Prostate-specific membrane antigen (PSMA) ligands and their use

Abstract

This invention provides prostate-specific membrane antigen (PSMA) ligands, as well as the use of these compounds in the imaging and treatment of prostate cancer. [Solution] A PSMA ligand is provided having a chelating agent that can contain a glutamate-urea-lysine (GUL) component, a radioisotope, and a radiometal.

Description

Technical Field

[0001] The present disclosure relates to prostate-specific membrane antigen (PSMA) ligands. In particular, the present disclosure relates to PSMA ligands having a glycine-urea-lysine (GUL) component, a radioisotope, and a chelating agent that can include a radioactive metal.

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

Background Art

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

[0004] In the context of nuclear medicine, theragnostics refers to the use of molecular target molecules labeled with diagnostic radioactive metals (e.g., positron or gamma emitters) or therapeutic radioactive metals (e.g., beta emitters) for the diagnosis and therapy of specific diseases. The most developed approach is based on radiolabeling target molecules with high affinity for receptors expressed on tumor cells with gallium Ga-68 for diagnostic purposes or lutetium Lu-177 for therapeutic purposes. Thus, following molecular imaging diagnosis and disease diagnosis, individualized treatment using the same molecular target compound can be effectively performed.

[0005] This is because it allows for the selection of therapies or different treatment approaches, as well as follow-up surveys after treatment. ru.

[0006] For patients, theragnostics ultimately result in more effective medical care and eliminate unnecessary treatments. Reduce or eliminate treatment, and tailor therapeutic interventions to the patients who will benefit the most. It is possible that the patient may not respond to unnecessary treatment, or otherwise experience side effects. By predicting which patients will experience this condition, the theragnostic approach is efficient. It's not just about being patient-centered, but also about being patient-centered.

[0007] For physicians, theragnostics is the optimal therapy for diagnosing and staging diseases. To select, as well as to monitor treatment effectiveness and disease progression, to improve one's own abilities and health To improve the above outcomes, we can safely and effectively improve predictive capabilities. ru.

[0008] For payers, the theragnostic approach is not the optimal diagnostic and therapeutic method. To reduce associated costs and shorten the time required for diagnosis, and to provide effective individualized treatment plans. It can treat patients.

[0009] Prostate cancer is one of the most widespread cancers in the United States and Europe. In particular, metastatic pre-prostate cancer is common. Prostate carcinoma (mCRPC) is associated with a poor prognosis and a reduced quality of life.

[0010] Recently, PSMA ligand-based internal radiotherapy (endo-radiotherapy) has been gaining popularity. rapy) is an example of a new development trend in the treatment of prostate cancer, PSM A is overexpressed in primary cancer lesions and in soft tissue / bone metastatic diseases, therefore It is considered a suitable target for imaging diagnosis and therapy. Furthermore, PSMA expression is associated with disease. This appears to be even more pronounced in the castration-resistant variant, which is the most malignant of the variants. This is a typical example of a patient population with high medical needs that has not yet been addressed (March 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 that target PSMA, urea-based low-molecular-weight active agents are These were the most extensively investigated. These active ingredients were used in the clinical evaluation and PR of prostate cancer. It has been shown to be suitable for RT therapy. Some of these active ingredients are used as target scaffolds. It contains glutamate-urea-lysine (GUL).

[0012] Some radiolabeled small molecule inhibitors of PSMA were designed using this as a starting point (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 certain circumstances, the use of radioactive metals for diagnostic purposes may be limited (6 (Problems arising from the availability of 8Ga and the fragmentation of its production.)

[0014] On the other hand, 68Ga has a physical half-life of only 68 minutes. Therefore, 68Ga- PSMA-PET scans are preferably performed in-house and with sufficient tracer radioactivity. Delivery to remote centers is difficult. As a result, large-scale facilities with many patients The center requires production several times a day, or the simultaneous operation of multiple production machines. It requires movement, which increases costs. Meeting the quantitative demand for such centers... To overcome these limitations, the use of 18F-labeled PSMA tracers is also possible. Good. A PET radiopharmaceutical pharmacy with a cyclotron on site (radiophar Macy can produce highly radioactive 18F at an affordable cost. 18F labeling The physical half-life of PSMA tracers (110 minutes) is also a factor in the centralization of production and remote satellites. This could enable delivery to the light center. 18F also has a lower positron energy than 68Ga. It has energy (0.65 vs. 1.90 MeV) and theoretically leads to an improvement in spatial resolution.

