaging for the preparation of tissue imaging agents. The present application further includes one or more compounds or complexes of the present application containing radionuclides for imaging for tissue imaging. The present application also includes a method of imaging a subject's tissue by administering a therapeutically effective amount of one or more compounds or complexes of the present application for imaging to a subject in need, and applying imaging technology to detect the emitted gamma rays. The present application also includes the use of one or more compounds or complexes of the present application for imaging tissues, and the use of one or more compounds or complexes of the present application containing radionuclides for imaging for the preparation of tissue imaging agents. The present application further includes one or more compounds or complexes of the present application containing radionuclides for imaging for tissue imaging. In some embodiments, the use further includes applying imaging technology to detect the emitted gamma rays. In one embodiment, the one or more compounds or complexes comprise a radionuclide for imaging, optionally99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F. 203 Pb or 123 I.

[0248] The present application also includes a method for diagnosing cancer in a subject, by administering a diagnostically effective amount of one or more compounds or complexes of the present application to a subject in need thereof, and applying imaging technology to detect emitted gamma rays. The present application also includes a method for diagnosing cancer in a subject, by administering a therapeutically effective amount of one or more compounds or complexes of the present application to a subject in need thereof, and applying imaging technology to detect emitted gamma rays. The present application also includes the use of one or more compounds or complexes of the present application for diagnosing cancer, and the use of one or more compounds or complexes of the present application for diagnosing cancer. The present application further includes one or more compounds or complexes of the present application containing radionuclides for imaging for use in diagnosing cancer. In some embodiments, the use further includes applying imaging technology to detect emitted gamma rays. In one embodiment, the one or more compounds or complexes contain radionuclides for imaging, optionally 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu,64 Cu, 62 Cu, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F or 123 I.

[0249] In some embodiments, diagnosing cancer comprises identifying and locating the primary tumor mass and potential local and distant metastases. In some embodiments, diagnosing cancer comprises determining tumor volume.

[0250] The present application also includes a radionuclide therapy method, which comprises administering an effective amount of one or more complexes of the present application to a subject in need thereof.

[0251] The present application also includes the use of one or more complexes of the present application for radionuclide therapy, or the use of one or more complexes of the present application for preparing radionuclide therapy agents.

[0252] The present application also includes a therapeutic diagnostic treatment method, which comprises administering an effective amount of one or more complexes of the present application to a subject in need thereof and performing a medical diagnostic method on the subject.

[0253] The present application also includes the use of one or more of the complexes of the present application for therapeutic diagnostic treatment or the use of one or more of the complexes of the present application for the preparation of therapeutic diagnostic treatment agents. For therapeutic diagnostic treatment, the same compound of the present application is bound to both imaging radionuclides and therapeutic radionuclides, which means that the compound effectively and stably binds two different radiometals.

[0254] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In one embodiment, the subject is a non-human animal. In one embodiment, the subject is a canine. In one embodiment, the subject is a feline. Thus, the compounds, methods, and uses of the present application relate to human and veterinary diseases, disorders, and conditions.

[0255] In some embodiments, a subject in need is a subject in need of imaging. In some embodiments, a subject in need of imaging is a subject in need of diagnosis, in need of locating a location for therapeutic intervention, in need of evaluating the function of a body part, and / or in need of evaluating the presence or absence of a condition.

[0256] In some embodiments, the imaging type used in the methods of the present application is positron emission tomography (PET), single photon emission computed tomography (SPECT), radioisotope nephrography and scintigraphy. The method of carrying out such imaging technology is well known to those skilled in the art.

[0257] In some embodiments, for use in diagnostic or therapeutic methods, the one or more compounds and / or complexes are contained in a pharmaceutical composition as described above.

[0258] IV. Methods for preparing the compounds of the present application

[0259] The compound and / or complex or contrast compound of the present application can be prepared by various synthetic methods. The selection of specific structural features and / or substituents may affect the selection of a method rather than another method. It is within the capabilities of those skilled in the art to select a specific method to prepare a given compound and / or complex or contrast compound of the present application. Some starting materials for preparing the compound of the present application can be obtained from commercial chemical sources. For example, other starting materials as described below can be easily prepared by available precursors using direct conversions well known in the art.

[0260] In one embodiment, the compound of Formula I is prepared as shown in Scheme 1, wherein X is O, S or NR 4 and L contains the terminal W a , where W a It is used for NR connected with E 7 Thus, under certain conditions, for example under palladium-catalyzed coupling conditions such as Buchwald-Hartwig amination conditions, in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) and ci cyclohexyl[2′,4′,6′-tri(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane The compound of formula A is coupled with a compound of formula B (wherein PG is a protecting group) in the presence of to provide a compound of formula C, which is subsequently deprotected to provide a compound of formula D. The compound of formula D is then coupled with a compound of formula E (wherein FG is a functional group attached to the chelating group E (e.g., CO) under amide forming conditions, such as in the presence of a coupling reagent (e.g., (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU)) and a base such as an organic base (e.g., diethylamine (DIEA)). 2 H)) to provide compounds of formula I.

[0261]

[0262] One skilled in the art will recognize that in some embodiments, the compound of Formula D is a compound of Formula II, and thus, the compound of Formula II can be prepared as shown in Scheme I for the compound of Formula D.

[0263] In one embodiment, the compound of Formula I is prepared as shown in Scheme 2, wherein X is NR 4 C(O) and L contains at least one terminal W a , one of which is W a Independently for NR used in connection with E 7 Thus, under amination conditions, for example palladium-catalyzed amination conditions such as the Buchwald-Hartwig amination conditions, in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) and ci cyclohexyl[2′,4′,6′-tri(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane In the presence of 1 is a protecting group) to provide a compound of formula G, which is subsequently deprotected to provide a compound of formula H. The compound of formula H is then reacted with a compound of formula J (wherein LG is a leaving group and L' is a fragment of L) in the presence of a base such as an organic amine base to provide a compound of formula K. The compound of formula K is then reacted with a compound of formula L (wherein PG 2 is a protecting group and L" is a fragment of L) to provide a compound of formula M, which is subsequently deprotected to provide a compound of formula N. The compound of formula N is then reacted with a compound of formula O (where FG is a protecting group and L" is a fragment of L) under amide forming conditions, such as in the presence of a coupling reagent (e.g., (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU)) and a base such as an organic base (e.g., diethylamine (DIEA)) 1 is a functional group (e.g. CO 2 H)) to provide compounds of formula I.

[0264]

[0265] One skilled in the art will recognize that in some embodiments, the compound of Formula N is a compound of Formula II, and thus, the compound of Formula II can be prepared as shown in Scheme 2 for the compound of Formula N.

[0266] The starting materials in the above schemes can be purchased or synthesized using methods known in the art, for example, as described in the Examples below. In some embodiments, compounds of Formula A are synthesized using methods known in the art, for example, as described in US Pat. No. 5,723,482 or as described in the Examples below.

[0267] In some embodiments, compounds of Formula I or comparative compounds such as C-1 are prepared in whole or in part using solid phase peptide synthesis (SPPS) or solution phase coupling techniques known in the art, for example, using the synthetic procedures found in Stewart and Young, 1984, Solid Phase Synthesis, 2nd Edition, Pierce Chemical Co., Rockford, Ill.; Fields and Noble, 1990, "Solid phase peptide synthesis utilizing 9-fluorenylmethyloxycarbonylamino acids," Int. J. Pept. Protein Res. 35: 161-214; Geysen et al., 1987, J. Immunol. Methods 102: 259-274.

[0268] Thus, in some embodiments, in SPPS, an Nα-protected linking group, such as tert-butyloxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc) amino acid linking group is activated at the α-carbonyl and coupled to the deprotected Nα functionality of the solid support. If necessary, the newly added Nα-protected linking group is then deprotected and coupled to the next Nα-protected linking group until the final cleavage step. Those skilled in the art will recognize that the chemistry of the final cleavage step of coupling, deprotection, and linker from the solid support depends on the choice of the αN-protecting group. In some embodiments, cleavage is achieved by treatment with an acid, such as trifluoroacetic acid (TFA), optionally in the presence of a scavenging agent such as triisopropylsilane. In some embodiments, when the αN-protecting group is Fmoc, cleavage in the acid will also result in deprotection of the side chain.

[0269] Chelating groups can be synthesized by methods known in the art or can be purchased commercially. For example, DOTA can be obtained from Sigma-Aldrich (St. Louis, Missouri, United States).

[0270] Using known active ester chemistry (e.g., known in the art for forming amides), a chelating group such as DOTA is conjugated to a linker fragment, such as an amine on the end of a linker fragment or a linker fragment that is attached to the rest of the structure of X and / or the compound of Formula I. For example, DOTA is combined with a linker fragment comprising an amine at one end in the presence of a base such as an organic amine.

[0271] Amide bond formation conditions include any known method for coupling carboxylic acids and amines that is compatible with the intermediates and products shown in the above schemes or can be used to prepare the compounds of the present application. Known methods for preparing amides by coupling carboxylic acids and amines include using coupling reagents or by converting carboxylic acids into activated derivatives in advance. Coupling reagents include, but are not limited to, any known peptide coupling reagents, such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC)), benzotriazole tetramethyluronium hexafluorophosphate (HBT U), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), benzotriazole-1-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole-1-oxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), and propanephosphonic anhydride.

[0272] In some embodiments, racemization of the enantiomers of the carboxylic acid occurs during amide bond formation using a coupling reagent. In some embodiments, racemization is overcome with a "racemization inhibiting" additive such as the triazoles 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), and ethyl cyanohydroxyiminoacetate (Oxyma).

[0273] Nucleophilic displacement reaction conditions include any known method for the reaction of nucleophilic reagent displacement of leaving group to form a bond compatible with the intermediates and products shown in the above schemes or that can be used to prepare the compounds of the present application. In some embodiments, such conditions include combining reactants in a suitable solvent in the presence of a base.

[0274] In the whole method described herein, it is to be understood that, where appropriate, suitable protecting groups are added to various reactants and intermediates and subsequently removed in a manner readily understood by those skilled in the art. Conventional procedures using such protecting groups and examples of suitable protecting groups are described in, for example, "Protective Groups in Organic Synthesis", TW Green, PGM Wuts, Wiley-Interscience, New York, (1999).

[0275] It is also to be understood that by chemical manipulation a group or substituent is converted into another group or substituent can be carried out on any intermediate or final product on the synthetic path of the final product, wherein the possible transformation type is only subject to the inherent incompatibility of the conditions or reagents used in the transformation of other functional groups carried by the molecule at this stage. Those skilled in the art will readily understand such inherent incompatibility and the way to circumvent them by carrying out appropriate transformation and synthesis steps in the appropriate order. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited to the universal groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are also given in " Comprehensive Organic Transformations - A Guide to Functional Group Preparations " RC Larock, VHC Publishers, Inc. (1989), " Advanced Organic Chemistry ", March, the 4th edition, McGraw Hill (1992) or " Organic Synthesis ", Smith, McGraw Hill, (1994).

[0276] Techniques for purification of intermediates and final products include, for example, normal and reverse phase chromatography on columns or spinning plates, recrystallization, distillation and liquid-liquid or solid-liquid extraction, as will be readily appreciated by those skilled in the art.

[0277] The products of the methods of the present application can be isolated according to known methods, for example, the compounds can be isolated by evaporating the solvent, by filtration, centrifugation, chromatography or other suitable methods.

[0278] Typically, the above reaction is carried out in a suitable inert organic solvent at a temperature and time that optimizes the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, dichloromethane, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0279] The formation of salts of the desired compounds is achieved using standard techniques, for example, by treating the neutral compound with an acid or base in a suitable solvent and isolating the salt formed by filtration, extraction or any other suitable method.

[0280] The formation of solvates varies according to compounds and solvates. Typically, solvates are formed by dissolving the compound in a suitable solvent and separating the solvates by cooling or using an anti-solvent. Solvates are typically dried or azeotropic at ambient conditions. Selection of suitable conditions for forming a specific solvate can be performed by those skilled in the art. Examples of suitable solvents are ethanol, water, etc. When water is a solvent, the molecule is referred to as a "hydrate". The formation of solvates of the compounds of the present application varies according to compounds and solvates. Typically, solvates are formed by dissolving the compound in a suitable solvent and separating the solvates by cooling or using an anti-solvent. Solvates are typically dried or azeotropic at ambient conditions. Selection of suitable conditions for forming a specific solvate can be performed by those skilled in the art.

[0281] The prodrug of the compound of the present application can be, for example, a conventional ester formed by an available hydroxyl, thiol, amino or carboxyl group. For example, an available hydroxyl or amino group can be acylated using an activated acid in the presence of a base and optionally in an inert solvent (e.g., an acyl chloride in pyridine).

[0282] A specific enantiomer or diastereomer of a compound of the present application can be obtained by using the corresponding single enantiomer or diastereomer of the corresponding starting material.

[0283] In some embodiments, the compound of the present application is reacted with one or more radionuclides under the conditions of forming a complex. In some embodiments, the compound of the present application is reacted with a radionuclide. In some embodiments, the compound of the present application is reacted with two radionuclides. In some embodiments, the conditions for forming a complex include dissolving the compound of the present application in a suitable solvent, such as a polar solvent or a polar solvent mixture miscible with an aqueous solution, and merging the resulting solution with an aqueous solution of a salt of the desired radionuclide. In some embodiments, heat is used to promote the dissolution of the compound of the present application and / or the reaction with a radionuclide salt. In some embodiments, the resulting complex solution containing radionuclides is used within one day after preparation.

[0284] The following non-limiting examples illustrate the present application.

[0285] Example

[0286] A. Synthesis of Exemplary Compounds

[0287] General approach

[0288] Preparative HPLC conditions

[0289] A DMF solution of the crude compound was purified by reverse phase preparative HPLC (Waters DeltaPrep 4000) using a C18-reverse phase column. Mobile phase: A: 0.1% TFA H2O; B: 0.1% TFA acetonitrile (ACN). The relevant fractions were analyzed by analytical UPLC. The pure fractions were pooled and freeze dried.

[0290] LC-MS conditions

[0291] Instrument: Agilent prime-6125B_2LCMS

[0292] Column: Boltimate EXT C18 CoreShell 4.6x50mm, 2.7μm

[0293] Detection: UV (254nm 214nm 280nm) and MS (ESI, 100 to 1000amu)

[0294] Mobile phase: A: H2O (0.05% formic acid); B: ACN (0.05% formic acid)

[0295] Flow rate: 2.0mL / min

[0296] Column temperature: 45°C

[0297] Gradient: 10% to 95% B in 1.5 min, then 95% B for 1.0 min

[0298] Analytical HPLC conditions

[0299] Instrument:WATERS ARC UPLC

[0300] Column: XBridge BEH peptide BEH C18, 3.5 μm, 2.1 mm x 150 mm

[0301] Detection: UV 254nm, 214nm, 280nm

[0302] Mobile phase: A: H2O (0.1% TFA); B: ACN (0.1% TFA)

[0303] Column temperature: 40℃

[0304] Flow rate: 0.6mL / min

[0305] gradient:

[0306] Time (min) 0 1 11 13 13.5 15 A％ 90 90 5 5 90 90 B％ 10 10 95 95 10 10

[0307] Suppliers of key intermediates: tert-butyl 2-aminoadamantane-2-carboxylate was purchased from JiangSu Aikon; DOTA-tri(t-Bu ester) and 1,8-diamino-3,6-dioxaoctane were purchased from Bidepharmatech; 3,3′-diamino-N-methyldipropylamine was purchased from Adamas-beta; and N,N-bis[3-(methylamino)propyl]methylamine was purchased from Aladdin Bio-Chem.

