Prostate specific membrane antigen (PSMA) ligands and uses thereof

Abstract

The present disclosure relates to prostate specific membrane antigen (PSMA) ligands. In particular, the disclosure relates to PSMA ligands having a glutamate-urea-lysine (GUL) moiety, a radioisotope, and a chelating agent that may comprise a radioactive metal.

Description

[0001] This application is a divisional application of Chinese patent application 202080047833.7. The filing date of the original application is June 30, 2020, and the name is “Prostate-specific membrane antigen (PSMA) ligand and its use”. Technical Field

[0002] 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 may contain a radiometal.

[0003] The disclosure also relates to the use of these compounds in imaging and prostate cancer treatment. Background Art

[0004] Theragnostics is a patient management strategy that involves the integration of diagnosis and treatment.

[0005] In the context of nuclear medicine, theranostics refers to the use of molecularly targeted molecules labeled with diagnostic radiometals (e.g., positron or gamma emitters) or therapeutic radiometals (e.g., beta emitters) to diagnose and treat specific diseases. State-of-the-art platforms are based on radiolabeling targeting molecules with high affinity for receptors expressed on tumor cells, either with gallium Ga-68 for diagnostic purposes or with lutetium Lu-177 for therapeutic purposes. Thus, molecular imaging and diagnosis of diseases can be performed efficiently, followed by personalized treatment using the same molecularly targeted compounds.

[0006] Using the same targeted compound in this way also allows for a more complete approach to patient management, as the diagnostic can serve multiple functions simultaneously: diagnosis, restaging, monitoring, selection of therapy or a different course of treatment using the same molecule labeled with a therapeutic radionuclide, and follow-up after treatment.

[0007] For patients, theranostics can lead to more efficient care, tailoring therapeutic interventions to those who will benefit most, while reducing or eliminating unnecessary treatments. By predicting patients who may not respond to or experience side effects from unnecessary treatments, theranostics are both efficient and patient-centric.

[0008] For physicians, theranostics can improve their ability to diagnose and stage disease, select optimal therapy, and monitor treatment response and disease progression, improving prognostic capabilities for better health outcomes in a safe and effective manner.

[0009] For payers, theranostic approaches can reduce costs associated with suboptimal diagnosis and treatment and shorten the time required to diagnose and treat patients through effective personalized treatment plans.

[0010] Prostate cancer is one of the most prevalent cancers in the United States and Europe. In particular, metastatic prostate cancer (mCRPC) is associated with a poor prognosis and decreased quality of life.

[0011] Recently, a new development stream for the treatment of prostate cancer is represented by PSMA ligand-based internal radiotherapy, as PSMA is considered a suitable target for imaging and therapy due to its overexpression in primary cancer lesions and soft tissue / bone metastatic disease. In addition, PSMA expression appears to be higher in the most aggressive castration-resistant variants of the disease, which represents a patient population with unmet medical needs. (Marchal et al., Histol Histopathol [Histology and Histopathology], 2004 Jul; 19(3):715-8; Mease et al., Curr Top Med Chem [Current Topics in Medicinal Chemistry], 2013, 13(8):951-62).

[0012] Among the many small molecule ligands targeting PSMA, urea-based low molecular weight agents are the most widely studied ligands. These agents have been shown to be suitable for clinical evaluation of prostate cancer as well as for PRRT treatment. Some of these drugs use glutamate-urea-lysine (GUL) as a targeting scaffold.

[0013] Several radiolabeled small-molecule inhibitors of PSMA have been designed based on this platform (Kiess AP, Banerjee SR, Mease RC, et al. Prostate-specific membrane antigen as a target for cancer imaging and therapy. Q J Nucl Med Mol Imaging. 2015;59:241-268).

[0014] But the use of diagnostic radiometals may be limited in some cases (availability of 68Ga, problems due to decentralized production).

[0015] However, the physical half-life of 68Ga is only 68 minutes. Therefore, 68Ga-PSMA-PET scans are best performed in-house, and it is challenging to provide sufficient tracer activity to remote centers. Therefore, in large centers with many patients, multiple productions are required per day, or multiple generators need to be run simultaneously, increasing costs. To meet the quantitative needs of these centers, the use of 18F-labeled PSMA tracers may overcome these limitations. PET radiopharmaceuticals with on-site cyclotrons can produce highly active 18F at moderate costs. The physical half-life of 18F-labeled PSMA tracers (110 minutes) can also make centralized production and delivery to distant satellite centers possible. 18F also has a lower positron energy than 68Ga (0.65 compared to 1.90MeV), which theoretically improves spatial resolution.

