Prostate-specific membrane antigen (PSMA) ligands and uses thereof

Abstract

To provide prostate-specific membrane antigen (PSMA) ligands, and in particular, alternative multimodal PSMA ligands suitable for use as diagnostics and / or therapeutics.SOLUTION: The present disclosure provides PSMA ligands having: a glutamate-urea-lysine (GUL) moiety; a radioisotope; and a chelating agent that can comprise a radiometal.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to prostate specific membrane antigen (PSMA) ligands. In particular, the present disclosure relates to ligands for glutamate. GUL moieties, radioisotopes, and radiometals The present invention relates to a PSMA ligand having a chelator that can include a chelator having a chelator capable of containing a PSMA ligand.

[0002] The present disclosure also relates to the use of these compounds in the imaging and treatment of prostate cancer. Also relates to. [Background technology]

[0003] Theragnostics is a patient management strategy that involves the integration of diagnostic and therapeutic methods.

[0004] In the context of nuclear medicine, theragnostics involves the use of diagnostic radioactive metals (e.g., positrons or gamma emitters) or therapeutic radiometals (e.g. beta emitters). This refers to the use of targeted molecules for the diagnosis and therapy of specific diseases. The present invention relates to a method for detecting a target molecule having high affinity for a receptor expressed on a tumor cell, comprising: Radiolabeling with gallium Ga-68 for therapeutic purposes or lutetium Lu-177 for therapeutic purposes. Therefore, the same molecular targeting compounds can be used for molecular imaging and disease diagnosis. It is possible to effectively carry out individualized treatment using the substance.

[0005] This use of the same target compound also allows for a more thorough approach to patient management. This diagnostic method also has several simultaneous roles, using the same molecule labeled with radionuclides for diagnosis, reproduction, monitoring and therapy. This is because it allows the selection of the appropriate therapy or a different treatment plan, and allows follow-up after treatment. do.

[0006] For patients, theragnostics result in more effective medical care and less unnecessary treatment. Reduce or eliminate medical treatment and tailor therapeutic interventions to patients who will benefit most. Patients may not respond to unnecessary treatment or may otherwise experience side effects. By predicting which patients will experience It will be not only comprehensive but also patient-centered.

[0007] For physicians, theragnostics is the optimal therapy for diagnosing and staging disease. improve one's ability to select treatment options and monitor treatment outcomes and disease progression, The results suggest that the ability to predict outcomes may be improved safely and effectively. do.

[0008] For payers, theragnostic approaches are associated with suboptimal diagnostics and treatments. Reduce the costs associated with diagnosis and time required to diagnose and provide effective individualized treatment plans This allows patients to be treated.

[0009] Prostate cancer is one of the most prevalent cancers in the United States and Europe. Metastatic CRPC (mCRPC) is associated with poor prognosis and reduced quality of life.

[0010] Recently, PSMA ligand-based endo-radiotherapy has been rapy) is an example of a new trend in development for treating prostate cancer, and PSM Fraction A is overexpressed in primary cancer lesions and in soft tissue / bone metastatic disease. PSMA expression is considered a suitable target for imaging and therapy. The incidence appears to be even higher in the most aggressive castration-resistant variants, which may be due to They represent a patient population with high unmet medical need (March 2016). al et al.,Histol Histopathol,2004,Jul;19 (3):715-8;Mease et al.,Curr Top Med Chem ,2013,13(8):951-62).

[0011] Among the many small molecule ligands targeting PSMA, urea-based low-dose agents These agents have been the most extensively investigated in prostate cancer clinical evaluations and PR. Several of these agents have been shown to be suitable for RT therapy as targeting scaffolds. It has glutamate-urea-lysine (GUL).

[0012] Several radiolabeled small molecule inhibitors of PSMA have been designed based on this approach (K iess AP,Banerjee SR,Mease RC,et al.Prost ate-specific membrane antigen as a target t for cancer imaging and therapy.QJ Nuc l Med Mol Imaging.2015;59:241-268)

[0013] However, in some circumstances the use of diagnostic radiometals may be limited (6 (Problems due to availability of 8Ga and scattered production).

[0014] On the other hand, 68Ga has a physical half-life of only 68 minutes. PSMA-PET scans are preferably performed in-house to ensure sufficient tracer activity. Delivery to remote centers is difficult. As a result, large centers with many patients The center requires multiple production runs per day or multiple production units to be built simultaneously. It would require the relocation of facilities, which would increase costs. To overcome these limitations, we have used 18F-labeled PSMA tracers. Good. PET radiopharmaceutical specialty pharmacy with on-site cyclotron macy) can produce highly radioactive 18F at reasonable cost. The physical half-life of the PSMA tracer (110 min) also allows for centralized production and remote satellite 18F also has a lower positron energy than 68Ga, which may allow for delivery to light centers. It has a higher energy (0.65 vs. 1.90 MeV) and theoretically provides improved spatial resolution.

