High affinity agents targeting prostate-specific membrane antigens for internal radiotherapy of prostate cancer

Abstract

To provide a high affinity agent targeting a prostate-specific membrane antigen for internal radiotherapy of prostate cancer.SOLUTION: Compounds of formula (I) and pharmaceutically acceptable salts thereof are provided.SELECTED DRAWING: Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 311,697, filed March 22, 2016. and is incorporated herein by reference in its entirety.

[0002] Federally funded research or development This invention was made possible by grants K25CA148901-01A1 and U5 This invention was made with government support under 4CA1346751. The U.S. Government has certain rights in this invention. do. [Background technology]

[0003] Prostate cancer is the leading cancer in the United States and the second leading cause of cancer deaths in men. Treatment of locally advanced disease remains controversial, with an increasing number of different New options are becoming available: high-affinity radiation therapy for prostate cancer Therapeutic drugs have been developed using prostate-specific membrane antigen (PSMA) as a target. is a marker of progenitor-independent disease, which also occurs in the neovasculature of solid (non-prostate) tumors. It is manifested. Summary of the Invention [Means for solving the problem]

[0004] summary In some embodiments, the invention disclosed herein provides a compound of formula (I): [ka] where Z is tetrazole or COQ; Q is H or a protecting group; m is 1, 2, R is an integer selected from the group consisting of 3, 4, and 5; and R is independently H or -CH-R 1 Yes R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline. L is selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene and arylene; is the linker of choice; W is -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 - and -(C=S) -NR 2 - wherein each occurrence of L and W is the same or different; It's okay to be there;R 2 is H or C1-C4 alkyl; n is selected from the group consisting of 1, 2, and 3 Ch is a chelating agent that can contain a metal or radioactive metal; and pharmaceutically acceptable salts thereof.

[0005] In a specific embodiment of the compound of formula (I), R 1 is the following: [ka] wherein X is independently Br or I; is selected from the group consisting of:

[0006] In a further specific embodiment of the compound of Formula (I), the chelating agent is: [ka] is selected from the group consisting of:

[0007] In another aspect, the invention disclosed herein is directed to one or more PSMA-expressing tumors or a method comprising contacting a cell with an effective amount of a compound of formula (I), The compound of the formula: [ka] where Z is tetrazole or COQ; Q is H or a protecting group; m is 1, 2, R is an integer selected from the group consisting of 3, 4, and 5; and R is independently H or -CH-R 1 in Yes;R 1 is substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is C1-C6 alkylene and a lysine selected from the group consisting of C3-C6 cycloalkylene and arylene W is -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 - and -(C=S)-NR 2 - Karana wherein each occurrence of L and W may be the same or different; R 2 is H or C1-C4 alkyl; n is an integer selected from the group consisting of 1, 2, and 3. Ch is a chelating agent containing a radioactive metal suitable for radiotherapy; and its pharmaceutical use acceptable salts, The present invention provides a method for treating tumors or cells that express one or more PSMAs, comprising:

[0008] In another aspect, the invention disclosed herein provides a method for treating one or more prostate-specific membrane antigen (PSMA) A method for imaging tumors or cells is provided, the method comprising: , contacting the subject with an effective amount of a compound of formula (I), and imaging.

[0009] In yet another aspect, the invention disclosed herein comprises a compound of formula (I) Provide a kit.

[0010] Certain aspects of the presently disclosed invention described above in this specification are The present invention is described in whole or in part by the present invention, other aspects of which are best described below. As will become apparent from the description and the accompanying drawings, [Brief explanation of the drawings]

[0011] Having now described in general terms the invention disclosed herein, reference will now be made to the accompanying drawings, in which: Not necessarily drawn to scale. Here: [Figure 1] Chemical structures of representative radiotherapy agents are shown; [Figure 2] presents a comparative study of the clonogenic efficacy of 177Lu-1 and known agents SR6, PSMA-617, and PSMA-I&T; [Figure 3] The distribution rate of PSMA+ tumors in the kidney for 177Lu-1, 177Lu-2, 177Lu-SR6, 177Lu-PSMA-617, and 177Lu-PSMA-I&T is shown; [Figure 4] Shown is SPECT-CT imaging of 177Lu-1 during a study of treatment with a single dose of 3 mCi; [Figure 5] Relative body weights of mice during the treatment study; and [Figure 6] Figures 6A and 6B show the relative tumor volumes of mice during the treatment study (Figure 6A) and Kaplan-Meier survival curves up to 60 days after treatment (Figure 6B). DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description The invention disclosed herein is described more fully below with reference to the accompanying drawings, in which: Although several embodiments of the invention disclosed herein are shown therein, Like numbers refer to like elements throughout. The disclosed invention may be embodied in many different forms and the embodiments set forth herein may be modified in any way. These embodiments should not be construed as limiting the scope of the present disclosure; rather, they are illustrative of the principles to which the present disclosure is applicable. Indeed, the foregoing description and accompanying drawings provide a basis for determining whether a particular device is suitable for use in a particular application. Those skilled in the art to which the invention(s) disclosed herein may relate, having the benefit of the teachings set forth herein, to the practice of the invention(s) disclosed herein. Many modifications and other embodiments of the invention disclosed herein come to mind. Therefore, it is to be understood that the invention disclosed herein is not limited to the particular embodiments disclosed. and modifications and other embodiments are intended to be within the scope of the appended claims. Please understand that this is intended.

[0013] I. High-affinity drugs targeting prostate-specific membrane antigen for internal radiotherapy of prostate cancer Agent

[0014] A. Compounds of Formula (I)

[0015] Thus, in one aspect, the invention disclosed herein provides a compound of formula (I): [ka] where Z is tetrazole or COQ; Q is H or a protecting group; m is 1, 2, R is an integer selected from the group consisting of 3, 4, and 5; and R is independently H or -CH-R 1 Yes R 1is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline. L is selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene, and arylene. and W is a linker selected from -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 - and -(C= S)-NR 2 - wherein each occurrence of L and W may be the same or different. It's okay to have it;R 2 is H or C1-C4 alkyl; n is selected from the group consisting of 1, 2, and 3. Ch is a chelating agent that can contain a metal or radioactive metal; and pharmaceutically acceptable salts thereof.

[0016] "wherein each occurrence of L and W may be the same or different The phrase "current of L and W can be the same or different" refers to the variable "n" When is 2 or 3, one "L" group may be C1-C6 alkylene, where the other Either "L" group or groups may be C3-C6 cycloalkylene or arylene. Or, in other embodiments, each "L" group may be, for example, C1-C6 alkylene. For example, when "n" is 2 or 3, a "W" group may be -(C=O)-NR2-. The "W" group or groups may be -(C=S)-NR2-, or in other embodiments. In the form, each "W" may be, for example, -(C=O)-NR2-.

[0017] In specific embodiments of the compounds of formula (I), R 1 is the following: [ka] wherein X is independently Br or I; is selected from the group consisting of:

[0018] In a further embodiment of the compound of formula (I), the chelating agent is: [ka] is selected from the group consisting of:

[0019] In more specific embodiments of the compounds of formula (I), the chelating agent is: Y , Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc In further specific embodiments of the compound of Formula (I), the metal is Radioactive metals, including: 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.

[0020] In a specific embodiment, the compound of formula (I) is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] ; is selected from the group consisting of:

[0021] B. Use of Compounds of Formula (I) to Treat Tumors or Cells Expressing One or More PSMAs How to use

[0022] In one embodiment, the invention disclosed herein is directed to one or more PSMA-expressing tumors. 1. A method comprising contacting a tumor or cell with an effective amount of a compound of formula (I), (I) The compound of formula (I) is [ka] where Z is tetrazole or COQ; Q is H or a protecting group; m is 1, 2, R is an integer selected from the group consisting of 3, 4, and 5; and R is independently H or -CH-R 1 Yes R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline. L is selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene, and arylene. and W is a linker selected from -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 - and -(C= S)-NR 2 - wherein each occurrence of L and W may be the same or different. It's okay to have it;R 2 is H or C1-C4 alkyl; n is selected from the group consisting of 1, 2, and 3. Ch is a chelating agent containing a radioactive metal suitable for radiotherapy; and pharmaceutically acceptable salts thereof, The present invention provides a method for treating tumors or cells that express one or more PSMAs, comprising:

[0023] "Contacting" means contacting at least one PSMA-expressing tumor or at least one agent comprising a therapeutic agent of the present invention in physical contact with the cell; Contacting refers to any action that results in the formation of a compound. and contacting said compound with at least one cell or tumor in an amount sufficient to effect said compound. The method may include exposing the cell or tumor to a culture dish or tube. The compound and cells or tumors are placed in a controlled environment, such as a chamber, and preferably The method can be carried out in vitro or ex vivo by mixing. The contacting can be performed in vivo, in which case the contacting comprises administering the compound to a subject. At least one cell or tumor in a subject is treated with the antibody or antibody compound by administering the antibody or antibody compound by any suitable route. Exposure to one or more of the compounds of the presently disclosed inventions is also meant.

[0024] As used herein, the term "treating" refers to any disease for which such term is appropriate. The disease, disorder or condition for which it is used, or One or more symptoms or manifestations of a disease, disorder, or illness s) and prevent or reduce the likelihood of their progression. Prevention means preventing the onset of a disease, disorder, illness, or any of its symptoms or signs. This means preventing the onset of symptoms or the worsening of their severity. Thus, the compounds of the present invention can be administered prophylactically to prevent the onset or recurrence of a disease, disorder, or condition. can be prevented or mitigated.