[0016] However, there is a constant need to develop alternative PSMA ligands. This is why it may be advantageous to develop alternative multimodal PSMA ligands suitable for use as diagnostics and / or therapeutics. Summary of the invention

[0017] In a first aspect, the present disclosure relates to compounds having formula (I):

[0018]

[0019] in:

[0020] Z is tetrazole or COOQ, preferably Z is COOQ;

[0021] Q is independently H or a protecting group, preferably Q is H;

[0022] m is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably m is 4;

[0023] q is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6, preferably q is 1;

[0024] R is selected from the group consisting of: C6-C 10 Aryl and heteroaryl containing 5-10 ring atoms, said aryl and heteroaryl being substituted one or more times by X;

[0025] X is -ZY;

[0026] Z is a bond or a C1-C6 alkylene group, preferably Z is a bond;

[0027] Y is a radioactive isotope;

[0028] L is a linker selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene and C6-C 10Arylene, the alkylene, cycloalkylene and arylene groups are optionally substituted with one or more substituents selected from the group consisting of -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -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', -CN and -NO2, with the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R", R'" and R"" may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

[0029] W chooses freedom-NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -and-(C=S)-NR 2 -, preferably, W is -(C=O)-NR 2 -;

[0030] Each occurrence of L and W can be the same or different;

[0031] R 2 is H or C1-C4 alkyl, preferably R 2 It is H;

[0032] n is an integer selected from the group consisting of 1, 2 and 3;

[0033] Ch is a chelating agent optionally comprising a metal or a radiometal;

[0034] and pharmaceutically acceptable salts thereof.

[0035] Compounds of formula (I) contain radioactive isotopes and chelators that may contain radioactive metals. The fact that PSMA ligands can be labeled in different ways allows for the expansion of their use. For example, compounds of formula (I) may contain radioactive halogens and metals for nuclear medicine imaging or therapeutic purposes.

[0036] In a second aspect, the present disclosure relates to a pharmaceutical composition comprising a compound having formula (I) and at least one pharmaceutically acceptable carrier.

[0037] In a third aspect, the disclosure relates to compounds of formula (I) for use as medicaments.

[0038] In a fourth aspect, the disclosure relates to compounds of formula (I) for use in treating cancer, particularly prostate cancer.

[0039] In a fifth aspect, the disclosure relates to compounds of formula (I) for use in imaging.

[0040] In a sixth aspect, the present disclosure also relates to a method of treating prostate cancer, the method comprising contacting the cancer cells with an effective amount of a compound having formula (I).

[0041] In a seventh aspect, the present disclosure also relates to a method of imaging, the method comprising contacting a cancer cell with an effective amount of a compound having formula (I) and detecting a signal derived from the decay of a radioactive isotope present in the compound. DETAILED DESCRIPTION

[0042] definition

[0043] As used herein, the term "protecting group" with respect to a compound of formula (I) refers to a chemical substituent that can be selectively removed by readily available reagents that do not attack regenerating or other functional groups in the molecule. Suitable protecting groups are known in the art and are being developed. Suitable protecting groups can be found in, for example, Wutz et al. ("Greene's Protective Groups in Organic Synthesis," 4th edition, Wiley-Interscience, 2007). In certain embodiments, protecting groups for protecting carboxyl groups as described by Wutz et al. (pp. 533-643) are used. In certain embodiments, the protecting group can be removed by acid treatment.

[0044] Representative examples of protecting groups include, but are not limited to, benzyl, p-methoxybenzyl (PMB), tert-butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS) and triphenylmethyl (trityl, Tr). Those skilled in the art will recognize the appropriate circumstances requiring protecting groups, and will be able to select appropriate protecting groups for particular circumstances.

[0045] As used herein, the term "alkyl" by itself 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, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl) and hexyl and its isomers (e.g., n-hexyl, isohexyl).

