Compounds, method of treating one or more psma-expressing cells or tumors in vitro or ex vivo using said compounds and use thereof to treat psma-expressing tumors or cells

Abstract

High-affinity agents targeted by prostate-specific membrane antigen for prostate cancer endoradiotherapy are revealed.

Description

1 / 69 “COMPOUNDS, METHOD FOR TREATING ONE OR MORE CELLS OR TUMORS EXPRESSING PSMA IN VITRO OR EX VIVO USING SAID COMPOUNDS AND USE THEREOF TO TREATS TUMORS OR CELLS EXPRESSING PSMA” CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of U.S. Provisional Application No. 62 / 311,697 filed March 22, 2016, which is incorporated herein by reference in its entirety. DEVELOPMENT OR RESEARCH WITH FEDERAL SUPPORT

[002] This invention was made with government support under K25CA148901-01A1 and U54CA1346751 granted by the National Institutes of Health (NIH). The government holds certain rights in the invention. BACKGROUND OF THE INVENTION

[003] Prostate cancer is the leading cancer in the US population and the second leading cause of cancer death in men. Therapy for locally advanced disease remains controversial, and a growing number of different options are available. Novel high-affinity radiotherapy agents for prostate cancer have been developed using prostate-specific membrane antigen (PSMA) as a target. PSMA is an androgen-independent disease marker that is also expressed in solid (non-prostate) tumor neovasculature. SUMMARY

[004] In some respects, the matter presently revealed provides a compound of Formula (I): (I) Petition 870260033219, dated 09 / 04 / 2026, page 6 / 182 2 / 69 where: Z is tetrazole or CO2Q; Q is H or a protecting group; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; R is independently H or -CH2-R1; R1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a ligand selected from the group consisting of C1-C6 alkylene and C3-C6 cycloalkylene, and arylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2(C=S)-, -(C=O)-NR2-, and -(C=S)-NR2-; where each occurrence of L and W may be the same or different; R2 is H or a C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent which may comprise a metal or radioactive metal; and pharmaceutically acceptable salts thereof.

[005] In particular aspects of the compound of Formula (I), R1 is selected from the group consisting of: / WW where X is independently Br or I.

[006] In still other more particular aspects of the compound of Formula (I), the chelating agent is selected from the group consisting of: HO / O HO O n; .oh N .OH HO .0HOv / ° HO OO^ / OH N. .OH N. .OH Petition 870260033219, dated 09 / 04 / 2026, p. 7 / 182 3 / 69

[007] In other respects, the matter now disclosed provides a method for treating one or more cells or tumors expressing PSMA, the method comprising contacting one or more cells or tumors expressing PSMA with an effective amount of a compound of formula (I), wherein the compound of formula (I) comprises: (I); where: Z is tetrazole or CO2Q; Q is H or a protecting group; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; R is independently H or -CH2-R1; R1 consists of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a ligand selected from the group consisting of C1-C6 alkylene and C3-C6 cycloalkylene, and arylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2-(C=S)-, -(C=O)-NR2-, and -(C=S)NR2-; where each occurrence of L and W may be the same or different; R2 is H or a C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent comprising a radioactive metal suitable for radiotherapy; and pharmaceutically acceptable salts thereof.

[008] In other respects, the matter now disclosed provides a method for imaging one or more prostate-specific membrane antigen (PSMA) tumors or cells, wherein the method comprises contacting one or more tumors or cells with an effective amount of a compound of Formula (I) and producing an image. Petition 870260033219, dated 09 / 04 / 2026, p. 8 / 182 4 / 69

[009] In still other respects, the matter now disclosed provides a kit comprising a compound of Formula (I).

[010] Certain aspects of the matter now disclosed have been stated above in this document, which are addressed wholly or partially by the matter now disclosed; other aspects will become apparent as the description progresses when taken in connection with the Examples and Figures attached as more fully described in this document below. BRIEF DESCRIPTION OF THE FIGURES

[011] Having thus described the matter now revealed in general terms, reference will now be made to the attached Figures, which are not necessarily drawn to scale, and in which:

[012] Figure 1 shows chemical structures of representative radiotherapeutic agents;

[013] Figure 2 shows a comparative study of the clonogenic efficacy of 177Lu-1, and known agents SR6, PSMA-617 and PSMA-I&T;

[014] Figure 3 shows PSMA+ tumor-to-kidney ratios of177Lu-1,177Lu-2,177Lu-SR6,177Lu-PSMA-617 and177Lu-PSMA-I&T;

[015] Figure 4 shows SPECT-CT imaging of 177Lu-1 during treatment studies using a single dose of 3 mCi;

[016] Figure 5 shows the relative body weight of the mice during the treatment studies; and

[017] Figure 6A and Figure 6B show the relative tumor volume of mice (Figure 6A) during treatment studies and the Kaplan-Meier survival curve (Figure 6B) up to 60 days post-treatment. DETAILED DESCRIPTION

[018] The matter now revealed will now be described more fully with reference to the attached Figures, in which some, but Petition 870260033219, dated 09 / 04 / 2026, page 9 / 182 5 / 69 Not all embodiments of the matter presently disclosed are shown. Similar numbers refer to similar elements throughout the document. The matter presently disclosed can be embodied in many different forms and should not be interpreted as limited to the embodiments presented in this document; rather, these embodiments are provided in such a way that this disclosure satisfies applicable legal requirements. In fact, many modifications and other embodiments of the matter presently disclosed presented in this document will occur to a person skilled in the art to which the matter presently disclosed pertains, who will benefit from the teachings presented in the preceding descriptions and associated Figures.Therefore, it should be understood that the matter presently disclosed should not be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. I. High-affinity agents targeted by antigen of Specific prostate membrane for endoradiotherapy of PROSTATE CANCER A. COMPOUNDS OF FORMULA (I)

[019] Consequently, in some embodiments, the matter presently disclosed provides a compound of Formula (I): (I); where: Z is tetrazole or CO2Q; Q is H or a protecting group; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; R is independently H or -CH2-R1; R1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a ligand selected from the group consisting of C1-C6 alkylene and C3-C6 cycloalkylene. Petition 870260033219, dated 09 / 04 / 2026, p. 10 / 182 6 / 69 and arylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2(C=S)-, -(C=O)-NR2-, and -(C=S)-NR2-; where each occurrence of L and W may be the same or different; R2 is H or a C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent which may comprise a metal or radioactive metal; and pharmaceutically acceptable salts thereof.

[020] The phrase “where 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 C1-C6 alkylene, while the other “L” group or groups may be C3-C6 cycloalkylene or arylene, or, in other embodiments, each “L” group may be, for example, C1-C6 alkylene. Similarly, for example, when “n” is 2 or 3, one “W” group may be -(C=O)NR2- and the other “W” group or groups may be -(C=S)-NR2-, or, in other embodiments, each “W” may be, for example, -(C=O)-NR2-.

[021] In particular embodiments of the compound of Formula (I), R1 is selected from the group consisting of: x T -X ΛΛΛΛ X, , ; ^ ; and । ; where X is Regardless of whether it's Brazilian or Italian.

[022] In even more particular embodiments of the compound of Formula (I), the chelating agent is selected from the group consisting of: Petition 870260033219, dated 09 / 04 / 2026, p. 11 / 182 7 / 69

[023] In even more particular embodiments of the compound of Formula (I), the chelating agent comprises a metal selected from the group consisting of: Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc. In further particular embodiments of the compound of Formula (I), the metal is a radioactive metal and is selected from the group consisting of: 68Ga, 64Cu, 86Y, 90Y, 89Zr, 111In, 99mTc, 177Lu, 153Sm, 186Re, 188Re, 67Cu, 212Pb, 225Ac, 213Bi, 212Bi, 212Pb, 67Ga, 203Pb, 47Sc, and 166Ho.

[024] In particular forms, the compound of Formula (I) is selected from the group consisting of: O H H O OH OH OHHO Petition 870260033219, dated 09 / 04 / 2026, p. 12 / 182 8 / 69 JJ Petition 870260033219, dated 09 / 04 / 2026, p. 13 / 182 9 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 14 / 182 10 / 69 P9 P10 P9 P9 JJ Petition 870260033219, dated 09 / 04 / 2026, p. 15 / 182 11 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 16 / 182 12 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 17 / 182 13 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 18 / 182 14 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 19 / 182 15 / 69 B. METHODS OF USING COMPOUNDS OF FORMULA (I) TO TREAT Petition 870260033219, dated 09 / 04 / 2026, p. 20 / 182 16 / 69 One or more tumors or cells that express PSMA.

[025] In some embodiments, the presently disclosed matter provides a method for treating one or more cells or tumors expressing PSMA, wherein the method comprises contacting one or more cells or tumors expressing PSMA with an effective amount of a compound of formula (I), wherein the compound of formula (I) comprises: (I) where: Z is tetrazole or CO2Q; Q is H or the protecting group; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; R is independently H or -CH2-R1; R1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a ligand selected from the group consisting of C1-C6 alkylene and C3-C6 cycloalkylene, and arylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2(C=S)-, -(C=O)-NR2-, and -(C=S)-NR2-; where each occurrence of L and W may be the same or different; R2 is H or the C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent comprising a radioactive metal suitable for radiotherapy; and pharmaceutically acceptable salts thereof.