[0308] Synthesis of Exemplary Compounds of Formula I of the Present Application

[0309] Example 1: Synthesis of I-1

[0310]

[0311] Synthesis route of I-1

[0312]

[0313] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(trityl)amino)propyl)amino)propyl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (4)

[0314]

[0315] To a solution of compound 3 (350 mg, 0.48 mmol) in dioxane (10 mL) were added compound 2 (1.0 g, 2.10 mmol), Cs 2 CO 3 (471.5 mg, 1.45 mmol), x-phos (23.2 mg, 0.05 mmol) and Pd 2 (dba) 3 (44.7 mg, 0.05 mmol). The reaction mixture was stirred at 120 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with ethyl acetate (EA) (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using acetonitrile (ACN) and H 2 O as mobile phase in 35 minutes from 5% to 95% % ACN gradient flash chromatography to give compound 4 as a yellow solid (370 mg, 76.7% yield). Calculated molecular weight: 1012.6 g / mol. LC-MS determination: (M + H) +: 1013.6.

[0316] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(4-methyl-7-(methylamino)heptyl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (5)

[0317]

[0318] Compound 4 (370 mg, 0.37 mmol) was dissolved in TFA / DCM (2 / 10 mL) and the resulting solution was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to obtain compound 5 (35 mg, 13.2% yield) as a white solid. Calculated molecular weight: 713.5 g / mol. Determined by LC-MS: (M+H)+: 714.5.

[0319] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(N-methyl-2-(4,7,10-tri(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetylamino)propyl)amino)propyl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (6)

[0320]

[0321] To a solution of DOTA-tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid)(42.1 mg, 0.07 mmol) was added TBTU (23.6 mg, 0.07 mmol) and DIEA (19.0 mg, 0.15 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature for 1 hour, compound 5 (35.0 mg, 0.05 mmol) was added, and stirring was continued at room temperature overnight. The residue was treated with H 2 O (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to obtain compound 6 (60 mg, crude) as a yellow oil. Calculated molecular weight: 1268.8 g / mol. Determined by LC-MS: (M+H)+: 1269.8.

[0322] Synthesis of 2,2',2"-(10-(2-((3-((3-((4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)(methyl)amino)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-1)

[0323]

[0324] To a solution of compound 6 (60 mg, crude) in TFA / DCM (3 / 3 mL) was added a drop of (iPr) 3 SiH. The reaction mixture was stirred at room temperature overnight. The residue was purified by preparative HPLC to give I-1 (16.2 mg, 33.8% yield) as a white solid. Calculated molecular weight: 1100.6 g / mol. Determined by LC-MS: (M+2H)2+: 551.5; (M+3H)3+: 368.0. Purity by UPLC (214 nm): 97.0%.

[0325] Embodiment 2: Synthesis of I-2

[0326]

[0327] Synthesis route of I-2

[0328]

[0329] Synthesis of tert-butyl 2-(1-(4-((3-((3-aminopropyl)(methyl)amino)propyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0330]

[0331] To a solution of compound 1 (2.0 g, 2.76 mmol) in dioxane (30 mL) were added compound 2 (1.60 mg, 11.04 mmol), Cs 2 CO 3 (2.7 g, 8.28 mmol), x-phos (132 mg, 0.28 mmol) and Pd 2 (dba) 3 (253 mg, 0.28 mmol). The reaction mixture was stirred at 115 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95%% % ACN gradient flash chromatography to give compound 3 as a yellow solid (750 mg, 37% yield). Calculated molecular weight: 743 g / mol. LC-MS determination: (M + H) +: 744.

[0332] Synthesis of di-tert-butyl 2,2'-(7-(tert-butoxycarbonyl)-10-(2-((3-((4-(3-((2-(tert-butoxycarbonyl)adamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)propyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetate (4)

[0333]

[0334] To a solution of DOTA-tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid)(173.2 mg, 0.30 mmol) was added TBTU (97.2 mg, 0.30 mmol) and DIEA (78.1 mg, 0.61 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature for 1 hour, then compound 3 (150.0 mg, 0.20 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The residue was treated with H 2 O (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to obtain compound 4 (120 mg, crude) as a yellow oil. Calculated molecular weight: 1283.8 g / mol. Determined by LC-MS: (M+H)+: 1284.8.

[0335] Synthesis of 2,2',2"-(10-(2-((3-((3-((4-(3-((-2-carboxyamantadane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)propyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-2)

[0336]

[0337] To a solution of compound 4 (120 mg, crude) in TFA / DCM (5 / 5 mL) was added (iPr) 3 SiH (1 drop). The reaction mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to give I-2 (18.2 mg, 10.2% yield) as a white solid. Calculated molecular weight: 1072.6 g / mol. Determined by LC-MS: (M+2H)2+: 537.4; (M+3H)3+: 358.8. Purity by UPLC (214 nm): 97.4%.

[0338] Embodiment 3: Synthesis of I-3

[0339]

[0340] Synthesis route of compound I-3

[0341]

[0342] Synthesis of tert-butyl 2-(1-(4-((3-((3-aminopropyl)(methyl)amino)propyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0343]

[0344] To a solution of compound 1 (2.0 g, 2.75 mmol) in dioxane (30 mL) were added compound 2 (599.2 mg, 4.13 mmol), Cs 2 CO 3 (2.7 g, 8.27 mmol), x-phos (262.8 mg, 0.55 mmol) and Pd 2 (dba) 3 (504.1 mg, 0.55 mmol). The reaction mixture was stirred at 120 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 The residue was purified by flash chromatography on reverse phase silica gel (ACN / H 2O=5%〜95%,35min) to obtain compound 3 (1.6g, 85.8% yield) as a yellow solid. Calculated molecular weight: 742.5g / mol; determined by LC-MS: (M+H)+: 743.5.

[0345] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-((2,2,18-trimethyl-4,13-dioxo-3,8,11-trioxa-5,14,18-triazaheneicosan-21-yl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (5)

[0346]

[0347] To a solution of compound 4 (100 mg, 0.35 mmol) in DMF (5 mL) was added DIEA (67.7 mg, 0.52 mmol) and TBTU (168.4 mmol, 0.52 mmol) in an ice-water bath. The mixture was stirred for 30 minutes, and then compound 3 (260 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature overnight. The residue was treated with H 2 O (20 mL) and extracted with EA (30 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to give compound 5 as brown oil (200 mg, 57.8% yield). Calculated molecular weight: 987.6 g / mol; determined by LC-MS: (M+H)+: 988.7.

[0348] Synthesis of 2-(1-(4-((1-amino-13-methyl-8-oxo-3,6-dioxa-9,13-diazahexadecane-16-yl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (6)

[0349]

[0350] To a solution of compound 5 (200.0 mg, 0.20 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC to give compound 6 (50 mg, 30% yield) as a white solid. Calculated molecular weight: 831.5 g / mol; determined by LC-MS: (M+H)+: 832.5.

[0351] Synthesis of (5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-((16-methyl-2,11-dioxo-1-(4,7,10-tris(2-(tert-butyloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-6,9-dioxa-3,12,16-triazanonadecan-19-yl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (7)

[0352]

[0353] To a solution of DOTA-tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid)(51.6 mg, 0.09 mmol) was added TBTU (28.9 mg, 0.09 mmol) and DIEA (11.6 mg, 0.18 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 1 hour, then compound 6 (50.0 mg, 0.06 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was treated with H 2 O (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to give compound 7 (60 mg, crude) as a yellow oil. Calculated molecular weight: 1385.9 g / mol; determined by LC-MS: (M+H)+: 1386.9.

[0354] Synthesis of 2,2',2"-(10-(19-((4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)-16-methyl-2,11-dioxo-6,9-dioxa-3,12,16-triazanonadecanyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-3)

[0355]

[0356] To a solution of compound 7 (60 mg, crude) in TFA / DCM (3 / 3 mL) was added (iPr) 3Si (1 drop). The reaction mixture was stirred at room temperature overnight. The residue was purified by preparative HPLC to give I-3 (4.8 mg, 6.6% yield) as a white solid. Calculated molecular weight: 1217.7 g / mol; determined by LC-MS: (M+2H)2+: 610.0. Purity by UPLC (214 nm): 77.2%.

[0357] Embodiment 4: Synthesis of I-4

[0358]

[0359] Synthesis route of I-4

[0360]

[0361] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(methylamino)propyl)amino)propyl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0362]

[0363] To a solution of compound 1 (2.0 g, 2.75 mmol) in dioxane (30 mL) were added compound 2 (714.9 mg, 4.13 mmol), Cs 2 CO 3 (2.7 g, 8.27 mmol), x-phos (262.8 mg, 0.55 mmol) and Pd 2 (dba) 3 (504.1 mg, 0.55 mmol). The reaction mixture was stirred at 120 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 The residue was purified by flash chromatography on reverse phase silica gel (ACN / H 2 O=5%〜95%,35min) to obtain compound 3 (800mg, 38% yield) as a yellow solid. Calculated molecular weight: 770.5g / mol; determined by LC-MS: (M+H)+: 771.5.

[0364] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(2,2,14,18-tetramethyl-4,13-dioxo-3,8,11-trioxa-5,14,18-triazaheneicosan-21-yl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (5)

[0365]

[0366] To a solution of compound 4 (61.4 mg, 0.23 mmol) in DMF (5 mL) was added DIEA (90.4 mg, 0.70 mmol) and TBTU (112.4 mmol, 0.35 mmol) in an ice-water bath. The mixture was stirred for 30 minutes, and then compound 3 (180 mg, 0.23 mmol) was added. The resulting mixture was stirred at room temperature overnight, and then heated with H 2 O (20 mL) and extracted with EA (30 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to give crude compound 5 as orange oil (150 mg, 64% yield). Calculated molecular weight: 1015.6 g / mol; determined by LC-MS: (M+H)+: 1016.6.

[0367] Synthesis of (1-(4-((1-amino-9,13-dimethyl-8-oxo-3,6-dioxa-9,13-diazahexadecane-16-yl)(methyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (6)

[0368]

[0369] To a solution of compound 5 (150 mg, 0.15 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated and purified by preparative HPLC to give compound 6 (50 mg, 39% yield) as a white solid. Calculated molecular weight: 859.5 g / mol; determined by LC-MS: (M+H)+: 860.5.

[0370] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(4-((12,16-dimethyl-2,11-dioxo-1-(4,7,10-tris(2-(tert-butyloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-6,9-dioxa-3,12,16-triazanonadecan-19-yl)(methyl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (7)

[0371]

[0372] To a solution of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (33.3 mg, 0.06 mmol), TBTU (30.0 mg, 0.09 mmol) and DIEA (22.5 mg, 0.17 mmol) in DMF (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, compound 6 (50.0 mg, 0.06 mmol) was added, and stirring was continued at room temperature overnight. The residue was treated with H 2 O (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to give compound 6 (60 mg, crude) as a yellow oil. Calculated molecular weight: 1413.9 g / mol; determined by LC-MS: (M+H)+: 1414.9.

[0373] Synthesis of 2,2',2"-(10-(2-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-6,10-dimethyl-11,20-dioxo-13,16-dioxa-2,6,10,19-tetraazahenedecane-21-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-4)

[0374]

[0375] To a solution of compound 7 (60.0 mg, crude) in TFA / DCM (3 / 3 mL) was added (iPr) 3Si (1 drop). The reaction mixture was stirred at room temperature overnight. The residue was purified by preparative HPLC to give I-4 (12.5 mg, 34% yield) as a white solid. Calculated molecular weight: 1245.7 g / mol; determined by LC-MS: (M+2H)2+: 624.0. Purity by UPLC (214 nm): 97.7%.

[0376] Example 5: Synthesis of I-5

[0377]

[0378] Synthesis route of I-5

[0379]

[0380] Synthesis of tert-butyl 2-(1-(4-(((benzyloxy)carbonyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (2)

[0381]

[0382] To a solution of compound 1 (200 mg, 0.28 mmol) in dioxane (20 mL) were added benzyl carbamate (83.3 mg, 0.56 mmol), Cs 2 CO 3 (274 mg, 0.84 mmol), x-phos (67 mg, 0.14 mmol) and Pd 2 (dba) 3 (26 mg, 0.028 mmol). The reaction mixture was stirred at 115 °C under N 2 The reaction mixture was stirred overnight under a balloon. 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95% % ACN gradient flash chromatography to give compound 2 as a yellow solid (192 mg, 93% yield). Calculated molecular weight: 748 g / mol. LC-MS determination: (M + H) +: 749.

[0383] Synthesis of tert-butyl 2-(1-(4-amino-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0384]

[0385] Pd / C (20 mg) was added to a solution of compound 2 (200 mg, 0.27 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, washed with THF (10 mL x 2) and concentrated to obtain a crude compound 3 (150 mg, 92% yield) as a yellow solid. Calculated molecular weight: 614 g / mol. Measured by LC-MS: (M+H)+: 615.

[0386] Synthesis of tert-butyl 2-(1-(4-(4-bromobutyrylamino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (4)

[0387]

[0388] To a solution of compound 3 (100 mg, 0.16 mmol) in DCM (15 mL) were added 4-bromobutyryl chloride (86.2 mg, 0.47 mmol), DIEA (90.4 mg, 0.70 mmol) and DMAP (3.2 mg, 0.02 mmol). The reaction mixture was stirred at 25 °C under N 2 Stir under balloon for 2 h. 2 O (20 mL) and extracted with DCM (20 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by preparative HPLC to give crude compound 4 (120 mg, 96% yield) as a yellow oil. Calculated molecular weight: 764 g / mol. Determined by LC-MS: (M+H)+: 765.

[0389] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(4-(methyl(3-(methylamino)propyl)amino)butyrylamino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (5)

[0390]

[0391] To a solution of compound 4 (120 mg, 0.15 mmol) in DMF (5 mL) were added N1,N3-dimethylpropane-1,3-diamine (40.1 mg, 0.39 mmol) and NaI (23.6 mg, 0.15 mmol). The reaction mixture was stirred at 25 °C under N 2Stir overnight under balloon. The residue was purified by preparative HPLC to give compound 5 as a white solid (10 mg, 8% yield). Calculated molecular weight: 785 g / mol. Determined by LC-MS: (M+H)+: 786.