[0015] However, the development of alternative PSMA ligands is always desirable. The reason is that diagnostic methods... The development of a diverse range of alternative PSMA ligands suitable for use as both a therapeutic agent and / or treatment would be beneficial. Because it could become that. [Overview of the Initiative]

[0016] In a first embodiment, this disclosure relates to 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 It consists of an aryl and a heteroaryl containing 5 to 10 ring atoms. Selected from the group, the aryl and heteroaryl are substituted with X one or more times; X is -ZY; Z is a bond or a C1-C6 alkylene, preferably Z is a bond; Y is a radioactive isotope; L is C1-C6 alkylene, C3-C6 cycloalkylene, and C6-C 10 Allire A linker selected from the group consisting of, the alkylene, cycloalkylene, and Arirene 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 Therefore, it is arbitrarily replaced with a number in the range of zero to (2m'+l), where m' is such This is the total number of carbon atoms in a group. R', R'', R''', and R'''' are... Each independently consists of hydrogen, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. This may also refer to kill, aryl, and heteroaryl compounds; W is -NR 2 -(C=O), -NR 2-(C=S), -(C=O)-NR 2 -, and - (C=S)-NR 2 Selected from the group consisting of -, preferably, W is -(C=O)-N R 2 -; Each occurrence of L and W can 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 optionally containing a metal or a radioactive metal) relates to compounds of ) and their pharmaceutically acceptable salts.

[0017] The compounds of formula (I) contain both a chelating agent that can contain a radioisotope and a radioactive metal. The fact that the PSMA ligand may be labeled via various modes makes it possible to expand its use. For example, the compounds of formula (I) can contain radioactive halogens and metals used for the purposes of diagnostic or therapeutic imaging in nuclear medicine. In a second aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier.

[0018] In a third aspect, the present disclosure relates to a compound of formula (I) for use as a pharmaceutical. In a fourth aspect, the present disclosure relates to a compound of formula (I) for use in treating cancer, especially prostate cancer.

[0019] In a fifth aspect, the present disclosure relates to a compound of formula (I) for use in diagnostic imaging.

[0020] In a fifth aspect, the present disclosure relates to a compound of formula (I) for use in diagnostic imaging.

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

[0022] In a sixth aspect, the disclosure also relates to a method for treating prostate cancer, wherein cancer cells The present invention also relates to a method that involves contacting the compound of formula (I) with an effective amount of the compound of formula (I).

[0023] In a seventh aspect, the disclosure also relates to a method for imaging diagnostics, which effectively targets cancer cells. Contact with the compound of formula (I) and the decay of radioactive isotopes present in the compound This also relates to methods that include detecting signals obtained from destruction. [Modes for carrying out the invention]

[0024] definition As used herein, the term “protecting group” in relation to the compound of formula (I) means Selected by readily available reagents that do not attack the resulting functional group or other functional groups in the molecule. This refers to chemical substituents that can be removed. Suitable protecting groups are known in the art. It is being developed and is still being researched. Suitable protecting groups include, for example, Wutz et al. (" Greene's Protective Groups in Organic Sy nthesis, Fourth Edition”, Wiley-Interscien Protecting groups for protecting the carboxyl group may be found in (ce, 2007). As described in Wutz et al. (pages 533-643), a certain actual It is used in application forms. In some embodiments, the protecting group is obtained by treatment with an acid. It can be removed.

[0025] Typical examples of protecting groups are benzyl, p-methoxybenzyl (PMB), and tertiary butyl (t- Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl Chill (MTM), tetrahydropyranil (THP), tetrahydrofuranil (THF), Benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (T ES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl) This includes, but is not limited to, Tr. Those skilled in the art will know the appropriate conditions under which the protecting group is required. It is possible to recognize and select the appropriate protecting group for use in specific situations. Ro.

[0026] As used herein, the term "alkyl" means either alone or with another substituent. The term refers to a linear or branched alkyl functional group having 1 to 12 carbon atoms. Suitable A The propyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and their 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 the divalent alkyl group as defined above.

[0028] As used herein, the term "cycloalkyl" refers to a group of 3 to 6 carbon atoms. This refers to a saturated or unsaturated cyclic group having [a specific characteristic]. Suitable cycloalkyl groups include cyclopropyl and cyclopropyl. It contains clobutyl, cyclopentyl, and cyclohexyl.

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

[0030] As used herein, the term "aryl" means that at least one ring is aromatic A group of aromatic rings containing 6 to 10 ring atoms, either a single ring or multiple aromatic rings fused together. This refers to the polyunsaturated aromatic hydrocarbyl group it possesses. The aromatic ring is optionally fused to it. One or two additional rings (cycloalkyl, heterocyclyl as defined herein) It may also contain (or heteroaryl). Suitable aryl groups include benzopyranyl, benzopyranyl, and benzopyranyl. Heterocycline compounds such as benzodioxalil, benzodioxanil, and other similar compounds. It contains phenyl, naphthyl, and phenyl rings fused to the compound.