[026] “Contacting means any action that results in at least one compound comprising the therapeutic agent of the presently disclosed matter physically contacting at least one tumor or cell expressing PSMA. Contacting may include exposing the cell (or cells) or tumor (or tumors) to the compound in a sufficient amount to result in contact of at least one compound with at least one cell or tumor. The method may be practiced in vitro or ex vivo by introducing, and preferably mixing, the compound and cell (or cells) or Petition 870260033219, dated 09 / 04 / 2026, page 21 / 182 17 / 69 tumor (or tumors) in a controlled environment, such as a culture tube or dish. The method can be practiced in vivo, in which case contacting means exposing at least one cell or tumor in an individual to at least one compound of the matter presently disclosed, such as administering the compound to an individual via any suitable route.

[027] As used in this document, the term “treating” may include reversing, attenuating, inhibiting the progression of, preventing, or reducing the likelihood of the disease, disorder, or condition to which this term applies, or one or more symptoms or manifestations of such disease, disorder, or condition. Preventing refers to causing a disease, disorder, condition, or symptom or manifestation thereof, or worsening of its severity, not to occur. Consequently, the compounds presently disclosed may be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.

[028] In general, the “effective amount” of an active agent refers to the amount required to elicit the desired biological response. As will be understood by those of common skill in this technique, the effective amount of an agent or device may vary depending on factors such as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical compound, the target tissue, and the like.

[029] The term “combination” is used in its broadest sense and means that an individual is administered at least two agents, more particularly a compound of Formula (I) and at least one other active agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of, for example, a single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as Petition 870260033219, dated 09 / 04 / 2026, page 22 / 182 18 / 69 separate dosage forms that are administered alternately or sequentially at midday or on separate days. In one embodiment of the matter presently disclosed, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., where it is desirable to vary the amount of one, but not the other). The single dosage form may include additional active agents for the treatment of the disease state.

[030] In particular modalities, R1 is selected from the group consisting of: where X is independently Br or I.

[031] In more specific forms, the chelating agent is selected from the group consisting of: HO. ,0 HO.,0 HO .o HO O Ni, OH HO 0 HO O KL PH HO. O HOχ / P

[032] In even more particular forms, the appropriate radioactive metal Petition 870260033219, dated 09 / 04 / 2026, p. 23 / 182 19 / 69 for radiotherapy is selected from the group consisting of: 90Y, 177Lu, 211At, 111In, 153Sm, 186Re, 188Re, 67Cu, 212Pb, 225Ac, 213Bi, 212Bi, 212Pb and 67Ga.

[033] In even more particular forms, the compound of formula (I) is selected from the group consisting of: O H H O OH OHHO OH; Petition 870260033219, dated 09 / 04 / 2026, p. 24 / 182 20 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 25 / 182 21 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 26 / 182 22 / 69 P9 P10 P9 P9 JJ Petition 870260033219, dated 09 / 04 / 2026, p. 27 / 182 23 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 28 / 182 24 / 69 Petition 870260033219, dated 09 / 04 / 2026, p. 29 / 182 25 / 69 ho z HO 0<^\ ho ZN HO^' O< H2N [ °< H2N [ H2N í (yo o. -^nh2 ' h2n L , 1 ,NN ° h2n^ \— / nn N Π / Vn Η Η H 1 II J 0 ° ,.°h0 V JP17 hVOH-H A^H A^H ; UAU Η Η Η II A 0 ^''if \ O^OH ° \ oy P17 hVnAnVH 0 HH â ; 0 r^=\ D ^nh2 Vnh2 / \^Br \ / \ ) Η H ,NN ^ΝγΝ^^γΝ >^νΛ o JA\H ° An. ί ; J °X r==\ I y^NH2 VNH2 í A1 \ / \ ) Η Η ,NN ^ΝγΝ^^γΝ hoAnAã°hΟ o HH o ; J o D k^NH2 ~ΑΝΗ2 J ^ABr ( / \ ) Η H KÍ^N ,NN ^ΝγΝ^^γ,Ν S ° \ o Z ^Z hoZn*nJyoh ° J 5 ; J ^nh2 η h Ky Ί \ TVTZ °v0H Z^Zaa s 0 1 J ' ηο'χΑκΑμλ^οη A ANNA O II uu II Ο π n O ; J Petition 870260033219, of 09 / 04 / 2026, p. 30 / 182 26 / 69 Petition 870260033219, of 09 / 04 / 2026, p. 31 / 182 27 / 69

[034] In other modalities, one or more tumors or cells expressing PSMA are selected from the group consisting of: a tumor or Petition 870260033219, dated 09 / 04 / 2026, page 32 / 182 28 / 69 prostate 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 stomach tumor or cell, and combinations thereof. In some other embodiments, one or more tumors or cells expressing PSMA consist of a prostate tumor or cell.

[035] In other modalities, one or more tumors or cells expressing PSMA are in vitro, in vivo or ex-vivo. In still other modalities, one or more tumors or cells expressing PSMA are present in an individual.

[036] The individual treated by the methods presently disclosed in their many modalities is, desirably, a human individual, although it is understood that the methods described in the present document are effective in relation to all vertebrate species, which are intended to be included in the term “individual.” Consequently, an “individual” may include a human individual for medical purposes, such as one for the treatment of an existing condition or disease or prophylactic treatment to prevent the onset of a condition or disease, or an animal (non-human) individual for medical, veterinary, or developmental purposes.The individual animals include mammals, which include, without limitation, primates, for example, humans, monkeys, apes, and similar animals; bovine animals, for example, cattle, oxen, and similar animals; ovine animals, for example, sheep and similar animals; caprine animals, for example, goats and similar animals; porcine animals, for example, domesticated pigs, hogs, and similar animals; equine animals, for example, horses, donkeys, zebras, and similar animals; feline animals, including wild and domesticated cats; canine animals, including dogs; lagomorphs, including rabbits, hares, and similar animals; and rodents, including mice, rats, and similar animals. An animal may be a transgenic animal. In some embodiments, the individual is a human, which includes, without limitation, individuals. Petition 870260033219, dated 09 / 04 / 2026, page 33 / 182 29 / 69 fetal, neonatal, infant, juvenile, and adult. Additionally, an “individual” may include a patient afflicted with, or suspected of being afflicted with, an illness or disease. Therefore, the terms “individual” and “patient” are used interchangeably in this document.

[037] In some other modalities, the method results in the inhibition of tumor growth. C. METHODS OF USING FORMULA (I) COMPOUNDS TO IMAGE ONE OR MORE TUMORS OR PSMA-EXPRESSING CELLS

[038] In other embodiments, the matter now disclosed provides a method for imaging one or more prostate-specific membrane antigen (PSMA) tumors or cells, wherein the method comprises contacting one or more tumors or cells with an effective amount of a compound of Formula (I) and producing an image, wherein the compound of Formula (I) comprises: (I) where: Z is tetrazole or CO2Q; Q is H or a protecting group; m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; R is independently H or -CH2-R1; R1 consists of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a ligand selected from the group consisting of C1-C6 alkylene and C3-C6 cycloalkylene, and arylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2-(C=S)-, -(C=O)-NR2-, and -(C=S)NR2-; where each occurrence of L and W may be the same or different; R2 is H or C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent comprising a radioactive metal suitable for imaging; and pharmaceutically acceptable salts thereof. D. KITS Petition 870260033219, dated 09 / 04 / 2026, p. 34 / 182 30 / 69

[039] In still other forms, the matter now disclosed provides a kit comprising a compound of Formula (I).

[040] In certain embodiments, the kit provides packaged pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the invention. In certain embodiments, the packaged pharmaceutical composition will comprise the reaction precursors necessary to generate the compound of the invention by combining it with a radiolabeled precursor. Other packaged pharmaceutical compositions provided by the present invention further comprise instructions comprising at least one of: instructions for preparing compounds according to the invention from the precursors provided, instructions for using the composition to image cells or tissues expressing PSMA, or instructions for using the composition to image glutamatergic neurotransmission in a patient suffering from a stress-related disorder, or instructions for using the composition to image prostate cancer. E. Pharmaceutical Compositions and Administration

[041] In another aspect, the present disclosure provides a pharmaceutical composition that includes a compound of Formula (I) alone or in combination with one or more additional therapeutic agents in addition mixtures with a pharmaceutically acceptable excipient. A person skilled in the art will recognize that pharmaceutical compositions include pharmaceutically acceptable salts of the compounds described above. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and include salts of active compounds that are prepared with relatively non-toxic bases or acids, depending on the particular substituent chemical moieties found in the compounds described herein. When the compounds of the present disclosure contain relatively acidic functionalities, base addition salts Petition 870260033219, dated 09 / 04 / 2026, page 35 / 182 31 / 69 can be obtained by contacting the neutral form of these compounds with a sufficient quantity of the desired base, pure or in a suitable inert solvent, or by ion exchange, whereby a basic counterion (base) in an ionic complex is replaced by another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt or a similar salt.

