Prostate specific membrane antigen targeted high affinity agents for endoluminal radiation therapy of prostate cancer

Abstract

The present application relates to prostate specific membrane antigen targeted high affinity agents for endoluminal radiation therapy of prostate cancer. Compounds of formula (I) and pharmaceutically acceptable salts thereof, 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 a substituted aryl group, a substituted pyridine group, and an unsubstituted isoquinoline group; l is a linking group selected from the group consisting of a C1-C6 alkylene group and a C3-C6 cycloalkylene group and an arylene group; w is selected from the group consisting of-NR2-(C = O)-,-NR2-(C = S)-,-(C = O)-NR2-, and-(C = S)-NR2-; l and W are the same or different in each occurrence; r2 is H or a C1-C4 alkyl group; n is an integer selected from the group consisting of 1, 2, and 3; ch is a chelating agent comprising a metal or a radioactive metal. # imgabs0 #

Description

[0001] This application is a divisional application of the application with the filing date of March 22, 2017, application number 202210306552.X, and invention title "High-affinity agents targeting prostate-specific membrane antigen for intracavitary radiotherapy of prostate cancer".

[0002] The application with the filing date of March 22, 2017, application number 202210306552.X, and invention title "High-affinity agents targeting prostate-specific membrane antigen for intracavitary radiotherapy of prostate cancer" is a divisional application of the application with the filing date of March 22, 2017, application number 201780031580.2, and invention title "High-affinity agents targeting prostate-specific membrane antigen for intracavitary radiotherapy of prostate cancer".

[0003] Cross-reference to related applications

[0004] This application claims the benefit of U.S. Provisional Application No. 62 / 311,697, filed on March 22, 2016, which is incorporated herein by reference in its entirety. Background

[0006] Prostate cancer is the leading cancer in the U.S. population and the second leading cause of cancer death in men. Therapies for locally advanced disease remain controversial, and an increasing number of different options are available. New, high-affinity, radiotherapy agents for prostate cancer have been developed using prostate-specific membrane antigen (PSMA) as a target. PSMA is a marker for androgen-independent disease and is also expressed in the neovasculature of solid (non-prostate) tumors. Overview

[0008] In some aspects, the presently disclosed subject matter provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0009]

[0010] Wherein: 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-R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a linking group selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene, and arylene; W is selected from -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2- a group consisting of; where each occurrence of L and W can be the same or different; R 2 is H or a C1-C4 alkyl group; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent which may contain a metal or a radioactive metal.

[0011] In a particular aspect of the compound of formula (I), R 1 is selected from the group consisting of:

[0012] wherein X is independently Br or I.

[0013] In an even more particular aspect of the compound of formula (I), the chelating agent is selected from the group consisting of:

[0014]

[0015]

[0016] In other aspects, the presently disclosed subject matter provides a method for treating one or more PSMA-expressing tumors or cells, the method comprising contacting one or more PSMA-expressing tumors or cells with an effective amount of a compound of formula (I), the compound of formula (I) comprising:

[0017]

[0018] wherein: 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-R 1 ; R 1 is selected from the group consisting of a substituted aryl group, a substituted pyridine, and an unsubstituted isoquinoline; L is a linking group selected from the group consisting of a C1-C6 alkylene group, a C3-C6 cycloalkylene group, and an arylene group; W is selected from the group consisting of -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 -; where each occurrence of L and W can be the same or different; R 2 is H or a C1-C4 alkyl group; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent which contains a radioactive metal suitable for radiotherapy; and its pharmaceutically acceptable salts.

[0019] In other aspects, the presently disclosed subject matter provides methods for imaging one or more prostate specific membrane antigen (PSMA) tumors or cells, the methods comprising contacting the one or more tumors or cells with an effective amount of a compound of formula (I) and imaging.

[0020] In still other aspects, the presently disclosed subject matter provides kits comprising a compound of formula (I).

[0021] Certain aspects of the presently disclosed subject matter have been set forth above, which are solved in whole or in part by the presently disclosed subject matter, other aspects will become apparent as the description proceeds and when taken in conjunction with the appended examples and drawings, as best described hereinbelow. Brief Description of the Drawings

[0023] The presently disclosed subject matter has been described generally above, and will now be described with reference to the drawings, which are not necessarily to scale and in which:

[0024] Figure 1 shows the chemical structure of a representative radiotherapeutic agent;

[0025] Figure 2 shows 177 a comparative study of the clonogenic efficacy of Lu-1 and the known agents SR6, PSMA-617 and PSMA-I&T;

[0026] Figure 3 shows 177 Lu-1, 177 Lu-2, 177 Lu-SR6, 177 Lu-PSMA-617 and 177 the PSMA+ tumor to kidney ratio of Lu-PSMA-I&T;

[0027] Figure 4 shows SPECT-CT imaging of Lu-1 using a single dose of 3 mCi during a treatment study; 177 Lu-1;

[0028] Figure 5 shows the relative body weight of mice during a treatment study; and

[0029] Figure 6A and Figure 6B shows the relative tumor volume of mice during a treatment study ( Figure 6A ) and the Kaplan-Meier survival curve up to 60 days of treatment ( Figure 6B ). Detailed Description

[0031] The presently disclosed subject matter will now be described more fully hereinafter with reference to the accompanying drawings, in which certain, but not all, embodiments of the presently disclosed subject matter are shown. The same numbers refer to the same elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter will come to mind to those skilled in the art in the field to which the presently disclosed subject matter pertains, having the benefit of the teachings presented in the foregoing description and the related drawings. Accordingly, it is to be understood that the presently disclosed subject matter is not limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0032] I. High-Affinity Agents Targeting Prostate-Specific Membrane Antigen for Brachytherapy of Prostate Cancer

[0033] A. Compounds of Formula (I)

[0034] Thus, in some embodiments, the presently disclosed subject matter provides compounds of Formula (I) and their pharmaceutically acceptable salts:

[0035]

[0036] wherein: 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-R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a linking group selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene, and arylene; W is selected from the group consisting of -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 -; wherein each occurrence of L and W may be the same or different; R 2 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, which may contain a metal or a radioactive metal.

[0037] The phrase "each occurrence of L and W can be the same or different" means that when the variable "n" is 2 or 3, one "L" group can be a C1-C6 alkylene group, and the other "L" group or groups can be a C3-C6 cycloalkylene or arylene group, or, in other embodiments, each "L" group can be, for example, a C1-C6 alkylene group. Similarly, for example, when "n" is 2 or 3, one "W" group can be -(C=O)-NR 2 -, and the other "W" group or groups can be -(C=S)-NR 2 -, or, in other embodiments, each "W" can be, for example, -(C=O)-NR 2 -.

