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

Abstract

The present disclosure relates to prostate-specific membrane antigen (PSMA) ligands. In particular, the present disclosure relates to PSMA ligands having a glutamate-urea-lysine (GUL) moiety, a radioisotope, and a chelator that can include 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 glutamate-urea-lysine (GUL) moiety, a radioisotope, and a chelator that can include a radiometal.

[0002] The disclosure also relates to the use of these compounds in the imaging and treatment of prostate cancer. [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 refers to the use of molecular targeting molecules labeled with diagnostic radiometals (e.g., positron or gamma emitters) or with therapeutic radiometals (e.g., beta emitters) for the diagnosis and therapy of specific diseases. The most developed launch pads are based on radiolabeling of targeting molecules with high affinity for receptors expressed on tumor cells with gallium Ga-68 for diagnostic applications or lutetium Lu-177 for therapeutic purposes. Thus, molecular imaging and disease diagnosis can be followed effectively by personalized therapy utilizing the same molecular targeting compounds.

[0005] The use of the same target compound in this way also allows a more thorough approach to patient management, since this diagnostic method can also fulfill several simultaneous roles: diagnosis, reproduction, monitoring, choice of therapy using the same molecule labeled with a therapeutic radionuclide or a different treatment course, and post-treatment follow-up.

[0006] For patients, theragnostics can result in more effective medicine, reducing or eliminating unnecessary treatments and tailoring therapeutic interventions to patients who will benefit most. By predicting which patients are likely to not respond to unnecessary treatments or who will otherwise experience side effects, theragnostic approach is not only efficient, but also patient-centered.

[0007] For physicians, theragnostics can improve their ability to diagnose and stage disease, select optimal therapies, and monitor treatment efficacy and disease progression, safely and effectively improving predictive capabilities for better health outcomes.

[0008] For payers, a theragnostic approach can reduce the costs associated with suboptimal diagnostics and treatments, shorten the time needed to diagnose, and treat patients with effective individualized treatment plans.

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

[0010] Recently, PSMA ligand-based endo-radiotherapy has become an example of a new trend in development for treating prostate cancer, and PSMA is considered to be a suitable target for imaging and therapy since it is overexpressed in primary cancer lesions and in soft tissue / bone metastatic disease. Moreover, PSMA expression appears to be even higher in the most aggressive castration-resistant variants of the disease, which represent a patient population with high unmet medical need (Marchal 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 have been the most extensively investigated. These agents have been shown to be suitable for prostate cancer clinical evaluation and PRRT therapy. Some of these agents have glutamate-urea-lysine (GUL) as the targeting scaffold.

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

[0013] However, in certain circumstances the use of diagnostic radiometals may be limited (issues due to availability of 68Ga, decentralized 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 it is difficult to deliver sufficient tracer activity to remote centers. As a result, large centers with many patients require several productions per day or multiple production machines to run simultaneously, increasing costs. To meet the quantitative demands of such centers, these limitations may be overcome by the use of 18F-labeled PSMA tracers. PET radiopharmacies with on-site cyclotrons can produce highly radioactive 18F at reasonable costs. The physical half-life of 18F-labeled PSMA tracers (110 minutes) may also allow centralization of production and delivery to distant satellite centers. 18F also has a lower positron energy than 68Ga (0.65 vs. 1.90 MeV), theoretically resulting in improved spatial resolution.

[0015] However, the development of alternative PSMA ligands is always desirable, as it would be beneficial to develop alternative and diverse PSMA ligands suitable for use as diagnostics and / or therapeutics. 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, 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 selected from the group consisting of aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted one or more times by X; X is -ZY; Z is a bond or C 1 ~C 6 alkylene, preferably Z is a bond; Y is a radioisotope; L is for C 1 ~C 6 Alkylene, C 3 ~C 6 Cycloalkylene, and C 6 ~C 10a linker selected from the group consisting of arylene, wherein the alkylene, cycloalkylene, and arylene are selected from the group consisting of: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -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 optionally substituted with one or more substituents ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, 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)-NR 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. as well as pharma- ceutically acceptable salts thereof.

[0017] The compound of formula (I) includes both radioisotopes and chelators that can contain radioactive metals.The fact that PSMA ligands can be labeled in various ways allows its use to be expanded.For example, the compound of formula (I) can include radioactive halogens and metals that are used in nuclear medicine for imaging diagnostics or therapeutic purposes.

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

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

[0020] In a fourth aspect, the present disclosure relates to a compound of formula (I) for use in treating cancer, particularly prostate cancer.

