Prostate-specific membrane antigen-targeted high-affinity agents for intracavitary radiotherapy of prostate cancer

Abstract

A high affinity agent for prostate-specific membrane antigen targeting for intracavitary radiotherapy of prostate cancer. It relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, 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 linker 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 ‑group; L and W are the same or different each time they appear; 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 containing a metal or a radioactive metal. #imgabs0#

Description

[0001] The present application is a divisional application of an application filed on March 22, 2017, with application number 201780031580.2 and invention name “High-affinity agent targeting prostate-specific membrane antigen for intracavitary radiotherapy of prostate cancer”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] 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

[0004] Prostate cancer is the main cancer in the U.S. population and is the second leading cause of cancer death in men. The therapy for locally advanced disease is still controversial, and different options for increasing numbers are available. New, high-affinity, radiotherapeutic agents for prostate cancer have been developed using prostate-specific membrane antigen (PSMA) as a target. PSMA is a marker for androgen-independent diseases, which is also expressed in solid (non-prostate) tumor neovasculature.

[0005] Overview

[0006] In some aspects, the presently disclosed subject matter provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0007]

[0008] Where: Z is tetrazole or CO 2 Q; 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 -CH 2 -R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine and unsubstituted isoquinoline; L is selected from the group consisting of C 1 -C 6 Alkylene and C 3 -C 6 A linker group consisting of a cycloalkylene group and an arylene group; 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; wherein each occurrence of L and W may be the same or different; R 2 Is H or C 1 -C 4alkyl; 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.

[0009] In a particular aspect of the compounds of formula (I), R 1 Selected from the group consisting of:

[0010] wherein X is independently Br or I.

[0011] In yet more specific aspects of the compounds of formula (I), the chelating agent is selected from the group consisting of:

[0012]

[0013] In other aspects, the presently disclosed subject matter provides methods for treating one or more PSMA-expressing tumors or cells, the methods 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:

[0014]

[0015] Where: Z is tetrazole or CO 2 Q; 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 -CH 2 -R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine and unsubstituted isoquinoline; L is selected from the group consisting of C 1 -C 6 Alkylene and C 3 -C 6 A linker group consisting of a cycloalkylene group and an arylene group; 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; wherein each occurrence of L and W may be the same or different; R 2 Is H or C 1 -C 4 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.

[0016] 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 producing an image.

[0017] In yet other aspects, the presently disclosed subject matter provides kits comprising a compound of Formula (I).

[0018] Certain aspects of the presently disclosed subject matter have been set forth above which are wholly or partially addressed by the presently disclosed subject matter, other aspects will become apparent as the description proceeds, when considered in conjunction with the accompanying examples and drawings, as best described herein below. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Having thus generally described the presently disclosed subject matter, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and in which:

[0020] Figure 1 The chemical structures of representative radiotherapeutic agents are shown;

[0021] Figure 2 Shows 177 Comparative study of the clonogenic efficacy of Lu-1 and known agents SR6, PSMA-617, and PSMA-I&T;

[0022] Figure 3 Shows 177 Lu-1, 177 Lu-2, 177 Lu-SR6, 177 Lu-PSMA-617 and 177 the ratio of PSMA+ tumors to kidneys by Lu-PSMA-I&T;

[0023] Figure 4 A single dose of 3 mCi was used during the treatment study. 177 SPECT-CT imaging of Lu-1;

[0024] Figure 5 The relative body weights of mice during the treatment study are shown; and

[0025] Fig. 6A and Figure 6B The relative tumor volumes of mice during the treatment study are shown ( Fig. 6A ) and Kaplan-Meier survival curves after up to 60 days of treatment ( Figure 6B ). Detailed Description

[0026] The presently disclosed subject matter will now be described more fully hereinafter with reference to the accompanying drawings, in which some but not all embodiments of the presently disclosed subject matter are shown. The same numbers refer to the same elements throughout the text. The presently disclosed subject matter can be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein; on the contrary, these embodiments are provided so that the present disclosure will satisfy applicable legal requirements. In fact, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to those skilled in the art to which the presently disclosed subject matter belongs, with the benefit of the teachings presented in the preceding description and the associated drawings. Therefore, it should 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.

[0027] I. Prostate-specific membrane antigen-targeted high-affinity agents for intracavitary radiotherapy of prostate cancer

[0028] A. Compounds of formula (I)

[0029] Thus, in some embodiments, the presently disclosed subject matter provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0030]

[0031] Where: Z is tetrazole or CO 2 Q; 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 -CH 2 -R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine and unsubstituted isoquinoline; L is selected from the group consisting of C 1 -C 6 Alkylene and C 3 -C 6 A linker group consisting of a cycloalkylene group and an arylene group; 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; wherein each occurrence of L and W may be the same or different; R 2 Is H or C 1 -C 4 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.

[0032] The phrase "wherein each occurrence of L and W may be the same or different" means that when the variable "n" is 2 or 3, one "L" group may be C 1 -C 6 alkylene, and the other "L" group or more "L" groups can be C 3 -C 6 Cycloalkylene or arylene, or, in other embodiments, each "L" group can be, for example, C 1 -C 6 Likewise, for example, when "n" is 2 or 3, a "W" group can be -(C=O)-NR 2 -, and another "W" group or more "W" groups may be -(C=S)-NR 2 -, or, in other embodiments, each "W" may be, for example, -(C=O)-NR 2 -.

[0033] In certain embodiments of the compounds of formula (I), R 1 Selected from the group consisting of:

[0034] wherein X is independently Br or I.

[0035] In yet more specific embodiments of the compounds of formula (I), the chelating agent is selected from the group consisting of:

[0036]

[0037]

[0038] In still more specific embodiments of the compounds 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 specific embodiments of the compounds 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, 213Bi, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc, and 166 Ho.