[0392] Synthesis of tri-tert-butyl 2,2',2"-(10-(2-((3-((4-((4-(3-((2-(tert-butoxycarbonyl)adamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)-4-oxobutyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (6)

[0393]

[0394] To a solution of DOTA-tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid)(10.9 mg, 0.02 mmol) in DMF (5 mL) were added TBTU (6.1 mg, 0.02 mmol) and DIEA (4.9 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then compound 5 (10.0 mg, 0.01 mmol) was added. The resulting mixture was stirred at room temperature overnight, and then treated with H 2 O (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to obtain compound 6 (20 mg, crude) as a yellow oil. Calculated molecular weight: 1339 g / mol. Determined by LC-MS: (M+H)+: 1340.

[0395] Synthesis of 2,2',2"-(10-(2-((3-((4-((4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)-4-oxobutyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-5)

[0396]

[0397] To a solution of compound 6 (20.1 mg, crude) in TFA / DCM (3 / 3 mL) was added (iPr)3SiH (1 drop). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to give I-5 (5.4 mg, 34% yield) as a white solid. Calculated molecular weight: 1115.4 g / mol; determined by LC-MS: (M+2H)2+: 558.8. Purity by UPLC (214 nm): >99%.

[0398] Example 6: Synthesis of I-6

[0399]

[0400] Synthesis route of I-6

[0401]

[0402] Synthesis of (9H-fluoren-9-yl)methyl (2-(2-(2-chloro-2-oxoethoxy)ethoxy)ethyl)carbamate (2)

[0403]

[0404] To a solution of compound 1 (560 mg, 1.45 mmol) in DCM (4 mL) were added oxalyl chloride (0.9 mL, 8.74 mmol) and DMF (0.05 mL). The reaction mixture was stirred at room temperature under N 2 The residue was concentrated and redissolved in DCM (4 mL).

[0405] Synthesis of tert-butyl 2-(1-(4-(2-(2-(2-aminoethoxy)ethoxy)-N-(3-(dimethylamino)propyl)acetylamino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (4)

[0406]

[0407] To a solution of compound II-1 (50 mg, 0.07 mmol) in DCM (1 mL) was added a DCM solution of acid chloride 2 (400 μL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was treated with 20% piperidine / DMF (0.25 mL) for 10 minutes. The crude solution was washed with H 2 0 dilution and purified by preparative HPLC to give compound 5 (9 mg) as a white solid. Calculated molecular weight: 845.1 g / mol; determined by LC-MS: (M+H)+: 846.1.

[0408] Synthesis of I-6

[0409]

[0410] To a solution of compound 4 (9 mg, 0.012 mmol) in DMF (1 mL) was added DOTA-tris(t-Bu ester) (8.1 mg, 0.014 mmol), TBTU (6 mg, 0.018 mmol) and DIEA (5 mg, 0.036 mmol). The reaction mixture was stirred at 25 °C for 2 h. The residue was diluted with EA (5 mL) and washed with H 2 O (5mL x 3). The combined organic phases were purified by Na 2 SO 4 Dried, filtered and concentrated. The residue was treated with 50% TFA / DCM (2 mL) at room temperature for 16 hours. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to give I-6 (1.8 mg) as a white solid. Calculated molecular weight: 1175.4 g / mol; determined by LC-MS: (M+2H)2+: 588.4; (M+3H)3+: 392.6. Purity by UPLC (214 nm): >99.0%.

[0411] Example 7: Synthesis of I-7

[0412]

[0413] Synthetic route of I-7

[0414]

[0415] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-(3-hydroxypropoxy)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (2)

[0416]

[0417] To a solution of compound 1 (600 mg, 0.83 mmol) in propane-1,3-diol (15 mL) were added CuI (158.1 mg, 0.83 mmol) and Cs 2 CO 3 (808.6 mg, 2.48 mmol). The reaction mixture was stirred at 120 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO4 Dry, filter and concentrate. The residue was purified by flash chromatography on silica gel (PE / EA=1 / 1) to give compound 2 (400 mg, 72% yield) as a yellow solid. Calculated molecular weight: 673.9 g / mol; determined by LC-MS: (M+H)+: 674.8.

[0418] Synthesis of tert-butyl 2-(1-(4-(3-bromopropoxy)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0419]

[0420] To a solution of compound 2 (50 mg, 0.07 mmol) in DCM (2 mL) was added PPh 3 (27.5 mg, 0.11 mmol) and CBr 4 (36.5 mg, 0.11 mmol). The reaction mixture was stirred at room temperature overnight. The residue was purified by HPLC. 2 O (10 mL) and extracted with DCM (10 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash chromatography on silica gel (PE / EA=2 / 1) to give compound 3 (27.3 mg, 50% yield) as a yellow solid. Calculated molecular weight: 736.8 g / mol; determined by LC-MS: (M+H)+: 737.8.

[0421] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(3-(methyl(3-(methylamino)propyl)amino)propoxy)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (4)

[0422]

[0423] To a solution of compound 3 (95 mg, 0.13 mmol) in DMF (2 mL) was added N 1 ,N 3 -dimethylpropane-1,3-diamine (64.5 mg, 0.63 mmol) and Cs 2 CO 3 (127.1 mg, 0.39 mmol). The reaction mixture was stirred at 80 °C under N 2Stir overnight under balloon. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 4 (30 mg, 31% yield) as a white solid. Calculated molecular weight: 758.0 g / mol; determined by LC-MS: (M+H)+: 759.0.

[0424] Synthesis of tri-tert-butyl 2,2',2"-(10-(2-((3-((3-(4-(3-((2-(tert-butoxycarbonyl)adamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenoxy)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5)

[0425]

[0426] A mixture of DOTA-tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid) (15 mg, 0.026 mmol), TBTU (8.5 mg, 0.026 mmol), DIEA (4 mg, 0.026 mmol) in DMF (1 ml) was stirred at room temperature for 1 hour, and then compound 4 (10 mg, 0.013 mmol) was added. The reaction mixture was heated at 25° C. under N 2 Stir under balloon for 2 h. 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to give compound 5 (10 mg, crude) as a yellow oil. Calculated molecular weight: 1311.8 g / mol; determined by LC-MS: (M+2H)2+: 657.0.

[0427] Synthesis of 2,2',2"-(10-(2-((3-((3-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenoxy)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-7)

[0428]

[0429] To a solution of compound 5 (10 mg, crude) in TFA / DCM (1 / 1 mL) was added (iPr)3 Si (1 drop), and the mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to give I-7 (4.3 mg, 52% yield) as a white solid. Calculated molecular weight: 1087.6 g / mol; determined by LC-MS: (M+2H)2+: 545.0. Purity by UPLC (214 nm): 96.6%.

[0430] Example 8: Synthesis of I-8

[0431]

[0432] Synthesis route of I-8

[0433]

[0434] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-((3-hydroxypropyl)thio)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (2)

[0435]

[0436] To a solution of compound 1 (500 mg, 0.69 mmol) in DMSO (10 mL) were added 3-mercaptopropan-1-ol (317 mg, 3.4 mmol), Cs 2 CO 3 (674 mg, 2.07 mmol) and CuI (131 mg, 0.69 mmol). The reaction mixture was stirred at 120 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash chromatography on reverse phase silica gel (ACN / H2O=2% to 65%, 35 min) to give compound 2 as a white solid (300 mg, 63% yield). Calculated molecular weight: 689.9 g / mol; determined by LC-MS: (M+H)+: 690.9.

[0437] Synthesis of 2'-(1-(4-((3-bromopropyl)thio)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl)-5'H-spiro[adamantan-2,4'-oxazol]-5'-one (3)

[0438]

[0439] To a solution of compound 2 (250 mg, 0.36 mmol) in ACN (5 mL) was added Ph 3 P (427 mg, 1.63 mmol) and CBr 4 (541 mg, 1.63 mmol), and the mixture was stirred at 60 ° C for 2 hours. The solvent was then removed by rotary evaporator, and the residue was purified by flash chromatography on reversed phase silica gel (PE / EA=9 / 1) to obtain compound 3 as a white solid (160 mg, 65% yield). Calculated molecular weight: 678.7 g / mol; determined by LC-MS: (M+H)+: 679.7.

[0440] Synthesis of 2'-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-((3-(methyl(3-(methylamino)propyl)amino)propyl)thio)phenyl)-1H-pyrazol-3-yl)-5'H-spiro[adamantan-2,4'-oxazol]-5'-one (4)

[0441]

[0442] To a solution of compound 3 (20 mg, 0.03 mmol) in ACN (2 mL) was added N 1 ,N 3 -dimethylpropane-1,3-diamine (9 mg, 0.09 mmol), KI (10 mg, 0.06 mmol) and K 2 CO 3 (8.1 mg, 0.06 mmol). The resulting mixture was stirred at 80 °C under N 2 The mixture was stirred for 2 hours at 4 °C, filtered, and the filtrate was concentrated and used directly in the next step. Calculated molecular weight: 700.0 g / mol; determined by LC-MS: (M+H)+: 701.0.

[0443] Synthesis of tri-tert-butyl 2,2',2"-(10-(2-((3-((3-((4-(5-(2,6-dimethoxyphenyl)-3-(5'-oxo-5'H-spiro[adamantan-2,4'-oxazole]-2'-yl)-1H-pyrazol-1-yl)-3-isopropylphenyl)thio)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5)

[0444]

[0445] A mixture of DOTA tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) (33 mg, 0.057 mmol), TBTU (18.3 mg, 0.057 mmol) and DIEA (7.4 mg, 0.057 mmol) in DMF (1 mL) was stirred at room temperature for 1 hour, and then compound 4 was added. The resulting reaction solution was heated at 25° C. under N 2 Stir under balloon pressure for 2 h, then 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to give compound 6 (20 mg, crude) as a yellow oil. Calculated molecular weight: 1253.7 g / mol; determined by LC-MS: (M+2H)2+: 628.0.

[0446] Synthesis of 2,2',2"-(10-(2-((3-((3-((4-(5-(2,6-dimethoxyphenyl)-3-(5'-oxo-5'H-spiro[adamantan-2,4'-oxazole]-2'-yl)-1H-pyrazol-1-yl)-3-isopropylphenyl)thio)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (6)

[0447]

[0448] To a solution of compound 5 (20 mg, crude) in TFA / DCM (1 / 1 mL) was added 1 drop of (iPr)3Si. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo to give compound 6 (20 mg, crude) as a yellow oil. Calculated molecular weight: 1085.6 g / mol; determined by LC-MS: (M+2H)2+: 543.8.

[0449] Synthesis of 2,2',2"-(10-(2-((3-((3-((4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)thio)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-8)

[0450]

[0451] To a solution of compound 6 (20 mg, crude) in ACN (1 mL) was added one drop of concentrated HCl. The resulting mixture was stirred at room temperature for 0.5 h, then the solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to give I-8 (5.5 mg, 27% yield) as a white solid. Calculated molecular weight: 1103.6 g / mol; determined by LC-MS: (M+2H)2+: 553.0. Purity by UPLC (214 nm): 91.2%.

[0452] Example 9: Synthesis of I-9

[0453]

[0454] Synthetic route of I-9

[0455]

[0456] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-(4-hydroxybut-1-yn-1-yl)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (2)

[0457]

[0458] To a solution of compound 1 (500 mg, 0.69 mmol) in DMF (4 mL) were added but-3-yn-1-ol (96.6 mg, 1.38 mmol), Pd(PPh 3 ) 2 Cl 2 (96.7 mg, 0.14 mmol), triethylamine (0.5 ml) and CuI (52.4 mg, 0.27 mmol). The reaction mixture was stirred at 120 °C under N 2 Stir under balloon pressure for 3 h, then 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash chromatography on reverse phase silica gel (PE / EA=72 / 28) to give compound 2 (460 mg, 100% yield) as a yellow solid. Calculated molecular weight: 667.4 g / mol; determined by LC-MS: (M+H)+: 668.6.

[0459] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-(4-hydroxybutyl)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0460]

[0461] To a solution of compound 2 (460 mg, 0.69 mmol) in ethanol (5 mL) was added PtO 2 (31 mg, 0.14 mmol). The reaction mixture was stirred at 20 °C under H 2 Stirred under balloon for 16 hours, then filtered and concentrated. The crude product was purified by flash chromatography on reverse phase silica gel (PE / EA=6 / 4) to give compound 3 (385 mg, 83% yield) as a yellow solid. Calculated molecular weight: 671.4 g / mol; determined by LC-MS: (M+H)+: 672.4.

[0462] Synthesis of tert-butyl 2-(1-(4-(4-bromobutyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (4)

[0463]

[0464] To a solution of compound 3 (400 mg, 0.60 mmol) in ACN (5 mL) was added Ph 3 P (702 mg, 2.68 mmol) and CBr 4 (890 mg, 2.68 mmol). The reaction mixture was stirred at 60 ° C for 2 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography on reverse phase silica gel (PE / EA=82 / 18) to give compound 4 as a white solid (270 mg, 61% yield). Calculated molecular weight: 733.3 g / mol; determined by LC-MS: (M+H)+: 734.3.

[0465] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(4-(methyl(3-(methylamino)propyl)amino)butyl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (5)

[0466]

[0467] To a solution of compound 4 (50 mg, 0.07 mmol) in ACN (2 mL) was added N 1 ,N 3 -dimethylpropane-1,3-diamine (20.9 mg, 0.2 mmol), KI (22.6 mg, 0.14 mmol) and K 2 CO 3(18.8 mg, 0.14 mmol). The reaction mixture was stirred at 80 °C under N 2 Stir under balloon for 2 hours. The solvent was removed in vacuo, and the residue was purified by flash chromatography on reverse phase silica gel (ACN / H2O=2%-80%, 35 min) to give compound 5 as a white solid (15 mg, 29% yield). Calculated molecular weight: 755.5 g / mol; determined by LC-MS: (M+H)+: 756.4.

[0468] Synthesis of tri-tert-butyl 2,2',2"-(10-(2-((3-((4-(4-(3-((2-(tert-butoxycarbonyl)adamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)butyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (6)

[0469]

[0470] A mixture of DOTA-tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid) (15 mg, 0.026 mmol), TBTU (8.5 mg, 0.026 mmol), DIEA (3.4 mg, 0.026 mmol) in DMF (1 ml) was stirred at room temperature for 1 hour, and then compound 5 (10 mg, 0.013 mmol) was added. The reaction mixture was heated under N 2 Stir under balloon for another 2 h and then rinse with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dried, filtered and concentrated to give compound 6 (10 mg, crude) as a yellow oil.

[0471] Synthesis of 2,2',2"-(10-(2-((3-((4-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)butyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-9)

[0472]

[0473] To a solution of compound 6 (10 mg, crude) in DCM (1 mL) was added TFA (1 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to give I-9 (1.5 mg, 18% yield) as a white solid. Calculated molecular weight: 1086.3 g / mol; determined by LC-MS: (M+2H)2+: 544.0. Purity by UPLC (214 nm): 90.7%.