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

[0032] Alkyl, cycloalkyl, and aryl monovalent and divalent derivative groups are -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', - One or more substituents selected from CN and -NO2, in the range of zero to (2m'+l) It can be substituted with a number spanning the range, where m' is the total number of carbon atoms in such a group. R', R'', R''', and R'''' are each independently hydrogen and alkyl. , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroalkyl It may also refer to the letter.

[0033] As used herein, the term "halogen" refers to fluoro(-F), chloro This refers to the (-Cl), bromo (-Br), or iodine (-I) group.

[0034] As used herein, the term "heteroalkyl" refers to a group of 1 to 6 carbon atoms. Furthermore, straight having 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S This refers to a chain or branched alkyl functional group, and the nitrogen and sulfur atoms may be optionally oxidized. The nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, and S are hetero Any internal position of the r-alkyl group or a position where the alkyl group is attached to the rest of the molecule It may be placed there.

[0035] As used herein, the term “heteroaryl” refers to a single ring or a combination of two rings. It has multiple fused or covalently bonded aromatic rings and contains 5 to 10 atoms. This refers to a valence-unsaturated aromatic ring system in which at least one ring is aromatic and at least one ring The atom is a heteroatom selected from N, O, and S. Nitrogen and sulfur heteroatoms are, The nitrogen heteroatom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Such rings may be fused to aryl, cycloalkyl, or heterocyclyl rings. Non-exclusive examples of heteroaryls include furanyl, thiophenyl, pyrrolyl, and pyrazo. Lyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl (oxatriazolyl), thiatriazolyl, pi Lydinyl, pyrimidyl, pyrazinyl, pyridadinyl, oxazinyl , dioxinyl, thiazinyl, triazinyl Lu, indolyl, isoindolyl, benzofuranyl, isoben Zofranil, benzothiophenyl, isobenzothiophenyl phenyl), indazolyl, benzimidazolyl, benzoxazolyl, prinyl, Benzothiadiazolyl, quinolinil, isoquinolinil, cinnolinil, quinazolinil, and Contains quinoxalinyl.

[0036] As used herein, the term "heterocycloalkyl" means 5 to 10 This refers to a saturated or unsaturated cyclic group having a ring atom, where at least one ring atom is N, O, and It is a heteroatom selected from S. Nitrogen and sulfur heteroatoms are optionally oxidized. Furthermore, nitrogen heteroatoms may be optionally quaternized. An example of a heterocycle is tetrahedron. Tetrahydropyridyl, piperidinil, morpholinil, Tetrahydrofuranil, Hittrahydrothienyl, Piperazinil, 1-azepanil, Imida This includes, but is not limited to, zolinyl, 1,4-dioxanyl, and other similar substances. stomach.

[0037] Various embodiments of this disclosure are described herein. Each embodiment is specified in The features described may be combined with other specific features to provide further embodiments. This will be recognized.

[0038] This disclosure relates to compounds of formulas (I), (II), (III), and (IV), and their stereochemical compounds. Sexual compounds, tautomers, enantiomers, diastereomers, racemates, or mixtures thereof, This includes their hydrates, solvates, or pharmaceutically acceptable salts.

[0039] The term "pharmaceutically acceptable salt" means that the salt retains the biological efficacy and properties of the compound of this disclosure. It also refers to salts that are not generally undesirable from a biological or other standpoint.

[0040] "Pharmacologically" or "pharmaceutically acceptable" means that it is administered appropriately to mammals, especially humans. Molecular substances that, when used, do not cause harmful, allergic, or other troublesome reactions. Refers to bodies and compositions. Pharmaceutically acceptable carriers or excipients are non-toxic solids, semi-solids, and so on. This refers to liquid bulking agents, diluents, mounting agents, or any type of pharmaceutical additive.

[0041] As used herein, the term “subject” means an animal, preferably a mammal, more Preferably refers to a human.

[0042] Compound of formula (I) In a first embodiment, this disclosure relates to 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 10It consists of an aryl and a heteroaryl containing 5 to 10 ring atoms. Selected from the group, the aryl and heteroaryl are substituted with X one or more times; X is -ZY; Z is a bond or a C1-C6 alkylene, preferably Z is a bond; Y is a radioactive isotope; L is C1-C6 alkylene, C3-C6 cycloalkylene, and C6-C 10 Allire A linker selected from the group consisting of, the alkylene, cycloalkylene, and Arirene 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 Therefore, it is arbitrarily replaced with a number in the range of zero to (2m'+l), where m' is such This is the total number of carbon atoms in a group. R', R'', R''', and R'''' are... Each independently consists of hydrogen, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. This may also refer to kill, aryl, and heteroaryl compounds; W is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -, and - (C=S)-NR 2 Selected from the group consisting of -, preferably W is -(C=O)-N R 2 -and; The existences of L and W may be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 H is; 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 radioactive metal. This relates to the compounds and their pharmaceutically acceptable salts.

