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

Abstract

To provide prostate-specific membrane antigen targeted high-affinity agents for endoradiotherapy of prostate cancer.SOLUTION: The invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. (In the formula: Z is tetrazole or CO2Q; Q is H or a protecting group; L is a linker selected from the group consisting of C1-C6 alkylene and C3-C6 cycloalkylene, and arylene; W is -NR2-(C=O)-, -NR2-(C=S)-, or the like; and Ch is a chelating agent that can comprise a metal or radiometal.)SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Application No. 62 / 512,515, filed May 30, 2017. and is incorporated herein by reference in its entirety.

[0002] [Federally funded research or development] This invention was made in accordance with grants K25CA148901-01A1 and U5 from the National Institutes of Health (NIH). This invention was made with government support under 4CA1346751. The U.S. Government has certain rights in this invention. do.

[0003] Prostate cancer is the leading cancer in the U.S. population and the second leading cause of cancer deaths in men. Treatment of locally advanced disease remains controversial, with an increasing number of Different options are becoming available. New, high-affinity, radioactive materials for prostate cancer. Radiotherapy agents have been developed using prostate-specific membrane antigen (PSMA) as a target. PSMA is a marker for androgen-independent disease, which is the development of solid (non-prostate) tumors. It is also expressed in the vasculature. Summary of the Invention [Means for solving the problem]

[0004] [summary] In one embodiment, the subject of the present invention is 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 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 be 2 is H or C1-C4 alkyl; n is selected from the group consisting of 1, 2 and 3. is an integer selected; Ch is a chelating agent that can contain a metal or a radioactive metal; and pharma- ceutically acceptable salts thereof.

[0005] In a particular 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 embodiment of the compound of formula (I), the chelating agent is: [ka] is selected from the group consisting of:

[0007] In another aspect, the subject invention provides a method for treating one or more PSMA-expressing tumors or cells by administering an effective amount of with a compound of formula (I) of : [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 H, -CH-R 1 ;R 1 is substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is C1-C6 A aryl group selected from the group consisting of alkylene, 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 radiation therapy; and A physiologically acceptable salt, The present invention provides a method for treating a tumor or cell that expresses one or more PSMAs, comprising:

[0008] In another aspect, the subject invention relates to one or more prostate specific membrane antigen (PSMA) tumors or cells. The present invention provides a method for imaging a tumor or cell comprising administering to a subject a subject a therapeutically effective amount of a compound of the formula: (I) and imaging.

[0009] In yet another aspect, the present subject matter provides kits comprising a compound of formula (I).

[0010] Certain aspects of the subject matter of the invention described hereinabove are wholly or partly subject to the invention. Thus, other aspects are best explained below in the accompanying examples and drawings. This will become clear as it is described in relation to the above. [Brief description of the drawings]

[0011] Having now described the subject matter of the invention in general terms, reference is made to the accompanying drawings, in which, although not necessarily in a specific form, Not drawn to scale. Here: [Figure 1] Figure 1 shows the chemical structures of representative radiotherapy agents; [Diagram 2] Figure 2 shows a comparative study of the efficacy of 177Lu-8 and known agents SR6, PSMA-617 and PSMA-I&T on clonogenesis; [Diagram 3] Figure 3 shows the distribution ratio of 177Lu-8, 177Lu-1, 177Lu-SR6, 177Lu-PSMA-617 and 177Lu-PSMA-I&T to PSMA+ tumors relative to kidney; [Figure 4] Figure 4 shows SPECT-CT imaging of 177Lu-8 during a therapeutic study using a single dose of 3 mCi; [Diagram 5] Figure 5 shows the relative body weights of mice during the treatment study; [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); [Figure 7]Figure 7 shows (left) in vitro cellular uptake of 213Bi-1 at 37°C. Specific cellular uptake in PSMA(+)PC3 PIP cells (blue) and PSMA(-)PC3 flu cells (black) and when blocked with 1 mM ZJ43 (red). (middle and right) Specific cell killing for 213Bi-1 and 225 Ac-1 after 2 hours at 37°C; [Figure 8] Figure 8 shows tissue biodistribution of 213Bi-1 (% ID / g); [Figure 9] Figure 9 shows the efficacy of 225Ac-1 in the PSMA+ PIP flank tumor model (male NSG mice) (top). (middle) Changes in body weight during the treatment trial. (bottom) Kaplan-Meier survival curves of the treatment trial using the micrometastatic PC3-ML-Luc-PSMA model, median survival of 51 days (untreated) vs. 52 days for 177Lu-PSMA-617 (37 MBq), 56 days for 225Ac-1 (37 kBq), and 79 days for 225Ac-1 (74 kBq); [Figure 10] Figure 10 shows SPECT-CT imaging (top) and tissue biodistribution data (bottom) of 203Pb-2 and 203Pb-3 (14.8 MBq.). T+: PSMA(+) PC3 PIP, T(-) PC3 flu; [Figure 11] Figures 11A, 11B, 11C, 11D, and 11E show the distribution of 0.37 MBq 225Ac-1 (A) and 1.85 MBq 213Bi-1 (+2 nmol 9) (B) in PSMA+ PC3 PIP tumors (T) and kidneys (K) as documented by alpha camera imaging. Co-injection with 2 nmol 9 specifically cleared activity from the renal cortex but not from PSMA+ tumors. (C) IHC of 225Ac-9 treated PSMA+ tumors shows reduced PSMA-expression after 24 hours compared to untreated PSMA+ tumors, (D, E) PSMA+ staining (IHC) after 2 hours of kidneys from the same mice as in (A); [Figure 12] Figure 12 shows the biodistribution of 177Lu-1 with increasing amounts of 1, demonstrating that it is a partial renal blocking ligand at 2 hours; [Figure 13] Figures 13A and 13B show (Figure 13A) the first patient with extensive metastatic disease scanned with type I (with high tumor and kidney uptake) and type II (with high tumor and low kidney uptake) contrast agents at 2 hours post-injection, and (Figure 13B) 68Ga-2, including sub-centimeter perihilar and thoracic lymph nodes (axial panel, arrows) (left) (Reference 34); selected 68Ga / 177Lu-labeled PSMA-binding agent (right); [Figure 14] FIG. 14 shows comparative cellular uptake and internalization data for selected compounds (head-to-head comparison study); [Figure 15] Figure 15 shows comparative tissue biodistribution data for selected compounds (head-to-head comparison study); [Figure 16] Figure 16 shows comparative tissue biodistribution data for selected compounds (head-to-head study, also shown in Figure 15 ); [Figure 17] FIG. 17 shows the biodistribution data of 177Lu-1, 177Lu-7, 177Lu-8, 177Lu-9, 177Lu-10, and 177Lu-14; [Figure 18] Figures 18A and 18B show SPECT / CT imaging with 177Lu-1 (37 MBq) (Figure 18A); Figure 18B. Immunohistochemistry for PSMA expression in PC3 PIP tumors administered without or with 37 MBq of 177Lu-1; [Figure 19] FIG. 19 shows SPECT / CT imaging after intravenous administration of 177Lu-14; [Figure 20] FIG. 20 shows partial autoblockade of 177Lu-1 and 177Lu-9 2 hours after injection; [Figure 21]Figures 21A and 21B show radionuclide therapy with PSMA-based 177Lu-labeled low molecular weight agents 177Lu-1, 177Lu-3, 177Lu-5 and 177Lu-PSMA-617. Tumor growth inhibition (Figure 21A) and survival (Figure 21B) after a single dose of ~111 MBq of individual agents via tail vein injection and control saline injection (n = 10 for 177Lu-1, 177Lu-3, 177Lu-5, n = 9 for 177Lu-PSMA-617). Relative tumor volumes and body weights of individual mice are shown after 4 and 8 weeks of treatment; [Figure 22] FIG. 22 shows the relative volume, weight and survival rate (%) of 111 MBq of 177Lu-PSMA-617 and 177Lu-1; [Diagram 23] Figure 23 shows hemoglobin and blood counts 8 weeks after radiation therapy with 177Lu-1, 177Lu-3, 177Lu-5, 177Lu-PSMA-617. Data are mean ± SEM, n = 3 / group; [Figure 24] Figure 24 shows 177Lu-1 radionuclide therapy after a single dose of 111 MBq administered via tail vein injection, followed by a saline control injection (n = 10 for 177Lu-1, 177Lu-3, 177Lu-5, n = 9 for 177Lu-PSMA-617). Relative tumor volumes and body weights of individual mice are shown after 4 and 8 weeks of treatment; and [Diagram 25]25A, 25B, 25C, 25D, and 25E show hematoxylin and eosin (H&E) staining. (25A, 25B, 25C) Extraorbital lacrimal gland, 25A. Control untreated; 25B. Adjacent parotid gland (arrowhead); 25C. Higher magnification of 25B showing acinar loss with chronic and active inflammation affecting the lacrimal gland (177Lu-PSMA-617) (25D and 25E). Testis 25D. Control untreated, active spermatogenesis, some tubules (arrowheads) contain only Sertoli cells. This is expected near the rete testis; 25E. No spermatogenesis, diffuse seminiferous tubules smaller than A (same magnification), aligned with only Sertoli cells, some tubules with a few germ cells. In this specimen, interstitial cells are prominent between the tubules. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] [Detailed Description] The subject matter of the present invention will be described more fully hereinafter with reference to the accompanying drawings, in which: Some, but not all, embodiments of the invention disclosed in the specification are shown. The present subject matter may be embodied in many different forms. and should not be construed as being limited to the embodiments set forth herein; rather These embodiments are provided so that this disclosure will satisfy applicable legal requirements. having the benefit of the teachings presented in the foregoing descriptions and the accompanying drawings, and which relate to the subject matter of the present invention. Those skilled in the art will recognize that many modifications and other implementations of the invention disclosed herein are possible. Accordingly, the invention disclosed herein is not limited to the specific embodiments disclosed. The present invention is not limited to the above embodiment, and modifications and other embodiments are within the scope of the appended claims. It should be understood that the disclosure is intended to be provided in a manner that is consistent with the principles of the present invention.