[042] When the compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient quantity of the desired acid, pure or in a suitable inert solvent, or by ion exchange, whereby an acidic counterion (acid) in an ionic complex is replaced by another. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrodiodic, or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic and the like.Also included are amino acid salts such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1 to 19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.

[043] Consequently, pharmaceutically acceptable salts suitable for use with the matter presently disclosed include, by way of example, but Petition 870260033219, dated 09 / 04 / 2026, p. 36 / 182 32 / 69 no limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsilate, carbonate, citrate, edetate, edisilate, estolate, esilate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate or theoaclate. Other pharmaceutically acceptable salts can be found in, for example, Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). In therapeutic and / or diagnostic applications, the developing compounds can be formulated for a variety of administration methods, including systemic and topical or localized administration.The techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[044] Depending on the specific conditions being treated, these agents may be formulated in liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a prolonged or timed slow-release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal, or intestinal administration; parenteral delivery, which includes intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra-sternal, intra-synovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery. Petition 870260033219, dated 09 / 04 / 2026, page 37 / 182 33 / 69

[045] For injection, the developing agents may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers like Hank's solution, Ringer's solution, or physiological saline buffer. For this transmucosal administration, penetrants suitable for the barrier to be permeated are used in the formulation. Such penetrants are generically known in the art.

[046] The use of pharmaceutically acceptable inert carriers to formulate the compounds in the present disclosure in dosages suitable for systemic administration is covered within the scope of the disclosure. With a suitable choice of carrier and proper manufacturing practice, the compositions of the present disclosure, in particular those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be readily formulated using well-known pharmaceutically acceptable carriers in dosages suitable for oral administration. These carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, fluid pastes, suspensions and the like, for oral ingestion by an individual (e.g., patient) to be treated.

[047] For nasal or inhalation delivery, the developing agents may also be formulated by methods known to those skilled in the art, and may include, for example, without limitation, examples of solubilizing, diluting or dispersing substances, such as a saline solution; preservatives, such as a benzyl alcohol; absorption enhancers; and fluorocarbons.

[048] Pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. Determining effective amounts is well within the capacity of those skilled in the art. Petition 870260033219, dated 09 / 04 / 2026, page 38 / 182 34 / 69 techniques, especially in light of the detailed disclosure provided in this document. In general, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1,000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the individual being treated, the body weight of the individual being treated, the bioavailability of the compound (or compounds), the adsorption, distribution, metabolism and excretion toxicity (ADME) of the compound (or compounds), and the preference and experience of the attending physician.

[049] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the active compounds into preparations that can be used pharmaceutically. Preparations formulated for oral administration may be in the form of tablets, coated tablets, capsules or solutions.

[050] Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally triturating a resulting mixture, and processing the granule mixture, after suitable additional excipients if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Petition 870260033219, dated 09 / 04 / 2026, page 39 / 182 35 / 69

[051] The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the coatings of tablets or dragees for identification or to characterize different combinations of doses of the active compound.

[052] Pharmaceutical preparations that can be used orally include press-fit capsules made of gelatin, as well as soft-sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Press-fit capsules may contain the active ingredients in a mixture by addition with a filler such as lactose, binders such as starches, and / or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added. II. GENERAL DEFINITIONS

[053] Although specific terms are employed in this document, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used in this document have the same meaning commonly understood by a person of ordinary skill in the art to which the subject matter described herein pertains.

[054] Although it is believed that the following terms relating to the compounds of Formula (I) are well understood by a person of ordinary skill in the art, the following definitions are presented to facilitate the explanation of the matter presently disclosed. These definitions are intended to Petition 870260033219, dated 09 / 04 / 2026, page 40 / 182 36 / 69 supplement and illustrate, not preclude, definitions that would be evident to a person of ordinary skill in the art upon review of the present disclosure.

[055] The substituted terms, regardless of whether they are preceded by the term “optionally” or not, and substituent, as used in this document, refer to the ability, as understood by a person skilled in the art, to change one functional group for another functional group in a molecule, provided that the valence of all atoms is maintained. When more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at every position. Substituents may also be additionally substituted (for example, an aryl group substituent may have another substituent outside of it, such as another aryl group, which is additionally substituted at one or more positions).

[056] When substituent groups or linking groups are specified by their conventional chemical formulas, written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left, for example, -CH2O is equivalent to -OCH2-; -C(=O)O- is equivalent to -OC(=O)-; -OC(=O)NR- is equivalent to -NRC(=O)O- and the like.

[057] When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as R1, R2, and the like, or variable, such as “m” and “n”), may be identical or different. For example, both R1 and R2 may be substituted alkyls, or R1 may be hydrogen and R2 may be a substituted alkyl and the like.

[058] The terms “a,” “an,” or “an(an),” when used in reference to a group of substituents in this document, mean at least one. For example, when a compound is substituted by “an” alkyl or aryl group, the compound Petition 870260033219, dated 09 / 04 / 2026, p. 41 / 182 37 / 69 is optionally replaced by at least one alkyl and / or at least one aryl group. Furthermore, when a chemical moiety is replaced by an R substituent, the group may be referred to as “R-substituted”. When a chemical moiety is R-substituted, the chemical moiety is replaced by at least one R substituent, and each R substituent is optionally different.

[059] A so-called “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless otherwise specified herein. For illustrative purposes, certain representative “R” groups as presented above are defined below.

[060] The descriptions of the compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Consequently, when a group can be substituted by one or more of several substituents, these substitutions are selected for the purpose of conforming to the principles of chemical bonding and generating compounds that are not inherently unstable and / or would be known to a person of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and various known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is attached to the remainder of the molecule by means of a ring heteroatom in accordance with the principles of chemical bonding known to those skilled in the art, thus avoiding inherently unstable compounds.

[061] Unless explicitly defined otherwise, a “substituent group,” as used herein, includes a functional group selected from one or more of the following chemical moieties, which are defined herein:

[062] The term hydrocarbon, as used in this document, is Petition 870260033219, dated 09 / 04 / 2026, page 42 / 182 38 / 69 refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to a person skilled in this art, all valences must be satisfied when making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethinyl, cyclohexyl, and the like.

[063] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched chain, acyclic or cyclic hydrocarbon group, or combination thereof, which may be fully saturated, mono- or polyunsaturated and may include di- and multivalent groups, having the designated number of carbon atoms (i.e., C1-C10 means one to ten carbons, which includes 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons).In particular embodiments, the term “alkyl” refers to C1-20 inclusive, which includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbons, linear (i.e., “linear chain”), branched, or cyclic hydrocarbon radicals, saturated or at least partially and in some cases completely unsaturated (i.e., alkenyl and alkynyl) derived from a hydrocarbon chemical moiety containing between one and twenty carbon atoms by the removal of a single hydrogen atom.

[064] Representative saturated hydrocarbon groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, ndecyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl and homologs and isomers thereof.

[065] “Branched” refers to an alkyl group in which an alkyl group Petition 870260033219, dated 09 / 04 / 2026, p. 43 / 182 39 / 69 lower, such as a methyl, ethyl, or propyl group, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-e alkyl), for example, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Upper alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, “alkyl” refers in particular to C1-8 linear chain alkyls. In other embodiments, “alkyl” refers in particular to C1-8 branched chain alkyls.

[066] Alkyl groups may optionally be substituted (a “substituted alkyl”) by one or more alkyl group substituents, which may be the same or different. The term “substituted alkyl group” includes, without limitation, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo and cycloalkyl. Optionally, one or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms may be inserted along the alkyl chain, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.

[067] Therefore, as used in this document, the term “substituted alkyl” includes alkyl groups, as defined in this document, in which one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group, which includes, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate and mercapto.

[068] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable branched or linear chain, or cyclic hydrocarbon group, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the Petition 870260033219, dated 09 / 04 / 2026, p. 44 / 182 40 / 69 group consisting of O, N, P, Si and S, in which the nitrogen, phosphorus and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (or heteroatoms) O, N, P and S and Si may be placed in any interior position of the heteroalkyl group or in the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[069] As described above, heteroalkyl groups, as used herein, include those groups that are attached to the rest of the molecule via a heteroatom, such as -C(O)NR', ​​-NR'R”, -OR', -SR, -S(O)R, and / or S(O2)R'. When “heteroalkyl” is cited, followed by citations of specific heteroalkyl groups, such as -NR'R or similar, it will be understood that the terms heteroalkyl and -NR'R” are not redundant or mutually exclusive. Instead, specific heteroalkyl groups are cited for clarity. Therefore, the term “heteroalkyl” should not be interpreted in this document as excluding specific heteroalkyl groups, such as -NR'R” or similar.

[070] “Cyclic” and “cycloalkyl” refers to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The cycloalkyl group may optionally be partially unsaturated. The cycloalkyl group may also be optionally substituted by an alkyl substituent group as defined herein, oxo and / or alkylene. One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms may optionally be inserted along the cyclic alkyl chain, where the nitrogen substituent is hydrogen, Petition 870260033219, dated 09 / 04 / 2026, p. 45 / 182 41 / 69 unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems such as dihydro and tetrahydronaphthalene, and the like.