[0046] Alkylene refers to a divalent alkyl group as defined above.

[0047] 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.

[0048] Cycloalkylene refers to a divalent cycloalkyl group as defined above.

[0049] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon radical having a single ring or multiple aromatic rings fused together, containing 6 to 10 ring atoms, at least one of which is aromatic. The aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl or heteroaryl as defined herein) fused thereto. Suitable aryl groups include phenyl, naphthyl and a benzene ring fused to a heterocyclyl, such as benzopyranyl, benzodioxolyl, benzodioxane, and the like.

[0050] Arylene refers to a divalent aromatic group as defined above.

[0051] Alkyl, cycloalkyl and aryl monovalent and divalent derivative groups may be substituted with one or more substituents selected from the group consisting of -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -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', -CN and -NO2, with the number of substitutions 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.

[0052] As used herein, the term "halogen" refers to a fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I) group.

[0053] As used herein, the term "heteroalkyl" refers to a straight or branched chain 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, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The one or more heteroatoms 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 rest of the molecule.

[0054] As used herein, the term "heteroaryl" refers to a polyunsaturated aromatic ring system having a single ring or multiple aromatic rings fused together or linked covalently, containing 5 to 10 atoms; wherein 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 an aryl, cycloalkyl or heterocyclyl ring. Non-limiting examples of such heteroaryl groups include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxazinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0055] As used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated cyclic group having 5 to 10 ring atoms, wherein 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. Examples of heterocycles include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1-azepanyl, imidazolinyl, 1,4-dioxanyl, and the like.

[0056] Various embodiments of the present disclosure are described herein. It should be appreciated that the features specified in each embodiment can be combined with other specified features to provide further embodiments.

[0057] The present disclosure includes compounds of formula (I), (II), (III) and (IV), their stereoisomers, tautomers, enantiomers, diastereomers, racemates or mixtures thereof, and hydrates, solvates or pharmaceutically acceptable salts thereof.

[0058] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the disclosed compounds and, which typically are not biologically or otherwise undesirable.

[0059] "Pharmaceutical" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other undesirable reactions when properly administered to mammals, especially humans. Pharmaceutically acceptable carriers or excipients refer to non-toxic solid, semisolid or liquid fillers, diluents, encapsulating materials or any type of formulation auxiliary.

[0060] As used herein, the term "subject" refers to an animal, preferably a mammal, more preferably a human.

[0061] Compounds having formula (I)

[0062] In a first aspect, the present disclosure relates to compounds having formula (I):

[0063]

[0064] in:

[0065] Z is tetrazole or COOQ, preferably Z is COOQ;

[0066] Q is independently H or a protecting group, preferably Q is H;

[0067] m is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably m is 4;

[0068] q is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6, preferably q is 1;

[0069] R is selected from the group consisting of: C6-C 10 Aryl and heteroaryl containing 5-10 ring atoms, said aryl and heteroaryl being substituted one or more times by X;

[0070] X is -ZY;

[0071] Z is a bond or a C1-C6 alkylene group, preferably Z is a bond;

[0072] Y is a radioactive isotope;

[0073] L is a linker selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene and C6-C 10Arylene, the alkylene, cycloalkylene and arylene groups are optionally substituted with one or more substituents selected from the group consisting of -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -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', -CN and -NO2, with the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R", R'" and R"" may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

[0074] W chooses freedom-NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -and-(C=S)-NR 2 -, preferably, W is -(C=O)-NR 2 -;

[0075] Each occurrence of L and W can be the same or different;

[0076] R 2 is H or C1-C4 alkyl, preferably R 2 It is H;

[0077] n is an integer selected from the group consisting of 1, 2 and 3;

[0078] Ch is a chelating agent optionally comprising a metal or a radiometal;

[0079] and pharmaceutically acceptable salts thereof.

[0080] Compounds having formula (I) include stereoisomers having formula (Ia), (Ib), (Ic) and (Id):

[0081]

[0082] The phrase "wherein each occurrence of L and W may be the same or different" means that when the variable "n" is 2 or 3, one "L" group may be a C1-C6 alkylene group, and another one or more "L" groups may be a C3-C6 cycloalkylene group or an arylene group, or, in other embodiments, each "L" group may be, for example, a C1-C6 alkylene group. Similarly, for example, when "n" is 2 or 3, one "W" group may be -(C=O)-NR2 The other one or more "W" groups can be -(C=S)-NR 2 -, or in other embodiments, each "W" may be, for example, -(C=O)-NR 2 -.