[0474] Example 10: Synthesis of I-10

[0475]

[0476] Synthesis route of I-10

[0477]

[0478] Synthesis of tert-butyl 2-(1-(4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0479]

[0480] To a solution of compound 1 (300 mg, 0.41 mmol) in dioxane (20 mL) were added compound 2 (304 mg, 2.05 mmol), Cs 2 CO 3 (401 mg, 1.23 mmol), x-phos (97.7 mg, 0.21 mmol) and Pd 2 (dba) 3 (187.7 mg, 0.21 mmol). The reaction mixture was stirred at 115 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95% % ACN gradient flash chromatography to give compound 3 as a yellow solid (120 mg, 38% yield). Calculated molecular weight: 771 g / mol; by LC-MS determination: (M + H) +: 772.

[0481] Synthesis of tri-tert-butyl 2,2',2"-(10-(2-((2-(2-(2-((4-(3-((2-(tert-butoxycarbonyl)adamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (4)

[0482]

[0483] To a solution of DOTA-tri(t-Bu ester) (57.6 mg, 0.1 mmol) in DMF (2 mL) was added TBTU (32.1 mg, 0.1 mmol) and DIEA (27.09 mg, 0.21 mmol). After 10 minutes, compound 3 (50 mg, 0.07 mmol) was added. The reaction mixture was stirred at room temperature overnight. The residue was purified by HPLC. 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95% % ACN gradient flash chromatography to give compound 4 as a yellow solid (30 mg, 34% yield). Calculated molecular weight: 1300 g / mol; by LC-MS determination: (M + H) +: 1301.0.

[0484] Synthesis of 2,2',2"-(10-(2-((2-(2-(2-((4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-10)

[0485]

[0486] To a solution of compound 4 (30 mg, 0.023 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to obtain compound I-10 (10 mg, 40% yield) as a white solid. Calculated molecular weight: 1076.3 g / mol; determined by LC-MS: (M+2H)2+: 539.0. Purity by UPLC (214 nm): >99%.

[0487] Example 11: Synthesis of I-11

[0488]

[0489] Synthesis route of I-11

[0490]

[0491] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0492]

[0493] Compound 1 (250 mg, 0.658 mmol), compound 2 (434.2 mg, 0.598 mmol), L-proline (13.76 mg, 0.120 mmol), CuI (22.73 mg, 0.120 mmol) and K 2 CO 3 A solution of (165.07 mg, 1.20 mmol) in DMF (5 mL) was stirred at 140 °C (microwave) under Ar for 3 h. The mixture was poured into H 2 O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine and purified by Na 2 SO 4 The residue was purified by flash chromatography on reverse phase silica gel (ACN / H 2 O=5%〜95%,35min) to obtain compound 3 (50.0mg, 8.6% yield) as a white solid. Calculated molecular weight: 977.6g / mol; determined by LC-MS: (M+H)+: 978.7.

[0494] Synthesis of 2-(1-(4-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (4)

[0495]

[0496] A solution of compound 3 (50.0 mg, crude) in TFA / DCM (1 / 3 ml) was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain compound 4 (15 mg, 36% yield) as a white solid. Calculated molecular weight: 821.5 g / mol; determined by LC-MS: (M+H)+: 822.1.

[0497] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-((2-oxo-1-(4,7,10-tris(2-(tert-butyloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)amino)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (5)

[0498]

[0499] To a solution of DOTA tris(t-Bu ester)(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid)(15.7 mg, 0.03 mmol) in DMF (5 mL) were added TBTU (8.8 mg, 0.03 mmol) and DIEA (7.1 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then compound 4 (15.0 mg, 0.02 mmol) was added. The resulting solution was stirred at room temperature overnight and heated with H 2 O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to give compound 5 (30.8 mg, crude) as a yellow oil. Calculated molecular weight: 1375.8 g / mol; determined by LC-MS: (M+H)+: 1376.9.

[0500] Synthesis of 2,2',2"-(10-(20-((4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (I-11)

[0501]

[0502] To a solution of compound 5 (30.8 mg, crude) in TFA / DCM (3 / 3 mL) was added (iPr) 3 Si (1 drop). The reaction mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to give I-11 (7.2 mg, 33.1% yield) as a white solid after freeze drying. Calculated molecular weight: 1208.4 g / mol; determined by LC-MS: (M+2H)2+: 605.0. Purity by UPLC (214 nm): 97.0%.

[0503] Example 12: Synthesis of I-12

[0504]

[0505] Compound I-12 was prepared according to a similar route to the synthesis of compound I-6 as described above. Calculated molecular weight (average): 1090.2 g / mol

[0506] Determined by LC-MS: (M+H)+1090.4; (M+2H)2+:545.8;

[0507] Purity by UPLC (214nm): >99.0%

[0508] Example 13: Synthesis of I-13

[0509]

[0510] Compound I-13 was prepared according to a similar route to the synthesis of compound I-6 as described above. Calculated molecular weight (average): 1074.3 g / mol

[0511] Determined by LC-MS: (M+H)+: 1075.4; (M+2H)2+: 537.8

[0512] Purity by UPLC (214nm): 90%

[0513] Example 14: Synthesis of I-14

[0514]

[0515] Compound I-14 was prepared according to a similar route to the synthesis of compound I-10 as described above. Calculated molecular weight (average): 975.1 g / mol

[0516] Determined by LC-MS: (M+H)+: 976.4; (M+2H)2+: 488.4

[0517] Purity by UPLC (214 nm): 95.6%

[0518] Synthesis of Exemplary Compounds of Formula II of the Present Application

[0519] Example 15: II-1

[0520]

[0521] Synthesis route of II-1

[0522]

[0523] Synthesis of 4-iodo-2-isopropylaniline (2)

[0524]

[0525] Compound 1 (5.00 g, 37.04 mmol) was dissolved in MeOH / H 2 NaOH (2.96 g, 74.07 mmol) and NIS (8.75 g, 38.89 mmol) were added to a solution of 1% 4-nitropropene (2% ethyl acetate, 1% sodium bicarbonate) (2% sodium bicarbonate, 1 ... 2 O (50 mL) and extracted with EA (50 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (PE / EA=10 / 1-5 / 1) to give compound 2 (8.34 g, 86% yield) as a yellow oil. Calculated molecular weight: 261 g / mol. Determined by LC-MS: (M+H)+: 262.

[0526] Synthesis of (4-iodo-2-isopropylphenyl)hydrazine (3)

[0527]

[0528] To a solution of compound 2 (1.0 g, 3.83 mmol) in 6N HCl (0.8 mL) was added 2 mL of H 2 NaNO in O 2 (0.53 g, 7.66 mmol) for 2 minutes. After 1 hour, SnCl in 2 mL 6N HCl was added at 0 °C over 2 minutes. 2 ·H 2 O (2.85 g, 12.64 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and washed with Et 2 O (10 mL) and concentrated to give compound 3 (0.61 g, 58% yield) as a yellow solid. Calculated molecular weight: 276 g / mol. LC-MS determination: (M+H)+: 277.

[0529] Synthesis of 5-(2,6-dimethoxyphenyl)-1-(4-iodo-2-isopropylphenyl)-1H-pyrazole-3-carboxylic acid methyl ester (6)

[0530]

[0531] To a solution of compound 5 (600 mg, 2.25 mmol) in AcOH (20 mL) was added compound 3 (747 mg, 2.7 mmol) at room temperature, and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature and treated with Na 2 CO 3 The solution was adjusted to pH>7 and extracted with EA (50 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to give compound 6 (638 mg, 56% yield) as a yellow solid. Calculated molecular weight: 506 g / mol. Determined by LC-MS: (M+H)+: 507. 1 H NMR (400 MHz, CDCl 3 )δ:7.50(s,1H),7.45(d,J=8.0Hz,1H),7.26(m,1H),7.04(d,J=8.0Hz,1H),6.93( s,1H),6.46(J=8.0Hz,2H),3.94(s,3H),3.64(s,6H),2.61(m,1H),0.94(brs,6H).

[0532] Synthesis of 5-(2,6-dimethoxyphenyl)-1-(4-iodo-2-isopropylphenyl)-1H-pyrazole-3-carboxylic acid (7)

[0533]

[0534] To a solution of compound 6 (560 mg, 1.11 mmol) in MeOH (10 mL) was added NaOH (88.5 mg, 2.22 mmol) at room temperature. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was concentrated and the residue was purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95%% % ACN gradient flash chromatography to give compound 7 as a yellow solid (500 mg, 92% yield). Calculated molecular weight: 492 g / mol. LC-MS determination: (M + H) +: 493.

[0535] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-iodo-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (8)

[0536]

[0537] To a solution of compound 7 (400 mg, 0.81 mmol) in DMF (15 mL) was added DIEA (313.5 mg, 2.43 mmol) and PyBOP (632.3 mmol, 1.22 mmol) in an ice-water bath. The mixture was stirred for 10 minutes, and then tert-butyl 2-aminoadamantane-2-carboxylate (244.2 mg, 0.97 mmol) was added. The reaction mixture was stirred at 90 °C overnight. The residue was treated with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95% % ACN gradient flash chromatography to give compound 8 as a yellow solid (240 mg, 41% yield). Calculated molecular weight: 725 g / mol. LC-MS determination: (M + H) +: 726. 1H NMR(400MHz, DMSO-d6)δ:7.70(d,J=2.0,1H),7.54(dd,J=8.4,2.0Hz,1H),7.33(d,J=8.4,1H),7.28(d,J=3.2,1H),6.93(d,J=8.4Hz,1H) ,6.65(s,1H),6.62(d,J=8.8Hz,2H),3.64(s,6H),2.50(m,3H),2.01–1.93(m,4H),1.80-1.60(m8H),1.39(s,9H),1.03(d,J=6.4Hz,6H).

[0538] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-((3-(dimethylamino)propyl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (9)

[0539]

[0540] To a solution of compound 8 (50 mg, 0.07 mmol) in dioxane (15 mL) were added N,N-dimethyl-1,3-propanediamine (8.4 mg, 0.08 mmol), Cs 2 CO 3 (68.5 mg, 0.21 mmol), x-phos (16.7 mg, 0.04 mmol) and Pd 2 (dba) 3 (36.6 mg, 0.04 mmol). The reaction mixture was stirred at 115 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography on reverse phase silica gel under a % ACN gradient from 5% to 95% over 35 minutes to give compound 9 (30 mg, 62% yield) as a yellow solid. Calculated molecular weight: 700.0 g / mol. Determined by LC-MS: (M+H)+: 701.0.

[0541] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(4-((3-(dimethylamino)propyl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (II-1)

[0542]

[0543] To a solution of compound 9 (30 g, 0.042 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give II-1 (10 mg, 36% yield) as a white solid. Calculated molecular weight: 643.8 g / mol. Determined by LC-MS: (M+H)+: 644.4. Purity by UPLC (214 nm): 97.2%. 1 H NMR (400 MHz, DMSO-d 6 )δ:12.39(brs,1H),9.34(brs,1H),7.30-7.26(m,2H),6.91(d,J=8.4Hz,1H),6.5 9(t,J=7.0Hz,3H),6.41(d,J=2.4Hz,1H),6.30-6.27(m,1H),5.86(brs,1H),3.65 (s,6H),3.11(t,J=7.6Hz,2H),3.04(t,J=6.6Hz,2H),2.77(s,6H),2.49-2.45(m, 2H), 1.95 (d, J = 12.4Hz, 2H), 1.86-1.81 (m, 2H), 1.76-1.61 (m, 10H), 1.01 (s, 6H).

[0544] Example 16: II-2

[0545]

[0546] Synthesis route of II-2

[0547]

[0548] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-((4-(dimethylamino)butyl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0549]

[0550] To a solution of compound 1 (90 mg, 0.12 mmol) in dioxane (5 mL) were added compound 2 (17.3 mg, 0.15 mmol), Cs 2 CO 3 (121.2 mg, 0.37 mmol), x-phos (5.7 mg, 0.01 mmol) and Pd 2 (dba) 3(11.0 mg, 0.01 mmol). The reaction mixture was stirred at 120 °C under N 2 The reaction solution was stirred overnight under a balloon. 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 The residue was purified by flash chromatography on reverse phase silica gel (ACN / H 2 O=5%〜95%,35min) to obtain compound 3 (35mg, 41% yield) as orange oil. Calculated molecular weight: 713.5g / mol; determined by LC-MS: (M+H)+: 714.5.

[0551] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(4-((4-(dimethylamino)butyl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (II-2)

[0552]

[0553] To a solution of compound 2 (35 mg, 0.05 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated by rotary evaporator, and the residue was purified by preparative HPLC to obtain compound II-2 (8.2 mg, 31% yield) as a white solid. Calculated molecular weight: 657.4 g / mol; Determined by LC-MS: (M+H)+: 658.4. Purity by UPLC (214 nm): 98.6%.

[0554] Example 17: II-3

[0555]

[0556] Synthesis route of II-3

[0557]

[0558] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-((5-(dimethylamino)pentyl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (3)

[0559]

[0560] To a solution of compound 1 (90 mg, 0.12 mmol) in dioxane (5 mL) were added compound 2 (19.4 mg, 0.15 mmol), Cs 2 CO 3 (121.2 mg, 0.37 mmol), x-phos (5.7 mg, 0.01 mmol) and Pd 2 (dba) 3 (11.0 mg, 0.01 mmol). The reaction mixture was stirred at 120 °C under N 2 The mixture was stirred overnight under a balloon. The residue was washed with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 The residue was purified by flash chromatography on reverse phase silica gel (ACN / H 2 O=5%〜95%,35min) to obtain compound 3 (30mg, 34% yield) as orange oil. Calculated molecular weight: 727.5g / mol; determined by LC-MS: (M+H)+: 728.5.

[0561] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(4-((5-(dimethylamino)pentyl)amino)-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (II-3)

[0562]

[0563] To a solution of compound 3 (30.0 mg, 0.05 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated by rotary evaporator, and the residue was purified by preparative HPLC to obtain compound II-3 (8.2 mg, 30% yield) as a white solid. Calculated molecular weight: 671.4 g / mol; determined by LC-MS: (M+H)+: 672.3. Purity by UPLC (214 nm): >99.0%.

[0564] Synthesis of comparative compounds of the present application

[0565] Example 18: Comparator 1 (C-1, DOTA-NT-20.3)

[0566]

[0567] C-1 was prepared by standard solid phase peptide synthesis. Calculated molecular weight: 1484.8 g / mol. Determined by LC-MS: (M+2H)2+: 743.4; (M+3H)3+: 495.8. Purity by UPLC (214 nm): >99%.

[0568] Example 19: Comparative 2 (C-2,3BP-227)

[0569]

[0570] Synthesis route of C-2

[0571]

[0572] Synthesis of 4-iodo-2-isopropylaniline (2)

[0573]

[0574] Compound 1 (5.00 g, 37.04 mmol) was dissolved in MeOH / H 2 To the solution in 1% 4% iodine (2.96 g, 74.07 mmol) was added NaOH (2.96 g, 74.07 mmol) and N-iodosuccinimide (NIS) (8.75 g, 38.89 mmol) for 20 minutes. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified by HPLC. 2 O (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (petroleum / ethyl acetate = 10 / 1-5 / 1) to obtain compound 2 (8.34 g, 86% yield) as a yellow oil. Calculated molecular weight (average): 261 g / mol. Determined by LC-MS: (M+H)+: 262.