[0025] Generally, an "effective amount" of an active agent is that amount required to elicit a desired biological response. As will be appreciated by those skilled in the art, an effective amount of a drug or device refers to the amount necessary to achieve a desired effect. The desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, etc. It may vary depending on factors.

[0026] The term "combination" is used in its broadest sense and means at least two Two drugs, more specifically a compound of formula (I) and at least one other active drug, are tested. More specifically, the term "in combination" refers to a compound administered to the body. ) refers to the simultaneous administration of two (or more) active agents, e.g., for the treatment of a single disease state. As used herein, the active agent is administered in a single agent. They may be administered in combination, simultaneously as separate agents, or on the same day or may be administered as separate agents administered alternately or sequentially on separate days. In some embodiments of the disclosed invention, the active agents are administered in combination in a single agent. In another embodiment, the active agents are administered in separate dosage forms (e.g., varying the amount of one). (It is desirable to increase the amount of one agent and not change the amount of the other.) The composition may additionally contain an active agent for:

[0027] In specific embodiments, R 1 is the following: [ka] wherein X is independently Br or I; is selected from the group consisting of:

[0028] In more specific embodiments, the chelating agent is: [ka] is selected from the group consisting of:

[0029] In a more specific embodiment, said radiometal suitable for radiotherapy is: 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.

[0030] In a more specific embodiment, the compound of formula (I) is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] ; is selected from the group consisting of:

[0031] In other embodiments, the tumor or cells expressing one or more of the following: a prostate tumor or cells, metastatic prostate tumors or cells, lung tumors or cells, renal tumors or cells, glioblastoma, Pancreatic tumors or cells, bladder tumors or cells, sarcoma, melanoma, breast tumors or cells, colon tumors or cells, germ cells, pheochromocytoma, esophageal tumor or cells, gastric tumor or cells, and combinations thereof In certain other embodiments, the one or more PS The MA-expressing tumor or cell is a prostate tumor or cell.

[0032] In another embodiment, the one or more PSMA-expressing tumors or cells are isolated in vitro, in In yet another embodiment, the one or more PSMA-expressing cells are in vitro or ex vivo. The tumor or cell is present in the subject.

[0033] The methods described herein are intended to encompass all subjects that are intended to be encompassed by the term "subject." It should be understood that the method is effective for all vertebrate species, but in many embodiments Therefore, the subject treated by the method of the present invention is preferably a human subject. Therefore, a "subject" is a subject to be treated for an existing disease or disorder or to be treated for an illness or disorder. or human subjects for medical purposes, such as prophylactic treatment to prevent the onset of disease, or may include animal (non-human) subjects for medical, veterinary, or development purposes. Suitable animal subjects include, but are not limited to, primates (e.g., humans, monkeys, apes, etc.) etc.); bovines (e.g., cattle, bulls, etc.); ovines (e.g., sheep); caprines (e.g., goats); porcines (e.g., pigs, hogs, etc.); equines ) (e.g., horses, donkeys, zebras, etc.); Felidae (f elines (including wild and pet cats); canines (dogs) lagomorphs (including rabbits, hares, etc.) ); rodents (including mice, rats, etc.); etc. The animal may be a transgenic animal. In some embodiments, The subject may include, but is not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Furthermore, a "subject" is a person suffering from a disease or disorder. Therefore, the term "subject" may include a patient who has or is suspected of having the disease. "Subject" and "patient" are used interchangeably herein.

[0034] In yet certain other embodiments, the method results in an inhibition of growth of the tumor.

[0035] C. Compounds of Formula (I) for Imaging Tumors or Cells Expressing One or More PSMAs How to use the compound

[0036] In other embodiments, the invention disclosed herein is directed to one or more PSMA-expressing tumors. a method comprising contacting a tumor or cell with an effective amount of a compound of formula (I) and imaging. wherein the compound of formula (I) is [ka] where Z is tetrazole or COQ; Q is H or a protecting group; m is 1, 2, R is an integer selected from the group consisting of 3, 4, and 5; and R is independently H or -CH-R 1 in Yes;R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline. L is selected from the group consisting of C1-C6 alkylene, C3-C6 cycloalkylene and arylene. and W is a linker selected from -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 - and -(C= S)-NR 2 - wherein each occurrence of L and W may be the same or different. It's okay to have it;R 2 is H or C1-C4 alkyl; n is selected from the group consisting of 1, 2, and 3. is a selected integer; Ch is a chelating agent containing a radioactive metal suitable for imaging. and pharmaceutically acceptable salts thereof, and (c) providing a method for imaging tumors or cells that express one or more PSMAs, the method comprising: do.

[0037] D. Kit

[0038] In yet another embodiment, the invention disclosed herein comprises a compound of formula (I): Provide a kit.

[0039] In one embodiment, the kit comprises a pharmaceutically acceptable carrier and a compound of the invention. In one embodiment, the packaged pharmaceutical composition is The pharmaceutical composition comprises the reaction required to produce the compound of the invention in combination with a radiolabeled precursor. Other packaged pharmaceutical compositions provided by the present invention include: and further comprising instructions including at least one of: instructions for preparing said method for imaging cells or tissues expressing PSMA; Instructions for use of the composition, glutamatergic activity in patients suffering from stress-related disorders Instructions for using said compounds for imaging neurotransmission or imaging prostate cancer. and instructions for using said composition for the treatment of a patient with atopic dermatitis.

[0040] E. Pharmaceutical Compositions and Administration

[0041] In another aspect, the present invention provides a compound of formula (I), alone or in combination with a pharmaceutically acceptable excipient. and one or more additional therapeutic agents in admixture with the compound. Some skilled in the art recognize that the pharmaceutical compositions include pharmaceutically acceptable salts of the above compounds. Pharmaceutically acceptable salts are generally known to those skilled in the art and are described herein. are prepared with relatively non-toxic acids or bases, depending on the particular substituent moieties found on the compound. Salts of the active compounds are included. When compounds of the present invention contain relatively acidic functional groups, base addition salts are also possible. The neutral form of such a compound can be reacted with a sufficient amount of HCl, either neat or in a suitable inert solvent. By contacting with the desired base or by ion exchange (removing the basic counter ion in the ionic complex) Pharmaceutically acceptable salts can be obtained by replacing one base with another. Examples of base addition salts include sodium, potassium, calcium, ammonium, organic amino, or includes magnesium salts, or similar salts.

[0042] When compounds of the present invention contain relatively basic functional groups, acid addition salts of such compounds The neutral form is contacted with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. or by ion exchange (where an acidic counterion (acid) in an ionic complex is replaced by another). Examples of pharmaceutically acceptable acid addition salts include those obtained by the addition of hydrochloric acid, hydrobromic acid, , nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogen phosphate dihydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogen sulfate ( salts derived from inorganic acids such as monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid; Acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid salts derived from relatively non-toxic organic acids such as carboxylic acid, citric acid, tartaric acid, methanesulfonic acid, Also included are salts of amino acids such as alginate, and glucuronic acid or galacturonate. Also included are salts of organic acids such as carboxylic acids (see, for example, Berge et al., "Pharmaceutical Salts," Journal of of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds herein are A basic function that allows the compound to be converted into either a base addition salt or an acid addition salt. It contains both functional groups and acidic functional groups.

[0043] Thus, pharmaceutically acceptable salts suitable for use with the invention disclosed herein are Examples of suitable salts include, but are not limited to, acetates, benzenesulfonates, benzoates, etc. Salt, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate late), carbonate, citrate, edetate, edisylate, estolate, esylate, Fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate Glycollylarsanilate, hexylresorcinol, hydrabamine, hydrobromide, Hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobion acid salts, malates, maleates, mandelates, mesylates, mucates, napsylate Salt, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, poly Galacturonate, salicylate, stearate, basic acetate, succinate, sulfate, Other pharmaceutically acceptable salts include tannate, tartrate, or octanoate. For example, Remington: The Science and Practice of Pharmacy (20th ed.), Lippincott, This can be seen in Williams & Wilkins (2000).

[0044] In therapeutic and / or diagnostic applications, the compounds of the present invention can be administered systemically, topically, or intravenously. It can be formulated for a variety of modes of administration, including localized or localized administration. The techniques and formulations are generally based on the principles of Remington: The Science and Practice of Pharmacy (2002). 0th ed.), Lippincott, Williams & Wilkins (2000).

[0045] Depending on the particular condition being treated, such drugs may be formulated into liquid or solid dosage forms. The agent can be administered systemically or locally, for example, as known to those skilled in the art. The formulation and administration techniques are well known. , Remington: The Science and Practice of Pharmacy (20th ed.), Lippincott, Willia The recommended routes of administration are oral, buccal, and inhalation spray. , sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; intramuscular, subcutaneous, intramedullary injection; as well as intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intra-synovial, and hepatic Parenteral delivery, including intravisceral, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injection; may include other delivery modalities.

[0046] For injection, the agents of the invention can be administered in solutions such as Hank's solution, Ringer's solution, or physiological saline buffer. It can be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as 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.

[0047] To practice the present invention, the compounds disclosed herein are formulated into formulations suitable for systemic administration. The use of pharmaceutically acceptable inert carriers for the preparation of pharmaceutical compositions is within the scope of the present invention. By appropriately selecting the manufacturing process, the compositions of the present invention, particularly those formulated as solutions, can be administered intravenously. The compounds can be administered parenterally, such as by intravenous injection. Using a carrier acceptable to the patient, the compound can be easily formulated into a preparation suitable for oral administration. Such carriers allow the compounds of the invention to be administered orally to a subject (e.g., a patient) receiving treatment. tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral administration It will be possible to formulate it as such.