[0083] According to one embodiment, L is a linker selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene and C6-C 10 Arylene, the alkylene, cycloalkylene and arylene groups are optionally substituted with one or more substituents selected from the group consisting of -OR', =O, =NR', -NR'R", -halogen, -OC(O)R', -C(O)R', -C02R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)OR', with the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R", R"' and R"" can each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0084] According to one embodiment, L is a linker selected from the group consisting of: C3-C6 alkylene optionally substituted with one or more substituents selected from the group consisting of: -OR', =O, =NR', -NR'R", -halogen, -OC(O)R', -C(O)R', -C02R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)OR', the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R", R"' and R"" can each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0085] Typically, the radioisotope Y is a radiohalogen and may be selected from the group consisting of: 18 F. 34 Cl, 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I. 131 I and 211 At, preferably Y is 18 F or 211 At.

[0086] According to one embodiment, R is selected from the group consisting of:

[0087]

[0088] wherein p is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably p is 1;

[0089] Preferably, R is selected from and,

[0090] More preferably, R is

[0091]

[0092] Advantageously, R is

[0093]

[0094] Ch can be selected from the group consisting of:

[0095]

[0096] and optionally contains a metal or a radioactive metal.

[0097] According to a specific embodiment, Ch is

[0098] and optionally contains a metal or a radioactive metal.

[0099] The metal or radiometal is preferably selected from metals and radiometals suitable for use in imaging methods or therapy.

[0100] According to one embodiment, Ch includes a metal selected from Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc. The metal may be selected from 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 Ho is a radioactive metal.

[0101] Advantageously, Ch comprises a radioactive metal 68 Ga or 177 Lu.

[0102] According to one embodiment, W is -(C=O)-NR 2 -, and Ch is and optionally contains a metal or a radioactive metal.

[0103] According to one embodiment, m is 4, Z is COOQ, and Q is H.

[0104] According to one embodiment, R is

[0105] And Ch is

[0106] and optionally contains a metal or a radioactive metal.

[0107] According to a specific embodiment, the compound of formula (I) is a compound of formula (II):

[0108]

[0109] wherein L is a linker selected from the group consisting of: C3-C6 alkylene optionally substituted with one or more substituents selected from the group consisting of: -OR', =O, =NR', -NR'R", -halogen, -OC(O)R', -C(O)R', -C02R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)OR', the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R", R"' and R"" can each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0110] Advantageously, the compound of formula (II) comprises a metal or a radioactive metal, preferably selected from 68 Ga, 67 Ga, 177 Lu and 176 Lu.

[0111] According to one specific embodiment, the compound having formula (II) comprises 68 Ga or 67 Ga.

[0112] According to another embodiment, the compound of formula (II) comprises 177 Lu or 176 Lu.

[0113] According to a specific embodiment, the compound having formula (I) is a compound having formula (III):

[0114] It optionally contains a metal or a radioactive metal.

[0115] Compounds having formula (III) include stereoisomers having formula (IIIa), (IIIb), (IIIc) and (IIId):

[0116]

[0117]

[0118] Advantageously, the compound of formula (III) comprises a metal or a radioactive metal, preferably selected from 68 Ga, 67 Ga, 177 Lu and 176 Lu.

[0119] According to one specific embodiment, the compound of formula (III) comprises 68 Ga or 67 Ga.

[0120] According to another specific embodiment, the compound having formula (III) comprises 177 Lu or 176 Lu.

[0121] According to one embodiment, the compound of formula (I) is a compound of formula (IV):

[0122]

[0123] Compounds of formula (IV) include stereoisomers of formula (IVa), (IVb), (IVc) and (IVd):

[0124]

[0125] According to another embodiment, the compound of formula (I) is a compound of formula (V):

[0126]

[0127] Compounds of formula (V) include stereoisomers of formula (Va), (Vb), (Vc) and (Vd):

[0128]

[0129]

[0130] Pharmaceutical composition

[0131] The present disclosure also relates to pharmaceutical compositions comprising a compound having Formula (I) to (V) and at least one pharmaceutically acceptable carrier.