[0575] Synthesis of 4-amino-3-isopropylbenzonitrile (3)

[0576]

[0577] To a solution of compound 2 (5.0 g, 19.2 mmol) in DMF (20 mL) was added CuCN (5.15 g, 57.5 mmol). The reaction mixture was stirred at 140 °C for 4 h. The reaction mixture was treated with H 2 O (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were purified by Na 2 SO 4Dry, filter and concentrate. The residue was purified by silica gel column chromatography (petroleum / ethyl acetate = 10 / 1-3 / 1) to obtain compound 3 as a brown solid (2.7 g, 88% yield). Calculated molecular weight (average): 160 g / mol, determined by LC-MS: (M+H)+: 161. 1 H NMR (400 MHz, CDCl 3 )δ:7.38(d,J=2.0Hz,1H),7.30-7.27(m,1H),6.64(d,J=8.0Hz,1H),2.87-2.77(m,1H),1.28-1.24(m,6H).

[0578] Synthesis of 4-amino-3-isopropylbenzoic acid (4)

[0579]

[0580] Compound 3 (2.7 g, 16.86 mmol) was dissolved in ethylene glycol / H 2 KOH (3.71 g, 67.44 mmol) was added to the solution in 4% HCl (9 mL / 3 mL). The reaction mixture was stirred at 140 °C for 4 hours. The reaction mixture was cooled to room temperature, adjusted to pH = 3 with 3N HCl, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to give compound 4 (2.7 g, 90% yield) as a yellow solid. Calculated molecular weight (average): 179 g / mol. Determined by LC-MS: (M+H)+: 180. 1 H NMR (400 MHz, DMSO-d 6 )δ:11.95(brs,1H),7.61(d,J=2.0Hz,1H),7.05(d,J=2.0Hz,1H),7.48(d ,J=2.0Hz,1H),5.68(s,2H),3.00-2.90(m,1H),1.16(s,3H),1.14(s,3H).

[0581] Synthesis of 4-hydrazino-3-isopropylbenzoic acid (5)

[0582]

[0583] To a solution of compound 4 (1.0 g, 5.58 mmol) in 6N HCl (1 mL) was added 1 mL of H 2 NaNO in O 2(0.77 g, 11.17 mmol) for 2 minutes. After 1 hour, SnCl in 2 mL 6N HCl was added at 0 °C. 2 ·H 2 O (2.52 g, 11.17 mmol) for 2 minutes. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and washed with Et 2 O (10 mL) and concentrated to give compound 5 (0.7 g, 70% yield) as a yellow solid. Calculated molecular weight (average): 194 g / mol. Determined by LC-MS: (M+H)+: 195. 1 H NMR (400 MHz, DMSO-d 6 )δ:10.53(s,2H),7.77(d,J=1.6Hz,1H),7.42-7.16(m,1H),7.05(d,J=8.4Hz,1H),3.23-3.14(m,1H),1.23-1.16(m,6H). MS calculated value:194; MS found value:195([M+H] + ).

[0584] Synthesis of methyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutanoate (7)

[0585]

[0586] To a solution of compound 6 (10 g, 55.5 mmol) in dioxane (50 mL) was added dimethyl oxalate (8.19 g, 69.4 mmol) and MeONa (5.4 mol / mL, 11.3 mL, 61.05 mmol) at room temperature. The reaction mixture was stirred at 70 °C overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 5 with 3N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (petroleum / ethyl acetate=5 / 1) to obtain compound 7 (14 g, 95% yield) as a yellow solid. Calculated molecular weight (average): 266 g / mol. Determined by LC-MS: (M+H)+: 267.

[0587] Synthesis of 4-(5-(2,6-dimethoxyphenyl)-3-(methoxycarbonyl)-1H-pyrazol-1-yl)-3-isopropylbenzoic acid (8)

[0588]

[0589] To a solution of compound 7 (8.0 g, 30 mmol) in acetic acid (50 mL) was added compound 5 (12.44 g, 45 mmol) at room temperature, and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature and quenched with Na 2 CO 3 The solution was adjusted to pH>7 and extracted with ethyl acetate (50 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to give compound 8 (8.0 g, 53% yield) as a yellow solid. Calculated molecular weight: 424.2 g / mol. Determined by LC-MS: (M+H)+: 425.0. 1 H NMR (400 MHz, DMSO-d 6 )δ:13.14(brs,1H),7.85(d,J=1.6Hz,1H),7.77-7.75(m,1H),7.32-7.27(m,2H),6.86(s,1H ), 6.60 (d, J = 8.8Hz, 2H), 3.84 (s, 3H), 3.61 (s, 6H), 2.67-2.59 (m, 1H), 0.95 (d, J = 6.0Hz, 6H).

[0590] N 1 ,N 3 -Dimethyl-N 1 -(3-(Methylamino)propyl)-N 3 -Synthesis of tritylpropane-1,3-diamine (A-2)

[0591]

[0592] To a solution of N-methyl-N,N-bis[3-(methylamino)propyl]amine A-1 (2.0 g, 13.8 mmol) in DMF (25 mL) was added K 2 CO 3 (7.6 g, 55.2 mmol) and TrtCl (3.8 g, 13.8 mmol). The reaction mixture was stirred at room temperature overnight. The residue was treated with H 2 O (20 mL) and extracted with EA (50 mL x 3). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate to obtain compound A-2 (2.2 g, crude) as a yellow oil. Calculated molecular weight: 415 g / mol. Determined by LC-MS: (M+H)+: 416.

[0593] Synthesis of 5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(trityl)amino)propyl)amino)propyl)carbamoyl)phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (9)

[0594]

[0595] To a solution of compound 8 (1.5 g, 3.54 mmol) in DMF (20 mL) were added HATU (2.02 g, 5.31 mmol) and DIEA (1.37 g, 10.62 mmol). The mixture was stirred for 10 minutes, and then compound A-2 (1.76 g, 4.24 mmol) was added. The reaction mixture was stirred at room temperature overnight. The residue was treated with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in a % ACN gradient from 5% to 95% over 35 minutes to obtain compound 9 as a yellow solid (2.07 g, 71% yield). Calculated molecular weight: 821 g / mol. Determined by LC-MS: (M+H-Trt)+: 580.

[0596] Synthesis of 5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(trityl)amino)propyl)amino)propyl)carbamoyl)phenyl)-1H-pyrazole-3-carboxylic acid (10)

[0597]

[0598] To a solution of compound 9 (2.07 g, 2.52 mmol) in MeOH (10 mL) was added NaOH (201.6 mg, 5.04 mmol) at room temperature. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was concentrated. The residue was purified by elution on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95% % ACN gradient flash chromatography to give compound 10 as a yellow solid (1.8g, 90% yield). Calculated molecular weight: 807g / mol. LC-MS determination: (M + H) +: 808.

[0599] Synthesis of tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(trityl)amino)propyl)amino)propyl)carbamoyl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylate (11)

[0600]

[0601] To a solution of compound 10 (200 mg, 0.25 mmol) in DMF (15 mL) was added DIEA (97 mg, 0.75 mmol) and PyBOP (195 mg, 0.80 mmol) in an ice bath. The mixture was stirred for 10 minutes, and then tert-butyl 2-aminoadamantane-2-carboxylate (75 mg, 0.30 mmol) was added. The reaction mixture was stirred at 60 °C overnight, and then heated with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95%% ACN gradient flash chromatography to give compound 11 as a yellow solid (180 mg, 70% yield). Calculated molecular weight: 1040 g / mol. LC-MS determination: (M+H)+: 1041.

[0602] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(methylamino)propyl)amino)propyl)carbamoyl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (12)

[0603]

[0604] To a solution of compound 11 (1.0 g, 0.96 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give a crude compound 12 (600 mg, 84% yield) as a yellow solid, which was used in the next step without further purification. Calculated molecular weight: 742 g / mol. Determined by LC-MS: (M+H)+: 743.

[0605] Synthesis of 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(N-methyl-2-(4,7,10-tri(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetamido)propyl)amino)propyl)carbamoyl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (13)

[0606]

[0607] To a solution of DOTA-tris(t-Bu)ester (347 mg, 0.61 mmol) in DMF (10 mL) was added TBTU (260 mg, 0.81 mmol) and DIEA (156.7 mg, 1.22 mmol). The mixture was stirred for 10 minutes, and then compound 12 (300 mg, 0.41 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then treated with H 2 O (20 mL) and extracted with EA (20 mL x 2). The combined organic phases were purified by Na 2 SO 4 Dry, filter and concentrate. The residue is purified by chromatography on reverse phase silica gel using ACN and H 2 O as mobile phase in 35 minutes from 5% to 95%% % ACN gradient flash chromatography to give compound 13 as a yellow solid (150 mg, 29% yield). Calculated molecular weight: 1297.7 g / mol. LC-MS determination: (M + H) +: 1298.7.

[0608] Synthesis of 2,2',2"-(10-(2-((3-((3-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (C-2)

[0609]

[0610] To a solution of compound 13 (150 mg, 0.12 mmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound C-2 (33.3 mg, 26% yield) as a white solid. Calculated molecular weight: 1129.4 g / mol. Determined by LC-MS: (M+2H)2+: 565.4. Purity by UPLC (214 nm): 94.4%

[0611] Example 20: Comparative 3 (C-3, SR142948, purchased from Tocris, Bristol, United Kingdom)

[0612]

[0613] Example 21: Comparative 4 (C-4) (Reference: WO9632382 A1 1996-10-17)

[0614]

[0615] Example 22: Comparative 5 (C-5) (reference: https: / / pubs.acs.org / doi / 10.1021 / acs.jmedchem.1c00523)

[0616]

[0617] Calculated molecular weight (average): 1115.3 g / mol

[0618] Determined by LC-MS: (M+H)+1116.3; (M+2H)2+:558.4;

[0619] Purity by UPLC (214 nm): 95.6%

[0620] B: Biological Data

[0621] Example 23 Stability Study of Exemplary Radionuclide Labeled Compounds of the Present Application

[0622] use 177 Lu-labeled exemplary compounds of the present application to evaluate the stability of the compounds after radionuclide labeling. Briefly, 4 μL of DMSO stock solution (2000 μM) of the exemplary compounds and 2 mCi 177Lu (ITM Isotope Technologies Munich) were mixed together in 0.5M NaOAc buffer (20-50 μL, pH = 4.5), and then incubated at 95°C for 15 minutes. The labeled complex was then subjected to radioactive TLC analysis (polyamide membrane, using methanol and 1M ammonium acetate as mobile phase, v / v: 4: 1, detected by Mini Scan) and radioactive HPLC analysis (column: Shim-pack GIST 5 μm 4.6 * 150 mm; buffer A: 0.2% formic acid H2O; buffer B: 0.1% formic acid acetonitrile; flow rate: 1 mL / min; gradient: 0-5 min: 10% B to 95% B; then 5-8 min: 95% B).

[0623] After radionuclide labeling, the complex was diluted to 1.5 mCi / 0.30 mL with PBS (pH 7.4) or PBS (pH 7.4) containing 3 mg / mL ascorbic acid. The diluted samples were then incubated at room temperature and then analyzed for stability by radio-HPLC at 0, 4, 24, 48, 72, and 120 hours of incubation. Figure 1 Illustration of representative complexes 177 Stability analysis of Lu-I-7. Figure 1 As shown in , after 120 h of incubation, the structure of the labeled complex remained stable and no significant degradation was detected.

[0624] Example 24 Binding Affinity of Exemplary Compounds of the Present Application

[0625] By using 177 The binding affinity of the test compounds was determined by radioligand competitive binding assay using Lu-labeled C-1 as the reference radioligand.

[0626] Briefly, 100 μL of HT-29 cells expressing human NTSR-1 were cultured at 1-2 × 10 6 The cells were mixed at a density of 10 cells / mL with binding buffer (RPMI-1640 medium supplemented with 0.25% bovine serum albumin) in each well of a 96-well filter plate (Millipore). 177 Lu-C-1 (0.55 μCi / well) and the test compound were incubated at 37°C for 1 hour (n=3). After incubation, unbound proteins in each well were removed by filtration using a Multiscreen vacuum manifold (Millipore). 177Lu-C-1 and the test compound, and the cells were further rinsed 5 times with binding buffer. The cells from each well were then collected and the radioactivity of the cells in each well was measured individually by a γ counter (2480WIZARD2, PerkinElmer). The best fit IC of the test compound was calculated by fitting the data with nonlinear regression using GraphPad Prism 8.0.1 50 Value (when the cell is bound 177 The inhibitory concentration at which 50% of Lu-C-1 is replaced.

[0627] Table 1 and Figure 2 Results from representative test compounds in a single radioligand competitive binding assay are shown. Figure 2 As shown in , compounds I-1, I-2 and II-2 exhibited higher binding affinity than comparative compound C-1 or C-3.

[0628] Table 1. IC50 values ​​of representative compounds from single radioligand competitive binding assays

[0629]

[0630] Table 2 further shows the average IC values ​​of the tested compounds in the radioligand competitive binding assay from multiple experiments. 50 , and the relative binding affinity compared to C-1 (measured by the average IC 50 / Average IC of the tested compounds 50 calculate).

[0631] Table 2. Average IC50 and relative binding affinity of the tested compounds

[0632]

[0633]

[0634] Based on the radioligand competitive binding assay, it can be seen that the compounds of the present application are highly active against NTSR-1, with IC 50 The values ​​range from about 0.01 nM to about 1 nM, suggesting that the structure of the linker connecting the aromatic motif of the molecule and the chelator may have an unexpected effect on the binding affinity.

[0635] The binding affinity of representative compounds was also evaluated by FLIPR assay. Neurotensin receptor 1 belongs to the G protein coupled receptor (GPCR) family. Activation of NTSR-1 by its ligand neurotensin can induce intracellular calcium mobilization. In the FLIPR assay, the test compound and neurotensin are incubated with cells expressing NTSR-1 to measure the inhibition of intracellular calcium mobilization by the test compound, thereby evaluating its binding affinity.

[0636] Briefly, HEK293 cells stably expressing human NTSR-1 were plated in 384-well plates. 20ul of 10x10 5 A cell suspension of 100 μl / ml was inoculated in each well and incubated at 37°C with 5% CO 2 The cells in each well were then incubated overnight at 4 °C. Then, 20 ul of probenecid assay buffer, 20 ul of 8 uM Fluo-4 Direct TM The loading buffer, 6×EC80 of neurotensin and 10 μl of the diluted test compound were mixed and incubated at 37°C with 5% CO 2 The plates were then incubated for 50 minutes at 4 °C and then at room temperature for 10 minutes. The plates were then subjected to FLIPR analysis.

[0637] Table 3 shows the average IC values ​​of the tested compounds in the FLIPR assay. 50 As can be seen from Table 3, compared with the comparative compound C-2, the compounds I-5, I-6 and I-7 of the present application all exhibit lower IC 50 , further indicating that they have superior binding affinity than C2.