[0038] In a specific embodiment of the compound of formula (I), R 1 is selected from the group consisting of:

[0039] wherein X is independently Br or I.

[0040] In a yet more specific embodiment of the compound of formula (I), the chelating agent is selected from the group consisting of:

[0041]

[0042] In a still more specific embodiment 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 another specific embodiment of the compound of formula (I), the metal is a radioactive metal and is selected from the group consisting of: 68 Ga, 64 Cu, 86 Y, 90 Y, 89 Zr, 111 In, 99m Tc, 177 Lu, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc, and 166 Ho.

[0043] In certain embodiments, the compounds of formula (I) are selected from the group consisting of:

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054] B. Method of using a compound of formula (I) for treating one or more PSMA-expressing tumors or cells

[0055] In some embodiments, the presently disclosed subject matter provides a method for treating one or more PSMA-expressing tumors or cells, the method comprising contacting the one or more PSMA-expressing tumors or cells with an effective amount of a compound of formula (I), the compound of formula (I) comprising:

[0056]

[0057] wherein: 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-R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a linking group selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene, and arylene; W is selected from the group consisting of -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 -; wherein each occurrence of L and W can be the same or different; R 2is H or a C1-C4 alkyl group; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelating agent that includes a radioactive metal suitable for radiotherapy; and pharmaceutically acceptable salts thereof.

[0058] "Contacting" means any action that causes at least one compound comprising a therapeutic agent of the presently disclosed subject matter to physically contact at least one PSMA-expressing tumor or cell. Contacting can include exposing the cell or tumor to an amount of the compound sufficient to cause at least one compound to contact at least one cell or tumor. The method can be practiced in vitro or ex vivo by introducing, and preferably mixing, the compound and the cell or tumor in a controlled environment such as a culture dish or tube. The method can be practiced in vivo, in which case contacting means exposing at least one cell or tumor in a subject to at least one compound of the presently disclosed subject matter, such as by administering the compound to the subject via any suitable route.

[0059] As used herein, the term "treatment" can include reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of a disease, disorder, or condition to which such terms apply, or one or more symptoms or manifestations of such a disease, disorder, or condition. Preventing refers to causing such a disease, disorder, condition, or symptom or manifestation, or worsening of such severity, not to occur. Thus, the presently disclosed compounds can be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder, or condition.

[0060] Generally, an "effective amount" of an active agent refers to the amount necessary to elicit a desired biological response. As will be understood by one of ordinary skill in the art, the effective amount of an agent or device can vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, and the like.

[0061] The term "combination" is used in its broadest sense and means that a subject is administered at least two agents, and more particularly, a compound of formula (I) and at least one other active agent. More particularly, the term "combination" refers to the simultaneous administration of two (or more) active agents for the treatment of, for example, a single disease state. As used herein, the active agents can be combined and administered in a single dosage form, can be administered simultaneously as separate dosage forms, or can be administered as separate dosage forms administered alternately or sequentially on the same or separate days. In one embodiment of the presently disclosed subject matter, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered as separate dosage forms (e.g., where it is desirable to vary the amount of one dosage form but not the other). The single dosage form can include additional active agents for the treatment of the disease state.

[0062] In certain embodiments, R 1Selected from the group consisting of:

[0063]

[0064] wherein X is independently Br or I.

[0065] In a more specific embodiment, the chelating agent is selected from the group consisting of:

[0066]

[0067]

[0068] In an even more specific embodiment, the radioactive metal suitable for radiotherapy is selected from the group consisting of: 90 Y, 177 Lu, 211 At, 111 In, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb, and 67 Ga.

[0069] In an even more specific embodiment, the compound of formula (I) is selected from the group consisting of:

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] In other embodiments, one or more PSMA-expressing tumors or cells are selected from the group consisting of: prostate tumors or cells, metastatic prostate tumors or cells, lung tumors or cells, kidney tumors or cells, glioblastoma, pancreatic tumors or cells, bladder tumors or cells, sarcoma, melanoma, breast tumors or cells, colon tumors or cells, germ cells, pheochromocytoma, esophageal tumors or cells, stomach tumors or cells, and combinations thereof. In some other embodiments, one or more PSMA-expressing tumors or cells are prostate tumors or cells.

[0081] In other embodiments, one or more PSMA-expressing tumors or cells are in vitro, in vivo, or ex vivo. In still other embodiments, one or more PSMA-expressing tumors or cells are present in a subject.

[0082] The subject treated by the presently disclosed methods in many of its embodiments is desirably a human subject, however, it should be understood that the methods described herein are effective with respect to all vertebrate species, and all vertebrate species are intended to be included within the term "subject". Thus, a "subject" can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or for prophylactic treatment to prevent the onset of a condition or disease, or an animal (non-human) subject for medical, veterinary, or developmental purposes. Suitable animal subjects include mammals, including but not limited to, primates, such as humans, monkeys, apes, and the like; bovines, such as cattle, oxen, and the like; ovines, such as sheep and the like; caprines, such as goats and the like; porcines, such as pigs, hogs, and the like; equines, such as horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like. The animal can be a transgenic animal. In some embodiments, the subject is human, including but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Additionally, a "subject" can include a patient having or suspected of having a condition or disease. Thus, the terms "subject" and "patient" are used interchangeably herein.

[0083] In still some other embodiments, the method results in inhibition of tumor growth.

[0084] C. Method of using a compound of formula (I) for imaging one or more PSMA-expressing tumors or cells

[0085] In other embodiments, the presently disclosed subject matter provides methods for imaging one or more prostate specific membrane antigen (PSMA) tumors or cells, the methods comprising contacting an effective amount of a compound of formula (I) with one or more tumors or cells and making an image, the compound of formula (I) comprising:

[0086]

[0087] wherein: 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-R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is a linking group selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene, and arylene; W is selected from the group consisting of -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 -; wherein each occurrence of L and W may be the same or different; R 2 is H or C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3; Ch is a chelator comprising a radioisotope suitable for imaging; and pharmaceutically acceptable salts thereof.

[0088] D. Kits

[0089] In yet other embodiments, the presently disclosed subject matter provides kits comprising a compound of formula (I).

[0090] In certain embodiments, the kit provides a packaged pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention. In certain embodiments, the packaged pharmaceutical composition will contain the reaction precursors necessary to produce the compound of the invention upon combination with a radiolabeled precursor. Other packaged pharmaceutical compositions provided by the invention further include indicia comprising at least one of the following: instructions for preparing a compound according to the invention from the supplied precursors, 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.