[0013] I. Prostate-specific membrane antigen-targeted high-density cytoplasmic reductase (HSCA) for internal radiotherapy of prostate cancer Affinity drugs

[0014] A. Compounds of Formula (I)

[0015] Thus, in one embodiment, the subject of the present invention is 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 H or -CH-R 1 Yes R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is 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 an integer selected from the group consisting of a chelating agent that can contain a metal or a radioactive metal. and pharma- ceutically acceptable salts thereof.

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

[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 a further specific embodiment of the compound of formula (I), the chelator is Selected from the group consisting of 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 metals, such as: 68 Ga, 64 Cu, 86 Y, 90 Y, 89 Zr, 111 In, 99m Tc, 177 Lu, 153 Sm, 186 R e, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 67 Ga, 203 Pb, 47 Sc and 166 Ho is selected from the group consisting of:

[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 PSMA How to use

[0022] In one embodiment, the subject invention relates to a method for the treatment of tumors or cells expressing one or more PSMA. said compound of formula (I) being: below: [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 H or -CH-R 1 Yes R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is 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 an integer selected from the group consisting of a radioactive metal chelator suitable for radiation therapy. and pharma- ceutically acceptable salts thereof. The present invention provides a method for treating a tumor or cell that expresses one or more PSMAs, comprising:

[0023] "Contacting" refers to contacting at least one of the subject therapeutic agents of the present invention. The compound is placed in physical contact with at least one tumor or cell expressing PSMA. Contacting refers to any act of contacting at least one compound with at least and administering to said cell or tumor a compound in an amount sufficient to contact said cell or tumor. The method may include exposing a container, such as a culture dish or tube, to The compound and the cell or tumor are placed in a controlled environment and preferably mixed. The method may be carried out in vitro or ex vivo, depending on the method. In some cases, contacting may involve administering the compound to a subject via any suitable route. At least one cell or tumor of the subject is treated with at least one of the subject's compounds of the present invention, such as by administering the compound to the subject. This means exposure to a compound of

[0024] As used herein, the term "treating" refers to such the disease, disorder or condition to which the term applies, or One or more symptoms or manifestations of such disease, disorder or illness Reverse, mitigate, or inhibit the progression of, or prevent or reduce the likelihood of, Prevention may include preventing or curing a disease, disorder, illness, or any symptom or sign thereof. It means to prevent something from happening or becoming worse in severity. Thus, the compounds of the present invention can be administered prophylactically to prevent or reduce the onset or progression of a disease, disorder, or condition. Recurrence can be prevented or reduced.

[0025] Generally, an "effective amount" of an active agent is that amount sufficient 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 The desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, It may change depending on factors such as:

[0026] The term "combination" is used in its broadest sense and includes at least Two drugs, more specifically a compound of formula (I) and at least one other active drug, More specifically, the term "in combination" refers to a combination of "Bination" refers to the combination of two (or more) active agents, for example for the treatment of a single disease condition. As used herein, the active agent is administered in combination with They may be administered in combination in a single agent, simultaneously as separate agents, or simultaneously. The compounds may be administered as separate agents, either alternating or sequentially, on the same or different days. In certain embodiments of the invention disclosed herein, 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., the amount of one is administered in (It is preferable to vary the amount of one agent and not the other.) The single agent is effective in treating a disease state. The composition may further comprise an active agent for the treatment of

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

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

[0029] In a more specific embodiment, the 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: prostate tumor or cells, metastatic prostate tumors or cells, lung tumors or cells, renal tumors or cells, glioblastomas, Pancreatic tumor or cell, bladder tumor or cell, sarcoma, melanoma, breast tumor or cell, colon tumor or cells, germ cells, pheochromocytoma, esophageal tumor or cells, gastric tumor or cells, and combinations thereof In certain other embodiments, the one or more PSMA The tumor or cell expressing the IL-1 ... is a prostate tumor or cell.

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

[0033] The methods described herein are all intended to be encompassed by the term "subject." It should be understood that the present invention is effective against all vertebrate species, but in many embodiments, The subject to be treated by the method of the present invention is preferably a human subject. "(Subject)" means a drug that treats an existing illness or disease or prevents the onset of an illness or disease. For human subjects for medical purposes, such as prophylactic treatment to prevent, or for medical or veterinary purposes Suitable animal subjects may include animal (non-human) subjects for clinical or developmental purposes. Examples of such animals include, but are not limited to, primates (e.g., humans, monkeys, apes, etc.); bovine animals bovines (e.g. cattle, bulls, etc.); ovines (e.g. sheep) ep); caprines (e.g. goats); porcines (e.g. For example, pigs, hogs, etc.; equines (for example, horses, etc.) ses, donkeys, zebras, etc.); felines (wild and domestic cats); canines (including dogs); lagomorphs agomorphs (including rabbits, hares, etc.); rodents ) (including mice, rats, etc.); and other mammals. The subject may be a transgenic animal. Humans include, but are not limited to, fetuses, neonates, infants, juveniles and adult subjects. In other words, a "subject" is someone who is suffering from or suspected of suffering from a disease or disorder. Thus, the terms "subject" and "patient" are used interchangeably. " are used interchangeably herein.