[0048] For nasal or inhalation delivery, the agents of the present invention may also be prepared by methods known to those skilled in the art. The formulation may be prepared in a suitable solution such as, but not limited to, saline. Examples of solubilizing, diluting or dispersing agents include: preservatives such as benzyl alcohol; absorption enhancers; and May contain fluorocarbons.

[0049] Pharmaceutical compositions suitable for use in the present invention include those containing active ingredients that achieve their intended purpose. Determining the effective amount is particularly important in the context of the present specification. This is well within the capabilities of those skilled in the art in light of the detailed disclosure provided herein. The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adults , 0.01 to 1000 mg per day, 0.5 to 100 mg, 1 to 50 mg per day, and 5 Doses of 10 to 40 mg per day are examples of doses that may be used. Non-limiting doses include 10 to 40 mg per day. The exact dose will depend on the route of administration, the form in which the compound is administered, the patient receiving treatment, and the individual. the subject receiving the treatment, the weight of the subject receiving the treatment, the bioavailability of the compound Absorption, distribution, metabolism and excretion (ADME), toxicity and physician preference of the compound. It depends on experience and knowledge.

[0050] In addition to the active ingredient, these pharmaceutical compositions are formulated for pharmaceutically acceptable use. Suitable pharmaceutically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of the active compound. Pharmaceutical preparations formulated for oral administration may include tablets, dragees, It may take the form of a capsule or a solution.

[0051] If necessary, add suitable auxiliaries to obtain tablets or dragee cores. The active compound is mixed with a solid excipient, and the resulting mixture is optionally milled to form a granular mixture. The mixture can be processed to obtain a pharmaceutical preparation for oral administration. The agent may be, inter alia, a sugar, including lactose, sucrose, mannitol, or sorbitol. Any filler; e.g., corn starch, wheat starch, rice starch, potato starch Pu, gelatin, tragacanth gum, methyl cellulose, hydroxypropyl methyl -cellulose, sodium carboxymethylcellulose (CMC), and / or polyvinyl alcohol cellulose preparations such as polyvinylpyrrolidone (PVP: povidone). cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts (e.g., sodium alginate) A disintegrant such as sodium may be added.

[0052] Dragee cores are provided with suitable coatings. For this purpose, gum arabic, Talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG ), and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures A concentrated sugar solution can be used, optionally containing dye-stuffs or color. pigments to identify or characterize different combinations of doses of the active compound For this purpose, they may be added to tablets or dragee coatings.

[0053] Orally available pharmaceutical preparations include those containing gelatin push-fit capsules. cells, soft sealed capsules made of gelatin, and plasticizers such as glycerol or sorbitol Push-fit capsules can also contain the active ingredients, a filler such as lactose, or other additives. Fillers, binders such as starch, and / or talc or magnesium stearate It may contain lubricants and, optionally, stabilizers as a mixture. In the formulation, the active compound is dissolved in a solution of fatty oil, liquid paraffin, or liquid polyethylene glycol. It can be dissolved or suspended in a suitable liquid such as polyethylene glycol (PEG). You may add it.

[0054] II. General Definitions

[0055] Although specific terms are employed herein, they are used in a generic and descriptive sense only. Unless otherwise defined, the terms used herein are used to refer to the same or similar entities and are not intended to be limiting. All technical and scientific terms used herein are within the scope of the art to which the invention described herein belongs. has the same meaning as commonly understood by one of ordinary skill in the art.

[0056] The following terms relating to compounds of formula (I) will be well understood by those of ordinary skill in the art: However, in order to facilitate the explanation of the invention disclosed in this specification, The following definitions are provided, which may be of use to one of ordinary skill in the art upon consideration of the present invention. They are intended to supplement and explain definitions that may be apparent, but not to preclude them. .

[0057] As used herein, substituted and substitute The term "optionally" may be used whether or not preceded by the term "optionally." Regardless of the above, as will be understood by those skilled in the art, the valence of all atoms is maintained. This means that one functional group on a molecule can be changed to another functional group under More than one position in a given structure may have more than one substituent selected from a particular group. When substituted with groups, the substituents may be the same or different at every position. The substituent may be further substituted (for example, the substituent of an aryl group may be one or more). It may be replaced by another substituent, such as another aryl group, further substituted at the above positions. stomach).

[0058] Where substituents or linking groups are identified by their conventional chemical formula written from left to right, In this case, they are chemically identical positions that would result from writing the structure from right to left. Substituents are included equally (e.g., -CH2O- is equivalent to -OCH2-; -C(=O)O- is equivalent to -OC(=O) - is equivalent to -; -OC(=O)NR- is equivalent to -NRC(=O)O-, etc.).

[0059] When the term "independently selected" is used, The substituents (e.g., R groups such as groups R1, R2, or variables such as "m" and "n") may be the same or For example, both R1 and R2 may be substituted alkyl, or R1 In some cases, R is hydrogen and R2 is substituted alkyl.

[0060] The terms "a," "an," or "a(n)," when used in reference to a group of substituents herein, For example, if a compound is substituted with "an" alkyl or aryl, If present, the compound may optionally comprise at least one alkyl and / or The moiety is substituted with at least one aryl. When a moiety is R-substituted, the group is sometimes referred to as "R-substituted." If present, the moiety is substituted with at least one R substituent, and each R substituent is optionally selectively different.

[0061] A named "R" or group generally refers to that name unless otherwise specified herein. For purposes of illustration, the structures are recognized in the art as corresponding to groups having the formula: For purposes of clarity, certain representative "R" groups listed above are defined below.

[0062] The description of the compounds of this invention is limited by principles of chemical bonding known to those skilled in the art. Thus, when a group may be substituted with one or more substituents, such substitutions are The substituents are selected to conform to principles of chemical bonding, are not inherently labile, and / or are hydrophilic. may be unstable under ambient environmental conditions, such as neutral and some known physiological conditions. Those skilled in the art will recognize that there is a possibility that The alkyl or heteroaryl groups are ring heteroaryls according to principles of chemical bonding known to those skilled in the art. It is bonded to the rest of the molecule through an atom, thereby avoiding inherently unstable compounds.

[0063] Unless expressly defined otherwise, as used herein, "substituent group" means a group selected from the group consisting of aryl, ... " includes a functional group selected from one or more of the following moieties, as defined herein:

[0064] The term hydrocarbon, as used herein, refers to any hydrocarbon containing hydrogen and carbon. The term "hydrocarbon" refers to any chemical group. The hydrocarbon may be substituted or unsubstituted. As we know, all valences must be satisfied when making any substitution. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Exemplary hydrocarbons are further defined herein below, for example: Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl butyl, ethynyl, cyclohexyl, and the like.

[0065] The term "alkyl," by itself or as part of another substituent, unless otherwise specified, a straight-chain (i.e., "unbranched"), branched-chain, acyclic or cyclic hydrocarbon group, It refers to any combination thereof, which may be fully saturated, monounsaturated or polyunsaturated. , divalent and polyvalent groups having the specified number of carbon atoms (i.e., C1-C 10 means 1 to 10 carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons In specific embodiments, the term "alkyl" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbon atoms. 1-20 comprehensive linear (i.e., "straight-chain"), branched, or cyclic, saturated, or The removal of one hydrogen atom from a hydrocarbon moiety containing 1 to 20 carbon atoms At least partially, and in some cases completely unsaturated (i.e., alkenyl) (alkynyl and alkynyl) hydrocarbon radicals.

[0066] 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 methyl, cyclopropylmethyl, and homologs and isomers thereof.

[0067] "Branched" means that a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl group. "Lower alkyl" refers to an alkyl group attached to an alkyl chain. Alkenyl groups having from 1 to about 8 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. alkyl groups (i.e., C 1-8 "Higher alkyl" refers to a group of alkyls with a molecular weight of about 1 0 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 In one embodiment, "alkyl" refers to an alkyl group having 1 to 10 carbon atoms. " is especially 1-8 refers to a straight chain alkyl. In another embodiment, "alkyl" refers to In particular, C 1-8 Refers to branched chain alkyl.

[0068] The alkyl group may be optionally substituted with one or more alkyl group substituents (" "substituted alkyl" where the substituents may be the same or different The term "alkyl group substituent" is not intended to be limiting. alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryl Oxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl (aralkylo xyl), aralkylthio, carboxyl, alkoxycarbonyl, oxo and cycloalkoxy. Optionally, one or more oxygen, sulfur or substituents along the alkyl chain. may be substituted with an unsubstituted nitrogen atom, wherein the nitrogen substituent is hydrogen, lower alkyl, or (also referred to herein as "alkylaminoalkyl") or It's a reel.

[0069] Thus, as used herein, the term "substituted alkyl" " refers to the fact that one or more atoms or functional groups of an alkyl group are bonded to another atom or functional group (e.g., an alkyl group). aryl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, Includes nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto. and substituted with .

[0070] The term "heteroalkyl," alone or in combination with another term, particularly Unless otherwise specified, any stable straight-chain, branched-chain, or cyclic hydrocarbon group or combination thereof and at least one carbon atom and one or more atoms selected from the group consisting of O, N, P, Si, and S. and at least one heteroatom, wherein the nitrogen, phosphorus, and sulfur atoms are The nitrogen atom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S and Si may be any of the heteroalkyl groups. It may be placed at an interior position or at the position at which the alkyl group is attached to the remainder of the molecule. Non-limiting examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2- N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH 25 -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3 , -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3 and -CN. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3, which contain up to two or three hydroxyl groups. The heteroatoms may be consecutive.