[0039] In a particular embodiment, the compound of formula (I) is selected from the group consisting of:

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] B. Methods of using the compounds of formula (I) for treating one or more tumors or cells expressing PSMA

[0051] In some embodiments, the presently disclosed subject matter provides methods for treating one or more PSMA-expressing tumors or cells, the methods 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:

[0052]

[0053] Where: Z is tetrazole or CO 2 Q; 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 -CH 2 -R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine and unsubstituted isoquinoline; L is selected from the group consisting of C 1 -C 6 Alkylene and C 3 -C 6A linker group consisting of a cycloalkylene group and an arylene group; 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; wherein each occurrence of L and W may be the same or different; R 2 Is H or C 1 -C 4 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.

[0054] "Contacting" means any action that causes at least one compound of the presently disclosed subject matter comprising a therapeutic agent to physically contact at least one PSMA-expressing tumor or cell. Contacting can include exposing a 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.

[0055] As used herein, the term "treating" may include reversing, alleviating, inhibiting the progression of, preventing or reducing the likelihood of a disease, disorder or condition to which such term applies, 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 such worsening of severity, not to occur. Thus, the presently disclosed compounds may be administered prophylactically to prevent or reduce the occurrence or recurrence of a disease, disorder or condition.

[0056] Typically, an "effective amount" of an active agent refers to the amount necessary to elicit a desired biological response. As will be appreciated by one of ordinary skill in the art, the effective amount of an agent or device may 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.

[0057] The term "combination" is used in its broadest sense, and means that the subject is administered at least two agents, 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, active agents can be combined and administered in a single dosage form, can be administered as a separate dosage form at the same time, or can be administered as a separate dosage form administered alternately or sequentially on the same or separate days. In one embodiment of the currently disclosed theme, active agents are combined and administered in a single dosage form. In another embodiment, active agents are administered in a separate dosage form (for example, where it is desirable to change the amount of a dosage form but not the amount of another dosage form). A single dosage form can include additional active agents for the treatment of a disease state.

[0058] In certain embodiments, R 1 Selected from the group consisting of:

[0059]

[0060] wherein X is independently Br or I.

[0061] In more specific embodiments, the chelating agent is selected from the group consisting of:

[0062]

[0063]

[0064] In yet more specific embodiments, the radiometal suitable for radiation therapy 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.

[0065] In yet more specific embodiments, the compound of formula (I) is selected from the group consisting of:

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] In other embodiments, the 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, glioblastomas, pancreatic tumors or cells, bladder tumors or cells, sarcomas, melanomas, breast tumors or cells, colon tumors or cells, germ cells, pheochromocytomas, esophageal tumors or cells, gastric tumors or cells, and combinations thereof. In some other embodiments, the one or more PSMA-expressing tumors or cells are prostate tumors or cells.

[0077] In other embodiments, the one or more PSMA-expressing tumors or cells are in vitro, in vivo, or ex vivo. In still other embodiments, the one or more PSMA-expressing tumors or cells are present in a subject.

[0078] The subject treated by the presently disclosed methods in many of their embodiments is desirably a human subject, however it should be understood that the methods described herein are effective with respect to all vertebrate species, all of which are intended to be included in the term “subject.” Thus, a “subject” may include a human subject used for medical purposes, such as for 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 used for medical purposes, veterinary purposes, 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; swine, 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 may be a transgenic animal. In some embodiments, the subject is a human, including but not limited to fetuses, newborns, infants, juveniles, and adult subjects. In addition, a "subject" may include a patient who suffers from or is suspected of having a condition or disease. Therefore, the terms "subject" and "patient" are used interchangeably herein.

[0079] In yet other embodiments, the method results in inhibition of tumor growth.

[0080] C. Methods of using the compounds of Formula (I) for imaging one or more tumors or cells expressing PSMA

[0081] 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 one or more tumors or cells with an effective amount of a compound of formula (I) comprising:

[0082]

[0083] Where: Z is tetrazole or CO 2 Q; 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 -CH 2 -R 1 ; R 1 is selected from the group consisting of substituted aryl, substituted pyridine and unsubstituted isoquinoline; L is selected from the group consisting of C 1 -C6 Alkylene and C 3 -C 6 A linker group consisting of a cycloalkylene group and an arylene group; 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; wherein each occurrence of L and W may be the same or different; R 2 Is H or C 1 -C 4 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.

[0084] D. Test kit

[0085] In yet other embodiments, the presently disclosed subject matter provides kits comprising a compound of Formula (I).

[0086] 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 reactive precursors necessary to produce the compound of the invention after combination with a radiolabeled precursor. Other packaged pharmaceutical compositions provided by the present invention also include an indicia, the indicia including at least one of the following: instructions for use in preparing a compound of the invention from a supplied precursor, instructions for use of the composition to image cells or tissues expressing PSMA, or instructions for use of the composition to image glutamate neurotransmission in patients with stress-related disorders, or instructions for use of the composition to image prostate cancer.

[0087] E. Pharmaceutical Compositions and Administration

[0088] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) alone or in combination with one or more additional therapeutic agents and a pharmaceutically acceptable excipient mixture. 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 active compounds prepared with relatively nontoxic acids or bases, depending on the specific 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 such compounds in a neutral form with a sufficient amount of a desired base, either pure or in a suitable inert solvent or by ion exchange, so that one basic counterion (base) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino or magnesium salts, or similar salts.

[0089] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, so that one acidic counterion (acid) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable acid addition salts include those derived from 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, and salts derived from relatively nontoxic 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, and 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 specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0090] Thus, pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, for example, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, etopoate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolylaminobenzoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, mucate, naphthylate, nitrate, pamoate (pamoate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or theoclate. Other pharmaceutically acceptable salts can be found, for example, in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[0091] In therapeutic and / or diagnostic applications, the compounds of the present disclosure can be formulated for a variety of modes of administration, including systemic administration and topical or local administration. Techniques and formulations generally can be found in Remington: The Science and Practice of Pharmacy (20th Edition) Lippincott, Williams & Wilkins (2000).

[0092] Depending on the specific conditions being treated, such agents can be formulated as liquid dosage forms or solid dosage forms and are systemically or topically administered. Agents can, for example, be delivered in a time- or sustained-slow release form as known to those skilled in the art. The technology for preparation and application can be found in Remington: The Science and Practice of Pharmacy (20th edition) Lippincott, Williams & Wilkins (2000). Suitable approaches can include oral, buccal, by inhalation spray, sublingual, rectal, percutaneous, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection and intrathecal, direct intraventricular, intravenous, intraarticular, intrathoracic, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular injection or other delivery modes.