[0034] In yet certain other embodiments, the method results in 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 another embodiment, the subject invention relates to a method for the treatment of tumors or cells expressing one or more PSMA. and imaging, said method comprising contacting a subject with an effective amount of a compound of formula (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 H, -CH-R 1 in Yes;R 1 is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; L is 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 2is H or C1-C4 alkyl; n is the group consisting of 1, 2 and 3. Ch is an integer selected from the group consisting of a chelator containing a radioactive metal suitable for imaging. and pharma- ceutically acceptable salts thereof. The present invention provides a method for imaging tumors or cells that express one or more PSMAs, comprising: do.

[0037] D.Kit

[0038] In yet other embodiments, the present subject matter provides kits comprising a compound of formula (I).

[0039] In one embodiment, the kit comprises a pharma- ceutically 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 instructions for producing a compound according to the present invention from the provided precursor. 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 use of said compounds for imaging neurotransmission or imaging prostate cancer. and instructions for using said composition for the treatment of a patient suffering from 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 pharma- ceutically acceptable excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of formula (I) in combination with one or more additional therapeutic agents in admixture with the compound. One will appreciate that the pharmaceutical compositions include pharma- ceutically acceptable salts of the above compounds. Pharmaceutically acceptable salts are well known to those skilled in the art and may be used in the preparation of compounds described herein. Activated compounds prepared with relatively non-toxic acids or bases depending on the particular substituent moieties found in the When compounds of the present invention contain relatively acidic functional groups, base addition salts are also contemplated for such compounds. The neutral form of such a compound is dissolved in a sufficient amount of water, either neat or in a suitable inert solvent, to give the desired salt. by contacting with a group or by ion exchange (basic pair in an ionic complex) It can be obtained by replacing one ion (base) with another. Examples of base addition salts include sodium, potassium, calcium, ammonium, and organic amino salts. , or magnesium salts, or similar salts.

[0042] When compounds of the present invention contain relatively basic functional groups, acid addition salts of such compounds are The neutral form is contacted with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. or ion exchange (substituting an acidic counterion (acid) in an ionic complex with another) Examples of pharma- ceutically acceptable acid addition salts include hydrochloride, Hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, phosphoric acid monohydrate monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, sulfuric acid Derived from inorganic acids such as monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid. Salts of acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, amber Acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluic acid The compounds are derived from relatively non-toxic organic acids such as benzenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginates, and salts of glucuronic acid or Also included are salts of organic acids such as galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts ", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention The compounds are salts that allow the compounds to be converted into either base addition salts or acid addition salts. It contains both radical and acidic functional groups.

[0043] Thus, pharma- ceutically acceptable salts suitable for use with the subject invention include, but are not limited to, Typical examples are acetates, benzenesulfonates, benzoates, bicarbonates, bitartrates, Bromide salts, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, Gluconate, glutamate, glycollylarsanilate, Hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoic acid Salt, iodide, isethionate, lactate, lactobionate, malate, maleate Salt, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embol Phosphates), Pantothenates, Phosphates / Diphosphates, Polygalacturonates, Salicylates , stearate, basic acetate, succinate, sulfate, tannate, tartrate, or Other pharma- ceutically acceptable salts include the octanoate salt. ce and Practice of Pharmacy (20th ed.), Lippincott, Williams & Wilkins (2000). It is written.

[0044] In therapeutic and / or diagnostic applications, the compounds of the invention can be administered systemically, topically, or intramuscularly. The compositions can be formulated for a variety of modes of administration, including localized or localized administration. The techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy (20th ed.), Lippincott, Williams & Wilkins (2000).

[0045] Depending on the particular condition being treated, such agents may be formulated into liquid or solid dosage forms. The agent can be administered systemically or locally. The pharmaceutical composition may be delivered in a sustained or sustained release form, such as in a controlled release formulation. Techniques for formulation and administration are , Remington: The Science and Practice of Pharmacy (20th ed.), Lippincott, Willia. ms & Wilkins (2000). Suitable routes include oral, buccal, inhalation spray, Sublingual, rectal, transdermal, vaginal, mucosal, nasal or intestinal administration; intramuscular, subcutaneous, intramedullary injection, and and intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intra-synovial, and hepatic parenteral delivery, including intralesional, intracranial, intraperitoneal, intranasal, or intraocular injection, or Other delivery modalities may be included.

[0046] For injection, the agents of the invention are administered in Hank's solution, Ringer's solution or physiological saline buffer. Formulate and dilute in aqueous solutions, such as in physiologically compatible buffers, such as For such transmucosal administration, penetrants appropriate to the barrier to be permeated can be 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 preparations suitable for systemic administration. The use of pharma- ceutically acceptable inert carriers for the preparation of the pharmaceutical composition is within the scope of the present invention. By appropriately selecting the preparation method, the composition of the present invention, particularly the composition formulated as a solution, can be administered intravenously. The compounds can be administered parenterally, such as by injection. Using an acceptable carrier, the composition 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) to be treated. tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc. for This makes it possible to formulate the drug.

[0048] For nasal or inhalation delivery, the agents of the invention may also be formulated by methods known to those skilled in the art. and can be dissolved in a soluble solution such as, but not limited to, saline. Examples of additives, diluents or dispersants include preservatives such as benzyl alcohol; absorption enhancers; and and fluorocarbons.

[0049] Pharmaceutical compositions suitable for use in the present invention include those compositions containing the active ingredient in an amount sufficient to achieve its intended purpose. Determining the effective amount is particularly useful in the context of the present invention. In light of the detailed disclosure provided herein, this is well within the capabilities of those skilled in the art. The compounds of the invention are effective over a wide dosage range. , 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 vary depending on the route of administration, the form in which the compound is administered, the individual receiving the treatment, and the individual's overall dosage. the subject to be treated, the weight of the subject to be treated, the bioavailability of the compound ity of the compound, absorption, distribution, metabolism and excretion (ADME), toxicity and the preference and It depends on the skill and experience.

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

[0051] If necessary, suitable auxiliaries are added to obtain tablets or dragee cores, followed by mixing in advance. The active compound is mixed with a solid excipient, the resulting mixture is optionally milled, and the resulting granular mixture is then formed. The mixture can be processed to obtain a pharmaceutical formulation for oral use. 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, gum tragacanth, methyl cellulose, hydroxypropyl methyl -Cellulose, sodium carboxymethylcellulose (CMC), and / or polyvinyl chloride Optionally, crosslinking agents may be used, such as 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. Concentrated sugar solutions, optionally including dye-stuffs or colorants, may be used. The pigments are used 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] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin. Cells, soft sealed capsules made of gelatin, and plasticizers such as glycerol or sorbitol Push-fit capsules can contain the active ingredients, as well as a filler such as lactose. Fillers, binders such as starch, and / or talc or magnesium stearate It may contain as a mixture with lubricants and, optionally, stabilizers. In the formulation, the active compound is dissolved in a fatty oil, liquid paraffin, or liquid polyethylene glycol. The drug can be dissolved or suspended in a suitable liquid, such as polyoxyethylene (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 in their entirety and are not intended to be limiting. All technical and scientific terms used herein may be understood by one of ordinary skill in the art to which the subject matter of this invention belongs. has the same meaning as commonly understood by

[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 discussion of the subject matter of the present invention, the following definitions are provided: These definitions are intended to be understood as being within the scope of the present invention and are not intended to be limiting unless otherwise specified. It is intended to supplement and explain, not preclude.