[071] The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined above herein, which is attached to the parent molecular chemical moiety via an alkyl group, also as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[072] The terms “cycloheteroalkyl” or “heterocycloalkyl” refer to a non-aromatic ring system, a partially unsaturated or unsaturated ring system, such as an unsubstituted or substituted cycloalkyl ring system with 3 to 10 members, which includes one or more heteroatoms, which may be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and may optionally include one or more double bonds.

[073] The cycloheteroalkyl ring may optionally be fused to or otherwise attached to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group in which at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may optionally be oxidized), which includes, without limitation, Petition 870260033219, dated 09 / 04 / 2026, page 46 / 182 42 / 69 a bi- or tricyclic group comprising six-membered rings having between one and three heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, without limitation, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.

[074] The terms “cycloalkyl” and “heterocycloalkyl”, alone or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, without limitation, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Examples of heterocycloalkyl include, without limitation, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like. The terms “cycloalkylene” and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[075] An unsaturated alkyl group is one that has one or more double or triple bonds. Examples of unsaturated alkyl groups include, without limitation, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethinyl, 1- and 3-propynyl, 3-butynyl, and higher isomers and homologues. Alkyl groups that are limited to hydrocarbon groups are called Petition 870260033219, dated 09 / 04 / 2026, p. 47 / 182 43 / 69 “homoalkyl”.

[076] More particularly, the term “alkenyl” as used in this document refers to a monovalent group derived from a branched or linear inclusive C1-20 hydrocarbon chemical moiety that has at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[077] The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[078] The term “alkynyl” as used herein refers to a monovalent group derived from a branched or linear C1-20 hydrocarbon of a designated number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl and heptynyl groups and the like.

[079] The term “alkylene” by itself or as part of another substituent refers to a branched or linear bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The alkylene group may be linear, branched or cyclic. The alkylene group may also be optionally unsaturated and / or substituted by one or more “alkyl group substituents.” One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms (also referred to in this document as “alkylaminoalkyl”) may optionally be inserted, wherein the nitrogen substituent is alkyl as described above. Alkylene groups Petition 870260033219, dated 09 / 04 / 2026, p. 48 / 182 44 / 69 examples include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3); cyclohexylene (-C6H10-); -CH=CH-CH=CH-; -CH=CH-CH2-; -CH2CH2CH2CH2-, CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2, -(CH2)qN(R)-(CH2)r-, wherein each of qr is independently an integer from 0 to about 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2O-); and ethylenedioxyl (-O-(CH2)2-O-). An alkylene group may have about 2 to about 3 carbon atoms and may additionally have 6 to 20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, wherein those groups having 10 or fewer carbon atoms are some embodiments of the present disclosure. A “lower alkyl” or “lower alkylene” is a shorter-chain alkyl or alkylene group, which generally has eight or fewer carbon atoms.

[080] The term “heteroalkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited to, by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy either or both chain terminals (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Additionally, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the linking group formula is written. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -ROC(O)-.

[081] The term “aryl” means, unless otherwise stated, an aromatic hydrocarbon substituent which may be a single ring or multiple rings (such as 1 to 3 rings), which are fused or covalently linked. The term “heteroaryl” refers to aryl groups (or rings) containing one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the atom (or atoms) Petition 870260033219, dated 09 / 04 / 2026, p. 49 / 182 45 / 69 of the nitrogen atoms are optionally quaternized. A heteroaryl group can be attached to the rest of the molecule via a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidil, 4-pyrimidil, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinoline, 5-isoquinoline, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinoline, and 6-quinoline. The substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.

[082] For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Therefore, the terms “arylalkyl” and “heteroarylalkyl” are intended to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl and the like) which includes those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl and the like). However, the term “haloaryl”, as used herein, is intended to encompass only aryls substituted with one or more halogens.

[083] When a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (for example, “3 to 7 members”), the term “member” refers to a carbon or heteroatom.

[084] Additionally, a structure generally represented by the formula: Petition 870260033219, dated 09 / 04 / 2026, p. 50 / 182 46 / 69 As used herein, refers to a ring structure, for example, but not limited to, a 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, and similar aliphatic and / or cyclic aromatic compound, which includes a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group may be present or absent, and when present, one or more R groups may each be substituted onto one or more available carbon atoms of the ring structure. The presence or absence of the R group and the number of R groups is determined by the value of the variable “n,” which is an integer that generally has a value ranging from 0 to the number of carbon atoms in the ring available for substitution. Each R group, if there is more than one, is substituted onto an available carbon of the ring structure rather than onto another R group.For example, the structure above, where n is 0 to 2, would comprise compound groups that include, without limitation: R1R1R1 ^N,^.R2 I II. I II I II \^\r2 R2 and similar.

[085] A dashed line representing a link in a cyclic ring structure indicates that the link may be present or absent in the ring. That is, a dashed line representing a link in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a structure Petition 870260033219, dated 09 / 04 / 2026, p. 51 / 182 47 / 69 saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[086] The symbol (,ΛΛΛΛΛΛΛΛ' ) denotes the point of attachment of a chemical portion to the rest of the molecule.

[087] When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent”, the named atom is replaced by a direct bond.

[088] Each of the above terms (for example, “alkyl,” “heteroalkyl,” “cycloalkyl,” and “heterocycloalkyl,” “aryl,” “heteroaryl,” “phosphonate,” and “sulfonate,” as well as their divalent derivatives) are intended to include both substituted and unsubstituted forms of the indicated group. Optional substituents for each type of group are provided below.

[089] Substituents for divalent and monovalent alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl derivatives (which include those groups frequently referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) may be one or more of a variety of groups selected from, but not limited to: -OR', =O, =NR', =N-OR', -NR'R”, -SR', -halogen, -SiR'R”R'”, -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R”, -OC(O)NR'R”, -NR”C(O)R', -NR'-C(O)NR”R'”, NR”C(O)OR', -NR-C(NR'R”)=NR'”, -S(O)R', -S(O)2R', -S(O)2NR'R”, -NRSO2R', -CN and -NO2 in a number that is in the range of zero to (2m'+l), where m' is the total number of carbon atoms in these groups.R', R”, R'” and R”” may each independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. As used herein, an “alkoxy” group is a... Petition 870260033219, dated 09 / 04 / 2026, p. 52 / 182 48 / 69 alkyl attached to the rest of the molecule through a divalent oxygen. When a developing compound includes more than one R group, for example, each of the R groups is independently selected, as are each of the R', R'', R'' and R''' groups when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a ring with 4, 5, 6 or 7 members. For example, NR'R'' is intended to include, without limitation, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, a person skilled in the art will understand that the term "alkyl" is intended to include groups that include carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[090] Similar to the substituents described for alkyl groups above, exemplary substituents for aryl and heteroaryl (as well as their divalent derivatives) are varied and are selected from, for example: halogen, -OR', -NR'R”, -SR', -SiR'R”R'”, -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R”, -OC(O)NR'R”, NR”C(O)R', -NR'-C(O)NR”R'”, -NR”C(O)OR', -NRC(NR'R”R'”)=NR””, -NR-C(NR'R”)=NR'” -S(O)R', -S(O)2R', -S(O)2NR'R”, -NRSO2R', CN and -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alcohol, and fluoro(C1-C4)alkyl, in a number that is in the range from zero to the total number of open valences in the aromatic ring system; and where R', R”, R'” and R”” can be selected independently of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.When a development compound includes more than one R group, for example, each of the R groups is independently selected, as are each of the R', R'', R'' and R''' groups when more than one of these groups is present.

[091] Two of the substituents on adjacent atoms of the aryl ring or Petition 870260033219, dated 09 / 04 / 2026, p. 53 / 182 49 / 69 heteroaryl groups can optionally form a ring of the formula -TC(O)-(CRR')qU-, where T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced by a substituent of the formula -A-(CH2)rB-, where A and B are independently -CRR', -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 4.

[092] One of the only bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent aryl or heteroaryl ring atoms may optionally be replaced by a substituent of the formula -(CRR')s-X'-(C”R'”)d-, where sed are independently integers from 0 to 3, and X' is -O-, -NR'-, -S, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R” and R'” may be selected independently from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[093] As used in this document, the term “acyl” refers to an organic acid group in which the -OH of the carboxyl group has been replaced by another substituent and has the general formula RC(=O)-, where R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group as defined in this document. As such, the term “acyl” specifically includes aryl acyl groups, such as a 2-(furan-2-yl)acetyl)- group and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, -RC(=O)NR', ​​esters, -RC(=O)OR', ketones, -RC(=O)R', and aldehydes, -RC(=O)H.

[094] The terms “alcoxyl” or “alcoxy” are used interchangeably in Petition 870260033219, dated 09 / 04 / 2026, p. 54 / 182 50 / 69 of this document and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular chemical portion via an oxygen atom, wherein the terms “alkyl”, “alkenyl”, and “alkynyl” are as described above and may include saturated or unsaturated, linear, branched or cyclic C1-20 oxohydrocarbon chains inclusive, which include, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl and the like.