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

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

[0023] In a seventh aspect, the present disclosure also relates to a method for diagnostic imaging comprising contacting a cancer cell with an effective amount of a compound of formula (I) and detecting a signal resulting from the decay of a radioisotope present in said compound. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] definition As used herein, the term "protecting group" with respect to compounds of formula (I) refers to a chemical substituent that can be selectively removed by a readily available reagent that does not attack the resulting functional group or other functional groups in the molecule. Suitable protecting groups are known in the art and continue to be developed. Suitable protecting groups may be found, for example, in Wutz et al. ("Greene's Protective Groups in Organic Synthesis, Fourth Edition", Wiley-Interscience, 2007). Protecting groups for the protection of carboxyl groups are used in certain embodiments as described in Wutz et al. (pages 533-643). In some embodiments, the protecting group is removable by treatment with acid.

[0025] Representative examples of protecting groups include, but are not limited to, benzyl, p-methoxybenzyl (PMB), tertiary butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr). One of skill in the art will recognize the appropriate conditions under which protecting groups are required and will be able to select the appropriate protecting group for use in a particular situation.

[0026] As used herein, the term "alkyl," alone or as part of another substituent, refers to a straight or branched chain alkyl functional group having 1 to 12 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl).

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

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

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

[0030] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group having a single ring containing 6 to 10 ring atoms or multiple aromatic rings fused together, with at least one ring being aromatic. The aromatic ring may optionally contain 1 to 2 additional rings (cycloalkyl, heterocyclyl, or heteroaryl as defined herein) fused thereto. Suitable aryl groups include phenyl, naphthyl, and phenyl rings fused to heterocyclyls, such as benzopyranyl, benzodioxolyl, benzodioxanyl, and the like.

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

[0032] Alkyl, cycloalkyl, and aryl monovalent and divalent derivative groups include -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR',-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 2R′, R″, R′″, and R″″ may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

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

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

[0035] As used herein, the term "heteroaryl" refers to a polyunsaturated aromatic ring system containing 5 to 10 atoms, having a single ring or multiple aromatic rings fused or covalently bonded to one another, in which at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O, and S. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Such rings may be fused to aryl, cycloalkyl, or heterocyclyl rings. Non-limiting examples of such heteroaryls include furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0036] As used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated cyclic group having 5 to 10 ring atoms, at least one ring atom being a heteroatom selected from N, O, and S. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Examples of heterocycles include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1-azepanyl, imidazolinyl, 1,4-dioxanyl, and the like.

[0037] Various embodiments of the present disclosure are described herein. It will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments.

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

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

[0040] "Pharmaceutically" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.

[0041] As used herein, the term "subject" refers to an animal, preferably a mammal, and more preferably 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, 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 selected from the group consisting of aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted one or more times by X; X is -ZY; Z is a bond or C 1 ~C 6 alkylene, preferably Z is a bond; Y is a radioisotope; L is for C 1 ~C 6 Alkylene, C 3 ~C 6 Cycloalkylene, and C 6 ~C 10 a linker selected from the group consisting of arylene, wherein the alkylene, cycloalkylene, and arylene are selected from the group consisting of: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -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 optionally substituted with one or more substituents ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; W is -NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 - and -(C=S)-NR 2Preferably, W is selected from the group consisting of -(C=O)-NR 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. 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 the formula:

[0044] The phrase "each occurrence of L and W can be the same or different" means that when the variable "n" is 2 or 3, one "L" group can be C 1 ~C 6 alkylene and the other "L" group can be C 3 ~C 6 In other embodiments, each "L" group can be, for example, C 1 ~C 6 Similarly, for example, when "n" is 2 or 3, one "W" group can be -(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 C 1 ~C 6Alkylene, C 3 ~C 6 Cycloalkylene, and C 6 ~C 10 and arylene, wherein said alkylene, cycloalkylene, and arylene are optionally substituted with one or more substituents selected from -OR', =O, =NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR' in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0046] According to one embodiment, L is a C group optionally substituted with one or more substituents selected from -OR', =O, =NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR' in a number ranging from zero to (2m'+l). 3 ~C 6 alkylene, and m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0047] Typically, the radioisotope Y is a radioactive halogen, 18 F, 34 Cl, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, and211 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, 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 selected from metals and radiometals suitable for use in diagnostic imaging or in therapy.

[0053] According to one embodiment, Ch comprises a metal selected from 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 Bi, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc, and 166 The radioactive metal may be selected from the group consisting of H, Zn, and H.