[0057] As used herein, substituted and substitute The term "optionally" may be used interchangeably with "optionally" or "nt" if preceded by the term "optionally." Regardless, as will be appreciated by those of skill in the art, the valences of all atoms are maintained. This means that one functional group on a molecule can be changed to another functional group. More than one position in a given structure may have more than one substituent selected from a particular group. When substituted with , the substituents may be the same or different at every position. The substituents may be further substituted (e.g., the substituents on an aryl group may be one or more (It may be substituted with another substituent, such as another aryl group, which is further substituted at the -position).

[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 may be hydrogen and R2 may be a substituted alkyl.

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

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

[0062] The description of the compounds of the present 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 substituents are selected to conform to chemical bonding principles, are not inherently unstable, and / or are aqueous, May be unstable under environmental conditions such as sex and some known physiological conditions For example, heterocycloalkyl groups such as The heteroaryl or heteroaryl may be substituted with ring heteroatoms according to principles of chemical bonding known to those skilled in the art. , thereby avoiding inherently unstable compounds.

[0063] As used herein, unless expressly defined otherwise, the term "substituent group" means any 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, such as methyl, ... ethyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl , tert-butyl, ethynyl, cyclohexyl, and the like.

[0065] The term "alkyl," by itself or as part of another substituent, refers to any group, unless otherwise specified. linear (i.e., "unbranched"), branched, acyclic or cyclic hydrocarbon groups, It means any combination thereof, which may be fully saturated, monounsaturated or polyunsaturated. , divalent and polyvalent radicals 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 carbons. 1-20 comprehensive linear (i.e., "straight-chain"), branched, or cyclic, saturated or The removal of one hydrogen atom from a hydrocarbon moiety containing from 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 Examples of aryl include cyclopropyl, cyclopropyl, and their homologs and isomers.

[0067] "Branched" means that a lower alkyl group, such as methyl, ethyl, or propyl, is not linearly linked to the alkyl group. "Lower alkyl" refers to an alkyl group that is attached to a lower alkyl chain. Aryl groups having from 1 to about 8 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. C 1-8 "Higher alkyl" refers to a group of alkyl groups that are approximately 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 2 In one embodiment, "alkyl" refers to an alkyl group having 0 carbon atoms. )" is particularly 1-8 It refers to a straight chain alkyl. In another embodiment, "alkyl" refers to , especially C 1-8 Refers to branched chain alkyl.

[0068] The alkyl group may be optionally substituted with one or more alkyl group substituents (e.g., "Substituted alkyl" refers to alkyl groups in which the substituents may be the same or different. The term "alkyl group substituent" is not intended to be limiting. However, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryl Aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl loxyl), aralkylthio, carboxyl, alkoxycarbonyl, oxo and cycloa Optionally, one or more oxygen, sulfur or substituents along the alkyl chain. or an unsubstituted nitrogen atom may be inserted, where the nitrogen substituents are hydrogen, lower alkyl, lower aryl, lower alkyl ... alkyl (also referred to herein as "alkylaminoalkyl") or is aryl.

[0069] Thus, as used herein, the term "substituted alkyl" means , one or more atoms or functional groups of the alkyl group may be substituted with another atom or functional group (e.g., alkyl, Substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro (including bromide, amino, alkylamino, dialkylamino, sulfate, and mercapto, etc.) Includes substituted alkyl groups as defined herein.

[0070] The term "heteroalkyl," either alone or in combination with another term, is particularly Unless otherwise specified, any suitable linear or branched or cyclic hydrocarbon group or combination thereof. having at least one carbon atom and selected from the group consisting of O, N, P, Si and S. At least one heteroatom, wherein the nitrogen, phosphorus and sulfur atoms are The nitrogen heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S and Si may be any internal group of the heteroalkyl group. or at the position where the alkyl group is attached to the remainder of the molecule. Examples, but not limited to, are -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH 3)-CH3, -CH2-S-CH2-CH3, -CH2-CH 25 -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -S Includes i(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3 and -CN For example, up to two or three heterocyclic groups, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The atoms may be consecutive.

[0071] As mentioned above, as used herein, a heteroalkyl group is defined as -C(O)NR', ​​-NR'R The molecules may be linked via heteroatoms such as -OR', -SR, -S(O)R and / or -S(O2)R'. The term "heteroalkyl" includes the group bonded to the remainder of the alkyl group, followed by -NR'. When a specific heteroalkyl group is listed, such as R, the term heteroalkyl is used. It is understood that -alkyl) and -NR'R" are not overlapping or mutually exclusive. Rather, it is clearly understood that In order to provide a heteroalkyl group, specific heteroalkyl groups are listed. "Heteroalkyl" excludes certain heteroalkyl groups such as -NR'R". should not be construed herein as a

[0072] "Cyclic" and "cycloalkyl" refer to groups having from about 3 to about 10 cyclic 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 At least one oxygen, sulfur, or substituted or unsubstituted nitrogen atom may be inserted, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl or substituted aryl. Representative monocyclic cycloalkyl rings include Examples of cycloalkyl include cyclopentyl, cyclohexyl and cycloheptyl. The alkyl ring includes adamantyl, octahydronaphthyl, decalin, camphor, and camphane. and noradamantyl, and condensed, e.g. dihydro- and tetrahydronaphthalenes. ring systems.

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

[0074] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to "Terocycloalkyl" refers to a non-aromatic, unsaturated or partially unsaturated ring system. For example, a 3- or 4-terterocycloalkyl ring system. A substituted or unsubstituted cycloalkyl ring system having 1 to 10 members and containing one or more heteroatoms and The atoms can be the same or different. Heteroatoms are 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 heterocycle may be condensed or bonded to an aromatic hydrocarbon ring. and nitrogen, and , sulfur and nitrogen, wherein the nitrogen and sulfur heteroatoms may be optionally 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; This refers to polycyclic groups which are optionally oxidized, including but not limited to bicyclic groups. or tricyclic group, and having 1 to 3 independently selected from oxygen, sulfur and nitrogen. and (i) each 5-membered ring has 0 to 2 double heteroatoms. 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 or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyridine ... Lorinyl, Imidazolidinyl, Imidazolinyl, Pyrazolidinyl, Pyrazolinyl, Piperi Dimethyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl , thiadiazinanyl, tetrahydrofuranyl, and the like.

[0076] The terms "cycloalkyl" and "heterocycloalkyl" are "alkyl" or "yl", alone or in combination with other terms, each means "alkyl", unless otherwise specified. It also represents the cyclic versions of "alkyl" and "heteroalkyl". In the case of a heterocycloalkyl, a heteroatom is the ring at which the heterocycle is attached to the remainder of the molecule. Non-limiting examples of cycloalkyl include cycloalkyl, cycloalkyl, and cycloalkyl. Cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl Non-limiting examples of heterocycloalkyl include: 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-2-yl, tetrahydrothien-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl , 2-piperazinyl, and the like. The terms "cycloalkylene" and " "Heterocycloalkylene" refers to cycloalkyl and heterocycloalkylene, respectively. Refers to the divalent derivative of a tert-cycloalkyl.

[0077] An unsaturated alkyl group is an alkyl group that contains 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 Includes ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl." .

[0078] More specifically, the term "alkenyl" as used herein refers to a single alkyl group. Linear or branched hydrocarbons with at least one carbon-carbon double bond by removal of elementary molecules. C, which includes the elementary parts 1-20 The alkenyl group is, for example, , 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 an alkyl group having at least one Cycloalkenyl groups refer to cyclic hydrocarbons that contain two carbon-carbon double bonds. Examples of cycloalkenyl groups include Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexene cyclohexyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl and cyclo Contains octenyl.