[095] The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or ethoxymethyl group.

[096] “Aryloxyl” refers to an aryl-O- group in which the aryl group is as described above, which includes a substituted aryl. The term “aryloxyl” as used herein may refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or substituted alkoxyl, phenyloxyl or hexyloxyl.

[097] “Aralkyl” refers to an aryl-alkyl group in which the aryl and alkyl are as described above, and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[098] “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as described above. An exemplary aralkyloxyl group is benzyloxyl, that is, C6H5-CH2-O-. An aralkyloxyl group may be optionally substituted.

[099] “Alkoxycarbonyl” refers to an alkyl-OC(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

[0100] “Aryloxycarbonyl” refers to an aryl-OC(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl groups.

[0101] “Aralkoxycarbonyl” refers to an aralkyl-OC(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. Petition 870260033219, dated 09 / 04 / 2026, p. 55 / 182 51 / 69

[0102] “Carbamoyl” refers to an amide group of the formula -C(=O)NH2. “Alkylcarbamoyl” refers to an R'RN-C(=O)- group in which one of R and R' is hydrogen and the other of R and R' is alkyl and / or substituted alkyl as described above. “Dialkylcarbamoyl” refers to an R'RN-C(=O)- group in which each of R and R' is independently alkyl and / or substituted alkyl as described above.

[0103] The term carbonyldioxyl, as used in this document, refers to a carbonate group of the formula -OC(=O)-OR.

[0104] “Aciloxil” refers to an acyl-O- group where acyl is as described above.

[0105] The term “amino” refers to the -NH2 group and also refers to a nitrogen-containing group as known in the art derived from ammonia by the substitution of one or more hydrogen radicals by organic radicals. For example, the terms “acylamino” and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups, respectively.

[0106] An “aminoalkyl” as used herein refers to an amino group covalently linked to an alkylene ligand. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as defined above, attached to the parent molecular chemical portion via a nitrogen atom. The term alkylamino refers to a group having the structure -NHR' wherein R' is an alkyl group, as defined above; while the term dialkylamino refers to a group having the structure -NR'R”, wherein R' and R” are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R”R”', wherein R', R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, Petition 870260033219, dated 09 / 04 / 2026, p. 56 / 182 52 / 69 R', R”, and / or R'” taken together may optionally be -(CH2)k- where k is an integer from 2 to 6. Examples include, without limitation, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidine, trimethylamino, and propylamino.

[0107] The amino group is -NR'R”, where R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0108] The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., S-alkyl) or unsaturated (i.e., S-alkenyl and S-alkynyl) group attached to the parent molecular chemical moiety via a sulfur atom. Examples of thioalkoxyl chemical moieties include, without limitation, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0109] “Acylamino” refers to an acyl-NH- group where acyl is as described above. “Aroylamino” refers to an aroyl-NH- group where aroyl is as described above.

[0110] The term “carbonyl” refers to the -C(=O)- group, and may include an aldehyde group represented by the general formula RC(=O)H.

[0111] The term “carboxyl” refers to the -COOH group. These groups are also referred to in this document as a chemical moiety of “carboxylic acid”.

[0112] The terms “halo,” “halide,” or “halogen” as used herein refer to fluoro, chlorine, bromine, and iodine groups. Additionally, terms such as “haloalkyl” are intended to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” is intended to include, without limitation, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Petition 870260033219, dated 09 / 04 / 2026, p. 57 / 182 53 / 69

[0113] The term “hydroxyl” refers to the -OH group.

[0114] The term “hydroxyalkyl” refers to an alkyl group substituted by an -OH group.

[0115] The term “mercapto” refers to the -HS group.

[0116] The term “oxo” as used in this document means an oxygen atom that is double-bonded to a carbon atom or to another element.

[0117] The term “nitro” refers to the -NO2 group.

[0118] The term “thio” refers to a compound described earlier in this document in which a carbon or oxygen atom is replaced by a sulfur atom.

[0119] The term “sulfate” refers to the -SO4 group.

[0120] The term thiohydroxyl or thiol, as used in this document, refers to a group of the formula -SH.

[0121] More specifically, the term “sulfide” refers to the compound that has a group of the formula -SR.

[0122] The term “sulfone” refers to a compound that has a sulfonyl group -S(O2)R.

[0123] The term “sulfoxide” refers to a compound that has a sulfinyl group -S(O)R

[0124] The term ureide refers to a urea group with the formula -NH—CO—NH2.

[0125] The term “protecting group” in reference to compounds of formula (I) refers to a chemical substituent that can be selectively removed by readily available reagents that do not attack the regenerated 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 can be found, for example, in Wutz et al. (Greene's Protective Petition 870260033219, dated 09 / 04 / 2026, page 58 / 182 54 / 69 (Groups in Organic Synthesis, Fourth Edition, Wiley-Interscience, 2007). Protecting groups for carboxyl group protection, as described by Wutz et al. (Pages 533 to 643), are used in certain embodiments. In some embodiments, the protecting group is removable by acid treatment. Representative examples of protecting groups include, without limitation, 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). Those skilled in the technique will recognize appropriate situations where protective groups are needed and will be able to select a suitable protective group for use in a particular circumstance.

[0126] For all descriptive report and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optico- and stereoisomers, as well as racemic mixtures in which such isomers and mixtures exist.

[0127] Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include the compounds in racemic, scalemic, and optically pure forms. The optically active (R)- and (S)-, or D- and L- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When Petition 870260033219, dated 09 / 04 / 2026, page 59 / 182 55 / 69 the compounds described in this document contain olephenic linkages or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers.

[0128] Unless otherwise stated, the structures depicted herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, the unique stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are covered within the scope of the disclosure.

[0129] It will be evident to a person skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, wherein all such tautomeric forms of the compounds are encompassed within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another.

[0130] Unless otherwise stated, the structures depicted in this document are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the substitution of a hydrogen by a deuterium or tritium, or the substitution of a carbon by carbon enriched by 13C or 14C are covered within the scope of this disclosure.

[0131] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting those compounds. For example, the compounds may be labeled with radioactive isotopes such as, for example, tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are covered within the scope of the present disclosure.

[0132] The compounds of the present disclosure may exist as salts. A Petition 870260033219, dated 09 / 04 / 2026, p. 60 / 182 56 / 69 This present disclosure includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts such as a sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When the compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid, pure or in a suitable inert solvent, or by ion exchange.Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrodiodic, or phosphorous acids and the like, as well as organic acids derived from salts such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic and the like. Also included are amino acid salts such as arginate and the like, and salts of organic acids such as glucuronic or galactunic acids and the like. Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.

[0133] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. Petition 870260033219, dated 09 / 04 / 2026, page 61 / 182 57 / 69

[0134] Certain compounds of the present disclosure may exist in non-solvated forms as well as solvated forms, which include hydrated forms. In general, solvated forms are equivalent to non-solvated forms and are covered within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be covered within the scope of the present disclosure.

[0135] In addition to salt forms, the present disclosure provides compounds that are in a prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0136] Following long-standing patent law convention, the terms “a”, “an”, and “the” refer to “one or more” when used in this application, which includes the claims. Therefore, for example, reference to “an individual” includes a plurality of individuals, unless the context clearly dictates otherwise (e.g., a plurality of individuals), and so forth.

[0137] Throughout this descriptive report and claims, the terms “include,” “comprises,” and “that includes” are used in a non-exclusive sense, except where the context requires otherwise. Similarly, the term “includes” and its grammatical variants are intended to be non-limiting, so that citing items in a list is not to exclude other similar items. Petition 870260033219, dated 09 / 04 / 2026, p. 62 / 182 58 / 69 that can be replaced or added to the listed items.

[0138] For the purposes of this descriptive report and attached claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, proportions, formats, formulations, parameters, percentages, amounts, characteristics, and other numerical values ​​used in this descriptive report and claims shall be understood as being modified in all cases by the term “about” even though the term “about” may not expressly appear with the value, quantity or range.Consequently, unless otherwise indicated, the numerical parameters presented in the following descriptive report and appended claims are not and need not be exact, but may be approximate and / or larger or smaller as desired, reflecting tolerances, conversion factors, rounding, measurement error and the like, and other factors known to those skilled in the art depending on the desired properties sought to be obtained from the matter presently disclosed. For example, the term “about,” when referring to a value, may be intended to encompass variations, in some embodiments, ± 100%, in some embodiments ± 50%, in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ± 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% of the specified quantity, as such variations are suitable for carrying out the disclosed methods or employing the disclosed compositions.