[0132] The pharmaceutical composition may further comprise a compound comprising i) a PSMA-binding ligand, ii) optionally a linker, and iii) optionally a chelator comprising a metal or a radiometal.

[0133] 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:

[0134]

[0135] in:

[0136] Z is tetrazole or COOQ, preferably Z is COOQ;

[0137] Q is independently H or a protecting group, preferably Q is H;

[0138] m is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably m is 4;

[0139] q is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6, preferably q is 1;

[0140] R is selected from the group consisting of: C6-C 10 Aryl and heteroaryl containing 5-10 ring atoms, said aryl and heteroaryl being substituted one or more times by X;

[0141] X is -ZY;

[0142] Z is a bond or a C1-C6 alkylene group, preferably Z is a bond;

[0143] Y is halogen;

[0144] L is a linker selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene and C6-C 10Arylene, the alkylene, cycloalkylene and arylene groups are optionally substituted with one or more substituents selected from the group consisting of -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -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', -CN and -NO2, with the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R", R'" and R"" may each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

[0145] W chooses freedom-NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -and-(C=S)-NR 2 -, preferably, W is -(C=O)-NR 2 -;

[0146] Each occurrence of L and W can be the same or different;

[0147] R 2 is H or C1-C4 alkyl, preferably R 2 It is H;

[0148] n is an integer selected from the group consisting of 1, 2 and 3;

[0149] Ch is a chelating agent optionally comprising a metal or a radiometal;

[0150] and pharmaceutically acceptable salts thereof.

[0151] The form of the pharmaceutical composition, route of administration, dosage and regimen will naturally depend on the condition to be treated, the severity of the disease, the age, weight and sex of the patient, and the like.

[0152] The pharmaceutical compositions of the present disclosure may be formulated for intravenous, intramuscular or subcutaneous administration, among others.

[0153] Pharmaceutical compositions may take the form of aqueous solutions, such as injectable formulations containing at least one compound according to the present disclosure.

[0154] Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle for an injectable formulation. These may in particular be isotonic, sterile saline solutions (monosodium or disodium phosphate, sodium chloride, potassium chloride, calcium chloride or magnesium chloride, etc. or mixtures of these salts), or dry, especially lyophilized, compositions which, depending on circumstances after addition of sterile water or physiological saline, permit the constitution of an injectable solution.

[0155] The sterile injectable solution is prepared by incorporating the active compound in the required amount into a suitable solvent with several of the other ingredients enumerated above (as required), followed by filtration sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient and any additional desired ingredients from its previously sterile-filtered solution. After formulation, the solution will be administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. These formulations are readily administered in a variety of dosage forms, such as the type of injectable solution described above.

[0156] For example, for parenteral administration in an aqueous solution, the solution can be suitably buffered and first made isotonic with sufficient saline or glucose to render the liquid diluent. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, the sterile aqueous media that can be used will be known to those skilled in the art. For example, one dose can be dissolved in 1 ml of isotonic NaCl solution and then added to 1000 ml of a subcutaneous injection solution or injected at the proposed infusion site (see, for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035 - 1038 and 1570 - 1580). Depending on the condition of the subject being treated, the dosage will necessarily vary somewhat. In any case, the person responsible for administration will determine the appropriate dosage for the individual subject.

[0157] In a specific embodiment, the pharmaceutical composition comprises one or more excipients selected from stabilizers against radiation degradation, buffers, chelating agents and mixtures thereof.

[0158] As used herein, "stabilizers against radiation degradation" refers to stabilizers that protect organic molecules from radiolytic degradation, for example, when gamma rays emitted from a radionuclide cleave bonds formed between atoms of organic molecules and free radicals, those free radicals are then scavenged by the stabilizer, which prevents the free radicals from undergoing any other chemical reactions that may result in undesirable, potentially ineffective, or even toxic molecules. Therefore, these stabilizers are also referred to as "free radical scavengers" or simply "free radical scavengers". Other alternative terms for those stabilizers are "radiation stability enhancers", "radiation stabilizers" or simply "quenchers".