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

[0081] The term "alkylene," alone or as part of another substituent, means 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 A straight or branched divalent alkyl group derived from an alkyl group 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." The alkyl group may be substituted with one or more oxygen, sulfur, or alkyl group substituents. or a substituted or unsubstituted nitrogen atom (referred to herein as "alkylaminoalkyl"). can be optionally inserted along the alkylene group. , where the nitrogen substituent is alkyl as described above. Exemplary alkylenes include Groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclo Hexylene (-C6H 10 -);-CH=CH-CH=CH-;-CH=CH-CH2-;-CH2CH2CH2CH2-, -CH2CH=CHCH2- , -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r - includes, where Each of q and r is independently an integer from 0 to about 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), and R is hydrogen or a lower alkyl group. 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 include 6 Typically, an alkyl (or alkylene) group has 1 to 20 carbons. Groups having from 1 to 24 carbon atoms are preferred in some embodiments of the present invention, with groups having 10 or fewer carbon atoms being preferred. The term "lower alkyl" or "lower alkylene" is used herein as a general formula (I). e)" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. It is.

[0082] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a 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 alkyl groups, heteroatoms may also occupy either or both of the chain ends (e.g., For example, alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc. Furthermore, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is The formula of the linking group is not implied by the direction in which it is written. For example, the formula -C(O)OR'- Represents both -C(O)OR'- and -R'OC(O)-.

[0083] The term "aryl" refers to groups that are fused together or covalently bonded, unless otherwise specified. means aromatic hydrocarbon substituents which may be monocyclic or polycyclic (e.g. 1 to 3 rings) bonded to one or more of the rings. The term "heteroaryl" refers to one or more heteroaryl groups selected from N, O and S. Aryl containing 4 to 4 heteroatoms (in separate rings in the case of multiple rings) "R" refers to a group (or ring) in which the nitrogen and sulfur atoms are optionally oxidized and The nitrogen atom is optionally quaternized. A heteroaryl group is a group consisting of a carbon or heteroatom. 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-quinolyl The above aryl and heteroaryl groups include 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" are, respectively, refers to the divalent forms of aryl and heteroaryl.

[0084] For the sake of brevity, the term "aryl" is used interchangeably with other terms, such as aryloxy. When used in combination with aryloxy, arylthioxy, arylalkyl, the above defined The term "arylalkyl" includes both aryl and heteroaryl rings. "Heteroarylalkyl" and "heteroarylalkyl" refer to any group consisting of aryl or heteroaryl. Groups in which the aryl group is bonded to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.) It means that the carbon atom (e.g., methylene group) is For example, substituted with oxygen atoms (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1- naphthyloxy)propyl, etc. alkyl groups. However, as used herein The term "haloaryl" refers only to aryl substituted with one or more halogens. is meant to encompass.

[0085] When the heteroalkyl, heterocycloalkyl, or heteroaryl has a specific number of members (e.g., When the term "member" includes a carbon or a heteroatom, the term "member" includes a carbon atom or a heteroatom. Refers to the atom.

[0086] Furthermore, the formula: [ka] As used herein, the structure generally represented by the formula: Aliphatic and / or non-aliphatic groups include, but are 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, where the R group may be present or absent, and when present If one or more R groups are present, they may be bonded to one or more available carbon atoms of said ring structure. The presence or absence of an R group and the number of R groups are determined by the value of the variable "n." where n is generally an integer having a value ranging from 0 to the number of carbon atoms on the ring that can be substituted. Each R group, when present in plurality, 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. However, it would include classes of compounds including: [ka] etc.

[0087] A dashed line representing a bond in a cyclic ring system 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 said ring structure is a saturated ring. structures, partially saturated ring structures, and unsaturated ring structures.

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

[0089] When a specified atom of an aromatic or heteroaromatic ring is defined as "absent", In this case, the specified 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 as shown Both substituted and unsubstituted forms of the radicals are meant to be included. Representative substituents are shown below.

[0091] Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent derivatives A carbonyl group (alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, Cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl; Substituents for the alkyl group (including those groups often referred to as alkyl groups) are selected from, but not limited to, the following: 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 remainder of the molecule through a bond. Compounds of the invention may contain two or more R groups. For example, each of the R groups may be selected 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 ring. For example, -NR'R" can be, but is not limited to, a 1- From the above discussion of substituents, one of skill in the art will appreciate that the substituents are intended to include pyrrolidinyl and 4-morpholinyl. Some consider the term "alkyl" to mean 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 a group.

[0092] The aryl and heteroaryl groups are similar to the substituents described above for the alkyl groups. Exemplary substituents for (and their divalent derivatives) are varied and are, for example, selected from: 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 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 heptyl When the compounds of the invention contain more than one R group, For example, each of the R groups may be any combination of two or more of these groups, with each R', R", R'" and R"" group being any combination of two or more of these groups. If present, then 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 be optionally formed, where 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 hexacyclic ring may be Two substituents on adjacent atoms of the heteroaryl ring have the formula -A-(CH2) r -B- is substituted with a substituent In the formula, A and B may be independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2- , -S(O)2NR'- or a single bond, and r is an integer from 1 to 4.

[0094] One of the single bonds of the new ring thus formed is optionally replaced by 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 - substituents, where s and d are independently an integer of 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S( The substituents R, R', R" and R'" are hydrogen, substituted or is 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, The -OH of the carboxyl group is replaced by another substituent and has the general formula RC(=O)- (wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, As such, the term "acyl" is used herein as a heterocyclic or aromatic heterocyclic group. Specifically, "(acyl)" 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. are used interchangeably and are attached to the parent molecular moiety through an oxygen atom (i.e., alkyl-O- ) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) groups, where: 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-alkyl 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. "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 the 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, The aralkyl group is as described above. An exemplary aralkyloxy 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- 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 an alkyl and / or substituted alkyl group 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 substituted one or more hydrogen radicals with an organic radical. Also meant are nitrogen-containing groups known in the art derived from ammonia substituted with an alkyl group. For example, the terms "acylamino" and "alkylamino" are )" refer to certain N-substituted organic radicals with acyl and alkyl substituents, respectively. do.

[0108] As used herein, "aminoalkyl" refers to a cyclic alkylene linker. More specifically, the term alkyla refers to an amino group bonded to an alkyl group. alkylamino, dialkylamino and trialkylamino lkylamino) is a cyclic aryl group consisting of one, two, or three alkyl groups attached to the parent molecular moiety through a nitrogen atom. The term alkylamino means an alkyl group as defined above. means a group having the formula -NHR', where R' is an alkyl group as previously defined; The term dialkylamino refers to 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' R' and R'" are each independently selected from the group consisting of alkyl groups. ' and / or R''' taken together are optionally -(CH2) k - where: k is an integer from 2 to 6. Non-limiting examples include methylamino, dimethylamino, ethylamino, 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 isothio. Examples include isopropylthio and n-butylthio.

[0111] "Acylamino" refers to 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" means a -C(=O)- group and has the general formula RC(=O)H. It may contain aldehyde groups.

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

[0114] As used herein, the terms "halo," "halide," or "halogen" refer to "Halogen" means fluoro, chloro, bromo and iodo groups. Terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" means However, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl It is meant to include 3-bromopropyl, 3-bromopropyl, and the like.

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

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

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

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

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

[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] As used herein, the term thiohydroxyl or thiol 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 that has a sulfonyl group, -S(O2)R.