[0071] As mentioned above, as used herein, a heteroalkyl group is defined as -C(O)NR', ​​-NR'R ", -OR', -SR, -S(O)R and / or -S(O2)R' The term "heteroalkyl" is used to refer to a group that is bonded to a residue, followed by -NR'. When a specific heteroalkyl group is listed, such as R, the term heteroalkyl is used. It is understood that -NR'R" and -NR'R" are not redundant or mutually exclusive. Rather, Therefore, the specific heteroalkyl groups are listed. "Heteroalkyl" excludes certain heteroalkyl groups such as -NR'R". should not be construed herein as an indication of

[0072] "Cyclic" and "cycloalkyl" refer to a group having from about 3 to about 10 rings. non-aromatic monocyclic or polycyclic rings of carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms); The cycloalkyl group may be optionally partially unsaturated. The cycloalkyl group may also optionally be substituted with an alkyl group as defined herein. The cyclic alkyl chain may be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3 one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms may be inserted, The nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl. Thus, heterocyclic groups are provided. Representative monocyclic cycloalkyl rings include cycloalkyl groups such as Polycyclic cycloalkyl rings include pentyl, cyclohexyl, and cycloheptyl. , adamantyl, octahydronaphthyl, decalin, camphor, camphane and nora Damantyl and fused ring systems such as dihydro- and tetrahydronaphthalene. It can be enjoyed.

[0073] The term "cycloalkylalkyl" as used herein means any of the groups defined above. refers to a cycloalkyl group, as defined above, attached to the parent molecular moiety through an alkyl group, also defined above. Examples of cycloalkylalkyl groups are cyclopropylmethyl and cyclomethyl. Contains pentylethyl.

[0074] The terms "cycloheteroalkyl" or "heterocycloalkyl" are used interchangeably. "Terocycloalkyl" refers to a non-aromatic, unsaturated or partially unsaturated ring system. For example, a 3- or 4-terterocycloalkyl a 10- to 10-membered substituted or unsubstituted cycloalkyl ring system containing one or more heteroatoms and The atoms can be the same or different, and heteroatoms include nitrogen (N), oxygen (O), sulfur (S), selected from the group consisting of phosphorus (P) and silicon (Si), optionally containing one or more double bonds It may include.

[0075] The cycloheteroalkyl ring may optionally be joined to other cycloheteroalkyl rings and / or non-cycloheteroalkyl rings. The heterocyclic ring may be condensed or bonded to an aromatic hydrocarbon ring. and nitrogen, and , sulfur and nitrogen, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized; The nitrogen heteroatom may optionally be quaternized. In one embodiment, the term heterocycle (heterocylic) means a non-aromatic 5-, 6-, or 7-membered ring, or at least one ring atom is O heteroatoms selected from S and N, wherein the nitrogen and sulfur heteroatoms are optional; and the like, including but not limited to, bicyclic groups. a tricyclic group, and one to three independently selected from oxygen, sulfur, and nitrogen; and (i) each 5-membered ring has 0 to 2 double heteroatoms. bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 (ii) the nitrogen and sulfur heteroatoms are optionally oxidized. (iii) the nitrogen heteroatom may be optionally quaternized, and (iv) Any of the above heterocycles may be fused to an aryl ring or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl ... Rolinyl, Imidazolidinyl, Imidazolinyl, Pyrazolidinyl, Pyrazolinyl, Piperi Diazinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl , thiadiazinanyl, tetrahydrofuranyl, and the like.

[0076] The terms "cycloalkyl" and "heterocycloalk "yl"), alone or in combination with other terms, are each equivalent to "al" unless otherwise specified. "Cycloalkyl" refers to the cyclic versions of "alkyl" and "heteroalkyl." In the case of heterocycloalkyl, a heteroatom is the atom by which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, is cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohexyl Examples of heterocycloalkyl include, but are not limited to, cycloheptyl, and the like. Examples include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, and 3-piperidine. Lysinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-2-yl 3-fluorouranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 1-pipera The term "cycloalkylene" includes cycloalkylene, ... and "heterocycloalkylene" are cycloalkyl groups, respectively. and refers to the divalent derivatives of heterocycloalkyl.

[0077] An unsaturated alkyl group is an alkyl group that has one or more double or triple bonds. Non-limiting examples of unsaturated alkyl groups include vinyl, 2-propenyl, and crotyl. , 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl." do.

[0078] More specifically, the term "alkenyl" as used herein refers to a single alkyl group. It has at least one carbon-carbon double bond by removal of an elementary molecule, and C 1-20 The direct Alkenyl groups refer to monovalent groups derived from a chain or branched hydrocarbon moiety. , ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, Includes pentenyl, hexenyl, octenyl, allenyl and butadienyl.

[0079] As used herein, the term "cycloalkenyl" refers to a group consisting of at least one Cycloalkenyl groups refer to cyclic hydrocarbons containing two carbon-carbon double bonds. Examples of cycloalkenyl groups include cycloalkenyl groups, Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexene cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl and cyclo Octenyl is included.

[0080] As used herein, the term "alkynyl" refers to at least one carbon-carbon bond. Straight or branched chains of the intended number of carbon atoms, including a triple bond. 1-20 Derived from hydrocarbons Examples of "alkynyl" include ethynyl, 2-propyl, and 2-propyl. nyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, etc. Includes:

[0081] The term "alkylene," alone or as part of another substituent, refers to 1 to about 20 alkyl groups. carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1 straight or branched chain divalent alkyl groups derived from alkyl groups having 8, 19 or 20 carbon atoms The alkylene group may be linear, branched, or cyclic. The alkylene group may also be optionally unsaturated and / or contain one or more "alkyl groups." It may be substituted with one or more oxygen, sulfur or a substituted or unsubstituted nitrogen atom (referred to herein as "alkylaminoalkyl"). The alkylene groups can be optionally inserted along the alkylene groups. , where the nitrogen substituent is alkyl as described above. Exemplary Alkylene Groups Examples include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexane Xylene (-C6H 10 -);-CH=CH-CH=CH-;-CH=CH-CH2-;-CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2)r - contains, where q and r are each independently an integer from 0 to about 20 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), where R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). The alkylene group may have from about 2 to about 3 carbon atoms and may further have from 6 to 20 Typically, an alkyl (or alkylene) group has 1 to 24 carbon atoms. groups having 10 or fewer carbon atoms are preferred in some embodiments of the present invention. "Lower alkyl" or "lower alkylene" means , which are shorter chain alkyl or alkylene groups, generally having 8 or fewer carbon atoms .

[0082] The term "heteroalkylene" by itself or as part of another substituent , heteroalkyl, such as, but not limited to, Examples include -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. In the case of, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc.) Additionally, for alkylene and heteroalkylene linking groups, the orientation of the linking group is determined by the The direction in which the radical formula is written is not implied. For example, the formula -C(O)OR'- is written as -C Represents both -(O)OR'- and -R'OC(O)-.

[0083] The term "aryl" refers to groups that are fused or covalently bonded together unless otherwise specified. It refers to an aromatic hydrocarbon substituent which may be monocyclic or polycyclic (e.g., 1 to 3 rings) containing The term "heteroaryl" refers to one or more heteroaryls selected from N, O and S. aryl containing from 1 to 4 heteroatoms (in separate rings in the case of multiple rings); refers to a group (or ring) in which the nitrogen and sulfur atoms are optionally oxidized, The nitrogen atom is optionally quaternized. A heteroaryl group is a group consisting of carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include: Typical examples include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl. 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxo oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl 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-benzyl Midazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl The above aryl and heteroaryl groups include quinolyl, quinolyl, 3-quinolyl and 6-quinolyl. Substituents for each of the ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" respectively refer to refers to the divalent forms of aryl and heteroaryl.

[0084] For brevity, the term "aryl" is used interchangeably with other terms, such as aryloxy. , arylthioxy, arylalkyl), Thus, the term "arylalkyl" includes both aryl and heteroaryl rings. "(arylalkyl)" and "heteroarylalkyl" refer to aryl or The heteroaryl group may be an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, phenylmethyl, is meant to include groups attached to carbon atoms (e.g., methylene groups, methyl, etc.) ) is substituted with, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl , 3-(1-naphthyloxy)propyl, etc. alkyl groups. The term "haloaryl" as used herein means an aryl substituted with one or more halogens. This means that only the rule is included.

[0085] When the heteroalkyl, heterocycloalkyl, or heteroaryl has a specific number of members (e.g., When a molecule contains 3 to 7 members, the term "member" refers to a carbon or heteroatom. It refers to the atom.

[0086] Furthermore, the formula: [ka] As used herein, the structure generally represented by means of a ring structure, for example, Aliphatic and / or non-aliphatic groups such as, but not limited to, 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, etc. or aromatic cyclic compounds, which have saturated, partially saturated and unsaturated ring structures. and a substituent R group, wherein said R group may be present or absent, and when present If one or more R groups are present, they may be located on one or more available carbon atoms of said ring structure. The presence or absence of an R group and the number of R groups is determined by the value of the variable "n." where n is generally an integer ranging from 0 to the number of carbon atoms on the ring that can be substituted. Each R group, when present in multiple instances, is selected from available carbon atoms of the ring structure rather than from another R group. For example, the above structure where n is 0 to 2 is not limited. Although not listed, it would include a class of compounds including: [ka] etc.