[0015] However, the development of alternative PSMA ligands is always desirable because and / or the development of alternative, diverse PSMA ligands suitable for use as therapeutics would be beneficial. Because it could become. Summary of the Invention

[0016] In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and preferably m is , 4; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C6~C 10 Consists of aryl and heteroaryl containing 5 to 10 ring atoms wherein said aryl and heteroaryl are substituted one or more times by X; X is -ZY; Z is a bond or a C1-C6 alkylene, preferably, Z is a bond; Y is a radioisotope; L is C1-C6 alkylene, C3-C6 cycloalkylene, and C6-C 10 Arielle a linker selected from the group consisting of alkylene, cycloalkylene, and Arylene is -OR', =O, =NR', =N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2 R',-C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR', -NR'-C(NR ''R''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR one or more substituents selected from 'R'', -NRSO2R', -CN, and -NO2; , optionally replaced by a number ranging from zero to (2m'+l), where m' is such R', R'', R''', and R'''' are the total number of carbon atoms in the group. Each of them is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, may refer to alkyl, aryl, and heteroaryl; W is -NR 2 -(C=O), -NR 2-(C=S), -(C=O)-NR 2 -and- (C=S)-NR 2 -, preferably W is selected from the group consisting of -(C=O)-N R 2 - and; Each occurrence of L and W may be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or a radioactive metal. as well as pharma- ceutically acceptable salts thereof.

[0017] The compounds of formula (I) are chelating agents that can contain radioisotopes and radiometals. The fact that the PSMA ligand may be labeled via a variety of modalities includes both. For example, the compounds of formula (I) can be used in nuclear medicine to extend the use of imaging. It may include radioactive halogens and metals used for diagnostic or therapeutic purposes.

[0018] In a second aspect, the present disclosure provides a compound of formula (I) and at least one pharma- ceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition comprising a carrier such as

[0019] In a third aspect, the disclosure relates to a compound of formula (I) for use as a medicament. do.

[0020] In a fourth aspect, the present disclosure provides a method for treating cancer, particularly prostate cancer, comprising administering to said patient a therapeutically effective amount of Concerning compounds of formula (I):

[0021] In a fifth aspect, the disclosure relates to a compound of formula (I) for use in diagnostic imaging. Regarding.

[0022] In a sixth aspect, the present disclosure also provides a method for treating prostate cancer, comprising administering to cancer cells with an effective amount of a compound of formula (I).

[0023] In a seventh aspect, the present disclosure also provides a method for diagnostic imaging, comprising: and contacting the compound of formula (I) with an amount of the compound and determining whether the compound is capable of decaying. detecting a signal resulting from the destruction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] definition As used herein, the term "protecting group" in reference to compounds of formula (I) refers to a protecting group that is Selected by readily available reagents that do not attack the resulting functional group or other functional groups in the molecule. Protective groups refer to chemical substituents that can be selectively removed. Suitable protecting groups are known in the art. Suitable protecting groups have been developed and continue to be developed. Greene's Protective Groups in Organic Sy nthesis, Fourth Edition”, Wiley-Interscien ce, 2007). The protecting groups for the carboxyl groups are As described in Wutz et al. (pp. 533-643), In some embodiments, the protecting group can be converted to a carboxylic acid by treatment with an acid. It can be removed by this.

[0025] Representative examples of protecting groups are benzyl, p-methoxybenzyl (PMB), tertiary butyl (t- Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl Tetrahydropyranyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), Benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (T ES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl Those skilled in the art will recognize the appropriate conditions under which protecting groups are required. and be able to select the appropriate protecting group for use in a particular situation. Wax.

[0026] As used herein, the term "alkyl" refers to any group, either alone or as part of another substituent. As a moiety, it refers to a linear or branched alkyl functional group having 1 to 12 carbon atoms. The alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-Butyl, t-Butyl, pentyl and its isomers (e.g. n-pentyl, iso- pentyl), as well as hexyl and its isomers (e.g., n-hexyl, iso-hexyl) Includes.

[0027] Alkylene refers to a divalent alkyl as defined above.

[0028] As used herein, the term "cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, ... Includes cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] Cycloalkylene refers to a divalent cycloalkyl as defined above.

[0030] As used herein, the term "aryl" refers to a group in which at least one ring is aromatic. A single ring or multiple aromatic rings fused together containing 6 to 10 ring atoms, which are of the aromatic ring group The aromatic ring may optionally have a ring fused thereto. 1 to 2 additional rings (cycloalkyl, heterocyclyl, Suitable aryl groups include benzopyranyl, benzyl, benzoic acid, Heterocyclyls such as benzodioxolyl, benzodioxanil, and the like. Examples of aryl include phenyl, naphthyl, and phenyl rings fused to a cyclic ring.

[0031] Arylene refers to a divalent aryl as defined above.

[0032] Alkyl, cycloalkyl, and aryl monovalent and divalent derived groups include -OR', =O, =NR', =N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R ''', -OC(O)R', -C(O)R', -CO2R',-C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R' '', -NR''C(O)OR', -NR'-C(NR''R''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', - With one or more substituents selected from CN and -NO2, the range is from zero to (2m'+l). and m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' are each independently hydrogen, alkyl, , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. It may also refer to a rule.

[0033] As used herein, the term "halogen" includes fluoro (-F), chloro (-C), (-Cl), bromo (-Br), or iodo (-I) groups.