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

[0044] The phrase "The existences of L and W may be the same or different" is a variable If n is 2 or 3, one of the L groups can be a C1-C6 alkylene. The other "L" group can be a C3-C6 cycloalkylene or arylene. In one or another embodiment, each "L" group is, for example, a C1-C6 alkylene. This means that it is possible. Similarly, for example, if "n" is 2 or 3, then one of "W" The base is -(C=O)-NR 2 -This can be done, and the other "W" group is -(C=S)- NR 2 -In other embodiments, each "W" may be, for example, -(C=O )-NR 2 - This can be done.

[0045] According to one embodiment, L is C1-C6 alkylene, C3-C6 cycloalkylene, and bi C6~C 10 A linker selected from the group consisting of arylenes, wherein the alkylene, Cycloalkylenes and arylenes are -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 ''', one or more substituents selected from -NR''C(O)OR', zero ~ (2 It is optionally substituted with a number in the range of m'+l), where m' is the carbon in such a group. This is the total number of atoms. R', R'', R''', and R'''' are each independent of each other. Hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, It may also refer to heteroaryls.

[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' by one or more substituents selected from 2m'+l A number of C3-C6 alkylenes is arbitrarily selected to replace them in the range of ). It is a linker, and m' is the total number of carbon atoms in such a group. R', R '', R'''', and R'''' are, independently, hydrogen, alkyl, and heteroal. Refers to cycloalkyl, heterocycloalkyl, aryl, and heteroaryl compounds. That's good too.

[0047] Typically, the radioactive isotope 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 You can choose from the following group, preferably Y is 18 F or 211 It is 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 , is 1; Preferably, R is [ka] Selected from, Comfortable, R is [ka] That is the case.

[0049] To the advantage, R is [ka] That is the case.

[0050] Ch is selected from the following group: [ka] Optionally, it may contain metal or radioactive metal.

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

[0052] Metals or radioactive metals are preferably suitable for use in diagnostic imaging or therapy. It is selected from metals and radioactive metals.

[0053] According to one embodiment, Ch is Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb , including metals selected from Ac, Bi, Al, Ga, Re, Ho, and Sc. The metals are, 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 It can be a selected radioactive metal.

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

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

[0058] According to a particular embodiment, the compound of formula (I) is formula (II): [ka] It is a compound of -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 One or more substituents selected from ''C(O)OR' in the range of zero ~ (2m'+l) A number of C3-C6 alkylenes are arbitrarily selected to replace a number within the range. R', R'', R ''', and R'''' are independently hydrogen, alkyl, heteroalkyl, and cy This may also refer to chloroalkyl, heterocycloalkyl, aryl, and heteroaryl compounds.

[0059] Advantageously, the compound of formula (II) is preferably 68 Ga, 67 Ga, 177 Lu, and 176Includes metals or radioactive metals selected from Lu.

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

[0061] According to another specific 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) is formula (III): [ka] It is a compound that optionally contains a metal or a radioactive metal.

[0063] The compounds of formula (III) are formulas (IIIa), (IIIb), (IIIc), and (II ID): [ka] This includes stereoisomers.

[0064] Advantageously, the compound of formula (III) is preferably 68 Ga, 67 Ga, 177 Lu, and Beauty 176 Includes metals or radioactive metals selected from Lu.

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

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

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

[0068] The compounds of formula (IV) are (IVa), (IVb), (IVc), and (IVd): [ka] This includes stereoisomers.

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

[0070] The compounds of formula (V) are (Va), (Vb), (Vc), and (Vd): [ka] This includes stereoisomers.

[0071] Pharmaceutical composition This disclosure also relates to compounds of formulas (I) to (V) and at least one pharmaceutically acceptable compound. This also relates to pharmaceutical compositions containing carriers.

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

[0073] According to one embodiment, the pharmaceutical composition contains a compound of formula (I) which is a compound of formula (I'). Furthermore, Y is a halogen and not a radioactive isotope. The compound of formula (I') is The following formula: [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 It consists of an aryl and a heteroaryl containing 5 to 10 ring atoms. Selected from the group, the aryl and heteroaryl are substituted with X one or more times; 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 Allire A linker selected from the group consisting of, the alkylene, cycloalkylene, and Arirene 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 Therefore, it is arbitrarily replaced with a number in the range of zero to (2m'+l), where m' is such This is the total number of carbon atoms in a group. R', R'', R''', and R'''' are... Each independently consists of hydrogen, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. This may also refer to kill, aryl, and heteroaryl compounds; W is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -, and - (C=S)-NR 2 Selected from the group consisting of -, preferably W is -(C=O)-N R 2 -and; The existences of L and W may be the same or different; R 2 is H or C1-C4 alkyl, preferably R 2 H is; 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 radioactive metal. It also has pharmaceutically acceptable salts thereof.