[0093] For injection, the agents of the present disclosure can be formulated and diluted in aqueous solutions, e.g., in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0094] It is within the scope of the present disclosure to use a pharmaceutically acceptable inert carrier to prepare 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, such as by intravenous injection. The compounds can be easily 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 intake by a subject to be treated (e.g., a patient).

[0095] For nasal or inhaled delivery, the agents of the present disclosure may also be formulated by methods known to those skilled in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives such as benzyl alcohol; absorption enhancers; and fluorocarbons.

[0096] The pharmaceutical composition suitable for use in the present disclosure includes a composition in which the active ingredient is contained in an effective amount to achieve its intended purpose. The determination of the effective amount is fully within the ability of those skilled in the art, especially according to the detailed disclosure provided herein. Generally, the compound according to the present disclosure is effective in a wide dosage range. For example, in the treatment of adults, a dosage of from 0.01mg to 1000mg, from 0.5mg to 100mg, from 1mg to 50mg and from 5mg to 40mg per day is an example of a dosage that can be used. A non-limiting dose is 10mg to 30mg 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 body 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.

[0097] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers containing excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Preparations formulated for oral administration may be in the form of tablets, dragees, capsules or solutions.

[0098] Pharmaceutical preparations 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 particles after adding suitable auxiliary agents if desired to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose products, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added.

[0099] The dragee core is provided with a suitable coating. For this purpose, concentrated sugar solution can be used, which can optionally comprise gum arabic, talcum, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dye or pigment can be added to tablet or dragee coating for identification or characterization of the different combinations of active compound dosage.

[0100] Pharmaceutical preparations 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 may 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 optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or a liquid polyethylene glycol (PEG). In addition, a stabilizer may be added.

[0101] II. General Definitions

[0102] Although specific terms are employed herein, 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 herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently described subject matter belongs.

[0103] Although the following terms with respect to compounds of formula (I) are considered to be well understood by those of ordinary skill in the art, the following definitions are set forth to aid in explaining the presently disclosed subject matter. These definitions are intended to supplement and illustrate, rather than exclude, definitions that would be obvious to those of ordinary skill in the art after reviewing the present disclosure.

[0104] As used herein, the term substituted, whether preceded by the term "optionally" or not, and substituents, refers to the ability to change one functional group on a molecule to another functional group, as understood by those skilled 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 specified 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 additional aryl groups, which are further substituted at one or more positions).

[0105] Where substituent groups or linking groups are specified by their conventional chemical formula written from left to right, they also encompass chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -; -C(=O)O- is equivalent to -OC(=O)-; -OC(=O)NR- is equivalent to -NRC(=O)O-, and the like.

[0106] When the term "independently selected" is used, the substituents referred to (eg, an R group such as a group R 1 , R 2 and the like, or variables, such as "m" and "n"), can be the same or different. For example, R 1 and R 2 Both can be substituted alkyl, or R 1 can be hydrogen and R 2 It may be a substituted alkyl group, and the like.

[0107] When used with respect to a substituent group in this article, the term "a (one)", "an (one)" or "a (n) (one)" means at least one. For example, in the case where the compound is substituted with an "an (one)" alkyl or aryl group, the compound is optionally substituted with at least one alkyl group and / or at least one aryl group. In addition, in the case where a portion is substituted with an R substituent, the group may be referred to as "R-substituted". In the case where a portion is R-substituted, the portion is substituted with at least one R substituent and each R substituent is optionally different.

[0108] A named "R" or group will generally have a structure recognized in the art as corresponding to the group having that name, unless otherwise specified herein. For purposes of illustration, certain representative "R" groups as set forth above are defined below.

[0109] 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, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to conform to the principles of chemical bonding and give compounds that are not inherently unstable and / or that would 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 group 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.

[0110] Unless specifically defined otherwise, a "substituent group" as used herein includes a functional group selected from one or more of the following moieties as defined herein.

[0111] As used herein, the term hydrocarbon refers to any chemical group comprising hydrogen and carbon. Hydrocarbons can be substituted or unsubstituted. As will be known to those skilled in the art, all valences must be satisfied when any substitution is made. Hydrocarbons can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Illustrative hydrocarbons are also defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.

[0112] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight chain (i.e., unbranched) or branched, acyclic or cyclic hydrocarbon radical, or combinations thereof, which may be fully saturated, monounsaturated or polyunsaturated and may include divalent and polyvalent radicals, having a specified number of carbon atoms (i.e., C 1 -C 10 means 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 a C 1-20 (including C 1 and C 20 ), including 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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbon atoms, which are derived from a hydrocarbon moiety containing between 1 and 20 carbon atoms by the removal of a single hydrogen atom.

[0113] 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.

[0114] "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 1 to about 8 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., C 1-8 "Higher alkyl" refers to an alkyl group having from 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" specifically refers to C 1-8 In other embodiments, "alkyl" refers specifically to C 1-8 Branched chain alkyl.

[0115] The alkyl group may be optionally substituted with one or more alkyl group substituents ("substituted alkyl") which 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, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be optionally inserted along the alkyl chain, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0116] Thus, as used herein, the term "substituted alkyl" includes alkyl groups as defined herein, wherein one or more atoms or functional groups of the alkyl group are replaced by another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, and thiol.

[0117] Unless otherwise stated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain, or cyclic hydrocarbon group, or a combination 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, and wherein the nitrogen, phosphorus and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P and 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, -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 25 -S(O)-CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH=CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH=N-OCH 3 、-CH=CH-N(CH 3 )-CH 3 、O-CH 3 、-O-CH 2 -CH 3 , and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .

[0118] As described above, heteroalkyl groups as used herein include those groups that are 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(O)R. 2)R'. 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 interpreted herein to exclude specific heteroalkyl groups, such as -NR'R" or the like.