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

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

[0127] With respect to the compounds of formula (I), the term "protecting group" refers to a group that Readily available, does not attack regenerated functional groups or other functional groups A protecting group refers to a chemical substituent that can be selectively removed by a reactive reagent. Suitable protecting groups include Suitable protecting groups are known in the art and continue to be developed. (“Greene's Protective Groups in Organic Synthesis, 4th Edition” Wiley-Interscience As described by Wutz et al. (pp. 533-643), In some embodiments, a protecting group for protection of the carboxyl group is used. In the case of , the protecting group can be removed by acid treatment. Representative examples of protecting groups include, but are not limited to, Although not specified, benzyl, p-methoxybenzyl (PMB), tert-butyl (t-Bu), meth Dimethyl (MOM), Methoxyethoxymethyl (MEM), Methylthiomethyl (MTM), Tetramethylthiomethyl (Tetrmethyl) Hydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM) , trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDM Protecting groups include triphenylmethyl (trityl, Tr) and triphenylmethyl (S). Recognize the appropriate situations for which protecting groups are used and be able to select the appropriate protecting group for use in a particular situation. It will be.

[0128] Throughout the specification and claims, a given chemical formula or name refers to all tautomers. , homologs and optical isomers and stereoisomers, as well as mixtures of such isomers. Racemic mixtures are included.

[0129] Certain compounds of the present invention contain asymmetric carbon atoms (optical or chiral centers) or double bonds. They can be called 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 stereoisomers, are included in the present invention. 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 This 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 structures. The term "asymmetric" is intended to include both R and S configurations for each asymmetric center. Single stereochemical isomers as well as enantiomeric and diastereomeric forms of the compounds Mixtures of these 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. For example, deuterium or tritium are also included. Substitution of hydrogen by thium, or 13 C- orI4 C- Books with replacement of carbon with enriched carbon Compounds having the inventive structures are within the scope of the invention.

[0133] The compounds of the present invention may also contain non-naturally occurring groups 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) radioactively labeled with a radioisotope such as 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, etc. Leylate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)- tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates and glutamines These salts may be prepared by methods known to those skilled in the art. It can also be produced with sodium, potassium, calcium, ammonium, organic ions, etc. Also included are base addition salts, such as amine 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 is converted to the neutral form of the compound by its Contact 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, dihydrogenphosphoric, sulfuric acid, monohydrogensulf uric), 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 Also included are salts derived from organic acids such as carboxylic acids, methanesulfonic acids, 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 are disclosed herein in that the compounds can 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 a conventional manner. The parent form of the compound can be regenerated by isolating it from the solubility in polar solvents. The various salt forms differ in certain physical properties, such as:

[0136] Certain compounds of the present invention can 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 within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. However, 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.

[0137] In addition to salt forms, the present invention provides compounds that are in prodrug form. Prodrugs of the compounds described above are easily chemically transformed under physiological conditions to give the compounds of the present invention. Additionally, prodrugs can be synthesized by chemical or biochemical synthesis in an ex vivo environment. For example, a prodrug can be converted to a compound of the present invention by a suitable method. The compounds of the present invention may be administered in a transdermal patch reservoir together with an enzyme or chemical reagent. It is also possible to convert it smoothly.

[0138] In accordance with long-standing patent law practice, the terms "a," "an," and "the" are used As used herein, including "one or more," means "one or more." For example, the statement "a subject" is not a good fit if the context clearly indicates the opposite (e.g., a plurality of subjects). If the subject is not a plurality of subjects, then Hello, everyone.

[0139] Throughout this specification and claims, unless 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 It does not exclude other similar items which may be substituted 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 are All numbers expressing percentages, amounts, characteristics and other numerical values ​​are preceded by the term "about." In all cases, even if not expressly stated with a value, amount or range, (a) is to be understood as being modified by the term " Unless otherwise stated, the numerical parameters set forth in the following specification and attached claims are It is not, and need not be, exact, but is intended to be obtained by the subject matter of the present invention. Depending on the desired characteristics being achieved, tolerances, conversion factors, rounding, measurement errors, etc., and the like, may be taken into consideration by those skilled in the art. As desired, the method may be approximated and / or improved, taking into account other factors known to those skilled in the art. For example, when referring to a value, the term "about" is used. )" may vary from the specified amount by ±100% in some embodiments, by ±50% in some embodiments, or by In some embodiments, the range is ±20%, in some embodiments, ±10%, in some embodiments, ±5%, in some embodiments, In some embodiments, the variation is within ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1%. It is intended to encompass variations thereof, such variations being included in the practice of the methods of the invention, The compounds of the present invention are suitable for use.

[0141] In addition, when the term "about" is used in connection with one or more numbers or numerical ranges, When a range is used, it should be understood to mean all values ​​inclusive of all values ​​within the range. and the range is modified by extending the upper and lower boundaries of the stated numerical values. Reciting a numerical range by endpoints includes all numbers subsumed within that range. For example, whole integers, including fractions (e.g., writing 1 to 5 does not mean 1, 2, 3, 4, etc.) and 5, as well as fractions thereof (e.g. 1.5, 2.25, 3.75, 4.1, etc.), and any range therein. EXAMPLES

[0142] The following examples are provided to aid some of ordinary skill in carrying out representative embodiments of the subject invention. The present invention and the general level of skill of those skilled in the art will be understood to be within the scope of the present invention. However, those skilled in the art will recognize that the following examples are merely illustrative and do not depart from the scope of the present invention. It will be understood that many changes, modifications, and variations may be made without departing from the spirit and scope of the present invention. The synthetic descriptions and specific examples are intended for illustrative purposes only and are not intended to be limiting of the scope of the present invention by any other method. It should not be construed as a limitation on the methods for preparing the compounds of the invention.

[0143] Example 1 overview To enable imaging and radiation therapy of tumors expressing PSMA To detect PSMA-binding urinary markers, we used chelated radioactive metals bound via various linking groups. The use of fluorine has already been reported in several patent applications and publications (Tykvart et al. (2015) Journal of medicinal chemistry 58, 4357-63; Banerjee et al. (2015) Journal of nuclear medicine 56, 628-34;Benesova et al. (2015) Journal of nuclear medicine 5 6, 914-20;Weineisen et al. (2014) EJNMMI Res 4, 1-15;WO 2009002529 A2;WO 20090703 02 A1). A new class of high affinity binders has been developed that binds uridine diamines at the ε-amine position bearing a p-Br-benzyl group. The structures of the compounds of the present invention are shown in Figure 1. vinegar.

[0144] Without wishing to be bound by any particular theory, it is believed that the lysine type of the Lys-Glu-urea moiety When the silyl amino group was modified with a p-Br-benzyl group, it was possible to target prostate-specific membrane antigen (PSMA). -Targeted radiometal-chelating Glu-lysine urea-based theranostics The theranostic agent has high binding affinity and high activity against PSMA in tumors that express PSMA. uptake in the kidney and low uptake in standard mouse models of prostate cancer According to one embodiment, 177 Lu-1 is a mouse model of PSMA+ PC3 tumors. For mice, radiation therapy showed a significant effect, with remission of approximately 50%.