[0139] Additionally, the term “about” when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, which includes all numbers within a range and modifies that range by extending the thresholds above and below the numerical values ​​presented. The citation of numerical values ​​by periods includes all numbers, for example, whole numbers, which include fractions thereof, subsumed Petition 870260033219, dated 09 / 04 / 2026, p. 63 / 182 59 / 69 within that range (for example, the quotation from 1 to 5 includes 1, 2, 3, 4 and 5, as well as fractions thereof, for example, 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range. EXAMPLES

[0140] The following Examples have been included to provide guidance for a person of ordinary skill in the technique to practice representative modalities of the matter presently revealed. In light of the present revelation and the general level of skill in the technique, those versed in the technique may understand that the following Examples are intended to be merely illustrative and that numerous changes, modifications, and alterations may be employed without departing from the scope of the matter presently revealed. The synthetic descriptions and specific examples that follow are intended for illustrative purposes only and should not be construed as limiting in any way to producing compounds of the revelation by other methods. EXAMPLE 1 OVERVIEW

[0141] The use of PSMA-binding ureas conjugated to chelated radioactive metals via various linking groups for imaging and potential radiotherapy of PSMA-expressing tumors has been previously reported in several patent applications and publications (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-4363; Banerjee et al. (2015) Journal of nuclear medicine 56, 628-634; Benesova et al.). A novel class of high-affinity linking agent was prepared by modifying the urea ligand at the epsilon amine position with the p-Br-benzyl group. The structures of the presently disclosed compounds are shown in Figure 1.

[0142] Without wishing to be limited to any particular theory, it is believed that the Petition 870260033219, dated 09 / 04 / 2026, p. 64 / 182 60 / 69 theranostic agents based on radioactive metal-chelated Glu-Lysine urea targeting prostate-specific membrane antigen (PSMA), when modified with the p-Br-benzyl group in the epsilon amino group of lysine in the Lys-Gluurea chemical portion, demonstrate high binding affinity for PSMA and high uptake in PSMA-expressing tumors and low renal uptake in the standard mouse model of prostate cancer. One modality, 177Lu-1, showed significant radiotherapeutic efficacy, with approximately 50% remission in mice bearing PSMA+ PC3 tumors. EXAMPLE 2 MATERIALS AND METHODS

[0143] Chemical synthesis of 1. The synthesis of compound 1 is described in Scheme 1. Bromobenzaldehyde (121.0 mg, 0.654 mmol) was slowly added to a stirred solution of Boc-protected urea, 4, (300.0 mg, 0.615 mmol) in 5 ml of methanol in an ice bath and allowed to warm naturally to room temperature. After one hour, sodium cyanoborohydride (158.0 mg, 2.5 mmol) was added and the reaction was left on stirring overnight. The crude reaction mixture was evaporated, redissolved in dichloromethane, purified by normal-phase silica chromatography (95:5, methylene chloride:methanol), and subjected to vacuum drying to give 5 in satisfactory yield. Yield: 80%. ESI-MS: 656.56 [M+H]+, found: 656.5. TSTU (32.6 mg, 108 μmol), Boc-5-aminovaleric acid (23.5 mg, 108 pmol), and DIPEA (37.7 pL, 216 μmol) were dissolved in 300 pL of DMF and stirred at room temperature.After one hour, compound 5 (71.0 mg, 108 μmol) was added with three rinses of DMF (50 µl each). The reaction mixture was stirred for four hours and stored at 4 °C overnight. The crude reaction mixture was purified by semi-preparative HPLC on a C18 column (40% water (0.1 TFA) / 60% ACN (0.1 TFA) / for 5 minutes, 60 to 90% over 20 minutes. Rt 21 minutes. The purified fractions... Petition 870260033219, dated 09 / 04 / 2026, p. 65 / 182 61 / 69 were combined, evaporated, and subjected to high vacuum drying for 10 minutes. ESI-MS: 572.44 [M+H]+, found: 572.4. Compound 6 was dissolved in dichloromethane (1.5 ml) and cooled in an ice bath. After equilibration, TFA (1.5 ml) was added and the mixture was stirred for 3 hours, allowing it to warm naturally to room temperature during the process. The mixture was dried under a nitrogen stream, dissolved in water, and lyophilized to yield 31.8 mg of compound 7. Yield: 54 pmol, 54%. p-SCN-bn-DOTA (12.2 mg, 17.7 pmol) was added to a stirred solution of 6 (12.2 mg TFA salt) and DIPEA (15.2 pL, 87.0 μmol) in DMSO (130 pL) equilibrated at 40 °C. The reaction mixture was stirred at 40 °C for four hours and stored at 4 °C overnight. The reaction mixture was purified by reverse-phase HPLC (holding ACN at 20% for 5 minutes, then 20 to 40% over 19 minutes). TA for approximately 12 minutes.The purified fractions were combined, rotary evaporated to reduce volume, and then lyophilized. ESIMS: 1138.37 [M+H]+, found: 1138.5. Compound 1 was further purified by HPLC using a gradient method. The HPLC method is a gradient method containing a mobile phase of 88% water (containing 0.1% TFA) and 22% CH3CN (0.1% TFA) for 1 to 5 minutes followed by 0 to 5 minutes of 88% water (containing 0.1% TFA) and 12% CH3CN (0.1% TFA), and 5 to 25 minutes of 88% water to 44% water and 12% acetonitrile to 56% acetonitrile at a flow rate of 8 ml / min.

[0144] Chemical synthesis of 2. This compound was synthesized using the same intermediate 7 and coupled with commercially available DOTA-NHS ester. ESI-MS: 974.86. [M+H]+, found: 974.5

[0145] Chemical synthesis of 3. This compound was synthesized using intermediate 4 and coupled with commercially available Boc-5-aminovaleric acid and DOTA-NHS ester. ESI-MS: 970.05 [M+H]+, found: 970.1.

[0146] Radium labeling of 177Lu-1. 1.0 μl of 177LuCl3 (1 mCi) in 0.1 HCl Petition 870260033219, dated 09 / 04 / 2026, p. 66 / 182 62 / 69 70 μL of NH4OAC buffer (0.2 M, pH 4) was added to N, and 5 μL of 2 mM NH4OAC was added to 0.2 M. The pH of the mixture was approximately 4.0. The mixture was held at 80 °C for one hour and purified by HPLC. The HPLC method is a gradient method containing a mobile phase of 77% water (containing 0.1% TFA) and 23% CH3CN (0.1% TFA) for 1 to 5 minutes followed by 5 to 25 minutes of water, 77% to 57%, and acetonitrile, 23% to 43%. 25.01 to 30 minutes of water, 5% to 5%, and acetonitrile, 95% to 95%; 30.01 to 37 minutes of water, 77% to 77%, and acetonitrile, 23% to 23%. Flow rate: 1.0 ml / min; λ: 200 nm, and a Cs column (25x4.6 mm), Varian microsob-MV 100-5. Radium-labeled O177Lu-1 was eluted in 17.1 to 20 minutes, while the unlabeled chelating agent was eluted in 21 to 22 minutes.

[0147] The HPLC method was used to prepare 177Lu-2 and 177Lu-3: The HPLC method is a gradient method that contains a mobile phase of 88% water (containing 0.1% TFA) and 22% CH3CN (0.1% TFA) for 1 to 5 minutes followed by 5 to 27 minutes of water, 88% to 75% and acetonitrile, 12% to 25%; 27.01 to 32 minutes of water, 5% to 5%, and acetonitrile, 95% to 95%; 32.01 to 37 minutes of water, 88% to 18% and acetonitrile, 12% to 22%. Flow rate: 1.0 ml / min; λ: 200 nm, and a C8 column (25x4.6 mm), Varian microsob-MV 100-5. Radium-labeled O177Lu-2 was eluted in 13.1 to 15.0 minutes, while the unlabeled chelating agent was eluted in 16 to 17 minutes. Radium-labeled O177Lu-3 was eluted in 13.1 to 15.0 minutes, while the unlabeled chelating agent was eluted in 10 to 12 minutes and 18 to 20 minutes, and the unlabeled agent in 14 to 16 minutes. Scheme 1. Synthesis of compound 1 Petition 870260033219, dated 09 / 04 / 2026, p. 67 / 182 63 / 69 ( 1 the. A-Bromobenzaldehyde, NaBHjCN, MeOH, '1% acetic acid b. BocNH(CH2^CO2H, H.ATU, DIE.A, DMF; C.TFA / CH2CI2 d. DQTA-Bn-SCN, DMSQ, DIEA EXAMPLE 3 RESULTS AND DISCUSSION

[0148] Chemical and Radiochemical Syntheses and Characterization. The modified p-bromobenzyl group of Glu-Lys urea (2) was prepared by reductive alkylation of 2 with p-Bromobenzaldehyde in the presence of sodium cyanoborohydride in methanol in satisfactory yield to provide 4 following a procedure from the literature (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357 to 4363). A small aliphatic ligand, Boc-5-aminovaleric acid, was coupled to the same ε-Lys amine of 4 followed by removal of the BOC group and conjugation with commercially available DOTA-Bn-SCN with 6 to provide 1 in moderate yield. Compound 2 was synthesized using DOTA-NHS ester as the chelating agent and coupling with the same intermediate 6. Compound 3 was synthesized as a control agent, without any p-Bromobenzyl group. All three agents were radiolabeled with 177Lu in satisfactory yield and purity at pH 4 in ammonium acetate buffer at 80°C.The binding affinities of the new compounds are listed in Table 1. Both 1 and 2 modified with the p-Bromobenzyl group showed higher binding affinity compared to 3.___________________ ___________Table 1. Binding affinities of representative agents_________. Compound 1 2 3 ZJ43 (for ZJ43 (for 1, Petition 870260033219, dated 09 / 04 / 2026, page 68 / 182 64 / 69 2) 3) IC50 (nM) 0.57 nM 0.64 nM 2.16 nM 1.91 nM 2.7 nM Ki (nM) 1.15 nM 1.28 nM 0.43 nM 0.38 nM 0.66 nM ClogD -4.6 -3.5 -4.1 nd LogPoct / water -3.0 -3.53 -3.2 nd nd Polar Surface area 359 327 368 nd nd