[0119] "Cyclic" and "cycloalkyl" refer to non-aromatic monocyclic or polycyclic ring systems of about 3 to about 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Cycloalkyl groups may optionally be partially unsaturated. Cycloalkyl groups may also optionally be substituted with alkyl group substituents, oxo and / or alkylene groups as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be optionally inserted along the cyclic alkyl chain, wherein 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, decahydronaphthalene, camphor, camphane, and n-adamantyl, as well as fused ring systems, such as dihydronaphthalene and tetrahydronaphthalene, and the like.

[0120] The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group as defined above, attached to the parent molecular moiety through an alkyl group, also as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0121] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a non-aromatic ring system, an unsaturated or partially unsaturated ring system, such as a 3- to 10-membered substituted or unsubstituted cycloalkyl ring system, 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 which optionally may include one or more double bonds.

[0122] Cycloheteroalkyl rings may optionally be fused 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, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocycle refers to a non-aromatic 5-, 6-, or 7-membered ring or 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 be optionally oxidized), including, but not limited to, bicyclic groups or tricyclic groups, including fused six-membered rings having between one and three heteroatoms independently selected 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 be optionally oxidized, (iii) the nitrogen heteroatom may be optionally quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinyl, tetrahydrofuranyl, and the like.

[0123] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms represent the cyclic forms of "alkyl" and "heteroalkyl", respectively. In addition, for heterocycloalkyl, heteroatoms can 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 heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms "cycloalkylene" and "heterocycloalkylene" refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0124] Unsaturated alkyl groups are alkyl groups with one or more double bonds 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 homologues and isomers. Alkyl groups limited to hydrocarbon groups are referred to as "homoalkyl".

[0125] More specifically, the term "alkenyl" as used herein refers to a group derived from C 647 by removing a single hydrogen molecule having at least one carbon-carbon double bond. 1-20 (including C 1 and C 20 ). Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, propadienyl, and butadienyl.

[0126] 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, cycloheptatrienyl, and cyclooctenyl.

[0127] As used herein, the term "alkynyl" refers to a straight or branched chain C-alkyl group derived from a specified number of carbon atoms containing at least one carbon-carbon triple bond. 1-20 A monovalent group of a hydrocarbon. Examples of the "alkynyl group" include an ethynyl group, a 2-propynyl (propargyl) group, a 1-propynyl group, a pentynyl group, a hexynyl group, and a heptynyl group, and the like.

[0128] The term "alkylene" by itself or as part of another substituent refers to a straight or branched divalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, such as 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, branched or cyclic. The alkylene group can also be optionally unsaturated and / or substituted with one or more "alkyl group substituents". One or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") can be optionally inserted along the alkylene group, wherein the nitrogen substituent is an alkyl as previously described. Exemplary alkylene groups include methylene (-CH 2 -); ethylene (–CH 2 –CH 2 –); propylene (–(CH 2 ) 3 –); cyclohexylene (–C 6 H 10 –); –CH=CH–CH=CH–; –CH=CH–CH 2 –;-CH 2 CH 2 CH 2 CH 2-、-CH 2 CH=CHCH 2 -、-CH 2 CxD 2 -、-CH 2 CH 2 CH(CH 2 CH 2 CH 3 )CH 2 -、-(CH 2 ) q -N(R)-(CH 2 ) r -, wherein 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-CH 2 –O–); and ethylenedioxy (-O-(CH 2 ) 2 -O-). Alkylene groups can have from about 2 to about 3 carbon atoms and can also have 6-20 carbons. Typically, alkyl (or alkylene) groups will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure. "Lower alkyl" or "lower alkylene" are shorter chain alkyl or alkylene groups, typically having 8 or fewer carbon atoms.

[0129] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited to, -CH 2 -CH 2 -S-CH 2 -CH 2 -and-CH 2 -S-CH 2 -CH 2 -NH-CH 2 -. For heteroalkylene groups, heteroatoms may also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, 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)-.

[0130] Unless otherwise stated, the term "aryl" means an aromatic hydrocarbon substituent which may 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 each individual ring in the case of multiple rings), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the remainder 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-pyrimidyl, 4-pyrimidyl, 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.

[0131] 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. Thus, the terms "arylalkyl" and "heteroarylalkyl" are meant to include those groups in which an aryl group or a heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furanylmethyl, and the like), including 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, the term "haloaryl" as used herein is meant to cover only aryl groups substituted by one or more halogens.

[0132] In cases where the heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (eg, "3- to 7-membered"), the term "member" refers to a carbon or heteroatom.

[0133] Additionally, as used herein, structures generally represented by the formula:

[0134]

[0135] Refers to a ring structure comprising 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, wherein the R group may be present or absent, and when present, one or more R groups may 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 the R group are determined by the value of the variable "n", which is an integer generally 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 structure above wherein n is 0 to 2 will include a compound group, including but not limited to:

[0136]

[0137] and the like.

[0138] A dotted line representing a bond in a cyclic ring structure indicates that the bond may or may not be present in the ring. That is, a dotted line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[0139] symbol Indicates the point at which the moiety is attached to the rest of the molecule.

[0140] When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as "absent", the named atom is replaced by a direct bond.

[0141] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," and "heterocycloalkyl," "aryl," "heteroaryl," "phosphonate," and "sulfonate," and divalent derivatives thereof) is intended to include both substituted and unsubstituted forms of the indicated radical. Optional substituents for each type of radical are provided below.

[0142] Substituents for alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent derivatives and divalent derivatives (including those groups generally 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, the following in a number ranging from zero to (2m'+1): -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO 2R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(O)OR', -NR-C(NR'R")=NR'", -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", -NRSO 2 R', -CN and -NO 2 , where m' is the total number of carbon atoms in such a group. R', R", R'" and R"" can 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 1-3 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 via a divalent oxygen. When a compound of the present disclosure includes more than one R group, for example, each of the R groups is independently selected, as are each R', R", R'" and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-membered ring, a 5-membered ring, a 6-membered ring, or a 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, one skilled in the art will understand that the term "alkyl" is meant to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl groups (e.g., -C(O)CH 3 、-C(O)CF 3 、-C(O)CH 2 OCH 3 and the like).