[0034] As used herein, the term "heteroalkyl" refers to an alkyl group having 1 to 6 carbon atoms. and a straight chain having 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S. refers to a chain or branched alkyl functional group, the nitrogen and sulfur atoms of which may optionally be oxidized; The nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, and S are Any interior position of the alkyl group or the position at which the alkyl group is attached to the remainder of the molecule may be placed in

[0035] As used herein, the term "heteroaryl" refers to a single ring or to two rings, each of which is heterocyclic. Polycyclic aromatic compounds having multiple aromatic rings fused or covalently bonded together and containing 5 to 10 atoms refers to a cyclic unsaturated aromatic ring system in which at least one ring is aromatic and at least one ring is The atom is a heteroatom selected from N, O, and S. The nitrogen and sulfur heteroatoms are It may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Such rings may be fused to an aryl, cycloalkyl, or heterocyclyl ring. Non-limiting examples of heteroaryls such as furanyl, thiophenyl, pyrrolyl, pyrazo aryl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl (oxatriazolyl), thiatriazolyl, Lysinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl , dioxinyl, thiazinyl, triazinyl Indolyl, indolyl, isoindolyl, benzofuranyl, isoben Zofranil, benzothiophenyl, isobenzothiophenyl phenyl), indazolyl, benzimidazolyl, benzoxazolyl, purinyl, Benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and and quinoxalinyl.

[0036] As used herein, the term "heterocycloalkyl" refers to a heterocyclic alkyl group having 5 to 10 aryl groups. refers to a saturated or unsaturated cyclic group having ring atoms, at least one of which is selected from the group consisting of N, O, and The nitrogen and sulfur heteroatoms are optionally oxidized. The nitrogen heteroatom may be optionally quaternized. An example of a heterocycle is a tetrahydrofuran. Tetrahydropyridyl, piperidinyl, morpholinyl, Tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1-azepanyl, imidazoline These include, but are not limited to, zolinyl, 1,4-dioxanyl, and the like. stomach.

[0037] Various embodiments of the present disclosure are described herein. The features described herein may be combined with other specific features to provide further embodiments. will be recognized.

[0038] The present disclosure relates to compounds of formula (I), (II), (III), and (IV), their stereoisomers, isomers, tautomers, enantiomers, diastereomers, racemates, or mixtures thereof, This includes hydrates, solvates, or pharma- ceutically acceptable salts thereof.

[0039] The term "pharmaceutically acceptable salts" refers to compounds that retain the biological effectiveness and properties of the compounds of the present disclosure. "Salts" refers to salts which are generally not biologically or otherwise undesirable.

[0040] "Pharmaceutically" or "pharmaceutically acceptable" means a substance that is suitable for administration to a mammal, particularly a human. Molecular entities that do not cause adverse, allergic, or other untoward reactions when administered Pharmaceutically acceptable carriers or excipients refer to non-toxic solid, semi-solid or Or it refers to a liquid filler, diluent, encapsulating agent, or formulation auxiliary of any type.

[0041] As used herein, the term "subject" refers to an animal, preferably a mammal, more preferably a mammalian animal. Preferably it refers to a human.

[0042] Compounds of formula (I) In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and preferably m is , 4; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C6~C 10Consists of aryl and heteroaryl containing 5 to 10 ring atoms wherein said aryl and heteroaryl are substituted one or more times by X; X is -ZY; Z is a bond or a C1-C6 alkylene, preferably, Z is a bond; Y is a radioisotope; L is C1-C6 alkylene, C3-C6 cycloalkylene, and C6-C 10 Arielle a linker selected from the group consisting of alkylene, cycloalkylene, and Arylene is -OR', =O, =NR', =N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2 R',-C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR', -NR'-C(NR ''R''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR one or more substituents selected from 'R'', -NRSO2R', -CN, and -NO2; , optionally replaced by a number ranging from zero to (2m'+l), where m' is such R', R'', R''', and R'''' are the total number of carbon atoms in the group. Each of them is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, may refer to alkyl, aryl, and heteroaryl; W is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -and- (C=S)-NR 2 -, preferably W is selected from the group consisting of -(C=O)-N R 2 - and; Each occurrence of L and W may be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or a radioactive metal. as well as pharma- ceutically acceptable salts thereof.

[0043] The compounds of formula (I) have the formulas (Ia), (Ib), (Ic), and (Id): [ka] This includes stereoisomers of:

[0044] The phrase "each occurrence of L and W may be the same or different" refers to the variable " When "n" is 2 or 3, one "L" group can be a C1-C6 alkylene. and the other "L" group can be a C3-C6 cycloalkylene or arylene. In other embodiments, each "L" group can be, for example, a C1-C6 alkylene. Similarly, for example, if "n" is 2 or 3, then one "W " group is -(C=O)-NR 2 - and the other "W" group can be -(C=S)- NR 2 or in other embodiments, each "W" can be, for example, -(C=O )-NR 2 --It can be.

[0045] According to one embodiment, L is C1-C6 alkylene, C3-C6 cycloalkylene, and and C6~C 10 arylene, wherein the linker is selected from the group consisting of alkylene, Cycloalkylene and arylene include -OR', ═O, ═NR', -NR'R'', - Halogen, -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R'' , -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R ''', -NR', -C(O)OR', and one or more substituents selected from zero to (2 m' is a number ranging from 0 to 1, and ... is the total number of atoms. R', R'', R''', and R'''' are each independently Hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0046] According to one embodiment, L is -OR', =O, =NR', -NR'R'', -halogen. , -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R'', -OC (O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR'' with one or more substituents selected from zero to (2m'+l ) C3-C6 alkylene optionally substituted with a number ranging from R', R R'', R''', and R'''' are each independently hydrogen, alkyl, heteroaryl, refers to alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl Good too.