[0091] E. Pharmaceutical Compositions and Administration

[0092] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) alone or a compound of formula (I) in combination with a mixture of one or more additional therapeutic agents and a pharmaceutically acceptable excipient. Those skilled in the art will recognize that the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound described above. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art and include salts of the active compound prepared with relatively non-toxic acids or bases, depending on the particular substituent moieties found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent or by ion exchange, such that one of the basic counterions (bases) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts.

[0093] When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent or by ion exchange, such that one of the acidic counterions (acids) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable acid addition salts include those derived from the following inorganic acids: such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid and the like, as well as salts derived from the following relatively non-toxic organic acids: such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginine and the like, as well as salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain particular compounds of the present disclosure contain both basic and acidic functional groups, which allows the compounds to be converted into base addition salts or acid addition salts.

[0094] Accordingly, pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, for example, but are not limited to, acetate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, ethohexylate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, pectinate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts can be found, for example, in Remington: The Science and Practice of Pharmacy (20th Edition) Lippincott, Williams & Wilkins (2000).

[0095] In therapeutic and / or diagnostic applications, the compounds of the present disclosure can be formulated for a variety of modes of administration, including systemic and topical or local administration. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy (20th Edition) Lippincott, Williams & Wilkins (2000).

[0096] Depending on the particular condition being treated, such agents can be formulated as a liquid dosage form or a solid dosage form and administered systemically or locally. The agents can be delivered, for example, in a time- or sustained-release form known to those skilled in the art. Techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy (20th Edition) Lippincott, Williams & Wilkins (2000). Suitable routes can include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intra-articular, intrathoracic, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injection or other delivery modes.

[0097] For injection, the agents of the present disclosure can be formulated and diluted in an aqueous solution, for example, in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or saline buffer. For such transmucosal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art.

[0098] It is within the scope of the present disclosure to use pharmaceutically acceptable inert carriers to formulate the compounds disclosed herein for practicing the present disclosure into dosages suitable for systemic administration. With appropriate selection of carriers and suitable manufacturing practices, the compositions of the present disclosure, particularly those formulated as solutions, can be administered parenterally, for example, by intravenous injection. The compounds can be readily formulated into dosages suitable for oral administration using pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present disclosure to be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by the subject to be treated (e.g., a patient).

[0099] For nasal or inhalation delivery, the agents of the present disclosure can also be formulated by methods known to those skilled in the art and can include, for example, but not limited to, solubilizing, diluting, or dispersing substances such as saline; preservatives such as benzyl alcohol; absorption promoters; and fluorocarbons.

[0100] Drug compositions suitable for use in the present disclosure include those in which the active ingredient is included in an effective amount to achieve its intended purpose. Determination of the effective amount is entirely within the ability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the present disclosure are effective over a wide dosage range. For example, in treating adults, dosages of from 0.01 mg to 1000 mg per day, from 0.5 mg to 100 mg per day, from 1 mg to 50 mg per day, and from 5 mg to 40 mg per day are examples of dosages that can be used. A non-limiting dosage is from 10 mg to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, the bioavailability of the compound, the absorption, distribution, metabolism, and excretion (ADME) toxicity of the compound, and the preference and experience of the attending physician.

[0101] In addition to the active ingredient, these drug compositions can contain suitable pharmaceutically acceptable carriers containing excipients and adjuvants that aid in processing the active compound into a pharmaceutically usable article. Preparations for oral administration can be in the form of tablets, dragees, capsules, or solutions.

[0102] A pharmaceutical preparation for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, if desired, after adding suitable auxiliaries, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose products such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrants can be added, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0103] The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbomer gels, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablet or dragee coatings for identifying or characterizing different combinations of active compound doses.

[0104] Pharmaceutical products that can be used orally include push-fit capsules made of gelatin, and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and an optional stabilizer. In the soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin or liquid polyethylene glycol (PEG). In addition, stabilizers can be added.

[0105] II. General Definitions

[0106] Although specific terms are employed herein, they are used in a general and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently described subject matter belongs.

[0107] Although the following terms regarding the compounds of formula (I) are considered to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate the explanation of the presently disclosed subject matter. These definitions are intended to supplement and clarify and not to exclude definitions that will be apparent to one of ordinary skill in the art upon review of the present disclosure.

[0108] As used herein, the term "substituted", whether preceded by the term "optionally" or not, and substituents, refer to the ability to change one functional group on a molecule to another functional group, as understood by one of ordinary skill in the art, 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 designated group, the substituents can be the same or different at each position. Substituents can also be further substituted (e.g., an aryl group substituent can have additional substituents away from it, such as another aryl group, which is further substituted at one or more positions).

[0109] In cases where substituent groups or linking groups are designated by their conventional chemical formulas written from left to right, they equally encompass the chemically identical substituents obtained by writing the structure from right to left, e.g., -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.

[0110] When the term "independently selected from" is used, the substituents mentioned (e.g., R groups such as groups R1, R2, and the like, or variables such as "m" and "n") can be the same or different. For example, both R1 and R2 can be substituted alkyls, or R1 can be hydrogen and R2 can be a substituted alkyl, and the like.

[0111] When the term "a", "an", or "a(n)" is used with respect to groups of substituents herein, it means at least one. For example, in the case where a compound is "an" alkyl or aryl substituted, the compound is optionally substituted by at least one alkyl and / or at least one aryl. Further, in the case where a moiety is substituted by R substituents, the group can be referred to as "R-substituted". In the case where a moiety is R-substituted, the moiety is substituted by at least one R substituent and each R substituent is optionally different.

[0112] The named "R" or group will generally have a structure in the art that is considered to correspond to the group having that name, unless otherwise specified herein. For illustrative purposes, some representative "R" groups as set forth above are defined below.

[0113] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, in cases where a group can be substituted by one or more of a number of substituents, such substitutions are chosen so as to conform to the principles of chemical bonding and to give compounds that are not inherently unstable and / or that would not be known to those of ordinary skill in the art to be likely to be unstable under environmental conditions such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0114] Unless otherwise expressly defined, "substituent group" as used herein includes one or more functional groups selected from the portions defined herein.

[0115] As used herein, the term "hydrocarbon" refers to any chemical group containing hydrogen and carbon. The hydrocarbon can be substituted or unsubstituted. As will be known to those skilled in the art, all valences must be satisfied when making any substitutions. The hydrocarbon can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are also defined hereinbelow and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.

[0116] Unless otherwise stated, the term "alkyl" by itself or as part of another substituent means a straight-chain (i.e., unbranched) or branched, acyclic or cyclic hydrocarbon group or combination thereof, which can be fully saturated, monounsaturated or polyunsaturated and can include divalent and polyvalent groups, having the specified number of carbon atoms (i.e., C1-C 10 means from one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In certain embodiments, the term "alkyl" refers to C 1-20 (including C1 and C 20 ) and includes linear (i.e., "straight-chain"), branched or cyclic, saturated or at least partially unsaturated and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon groups of from 1 to 20 carbon atoms, said hydrocarbon groups being derived by removal of a single hydrogen atom from a hydrocarbon moiety containing between 1 and 20 carbon atoms.