[0143] Similar to the substituents described above for the alkyl groups, exemplary substituents for aryl and heteroaryl groups (and their divalent derivatives) are varied and are selected in a number ranging from zero to the total number of open valences on the aromatic ring system, for example: halogen, -OR', -NR'R", -SR', -SiR'R"R'", -OC(O)R', -C(O)R', -CO 2R', -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) 2 R', -S(O) 2 NR'R", -NRSO 2 R', -CN and -NO 2 , -R', -N 3 、-CH(Ph) 2 , fluorinated (C 1 -C 4 ) alkoxy, and fluorinated (C 1 -C 4 )alkyl; and wherein R', R", R'" and R"" can be independently 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 a compound of the present disclosure includes more than one R group, for example, each of the R groups is independently selected, as are each R', R", R'" and R"" groups when more than one of these groups is present.

[0144] Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a group of the formula -TC(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)- 2 -、-S(O) 2 NR'- or a single bond, and r is an integer from 1 to 4.

[0145] One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a double bond of the formula -(CRR') s -X'-(C"R'") d -, wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -or-S(O)2 NR'-. The substituents R, R', R" and R'" may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0146] 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)-, wherein R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a carbocyclic group, a heterocyclic group, or an aromatic heterocyclic group as defined herein. Thus, the term "acyl" particularly includes aryl acyl groups, such as 2-(furan-2-yl)acetyl groups and 2-phenylacetyl groups. 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.

[0147] The terms "alkoxyl" or "alkoxy" are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as previously described and may include C 1-20 (including C 1 and C 20 ) of a linear, branched or cyclic, saturated or unsaturated oxyhydrocarbon chain, including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and n-pentoxy, neopentoxy, n-hexoxy and the like.

[0148] The term "alkoxyalkyl" as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl group or an ethoxymethyl group.

[0149] "Aryloxy" refers to an aryl-O-group, wherein the aryl group is as previously described, including substituted aryl groups. As used herein, the term "aryloxy" may refer to phenyloxy or hexyloxy, and alkyl, substituted alkyl, halo, or alkoxy substituted phenyloxy or hexyloxy.

[0150] "Aralkyl" refers to an aryl-alkyl- group in which the aryl and alkyl are as previously described, and include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0151] "Aralkyloxy" refers to an aralkyl-O- group in which the aralkyl group is as previously described. An exemplary aralkyloxy group is benzyloxy, i.e., C 6 H 5 -CH 2 -O-. Aralkyloxy groups may be optionally substituted.

[0152] "Alkoxycarbonyl" refers to an alkyl-OC(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl.

[0153] "Aryloxycarbonyl" refers to an aryl-OC(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphthoxy-carbonyl.

[0154] "Aralkyloxycarbonyl" refers to an aralkyl-OC(=O)- group. An exemplary aralkyloxycarbonyl group is benzyloxycarbonyl.

[0155] "Carbamoyl" refers to a group of the formula -C(=O)NH 2 "Alkylcarbamoyl" refers to an R'RN-C(=O)- group, wherein one of R and R' is hydrogen, and the other of R and R' is an alkyl and / or substituted alkyl group as previously described. "Dialkylcarbamoyl" refers to an R'RN-C(=O)- group, wherein each of R and R' is independently an alkyl and / or substituted alkyl group as previously described.

[0156] The term carbonyldioxy as used herein refers to a carbonate group of formula -OC(=O)-OR.

[0157] "Acyloxy" means an acyl-O- group in which the acyl group is as previously described.

[0158] The term "amino" refers to the –NH 2 The term "acylamino" refers to a specific N-substituted organic group having an acyl group and an alkyl group, and also refers to a nitrogen-containing group as known in the art derived from ammonia by replacing one or more hydrogen groups with an organic group. For example, the terms "acylamino" and "alkylamino" refer to specific N-substituted organic groups having acyl and alkyl substituent groups, respectively.

[0159] As used herein, "aminoalkyl" refers to an amino group covalently bonded to an alkylene linker. More specifically, the terms alkylamino, dialkylamino, and trialkylamino, as used herein, refer to one, two, or three alkyl groups, as previously defined, respectively, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', wherein R' is an alkyl group as previously defined; 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. In addition, R', R" and / or R"' together may optionally be -(CH 2 ) k -, wherein k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidinyl, trimethylamino, and propylamino.

[0160] An amino group is -NR'R", wherein 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.

[0161] The terms alkylthioether 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.

[0162] "Acylamino" refers to an acyl-NH- group in which the acyl group is as previously described. "Aroylamino" refers to an aroyl-NH- group in which the aroyl group is as previously described.

[0163] The term "carbonyl" refers to a -C(=O)- group, and may include an aldehyde group represented by the general formula RC(=O)H.

[0164] The term "carboxyl" refers to a -COOH group. Such groups are also referred to herein as "carboxylic acid" moieties.

[0165] As used herein, the term "halo", "halide" or "halogen" refers to fluoro, chloro, bromo and iodo groups. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1-C 4 )alkyl" is meant to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[0166] The term "hydroxy" refers to an -OH group.

[0167] The term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0168] The term "mercapto" refers to a -SH group.

[0169] The term "oxo" as used herein means an oxygen atom double-bonded to a carbon atom or another element.

[0170] The term "nitro" refers to -NO 2 Group.

[0171] The term "thio" refers to compounds previously described herein wherein a carbon atom or an oxygen atom is replaced by a sulfur atom.

[0172] The term "sulfate" refers to -SO 4 Group.

[0173] As used herein, the term thiol or thiol refers to a group of formula -SH.

[0174] More particularly, the term "sulfide" refers to a compound having a group of formula -SR.

[0175] The term "sulfone" refers to a sulfone having a sulfonyl group -S(O 2 )R compound.

[0176] The term "sulfoxide" refers to a compound having a sulfinyl group -S(O)R.

[0177] The term urea group refers to a group of the formula –NH—CO—NH 2 of urea groups.

[0178] The term "blocking group" about the compound of formula (I) refers to a chemical substituent that can be selectively removed by an easily available reagent that does not attack the regenerated functional group or other functional groups in the molecule. Suitable blocking groups are known in the art and continue to be developed. Suitable blocking groups can be found, for example, in Wutz et al. (" Greene's Protective Groups in Organic Synthesis, 4th edition, " Wiley-Interscience, 2007). The blocking group for protecting a carboxyl group as described by Wutz et al. (pages 533-643) is used in certain embodiments. In some embodiments, the blocking group is removed by treating with an acid. Representative examples of blocking 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 that the appropriate situation of blocking groups is needed and will be able to select the appropriate blocking group for use in a particular environment.