[0047] Typically, the radioisotope Y is a radioactive halogen, 18 F, 34 Cl, 75 Br , 76Br, 77 Br, 123 I, 124 I, 125 I, 131 I, and 211 From At Preferably, Y is selected from the group consisting of: 18 F or 211 At.

[0048] According to one embodiment, R is selected from the group consisting of: [ka] p is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and preferably p is , 1; Preferably, R is [ka] is selected from More preferably, R is [ka] It is.

[0049] Advantageously, R is [ka] It is.

[0050] Ch is selected from the group consisting of: [ka] Optionally, it comprises a metal or a radioactive metal.

[0051] According to a particular embodiment, Ch is [ka] and optionally comprising a metal or a radioactive metal.

[0052] The metal or radiometal is preferably suitable for use in diagnostic imaging or in therapy. The metals are selected from metals that are radioactive and metals that are radioactive.

[0053] According to one embodiment, Ch is Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb , Ac, Bi, Al, Ga, Re, Ho, and Sc. 68 Ga, 64 Cu, 86 Y, 90 Y, 89 Zr, 111 In, 99m Tc, 177 Lu , 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 B i, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc, and 166 Select from Ho The radioactive metal may be selected from the group consisting of fluorine, iodine, fluorine-containing compounds, and fluorine-containing ... compounds.

[0054] Advantageously, Ch is a radioactive metal 68 Ga or 177 Contains Lu.

[0055] According to one embodiment, W is -(C=O)-NR 2 and Ch is [ka] and optionally comprising a metal or a radioactive metal.

[0056] According to one embodiment, m is 4, Z is COOQ and Q is H.

[0057] According to one embodiment, R is [ka] and Ch is [ka] and optionally comprising a metal or a radioactive metal.

[0058] According to a particular embodiment, the compound of formula (I) has the formula (II): [ka] where L is -OR', =O, =NR', -NR'R'', -halogen, -O C(O)R', -C(O)R', -CO2R', -C(O)NR'R'', -OC(O) NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR 'C(O)OR' with one or more substituents ranging from zero to (2m'+l) A alkylene group selected from the group consisting of C3-C6 alkylene, optionally substituted with a number ranging from R', R'', R are each an alkyl group, and m' is the total number of carbon atoms in such a group. R''' and R'''' are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, It may refer to cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0059] Advantageously, the compound of formula (II) is preferably 68 Ga, 67 Ga, 177 Lu, and 176Lu.

[0060] According to a particular embodiment, the compound of formula (II) is 68 Ga or 67 Contains Ga.

[0061] According to another particular embodiment, the compound of formula (II) is 177 Lu or 176 Contains Lu nothing.

[0062] According to a particular embodiment, the compound of formula (I) has the formula (III): [ka] and optionally containing a metal or a radioactive metal.

[0063] The compounds of formula (III) are represented by the formulae (IIIa), (IIIb), (IIIc), and (IIIa). Id): [ka] This includes stereoisomers of the formula:

[0064] Advantageously, the compound of formula (III) is preferably 68 Ga, 67 Ga, 177 Lu, and Beauty 176 Lu.

[0065] According to a particular embodiment, the compound of formula (III) is 68 Ga or 67 Contains Ga.

[0066] According to another particular embodiment, the compound of formula (III) is 177 Lu or 176 Lu include.

[0067] According to one embodiment, the compound of formula (I) has formula (IV): [ka] It is a compound of the formula:

[0068] Compounds of formula (IV) include those of formulas (IVa), (IVb), (IVc), and (IVd): [ka] This includes stereoisomers of the formula:

[0069] According to another embodiment, the compound of formula (I) has the formula (V): [ka] It is a compound of the formula:

[0070] Compounds of formula (V) include those of formulas (Va), (Vb), (Vc), and (Vd): [ka] This includes stereoisomers of the formula:

[0071] Pharmaceutical Compositions The present disclosure also provides a method for the preparation of a compound of Formula (I)-(V) and at least one pharma- ceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising the carrier.

[0072] The pharmaceutical composition comprises i) a PSMA-binding ligand, ii) optionally a linker, and iii) The compound may further include a chelating agent that optionally includes a metal or radiometal. .

[0073] According to one embodiment, the pharmaceutical composition further comprises a compound of formula (I') which is a compound of formula (I). and Y is a halogen and is not a radioisotope. The formula below: [ka] (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and preferably m is , 4; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C6~C 10 Consists of aryl and heteroaryl containing 5 to 10 ring atoms wherein said aryl and heteroaryl are substituted one or more times by X; X is -ZY; Z is a bond or a C1-C6 alkylene, preferably, Z is a bond; Y is a halogen; L is C1-C6 alkylene, C3-C6 cycloalkylene, and C6-C 10 Arielle a linker selected from the group consisting of alkylene, cycloalkylene, and Arylene is -OR', =O, =NR', =N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2 R',-C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR', -NR'-C(NR ''R''')=NR'''', -S(O)R', -S(O)2R', -S(O)2NR one or more substituents selected from 'R'', -NRSO2R', -CN, and -NO2; , optionally replaced by a number ranging from zero to (2m'+l), where m' is such R', R'', R''', and R'''' are the total number of carbon atoms in the group. Each of them is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, may refer to alkyl, aryl, and heteroaryl; W is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -and- (C=S)-NR 2 -, preferably W is selected from the group consisting of -(C=O)-N R 2 - and; Each occurrence of L and W may be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or a radioactive metal. as well as pharma- ceutically acceptable salts thereof.