[0117] Representative saturated hydrocarbon groups include, but are not limited to, 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, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof.

[0118] "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having from 1 to about 8 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C 1-8 alkyl). "Higher alkyl" refers to an alkyl group having from about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" particularly refers to C 1-8 straight-chain alkyl. In other embodiments, "alkyl" particularly refers to C 1-8 branched alkyl.

[0119] An alkyl group may optionally be substituted with one or more alkyl group substituents ("substituted alkyl"), and the alkyl group substituents may be the same or different. The term "alkyl group substituent" includes, but is not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxy, aryloxy, alkoxy, alkylthio, arylthio, arylalkyloxy, arylalkylthio, carboxy, alkoxycarbonyl, oxo, and cycloalkyl. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be optionally inserted along the alkyl chain, where the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0120] Thus, as used herein, the term "substituted alkyl" includes an alkyl group as defined herein, where one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group, and the other atom or functional group includes, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

[0121] Unless otherwise stated, the term "heteroalkyl" by itself or in combination with another term means a stable straight-chain, branched-chain, or cyclic hydrocarbon group, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder 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-CH2-CH3, -CH2-CH 25 -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=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.

[0122] As described above, heteroalkyl groups as used herein include those groups attached to the remainder of the molecule through a heteroatom, such as -C(O)NR', -NR'R", -OR', -SR, -S(O)R, and / or -S(O2)R'. In instances where "heteroalkyl" is recited followed by a specific heteroalkyl group (e.g., -NR'R or the like), it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for added clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, such as -NR'R" or the like.

[0123] "Cyclic" and "cycloalkyl" refer to non-aromatic monocyclic or polycyclic ring systems of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can optionally be partially unsaturated. The cycloalkyl group can also optionally be substituted with alkyl group substituents, oxo, and / or alkylene substituents as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms can be optionally inserted along the cyclic alkyl chain, where the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, bornane, and noradamantyl, and fused ring systems such as dihydronaphthalene and tetrahydronaphthalene, and the like.

[0124] As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group as defined above, which is attached to the parent molecular moiety by an alkyl group as also defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0125] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a non-aromatic ring system, an unsaturated or partially unsaturated ring system, including one or more heteroatoms, e.g., a 3- to 10-membered substituted or unsubstituted cycloalkyl ring system, and optionally can include one or more double bonds, where the heteroatoms can be the same or different and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si).

[0126] 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 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. In certain embodiments, the term heterocycle refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group where at least one ring atom is a heteroatom selected from O, S, and N (where the nitrogen and sulfur heteroatoms may optionally be oxidized), including, but not limited to, bicyclic or tricyclic groups, including fused six-membered rings having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, where (i) each 5-membered ring has from 0 to 2 double bonds, each 6-membered ring has from 0 to 2 double bonds, and each 7-membered ring has from 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatoms may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl ring or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, dihydroindolyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiodiazinyl, tetrahydrofuryl, and the like.

[0127] Unless otherwise stated, the terms “cycloalkyl” and “cycloheteroalkyl” by themselves or in combination with other terms respectively denote the cyclic forms of “alkyl” and “heteroalkyl”. Further, for cycloheteroalkyl, the heteroatom may occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of cycloheteroalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms “cycloalkylene” and “cycloheteroalkylene” respectively refer to the divalent derivatives of cycloalkyl and cycloheteroalkyl.

[0128] Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, butenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups limited to hydrocarbon groups are called “homoalkyl”.

[0129] More particularly, as used herein, the term "alkenyl" refers to a monovalent group derived from a straight-chain or branched-chain hydrocarbon moiety having at least one carbon-carbon double bond by removal of a single hydrogen molecule from a C 1-20 (including C1 and C 20 ). Alkenyl groups include, for example, vinyl (i.e., ethenyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allene, and butadiene.

[0130] As used herein, the term "cycloalkenyl" 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, cycloheptatriene, and cyclooctenyl.

[0131] As used herein, the term "alkynyl" refers to a monovalent group derived from a straight-chain or branched-chain C 1-20 hydrocarbon having at least one carbon-carbon triple bond and having the specified number of carbon atoms. Examples of "alkynyl" include ethynyl group, 2-propynyl (propargyl) group, 1-propynyl group, pentynyl group, hexynyl group, and heptynyl group, and the like.

[0132] The term "alkylene" by itself or as part of another substituent refers to a straight-chain or branched-chain divalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, said from 1 to about 20 carbon atoms being, 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 can be straight-chain, branched-chain or cyclic. The alkylene group can also optionally be unsaturated and / or substituted by one or more "alkyl group substituents". One or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms can optionally be inserted along the alkylene group (also referred to herein as "alkylaminoalkyl"), where the nitrogen substituent is an alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6H 10 -); -CH=CH-CH=CH-; -CH=CH-CH2-; -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r-, where each of q and r is independently an integer from 0 to about 20, such as 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; methylenedioxy (-O-CH2-O-); and ethylenedioxy (-O-(CH2)2-O-). The alkylene group can have from about 2 to about 3 carbon atoms and can also have 6 - 20 carbons. Typically, the alkyl (or alkylene) group will have from 1 to 24 carbon atoms, and those groups having 10 or fewer carbon atoms are some embodiments of the present disclosure. "Lower alkyl" or "lower alkylene" are shorter-chain alkyl groups or alkylene groups, typically having 8 or fewer carbon atoms.

[0133] The term "heteroalkylene" by itself or as part of another substituent means a divalent group derived from heteroalkyl, by way of example and not limitation, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkylamino, alkylenediamino, and the like). Additionally, for alkylene and heteroalkylene linking groups, the orientation of the linking group does not imply the direction in which the formula of the linking group is written. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0134] Unless otherwise stated, the term "aryl" means an aromatic hydrocarbon substituent that can be a single ring or multiple rings (e.g., from 1 to 3 rings) fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing from 1 to 4 heteroatoms selected from N, O, and S (in the case of multiple rings, in each individual ring), where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group can be attached to the remainder of the molecule through a carbon or a heteroatom. Non-limiting examples of aryl groups 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-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the aryl and heteroaryl ring systems mentioned above 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.

[0135] For the sake of brevity, the term "aryl", when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl rings and heteroaryl rings as defined above. Thus, the terms "arylalkyl" and "heteroarylalkyl" mean those groups in which an aryl group or a heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like), and the alkyl group includes those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced, for example, by an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like). However, as used herein, the term "haloaryl" means only aryl substituted by one or more halogens.