[0074] The form of the pharmaceutical composition, the route of administration, the dosage, and the regimen are, of course, determined by the condition being treated. It depends on the severity of the illness, the patient's age, weight, and sex, etc.

[0075] The pharmaceutical compositions disclosed herein are intended for intravenous, intramuscular, subcutaneous, and other similar administration. It can be formulated into a pharmaceutical product.

[0076] The pharmaceutical composition is an aqueous solution, for example, an injectable solution comprising at least one compound according to this disclosure. It can take the form of a drug.

[0077] Preferably, the pharmaceutical composition is pharmaceutically acceptable for an injectable formulation. It contains vehicles. These are especially isotonic, sterile, and contain saline solutions (monosodium phosphate or similar). The alternatives are disodium, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride. Nesium and other similar substances or mixtures of such salts) or, as appropriate, sterilization When adding water or saline solution, drying is required to enable the preparation of an injectable solution, particularly freeze-drying. It may also be a dry composition.

[0078] The sterile injection solution, along with several other components listed above, is prepared in a suitable solvent. It is prepared by incorporating the active compound in the required amount, and then, if necessary, subsequently dissolved. The bacteria are filtered out. Generally, the dispersion contains various sterilizing active ingredients in a basic dispersion medium and the above-mentioned components. By incorporating it into a sterile vehicle containing other necessary components from the available materials, It is prepared in this way. In the case of sterile powder for the preparation of sterile injection solution, the preferred method of preparation is... The method involves extracting the active ingredient and any additional desired ingredients from the pre-sterilized and filtered solution. This is a vacuum drying and freeze-drying technology that produces powder. In the formulation process, the solution is used with the drug formulation. It will be administered in a suitable manner and in a therapeutically effective dose. The formulation is as described above. It can be easily administered in various dosage forms, such as injectable solutions.

[0079] For parenteral administration in aqueous solutions, for example, the solution should be properly treated with a buffer and diluted. The agent may first be made isotonic with sufficient saline solution or glucose. These specific water The solution is particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. The sterile aqueous media that can be used will be apparent to those skilled in the art in consideration of this disclosure. For example, one dose is dissolved in 1 ml of isotonic NaCl solution and administered by subcutaneous injection of 1000 ml. It may be added to the therapeutic fluid or injected into the site where it is intended to be injected (for example) "Remington's Pharmaceutical Sciences" 15 See pages 1035-1038 and 1570-1580 of the th Edition. i) Some variation in the dosage is inevitable depending on the condition of the patient being treated. It will happen. The person administering the medication will, in any case, determine the appropriate dose for each individual patient. It will be determined.

[0080] In certain embodiments, pharmaceutical compositions, stabilizers against radiolysis, buffers, It comprises one or more excipients selected from a metal ion shielding agent and a mixture thereof.

[0081] As used herein, “stabilizer for radiolysis” means, for example, Gamma rays emitted from radioactive nuclides break the bonds between atoms in organic molecules, forming radicals. In that case, it refers to a stabilizer that protects organic molecules from radiolysis, and then, those radios Does CAL bring about unwanted, potentially ineffective, or even toxic molecules? By using stabilizers that prevent radicals from undergoing any other chemical reactions, They are captured. Therefore, these stabilizers are also called "free radical scavengers" or, for short, " They are also called "radical scavengers." Other alternative terms for these stabilizers include "radiation." These are called "linear stability enhancers," "radiolysis stabilizers," or simply "inactivators."

[0082] As used herein, “metal ion shielding agent” refers to free radioactive nuclei in the formulation. This refers to a chelating agent suitable for seed metal complex ions (it does not form complexes with radiolabeled peptides).

[0083] The buffers include acetate buffer, citrate buffer, and phosphate buffer.

[0084] The dose used for administration is a function of various parameters, in particular, of the dose used. Adjust as a function of the mode, the associated pathological condition, or, instead, the desired duration of treatment. The appropriate dosage of the compound and the composition containing the compound may vary depending on the patient. It will be understood that this is obtained. Determining the optimal dosage is described herein. Regarding the level of therapeutic benefit compared to any risks or adverse side effects of the treatment being performed. It generally involves balancing. The level of dosage selected depends on the activity of the specific compound. Route of administration, time of administration, rate of compound elimination, duration of treatment, and combinations used. Other pharmaceuticals, compounds, and / or materials, as well as the patient's age, sex, weight, condition, and health status. This could be due to a variety of factors, including, but not limited to, past medical history.