[0074] The form of the pharmaceutical composition, the route of administration, the dosage and the regimen will, of course, depend on the condition to be treated, It depends on the severity of the disease, the patient's age, weight, and sex, etc.

[0075] The pharmaceutical compositions of the present disclosure are intended for intravenous, intramuscular, or subcutaneous administration and the like. It can be formulated.

[0076] The pharmaceutical composition may be an aqueous solution, e.g., an injectable formulation, that contains at least one compound according to the present disclosure. The composition may take the form of a pharmaceutical preparation.

[0077] Preferably, the pharmaceutical composition is a pharma- ceutical acceptable for injectable formulation. These contain vehicles, particularly isotonic, sterile, saline solutions (monosodium phosphate or or disodium, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride nesium, and other similar or mixtures of such salts) or, where appropriate, sterilized. Drying, especially lyophilization, which allows the preparation of an injectable solution upon addition of water or saline It may also be a dry composition.

[0078] Sterile injectable solutions can be prepared by mixing 1,2-dichlorophenyl ether in an appropriate solvent with any other ingredients listed above. It is prepared by incorporating the active compound in the required amount, followed by sterilization, if desired. Generally, dispersions are prepared by incorporating the various sterilized active ingredients in a basic dispersion medium and the By incorporating the composition into a sterile vehicle containing the required other ingredients from In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is The method comprises the steps of: mixing the active ingredient and any additional desired ingredients from a previously sterile filtered solution thereof; The vacuum drying and freeze drying techniques yield powders of the formula They will be administered in a compatible manner and in such amount as is therapeutically effective. It is easily administered in a variety of dosage forms, such as a type of injectable solution.

[0079] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered and contain a liquid diluent. The agent may first be made isotonic with sufficient saline or glucose. The solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Sterile aqueous media that can be used will be known to those of skill in the art in light of the present disclosure. For example, one dosage is dissolved in 1 ml of isotonic NaCl solution and injected subcutaneously into 1000 ml of It may be added to the therapeutic fluid or injected into the intended site of injection (e.g. "Remington's Pharmaceutical Sciences" 15 th Edition, pages 1035-1038 and 1570-1580. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. It is the responsibility of the individual administering the drug to determine the appropriate dose for the individual. will be determined.

[0080] In certain embodiments, the pharmaceutical composition contains stabilizers against radiation degradation, buffers, and mixtures thereof.

[0081] As used herein, a "radiolytic stabilizer" refers to a compound that, for example, Gamma rays emitted from radioactive nuclides break the bonds between atoms in organic molecules, forming radicals. It refers to stabilizers that protect organic molecules from radiolysis when they are mixed together and then Cal will result in unwanted, potentially ineffective or even toxic molecules. The radicals are captured by stabilizers that prevent them from undergoing any other chemical reactions that they might undergo. Therefore, these stabilizers are also called "free radical scavengers" or "free radical scavengers" for short. They are also called "radical scavengers." Another alternative term for these stabilizers is "radioactive These are called "radiolytic stabilizers", "radiolytic stabilizers", or simply "quenchers".

[0082] As used herein, a "metal ion sequestering agent" refers to a metal ion sequestering agent that sequesteres the free radioactive nuclei in the formulation. Refers to a chelating agent suitable for complexing with a species metal ion (does not complex with radiolabeled peptides).

[0083] Buffers include acetate buffers, citrate buffers, and phosphate buffers.

[0084] The dose used for administration is a function of various parameters, in particular the dosage used. Adjust as a function of the mode, the pathology involved, or alternatively, the desired duration of treatment. The appropriate dosage of the compounds and compositions containing the compounds may vary from patient to patient. It will be appreciated that determining optimal dosages may be accomplished using the methods described herein. The level of therapeutic benefit relative to any risks or adverse side effects of the proposed treatment. The dosage level selected generally involves a balancing act between the activity of the particular compound, The route of administration, time of administration, rate of excretion of the compound, duration of treatment, and combinations used Other medicines, compounds, and / or materials, as well as the patient's age, sex, weight, condition, and health status The severity of the condition may depend on a variety of factors, including, but not limited to, the severity of the condition, and previous medical history.

[0085] Compounds of formula (I)-(V) for use as pharmaceuticals and methods thereof The present disclosure also relates to compounds of formulas (I)-(V) for use as pharmaceuticals. Compounds (I) to (V) have the following properties as shown in the tests provided in the Examples: They exhibit beneficial pharmaceutical properties and are therefore desirable for therapy.