[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] wherein L is C optionally substituted with one or more substituents selected from -OR', =O, =NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR' in a number ranging from zero to (2m'+l). 3 ~C 6 alkylene, and m' is the total number of carbon atoms in such group. R', R", R'", and R"" may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

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

[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.

[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) include those of formulas (IIIa), (IIIb), (IIIc), and (IIId): [ka] This includes stereoisomers of the formula:

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

[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:

[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:

[0071] Pharmaceutical Compositions The present disclosure also relates to pharmaceutical compositions comprising a compound of Formulas (I)-(V) and at least one pharma- ceutically acceptable carrier.

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

[0073] According to one embodiment, the pharmaceutical composition further comprises a compound of formula (I'), which is a compound of formula (I), wherein Y is a halogen and is not a radioisotope. The compound of formula (I') has 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, 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 10selected from the group consisting of aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted one or more times by X; X is -ZY; Z is a bond or C 1 ~C 6 alkylene, preferably Z is a bond; Y is a halogen; L is for C 1 ~C 6 Alkylene, C 3 ~C 6 Cycloalkylene, and C 6 ~C 10 a linker selected from the group consisting of arylene, wherein the alkylene, cycloalkylene, and arylene are selected from the group consisting of: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -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 optionally substituted with one or more substituents ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, 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)-NR 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. 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, the severity of the disease, the age, weight, and sex of the patient, etc.

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

[0076] The pharmaceutical composition may take the form of an aqueous solution, for example an injectable formulation, containing at least one compound according to the present disclosure.

[0077] Preferably, the pharmaceutical compositions contain pharma- ceutically acceptable vehicles for injectable preparations, which may in particular be isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium chloride, potassium chloride, calcium chloride or magnesium chloride, and other similar or mixtures of such salts) or, where appropriate, dried, especially lyophilized compositions, which allow the preparation of injectable solutions upon addition of sterile water or saline.

[0078] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in a suitable solvent together with some other ingredients listed above, and then optionally sterile filtered.Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other required ingredients from those listed above.In the case of sterile powders for preparing sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze-drying technology, which produces a powder of the active ingredient and any additional desired ingredients from its previously sterile-filtered solution.When formulated, the solution will be administered in a manner compatible with the dosage formulation and in an amount that is therapeutically effective.The formulations are easily administered in various dosage forms, such as the type of injectable solutions described above.

[0079] For parenteral administration in aqueous solution, for example, the solution may be suitably buffered and the liquid diluent may first be rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, the sterile aqueous medium that may be used will be known to those skilled in the art in view of this disclosure. For example, one dosage may be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of subcutaneous injection therapy liquid or injected at the intended site of injection (see, for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person administering will, in any event, determine the appropriate dose for the individual subject.

[0080] In certain embodiments, the pharmaceutical composition comprises one or more excipients selected from stabilizers against radiolysis, buffers, metal ion sequestering agents, and mixtures thereof.

[0081] As used herein, "radiolytic stabilizers" refers to stabilizers that protect organic molecules from radiolytic decomposition, for example when gamma radiation emitted from a radionuclide breaks bonds between the atoms of the organic molecule and radicals are formed, which are then trapped by a stabilizer that prevents the radicals from undergoing any other chemical reactions that may result in unwanted, potentially ineffective or even toxic molecules. Therefore, these stabilizers are also referred to as "free radical scavengers" or "radical scavengers" for short. Other alternative terms for these stabilizers are "radiostability promoters", "radiolytic stabilizers", or simply "quenchers".

[0082] As used herein, "metal ion sequestering agent" refers to a chelating agent suitable for complexing free radionuclide metal ions in the formulation (not complexed with the radiolabeled peptide).

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

[0084] The dosage used for administration can be adjusted as a function of various parameters, in particular as a function of the mode of administration used, the pathology involved, or alternatively, the desired duration of treatment. It will be understood that the appropriate dosage of the compounds and compositions containing the compounds may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects of the treatment described herein. The dosage level selected will depend on a variety of factors, including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, and / or materials used in combination, and the patient's age, sex, weight, condition, health, 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. The compounds of formulas (I)-(V) exhibit valuable pharmaceutical properties and are therefore desirable for therapy, as shown in the tests provided in the Examples.

[0086] The present disclosure also relates to compounds of Formulae (I)-(V) for use in treating cancer, particularly by targeted alpha radiation therapy or by beta radiation.