[0159] As used herein, "chelator" refers to a chelating agent suitable for complexing free radionuclide metal ions (not complexed with a radiolabeled peptide) in a formulation.

[0160] Buffers include acetate buffer, citrate buffer, and phosphate buffer.

[0161] The dosage for administration can be adjusted according to various parameters, in particular according to the mode of administration used, the associated pathology or alternatively the desired duration of treatment. It should be understood that the appropriate dosage of the compound and the composition comprising these compounds may vary from patient to patient. Determining the optimal dosage generally involves a balance between the level of therapeutic benefit and any risk or harmful 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 specific compound, the route of administration, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination, and the age, sex, weight, condition, overall health and previous medical history of the patient.

[0162] Compounds of formula (I) to (V) for use as medicaments and methods thereof

[0163] The present disclosure also relates to compounds of formula (I) to (V) for use as medicaments. As shown in the tests provided in the examples, the compounds of formula (I) to (V) exhibit valuable pharmaceutical properties and are therefore suitable for use in therapy.

[0164] The present disclosure also relates to compounds of formula (I) to (V) for use in treating cancer, in particular treating cancer by targeted alpha therapy or beta radiation

[0165] The compounds of formula (IV) are particularly suitable for use as medicaments, preferably for the treatment of cancer.

[0166] As used herein, the term "cancer" has its ordinary meaning in the art and includes an abnormal state or condition characterized by rapidly proliferating cell growth. The term is intended to include all types of cancerous growths or oncogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of the histopathological type or stage of invasion. The term cancer includes malignancies of various organ systems, such as those affecting the skin, lungs, breasts, thyroid, lymphatics, gastrointestinal tract, and genitourinary tract, and adenocarcinomas, which include malignancies such as most colon cancers, renal cell carcinomas, prostate cancers, and / or testicular tumors, non-small cell lung cancers, small intestinal cancers, and esophageal cancers.

[0167] Examples of cancer include, but are not limited to, hematological malignancies, such as B-cell lymphomas, T-cell lymphomas, non-Hodgkin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphomas, and myeloid tumors. 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.

[0168] In a specific embodiment, the cancer is a cancer having a tumor or cells that express PSMA.

[0169] In a particular embodiment, the present disclosure also relates to compounds of Formula (I) to (V) for use in treating prostate cancer.

[0170] In a specific embodiment, the prostate cancer is metastatic prostate cancer.

[0171] The present disclosure also relates to compounds of Formula (I) to (V) for use in treating tumors or cells expressing PSMA.

[0172] The PSMA-expressing tumor or cell can be selected from the group consisting of a prostate tumor or cell, a metastatic prostate tumor or cell, a lung tumor or cell, a kidney tumor or cell, a glioblastoma, a pancreatic tumor or cell, a bladder tumor or cell, a sarcoma, a melanoma, a breast tumor or cell, a colon tumor or cell, a germ cell, a pheochromocytoma, an esophageal tumor or cell, a gastric tumor or cell, and combinations thereof. In some other embodiments, the PSMA-expressing tumor or cell is a prostate tumor or cell.

[0173] Therefore, the present disclosure also relates to a method of treating cancer, comprising contacting a cancer cell with a therapeutically effective amount of a compound having Formula (I) to (V).

[0174] In a specific embodiment, the cancer to be treated is one that has tumors or cells that express PSMA.

[0175] The cancer to be treated may preferably be prostate cancer, typically prostate cancer including metastatic prostate cancer.

[0176] The present disclosure also relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject, preferably a human subject, a therapeutically effective amount of a compound having Formula (I) to (V).

[0177] As used herein, the term "contacting" refers to any action that causes at least one compound constituting the therapeutic agent of the present disclosure to physically contact at least one cancer cell. Contacting can include exposing one or more cells or one or more tumors to an amount of compound sufficient to cause at least one compound to contact at least one cell or tumor. The method can be implemented in vitro or ex vivo by introducing and preferably mixing the compound and one or more cells or one or more tumors in a controlled environment such as a culture dish or tube. The method can be implemented 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 present disclosure theme, such as administering the compound to the subject by any suitable route. Typically, the compound is administered by an intravenous route.