[0085] Compounds of formulas (I) to (V) for use as pharmaceuticals and methods thereof. This disclosure also relates to compounds of formulas (I) to (V) for use as pharmaceuticals. Compounds (I) to (V) are, as shown in the tests provided in the examples, It exhibits beneficial pharmaceutical properties, and therefore is desirable for therapy.

[0086] This disclosure also relates to treating cancer, particularly by targeted alpha-ray therapy or beta-ray therapy. This also relates to the compounds of formulas (I) to (V) used in the process.

[0087] Compounds of formula (IV) are particularly preferred for use as pharmaceuticals to treat cancer. It is suitable for use in that situation.

[0088] As used herein, the term "cancer" is a general term in the art. An abnormal situation or condition characterized by the growth of meaningful and rapidly proliferating cells. This includes all types, regardless of histopathological type or stage of invasion. Cancerous growth or carcinogenic process, metastatic tissue or malignantly transformed cells, tissues, or It means including organs. The term cancer can refer to the skin, lungs, breasts, thyroid, lymphatic system, digestive system, etc. Malignant tumors of various organ systems, including those affecting the ducts and urogenital system, as well as most colon Cancer, renal cell tumor, prostate cancer and / or testicular tumor, non-small cell lung cancer, small intestine cancer, and esophageal (o This includes adenocarcinomas, which are malignant tumors such as cancers of esophages.

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

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

[0091] In certain embodiments, the disclosure also relates to a formula for use in treating prostate cancer. This also relates to compounds I) to (V).

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

[0093] This disclosure also relates to formulas (I) to ( for use in treating PSMA-expressing tumors or cells). This also relates to compound V).

[0094] PSMA-expressing tumors or cells can be selected from the following group: prostate tumors or cells, metastatic prostate tumors or cells, lung tumors or cells, kidney tumors or cells, glioblastoma, pancreatic tumors or cells, bladder tumor or cells, sarcoma, melanoma, breast tumor or cells, colon tumor or cells, living Cellular proliferative tumors, pheochromocytomas, esophageal tumors or cells, gastric tumors or cells, and combinations thereof. How many? In another embodiment, the PSMA-expressing tumor or cells are prostate tumors or cells.

[0095] Therefore, this disclosure also relates to a method for treating cancer, which involves treating cancer cells in a therapeutically efficient manner. This also relates to methods that involve contacting the compounds of the formulas (I) to (V) in terms of quantity.

[0096] In a particular embodiment, the cancer to be treated is a cancer having PSMA-expressing tumors or cells. be.

[0097] The cancer to be treated is preferably prostate cancer, typically including metastatic prostate cancer. It can be done this way.

[0098] This disclosure also relates to a method for treating cancer in a person in need of such treatment. A therapeutically efficient amount of the compound according to formulas (I) to (V) is administered to the subject, preferably a human subject. This also concerns methods, including how to do something.

[0099] As used herein, the term “to bring into contact” means the treatment of the subject matter of this disclosure. At least one compound containing the drug comes into physical contact with at least one cancer cell. This means any action that results in contact with at least one compound. Exposing a cell or tumor to a compound in an amount sufficient to bring it into contact with the cell or tumor. This may include the following: By introducing compounds and cells or tumors into the body and preferably mixing them, in vitro or This can be done ex vivo. The method can be done in vivo. In this case, contact is the administration of the compound to the subject via any suitable route. For example, at least one compound of the subject matter of this disclosure has at least This means exposing a single cell or tumor. Typically, the compound is administered via an intravenous route. It is administered as follows.

[0100] As used herein, the term "to treat" is used in the context of the application of such terminology. A disease, disorder, or condition, or one or more of such diseases, disorders, or conditions. To reverse, alleviate, inhibit, or prevent the progression of symptoms or signs. , or reducing the likelihood thereof. Prevention includes preventing disease, disability, condition, or so To prevent the occurrence of symptoms or signs of such conditions, or the worsening of the severity of such conditions. This refers to causing the onset or recurrence of a disease, disorder, or condition. For prevention or reduction, it can be administered prophylactically.

[0101] As used herein, the term "therapeutically effective amount" of a compound refers to an amount of the compound that will induce a biological or medical response in a subject, e.g., relieve symptoms, attenuate a condition, slow or delay disease progression, or prevent a disease.

[0102] The present disclosure also relates to the use of a compound of formula (I)-(V) or a compound of formula (I)-(V) and at least one pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment of cancer, preferably prostate cancer.

[0103] The present disclosure also relates to the use of a compound of formula (I)-(V) or a compound of formula (I)-(V) and at least one pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment of PSMA-expressing tumors or cells.

[0104] Compounds of formula (I)-(V) and methods thereof for use in diagnostic imaging The present disclosure also relates to compounds of formula (I)-(V) for use in diagnostic imaging, preferably in vivo diagnostic imaging.