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

[0088] As used herein, the term "cancer" has its general meaning in the art and includes an abnormal state or condition characterized by the growth of rapidly proliferating cells. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasion. The term cancer includes malignancies of various organ systems, such as those affecting the skin, lung, breast, thyroid, lymphatic system, gastrointestinal tract, and genitourinary tract, as well as adenocarcinomas, including most colon cancers, renal cell carcinomas, prostate cancer and / or testicular cancers, non-small cell lung cancer, cancer of the small intestine, and cancer of the oesophages.

[0089] Examples of cancers include, but are not limited to, hematological malignancies such as B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, non-Hodgkin's lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK cell lymphoid neoplasms, and myeloid lineage neoplasms. Examples of non-hematological cancers include, but are not limited to, skin 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.

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

[0091] In certain embodiments, the present disclosure also relates to compounds of Formulae (I)-(V) for use in treating prostate cancer.

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

[0093] The present disclosure also relates to compounds of Formulas (I)-(V) for use in treating PSMA-expressing tumors or cells.

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

[0095] Thus, the present disclosure also relates to a method for treating cancer, comprising contacting cancer cells with a therapeutically effective amount of a compound of Formulae (I)-(V).

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

[0097] The cancer to be treated may preferably be prostate cancer, typically prostate cancer including metastatic prostate cancer.

[0098] The present disclosure also relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject, preferably a human subject, a therapeutically effective amount of a compound of Formulas (I)-(V).

[0099] As used herein, the term "contacting" refers to any treatment that results in physical contact of at least one compound, including the therapeutic agent of the subject of the present disclosure, with at least one cancer cell. Contacting can include exposing the cell or tumor to the compound in an amount sufficient to bring at least one compound into contact with at least one cell or tumor. The method can be performed in vitro or ex vivo by introducing and preferably mixing the compound and the cell or tumor in a controlled environment, such as a culture dish or tube. The method can be performed in vivo, in which case contacting refers to exposing at least one cell or tumor in a subject to at least one compound of the subject of the present disclosure, such as administering the compound to the subject via any suitable route. Typically, the compound is administered via an intravenous route.

[0100] As used herein, the term "treating" includes reversing, alleviating, inhibiting, preventing, or reducing the likelihood of progression of the disease, disorder, or condition to which such term applies, or one or more symptoms or signs of such disease, disorder, or condition. Preventing refers to preventing a disease, disorder, condition, or a symptom or sign of such, or a worsening of the severity of such, from occurring. Thus, the compounds of the present disclosure can be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder, or condition.

[0101] As used herein, the term "therapeutically effective amount" of a compound refers to an amount of a compound that will elicit a biological or medical response in a subject, e.g., that will ameliorate symptoms, alleviate 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 pharmaceutical composition comprising a compound of Formula (I)-(V) and at least one pharma- ceutically 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 pharmaceutical composition comprising a compound of Formula (I)-(V) and at least one pharma- ceutically acceptable carrier for the manufacture of a medicament for the treatment of a PSMA-expressing tumor or cell.

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

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

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

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

[0108] Thus, the present disclosure also relates to a method for diagnostic imaging, comprising contacting cancer cells with an effective amount of a compound of Formulae (I)-(V).

[0109] The present disclosure also relates to a method for imaging a PSMA-expressing tumor or cell, comprising contacting a PSMA-expressing tumor or cell with a therapeutically effective amount of a compound of Formulas (I)-(V), which may further comprise detecting a signal resulting from the decay of a radioisotope and / or a radiometal present in the compound.

[0110] The present disclosure also relates to a method for in vivo imaging of PSMA-expressing tumors or cells in a subject, comprising administering to said subject, preferably a human, a therapeutically effective amount of a compound of Formulas (I)-(V) and detecting a signal resulting from the decay of a radioisotope and / or radiometal present in said compound.

[0111] In certain embodiments, the present disclosure provides a method for detecting the presence or absence of a PSMA-expressing tumor in a subject, comprising: (i) administering in said subject a compound of Formulae (I)-(V), for example as an intravenous injection; (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.

[0112] The present disclosure also relates to compounds of Formulas (I)-(V) for use in diagnostic methods, typically for use in diagnosing cancer disorders, such as PSMA-expressing cancers.

[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, comprising administering to said subject, preferably a human, a therapeutically effective amount of a compound of Formulas (I)-(V) and detecting a signal resulting from the decay of a radioisotope and / or radiometal present in said compound.