[0178] As used herein, the term "treat" includes reversing, alleviating, inhibiting the progression of, preventing or reducing the likelihood of a disease, disorder or condition to which the term applies, or one or more symptoms or manifestations of such disease, disorder or condition. Prevention refers to preventing a disease, disorder, condition or symptom, or a manifestation of these or a worsening of the severity of these from occurring. Therefore, the compounds of the present disclosure can be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder or condition.

[0179] As used herein, the term "therapeutically effective amount" of a compound refers to that amount of the compound that will elicit a biological or medical response in a subject (eg, improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease).

[0180] The present disclosure also relates to the use of a compound of formula (I) to (V) or a pharmaceutical composition comprising a compound of formula (I) to (V) and at least one pharmaceutically acceptable carrier in the preparation of a medicament for treating cancer, preferably prostate cancer.

[0181] The present disclosure also relates to the use of a compound having Formula (I) to (V) or a pharmaceutical composition comprising a compound having Formula (I) to (V) and at least one pharmaceutically acceptable carrier in the preparation of a medicament for treating a tumor or cell expressing PSMA.

[0182] Compounds of formula (I) to (V) for use in imaging and methods thereof

[0183] The disclosure also relates to compounds having formula (I) to (V) for use in imaging, preferably in vivo imaging.

[0184] The present disclosure also relates to compounds having Formula (I) to (V) for use in imaging a PSMA-expressing tumor or cell, such as a prostate tumor or cell, in a subject.

[0185] The compounds of formula (V) are particularly suitable for use in imaging, preferably for imaging tumors or cells expressing PSMA.

[0186] In a particular embodiment, the imaging method in which the compounds of formula (I) to (V) are used is PET (positron emission tomography) or SPECT (single photon emission computed tomography).

[0187] Thus, the present disclosure also relates to a method of imaging comprising contacting a cancer cell with an effective amount of a compound having Formula (I) to (V).

[0188] The present disclosure also relates to a method for imaging a PSMA-expressing tumor or cell, the method comprising contacting the PSMA-expressing tumor or cell with a therapeutically effective amount of a compound having Formula (I) to (V). The method further comprises the step of detecting a signal derived from the decay of a radioisotope and / or radiometal present in the compound.

[0189] The present disclosure also relates to a method for in vivo imaging of a tumor or cell expressing PSMA in a subject, the method comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound having Formula (I) to (V), and detecting a signal from the decay of a radioisotope and / or radiometal present in the compound.

[0190] In a specific embodiment, the present disclosure provides a method for detecting the presence of a PSMA-expressing tumor in a subject, the method comprising:

[0191] (i) administering a compound of Formula (I) to (V), for example as an intravenous injection in said subject;

[0192] (ii) acquiring images, typically by PET or SPECT imaging; and,

[0193] (iii) detecting the presence or absence of a PSMA-expressing tumor in the subject.

[0194] The present disclosure also relates to compounds having Formulae (I) to (V) for use in diagnosis, typically for diagnosing cancer disorders, such as PSMA-expressing cancers.

[0195] 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 having Formula (I) to (V), and detecting a signal from the decay of a radioisotope and / or radiometal present in the compound.

[0196] Synthesis of compounds of formula (I) to (V)

[0197] Compounds of formula (III) can be synthesized as disclosed in Scheme 1. The modified p-nitrobenzyl group of Glu-Lys urea 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 medicinalchemistry 58, 4357-63). Boc-5-aminopentanoic acid can then be coupled to the same -Lys amine of 2 to produce compound 3, for example using 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. Compound 3 can then be deprotected, for example using an acid such as trifluoroacetic acid, to produce compound 4. Conjugation with commercially available DOTA-NHS esters can be performed to produce compound 5. Finally, the 5-hydroxy-1-hydroxy-2-nitropropene can be prepared by using 18 F - The nitro group is replaced to obtain compound (III).

[0198] Compounds of formula (I), (II) and (III) can be radiolabeled using methods commonly used in the field of radiolabeling. Specifically, the method described in WO 2017 / 165473 can also be used. 177 The compound of formula (III) is radiolabeled with Lu to form a compound of formula (IV). The method described in WO 024013 can also be used. 68 The compound of formula (iii) is radiolabeled with Ga to form the compound of formula (V).