[0136] In the case where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g., "3-membered to 7-membered"), the term "member" refers to a carbon or a heteroatom.

[0137] In addition, as used herein, a structure generally represented by the following formula:

[0138]

[0139] Refers to a ring structure containing a substituent R group, such as, but not limited to, 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon and similar, aliphatic and / or aromatic cyclic compounds, including saturated ring structures, partially saturated ring structures and unsaturated ring structures, where the R group may or may not be present, and when present, one or more R groups may each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and the number of R groups are determined by the value of the variable "n", which is an integer typically having a value ranging from 0 to the number of carbon atoms available for substitution on the ring. Each R group, if more than one, is substituted on the available carbon of the ring structure rather than on another R group. For example, the above structure where n is from 0 to 2 will include a group of compounds including, but not limited to:

[0140]

[0141] and the like.

[0142] The dashed line indicating a bond in the cyclic ring structure indicates that the bond may or may not be present in the ring. That is, the dashed line indicating a bond in the cyclic ring structure indicates that the ring structure is selected from the group consisting of: saturated ring structures, partially saturated ring structures and unsaturated ring structures.

[0143] The symbol indicates the point of attachment of the moiety to the remainder of the molecule.

[0144] When a named atom of an aromatic ring or heteroaromatic ring is defined as "absent", the named atom is replaced by a direct bond.

[0145] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl" and "heterocycloalkyl", "aryl", "heteroaryl", "phosphonate" and "sulfonate" and their divalent derivatives) is meant to include both the substituted and unsubstituted forms of the indicated group. Optional substituents for each type of group are provided below.

[0146] Substituents for alkyl, heteroalkyl, cycloalkyl, hetero cycloalkyl monovalent and divalent derived groups (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, hetero cycloalkyl, cycloalkenyl and hetero cycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, the following, in a number ranging from zero to (2m'+l): -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, where m' is the total number of carbon atoms in such a group. Each of R', R", R'", and R"" can independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero cycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. As used herein, an "alkoxy" group is an alkyl group attached to the remainder of the molecule through a divalent oxygen. When the compounds of the present disclosure include more than one R group, for example, each of the R groups is independently selected, just as each R', R", R'", and R"" group is when more than one of these groups are present. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-membered, 5-membered, 6-membered or 7-membered ring. For example, -NR'R" is meant to include, but not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is meant to include groups containing carbon atoms bonded to groups other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3 and the like).

[0147] Substituents similar to those described above for alkyl groups, for aryl groups and heteroaryl groups (and their divalent derivatives), are variable and are selected in numbers ranging from zero to the total number of open valences on the aromatic ring system, such as, 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’, -NR-C(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)alkoxy, and fluoro(C1-C4)alkyl; and wherein R’, R”, R”’ and R”” can independently be selected from 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 the compounds of the present disclosure include more than one R group, for example, each of the R groups is independently selected, as is each R’, R”, R”’ and R”” group when more than one of these groups are present.

[0148] Two substituents on adjacent atoms of an aryl ring or heteroaryl ring can optionally form a ring of the formula -T-C(O)-(CRR’) q -U-, where T and U are independently -NR-, -O-, -CRR’- or a single bond, and q is an integer from 0 to 3. Optionally, two substituents on adjacent atoms of an aryl ring or heteroaryl ring can optionally be replaced by a substituent of the formula -A-(CH2) r -B-, 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.

[0149] One of the single bonds of the new ring so formed can optionally be replaced by a double bond. Optionally, two substituents on adjacent atoms of an aryl ring or heteroaryl ring can optionally be replaced by a substituent of the formula -(CRR’) s -X’-(C”R’”) dsubstituted by substituents, where s and d 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”’ can independently be selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0150] As used herein, 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 group, alkenyl group, alkynyl group, aryl group, carbocyclic group, heterocyclic group or aromatic heterocyclic group as defined herein. Thus, the term “acyl” specifically includes arylacyl groups, such as 2-(furan-2-yl)acetyl group and 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.

[0151] The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) groups attached to the parent molecular moiety through an oxygen atom, where the terms “alkyl”, “alkenyl” and “alkynyl” are as previously described and can include C 1-20 (including C1 and C 20 ) linear, branched or cyclic, saturated or unsaturated oxohydrocarbon chains, including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and n-pentyloxy, neopentyloxy, n-hexyloxy and the like.

[0152] The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl group or an ethoxymethyl group.

[0153] “Aryloxy” refers to an aryl-O- group, where the aryl group is as previously described and includes substituted aryl. The term “aryloxy” as used herein can refer to phenyloxy or hexyloxy, and phenyloxy or hexyloxy substituted with alkyl, substituted alkyl, halogen, or alkoxy.

[0154] “Aralkyl” refers to an aryl-alkyl- group, where aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl and naphthylmethyl.

[0155] "Aryalkyloxy" refers to an aryalkyl - O - group, where the aryalkyl group is as previously described. Exemplary aryalkyloxy groups are benzyloxy, i.e., C6H5 - CH2 - O -. The aryalkyloxy group may be optionally substituted.

[0156] "Alkoxycarbonyl" refers to an alkyl - O - C(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and tert - butoxycarbonyl.

[0157] "Aryloxycarbonyl" refers to an aryl - O - C(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy - carbonyl and naphthyloxy - carbonyl.

[0158] "Aryalkyloxycarbonyl" refers to an aryalkyl - O - C(=O)- group. An exemplary aryalkyloxycarbonyl group is benzyloxycarbonyl.

[0159] "Carbamoyl" refers to an amide group of the formula - C(=O)NH2. "Alkylcarbamoyl" refers to an R'RN - C(=O)- group, where one of R and R' is hydrogen and the other of R and R' is an alkyl and / or a substituted alkyl as previously described. "Dialkylcarbamoyl" refers to an R'RN - C(=O)- group, where each of R and R' is independently an alkyl and / or a substituted alkyl as previously described.

[0160] As used herein, the term carbonyldioxy refers to a carbonate group of the formula - O - C(=O)- OR.

[0161] "Acyl - oxy" refers to an acyl - O - group, where the acyl is as previously described.

[0162] The term "amino" refers to the - NH2 group and also refers to a nitrogen - containing group derived from ammonia by replacing one or more hydrogen groups with organic groups as known in the art. For example, the terms "acylamino" and "alkylamino" refer to specific N - substituted organic groups having acyl and alkyl substituent groups, respectively.