[0145] Example 2 Materials and Methods Chemical synthesis of 8. The synthesis of compound 1 is described in Scheme 1. Bromobenzaldehyde (121.0 mg, 0.654 mmol) was dissolved in 5 ml of methanol in an ice bath to prepare the Boc-protected urea 4 (300.0 mg, 0.615 mmol) was slowly added to a stirred solution of 100.0 g of 1,000 sulphate and allowed to warm to room temperature. After 1 h Sodium cyanoborohydride (158.0 mg, 2.5 mmol) was added and the reaction was stirred overnight. The crude reaction mixture was evaporated, redissolved in dichloromethane, and purified by normal phase silica chromatography. The product was purified by HPLC (95:5, methylene chloride:methanol) and dried in vacuum to give a good yield. 5 was obtained in a high yield. 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 1 μmol) was dissolved in 300 μL of DMF and stirred at room temperature. After 1 hour, compound 5 (71.0 mg The reaction mixture was then incubated for 4 h. The crude reaction mixture was stirred and stored at 4 °C overnight. 18 Purification by semi-preparative HPLC on column (40% water (0.1 TFA) / 60% ACN (0.1 TFA) / 5 min, 60-90%, over 20 min). t 2 1 min. The purified fractions were combined, evaporated and dried under high vacuum for 10 min. 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 it to warm to room temperature during the process. The mixture was dried under a stream of nitrogen, dissolved in water, and lyophilized to give 31.8 mg of compound 7. Yield: 54 μmol, 54%. 6 (12.2 mg of T) in DMSO (130 μL) equilibrated to 40 °C was To a stirred solution of p-SCN-bn-DOTA (12.2 mg, 1 The reaction mixture was stirred at 40 °C for 4 h and then stored at 4 °C overnight. The mixture was purified by reverse-phase HPLC (20% ACN for 5 min, followed by 20-40% in 19 mL of 100% ethanol). Rt approx. 12 min. The purified fractions were combined and rotary evaporated to reduce the volume, then Lyophilized. ESI-MS: 1138.37 [M+H] + , Actual value: 1138.5. Compound 1 was analyzed by gradient method. The product was further purified by HPLC using a mobile phase of 88% water (containing 0.1% TFA). ) and 22% CH3CN (0.1% TFA) for 1 to 5 min, followed by 88% water (containing 0.1% TFA) for 1 to 5 min. and 12% CH3CN (0.1% TFA) for 0 to 5 min, and 88% water to 44% water and 12% acetonitrile to 56% acetonitrile at a flow rate of 8 mL / min for 5 to 25 min. It is a gradient method that includes

[0146] Chemical synthesis of 2. This compound was synthesized using the same intermediate 7 and was synthesized using commercially available DOTA-NHS ester. 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 DOTA-NHS ester. ESI-MS: 970.05 [M+H] + , Actual value: 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 NH4OAc buffer (0.2 M, pH 4) and 5 μl of 2 mM in 0.2 M NH4OAc The pH of the mixture was about 4.0. The mixture was incubated 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 0.01 to 23% acetonitrile. Flow rate: 1.0 ml / min; λ: 200 nm, and C8 column (25 × 4.6 mm), Varian microsob-MV 100-5. 177 Lu-1 is 17. It eluted from 1 to 20 min, whereas the unlabeled chelator eluted from 21 to 22 min.

[0149] The HPLC method comprises: 177 Lu-1 and 177 The HPLC method used to prepare Lu-7 was The mobile phase was 88% water (containing 0.1% TFA) and 22% CH3CN (containing 0.1% TFA) for 1 to 5 min. , followed by 5 to 27 min, 88% to 75% water and 12% to 25% acetonitrile; 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 label177 Lu-2 elutes from 13.1 to 15.0 min, and the unlabeled chelator elutes from 16. It was eluted at 17 min from the starting point. 177 Lu-3 elutes between 13.1 and 15.0 min and is unlabeled. The chelating agent eluted at 10–12 and 18–20 min, respectively, and the unlabeled drug eluted at 14–16 min. It was eluted at .

[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 molecular biology) According to the method of the Journal of Physics, Vol. 58, No. 4357-63, the p-bromobenzyl group of Glu-Lys urea (2) was The modified product was treated with p-bromo 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 attached to the same ε-Lys amine of 4 to give The BOC group was then removed and 6 was conjugated with commercially available DOTA-Bn-SCN. Compound 2 was prepared by the reaction of DOTA-NHS ester with the chelating agent. Compound 3 was synthesized by coupling with the same intermediate 6. A control agent was synthesized without any p-bromobenzyl group. All three agents were synthesized at 80 °C. in ammonium acetate buffer at pH 4 in good yield and purity. 177 Radiolabeled with Lu The binding affinities of the novel compounds are shown in Table 1. Both 1 and 2 showed higher binding affinity compared to 3.

[0152] [Table 1]

[0153] Cell-binding properties. 177 Lu agents were administered to standard syngeneic cell lines PSMA+ PC3 PIP and PSMA- Further evaluation was performed in cells and animals using negative PC3 flu cells. 177 Lu-1 and 177 Lu-2 Both of 177 It showed higher uptake in PSMA+ PC3 cells compared with Lu-3. Furthermore, when studying internal migration, 177 Lu-1 177 The internal pressure is nearly twice as high as that of the Lu-3. All three drugs were shown to have translocation activity against PSMA-negative PC3 flu The cells showed significantly lower uptake. 177 Lu-1 was identified as a therapeutic target in a clonogenic assay. The therapeutic efficacy of the lead compound SR6 (Banerjee et al. (2015) Journal of Nuclear medicine 56, 628-34) and 177 Lu-PSMA-617(Benesova et al. (2015) Journal o f Nuclear 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 inhibits PSMA+ PC3 PIP cells In this study, a 10 μCi dose was used to produce approximately 100% cell killing, whereas in PSM A- No significant toxicity was observed against PC3 flu cells.

[0154] [Table 2]

[0155] Biodistribution. 177 Lu-1 and 177 An in vivo tissue biodistribution study was performed on Lu-2. The results are listed in Tables 3 and 4. PSMA+ PC3 PIP tumor uptake: 177 Lu-1 teeth, 177 Lu-2 showed significantly higher uptake and retention than Lu-2. 177 Lu-2 agents are 177 Lu-1 As shown in Figure 3, the compounds of the present invention showed a 5-fold lower kidney uptake than , Leading 177 Lu-SR6, 177 Lu-PSMA-617 and 177 Compared with that of Lu-PSMA-I&T. 17 7 The ratio of PSMA+ PC3 PIP tumor to kidney in Lu-2 was 177 It was higher than Lu-1. Since the uptake and retention by 177 For Lu-1, a pilot study was conducted using a small number of animals. In a clinical study, theranostic efficacy (imaging and therapeutic efficacy) The results were further evaluated.

[0156] [Table 3]

[0157] [Table 4]

[0158] Small animal SPECT imaging and therapeutic effects. Figure 4 shows the results of treatment over 1 to 8 days after injection. During the research period 177 SPECT imaging of Lu-1 is shown. 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 weekly by measuring body weight and tumor size. The mice were euthanized after 4 to 8 weeks due to tumor size exceeding 12 mm. In the study, tumors were completely eradicated in 50% of mice. These mice first lost weight. The weight of the rats decreased and recovered to the original weight after 2 weeks. The results are shown in Figure 5. Figures 6A and 6B show 177 L The therapeutic efficacy of u-1 (reduction in tumor volume) was compared with the control group using saline. Five mice had complete disease remission and survived for more than 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 , it chelates radiometals that target prostate-specific membrane antigen (PSMA). Theranostic agents based on Glu-lysine urea have been shown to be effective in treating prostate cancer. In standard mouse models of adenocarcinoma, tumors expressing PSMA showed high binding affinity to PSMA and One representative compound showed high uptake in the blood and low uptake in the kidney. 177 Lu-1 demonstrated a significant radiation therapy effect with approximately 50% remission in mice bearing PSMA+ PC3 tumors. Ta.