[0638] Table 3 Average IC values ​​of the tested compounds in the FLIPR assay 50

[0639] Compound <![CDATA[IC 50 (nM)]]> C-2 45.42 I-5 26.95 I-6 16.24 I-7 11.70

[0640] Example 25 Biodistribution of the radionuclide labeled complex of the present application

[0641] Xenograft models for biodistribution studies were established using BALB / c nude mice (Charles River, Beijing). All animal care and experimental procedures were performed according to animal protocols approved by the ethics committee of China Institute of Radiation Protection.

[0642] Briefly, each mouse was inoculated with approximately 4 × 10 6ASPC-1 cells (human pancreatic cancer cell line) or HT-29 cells (human colorectal adenocarcinoma cell line) expressing human NTSR-1 were used. Xenografted tumors were grown for 2-4 weeks after inoculation until tumor weights reached approximately 0.05 to 0.50 g (average 0.20 g).

[0643] Biodistribution studies were performed by administering radionuclide-labeled test compounds to each animal at a dose of -30-50 [mu]Ci (100 [mu]L in 0.9% NaCl, -1.11-1.85 MBq, specific activity 30-250 [mu]Ci / nmol) via tail vein injection.

[0644] At different time points after dosing, mice treated with each compound were euthanized. Tissues and organs of each group of animals were collected, excised, weighed and analyzed in a PerkinElmer 2480WIZARD2 gamma counter, and the percentage of injected dose (%ID) and %ID / g were calculated for each organ or tissue.

[0645] Tables 4-12 below show the biodistribution of the tested complexes in APSC-1 tumor-bearing mice at 1, 4, 24 and 72 hours, including 177 Lu-C-2, 177 Lu-C-5, 177 Lu-I-1, 177 Lu-I-2, 177 Lu-I-5, 177 Lu-I-6, 177 Lu-I-7, 177 Lu-I-8 and 177 Lu-I-10.

[0646] Figures 3A-3D Representative results are shown at different time points after administration. 177 Lu-labeled complex 177 Lu-C-2, 177 Lu-I-5, 177 Lu-I-10 and 177 Biodistribution of Lu-I-7 in ASPC-1 tumor-bearing mice.

[0647] Table 4. 177 Biodistribution of Lu-C-2 in ASPC-1 tumor-bearing mice (n=3)

[0648] Organ / Tissue %ID / g(1h) %ID / g(4h) %ID / g(24h) %ID / g(72h) kidney 3.34±1.53 2.6±0.93 1.36±0.42 0.46±0.08 Blood 13.87±0.17 4.46±0.64 0.31±0.1 0.09±0.01 Tumor 10.34±5.66 16.13±4.47 12.6±3.52 8.03±5.76 intestinal 1.98±0.63 1.62±0.41 0.44±0.11 0.15±0.06 Heart 4.83±1.1 1.72±0.18 0.37±0.07 0.16±0.04 liver 2.01±1.1 2.51±0.12 1.53±0.93 0.99±0.37 spleen 1.25±0.78 0.49±0.04 0.35±0.3 0.34±0.1 lung 3.67±2.25 1.92±0.99 0.69±0.14 0.23±0.06 Stomach 1.35±0.42 0.6±0.23 0.15±0.04 0.05±0 Femur 1.34±0.23 0.89±0.11 0.22±0.13 0.12±0.03 muscle 0.93±0.21 0.31±0.1 0.1±0.05 0.06±0.03 pancreas 0.8±0.47 0.27±0.06 0.1±0.02 0.07±0.03

[0649] Table 5. 177 Biodistribution of Lu-C-5 in ASPC-1 tumor-bearing mice (n=3)

[0650] Organ / Tissue %ID / g(1h) %ID / g(4h) kidney 0.87±0.05 0.33±0.09 Blood 3.18±0.24 0.22±0.07 Tumor 14.96±6.57 13.06±6.54 intestinal 1.28±0.11 0.42±0.16 Heart 1.46±0.24 0.16±0.06 liver 0.84±0.43 0.79±0.08 spleen 0.26±0.05 0.08±0.03 lung 1.66±0.93 0.3±0.15 Stomach 0.55±0.13 0.4±0.22 Femur 0.53±0.04 0.13±0.1 muscle 0.31±0.05 0.06±0.02 pancreas 0.26±0.05 0.06±0.02

[0651] Table 6. 177 Biodistribution of Lu-I-1 in ASPC-1 tumor-bearing mice (n=3)

[0652] Organ / Tissue %ID / g(4h) %ID / g(24h) %ID / g(72h) kidney 3.66±2.51 3.16±1.81 1.3±0.61 Blood 2.08±0.14 0.06±0.02 0.04±0.01 Tumor 6.93±0.71 22.56±1.81 7.23±4.46 intestinal 0.98±0.2 0.37±0.07 0.51±0.1 Heart 0.68±0.5 0.24±0.1 0.18±0.03 liver 1.81±0.43 0.97±0.45 1.06±0.46 spleen 0.42±0.16 0.53±0.25 0.24±0.08 lung 0.64±0.1 0.31±0.1 0.33±0.28 Stomach 0.57±0.16 0.28±0.17 0.1±0.02 Femur 0.72±0.05 0.19±0.09 0.15±0.06 muscle 0.47±0.25 0.13±0.05 0.06±0.01 pancreas 0.41±0.28 0.18±0.09 0.07±0.04

[0653] Table 7. 177 Biodistribution of Lu-I-2 in ASPC-1 tumor-bearing mice (n=3)

[0654] Organ / Tissue %ID / g(4h) %ID / g(24h) %ID / g(72h) kidney 2.03±0.38 2.39±0.77 1.69±1.04 Blood 9.23±0.36 0.28±0.03 0.07±0.01 Tumor 23.11±18.15 25.6±11.69 15.44±5.61 intestinal 2.00±0.18 1.00±0.18 0.55±0.11 Heart 3.78±0.03 0.4±0.13 0.18±0.1 liver 5.15±1.65 1.66±0.55 1.02±0.44 spleen 1.05±0.65 1.07±0.31 0.19±0.03 lung 1.77±0.37 0.39±0.11 0.17±0.02 Stomach 0.86±0.1 0.43±0.27 0.22±0.1 Femur 1.4±0.79 0.39±0.1 0.11±0.09 muscle 1.48±1.16 0.23±0.14 0.05±0.03 pancreas 0.54±0.14 0.32±0.15 0.08±0.02

[0655] Table 8. 177 Biodistribution of Lu-I-5 in ASPC-1 tumor-bearing mice (n=3)

[0656] Organ / Tissue %ID / g(4h) %ID / g(24h) %ID / g(72h) kidney 4.57±2.28 1.37±0.17 1.29±0.49 Blood 15.51±0.77 0.09±0.01 0.02±0 Tumor 27.56±12.51 36.67±18.25 12.83±4.23 intestinal 1.81±0.87 0.82±0.31 0.51±0.04 Heart 2.82±1.88 2.18±2.71 0.15±0.13 liver 3.87±2.36 1.27±0.29 0.96±0.07 spleen 2.39±1.4 0.63±0.05 0.34±0.04 lung 1.84±0.07 0.33±0.06 0.23±0.07 Stomach 3.52±0.4 0.28±0.2 0.15±0.05 Femur 2.21±0.63 0.38±0.23 0.17±0.09 muscle 1.29±0.37 0.17±0.08 0.05±0.01 pancreas 1.57±0.5 0.3±0.24 0.1±0.04

[0657] Table 9. 177 Biodistribution of Lu-I-6 in ASPC-1 tumor-bearing mice (n=3)

[0658] Organ / Tissue %ID / g(1h) %ID / g(4h) kidney 3.71±0.24 2.39±0.37 Blood 0.38±0.06 0.04±0.01 Tumor 12.71±4.57 13.64±2.5 intestinal 0.77±0.31 0.22±0.06 Heart 0.22±0.12 0.12±0.03 liver 0.51±0.22 0.53±0.16 spleen 0.09±0.01 0.13±0.03 lung 0.54±0.04 0.17±0.08 Stomach 0.27±0.19 0.21±0.05 Femur 0.12±0.01 0.12±0.09 muscle 0.06±0 0.08±0.02 pancreas 0.1±0.03 0.06±0.02

[0659] Table 10. 177 Biodistribution of Lu-I-7 in ASPC-1 tumor-bearing mice (n=3)

[0660] Organ / Tissue %ID / g(1h) %ID / g(4h) %ID / g(24h) %ID / g(72h) kidney 2.85±0.45 2.05±0.48 1.2±0.17 0.48±0.12 Blood 9.79±1.66 1.8±0.62 0.07±0.01 0.01±0 Tumor 15.27±8.72 19.97±10.42 22.83±1.14 18.07±0.98 intestinal 2.53±0.58 1.69±0.45 0.62±0.04 0.19±0.07 Heart 3.47±0.56 0.58±0.32 0.29±0.14 0.08±0.01 liver 3.93±0.43 1.88±1.00 0.84±0.09 0.23±0.01 spleen 0.63±0.19 0.58±0.15 0.23±0.11 0.06±0.01 lung 3.12±1.25 1.1±0.49 0.43±0.14 0.13±0.1 Stomach 1.01±0.82 0.58±0.59 0.21±0.08 0.04±0.01 Femur 1.65±0.23 0.49±0.25 0.12±0.04 0.06±0.03 muscle 1.1±0.3 0.27±0.2 0.34±0.3 0.01±0.01 pancreas 0.67±0.28 0.24±0.22 0.29±0.21 0.02±0.01

[0661] Table 11. 177 Biodistribution of Lu-I-8 in ASPC-1 tumor-bearing mice (n=4)

[0662] Organ / Tissue %ID / g(4h) %ID / g(24h) kidney 3.09±1.79 1.47±1.07 Blood 6.25±1.53 0.23±0.12 Tumor 16.7±10.49 26.12±10.63 intestinal 3.51±1.14 1.00±0.34 Heart 2.39±0.51 0.5±0.12 liver 7.4±2.9 1.86±0.97 spleen 0.71±0.16 1.22±0.22 lung 2.92±2.09 0.55±0.34 Stomach 1.74±1.36 0.69±0.46 Femur 0.89±0.74 0.4±0.16 muscle 0.54±0.28 0.34±0.14 pancreas 0.53±0.09 0.6±0.2

[0663] Table 12. 177 Biodistribution of Lu-I-10 in ASPC-1 tumor-bearing mice (n=3)

[0664] Organ / Tissue %ID / g(4h) %ID / g(24h) %ID / g(72h) kidney 3.02±0.39 0.31±0.11 0.04±0.01 Blood 0.93±0.29 0.04±0.00 0.01±0.00 Tumor 17.97±11.04 12.27±7.59 4.24±2.71 intestinal 1.86±0.58 0.14±0.01 0.04±0.01 Heart 0.41±0.13 0.04±0.02 0.01±0.01 liver 0.96±0.4 0.14±0.01 0.06±0.02 spleen 0.3±0.14 0.12±0.05 0.02±0.01 lung 0.74±0.72 0.4±0.26 0.05±0.03 Stomach 1.88±0.59 0.1±0.07 0.04±0.01 Femur 0.23±0.06 0.04±0.02 0.02±0 muscle 0.13±0.12 0.01±0.01 0.01±0.01 pancreas 0.07±0.01 0.04±0.02 0.01±0

[0665] Tables 13-15 show the different time points after administration 177 Lu-I-5, 177 Lu-I-6 and 177 Biodistribution of Lu-I-7 in HT-29 tumor-bearing mice. Figure 4A-4B Further shown are representative 177 Lu-labeled compounds 177 Lu-I-5 and 177Biodistribution of Lu-I-7 in HT-29 tumor-bearing mice.

[0666] Table 13. 177 Biodistribution of Lu-I-5 in HT-29 tumor-bearing mice (n=3)

[0667] Organ / Tissue %ID / g(1h) %ID / g(4h) %ID / g(24h) %ID / g(72h) %ID / g(120h) kidney 4.34±2.82 3.22±1.54 2.61±0.72 3.55±2.21 0.81±0.23 Blood 20.4±1.06 9.07±1.42 0.07±0.02 0.09±0.07 0.01±0 Tumor 9.74±2.44 20.7±2.21 17.4±4.53 10.02±6.15 6.61±1.12 intestinal 2.59±0.76 1.7±0.53 0.7±0.39 1.33±0.88 0.17±0.06 Heart 5.76±1.66 3.15±0.43 0.31±0.07 0.89±0.56 0.13±0.02 liver 5.26±1.02 4.41±1.88 2.21±0.36 4.44±3.4 0.55±0.3 spleen 1.76±0.41 1.22±0.16 0.43±0.09 1.61±1.35 0.8±0.32 lung 9.85±2.58 3.88±1.04 0.62±0.32 0.5±0.19 0.12±0.1 Stomach 1.29±0.31 1.35±0.68 0.29±0.11 0.54±0.53 0.07±0.01 Femur 1.84±1.19 0.99±0.18 0.29±0.1 0.73±0.82 0.13±0.05 muscle 1.07±0.14 0.66±0.21 0.12±0.04 0.37±0.34 0.06±0.02 pancreas 1.18±0.61 1.01±0.71 0.15±0.06 0.51±0.5 0.05±0.02

[0668] Table 14. 177 Biodistribution of Lu-I-6 in HT-29 tumor-bearing mice (n=3)

[0669] Organ / Tissue %ID / g(1h) %ID / g(4h) kidney 5.9±4.85 5.14±2.21 Blood 3.2±1.07 0.08±0.03 Tumor 10.31±4.72 7.53±3.52 intestinal 1.21±0.06 0.27±0.07 Heart 1.17±0.24 0.12±0.03 liver 1.28±0.47 0.83±0.27 spleen 0.45±0.19 0.26±0.1 lung 1.66±1.17 0.27±0.04 Stomach 0.69±0.23 0.32±0.2 Femur 0.68±0.18 0.2±0.03 muscle 0.57±0.15 0.09±0.04 pancreas 0.62±0.25 0.14±0.02

[0670] Table 15. 177 Biodistribution of Lu-I-7 in HT-29 tumor-bearing mice (n=3)

[0671] Organ / Tissue %ID / g(1h) %ID / g(4h) %ID / g(24h) %ID / g(72h) %ID / g(120h) kidney 4.41±2.41 1.73±0.79 1.43±1.04 0.7±0.3 0.4±0.15 Blood 16.51±0.56 2.85±1.23 0.06±0.02 0.03±0 0.01±0 Tumor 17.04±5.68 16.52±12.39 20.35±2.62 9.3±7.53 6.42±3.46 intestinal 2.84±1.07 1.71±0.23 0.66±0.29 0.29±0.23 0.19±0.01 Heart 5.28±0.74 1.31±0.53 0.16±0.01 0.11±0.01 0.05±0.03 liver 4.35±1.78 2.59±1.08 0.85±0.38 0.57±0.21 0.24±0.04 spleen 1.73±1.08 0.71±0.41 0.14±0.03 0.08±0.01 0.1±0.04 lung 4.47±3.31 1.81±0.77 0.35±0.14 0.23±0.01 0.07±0.02 Stomach 2.58±1.00 0.76±0.38 0.14±0.03 0.06±0.01 0.06±0.03 Femur 1.95±1.15 0.56±0.23 0.11±0.02 0.06±0.03 0.07±0.02 muscle 2.2±1.08 0.44±0.26 0.05±0.03 0.03±0.01 0.04±0.02 pancreas 1.48±0.29 0.38±0.17 0.07±0.04 0.03±0.01 0.04±0.01

[0672] Table 16 shows the results of the administration of 177 Lu-C5 and representative compounds of the present application 177 Radionuclide uptake in tumors relative to other tissues in ASPC-1 tumor-bearing mice 1 or 4 hours after Lu-I-6. 177 Compared with Lu-C5, 177 Lu-I-6 showed significantly higher uptake in tumor relative to blood, liver, and lung.