[0149] Cell binding properties. The 177Lu agents were further evaluated in cells and animals using standard isogenic PSMA+ PC3 PIP cell lines and PSMA-negative PC3 flu cells. Both 177Lu-1 and 177Lu2 demonstrated greater uptake in PSMA+ PC3 cells compared to 177Lu3. Additionally, internalization studies revealed that 177Lu-1 has almost 2 times greater internalized activity compared to 177Lu-3. All three agents showed significantly low uptake in PSMA-negative PC3 flu cells. O177Lu-1 was further evaluated for treatment efficacy in a clonogenic assay and compared to the previous lead compound SR6 (Banerjee et al. (2015) Journal of nuclear medicine 56, 628-634) and agents in clinical trials including 177Lu-PSMA-617 (Benesova et al. (2015) Journal of nuclear medicine 56, 914-920) and 177Lu PSMA-I&T (Weineisen et al. (2014) EJNMMI Res 4, 1-15).177Lu-1 was able to produce cell elimination efficacy of approximately 100% using a dose of 10 pCi in PSMA+ PC3 PIP cells, while no significant toxicity was seen in PSMA- PC3 flu cells. Table 2. Cell binding properties of the agents in 4-hour incubation (values ​​are expressed as percentage of dose incubated per million cells) (n = 3) Compound 177Lu-1 177Lu-2 177Lu-3 Cell uptake PSMA+ PC3 PIP 42.60 40.6 24.50 Cell uptake PSMA- PC3 flu 0.09 0.12 0.05 Internalization (Cell lysate) 15.88 nd 8.75 Petition 870260033219, dated 09 / 04 / 2026, page 69 / 182 65 / 69 Cell surface area 27.68 nd 12.50

[0150] Biodistribution. In vivo tissue biodistribution studies were performed for 177Lu-1 and 177Lu-2 and are listed in Tables 3 and 4. 177Lu-1 showed greater absorption and retention in the PSMA+ PC3 PIP tumor than 177Lu-2. Significantly, the agent 177Lu-2 showed a 5 times lower renal absorption than 177Lu-1, and as shown in Figure 3, the tumor / kidney ratio of the presently disclosed compounds was compared to the previous leading compounds 177Lu-SR6, 177Lu-PSMA-617, and 177Lu-PSMA-I&T. The tumor / kidney ratio of PSMA+ PC3 PIP to 177Lu-2 was greater than that of 177Lu-1. Due to greater retention and absorption in the tumor, 177Lu-1 was further evaluated for theranostic efficacy (imaging and therapeutic effect) in a pilot study using a small group of animals. Table 3. In vivo tissue biodistribution of 177Lu-1, Values ​​expressed as percentage of injected dose per gram ± standard deviation (N = 4) Tissue 2 hours 24 hours 48 hours 72 hours Blood 0.68 + 0.25 0.01 + 0.01 0.00 + 0.01 0.00 + 0.04 Heart 0.28 + 0.08 0.02 + 0.05 0.01 + 0.00 0.01 + 0.00 Lung 1.12 + 0.33 0.06 + 0.01 0.04 + 0.01 0.04 + 0.02 Liver 0.39 + 0.13 0.11 + 0.01 0.09 + 0.02 0.07 + 0.00 Stomach 0.87 + 0.63 0.04 + 0.01 0.05 + 0.04 0.04 + 0.00 Pancreas 0.28 + 0.09 0.02 + 0.00 0.01 + 0.01 0.01 + 0.00 Spleen 3.76 + 0.70 0.15 + 0.05 0.08 + 0.03 0.08 + 0.02 Fat 0.35 + 0.10 0.08 + 0.15 0.01 + 0.01 0.06 + 0.07 Kidney 87.10 + 25.99 1.65 + 0.30 1.02 + 0.58 0.62 + 0.04 Muscle 0.68 + 0.98 0.01 +0.00 0.00 + 0.00 0.02 + 0.02 Sm. Int. 0.51 +0.32 0.03 + 0.01 0.02 + 0.00 0.02 + 0.01 Sal.Gl 1.09 + 0.08 0.09 + 0.02 0.05 + 0.03 0.05 + 0.02 Bladder 3.39 + 2.78 0.31 + 0.13 0.12 + 0.07 0.06 + 0.03 PC-3 PIP 55.04 + 7.23 40.61 + 7.00 27.00 + 7.03 24.90 + 2.27 PC-3 Flu 0.39 + 0.03 0.10 + 0.02 0.05 + 0.01 0.06 + 0.01. Table 4. In vivo tissue biodistribution of 177Lu-2, Values ​​expressed as percentage of injected dose per gram ± standard deviation (N = 4) Tissue 2 hours 24 hours 48 hours Blood 0.81 +0.80 0.01 +0.01 0.00 +0.00 Heart 0.31 +0.19 0.02 +0.01 0.01 +0.01 Petition 870260033219, dated 09 / 04 / 2026, page 70 / 182 66 / 69 Lung 0.39 + 0.13 0.02 + 0.00 0.02 0 0.00 Liver 0.19 + 0.05 0.04 + 0.01 0.04 0 0.00 Stomach 7.95 + 4.17 0.03 + 0.02 0.03 0 0.01 Pancreas 0.19 + 0.08 0.02 + 0.02 0.01 0 0.00 Spleen 1.10 + 0.62 0.05 + 0.02 0.04 0 0.01 Fat 0.70 + 0.54 0.11 + 0.10 0.03 0 0.04 Kidney 14.04 + 8.19 0.73 + 0.70 0.24 0 0.07 Muscle 0.20 + 0.05 0.01 + 0.00 0.00 0 0.00 Sm. Int. 2.02 + 2.86 0.06 + 0.09 0.02 0 0.00 Salivary gland 0.89 + 0.51 0.04 + 0.02 0.02 0 0.01 Bladder 3.48 + 1.66 0.17 + 0.06 0.08 0 0.02 Bone 0.46 + 0.10 0.10 + 0.01 0.08 0 0.02 PC-3 PIP 43.18 + 5.32 24.76 + 5.13 20.13 0 3.35 PC-3 Flu 0.29 0 0.02 0.08 0 0.04 0.05 0 0.01

[0151] Small Animal SPECT Imaging and Therapeutic Effect. Figure 4 shows SPECT imaging of 177Lu-1 during treatment studies 1 to 8 days post-injection. A single 3 mCi dose was injected via caudal vein injection into mice (n = 10) bearing the PSMA+ PC3 PIP tumor (size 3 to 5 mm). Saline solution was injected into another group of mice (n = 10) for the control study. Mice were monitored for body weight and tumor size twice weekly. The control group of mice was euthanized after 4 to 8 weeks as tumor size was > 12 mm. For the treatment group, 50% of the mice showed complete eradication of the tumors. These mice initially underwent a baseline body weight loss that was recovered after 2 weeks. The results are shown in Figure 5.Figures 6A and 6B demonstrated the therapeutic efficacy (reduction in tumor volume) of 177Lu-1 compared to the control group using saline solution. Five mice showed complete remission of the disease and survived for more than five months.

[0152] In summary, theranostic agents based on radioactive metal-chelated urea-glu-lysine targeting prostate-specific membrane antigen (PSMA) when modified with the p-Br-benzyl group on the epsilon group Petition 870260033219, dated 09 / 04 / 2026, page 71 / 182 The 67 / 69 amino lysine group of the Lys-Glu-urea chemical moiety demonstrated high binding affinity for PSMA and high uptake in PSMA-expressing tumors, and low renal uptake in the standard mouse model of prostate cancer. A representative compound, 177Lu-1, showed significant radiotherapeutic efficacy, with approximately 50% remission in mice bearing PSMA+ PC3 tumors. REFERENCES

[0153] All publications, patent applications, patents and other references mentioned in the descriptive report are indicative of the level of those skilled in the art to which the matter presently disclosed pertains. All publications, patent applications, patents and other references (e.g., websites, databases, etc.) mentioned in the descriptive report are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent application, patent and other reference were specifically and individually indicated for incorporation by reference. It shall be understood that although various patent applications, patents and other references are mentioned herein, such reference does not constitute an admission that any of these documents form part of the common general knowledge in the art.In the event of a conflict between the descriptive report and any of the incorporated references, the descriptive report (including any amendments thereto, which may be based on an incorporated reference) shall prevail. The meanings of terms accepted by standard technique are used herein unless otherwise indicated. Standard abbreviations for various terms are used herein.