[0199] Scheme 1: Synthesis of compounds having formula (III)

[0200]

Claims

1. A compound having formula (I): in: 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 selected from the group consisting of: C 6 -C 10 Aryl and heteroaryl containing 5-10 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 radioactive isotope; L is a linker selected from the group consisting of: C 1 -C 6 Alkylene, C 3 -C 6 Cycloalkylene and C 6 -C 10 Arylene, the alkylene, cycloalkylene and arylene groups are optionally substituted with one or more substituents selected from the group consisting of -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -C02R', -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 , the number of substitutions ranges from zero to (2m'+1), where m' is the total number of carbon atoms in such a group, and R', R", R'" and R"" can each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; W chooses freedom-NR 2 -(C=O), -NR 2 -(C=S), -(C=O)-NR 2 -and-(C=S)-NR 2 -, preferably, W is -(C=O)-NR 2 -; Each occurrence of L and W can be the same or different; R 2 Is H or C 1 -C 4 Alkyl, preferably R 2 It is H; n is an integer selected from the group consisting of 1, 2 and 3; Ch is a chelating agent optionally comprising a metal or a radiometal; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 having formula (I), wherein the compound is a compound having formula (Ia), (Ib), (Ic) or (Id):

3. A compound of formula (I) according to claim 1 or 2, wherein Y is selected from 18 F. 34 Cl, 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I. 131 I and 211 At is a radioisotope of the group consisting of, preferably Y is 18 F or 211 At.

4. The compound of formula (I) according to claims 1 to 3, wherein R is selected from the group consisting of: wherein p is an integer selected from the group consisting of 1, 2, 3, 4 and 5, preferably p is 1; Preferably, R is selected from and, More preferably, R is 5. A compound of formula (I) according to any one of claims 1 to 4, wherein R is 6. A compound of formula (I) according to any one of claims 1 to 5, wherein Ch is selected from the group consisting of: and optionally contains a metal or a radioactive metal.

7. A compound of formula (I) according to any one of claims 1 to 6, wherein L is a linker selected from the group consisting of: C optionally substituted with one or more substituents selected from the following 3 -C 6 Alkylene: -OR', =O, =NR', -NR'R", -halogen, -OC(O)R', -C(O)R', -C02R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)OR', with the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such group, and R', R", R"' and R"" can each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

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

9. The compound of formula (I) according to claim 8, wherein the metal is selected from 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 Ho is a radioactive metal.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein the compound is a compound of formula (II): wherein L is a linker selected from the group consisting of: C optionally substituted with one or more substituents selected from 3 -C 6 Alkylene: -OR', =O, =NR', -NR'R", -halogen, -OC(O)R', -C(O)R', -C02R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)OR', the number of substitutions ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such group, and R', R", R"' and R"" can each independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

11. The compound of formula (II) according to claim 10, wherein the compound of formula (II) comprises 68 Ga or 67 Ga.

12. The compound of claim 10 having formula (II), wherein the compound of formula (II) comprises 177 Lu or 176 Lu.

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

14. The pharmaceutical composition of claim 13, wherein the composition further comprises a compound comprising i) a PSMA binding ligand, ii) optionally a linker, and iii) optionally a chelator comprising a metal or a radiometal.

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

16. Compound for use according to claim 15, wherein the compound is for use in the treatment of cancer, in particular by targeted alpha therapy and beta radiation.

17. The compound for use according to claim 15 or 16, wherein the compound is for use in the treatment of prostate cancer.

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

19. A compound according to any one of claims 1 to 12 for use in diagnosis, typically for use in diagnosing a cancer disorder, such as a PSMA expressing cancer.

20. A method of treating cancer, the method comprising contacting cancer cells with a therapeutically effective amount of a compound according to any one of claims 1 to 12.

21. An imaging method comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 12 and detecting a signal derived from the decay of a radioisotope and / or a radiometal present in the compound.

22. A method for diagnosing and / or detecting cancer cells or PSMA-expressing tumors or cells in a subject, the method comprising administering to the subject, preferably a human, a therapeutically effective amount of a compound according to any one of claims 1 to 12, and detecting a signal derived from the decay of a radioisotope and / or radiometal present in the compound.

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