[0087] A dashed line representing a bond in a cyclic ring structure indicates whether said bond is present or absent within said ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is a saturated ring. It indicates that the ring structure is selected from the group consisting of a partially saturated ring structure and an unsaturated ring structure.

[0088] symbol [ka] indicates the point of attachment of the moiety to the rest of the molecule.

[0089] When a specified atom of an aromatic or heteroaromatic ring is defined as "absent," In this case, the designated atom is replaced by a direct bond.

[0090] Each of the above terms (e.g., "alkyl," "heteroalkyl") "cycloalkyl" and "heterocycloalkyl" ", "aryl", "heteroaryl", "phosphonate "Phonate" and "sulfonate" and their divalent derivatives are shown. The optional choices for each type of radical are meant to include both substituted and unsubstituted forms of the radicals listed. Optional substituents are shown below.

[0091] Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent derivatives alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl; Substituents for the alkyl groups (including those often referred to as alkyl groups) are selected from, but not limited to: There may be one or more of the various groups: -OR', with a number ranging from zero to (2m'+l). =O, =NR', =N-OR', -NR'R”, -SR', -halogen, -SiR'R”R'”, -OC(O)R', -C(O )R', -CO2R', -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", - NR"C(O)OR', -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R R', -CN and -NO2 (where m' is the total number of carbon atoms in such group). , R”, R'” and R”” are each independently hydrogen, substituted or unsubstituted heteroalkyl; , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or an unsubstituted alkyl, alkoxy, or thioalkoxy group, or an arylalkyl As used herein, an "alkoxy" group refers to a divalent acid. The R group is an alkyl group attached to the rest of the molecule through a bond. For example, each of the R groups may be such that each R', R", R'" and R"" group is R' and R' are independently selected, such that when more than one is present, they are independently selected. When R" are attached to the same nitrogen atom, they combine with the nitrogen atom to form 4-, 5-, 6-, or 7-membered rings. For example, -NR'R" includes, but is not limited to, 1- From the above discussion of substituents, one skilled in the art will recognize that 4-morpholinyl is intended to include pyrrolidinyl and 4-morpholinyl. Some consider the term "alkyl" to include haloalkyl (e.g., -CF3 and -CH2CF3 ) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.) It will be understood that this is meant to include groups that contain a carbon atom bonded to another group.

[0092] Similar to the substituents described above for alkyl groups, aryl and heteroaryl groups Exemplary substituents for (and their divalent derivatives) are varied and may be selected from, for example: A number of halogen atoms ranging from zero to the total number of open valences in the aromatic ring system. -OR', -NR'R", -SR', -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -C(O)N R’R”, -OC(O)NR’R”, -NR”C(O)R’, -NR’-C(O)NR”R’”, -NR”C(O)OR’, -NR-C(N R'R"R'")=NR"", -NR-C(NR'R")=NR'" -S(O)R', -S(O)2R', -S(O)2NR'R", - NRSO2R', -CN and -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxo, and fluoro wherein R', R", R'" and R"" are independently 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 heptane. When a compound of the invention contains more than one R group, For example, each of the R groups may be a substituted or unsubstituted aryl group, with each R', R", R'" and R"" group being substituted or unsubstituted with two or more of these groups. If there is an above, it is independently selected, so that it is independently selected.

[0093] Two substituents on adjacent atoms of an aryl or heteroaryl ring are of the formula -TC(O)-(CRR') q A ring of -U- may optionally be formed, wherein T and U are independently -NR-, -O-, - CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, an aryl ring or a heterocyclic group Two substituents on adjacent atoms of the heteroaryl ring have the formula -A-(CH2) r -B- substituted In the formula, A and B may independently represent -CRR'-, -O-, -NR-, -S-, -S(O)-, or -S(O)2-. , -S(O)2NR'- or a single bond, and r is an integer from 1 to 4.

[0094] One of the single bonds of the new ring thus formed is optionally replaced with a double bond. Alternatively, two aryl or heteroaryl rings may be bonded to adjacent atoms. The substituent has the formula -(CRR') s -X'- (C"R'") d - may be substituted with a substituent, , s and d are independently an integer of 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, - The substituents R, R', R" and R'" are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; It is possible.

[0095] As used herein, the term "acyl" means an organic acid group, where The —OH of the carboxyl group is replaced by another substituent, and has the general formula RC(═O)— (wherein R is alkyl, alkenyl, alkynyl, aryl, carbocyclic, As such, the term "acyl" is used to refer to a heterocyclic or aromatic heterocyclic group. (acyl)" specifically includes 2-(furan-2-yl)acetyl- and 2-phenylacetyl Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also include amides, -RC(=O)NR', ​​esters, -RC(=O)OR', ketones, , -RC(=O)R' and aldehyde, -RC(=O)H.

[0096] The terms "alkoxyl" and "alkoxy" are used interchangeably herein. used interchangeably and are saturated (i.e., alkyl-O- ) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) groups, wherein: The terms "alkyl," "alkenyl," and "alkynyl" " is as described above, for example, C 1-20 Inclusive, linear, branched or cyclic, saturated or may contain unsaturated oxo-hydrocarbon chains, e.g., methoxy, ethoxy, propoxy, n-butoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n- These include pentoxyl, neopentoxyl, and n-hexoxyl.

[0097] As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkoxy group. means an alkyl ether, for example a methoxyethyl or ethoxymethyl group.

[0098] "Aryloxyl" means an aryl-O- group, where the aryl The groups are as described above, including substituted aryl. As used herein, the term "aryl" is "Aryloxyl" refers to phenyloxyl or hexyloxyl, and alkyloxyl. phenyloxyl, substituted alkyl, halo or alkoxyl substituted phenyloxyl or hexyloxyl It can also mean "ru."

[0099] "Aralkyl" means an aryl-alkyl group, where aryl and and alkyl are as previously described, including substituted aryl and substituted alkyl. Aralkyl groups include benzyl, phenylethyl and naphthylmethyl.

[0100] "Aralkyloxyl" means an aralkyl-O- group, where The aralkyl group is as described above. An exemplary aralkyloxyl group is benzyl oxyl, i.e., C6H5-CH2-O-. Aralkyloxyl groups are optionally substituted This may be the case.

[0101] "Alkoxycarbonyl" means an alkyl-OC(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

[0102] "Aryloxycarbonyl" means an aryl-OC(=O)- group Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl groups. Includes Nil.

[0103] "Aralkoxycarbonyl" means an aralkyl-OC(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

[0104] "Carbamoyl" means an amide group of the formula -C(=O)NH2. "Alkylcarbamoyl" means the group R'RN-C(=O)-, where R and R' are One of R and R' is hydrogen and the other of R and R' is alkyl and / or substituted alkyl as defined above. "Dialkylcarbamoyl" means the group R'RN-C(=O)-. wherein each of R and R' is independently alkyl and / or substituted alkyl as described above. It's Rukiru.

[0105] As used herein, the term carbonyldioxyl refers to a group of the formula -OC(=O)- Refers to the carbonate base of OR.

[0106] "Acyloxyl" means the group acyl-O-, where acyl is As described.

[0107] The term "amino" refers to the -NH2 group, which replaces one or more hydrogen radicals with an organic radical. Also meant are nitrogen-containing groups known in the art derived from ammonia substituted with a hydroxyl group. For example, the terms "acylamino" and "alkylamino" )" refer to certain N-substituted organic radicals with acyl and alkyl substituents, respectively. do.

[0108] As used herein, "aminoalkyl" refers to a group covalently attached to an alkylene linker. More specifically, the term alkylamino as used herein refers to an amino group attached to a alkylamino, dialkylamino and trialkylamino hydroxylamino) is a group consisting of one, two, or three amino groups attached to the parent molecular moiety through a nitrogen atom. The term alkylamino means an alkyl group as defined in the structural formula means a group having the formula -NHR', where R' is an alkyl group as previously defined; Dialkylamino means a group having the formula -NR'R", where R' and R" are each independently selected from the group consisting of alkyl groups; Trialkylamino means a group having the formula -NR'R"R"', where R', R'' and R'" are each independently selected from the group consisting of alkyl groups. ' and / or R''' taken together optionally represent -(CH2) k - where k is an integer from 2 to 6. Non-limiting examples include methylamino, dimethylamino, methylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethyl Amino, isopropylamino, piperidino, trimethylamino and propylamino can be.

[0109] An amino group is -NR'R", where R' and R" are typically hydrogen, substituted or Unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0110] The terms alkylthioether and thioalkoxyl represents a saturated (i.e., alkyl-S-) or unsaturated alkyl group attached to the parent molecular moiety through a sulfur atom. (i.e., alkenyl-S- and alkynyl-S-) groups. However, examples of thioalkoxyl moieties include methylthio, ethylthio, propylthio, and ethylthio. Examples include isopropylthio and n-butylthio.

[0111] "Acylamino" means the group acyl-NH-, where acyl is as defined above. "Aroylamino" means an aroyl-NH- group, Here, aroyl is as defined above.

[0112] The term "carbonyl" refers to the group -C(=O)- and has the general formula RC(=O)H. It may contain aldehyde groups.

[0113] The term "carboxyl" refers to a -COOH group. Such groups are defined herein as In literature, it is also referred to as the "carboxylic acid" moiety.

[0114] As used herein, the terms "halo," "halide," or "halogen" are used interchangeably. "Halogen" means fluoro, chloro, bromo and iodo groups. Terms such as "haloalkyl" and "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, but not limited to, the term "halo(C1-C4)alkyl" is intended to include alco(C1-C4)alkyl)" means trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutanol, The term "alkyl" is intended to include alkyl, 3-bromopropyl ... and the like.