[0163] As used herein, "aminoalkyl" refers to an amino group covalently attached to an alkylene linker. More particularly, as used herein, the terms alkylamino, dialkylamino, and trialkylamino refer to one, two, or three alkyl groups as previously defined attached to the parent molecular moiety through a nitrogen atom, respectively. The term alkylamino refers to a group having the structure -NHR', where R' is an alkyl group as previously defined; and the term dialkylamino refers to a group having the structure -NR'R", where 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"', where R', R", and R"' are each independently selected from the group consisting of alkyl groups. Additionally, R', R", and / or R"' together can optionally be -(CH2) k -, where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.

[0164] 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.

[0165] The terms alkylthio and thioalkoxy refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxy moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0166] "Acylamino" refers to an acyl-NH- group, where acyl is as previously described. "Aroylamino" refers to an aroyl-NH- group, where aroyl is as previously described.

[0167] The term "carbonyl" refers to a -C(=O)- group and can include an aldehyde group represented by the general formula R-C(=O)H.

[0168] The term "carboxyl" refers to a -COOH group. Such a group is also referred to herein as a "carboxylic acid" moiety.

[0169] As used herein, the terms "halo", "halide" or "halogen" refer to fluoro, chloro, bromo and iodo groups. Additionally, terms such as "haloalkyl" are meant to include both mono-haloalkyl and poly-haloalkyl. For example, the term "halo(C1-C4)alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[0170] The term "hydroxy" refers to the -OH group.

[0171] The term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0172] The term "mercapto" refers to the -SH group.

[0173] As used herein, the term "oxo" means an oxygen atom double-bonded to a carbon atom or another element.

[0174] The term "nitro" refers to the -NO2 group.

[0175] The term "thio" refers to a compound as previously described herein, wherein a carbon atom or an oxygen atom is replaced by a sulfur atom.

[0176] The term "sulfate group" refers to the -SO4 group.

[0177] As used herein, the term thiohydroxy or thiol refers to a group of the formula -SH.

[0178] More particularly, the term "sulfide" refers to a compound having a group of the formula -SR.

[0179] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R.

[0180] The term "sulfoxide" refers to a compound having a sulfinyl group -S(O)R.

[0181] The term ureido refers to a ureido group of the formula -NH—CO—NH2.

[0182] The term "protecting group" with respect to a compound of formula (I) refers to a chemical substituent that can be selectively removed by readily available reagents that do not attack the regenerated 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 Groups in Organic Synthesis, 4th Edition," Wiley-Interscience, 2007). Protecting groups for protecting carboxyl groups as described by Wutz et al. (pages 533 - 643) are used in certain embodiments. In some embodiments, the protecting group is removed by treatment with an acid. Representative examples of protecting groups include, but are not limited to, benzyl, p-methoxybenzyl (PMB), tert-butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr). Those skilled in the art will recognize the appropriate circumstances in which a protecting group is needed and will be able to select the appropriate protecting group for use in a particular context.

[0183] Throughout the specification and claims, a given chemical formula or name shall cover all tautomers, homologs, and optical and stereoisomers, and racemic mixtures in which such isomers are present.

[0184] Certain compounds of the present disclosure may have 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 for amino acids as D- or L-, and individual isomers are encompassed within the scope of the present disclosure. Compounds of the present disclosure do not include those compounds known in the art to be too unstable to be synthesized and / or isolated. The present disclosure is intended to include compounds in racemic form, scalemic form, and optically pure form. Optically active (R)- and (S)-isomers, or D- and L-isomers, can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0185] Unless otherwise stated, the structures depicted herein also mean to include all stereochemical forms of the structures; that is, the R and S configurations for each asymmetric center. Accordingly, the individual stereoisomers of the compounds, as well as enantiomeric and diastereomeric mixtures, are within the scope of the present disclosure.

[0186] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure. As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another.

[0187] Unless otherwise stated, the structures depicted herein also mean to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures are within the scope of the present disclosure in the case of replacing hydrogen with deuterium or tritium, or replacing carbon with 13 C- or 14 C-enriched carbon.

[0188] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0189] The compounds of the present disclosure may exist as salts. The present disclosure includes such salts. Examples of suitable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinate, benzoate, 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 sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, the acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include those derived from the following inorganic acids: such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfide, hydroiodic acid, or phosphorous acid, and the like, and salts derived from the following organic acids: such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids (e.g., arginine and the like) and salts of organic acids (such as glucuronic acid or galacturonic acid and the like). Certain specific compounds of the present disclosure contain both basic and acidic functional groups, which allows the compounds to be converted into base addition salts or acid addition salts.

[0190] The neutral form of the compound can be regenerated by contacting the salt with a base or an acid and isolating the parent compound in a conventional manner. The parent form of the compound differs in certain physical properties (e.g., solubility in polar solvents) from the various salt forms.

[0191] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms (including hydrated forms). Generally, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in polymorphic forms or amorphous forms. Generally, all physical forms are equivalent for the intended uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0192] In addition to the salt forms, the present disclosure provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical change under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical means in an ex vivo environment. For example, a prodrug can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir having a suitable enzyme or chemical reagent.

[0193] In accordance with longstanding patent law convention, when used in this application (including the claims), the terms "a," "an," and "the" refer to "one or more." Thus, for example, reference to "a subject" includes multiple subjects unless the context clearly dictates otherwise (e.g., multiple subjects), and so forth.

[0194] Throughout this specification and the claims, the terms "comprise," "comprises," and "comprising" are used in a non-exclusive sense, unless the context requires otherwise. Similarly, the term "include" and its grammatical variants are intended to be non-limiting, such that a listing of items in a list does not exclude other similar items that may be substituted or added to the listed items.

[0195] For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, dimensions, sizes, ratios, shapes, formulations, parameters, percentages, amounts, characteristics, and other numerical values used in the specification and claims should be understood to be modified in all instances by the term "about," even if the term "about" may not expressly appear with the value, amount, or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification 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 of skill in the art, depending upon the nature of the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term "about" when referring to a value can mean encompassing a difference of ±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% from the particular amount, as such differences are appropriate for practicing the disclosed methods or using the disclosed compositions.

[0196] In addition, when used in conjunction with one or more numbers or numerical ranges, the term "about" shall be understood to refer to all such numbers, including all numbers within the range and modifying the range by extending the boundaries above and below the stated values. The recitation of a numerical range by endpoints includes all numbers subsumed within that range (e.g., the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, such as 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range. Examples

[0197] The following examples have been included to provide guidance to those of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. Based on the present disclosure and the general level of those skilled in the art, those skilled in the art will understand that the following examples are intended to be merely exemplary and that many variations, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The following synthetic descriptions and specific examples are intended for illustrative purposes only and are not to be construed as limiting the preparation of the compounds of the present disclosure by any other method.