[0154] Publication of International PCT Patent Application under No. PCT / US2008 / 007947 by Pomper, MG, Ray, S., Mease, RC, Foss, C. for Labeled inhibitors of prostate specific membrane antigen (PSMA), biological evaluation, and use as imaging agents, published on 12 / 21 / 2008 (WO 2009 / 002529 A2); Petition 870260033219, dated 09 / 04 / 2026, page 72 / 182 68 / 69 Publication of International PCT Patent Application under No. PCT / US2008 / 013158 by Chandran SS, Ray S., Denmeade SR, Pomper MG, Mease RC for Prostate specific membrane antigen targeted nanoparticles for therapy of prostate cancer, published on 04 / 06 / 2009 (WO 2009070302 A1); Publication of International PCT Patent Application under No. PCT / US2010 / 028020 by Pomper MG, Mease RC; Ray S., Chen Y. for PSM targeting compounds and uses thereof, published on 23 / 09 / 2010 (WO 2010108125 A2); Banerjee, SR, Foss, CA, Pullambhatla, M., Wang, Y., Srinivasan, S., Hobbs, RF, Baidoo, KE, Brechbiel, MW, Nimmagadda, S., Mease, RC, Sgouros, G., and Pomper, MG (2015) Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates. Journal of nuclear medicine 56, 628 to 634; Benesova, M., Schafer, M., Bauder-Wust, U., Afshar-Oromieh, A., Kratochwil, C., Mier, W., Haberkorn, U., Kopka, K., and Eder, M. (2015) Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. Journal of nuclear medicine 56, 914 a 920; Tykvart, J., Schimer, J., Jancarik, A., Barinkova, J., Navratil, V., Starkova, J., Sramkova, K., Konvalinka, J., Majer, P., and Sacha, P. (2015) Design of Highly Potent Urea-Based, Exosite-Binding Inhibitors Selective for Glutamate Carboxypeptidase II. Journal of medicinal chemistry 58, 4.357 a 4.363; Weineisen, M., Simecek, J., Schottelius, M., Schwaiger, M., e Wester, H.-J. (2014) Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. EJNMMI Res 4, 1 a 15.

[0155] Although the preceding matter has been described in some detail by way of illustration and example for the sake of clarity, it will be understood Petition 870260033219, dated 09 / 04 / 2026, page 73 / 182 69 / 69 by those skilled in the art that certain changes and modifications may be made within the scope of the appended claims. Petition 870260033219, dated 09 / 04 / 2026, page 74 / 182

Claims

1 / 17 CLAIMS 1. Compound CHARACTERIZED by the suit having Formula (I): (I); wherein: Z is tetrazole or CO2Q; Q is H or a protecting group, wherein the protecting group is selected from the group consisting of 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); m is an integer selected from the group consisting of 1, 2, 3, 4 and 5; R is -CH2-R1; L is linear C1-C6 alkylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2-(C=S)-, (C=O)-NR2-, and -(C=S)-NR2-; where each occurrence of L and W may be the same or different; R2 is H or a C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent selected from the group consisting of: Petition 870260033219, dated 09 / 04 / 2026, p.75 / 182 2 / 17 ; ; said chelating agent comprising a metal or a radioactive metal; and pharmaceutically acceptable salts thereof.

2. Compound according to claim 1, CHARACTERIZED in that the chelating agent comprises a metal selected from the group consisting of: Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc.

3. Compound according to claim 2, CHARACTERIZED in that the metal is a radioactive metal and is selected from the group consisting of: 68Ga, 64Cu, 86Y, 90Y, 89Zr, 111In, 99mTc, 177Lu, 153Sm, 186Re, 188Re, 67Cu, 212Pb, 225Ac, 213Bi, 212Bi, 212Pb, 67Ga, 203Pb, 47Sc, and 166Ho.

4. Compound according to claim 1, CHARACTERIZED in that the compound of formula (I) is selected from: Petition 870260033219, dated 09 / 04 / 2026, p. 76 / 182 3 / 17 O HO HO O HO HO OH OH OH OH j OH OH HO N HO OH OH OH OH HO OH OH OH HO OH Petition 870260033219, dated 09 / 04 / 2026, p. 77 / 182 4 / 17 Petition 870260033219, dated 09 / 04 / 2026, p. 78 / 182 5 / 17 5. In vitro or ex vivo method for treating one or more cells or tumors expressing PSMA, CHARACTERIZED in that the method comprises placing one or more cells or tumors expressing PSMA in contact with an effective amount of a compound of formula (I), the compound of formula (I) comprising: .V\LA (CH2)m qo2c nn co2q H H 2 (I), where: Z is tetrazole or CO2Q; Q is H or a protecting group, wherein the protecting group is selected from the group consisting of 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); m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; R is -CH2-R1; R1 is selected from the group consisting of 1;where X is independently Br or I; L is a linear C1-C6 alkylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2-(C=S)-, (C=O)-NR2-, and -(C=S)-NR2-; where each occurrence of L and W may be the same or different; R2 is H or a C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent selected from the group consisting of: Petition 870260033219, dated 09 / 04 / 2026, p. 80 / 182 7 / 17 HO. / 0 HOΟκχΡ HO. .0 HO., ß e HO / 0 HO 0 HO 0 0^0H HO. .Q HO .0 N Nx OH said chelating agent comprising a radioactive metal suitable for radiotherapy; and pharmaceutically acceptable salts thereof.; 6. Method according to claim 5, CHARACTERIZED in that the radioactive metal is selected from the group consisting of: 90Y, 177Lu, 211At, 111In, 153Sm, 186Re, 188Re, 67Cu, 212Pb, 225Ac, 213Bi, 212Bi, 212Pb and 67Ga.

7. Method, according to claim 5, CHARACTERIZED in that one or more tumors or cells expressing PSMA are 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 stomach tumor or cell, and combinations thereof.

8. Method, according to claim 5, CHARACTERIZED by the fact that Petition 870260033219, dated 09 / 04 / 2026, page 81 / 182 8 / 17 that one or more tumors or cells expressing PSMA are prostate tumors or cells.

9. Method according to claim 5, CHARACTERIZED in that the method results in the inhibition of tumor growth.

10. Method according to claim 5, CHARACTERIZED in that the compound of formula (I) is selected from: II H IT H II O H H O Petition 870260033219, dated 09 / 04 / 2026, p. 82 / 182 9 / 17 HO- Petition 870260033219, dated 09 / 04 / 2026, p. 83 / 182 10 / 17 HO^ J Petition 870260033219, dated 09 / 04 / 2026, p. 84 / 182 11 / 17 o HH o ; and 11. Use of a compound of formula (I) CHARACTERIZED by the fact that it is for the manufacture of a medicament for the treatment of one or more tumors or cells expressing PSMA, the compound of formula (I) comprising: wherein: Z is tetrazole or CO2Q; Q is H or a protecting group, wherein the protecting group is selected from the group consisting of 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); Petition 870260033219, dated 09 / 04 / 2026, p.85 / 182 12 / 17 m is an integer selected from the group consisting of 1, 2, 3, 4 and 5; R is -CH2-R1; X; and L is linear C1-C6 alkylene; W is selected from the group consisting of -NR2-(C=O)-, -NR2-(C=S)-, (C=O)-NR2-, and -(C=S)-NR2-; wherein each occurrence of L and W may be the same or different; R2 is H or a C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2 and 3; Ch is a chelating agent selected from the group consisting of: ; ; said chelating agent comprising a radioactive metal suitable for Petition 870260033219, dated 09 / 04 / 2026, page 86 / 182 13 / 17 radiotherapy; and pharmaceutically acceptable salts thereof.

12. Use, according to claim 11, CHARACTERIZED in that the radioactive metal is selected from the group consisting of: 90Y, 177Lu, 211At, 111In, 153Sm, 186Re, 188Re, 67Cu, 212Pb, 225Ac, 213Bi, 212Bi, 212Pb and 67Ga.

13. Use, according to claim 11, CHARACTERIZED in that one or more tumors or cells expressing PSMA are 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 stomach tumor or cell, and combinations thereof.

14. Use, according to claim 11, CHARACTERIZED in that one or more tumors or cells expressing PSMA are prostate tumors or cells.

15. Use, according to claim 11, CHARACTERIZED in that one or more tumors or cells expressing PSMA are present in an individual.

16. Use, according to claim 15, CHARACTERIZED by the fact that the individual is a human being.

17. Use, according to claim 11, CHARACTERIZED in that the treatment results in the inhibition of tumor growth.

18. Use according to claim 11, CHARACTERIZED in that the compound of formula (I) is selected from: Petition 870260033219, dated 09 / 04 / 2026, p. 87 / 182 14 / 17 JJJ Petition 870260033219, dated 09 / 04 / 2026, p. 88 / 182 15 / 17 Petition 870260033219, dated 09 / 04 / 2026, p. 89 / 182 16 / 17 Petition 870260033219, dated 09 / 04 / 2026, p. 90 / 182 17 / 17 Petition 870260033219, dated 09 / 04 / 2026, page 91 / 182

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