[0105] The present disclosure also relates to compounds of formula (I)-(V) for use in diagnostic imaging of PSMA-expressing tumors or cells, e.g., prostate tumors or cells, in a subject.

[0106] Compounds of formula (V) are particularly suitable for use in diagnostic imaging, preferably for use in diagnostic imaging of PSMA-expressing tumors or cells.

[0107] In certain embodiments, imaging diagnostic methods using compounds of formulas (I) to (V) are PE T (positron emission tomography) or SPECT (single-photon emission computed tomography) )

[0108] Therefore, this disclosure also relates to a method for imaging diagnostics, wherein cancer cells are measured using an effective amount of formula (I) This also relates to methods that involve contact with the compound of (V).

[0109] This disclosure also relates to a method for imaging PSMA-expressing tumors or cells, and PSM Contact A-expressing tumors or cells with a therapeutically efficient amount of the compounds of formulas (I) to (V). The method also relates to a method that includes the radioactive material present in the compound. The step of detecting signals obtained from the decay of isotopes and / or radioactive metals further It can include.

[0110] This disclosure also relates to the in vivo imaging of PSMA-expressing tumors or cells in the subject. A method for which a therapeutically efficient amount of formula (I)~( is given to the subject, preferably a human) is given. Administering compound V) and radioactive isotopes and / or radioactive materials present in the compound This also relates to methods that include detecting signals obtained from the decay of projectile metals.

[0111] In certain embodiments, this disclosure concerns the presence or absence of PSMA-expressing tumors in the subject. A method for detecting, (i) In the subject, for example, administer the compounds of formulas (I) to (V) by intravenous injection. to do; (ii) Acquiring images typically by PET or SPECT imaging; and (iii) A method that includes detecting the presence or absence of PSMA-expressing tumors in the subject. Provide a method.

[0112] The present disclosure also relates to compounds of formulas (I)-(V) for use in diagnostic methods, typically for diagnosing cancer disorders such as PSMA-expressing cancers. Also related to compounds of formulas (I)-(V) for use in diagnosing cancer cells or PSMA-expressing tumors or cells, such as prostate tumors or cells, in a subject.

[0113] The present disclosure also relates to a method for diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells, such as prostate tumors or cells, in a subject, the method comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound of formulas (I)-(V) and detecting a signal obtained from the decay of a radioisotope and / or radioactive metal present in the compound. Preferably, the method comprises administering to the subject, preferably a human, a therapeutically effective amount of a compound of formulas (I)-(V) and detecting a signal obtained from the decay of a radioisotope and / or radioactive metal present in the compound. Preferably, the method comprises administering to the subject, preferably a human, a therapeutically effective amount of a compound of formulas (I)-(V) and detecting a signal obtained from the decay of a radioisotope and / or radioactive metal present in the compound. Preferably, the method comprises administering to the subject, preferably a human, a therapeutically effective amount of a compound of formulas (I)-(V) and detecting a signal obtained from the decay of a radioisotope and / or radioactive metal present in the compound. Preferably, the method comprises administering to the subject, preferably a human, a therapeutically effective amount of a compound of formulas (I)-(V) and detecting a signal obtained from the decay of a radioisotope and / or radioactive metal present in the compound.

[0114] Synthesis of Compounds of Formulas (I)-(V) The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 【58, 4357-63】). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- The compound of formula (III) can be synthesized as disclosed in Scheme 1. The p-nitrobenzyl group 2 modified with Glu-Lys urea can be prepared by reductive alkylation of Glu-Lys urea 1 with p-nitrobenzaldehyde in the presence of sodium cyanoborohydride in methanol. This type of procedure is described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). Then, an aliphatic linker, Boc-5-aminovaleric acid, is coupled to the same ε-Lys amine of 2, for example, with a base (such as N,N-diisopropylethylamine) and a coupling agent (N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b) Using a compound such as pyridinium 3-oxide hexafluorophosphate, This allows compound 3 to be produced. Compound 3 can then be, for example, trifluoro It can be deprotected to produce compound 4 using an acid such as acetic acid. Conjugation with available DOTA-NHS esters to produce compound 5 This can be done. Finally, compound (III) 18 F - Nitro group used This can be obtained by substitution.

[0115] Compounds of formulas (I), (II), and (III) are commonly used in the field of radiolabeling. It can be radiolabeled using the method described. In particular, the compound of formula (III) can also be Using the method described in International Publication No. 2017 / 165473, To form the compound of formula (IV), 177 It can also be radiated using Lu. (Formula) Compound (III) is also described in International Publication No. 024013. Using the method, to form the compound of formula (V), 68 Radiation labeling with Ga It's also possible.