[0198] Example 1

[0199] Review

[0200] The use of PSMA-binding ureas conjugated to chelated radioactive metals via various linker groups for imaging and potentially radiotherapy of tumors expressing PSMA has been previously reported in several patent applications and publications (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63; Banerjee et al. (2015) Journal of nuclear medicine 56, 628-34; Benesova et al. (2015) Journal of nuclear medicine 56, 914-20; Weineisen et al. (2014) EJNMMI Res 4, 1-15; WO 2009002529 A2; WO 2009070302 A1). A new class of high-affinity binders has been prepared by modifying the urea linker at the ε-amine position with a p-Br-benzyl group. The structures of the presently disclosed compounds are shown in Figure 1 as follows.

[0201] Without wishing to be bound by any particular theory, it is believed that a radiometal chelate-based Glu-lysine urea therapeutic agent targeting prostate-specific membrane antigen (PSMA), when modified with a p-Br-benzyl group on the ε-amino group of the lysine in the Lys-Glu-urea moiety, demonstrates high binding affinity for PSMA, high uptake in tumors expressing PSMA, and low renal uptake in a standard mouse model of prostate cancer. One embodiment, 177 Lu-1, showed significant radiotherapy efficacy, with a remission rate of approximately 50% in mice bearing PSMA+PC3 tumors.

[0202] Example 2

[0203] Materials and Methods

[0204] Chemical synthesis of 1. The synthesis of compound 1 is described in Scheme 1. Under an ice-cold bath, 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, and the mixture was allowed to warm to room temperature. After one hour, sodium cyanoborohydride (158.0 mg, 2.5 mmol) was added and the reaction was stirred overnight. The crude reaction mixture was evaporated, redissolved in dichloromethane, purified by normal-phase silica chromatography (95:5, dichloromethane:methanol), and dried in vacuo to afford 5 in good 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 μmol), and DIPEA (37.7 μL, 216 μmol) were dissolved in 300 μL of DMF and stirred at room temperature. After one hour, compound 5 (71.0 mg, 108 μmol) was added, rinsed three times with DMF (50 μL each). The reaction mixture was stirred for 4 hours and stored overnight at 4 °C. The crude reaction mixture was purified by semi-preparative HPLC on a C 18 column (40% water (0.1 TFA) / 60% ACN (0.1 TFA)) for 5 min, 60%-90% in 20 minutes. R t 21 minutes. The purified fractions were combined, evaporated, and dried under high vacuum for 10 minutes. ESI-MS: 572.44 [M+H] +, Measured: 572.4. Compound 6 was dissolved in dichloromethane (1.5 mL) and quenched in an ice bath. After equilibration, TFA (1.5 mL) was added and the mixture was stirred for 3 hours, allowing it to warm to room temperature during the process. The mixture was spun dry under a nitrogen stream, dissolved in water, and lyophilized to yield 31.8 mg of compound 7. Yield: 54 μmol, 54%. p-SCN-bn-DOTA (12.2 mg, 17.7 μmol) was added to a stirred solution of 6 (12.2 mg of the TFA salt) and DIPEA (15.2 μL, 87.0 μmol) in DMSO (130 μL) equilibrated to 40 °C. The reaction mixture was stirred at 40 °C for 4 hours and stored overnight at 4 °C. The reaction mixture was purified by reverse-phase HPLC (holding 20% ACN for 5 min, then 20%-40% in 19 min). Rt was approximately 12 minutes. The purified fractions were combined, rotary evaporated to reduce the volume, and then lyophilized. ESI-MS: 1138.37 [M+H] + , Measured: 1138.5. Compound 1 was further purified by HPLC using a gradient method. The HPLC method was a gradient method consisting of mobile phase 88% water (containing 0.1% TFA) and 12% CH3CN (0.1% TFA) for 1 min - 5 min, followed by 88% water (containing 0.1% TFA) and 12% CH3CN (0.1% TFA) for 0 min - 5 min, and from 5 min - 25 min 88% water to 44% water and 12% acetonitrile to 56% acetonitrile, with a flow rate of 8 mL / min.

[0205] 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] + , Measured: 974.5.

[0206] 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] + , Measured: 970.1.

[0207] 177 Radioactive labeling of Lu-1. 1.0 μl of 177LuCl3 (1 mCi) was added to 70 μl of NH4OAc buffer (0.2 M, pH 4), and added to 5 μl of 2 mM in 0.2 M NH4OAc. The pH of the mixture was approximately 4.0. The mixture was maintained at 80 °C for one hour and purified by HPLC. The HPLC method was a gradient method, consisting of mobile phase 77% water (containing 0.1% TFA) and 23% CH3CN (0.1% TFA) for 1 min - 5 min, followed by 5 min - 25 min with water from 77% to 57% and acetonitrile from 23% to 43%; from 25.01 min - 30 min, water 5% to 5% and acetonitrile 95% to 95%, from 30.01 min to 37 min, water 77% to 77% and acetonitrile 23% to 23%. Flow rate: 1.0 ml / min; λ: 200 nm, and C8 column (25 mm × 4.6 mm), Varian microsob-MV 100-5. The radioactively labeled 177 Lu-1 eluted at 17.1 min - 20 min, while the unlabeled chelating agent eluted at 21 min - 22 min.

[0208] The HPLC method was used for the preparation of 177 Lu-2 and 177 Lu-3: The HPLC method was a gradient method, consisting of mobile phase 88% water (containing 0.1% TFA) and 12% CH3CN (0.1% TFA) for 1 min - 5 min, followed by 5 min - 27 min with water from 88% to 75% and acetonitrile from 12% to 25%; from 27.01 min - 32 min, water 5% to 5% and acetonitrile 95% to 95%, from 32.01 min to 37 min, water from 88% to 18% and acetonitrile from 12% to 22%. Flow rate: 1.0 ml / min; λ: 200 nm, and C8 column (25 mm × 4.6 mm), Varianmicrosob-MV 100-5. The radioactively labeled 177 Lu-2 eluted at 13.1 min - 15.0 min, while the unlabeled chelating agent eluted at 16 min - 17 min. The radioactively labeled 177 Lu-3 eluted at 13.1 min - 15.0 min, while the unlabeled chelating agent eluted at 10 min - 12 min and 18 min - 20 min, and the unlabeled agent reached 14 min - 16 min.