[0673] Table 16. 177 Lu-C5 and 177 Comparison of Lu-I-6 uptake rates between tumors and selected normal organs in ASPC-1 tumor-bearing mice

[0674] Tumor / blood Tumor / liver Tumor / lung Tumor / kidney <![CDATA[ 177 Lu-I-6@1h]]> 33.3 25.0 23.7 3.42 <![CDATA[ 177 Lu-C5@1h]]> 4.7 17.9 9.0 17.2 <![CDATA[ 177 Lu-I-6@4h]]> 364 25.9 79.3 5.70 <![CDATA[ 177 Lu-C5@4h]]> 60.5 16.6 43.3 40.0

[0675] Table 17 shows the comparative 177 Lu-C2 and representativeness of this application 177 Comparison of the uptake AUC (0-72 hours) of Lu-labeled compounds in ASPC-1 tumor-bearing mice. As shown in Table 17, 177 Compared with Lu-C, the representativeness of this application 177 Lu-labeled complex 177 Lu-I-7, 177 Lu-I-5, 177 Lu-I-1 and 177 Lu-I-2 showed significantly higher tumor AUC within 72 hours. 177 Lu-I-7, 177 Lu-I-5, 177Lu-I-1, 177 Lu-I-2 and 177 In the Lu-I-10 group, the ratio of tumor AUC relative to normal organ AUC had been significantly improved.

[0676] Table 17. Selected comparative and exemplary 177 Comparison of uptake AUC (0-72 hours) of Lu-labeled complexes in ASPC-1 tumor-bearing mice

[0677]

[0678] The above biodistribution studies have demonstrated that all complexes of the present application exhibit good to excellent tumor uptake of the radionuclide and a favorable ratio of tumor AUC to normal organ AUC. The uptake of the radionuclide in tumors and normal organs (including blood, kidney and liver) was found to be greatly affected by the linker connecting the aromatic motif and the chelator of the molecule. In addition, structural variations in the linker region were found to play a role in determining the tumor residence time of the radionuclide and, more significantly, the elution kinetics of the radionuclide in normal organs such as blood, kidney, liver, lung, etc.

[0679] Embodiment 26 177 SPECT / CT Imaging Study of Lu-labeled Complexes

[0680] ASPC-1 tumor-bearing mice were intravenously injected with approximately 120 μCi of 177 Lu-labeled complexes were then anesthetized under 2% isoflurane / oxygen and placed on the scanner. SPECT / CT images were acquired for 30 minutes at three bed positions using a MILabs SPECT scanner. Whole-body SPECT images were acquired 1 hour, 4 hours, 24 hours, and 72 hours after injection of the radiotracer.

[0681] like Figure 5 As shown in 177 Lu-labeled complex 177 Lu-I-5 and 177 Lu-I-7 showed sustained retention in tumors (e.g. Figure 5 The white arrows in the figure indicate that the mitochondria are involved in the mitochondria and are rapidly cleared from other organs or tissues within 72 hours.

[0682] Embodiment 27 68 PEC / CT Imaging Study of Ga-labeled Complexes

[0683] ASPC-1 tumor-bearing mice were intravenously injected with 150 μCi of 68Ga labeled compound, then anesthetized under 2% isoflurane / oxygen and placed on the scanner. PET images were acquired in one bed position for 10 minutes using animal PET / SPECT / CT (Inliview-3000B). Whole body PET images were acquired at 30, 60, 120 and 180 minutes after injection of the radiotracer.

[0684] like Figure 6 As shown in 68 Ga-labeled complex 68 Ga-I-6 shows 68 Stronger tumor uptake / retention than Ga-C-5 (e.g. Figure 6 ) and better tumor / normal contrast within 180 minutes (eg, tumor / liver, as in Figure 6 marked by white triangles in the figure).

[0685] Embodiment 28 177 Lu and 225 Study on the efficacy of Ac-labeled complex

[0686] The present invention was evaluated in ASPC-1 tumor-bearing mice. 177 Lu-labeled complexes and 225 In vivo efficacy of the Ac-labeled complex. 177 Lu therapy studies, animals in each group were given vehicle or 0.6 mCi of radiolabeled complex on days 1 and 5, respectively. 225 For Ac therapy studies, animals in each group were given a single dose of vehicle, 18, 37, or 74 KBq of radiolabeled complex, respectively.

[0687] Tumor volume (V) was measured at different time points according to the equation (V = (π ÷ 6) × L × W × H), where L is the longest axis, W is the axis perpendicular to L, and H is the axis perpendicular to the plane of L and W. The endpoint (sacrifice) criterion was defined as when the tumor volume exceeded 1.5 cm 3 or 20% body weight loss.

[0688] like Fig. 7A As shown in, compared with the excipient group, the 177 Administration of Lu-labeled complexes significantly inhibited tumor growth, indicating 177 In vivo efficacy of Lu therapy. Figure 7B As shown in 177 Administration of Lu therapy did not significantly affect the body weight of the animals.

[0689] Fig. 8A and 8C Graphical representation 225The antitumor efficacy of Ac-labeled complexes at different doses. Fig. 8A and 8C As can be seen in Figure 2, all three doses including 18, 37 or 74 KBq showed significant tumor inhibition compared with the vehicle group, including 225 Ac-I-5 37 and 74KBq groups or 225 The 37 and 74 KBq groups of Ac-I-7 showed similar trends, indicating that the 37 KBq 225 Ac-I-5 or 225 Ac-I-7 is sufficient to achieve maximum effect in animals. Figure 8B and 8D As shown in 225 Administration of Ac therapy did not significantly affect the body weight of the animals.

[0690] Although the present application has been described with reference to examples, it should be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the entire specification.

[0691] All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. The disclosures of these publications are incorporated herein by reference in their entireties to more fully describe the prior art as known to those skilled in the art as of the filing date described and claimed herein.

[0692] Full citations to documents mentioned in the specification

[0693] Many publications are cited herein. Full citations to these references are provided below. Each of these references is hereby incorporated by reference into the present disclosure in its entirety, as if each reference was specifically and individually indicated to be incorporated by reference.

[0694] 1. Vincent, JP, Neurotensin receptors: binding properties, transduction pathways, and structure. Cell Mol Neurobiol 1995;15:501–12.

[0695] 2. Sarret, P. and Kitabgi, P., Neurotensin and receptors. Encycl Neurosci2010:1021–34.

[0696] 3. Gui et al., Increased neurotensin receptor-1 expression during progression of colonic adenocarcinoma. Peptides 2008; 29: 1609–15. http: / / dx.doi.org / 10.1016 / j.peptides.2008.04.014.

[0697] 4. Souzan et al., Expression of neurotensin and NT1 receptor in human breast cancer: a potential role in tumor progression. Cancer Res 2006; 66: 6243–9. http: / / dx.doi.org / 10.1158 / 0008-5472.CAN-06-0450.

[0698] 5. Ehlers, R.A. et al., Gut peptide receptor expression in human pancreatic cancers. Ann Surg 2000; 231: 838–48.

[0699] 6. Dupouy, S. et al., The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression. PLoS One. 2009; 4(1): e4223. doi:10.1371 / journal.pone.0004223. Epub 2009 Jan 19. PMID: 19156213; PMCID: PMC2626627.

[0700] 7. Gully D. et al., Biochemical and pharmacological activities of SR142948A, a new potent neurotensin receptor antagonist, J.Pharmacol Exp Ther. 1997 Feb; 280(2): 802-12. PMID: 9023294.

[0701] 8. Shultz J, et al., Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin Receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications, J Nucl Med. 2016 Jul;57(7):1120-3. doi:10.2967 / jnumed.115.170530. Epub 2016 Mar 3. PMID:26940767.

[0702] 9. Schulz J, et al., Proof of Therapeutic Efficacy of a 177 Lu-Labeled Neurotensin Receptor 1 Antagonist in a Colon Carcinoma Xenograft Model. J Nucl Med. 2017 Jun;58(6):936-941. doi:10.2967 / jnumed.116.185140. Epub 2017 Mar 2. PMID:28254866.

[0703] 10. Baum RP, et al., 177 Lu-3BP-227 for Neurotensin Receptor 1-Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results. J Nucl Med. 2018 May;59(5):809-814. doi:10.2967 / jnumed.117.193847. Epub 2017 Oct 12. PMID:29025990.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof in R 1 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens; R 2 Selected from H, halogen, NO2, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-3 Alkylene C 3-8 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens; R 3 Selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; X is selected from CH2, O, NR 4 、S、S(O)、SO2NR 4 and NR 4 C(O); L is the connector; E is a chelating group; R 4 Selected from H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C(O)C 1-6 Alkyl, C 1-10 Alkylene NR 5 R 6 , C 1-10 Alkenylene NR 5 R 6 and C 1-10 Alkynylidene NR 5 R 6 ;and R 5 and R 6 Independently selected from H and C 1-6 alkyl.

2. The compound according to claim 1, wherein R 1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens.

3. The compound according to claim 2, wherein R 1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, R 1 Selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, CH2cyclopropyl and CH2cyclobutyl, each of which is optionally substituted by one or more halogens.

4. The compound according to claim 3, wherein R 1 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, R 1 Selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl and CH2cyclopropyl, each of which is optionally substituted by 1 or 3 fluorines.

5. The compound according to claim 4, wherein R 1 It is CH3.

6. The compound according to any one of claims 1 to 5, wherein R 2 Selected from H, halogen, NO2, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens.

7. The compound according to claim 6, wherein R 2 Selected from halogen, NO2 and C 1-6 Alkyl, the latter group is optionally substituted by one or more halogens.

8. The compound according to claim 7, wherein R 2 Selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, each of which is optionally substituted by 1 or 3 fluorine groups.

9. The compound according to claim 8, wherein R 2 It is CH(CH3)2.

10. The compound according to any one of claims 1 to 9, wherein R 3 is a group having the formula 11. The compound according to claim 1, wherein the compound of formula I is a compound of formula IA or a pharmaceutically acceptable salt and / or solvate thereof wherein X, L and E are as defined in any one of claims 1 to 10.

12. The compound according to any one of claims 1 to 10, wherein X is selected from CH2, O, S, NR 4 and NR 4 C(O).

13. The compound of claim 11, wherein X is CH2. The compound according to claim 11 , wherein X is O. 14 .

15. The compound of claim 11, wherein X is S.

16. The compound according to claim 11, wherein X is NR 4 .

17. The compound according to claim 11, wherein X is NR 4 C(O).

18. A compound according to claim 16 or claim 17, wherein R 4 Selected from H, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C(O)C 1-6 Alkyl, C 1-8 Alkylene NR 5 R 6 , C 1-8 Alkenylene NR 5 R 6 and C 1-8 Alkynylidene NR 5 R 6 .

19. A compound according to claim 16 or claim 17, wherein R 4 Selected from H and C 1-4 alkyl.

20. The compound according to claim 16 or claim 17, wherein R 4 It is C 1-6 Alkylene NR 5 R 6 .

21. The compound according to any one of claims 1 to 20, wherein L comprises 1 to 20 independently selected from R a –W a , W a –R b , R a –W a –R b and W a –R b –W b A group of W a and W b independently selected from O, S, S(O), S(O)2, NR 7 、C(Q)、C(Q)N、NR 7 C(Q), NR 7 C(Q')NR 8 ; R a and R b Independently selected from C 1-20 Alkylene, C 1-20 Alkenylene and C 1-20 Alkynylidene; Each Q is independently selected from O and S; Each Q' is independently selected from O, S, NH and N(C 1-6 alkyl); R 7 and R 8 Independently selected from H and C 1-6 Alkyl, and R a and R b Each alkylene, alkenylene, alkynylene group in 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene is independently and optionally selected from halogen, CO2H, OH, SH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-6 Alkyl, OC 1-6 Alkyl and SC 1-6 The alkyl group is substituted with one or more substituents, wherein all alkyl groups are optionally further substituted with halogen, CO2H, OH, NH2, NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 alkyl) is substituted with one or more substituents.

22. The compound according to claim 21, wherein R a and R b Independently selected from C 1-15 Alkylene, C 1-15 Alkenylene and C 1-15 Alkyne, and R a and R b Each alkylene, alkenylene and alkynylene in is independently and optionally substituted by C 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 one or more interruptions of heteroarylene, and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene is independently and optionally selected from halogen, CO2H, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)(C 1-4 Alkyl), C 1-6 Alkyl and OC 1-6 The alkyl group is substituted with one or more substituents, wherein all alkyl groups are optionally further substituted with halogen, CO2H, OH, NH2, NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 alkyl) is substituted with one or more substituents.

23. The compound according to claim 22, wherein R a and R b Independently selected from C 1-10 Alkylene, C 1-10 Alkenylene and C 1-10 Alkyne group.

24. The compound according to claim 22, wherein R a and R b Independently for C 1-10 Alkylene.

25. A compound according to any one of claims 21 to 24, wherein each Q' is independently selected from O, S, NH and N(C 1-4 alkyl).

26. A compound according to any one of claims 21 to 25, wherein each Q is independently O.

27. A compound according to any one of claims 21 to 25, wherein W a and W b independently selected from O, S, S(O), S(O)2, NR 7 、C(O)、C(O)NR 7 NR 7 C(O),NR 7 C(O)NR 8 and NR 7 C(S)NR 8 .

28. A compound according to any one of claims 21 to 26, wherein W a and W b Independently selected from O, NR 7 and C(O).

29. The compound according to any one of claims 21 to 28, wherein L comprises 1 to 20 independently selected from C 1-10 Alkylene O, C 1-10 Alkylene NR 7 , OC 1-6 Alkylene, NR 7 C 1-10 Alkylene, C(O)C 1-10 Alkylene O, C(O)C 1-10 Alkylene NR 7 , OC 1-10 Alkylene C(O) and NR 7 C 1-10 alkylene C(O), and each alkylene, alkenylene and alkynylene is independently and optionally substituted by C 3-10 Cycloalkylene, C 4-10 Heterocycloalkylene, C 6-10 Arylene and C 5-10 One or two of the heteroarylene groups are interrupted, and each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene group is independently and optionally selected from halogen, CO2H, OH, C 1-6 Alkyl and OC 1-6 1 to 4 substituents of the alkyl group, wherein all alkyl groups are optionally further substituted with halogen, CO2H, OH, NH2, NHC 1-4 Alkyl and N(C 1-4 Alkyl)(C 1-4 alkyl) is substituted with 1 to 4 substituents.