[0115] The term "hydroxyl" refers to an --OH group.

[0116] The term "hydroxyalkyl" means an alkyl group substituted with an -OH group. Taste.

[0117] The term "mercapto" refers to the group --SH.

[0118] As used herein, the term "oxo" refers to a group that is double-bonded to a carbon atom or other element. This refers to the oxygen atom present.

[0119] The term "nitro" refers to the group --NO.sub.2.

[0120] The term "thio" refers to the compounds previously described herein, wherein the carbon Or the oxygen atom is replaced by a sulfur atom.

[0121] The term "sulfate" refers to the group -SO4.

[0122] The term thiohydroxyl or thiol as used herein means a group of formula -SH.

[0123] More specifically, the term "sulfide" refers to a compound having a group of formula -SR Taste.

[0124] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R.

[0125] The term "sulfoxide" refers to a compound having a sulfinyl group -S(O)R. Taste.

[0126] The term ureido means a urea group of formula -NH-CO-NH2.

[0127] The term "protecting group" in reference to compounds of formula (I) refers to a protecting group that is regenerated in said molecule. Does not attack regenerated functional groups or other functional groups and is readily available A suitable protecting group refers to a chemical substituent that can be selectively removed by a suitable reagent. Suitable protecting groups are known in the art and continue to be developed. Suitable protecting groups are described, for example, in Wutz et al. (“Greene's Protective Groups in Organic Synthesis, 4th Edition” Wiley-Interscience , 2007). As described by Wutz et al. (pp. 533-643) In some embodiments, a protecting group for protecting the carboxyl group is used. In some embodiments, the protecting group is removable by acid treatment. Representative examples of groups include benzyl, p-methoxybenzyl (PMB), tert-butyl (t-Bu), methyl Methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetramethyl Tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BO M), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (T Protecting groups include phenylmethyl (BDMS) and triphenylmethyl (trityl, Tr). Those skilled in the art will recognize that protecting groups are required. Recognizing the appropriate situations for protecting groups allows the user to select the appropriate protecting group for use in a particular situation. It will be possible.

[0128] Throughout the specification and claims, a given chemical formula or name refers to all tautomeric forms. The existence of isomers, homologues and optical isomers and stereoisomers, as well as mixtures of such isomers This includes racemic mixtures.

[0129] Certain compounds of the present invention have asymmetric carbon atoms (optical or chiral centers) or double bonds. enantiomers, racemates, diastereomers ( diastereomers, tautomers, geometric isomers, absolute stereochemically defined as (R)- or (S)-, or as D- or L- of amino acids; The stereoisomers, as well as the individual isomers, which may be defined as The compounds of the present invention are not too unstable to synthesize and / or isolate. The present invention does not include compounds known in the art that cannot be synthesized from racemic It is intended to include compounds in their optically pure, scalemic, and optically pure forms. Optically active (R)- and (S)- or D- and L-isomers are available as chiral synthons or Can be prepared using chiral reagents or resolved using conventional techniques When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, other Unless specified, the compounds are intended to include both E and Z geometric isomers.

[0130] Unless otherwise stated, structures depicted herein also represent all stereochemical forms of said structure. The term "asymmetric center" is intended to include both R and S configurations (i.e., R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric isomers of the compounds of the present invention are contemplated. Mixtures of stereomers are within the scope of the present invention.

[0131] It will be apparent to some skilled in the art that certain compounds of the present invention may exist in tautomeric forms. and all such tautomeric forms of the compounds are within the scope of the present invention. As used herein, the term "tautomer" refers to a compound that exists in equilibrium and has one isomer. It refers to one of two or more structural isomers that are readily converted from one isomeric form to another. Taste.

[0132] Unless otherwise stated, structures depicted herein may contain one or more isotopically enriched atoms. This also includes compounds that differ only in the presence of deuterium or tritium. Substitution of hydrogen by thium, or 13 C- or I4 Books with replacement of carbon by C-rich carbon Compounds having the inventive structures are within the scope of the invention.

[0133] The compounds of the present invention may also contain a non-naturally occurring group at one or more of the atoms that constitute such compounds. For example, the compounds may contain small proportions of atomic isotopes, such as tritium ( 3 H) , iodine-125( 125 I) or carbon-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are , are included within the scope of the present invention.

[0134] The compounds of the present invention may exist as salts. The present invention includes such salts. Examples of suitable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, malate, and the like. Leylate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)- tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates and glutamines These salts include salts of amino acids such as benzoic acid. These salts may be prepared by methods known to those skilled in the art. It can also be manufactured using sodium, potassium, calcium, ammonium, and organic acids. Also included are base addition salts, such as ammonium or magnesium salts, or similar salts of the compounds of the present invention. When a compound contains a relatively basic functional group, the acid addition salt can be converted into a neutral form of the compound by its contacting the compound with a sufficient amount of the desired acid, either as is or in a suitable inert solvent, or by ion exchange; Examples of acceptable acid addition salts are those obtained by addition of hydrochloric acid, hydrobromic acid, nitric acid, Acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate oric), dihydrogen phosphate (dihydrogenphosphoric), sulfuric acid, monohydrogen sulfate (monohydrogensulf salts derived from inorganic acids such as hydroiodic acid or phosphorous acid, as well as acetic acid, propionic acid, Acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, milk Acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid These include salts derived from organic acids such as methyl methyl esters, methanesulfonic acid, etc. Also included are salts derived from alginates, etc. Also included are salts of amino acids and salts of organic acids such as glucuronic acid or galacturonic acid. Certain specific compounds may be converted into either base or acid addition salts. The compound contains both basic and acidic functional groups that allow for

[0135] The neutral forms of the compounds can be readily prepared by contacting the salt with a base or acid to yield the parent compound in the conventional manner. The parent form of the compound can be regenerated by isolating it from the soluble form in polar solvents. It differs from the various salt forms in certain physical properties such as:

[0136] Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. All physical forms are equivalent for the uses contemplated by the present invention and are within the scope of the present invention. Something is intended to be.

[0137] In addition to salt forms, the present invention provides compounds that are in prodrug form. Prodrugs of the compounds described above readily undergo chemical changes under physiological conditions to give the compounds of the present invention. Furthermore, prodrugs can be synthesized by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be converted to compounds of the present invention by suitable methods. The compounds of the present invention can be used to induce the production of steroid hormones and steroid hormones by the use of suitable enzymes or chemical reagents when placed in a transdermal patch reservoir. You can also convert it slowly.

[0138] Following long-standing patent law practice, the terms "a," "an," and "the" are used to refer to the claims. When used in this application, including "one or more," it means "one or more." For example, the reference to "a subject" is not necessarily inappropriate unless the context clearly indicates otherwise (e.g., multiple subjects). A plurality of subjects, unless the subject is a plurality of subjects ects) etc.

[0139] Throughout this specification and claims, except where the context requires otherwise, The terms "comprise", "comprises" and "comprising" mean Similarly, the term "include" and its grammatical variations are used in a non-exclusive sense. are intended to be non-limiting, and the listing of items in a list does not necessarily imply the existence of any of the listed items. This does not exclude other similar items which may be substituted for or added to the above.

[0140] For purposes of this specification and the appended claims, unless otherwise indicated, Any amounts, sizes, dimensions, proportions, shapes, dosage forms, parameters, parts, etc. used in the claims All numbers expressing percentages, amounts, characteristics and other numerical values ​​are preceded by the word "about." In all cases, the word "about" is used even if it does not explicitly appear with the value, amount or range. " should be understood to be modified by the term ". Therefore, the opposite is not indicated. Unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims While not exact and need not be exact, the results obtained by the invention disclosed herein are Depending on the desired characteristics that need to be achieved, tolerances, conversion factors, rounding, measurement errors, etc. As close as desired, taking into consideration factors such as the amount of heat generated and the amount of heat generated, and other factors known to those skilled in the art. and / or greater than or less than. For example, when referring to a value, the term " "About" refers to a range of from the specified amount, in some embodiments, ±100%, and in some embodiments, ±50%. %, in some embodiments ±20%, in some embodiments ±10%, and in some embodiments ±5% , in some embodiments ±1%, in some embodiments ±0.5%, in some embodiments ±0.1% and such variations are intended to encompass variations of the method of the present invention. It is suitable to carry out and use the compounds of the present invention.

[0141] Additionally, the term "about" is used in connection with one or more numbers or numerical ranges. When a range is used, it is understood to mean all values, including all values ​​within the range. should not modify the range by extending the upper and lower boundaries of the stated numerical values. Writing a numerical range by endpoints includes all values ​​subsumed within that range. Numbers, e.g. whole integers, including fractions thereof (e.g. writing 1 to 5 is not 1, 2, 3, Includes 4 and 5, as well as their fractions (e.g., 1.5, 2.25, 3.75, 4.1, etc.) , and any range therein. [Example]

[0142] The following examples are provided to illustrate exemplary embodiments of the invention disclosed herein. The present invention and the general principles of the art are included to provide guidance to those skilled in the art. In light of the level, those skilled in the art will recognize that the following examples are merely illustrative and will not be construed as limiting the scope of the invention as set forth herein. Numerous changes, modifications and variations may be made without departing from the scope of the disclosed invention. The following synthetic descriptions and specific examples are for illustrative purposes only. is intended and should not be construed as limiting other methods for preparing the compounds of the invention. It should not be.