[0114] Synthesis of Compounds of Formulae (I)-(V) Compounds of formula (III) can be synthesized as disclosed in scheme 1. Glu-Lys urea modified p-nitrobenzyl group 2 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 has been described in the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63). An aliphatic linker, Boc-5-aminovaleric acid, can then be coupled to the same ε-Lys amine of 2 using, for example, a base (such as N,N-diisopropylethylamine) and a coupling agent (such as N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) to yield compound 3. Compound 3 can then be deprotected to yield compound 4 using, for example, an acid such as trifluoroacetic acid. Conjugation with commercially available DOTA-NHS ester can be carried out to yield compound 5. Finally, compound (III) can be converted to 18 F - can be obtained by displacement of the nitro group using

[0115] The compounds of formula (I), (II) and (III) can be radiolabeled using methods commonly used in the field of radiolabeling. In particular, the compound of formula (III) can also be radiolabeled using the methods described in WO 2017 / 165473 to form the compound of formula (IV): 177 Compounds of formula (III) can also be radiolabeled with Lu to form compounds of formula (V) using the methods described in WO 024013: 68 It can also be radiolabeled with Ga.

[0116] Scheme 1: Synthesis of compounds of formula (III) [ka] The present invention includes the following embodiments. [Claim 1] 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, 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 selected from the group consisting of aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted one or more times by X; X is -ZY; Z is a bond or C 1 ~C 6 alkylene, preferably Z is a bond; Y is a radioisotope; L is for C 1 ~C 6 Alkylene, C 3 ~C 6 Cycloalkylene, and C 6 ~C 10 a linker selected from the group consisting of arylene, wherein the alkylene, cycloalkylene, and arylene are selected from the group consisting of: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -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 R′, R″, R′″, and R″″ may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, 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)-NR 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. [Claim 2] The compound has formula (Ia), (Ib), (Ic), or (Id):

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Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Z is tetrazole or COOQ; Q is independently H or a protecting group selected from benzyl, p-methoxybenzyl, tert-butyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and triphenylmethyl; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6; R is 【Chemistry 6】 and L is C １ ~C ６ Alkylene, C ３ ~C ６ Cycloalkylene, and C ６ ~C １０ a linker selected from the group consisting of arylene, wherein the alkylene, cycloalkylene, and arylene are selected from the group consisting of -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -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 where m' is the total number of carbon atoms in such group. R', R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 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; Each occurrence of L and W can be the same or different; R ２ is H or C １ ~C ４ is alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is 【Chemistry 20】 and optionally containing a metal or 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. L is optionally substituted with one or more substituents selected from -OR', =O, =NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR' in a number ranging from zero to (2m'+l); ３ ~C ６ 3. The compound of formula (I) according to claim 1 or 2, wherein R, R'', R'', and R'''' each independently may refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

4. 4. The compound of formula (I) according to any one of claims 1 to 3, wherein Ch comprises a metal selected from Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho, and Sc.

5. The metal is ６８ G.A. 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 A c, ２１３ Bi, ２１２ Bi, ２１２ Pb, ６７ G.A. ２０３ Pb, ４７ Sc, and １６６ 5. The compound of formula (I) according to claim 4, wherein the radioactive metal is selected from the group consisting of:

6. The compound has the formula (II): 【Chemistry 8】 wherein L is optionally substituted with one or more substituents selected from -OR', =O, =NR', -NR'R'', -halogen, -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR' in a number ranging from zero to (2m'+l). ３ ~C ６ 6. The compound of formula (I) according to any one of claims 1 to 5, wherein R, R'', R''', and R'''' may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

7. The following moiety in formula (II): 【Chemistry 20】 teeth, ６８ Ga or ６７ 7. A compound of formula (II) according to claim 6, which contains Ga.

8. The following moiety in formula (II): 【Chemistry 20】 teeth, １７７ Lu or １７６ The compound of formula (II) according to claim 6, comprising Lu.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and at least one pharma- ceutically acceptable carrier.

10. 10. The pharmaceutical composition of claim 9, wherein the composition further comprises a compound comprising i) a PSMA-binding ligand, ii) optionally a linker, and iii) a chelator optionally comprising a metal or a radioactive metal.

11. A compound according to any one of claims 1 to 8 for use as a medicament.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in the treatment of cancer.

13. The pharmaceutical composition of claim 12 for use in the treatment of prostate cancer.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in diagnostic imaging.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in a diagnostic method.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in a method for treating cancer, the method comprising contacting cancer cells with a therapeutically effective amount of the compound.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in a method for diagnostic imaging, the method comprising administering to a subject an effective amount of the compound and detecting a signal resulting from decay of the radioisotope and / or the radiometal present in the compound.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 for use in a method for diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells in a subject, said method comprising administering to said subject a therapeutically effective amount of said compound and detecting a signal resulting from the decay of said radioisotope and / or said radiometal present in said compound.

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