[0179] Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0180] 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, and individual isomers that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or as D- or L- for amino acids are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those compounds known in the art to be too unstable to be synthesized and / or separated. The present disclosure is intended to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-isomers, or D- and L-isomers, may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0181] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the present disclosure.

[0182] 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 converted from one isomeric form to another.

[0183] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in the replacement of hydrogen with deuterium or tritium, or with 13 C- or 14 Compounds having the present structures are within the scope of the present disclosure where a C-rich carbon replaces the carbon.

[0184] 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 treated with, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radioactive isotope radiolabeling. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0185] The compounds of the present disclosure may exist as salts. The 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 may be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, organic amino or magnesium salts, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts may be obtained by contacting such compounds in neutral form 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, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, 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 (e.g., glucuronic acid or galacturonic acid and the like). Certain specific compounds of the present disclosure contain both basic and acidic functional groups, which allow the compound to be converted into base addition salts or acid addition salts.

[0186] 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.

[0187] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms (including hydrated forms). Typically, solvated forms are equivalent to 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. Typically, all physical forms are equivalent and intended to be within the scope of the present disclosure for the intended use of the present disclosure.

[0188] In addition to salt forms, the present disclosure provides compounds in the form of prodrugs. The prodrugs of compounds described herein are those compounds that are easily subjected to chemical changes under physiological conditions to provide compounds of the present disclosure. In addition, prodrugs can be converted into compounds of the present disclosure by chemical methods or biochemical methods in an isolated environment. For example, prodrugs can be slowly converted into compounds of the present disclosure when placed in a transdermal patch reservoir (transdermal patch reservoir) with a suitable enzyme or chemical reagent.

[0189] In accordance with long-standing patent law practice, when used in this application, including the claims, the terms "a," "an," and "the" mean "one or more." Thus, for example, reference to "a subject" includes a plurality of subjects unless the context clearly dictates otherwise (e.g., a plurality of subjects), etc.

[0190] Throughout this specification and claims, the terms "comprise," "comprises," and "comprising" are used in a non-exclusive sense, unless the context requires otherwise. Likewise, the term "include" and its grammatical variations are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

[0191] For the purpose of this specification and the appended claims, unless otherwise indicated, all numbers used in the specification and claims to indicate amount, size, dimension, ratio, shape, formulation, parameter, percentage, quantity, feature, and other numerical values ​​should be understood as modified by the term "about" in all cases, even if the term "about" may not be explicitly presented with a value, amount or range. Therefore, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are not exact and do not need to be exact, but may be approximate and / or larger or smaller as desired, reflecting tolerances, conversion factors, rounding, measurement errors and the like, and other factors known to those skilled in the art, depending on the desired properties to be sought to be obtained by the subject matter currently disclosed. For example, the term "about" when referring to a value can mean to cover differences with a specific amount 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%, because such differences are suitable for carrying out the disclosed method or using the disclosed composition.

[0192] In addition, when used in conjunction with one or more numbers or numerical ranges, the term "about" should be understood to refer to all such numbers, including all numbers within the range and to modify the range by extending the boundaries to above and below the numerical values ​​set forth. The description of numerical ranges by endpoints includes all numbers, such as all integers, within the range, including fractions thereof (e.g., the description of 1 to 5 includes 1, 2, 3, 4 and 5, and fractions thereof, such as 1.5, 2.25, 3.75, 4.1 and the like) and any range within the range. Example

[0193] 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, the skilled person will appreciate that the following examples are intended to be exemplary only, and that many variations, modifications, and changes may be employed without departing from the scope of the presently disclosed subject matter. The following synthetic descriptions and specific examples are intended only for illustrative purposes and are not to be construed as limiting in any way the compounds of the present disclosure prepared by other methods.

[0194] Example 1

[0195] Overview

[0196] The use of PSMA-binding ureas conjugated to chelated radiometals via a variety of linkers for imaging and possible radiotherapy of PSMA-expressing tumors has been previously reported in several patent applications and publications (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63; 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 epsilon amine position with a p-Br-benzyl group. The structures of the currently disclosed compounds are shown in Figure 1 Shown in.

[0197] Without wishing to be bound by any particular theory, it is believed that radiometal-chelated Glu-lysine urea-based therapeutics targeting prostate-specific membrane antigen (PSMA), when modified with a p-Br-benzyl group on the epsilon amino group of the lysine of the Lys-Glu-urea moiety, demonstrate high binding affinity to PSMA and high uptake in PSMA-expressing tumors and low renal uptake in a standard mouse model of prostate cancer. In one embodiment, 177 Lu-1 showed significant radiotherapeutic efficacy, with a remission rate of approximately 50% in mice bearing PSMA+PC3 tumors.

[0198] Example 2

[0199] Materials and methods

[0200] 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 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 provide 5 in good yield. Yield: 80%. ESI-MS: 656.56 [M+H] + , measured: 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 DMF and stirred at room temperature. After one hour, compound 5 (71.0 mg, 108 μmol) was added, wherein DMF (50 μL each) was rinsed three times. The reaction mixture was stirred for 4 hours and stored at 4 ° C overnight. The crude reaction mixture was purified by semi-preparative HPLC at C 18 Purification on column (40% water (0.1 TFA) / 60% ACN (0.1 TFA)) lasted 5 min, 60%-90% in 20 min. 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 equilibrium, TFA (1.5 mL) was added, and the mixture was stirred for 3 hours, allowing to warm to room temperature in the process. The mixture was dried under a stream of nitrogen, dissolved in water, and lyophilized to produce 31.8 mg of compound 7. Yield: 54 μmol, 54%. p-SCN-bn-DOTA (12.2 mg, 17.7 mol) was added to a stirred solution of 6 (12.2 mg of TFA salt) and DIPEA (15.2 μL, 87.0 μmol) in DMSO (130 μL) balanced to 40°C. The reaction mixture was stirred at 40°C for 4 hours and stored at 4°C overnight. The reaction mixture was purified by reverse phase HPLC (keeping 20% ​​ACN for 5 min, then 20%-40% in 19 minutes). Rt was about 12 minutes. The purified fractions were combined, rotary evaporated to reduce the volume, and then lyophilized. ESI-MS: 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, comprising a mobile phase of 88% water (containing 0.1% TFA) and 12% CH 3 CN (0.1% TFA) for 1 min-5 min, followed by 88% water (containing 0.1% TFA) and 12% CH 3 CN (0.1% TFA), and 88% water to 44% water and 12% acetonitrile to 56% acetonitrile from 5 min-25 min with a flow rate of 8 mL / min.