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

Claims

1. Equation (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 It consists of an aryl and a heteroaryl containing 5 to 10 ring atoms. Selected from the group, the aryl and heteroaryl are substituted with X one or more times; X is -Z-Y; Z is a combination or C １ ~C ６ It is an alkylene, preferably where Z is a bond; Y is a radioactive isotope; L is C １ ~C ６ alkylene, C ３ ~C ６ cycloalkylene, and C ６ ~C １０ arylene A linker selected from the group consisting of, the alkylene, cycloalkylene, and Arrine 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 One or more substituents selected from It is then arbitrarily replaced with a number in the range of zero to (2m' + l), where m' is such It is the total number of carbon atoms in a group. R', R'', R'''', and R'''' are... Each independently consists of hydrogen, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. This may also refer to kill, aryl, and heteroaryl compounds; W is -NR ２ -(C=O), -NR ２ -(C=S), -(C=O)-NR ２ - and - (C=S)-NR ２ Selected from the group consisting of -, preferably W is -(C=O)-N R ２ - and; The existences of L and W may be the same or different; R ２ is H or C １ ~C ４ It is alkyl, preferably R ２ H is; 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 radioactive metal. Compounds thereof and their pharmaceutically acceptable salts.

2. The aforementioned compounds are defined by formulas (Ia), (Ib), (Ic), or (Id): 【Chemistry 2】 A compound of formula (I) as described in claim 1, which is a compound of the above.

3. Yは、 １８ F、 ３４ Cl、 ７５ Br、 ７６ Br、 ７７ Br、 １２３ I、 １２４ I、 １２ ５ I, １３１ I, and ２１１ A radioactive isotope selected from the group consisting of At, preferred In other words, Y is, １８ F or ２１１ A compound of formula (I) according to claim 1 or 2, wherein At 。

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

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

6. Ch is selected from the following group: 【Transformation 7】 Optionally, formula (I) according to any one of claims 1 to 5, comprising a metal or a radioactive metal. A compound of [this].

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 One or more substituents selected from R' result in a number ranging from zero to (2m'+l). C is replaced by choice. ３ ~C ６ A linker selected from the group consisting of alkylenes. m' is the total number of carbon atoms in such a group. R', R'', R''', and R Each of the following is independently hydrogen, alkyl, heteroalkyl, and cycloalkyl. Claims 1 to 6 may refer to heterocycloalkyl, aryl, and heteroaryl A compound of formula (I) as described in any one of the items.

8. Ch is Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, A metal selected from Ga, Re, Ho, and Sc, according to any one of claims 1 to 7 The compound of formula (I) described above.

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

10. The aforementioned compound is given by formula (II): 【Transformation 8】 (In the formula, 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( One or more substituents selected from O)OR' in the range of zero to (2m'+l) C is replaced by a number of arbitrary selections. ３ ~C ６ A linker selected from the group consisting of alkylenes Yes, m' is the total number of carbon atoms in such a group. R', R'', R'''', And R'''' are independently hydrogen, alkyl, heteroalkyl, and cycloalkyl Compounds of the form (may refer to chloromethyl, 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 Formula (I) according to claim 10, including Ga Compound I).

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

13. The compound according to any one of claims 1 to 12 and at least one pharmaceutically acceptable A pharmaceutical composition containing a carrier.

14. The composition comprises i) a PSMA-binding ligand, ii) optionally a linker, and iii) Claim 13 further comprises a compound containing a chelating agent which optionally contains a metal or radioactive metal. The pharmaceutical composition described above.

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

16. The aforementioned compounds treat cancer, particularly by targeted alpha-ray therapy and beta-ray therapy. The compound for use according to claim 15, which is intended for use in the event of use.

17. The compound is for use in treating prostate cancer, claim 15 or 1 Compounds for use as described in 6.

18. Claims 1 to 12 for use in diagnostic imaging, preferably PET and SPECT. A compound listed in any one of the items.

19. Typically, it is used in diagnostic methods for cancer disorders such as PSMA-expressing cancer. A compound according to any one of claims 1 to 12 for the purpose of

20. A therapeutically effective amount of the compound according to any one of claims 1 to 12 is brought into contact with cancer cells. Methods for treating cancer, including the following.

21. Administering an effective amount of the compound described in any one of claims 1 to 12 to the target, and prior Obtained from the decay of the radioactive isotopes and / or radioactive metals present in the compound. A method for medical imaging, including the detection of a signal.

22. In the subject, to diagnose and / or detect cancer cells or PSMA-expressing tumors or cells. A method for doing so, wherein the therapeutically effective amount of the compound described in any one of claims 1 to 12 The above-mentioned subject, preferably a human, is administered to the above-mentioned subject, and the radioactive material present in the compound This includes detecting signals obtained from the decay of isotopes and / or radioactive metals. method.

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