[0143] Example 1 Abstract Chelated PSMA for imaging and possible radiotherapy of tumors expressing PSMA The use of PSMA-conjugated ureas conjugated to radiometals via various linking groups has been previously reported. It has been reported in several patent applications and publications (Tykvart et al. (2015) Journal of medic inal 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 High affinity binders are prepared by modifying the urea linker at the ε-amine position with a p-Br-benzyl group. The structures of the compounds of the present invention are shown in Figure 1.

[0144] Without wishing to be bound by any particular theory, it is believed that the isomerization of the lysine in the Lys-Glu urea moiety When the psilon amino group was modified with a p-Br-benzyl group, it was possible to target prostate-specific membrane antigen (PSMA). Glu-lysine urea-based theranostics targeting radioactive metals Anostic drugs have high binding affinity to PSMA and are highly uptaken in PSMA-expressing tumors. This suggests that the drug exhibits low renal uptake in standard mouse models of prostate cancer. In one embodiment, 177 Lu-1 inhibited the proliferation of PSMA + PC3 tumor-bearing mice. The radiotherapy showed a significant effect, with a remission rate of approximately 50%.

[0145] Example 2 Materials and Methods Chemical synthesis of 1. The synthesis of compound 1 is described in Scheme 1. Bromobenzaldehyde (121.0 mg, 0.654 mmol) was added to the Boc-protected urea 4 (300 The solution was slowly added to a stirred solution of 1.0 mg (0.615 mmol) of chloroform and allowed to warm to room temperature. After 1 hour, Sodium borohydride (158.0 mg, 2.5 mmol) was added and the reaction was left stirring overnight. The crude reaction mixture was evaporated, redissolved in dichloromethane, and purified by normal phase silica chromatography. The product was purified in a solvent (95:5, methylene chloride:methanol) and dried in vacuo to give 5 in good yield. Obtained. Yield: 80%. ESI-MS: 656.56 [M+H] + , Actual value: 656.5. TSTU (32.6 mg, 108 μmol), Boc-5-aminovaleric acid (23.5 mg, 108 μmol) and DIPEA (37.7 μL, 216 μmol) ) was dissolved in 300 μL of DMF and stirred at room temperature. After 1 hour, compound 5 (71.0 mg, 108 (μmol) was added with three rinses of DMF (50 μL each). The reaction mixture was stirred for 4 h. The crude reaction mixture was then cooled to 4°C and stored overnight at 4°C. 18 Purified by semi-preparative HPLC on a column (40% water (0.1 TFA) / 60% ACN (0.1 TFA) / 5 min, 60-90%, over 20 min). R t teeth twenty one The purified fractions were combined, evaporated, and dried under high vacuum for 10 minutes. ESI-MS: 572. 44 [M+H]+, found: 572.4. Compound 6 was dissolved in dichloromethane (1.5 mL) and cooled in an ice bath. After equilibration, TFA (1.5 mL) was added and the mixture was stirred for 3 h, allowing the temperature to rise to room temperature during the process. The mixture was dried under a stream of nitrogen, dissolved in water, and lyophilized to give compound 7 (31. 8 mg was obtained. Yield: 54 μmol, 54%. 6 (12.2 mg) in DMSO (130 μL) equilibrated to 40 °C was dissolved in 100 mL of DMSO. To a stirred solution of p-SCN-bn-DOTA (12.2 g of TFA salt) and DIPEA (15.2 μL, 87.0 μmol) mg, 17.7 μmol) was added. The reaction mixture was stirred at 40 °C for 4 h and then stored at 4 °C overnight. The reaction mixture was purified by reverse-phase HPLC (20% ACN for 5 min, followed by 19 min. The Rt was approximately 12 minutes. The purified fractions were combined and rotary evaporated to a volume of The resulting mixture was reduced in volume and then freeze-dried. ESI-MS: 1138.37 [M+H] + , measured value: 1138.5. Product 1 was further purified by HPLC using a gradient method. The HPLC method consisted of a mobile phase of 88% Water (containing 0.1% TFA) and 22% CH3CN (0.1% TFA) for 1 to 5 minutes, then 88% Water (containing 0.1% TFA) and 12% CH3CN (0.1% TFA) for 0 to 5 min, and % water to 44% water and 12% acetonitrile to 56% acetonitrile at a flow rate of 8 mL / min. The gradient method includes 5 to 25 minutes.

[0146] Chemical synthesis of 2. This compound was synthesized using the same intermediate 7 and was synthesized using commercially available DOTA-NHS esters. ESI-MS: 974.86 [M+H] + , Actual value: 974.5.

[0147] Chemical synthesis of 3. This compound was synthesized using intermediate 4 and commercially available Boc-5-aminovaleric acid and coupled with DOTA-NHS ester. ESI-MS: 970.05 [M+H] +, Actual measurement: 970.1 .

[0148] 177 Radiolabeling of Lu-1. 1.0 μl of 0.1 N HCl 177 LuCl3 (1 mCi) was added to 70 μl of NH4OAc buffer (0.2 M, pH 4) and made up to 5 μl of 2 mM in 0.2 M NH4OAc. The pH of the mixture was about 4.0. The mixture was heated at 80°C for 1 hour. The HPLC method consisted of a mobile phase of 77% water (containing 0.1% TFA) and 23% ethanol. % CH3CN (0.1% TFA) for 1 to 5 min, followed by 77% to 57% water for 5 to 25 min. and 23% to 43% acetonitrile; 25.01 to 30 min, 5% to 5% water and 9 5% to 95% acetonitrile, 30.01 to 37 min, 77% to 77% water and 23% The gradient was from 0.05 to 23% acetonitrile. Flow rate: 1.0 ml / min; λ: 200 nm; C8 column (25 × 4.6 mm), Varian microsob-MV 100-5. 177 Lu-1 is 17. It eluted between 1 and 20 min, whereas the unlabeled chelator eluted between 21 and 22 min.

[0149] The HPLC method comprises: 177 Lu-2 and 177 The HPLC method used to prepare Lu-3 was The mobile phase was 88% water (containing 0.1% TFA) and 22% CH3CN (containing 0.1% TFA) for 1 to 5 minutes. , followed by 88% to 75% water and 12% to 25% acetonitrile from 5 to 27 minutes; 7.01 to 32 min, 5% to 5% water and 95% to 95% acetonitrile, 32.01 to A gradient containing 88% to 18% water and 12% to 22% acetonitrile was used from 88 to 37 min. Flow rate: 1.0 ml / min; λ: 200 nm, C8 column (25 × 4.6 mm), Varian microsob-MV 1 00-5. radioactive label 177 Lu-2 eluted from 13.1 to 15.0 min, and the unlabeled chelator eluted from 16. It was eluted at 17 minutes from the initial stage. 177 Lu-3 eluted between 13.1 and 15.0 min and was unlabeled. The labeling agent eluted at 10-12 minutes and 18-20 minutes, while the unlabeled drug eluted at 14-16 minutes. Eluted.

[0150] Scheme 1. Synthesis of Compound 1 [ka] a. 4-Bromobenzaldehyde, NaBH3CN, MeOH, 1% acetic acid; b. BocNH(CH2)4CO2H, HATU, DIEA, DMF; c. TFA / CH2Cl2; d. DOTA-Bn-SCN, DMSO, DIEA

[0151] Example 3 Results and Discussion Chemical and radiochemical synthesis and characterization. Literature procedures (Tykvart et al. (2015) Journal of According to the method of the Journal of Chemistry 58, 4357-63, the p-bromobenzyl group of Glu-Lys urea (2) was The modified product was treated with p-bromomethylpropanol in the presence of sodium cyanoborohydride in methanol. The compound was prepared in good yield by reductive alkylation of 2 with benzaldehyde to give 4. The small aliphatic linker Boc-5-aminovaleric acid was then attached to the same ε-Lys amine of 4. The BOC group was then removed, and commercially available DOTA-Bn-SCN was conjugated with 6, resulting in a moderate The compound 2 was obtained with a yield of 1. The compound 2 was obtained using DOTA-NHS ester as the chelating agent. Compound 3 was synthesized by coupling with the same intermediate 6. A control compound was synthesized without any benzyl groups. All three compounds were then heated at 80°C in ammonium acetate. in ethanol buffer at pH 4 in good yield and purity. 177 The novel compound was radiolabeled with Lu. The binding affinities of 1 and 2 modified with p-bromo-benzyl groups are shown in Table 1. Both 1 and 2 were similar to 3. It showed a relatively high binding affinity.

[0152] [Table 1]

[0153] Cell-binding properties. 177 Lu agents were administered to standard syngeneic cell lines, PSMA+ PC3 PIP and PSMA-negative PC3 PIP. The effect was further evaluated in cells and animals using PC3 flu cells. 177 Lu-1 and 177 Both Lu-2 teeth, 177 It showed higher uptake in PSMA+ PC3 cells compared to Lu-3. When studying internal migration, 177 Lu-1 177 The internalization activity is nearly twice as high as that of Lu-3. All three drugs were found to be effective in PSMA-negative PC3 flu cells. showed significantly lower uptake. 177 Lu-1 was used to assess therapeutic efficacy in clonogenic assays. Further evaluation of the lead compound SR6 (Banerjee et al. (2015) Journal of Nuclear r medicine 56, 628-34) and 177 Lu-PSMA-617(Benesova et al. (2015) Journal of nucl Ear Medicine 56, 914-20) and 177 Lu PSMA-I&T (Weineisen et al. (2014) EJNMMI Res 4, 1-15) were compared with drugs currently in clinical trials. 177 Lu-1 inhibited the expression of PSMA in PC3 PIP cells. A 10 μCi dose was used to produce approximately 100% cell killing, whereas PSMA-PC3 No significant toxicity was observed against flu cells.