[0201] Chemical synthesis of 2. This compound was synthesized by using the same intermediate 7 and coupled with commercially available DOTA-NHS ester. ESI-MS: 974.86.[M+H] + , measured: 974.5.

[0202] Chemical synthesis of 3. This compound was synthesized by using intermediate 4 and coupling with commercially available Boc-5-aminopentanoic acid and DOTA-NHS ester. ESI-MS: 970.05 [M+H] + , measured: 970.1.

[0203] 177 Radiolabeling of Lu-1. Place 1.0 μl of 0.1 N HCl in 177 LuCl 3 (1 mCi) added to 70 μl NH 4 OAc buffer (0.2 M, pH 4) and added to 0.2 M NH 45 μl of 2 mM MgCl2 in 1% HCl was added. The pH of the mixture was about 4.0. The mixture was kept at 80°C for one hour and purified by HPLC. The HPLC method was a gradient method with a mobile phase of 77% water (containing 0.1% TFA) and 23% CH 3 CN (0.1% TFA) for 1 min-5 min, followed by 5 min-25 min water 77% to 57% and acetonitrile 23% to 43%; 25.01 min-30 min, water 5% to 5% and acetonitrile 95% to 95%, 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 C 8 Column (25 mm × 4.6 mm), Varian microsob-MV 100-5. Radiolabeled 177 Lu-1 eluted at 17.1 min-20 min, while the unlabeled chelator eluted at 21 min-22 min.

[0204] HPLC method was used for preparation 177 Lu-2 and 177 Lu-3: The HPLC method is a gradient method, comprising a mobile phase of 88% water (containing 0.1% TFA) and 12% CH 3 CN (0.1% TFA) for 1 min-5 min, followed by 5 min-27 min water 88% to 75% and acetonitrile 12% to 25%; 27.01 min-32 min water 5% to 5% and acetonitrile 95% to 95%, 32.01 min to 37 min water 88% to 18% and acetonitrile 12% to 22%. Flow rate: 1.0 ml / min; λ: 200 nm, and C 8 Column (25 mm × 4.6 mm), Varianmicrosob-MV 100-5. Radiolabeled 177 Lu-2 eluted at 13.1min-15.0min, while the unlabeled chelator eluted at 16min-17min. 177 Lu-3 eluted at 13.1min-15.0min, while the unlabeled chelator eluted at 10min-12min and 18min-20min, and the unlabeled agent reached 14min-16min.

[0205] Scheme 1. Synthesis of compound 1

[0206]

[0207] Example 3

[0208] Results and Discussion

[0209] Chemical and radiochemical synthesis and characterization. The modified p-bromobenzyl group of Glu-Lys urea (2) was prepared in good yields following literature procedures (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63) by reductive alkylation of 2 with p-bromobenzaldehyde in methanol in the presence of sodium cyanoborohydride to provide 4. A small aliphatic linker, Boc-5-aminopentanoic 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 in the case of 6 to provide 1 in moderate yields. Compound 2 was synthesized by using DOTA-NHS ester as a chelating agent and coupling with the same intermediate 6. Compound 3 was synthesized as a control reagent without any p-bromobenzyl group. All three reagents were used in ammonium acetate buffer at 80°C at pH 4 in good yields and purity. 177 The binding affinities of these novel compounds are listed in Table 1. Both 1 and 2 modified with p-bromobenzyl groups showed higher binding affinities compared to 3.

[0210]

[0211] Cell binding properties. 177 Lu agents were also evaluated in cells and animals using standard isogenic cell lines PSMA+ PC3 PIP and PSMA-negative PC3 flu cells. 177 Compared with Lu-3, 177 Lu-1 and 177 Lu-2 and Lu-2 demonstrated higher uptake in PSMA+PC3 cells. Further internalization studies revealed that 177 Compared with Lu-3, 177 Lu-1 had nearly 2-fold higher internalization activity. All three agents showed significantly low uptake in PSMA-negative PC3 flu cells. 177 The therapeutic efficacy of Lu-1 is comparable to that of the previous lead compound SR6 (Banerjee et al. (2015) Journal of nuclear medicine 56, 628-34) and the other two compounds in clinical trials. 177 Lu-PSMA-617 (Benesova et al. (2015) Journal of nuclear medicine 56, 914-20) and 177 Comparison of Lu PSMA-I&T (Weineisen et al. (2014) EJNMMI Res 4, 1-15). 177Lu-1 was able to produce approximately 100% cell killing efficacy in PSMA+PC3 PIP cells using a 10 μCi dose, while no significant toxicity was seen for PSMA-PC3 flu cells.

[0212]

[0213]

[0214] Biodistribution. 177 Lu-1 and 177 Lu-2 was subjected to in vivo tissue biodistribution studies and are listed in Tables 3 and 4. 177 Lu-1 showed a higher uptake in PSMA+PC3 PIP tumors 177 Lu-2 has higher uptake and retention. Significantly, 177 Lu-2 showed a 177 Lu-1 has a 5-fold lower renal uptake and Figure 3 As shown in the Figure 2, the tumor / kidney effects of the currently disclosed compounds were compared with those of the previous lead 177 Lu-SR6, 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T comparison. 177 Lu-2 PSMA+PC3 PIP tumor to kidney ratio 177 Lu-1 High. Due to higher tumor uptake and retention, it is also being evaluated in a small group of animals in a pilot study 177 Therapeutic efficacy of Lu-1 (imaging and therapeutic effects).