[0086] The present disclosure also provides a method for treating cancer, particularly with targeted alpha radiation therapy or with beta radiation. The present invention also relates to compounds of formulae (I)-(V) for use in

[0087] The compounds of formula (IV) are particularly suitable for use as medicines, preferably for treating cancer. It is suitable for use in

[0088] As used herein, the term "cancer" refers to any cancer that is commonly known in the art. An abnormal situation or condition characterized by significant and rapidly proliferating cell growth The term includes all types of tumors, regardless of histopathological type or stage of invasion. Cancerous growths or carcinogenic processes, metastatic tissues or malignantly transformed cells, tissues, or It is meant to include organs. The term cancer includes cancers of the skin, lung, breast, thyroid, lymphatic system, digestive system, Malignant tumors of various organ systems, including those affecting the colon, rectum, and genitourinary tract, as well as most colon Cancer, renal cell carcinoma, prostate and / or testicular cancer, non-small cell lung cancer, cancer of the small intestine, and cancer of the esophagus (o This includes adenocarcinomas, including malignant tumors such as cancer of the esophages.

[0089] Examples of cancers include hematological malignancies such as B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, non-Hodgkin lymphomas, and leukemias. Kin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small Lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK cell lymphoma Examples of non-hematological cancers include, but are not limited to, hematologic, myeloid lineage neoplasms. Cancer, colon cancer, breast cancer, lung cancer, brain cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, colorectal cancer, bone cancer , cervical cancer, liver cancer, oral cancer, esophageal cancer, thyroid cancer, kidney cancer, stomach cancer, and testicular cancer, Not limited to these.

[0090] In certain embodiments, the cancer is a cancer having PSMA-expressing tumors or cells.

[0091] In certain embodiments, the present disclosure also provides a compound of the formula: It also relates to compounds I) to (V).

[0092] In certain embodiments, the prostate cancer is metastatic prostate cancer.

[0093] The present disclosure also provides methods of treating PSMA-expressing tumors or cells comprising administering to a patient of formula (I)-(C) thereof a therapeutically effective amount of PSMA. The present invention also relates to compounds of formula V).

[0094] The PSMA-expressing tumor or cell may be selected from the group consisting of: prostate tumors. or cells, metastatic prostate tumors or cells, lung tumors or cells, renal tumors or cells, glioblastoma, pancreatic tumors or cells, bladder tumor or cells, sarcoma, melanoma, breast tumor or cells, colon tumor or cells, Germ cells, pheochromocytoma, esophageal tumor or cells, gastric tumor or cells, and combinations thereof. In some other embodiments, the PSMA-expressing tumor or cells are prostate tumors or cells.

[0095] Thus, the present disclosure also provides a method for treating cancer, comprising: treating cancer cells with a therapeutically effective The present invention also relates to a method of treating a subject with a compound of Formula (I)-(V).

[0096] In certain embodiments, the cancer to be treated is a cancer having a PSMA-expressing tumor or cells. be.

[0097] The cancer to be treated is preferably prostate cancer, typically prostate cancer, including metastatic prostate cancer. It can be said that:

[0098] The present disclosure also provides a method for treating cancer in a subject in need thereof, comprising: administering to said subject, preferably a human subject, a therapeutically effective amount of a compound of formula (I)-(V); The present invention also relates to a method comprising:

[0099] As used herein, the term "contacting" refers to the treatment of the subject matter of the present disclosure. At least one compound, including a drug, is in physical contact with at least one cancer cell. Contacting refers to any treatment that involves administering at least one compound to a subject. exposing the cell or tumor to the compound in an amount sufficient to result in contact with the cell or tumor; The method may include culturing the cells in a controlled environment, such as in a culture dish or tube. In vitro or in vitro assays are performed by introducing and preferably mixing the compound and the cells or tumors into the The method can be performed ex vivo. The method can be performed in vivo. In this case, contacting may involve administering the compound to the subject via any suitable route. At least one compound of the presently disclosed subject matter is administered to a subject at least This means exposing a single cell or tumor to the same. Typically, the compound is administered intravenously. It is administered as follows.

[0100] As used herein, the term "treating" refers to any condition to which such term is applicable. or one or more of such diseases, disorders, or conditions. Reversing, alleviating, inhibiting or preventing the progression of a symptom or sign Preventing includes preventing or reducing the likelihood of a disease, disorder, condition, or other condition. To prevent the occurrence of symptoms or signs of, or aggravation of the severity of, Thus, the compounds of the present disclosure are intended to prevent the onset or recurrence of a disease, disorder, or condition. It can be administered prophylactically to prevent or reduce.

[0101] As used herein, the term "therapeutically effective amount" of a compound refers to a will induce a biological or medical response in the animal, e.g., ameliorate a symptom, alleviate a condition, Compounds that may reduce, slow or retard disease progression, or prevent disease. Refers to the amount of.

[0102] The present disclosure also relates to a compound of formula (I) for the manufacture of a medicament for the treatment of cancer, preferably prostate cancer. or a compound of formula (I)-(V) and at least one pharma- ceutically acceptable salt thereof. The present invention also relates to the use of a pharmaceutical composition comprising such a carrier.

[0103] The present disclosure also provides a method for the preparation of a compound of formula (I) for the treatment of a PSMA-expressing tumor or cell. or a compound of formula (I)-(V) and at least one pharma- ceutically acceptable salt thereof The present invention also relates to the use of a pharmaceutical composition comprising such a carrier.