[0154] [Table 2]

[0155] Biodistribution. 177 Lu-1 and 177 In vivo tissue biodistribution studies were performed on Lu-2. The results are listed in Tables 3 and 4. PSMA+ PC3 PIP tumor uptake 177 Lu-1 is 177 It showed significantly higher uptake and retention than Lu-2. 177 Lu-2 agents are 177 5 than Lu-1 As shown in Figure 3, the tumor / kidney uptake of the compound of the present invention was 2-fold lower than that of the previous study. Card 177 Lu-SR6, 177 Lu-PSMA-617 and 177This was compared with that of Lu-PSMA-I&T. 177 Lu-2 PSMA+ PC3 PIP tumor-to-kidney ratio 177 Higher tumor uptake than Lu-1 and retention were shown, 177 Lu-1 was investigated in a pilot study using a small group of animals. This will further enhance theranostic efficacy (imaging and therapeutic effects). Evaluated.

[0156] [Table 3]

[0157] [Table 4]

[0158] SPECT imaging and treatment effects in small animals. Figure 4 shows the results of treatment over 1 to 8 days after injection. During the research period 177 SPECT imaging of Lu-1. PSMA+ PC3 PIP Tumor-bearing mice (n = 10) with tumors (3-5 mm in size) were administered a single dose of 3 mCi via tail vein injection. As a control, saline was administered to another group of mice (n = 10). Mice were monitored twice daily by measuring body weight and tumor size. Control mice showed no significant changes in tumor size. The animals were euthanized after 4 to 8 weeks because their length exceeded 12 mm. The tumors were completely eradicated in the mice. After 2 weeks, the mice regained their original weight and were initially The results are shown in Figure 5. Figures 6A and 6B show the results of the treatment compared to the control group using saline. Compared, 177The therapeutic efficacy of Lu-1 (reduced tumor volume) was demonstrated. Complete disease remission was observed in five mice. The patient is in remission and has been alive for over five months.

[0159] In summary, the epsilon-amino group of the lysine in the Lys-Glu-urea moiety is converted to a p-Br-benzyl group. When modified with chelated radiometals, they target prostate-specific membrane antigen (PSMA). Glu-lysine urea-based theranostic agents target PSMA-expressing It exhibits high binding affinity and uptake for PSMA in tumors with prostate cancer, In a mouse model, it showed low renal uptake. 177 Lu-1 is showed a significant radiation therapy effect, with approximately 50% remission in mice bearing PSMA+ PC3 tumors. .

[0160] References All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The invention disclosed herein is indicative of the level of ordinary skill in the art to which it pertains. All publications, patent applications, patents and other references (e.g. websites, databases, Each publication, patent application, patent, and other reference is specifically and individually cited. and to the extent that it is indicated that the invention is incorporated by reference in its entirety. Incorporated by reference. Numerous patent applications, patents and other references are cited herein. Although such references are provided, none of these documents are of common general interest in the art. It is understood that no admission is made that any of the foregoing forms part of the general knowledge of the present invention. In the event of a conflict between the present specification (which may be governed by the incorporated references) and the Unless otherwise specified herein, To the extent possible, standard, art-accepted meanings of terms are used. Use standard abbreviations for terms.

[0161] 1.International PCT Patent Application Publication No. PCT / US2008 / 007947 to Po mper, MG, Ray, S., Mease, RC, Foss, C. for Labeled inhibitors of prostate sp. ecific membrane antigen (PSMA), biological evaluation, and use as imaging agents , published 2008 / 12 / 31 (WO 2009 / 002529 A2); 2.International PCT Patent Application Publication No. PCT / US2008 / 013158 to Ch. andran SS, Ray S., Denmeade SR, Pomper MG, Mease RC for Prostate specifi c membrane antigen targeted nanoparticles for therapy of prostate cancer, publis hed 2009 / 06 / 04 (WO 2009070302 A1); 3.International PCT Patent Application Publication No. PCT / US2010 / 028020 to Po mper MG, Mease RC; Ray S., Chen Y. for PSMA-targeting compounds and uses th ereof, published 2010 / 09 / 23 (WO 2010108125 A2); 4.Banerjee, S. R., Foss, C. A., Pullambhatla, M., Wang, Y., Srinivasan, S., Ho bbs, R. F., Baidoo, K. E., Brechbiel, M. W., Nimmagadda, S., Mease, R. C., Sgour os, G., and Pomper, M. G. (2015) Preclinical evaluation of 86Y-labeled inhibitor s of prostate-specific membrane antigen for dosimetry estimates. Journal of nucl ear medicine 56, 628-34; 5.Benesova, M., Schafer, M., Bauder-Wust, U., Afshar-Oromieh, A., Kratochwil, C., Mier, W., Haberkorn, U., Kopka, K., and Eder, M. (2015) Preclinical Evaluati on of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. Journal of nuclear medicine 56, 914-20; 6.Tykvart, J., Schimer, J., Jancarik, A., Barinkova, J., Navratil, V., Starkov a, J., Sramkova, K., Konvalinka, J., Majer, P., and Sacha, P. (2015) Design of H ighly Potent Urea-Based, Exosite-Binding Inhibitors Selective for Glutamate Carb oxypeptidase II. Journal of medicinal chemistry 58, 4357-63; 7. 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.

[0162] The foregoing invention has been described in some detail by way of illustration and example for clarity of understanding. However, it will be apparent to those skilled in the art that changes and modifications may be practiced within the scope of the appended claims. will be understood.

Claims

1. Compounds of formula (I): 【Chemistry 1】 where: Z is tetrazole or CO 2 Q is; 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 and R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline. Re; L is C 1 -C 6 Alkylene and C 3 -C 6 From the group consisting of cycloalkylene and arylene is a selected linker; W is -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 - selected from the group consisting of wherein each occurrence of L and W may be the same or different; R 2 is H or C 1 -C 4 is alkyl; n is an integer selected from the group consisting of 1, 2 and 3; Ch is a chelating agent that can contain a metal or radioactive metal; and pharmaceutically acceptable salts thereof.

2. R 1 but the following: 【Chemistry 2】 wherein X is independently Br or I; 2. The compound of claim 1 selected from the group consisting of:

3. The chelating agent is selected from the group consisting of: 【Transformation 3】 2. The compound of claim 1 selected from the group consisting of:

4. The metal chelating agent is selected from the group consisting of Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, 10. The compound of claim 1, comprising a metal selected from the group consisting of Re, Ho, and Sc.

5. The metal is a radioactive metal, and 68 Ga, 64 Cu, 86 Y, 90 Y, 89 Zr, 111 In, 99m Tc, 17 7 Lu, 153 Sm, 186 Re, 188 Re, 67 copper, 212 Pb, 225 Ac, 213 Hi, 212 Hi, 212 Pb, 67 No, 203 Pb, 4 7 Sc and 166 The compound of claim 4 selected from the group consisting of Ho.

6. The compound of formula (I) is 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 2. The compound of claim 1 selected from the group consisting of:

7. contacting one or more PSMA-expressing tumors or cells with an effective amount of a compound of formula (I) wherein the compound of formula (I) is 【Chemistry 15】 where: Z is tetrazole or CO 2 Q is; 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 and R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline. Re; L is C 1 -C 6 Alkylene and C 3 -C 6 From the group consisting of cycloalkylene and arylene is a selected linker; W is -NR 2 -(C=O)-, -NR 2 -(C=S)-, -(C=O)-NR 2 -, and -(C=S)-NR 2 - selected from the group consisting of wherein each occurrence of L and W may be the same or different; R 2 is H or C 1 -C 4 is alkyl; n is an integer selected from the group consisting of 1, 2 and 3; Ch is a chelating agent containing a radioactive metal suitable for radiotherapy; and pharmaceutically acceptable salts thereof, 1. A method for treating a tumor or cell that expresses one or more PSMAs, comprising:

8. R 1 but the following: 【Chemistry 16】 wherein X is independently Br or I; 8. The method of claim 7, selected from the group consisting of:

9. The chelating agent is selected from the group consisting of: 【Chemistry 17】 8. The method of claim 7, selected from the group consisting of:

10. The radioactive metal is: 90 Y, 177 Lu, 211 At, 111 In, 153 Sm, 186 Re, 188 Re, 67 Cu, 2 12 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb and 67 Ga The method described.

11. The compound is selected from the group consisting of: [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 ; 8. The method of claim 7, selected from the group consisting of:

12. The one or more PSMA-expressing tumors or cells are selected from the group consisting of: prostate tumors or cells, metastatic tumors or cells, and prostate tumors or cells, lung tumors or cells, kidney tumors or cells, glioblastoma, pancreatic tumors or cells cysts, bladder tumors or cells, sarcomas, melanomas, breast tumors or cells, colon tumors or cells, reproductive cells, pheochromocytoma, esophageal tumor or cells, gastric tumor or cells, and combinations thereof 8. The method of claim 7, wherein the compound is selected from the group consisting of:

13. 2. The method of claim 1 , wherein the one or more PSMA-expressing tumors or cells are prostate tumors or cells.

7. The method according to claim 7.

14. The one or more PSMA-expressing tumors or cells are in vitro, in vivo, or ex vivo The method of claim 7, wherein

15. 8. The method of claim 7, wherein the one or more PSMA-expressing tumors or cells are present in a subject. How to do it.

16. 16. The method of claim 15, wherein the subject is a human.

17. 8. The method of claim 7, wherein said method results in inhibition of growth of said tumor.

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