[0215]

[0216]

[0217]

[0218] Small animal SPECT imaging and therapeutic efficacy. Figure 4 The results show that the treatment duration lasted from 1 day to 8 days after treatment. 177 SPECT imaging of Lu-1. A single dose of 3mCi was injected via tail vein injection in mice (n=10) bearing PSMA+PC3 PIP tumors (size 3mm-5mm). Saline was injected into another group of mice (n=10) for control studies. The body weight and tumor size metrics of the mice were monitored twice a week. When the size of the tumor exceeded >12mm, the mice in the control group were euthanized after 4-8 weeks. For the treatment group, 50% of the mice showed complete elimination of the tumor. These mice initially experienced recovery of the initial body weight after 2 weeks. The results were Figure 5Shown in. Fig. 6A and Figure 6B Compared with the control group using saline, 177 Therapeutic efficacy of Lu-1 (reduction in tumor volume). Five mice showed complete remission of disease, and survival lasted for more than five months.

[0219] In summary, radiometal-chelated Glu-lysine urea-based therapeutics targeting prostate-specific membrane antigen (PSMA), when modified with a p-Br-benzyl group on the epsilon amino group of the lysine of the Lys-Glu-urea moiety, demonstrated high binding affinity to PSMA and high uptake in PSMA-expressing tumors and low renal uptake in a standard mouse model of prostate cancer. A representative compound 177 Lu-1 showed significant radiotherapeutic efficacy, with a response rate of approximately 50% in mice bearing PSMA+ PC3 tumors.

[0220] References

[0221] All publications, patent applications, patents and other references mentioned in the specification indicate the level of technicians in the field of the currently disclosed subject matter. All publications, patent applications, patents and other references (such as websites, databases, etc.) mentioned in the specification are hereby incorporated by reference in their entirety, and their extent is as each individual publication, patent application, patent and other references are specifically and individually indicated to be incorporated by reference to the same extent. It will be understood that although many patent applications, patents and other references are mentioned in this article, such references do not constitute a part of admitting that any of these files form common general knowledge in the art. In the case of conflict between this specification and any incorporated reference, this specification (including any modification thereof, which may be based on the incorporated reference) should be used as the standard. The standard art-accepted meaning of the term is used herein, unless otherwise indicated. Standard abbreviations for various terms are used herein.

[0222] International PCT Patent Application No. PCT / US2008 / 007947 (WO2009 / 002529 A2) to Pomper, MG, Ray, S., Mease, RC, Foss, C., published on December 31, 2008, for labeled inhibitors of prostate specific membrane antigen (PSMA), biological evaluation, and use as imaging agents;

[0223] International PCT patent application No. PCT / US2008 / 013158 (WO2009070302 A1) of Chandran SS, Ray S., Denmeade SR., Pomper MG, Mease RC for Prostate specific membrane antigen targeted nanoparticles for therapy of prostate cancer, published on June 4, 2009;

[0224] International PCT patent application No. PCT / US2010 / 028020 (WO2010108125 A2) of Pomper M.G., Mease RC; Ray S., Chen Y. for PSMA-targeting compounds and uses thereof, published on September 23, 2010;

[0225] 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 medicine56,628-34;

[0226] 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 medicine56,914-20;

[0227] 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 GlutamateCarboxypeptidase II.Journal of medicinal chemistry 58,4357-63;

[0228] 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.

[0229] Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: 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 –CH2-R 1 ; R 1 is selected from the group consisting of phenyl substituted by halogen, 1-naphthyl substituted by halogen, 2-naphthyl substituted by halogen, pyridyl substituted by halogen and unsubstituted isoquinolyl, Where R 1 Do not select a group consisting of: wherein X is independently Br or I; 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 chooses freedom-NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 - A group consisting of; wherein each occurrence of L and W is 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, and the chelating agent contains a metal.

2. The compound of claim 1, wherein the chelating agent comprises a radioactive metal.

3. The compound of claim 1, wherein the chelating agent is selected from the group consisting of:

4. The compound of claim 1, wherein 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.

5. The compound of claim 4, wherein 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.

6. Use of a compound of formula (I) in the preparation of a pharmaceutical composition for treating one or more tumors or cells expressing prostate-specific membrane antigen, wherein an effective amount of the compound of formula (I) is contacted with the one or more tumors or cells expressing prostate-specific membrane antigen, and the compound of formula (I) is: in: 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 –CH2-R 1 ; R 1 is selected from the group consisting of phenyl substituted by halogen, 1-naphthyl substituted by halogen, 2-naphthyl substituted by halogen, pyridyl substituted by halogen, and unsubstituted isoquinolinyl; Where R 1 Do not select a group consisting of: wherein X is independently Br or I; 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 chooses freedom-NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 - A group consisting of; wherein each occurrence of L and W is 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 comprising a radioactive metal suitable for radiotherapy; or a pharmaceutically acceptable salt thereof.

7. The use according to claim 6, wherein the chelating agent is selected from the group consisting of:

8. The use according to claim 6, wherein the radioactive metal 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.

9. The use of claim 6, wherein the one or more tumors or cells expressing prostate-specific membrane antigen are selected from the group consisting of prostate tumors or cells, lung tumors or cells, kidney tumors or cells, glioblastomas, pancreatic tumors or cells, bladder tumors or cells, sarcomas, melanomas, breast tumors or cells, colon tumors or cells, germ cells, pheochromocytomas, esophageal tumors or cells, gastric tumors or cells, and combinations thereof.

10. The use of claim 6, wherein the one or more tumors or cells expressing prostate-specific membrane antigen are metastatic prostate tumors or cells.

11. The use of claim 6, wherein the one or more tumors or cells expressing prostate-specific membrane antigen are prostate tumors or cells.

12. The use of claim 6, wherein the one or more tumors or cells expressing prostate-specific membrane antigen are in vitro, in vivo or ex vivo.

13. The use of claim 6, wherein the one or more tumors or cells expressing prostate-specific membrane antigen are present in a subject.

14. The use of claim 13, wherein the subject is a human.

15. The use according to claim 6, wherein the pharmaceutical composition results in inhibition of tumor growth.

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