[0104] Compounds of formula (I)-(V) for use in diagnostic imaging and methods thereof The present disclosure also provides a method for the preparation of a method for the preparation of a diagnostic imaging device, the method comprising: The present invention also relates to compounds of formulae (I) to (V).

[0105] The present disclosure also provides methods for treating a PSMA-expressing tumor or cell, such as a prostate tumor or cell, in a subject. Also relates to compounds of formulae (I)-(V) for use in diagnostic imaging.

[0106] The compounds of formula (V) are particularly suitable for use in diagnostic imaging, preferably for the treatment of PSMA-expressing tumours. Or it is suitable for use in diagnostic imaging of cells.

[0107] In certain embodiments, the imaging method in which the compounds of Formulae (I)-(V) are used is T (positron emission tomography) or SPECT (single photon emission computed tomography ).

[0108] Thus, the present disclosure also provides a method for diagnostic imaging, comprising treating cancer cells with an effective amount of a compound represented by formula (I). The present invention also relates to a method comprising contacting a compound of formula (V) with a compound of formula (V).

[0109] The present disclosure also provides a method for imaging a PSMA-expressing tumor or cell, comprising: contacting the A-expressing tumor or cell with a therapeutically effective amount of a compound of formula (I)-(V). The method also relates to a method comprising the steps of: Detecting signals resulting from the decay of isotopes and / or radioactive metals. It can include.

[0110] The present disclosure also provides a method for in vivo imaging of PSMA-expressing tumors or cells in a subject. The method comprises administering to said subject, preferably a human, a therapeutically effective amount of a compound represented by formula (I)-( V) and administering the compound of formula (I) to the subject. detecting a signal resulting from the decay of the radioactive metal.

[0111] In certain embodiments, the present disclosure provides a method for determining the presence or absence of a PSMA-expressing tumor in a subject. A method for detecting (i) administering to said subject a compound of Formula (I)-(V), for example as an intravenous injection; To do so; (ii) acquiring an image, typically by PET or SPECT imaging; and (iii) detecting the presence or absence of a PSMA-expressing tumor in the subject. Provide the law.

[0112] The present disclosure also provides methods for the diagnosis of cancer disorders, typically PSMA-expressing cancers, for use in diagnostic methods. The present invention also relates to a compound of formula (I)-(V) for use in diagnosing a disorder.

[0113] The present disclosure also provides methods for treating cancer cells or PSMA-expressing tumors or cells, such as prostate cancer, in a subject. A method for diagnosing and / or detecting a tumor or cell, comprising administering to the subject, preferably administering to a subject, or a human, a therapeutically effective amount of a compound of formula (I)-(V) and The signal resulting from the decay of radioisotopes and / or radiometals present in the compound is detected. The present invention also relates to a method for producing the same, comprising:

[0114] Synthesis of Compounds of Formulae (I)-(V) Compounds of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea was reacted with cyanowater in methanol. In the presence of sodium borohydride, p-nitrobenzaldehyde stimulated the synthesis of Glu-L The ys-urea 1 can be prepared by reductive alkylation of the 1-urea 1. This type of procedure has been reported in the literature. The results are described in the article (Tykvart et al. (2015) Journal of of medicinal chemistry 58,4357-63). , an aliphatic linker, Boc-5-aminovaleric acid, is coupled to two identical ε-Lys amines, e.g. , a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N '-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] Pyridinium 3-oxide hexafluorophosphate) to form a bond to produce compound 3. Compound 3 can then be reacted with, for example, a trifluoro It can be deprotected using an acid such as acetic acid to yield compound 4. Conjugation with the available DOTA-NHS ester was performed to yield compound 5. Finally, compound (III) can be reacted with 18 F - Using the nitro group can be obtained by substitution of

[0115] The compounds of formula (I), (II) and (III) are of general use in the field of radiolabelling. In particular, the compound of formula (III) can also be radiolabeled using the methods described herein. Using the method described in WO 2017 / 165473, To form a compound of formula (IV), 177 It can also be radiolabeled with Lu. Compound (III) is also described in WO 024013. To form a compound of formula (V) using the method 68 Radiolabeling with Ga It is also possible.

[0116] Scheme 1: Synthesis of compounds of formula (III) [ka]

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Z is tetrazole or COOQ, preferably Z is COOQ; Q is independently H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and preferably m is , 4; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; R is C ６ ~C １０ Consists of aryl and heteroaryl containing 5 to 10 ring atoms wherein said aryl and heteroaryl are substituted one or more times by X; X is -Z-Y; Z is a bond or C １ ~C ６ alkylene, preferably Z is a bond; Y is a radioisotope; L is C １ ~C ６ Alkylene, C ３ ~C ６ Cycloalkylene, and C ６ ~C １０ Arielle a linker selected from the group consisting of alkylene, cycloalkylene, and Arylene is -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -Halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2 R', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR'R''', -NR'C(O)OR', -NR'-C(NR ’’R’’’)=NR’’’’、-S(O)R’、-S(O) ２ R’、-S(O) ２ NR 'R', -NRSO ２ R′, —CN, and —NO ２ and one or more substituents selected from , optionally replaced with a number ranging from zero to (2m'+l), where m' is such that R', R'', R''', and R'''' are the total number of carbon atoms in the group. Each of them is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, may refer to alkyl, aryl, and heteroaryl; W is -NR ２ -(C=O), -NR ２ -(C=S), -(C=O)-NR ２ --and-- (C=S)-NR ２ -, preferably W is selected from the group consisting of -(C=O)-N R ２ - and Each occurrence of L and W may be the same or different; R ２ is H or C １ ~C ４ alkyl, preferably R ２ is H; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that optionally contains a metal or a radioactive metal. and pharma- ceutically acceptable salts thereof.