30. The compound according to claim 29, wherein L comprises 1 to 10 independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 The group.

31. The compound according to claim 30, wherein L comprises 2 to 10 independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 The group.

32. The compound according to claim 29, wherein L comprises independently selected from C 1-6 Alkylene O, C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C(O)C 1-6 Alkylene NR 7 2 to 7 groups or 2 to 5 groups.

33. The compound according to claim 30, wherein L comprises 1 to 6 C 1-6 Alkylene NR 7 group, and each C 1-6 Alkylene NR 7 The groups may be the same or different.

34. according to the compound described in claim 33, wherein L comprises 2 to 4 C3 alkylene NR 7 group, and each C3 alkylene NR 7 The groups may be the same or different.

35. The compound according to claim 21, wherein X is selected from CH2, O, S, NR 4 and NR 4 C(O), and L is C3 alkylene NR 7 –C3 alkylene NR 7 .

36. The compound according to claim 30, wherein L comprises 3 to 10 independently selected from C 1-6 Alkylene NR 7 、C(O)C 1-6 Alkylene O and C 1-6 Alkylene O group.

37. The compound according to claim 36, wherein L comprises 3 C 1-6 Alkylene NR 7 group, and each C 1-6 Alkylene NR 7 The groups are the same or different, 1 C(O)C 1-6 Alkylene O group and 1 C 1-6 Alkylene O group.

38. The compound according to claim 36, wherein L is (C 1-6 Alkylene NR 7 )2–C(O)C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 .

39. The compound according to claim 30, wherein L comprises 3 to 8 independently selected from C(O)C 1-6 Alkylene O, C 1-6 Alkylene O and C 1-6 Alkylene NR 7 The group.

40. The compound according to claim 30, wherein L comprises 2 to 6 C 1-6 alkylene O group, and each C 1-6 The alkylene O groups are the same or different and 1 or 2 C 1-6 Alkylene NR 7 group, and each C 1-6 Alkylene NR 7 The groups may be the same or different.

41. The compound according to claim 40, wherein L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 .

42. The compound according to claim 40, wherein L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 .

43. The compound according to claim 21, wherein X is selected from CH2, O, S, NR 4 and NR 4 C(O), R 4 Selected from H and C 1-4 Alkyl, and L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 or C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 .

44. The compound according to claim 21, wherein X is selected from NR 4 and NR 4 C(O), R 4 It is C 1-6 Alkylene NR 5 R 6 , and L is C 1-6 Alkylene O–C 1-6 Alkylene O–C 1-6 Alkylene NR 7 .

45. A compound according to any one of claims 21 to 44, wherein R 7 and R 8 Independently selected from H and C 1-4 alkyl.

46. ​​The compound according to claim 45, wherein R 7 and R 8 Independently selected from H and CH3.

47. A compound according to any one of claims 1 to 46, wherein E is a chelating group derived from a chelating agent, and the chelating agent is selected from cyclic or acyclic bifunctional chelating agents capable of binding and / or complexing with one or more radionuclides.

48. The compound according to claim 47, wherein the chelating agent is selected from 1,4,7-Triazacyclononane (TACN); 1,4,7-Triazacyclononane-triacetic acid (NOTA); 1,4,7-Triazacyclononane-N-succinic acid-N',N"-diacetic acid (NOTASA); 1,4,7-Triazacyclononane-N-glutamic acid-N',N"-diacetic acid (NODAGA); 1,4,7-Triazacyclononane-N,N',N"-tri(methylenephosphonic) acid (NOTP); 1,4,7,10-tetraazacyclododecane ([12]aneN4) (cyclen); 1,4,7,10-tetraazacyclotridecane ([13]aneN4); 1,4,7,11- Tetraazacyclotetradecane (isocyclam); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-tetraazacyclododecane-1-yl) acetate (DO1A); 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid (DO2A); 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DO3A); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylphosphonic acid) (DOTP); 1,7-di(methylphosphonic acid) (DO2P); 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methylphosphonic acid) (DO3P); 1,4,7,10-tetraazacyclodecane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam); 1,4,8,12-tetraazacyclopentadecane ([15]aneN4); 1,5,9,13-tetraazacyclohexadecane ([16] aneN4); 1,4-ethano-1,4,8,11-tetraazacyclotetradecane (et-cyclam); 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,11-tetraazacyclotetradecane-1-yl)acetic acid (TE1A); 2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A); 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexaazabicyclo[6.6.6] Eicosane (Sar); 1,4,7,10-tetrakis-(2-carbamoyl-methyl)-cyclododecane (TCMC); N,N′-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine and its derivatives; porphyrin and its derivatives. .

49. The compound of claim 48, wherein the chelator is selected from NOTA, DOTA and DOTAGA.

50. The compound of claim 49, wherein the chelator is DOTA.

51. A compound according to any one of claims 48 to 50, wherein the one or more radionuclides are radioisotopes of C, N, F, S, Br, Ru, Pd, Tc, Ga, In, Zn, Gd, Bi, At, Cu, Pb, Fe, Ti, F, I, Y, Sr, Ra, P, Re, Sc, Zr, Rh, Pt, Rb, Au, Sn, Tl, Co, Pm, lanthanides or actinides.

52. The compound of claim 51, wherein the one or more radionuclides are selected from 14 C. 15 N. 18 F. 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I. 131 I. 35 S. 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F. 123 I. 188 Re, 186 Re, 153 Sm, 66 Ho, 86 Y. 87 Y. 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 103m Rh, 223 Ra, 224 Ra, 97 Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 125 I, 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co, 55 Co, 47 Sc, 149 Pm and 161 Ho.

53. The compound of claim 52, wherein the one or more radionuclides are used for imaging or for therapy.

54. The compound of claim 53, wherein the one or more radionuclides used for imaging are selected from 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F and 123 I.

55. The compound of claim 53, wherein the one or more radionuclides used in treatment are selected from 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 32 P. 161 Tb, 33 P. 125 I. 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co. 47 Sc, 149 Pm and 161 Ho.

56. The compound of claim 55, wherein the one or more radionuclides used in treatment are selected from 177 Lu, 212 Pb and 225 Ac.

57. The compound of claim 1, wherein the compound of formula I is selected from the following list of compounds: or a pharmaceutically acceptable salt and / or solvate thereof.

58. The compound of claim 57, wherein the compound of Formula I further comprises a radionuclide complexed to a chelating binding group.

59. A radionuclide complex or a pharmaceutically acceptable salt and / or solvate thereof, comprising a compound according to any one of claims 1 to 46 and 57 or a pharmaceutically acceptable salt and / or solvate thereof, and one or more radionuclides.

60. The radionuclide complex of claim 59, wherein the one or more radionuclides are radioisotopes of C, N, F, S, Br, Ru, Pd, Tc, Ga, In, Zn, Gd, Bi, At, Cu, Pb, Fe, Ti, F, I, Y, Sr, Ra, P, Re, Sc, Zr, Rh, Pt, Rb, Au, Sn, Tl, Co, Pm, lanthanides, or actinides.

61. The radionuclide complex of claim 60, wherein the one or more radionuclides are selected from 14 C. 15 N. 18 F. 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I. 131 I. 35 S. 99 Tc, 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F. 123 I. 188 Re, 186 Re, 153 Sm, 66 Ho, 86 Y. 87 Y. 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 198 Au, 199 Au, 193m Pt, 197 Pt, 103 Pd, 109 Pd, 105 Rh, 103m Rh, 223 Ra, 224 Ra, 97 Ru, 227 Th, 229 Th, 32 P, 161 Tb, 33 P, 149 Tb, 125 I, 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co, 55 Co, 47 Sc, 149 Pm and 161 Ho.

62. The radionuclide complex of claim 61, wherein the one or more radionuclides are used for imaging or for therapy.

63. The radionuclide complex of claim 62, wherein the one or more radionuclides used for imaging are selected from 99m Tc, 188 Re, 186 Re, 153 Sm, 67 Ga, 68 Ga, 111 In, 59 Fe, 63 Zn, 52 Fe, 45 Ti, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 82 Rb, 198 Au, 199 Au, 195m Pt, 191m Pt, 193m Pt, 117m Sn, 89 Zr, 177 Lu, 18 F and 123 I.

64. The radionuclide complex of claim 62, wherein the one or more radionuclides used for treatment are selected from 188 Re, 186 Re, 153 Sm, 66 Ho, 90 Y. 89 Sr. 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224 Ra, 227 Th, 229 Th, 149 Tb, 32 P. 161 Tb, 33 P. 125 I. 203 Pb, 212 Pb, 201 TI, 119 Sb, 58m Co. 47 Sc, 149 Pm and 161 Ho.

65. The radionuclide complex of claim 64, wherein the one or more radionuclides used for treatment are selected from 177 Lu, 212 Pb and 225 Ac.

66. A compound of formula II or a pharmaceutically acceptable salt and / or solvate thereof, in R 9 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens; R 10 Selected from H, halogen, NO2, C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-3 Alkylene-C 3-8 Cycloalkyl), the latter three groups are optionally substituted by one or more halogens; R 11 Selected from 2-amino-2-adamantanecarboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; Y is selected from CH2, O, NR 14 、S、S(O)、SO2NR 14 and NR 14 C(O); R 12 and R 13 Independently selected from H and C 1-6 alkyl; R 14 Selected from H and C 1-6 Alkyl; and n is an integer selected from 1 to 10.

67. The compound according to claim 66, wherein R 9 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens.

68. The compound according to claim 67, wherein R 9 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, R 1 Selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, CH2cyclopropyl and CH2cyclobutyl, each of which is optionally substituted by one or more halogens.

69. The compound according to claim 68, wherein R 9 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, R 1 Selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl and CH2cyclopropyl, each of which is optionally substituted by one or more fluorine.

70. The compound according to claim 69, wherein R 9 It is CH3.

71. A compound according to any one of claims 66 to 69, wherein R 10 Selected from H, halogen, NO2, C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-3 Alkylene C 3-6 Cycloalkyl, the latter three groups are optionally substituted by one or more halogens.

72. The compound according to claim 71, wherein R 10 Selected from halogen, NO2 and C 1-6 Alkyl, the latter group is optionally substituted by one or more halogens.

73. The compound according to claim 72, wherein R 10 Selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2.

74. The compound according to claim 73, wherein R 10 It is CH(CH3)2.

75. A compound according to any one of claims 66 to 74, wherein R 11 is a group having the formula 76. according to the compound described in any one of claim 66 to 75, wherein Y is selected from CH2, O, S, NR 14 and NR 14 C(O).

77. The compound of claim 76, wherein Y is CH2.

78. The compound of claim 76, wherein Y is O.

79. The compound of claim 76, wherein Y is S.

80. The compound of claim 76, wherein Y is NR 14 .

81. The compound of claim 76, wherein Y is NR 14 C(O).

82. The compound of claim 80 or claim 81, wherein R 14 Selected from H and C 1-4 alkyl.

83. The compound according to claim 82, wherein R 14 Selected from H and CH3.

84. The compound according to claim 82, wherein Y is S, and the compound of formula II is a compound of formula II-B or a pharmaceutically acceptable salt and / or solvate thereof Where R 9 , R 10 , R 11 , R 12 , R 13 and n is as defined in formula II in any one of claims 66 to 75.

85. according to the compound described in any one of claim 66 to 84, wherein R 12 and R 13 Independently selected from H and C 1-4 alkyl.

86. The compound according to claim 85, wherein R 12 and R 13 Selected from H and CH3.

87. A compound according to any one of claims 66 to 86, wherein n is an integer selected from 1 to 8.

88. A compound according to any one of claims 66 to 86, wherein n is an integer selected from 2 to 8.

89. The compound of claim 66, wherein the compound of formula II is selected from the following list of compounds: Or a pharmaceutically acceptable salt and / or solvate thereof.

90. A composition comprising one or more compounds according to any one of claims 1 to 58 or pharmaceutically acceptable salts and / or solvates thereof, one or more compounds according to any one of claims 66 to 90 or pharmaceutically acceptable salts and / or solvates thereof, or one or more radionuclide complexes according to any one of claims 59 to 65 or pharmaceutically acceptable salts and / or solvates thereof, and a carrier.

91. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 58 or pharmaceutically acceptable salts and / or solvates thereof, one or more compounds according to any one of claims 66 to 90 or pharmaceutically acceptable salts and / or solvates thereof, or one or more radionuclide complexes according to any one of claims 59 to 65 or pharmaceutically acceptable salts and / or solvates thereof, and a pharmaceutically acceptable carrier.

92. A method for treating a disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds according to any one of claims 1 to 58, or pharmaceutically acceptable salts and / or solvates thereof, one or more compounds according to any one of claims 66 to 89, or pharmaceutically acceptable salts and / or solvates thereof, or one or more radionuclide complexes according to any one of claims 59 to 65, or pharmaceutically acceptable salts and / or solvates thereof.

93. The method of claim 92, wherein the disease or disorder is cancer.

94. The method of claim 93, wherein the cancer is a neurotensin receptor positive cancer.

95. The method of claim 94, wherein the neurotensin receptor is neurotensin receptor 1 (NTR1).

96. The method of claim 93, wherein the cancer is selected from gastric cancer, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, meningioma, Ewing's sarcoma, head and neck cancer, pleural mesothelioma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, and non-small cell lung cancer.

97. A method for inhibiting proliferation activity in cells, comprising administering to the cells an effective amount of any one of claims 1 to 58 or a pharmaceutically acceptable salt and / or solvate thereof, one or more compounds according to any one of claims 66 to 89 or a pharmaceutically acceptable salt and / or solvate thereof, or one or more radionuclide complexes according to any one of claims 59 to 65 or a pharmaceutically acceptable salt and / or solvate thereof.

98. The method of claim 97, wherein the one or more compounds or complexes comprise a radionuclide for use in therapy as defined in claim 64 or claim 65.

99. A method of imaging tissue in a subject by administering an imaging effective amount of one or more compounds according to any one of claims 1 to 58 or pharmaceutically acceptable salts and / or solvates thereof or one or more radionuclide complexes according to any one of claims 59 to 65 or pharmaceutically acceptable salts and / or solvates thereof, and applying an imaging technique to detect emitted gamma rays.

100. A method of diagnosing cancer in a subject by administering a diagnostically effective amount of one or more compounds according to any one of claims 1 to 58, or a pharmaceutically acceptable salt and / or solvate thereof, or one or more radionuclide complexes according to any one of claims 59 to 65, or a pharmaceutically acceptable salt and / or solvate thereof, and applying imaging techniques to detect emitted gamma rays.

101. A method of therapeutic diagnostic treatment, comprising administering to a subject in need thereof an effective amount of one or more compounds according to any one of claims 1 to 58 or a pharmaceutically acceptable salt and / or solvate thereof or one or more radionuclide complexes according to any one of claims 59 to 65, and performing a medical diagnostic method on the subject.

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