[0209] Scheme 1. Synthesis of Compound 1

[0210]

[0211] Example 3

[0212] Results and Discussion

[0213] Chemical and radiochemical synthesis and characterization. The modified p-bromobenzyl group of Glu-Lys urea (2) was prepared in good yield by reductive alkylation of 2 with p-bromobenzaldehyde in methanol in the presence of sodium cyanoborohydride according to the literature procedure (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63) to afford 4. A small aliphatic linker Boc-5-aminovaleric acid was coupled to the same ε-Lys amine of 4, followed by removal of the BOC group and conjugation with the commercially available DOTA-Bn-SCN in the case of 6 to afford 1 in moderate yield. Compound 2 was synthesized by using DOTA-NHS ester as a chelator and coupling with the same intermediate 6. Compound 3 was synthesized as a control reagent without any p-bromobenzyl group. All three reagents were radiolabeled with 177 Lu at 80 °C at pH 4 in ammonium acetate buffer in good yield and purity. The binding affinities of these new compounds are listed in Table 1. Both 1 and 2 modified with the p-bromobenzyl group showed higher binding affinity compared to 3.

[0214]

[0215] Cell binding properties. 177 The 177 Lu agents were also evaluated in cells and animals using the standard syngeneic cell lines PSMA+PC3 PIP and PSMA-negative PC3 flu cells. Compared with 177 Lu-3, 177 both 177 Lu-1 and 177 Lu-2 demonstrated higher uptake in PSMA+PC3 cells. Further internalization studies revealed that 177 Lu-1 had a higher internalization activity nearly 2-fold higher compared to 177 Lu-3. All three agents showed significantly low uptake in PSMA-negative PC3 flu cells. The therapeutic efficacy of 177 Lu-1 was also evaluated in a clonogenic assay and compared with the previous lead compound SR6 (Banerjee et al. (2015) Journal of nuclear medicine 56, 628-34) and agents including177 Lu-1 was able to produce approximately 100% cell killing efficacy at a dose of 10 μCi in PSMA+PC3 PIP cells, with no significant toxicity seen for PSMA-PC3 flu cells.

[0216]

[0217]

[0218] Biodistribution. For 177 Lu-1 and 177 Lu-2, in vivo tissue biodistribution studies were conducted and are listed in Tables 3 and 4. 177 Lu-1 showed higher uptake and retention in PSMA+PC3 PIP tumor uptake than 177 Lu-2. Significantly, 177 the Lu-2 dose showed 5-fold lower renal uptake than 177 Lu-1, and as Figure 3 shown, the tumor / kidney of the currently disclosed compound was compared with that of the previous leads 177 Lu-SR6, 177 Lu-PSMA-617, and 177 Lu-PSMA-I&T. The PSMA+PC3 PIP tumor-to-kidney ratio for 177 Lu-2 was higher than that of 177 Lu-1. Due to the higher tumor uptake and retention, the therapeutic efficacy (imaging and therapeutic effects) of 177 Lu-1 was also evaluated in a small group of animals in preclinical studies.

[0219]

[0220]

[0221]

[0222] Small animal SPECT imaging and therapeutic effects. Figure 4 Shown is the SPECT imaging of 177 Lu-1 after 1-day - 8-day treatment during the treatment study. A single dose of 3 mCi was injected via the tail vein into mice (n = 10) bearing PSMA+PC3 PIP tumors (size 3 mm - 5 mm). Saline was injected into another group of mice (n = 10) for control study. The body weight and tumor size measurements of the mice were monitored twice a week. When the tumor size exceeded >12 mm, the mice in the control group were euthanized after 4 weeks - 8 weeks. For the treatment group, 50% of the mice showed complete elimination of the tumor. These mice initially experienced an initial body weight recovery after 2 weeks. The results are inFigure 5 is shown in Figure 6A and Figure 6B demonstrated the therapeutic efficacy (tumor volume reduction) of Lu-1 compared to the control group using saline. Five mice showed complete remission of the disease and survived for more than five months. 177 In summary, a therapeutic agent based on a radio-metal chelated Glu-lysine urea targeting prostate-specific membrane antigen (PSMA), when modified with a p-Br-benzyl group on the ε-amino group of the lysine in the Lys-Glu-urea moiety, demonstrated high binding affinity for PSMA, high uptake in PSMA-expressing tumors, and low renal uptake in a standard mouse model of prostate cancer. A representative compound

[0223] Lu-1 showed significant radiotherapy efficacy, with a remission rate of approximately 50% in mice bearing PSMA+PC3 tumors. 177 Lu-1 showed significant radiotherapy efficacy, with a remission rate of approximately 50% in mice bearing PSMA+PC3 tumors.

[0224] References

[0225] All publications, patent applications, patents, and other references mentioned in the specification indicate the level of skill of those of ordinary skill in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references (e.g., websites, databases, etc.) mentioned in the specification are hereby incorporated 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 to be incorporated by reference. It will be understood that although many patent applications, patents, and other references are mentioned herein, such references do not constitute an admission that any of these documents form a part of the common general knowledge in the art. In the event of a conflict between this specification and any incorporated reference, this specification (including any amendments thereto that may be based on the incorporated reference) shall govern. Standard art-accepted meanings of terms are used herein unless otherwise indicated. Standard abbreviations for various terms are used herein.

[0226] International PCT Patent Application Publication No. PCT / US2008 / 007947 (WO2009 / 002529 A2) by Pomper, M.G., Ray, S., Mease, R.C., Foss, C., published on December 31, 2008, for Labeled inhibitors of prostate specific membrane antigen (PSMA), biological evaluation, and use as imaging agents;

[0227] International PCT patent application publication No. PCT / US2008 / 013158 (WO2009070302 A1) by Chandran S.S., Ray S., Denmeade S.R., Pomper M.G., Mease R.C. published on June 4, 2009, for Prostate specific membrane antigen targeted nanoparticles for therapy of prostate cancer;

[0228] International PCT patent application publication No. PCT / US2010 / 028020 (WO2010108125 A2) by Pomper M.G., Mease R.C.; Ray S., Chen Y. published on September 23, 2010, for PSMA - targeting compounds and uses thereof;

[0229] Banerjee, S.R., Foss, C.A., Pullambhatla, M., Wang, Y., Srinivasan, S., Hobbs, R.F., Baidoo, K.E., Brechbiel, M.W., Nimmagadda, S., Mease, R.C., Sgouros, G., and Pomper, M.G. (2015) Preclinical evaluation of 86Y - labeled inhibitors of prostate - specific membrane antigen for dosimetry estimates. Journal of nuclear medicine 56, 628 - 34;

[0230] 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, 914-20;

[0231] 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, 4357-63;

[0232] Weineisen, M., Simecek, J., Schottelius, M., Schwaiger, M., and Wester, H.-J. (2014) Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. EJNMMI Res 4, 1-15.

[0233] Although the foregoing subject matter has been described in considerable detail for purposes of clear understanding by way of illustration and example, those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A compound having the following structure:

2. A compound having the following structure:

3. A compound having the following structure:

4. A compound having the following structure:

Images