2. The compound has formula (Ia), (Ib), (Ic), or (Id): 【Chemistry 2】 2. The compound of formula (I) according to claim 1, which is a compound of the formula:

3. Yは、 １８ F、 ３４ Cl、 ７５ Br、 ７６ Br、 ７７ Br、 １２３ I、 １２４ I、 １２ ５ I, １３１ I, and ２１１ Preferably, the radioisotope is selected from the group consisting of At, Or, Y is １８ F or ２１１ At is a compound of formula (I) according to claim 1 or 2. 。

4. R is selected from the group consisting of: 【Chemistry 3】 p is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and preferably p is , 1; Preferably, R is 【Chemistry 4】 is selected from More preferably, R is 【Chemistry 5】 A compound of formula (I) according to any one of claims 1 to 3,

5. R is 【Chemistry 6】 A compound of formula (I) according to any one of claims 1 to 4,

6. Ch is selected from the group consisting of: 【Chemistry 7】 Optionally, a compound of formula (I) according to any one of claims 1 to 5, which comprises a metal or a radioactive metal Compound.

7. L is -OR', ═O, ═NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)O R' may be one or more substituents ranging from zero to (2m'+l). Optionally substituted C ３ ~C ６ is a linker selected from the group consisting of alkylene; m' is the total number of carbon atoms in such group. R', R'', R''', and R Each "" is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, The aryl group of the aryl group of claims 1 to 6 may be heterocycloalkyl, aryl, and heteroaryl. A compound of formula (I) according to any one of the preceding claims.

8. Ch is Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, 8. The method according to claim 1, further comprising the step of: A compound of formula (I) as described above.

9. The metal is ６８ G.A. ６４ Cu, ８６ Y. ９０ Y. ８９ Zr, １１１ In, ９９ｍ T c、 １７７ Lu, １５３ Sm, １８６ Re, １８８ Re, ６７ Cu, ２１２ Pb, ２２５ A c, ２１３ Bi, ２１２ Bi, ２１２ Pb, ６７ G.A. ２０３ Pb, ４７ Sc, and １ ６６ 9. The compound of formula (I) according to claim 8, wherein the radiometal is selected from:

10. The compound has the formula (II): 【Chemistry 8】 (Wherein, L is -OR', ═O, ═NR', -NR'R'', -halogen, -OC(O) R', -C(O)R', -CO2R', -C(O)NR'R'', -OC(O)NR'R '', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C( O) OR', ranging from zero to (2m'+l) C optionally replaced with a number ３ ~C ６ A linker selected from the group consisting of alkylene and m' is the total number of carbon atoms in such group. and R"" are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, (which may refer to alkyl, heterocycloalkyl, aryl, and heteroaryl) A compound of formula (I) according to any one of claims 1 to 9,

11. The compound of formula (II) is ６８ Ga or ６７ The compound according to claim 10, which contains Ga, Compound I).

12. The compound of formula (II) is １７７ Lu or １７６ The formula of claim 10 comprising Lu Compound (II).

13. A compound according to any one of claims 1 to 12 and at least one pharma- ceutically acceptable salt thereof. A pharmaceutical composition comprising a carrier.

14. The composition comprises i) a PSMA-binding ligand, ii) optionally a linker, and iii) 13. The compound according to claim 12, further comprising a chelating agent optionally comprising a metal or a radioactive metal. The pharmaceutical composition described in

15. A compound according to any one of claims 1 to 12 for use as a medicament.

16. The compounds are useful for treating cancer, particularly by targeted alpha radiation therapy and by beta radiation.

16. The compound for use according to claim 15, which is for use in

17. The compound is for use in treating prostate cancer.

7. A compound for use as described in claim 6.

18. Claims 1 to 12 for use in diagnostic imaging, preferably PET and SPECT The compound according to any one of claims 1 to 5.

19. Typically, the antibody is used in a diagnostic method for use in cancer disorders, such as PSMA-expressing cancers. The compound according to any one of claims 1 to 12 for use in treating a chronic inflammatory condition.

20. Contacting cancer cells with a therapeutically effective amount of a compound according to any one of claims 1 to 12.

46. ​​A method for treating cancer comprising:

21. Administering to a subject an effective amount of a compound according to any one of claims 1 to 12, and obtained from the decay of said radioisotope and / or said radiometal present in said compound. A method for diagnostic imaging comprising detecting a signal.

22. For diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells in a subject. A method for administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 12. to said subject, preferably a human, and said radioactive compound present in said compound. detecting a signal resulting from the decay of the isotope and / or said radioactive metal; method.

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