[0160] Example 4 PSMA-based high-LET agents for prostate cancer SUMMARY In some embodiments, the present invention provides a method for the treatment of PSMA-targeted radiometal The pharmacokinetic optimization of the drug-based drug is the subject of prior research in the international PCT special. Nos. WO2009 / 002529 A2 and WO2010 / 108125A2, each of which is incorporated herein by reference. More particularly, in some embodiments, the present invention The subject of the disclosure is, but is not limited to, 213 Bi(t 1 / 2 46 min, E mean 8.4 MeV), 212 Pb(t 1 / 2 10.6 h, E mean 7.8 MeV), and 225 Ac(t 1 / 2 10d,E mean 6 MeV, 4α) Providing radioactive metal-labeled, low molecular weight (LMW) theranostic drugs targeting PSMA and reduce off-target effects that currently prevent widespread use of this promising treatment. The goal is to

[0161] The rationally designed alpha emitters and methods of use of the same of the present invention are described below with reference to the pharmacokinetics (PK), radioactive metal Through careful consideration of the physical half-life, and receptor By blocking the α-camera receptor and reducing uptake by normal tissue, Using imaging guidance, sub-organ localization (HO) is performed prior to therapeutic studies. The researchers quickly identified the two proteins that block the IL-11 signaling pathway (hot spots) and their interactions with the IL-11 signaling pathway.

[0162] Thus, in some embodiments, the subject of the present invention is a patient receiving prostate specific membrane antigen (PSMA) targeting therapy. The ε-amino group of the lysine in the Lys-Glu-urea moiety targeted for β-glucose synthesis is modified with a p-Br-benzyl group. The radioactive metal chelating Glu-lysine urea-based theranostic agent. The compound showed higher binding affinity to PSMA and inhibited the standard mouse tumor marker of prostate cancer. In the model, there was significantly lower renal uptake and higher tumor uptake in PSMA-expressing tumors These optimized drugs are highly toxic radioactive metals. 213 Bi, 212 Pb, and 22 5 Radiolabeled with Ac.

[0163] example [ka]

[0164] The ligands were synthesized as described above. The following compounds were also synthesized by the method of the present invention: You can: [ka]

[0165] 213 Bi-1 / 225 Ac-1 / 203 Radiolabeling of Pb-1. All radiolabeled compounds were 213 For Bi-1 Prepared according to the general method described. 213 Bi is manufactured by Oak Ridge National Laboratory. Ta 225 Ac / 213 Bi-Eluted from the generator. Freshly eluted 213 Bi (18.2 MBq) in 1 solution (10 μg) The solution was added and adjusted to 4 to 5 with 3M NH4OAc solution. The solution was heated in a microwave oven for 5 minutes. The mixture was heated at 95° C. and 40 watts of power for 5 min. Then, 10 μL of 1 mM Na-DTPA solution was added to the complex. Does not include 213 Added to Bi. 213 The specific activity of Bi-1 was > 7.4 MBq / μg in all experiments. 21 3 Bi-1 was added to Phenomenex C 18 Luna 10×250 mm 2 Column and Varian Prostar System (Palo Al The purification was performed using a Varian ProStar 325 UV-Vis variable wavelength detector and a 100% pure ... All were equipped with a Bioscan (Poway, CA) flow count in-line radioactivity detector. The flow rate was controlled by the xie software. The elution solvents were water (0.1% TFA) (A) and CH3CN (B). 0.1% TFA) (B) at 1 mL / min. To ensure uniform purity, 80% A and 20% B An isocratic solution of 1000 mg ... The specific radioactivity is the amount of radioactivity eluted at the retention time of the product during purification by preparative HPLC. The radioactivity was calculated as the ratio of the mass corresponding to the area under the curve for UV absorption. The purity of was >95% as determined by analytical HPLC using absorbance at 254 nm. The yield of radiolabeled compound was determined by column chromatography on silica gel with 0.9% sodium chloride as the mobile phase. The radiolabeled samples were also evaluated using gel instant TLC (ITLC). The solution was diluted with 10 mM diethylenetriaminepentaacetic acid (DTPA) at a pH of approximately 4. A diluted sample of the solution was spotted onto an ITLC silica gel strip and chromatographed. After the solvent front migration was complete, the ITLC sample was The strips were dried, cut in half, and analyzed using a Wallac Wizard γ counter (PerkinElmer). The radiolabeled product was counted in a 30-μl microcentrifuge (Miller, Boston, MA) to determine the radiolabeled product yield. was assessed by high performance liquid chromatography (HPLC) analysis.

[0166] Figures 7, 8, 9, 10, 11 and 12 show the in vitro and in vivo characterization. 225 Ac The biodistribution of -1 in the body is as shown in Table 5. [Table 5]

[0167] Development of receptor blockade for normal organs. Blocking effect of 1 177 Lu-1 was used to quantify the uptake in normal tissues. High uptake in PSMA(+) tumors A dramatic decrease in renal uptake was observed while maintaining the normal serum creatinine concentration (Figure 12). In our blocking study, we observed a decrease in uptake into the salivary glands, but the results were not statistically significant. This is 177In relation to the very low uptake of Lu-1 (< 0.5% at 2 h), This is probably due to a high margin of error.

[0168] Blocking strategies. All blocking tests were performed on long-lived, decaying daughter isotopes. 213 Bi and 221 Poison caused by Fr It has the best performance in terms of 225 Ac-labeling agents (e.g. 225 This is carried out using Ac-1). Once formed, these daughter nuclides have high atomic recoil energies as a result of alpha decay. Without wishing to be bound by any particular theory, I don't want to, but 225 Acute salivary gland toxicity caused by Ac-PSMA-617 is consistent with the internalization of PSMA-based drugs. This may be due to the release of daughter nuclides in the striatal ducts or acini after the administration of Using both biodistribution data and α-camera imaging, To avoid radiation toxicity in the kidneys and salivary glands, various pharmacological strategies were used. In addition to com-injection, 15 of 30 min of pre-injection blockade was performed. The study was carried out to determine whether any significant changes occurred due to the short half-life of the drug in the blood. We investigated whether combinations of two or three effective blocking agents could provide some improvement. Check if it can be done.

[0169] The following experiments may be carried out within the scope of the present subject matter:

[0170] Receptor blocking (auto-blocking) tests, e.g. 225 Free ligand 1 of Ac-1 (as in Figure 12) ;

[0171] Inhibition of PSMA-expressing normal tissues to provide synergistic receptor blockade and metal ion sequestration In the weaving 213 Competitive blocking using dithiol chelators that scavenge Bi;

[0172] 2,3-Dimercapto-1-propanesulfonic acid (DMPS) off-target effects using DMPS By doing so, the free 213 Use of dithiol chelating agents to remove Bi (which is Thiol chelating agents have been shown to be effective in a variety of animal and human studies. 213 Bi or other heavy metals (because it has been shown to enhance excretion of

[0173] Francium (Fr) is an alkali metal, like sodium and potassium, and therefore Na is an important transporter for acinar cell fluid and electrolyte secretion. + / K + / 2Cl- It can be absorbed by the salivary gland ducts via the transporter NKCC1.

[0174] Thus, as reported, the FDA-approved diuretics furosemide and bumeta Using Nido, Na + and K + By preventing reabsorption in the same way, 221 Fr is removed and

[0175] As reported, a suspension of bismuth subnitrate (100 mg / kg) competitively inhibited metal sequestering. In renal tubular cells, 213 Bi or cold Bi +3 Incorporation or binding of The effectiveness of competitive metal blockade of either site (metallothionein-like protein) can be evaluated.

[0176] Example 5 For PSMA-based radiopharmaceutical therapy, 177 Lu-labeled low molecular weight compounds

[0177] 5.1 Overview Prostate-specific membrane antigen (PSMA) is a radionuclide therapy for the treatment of metastatic castration-resistant prostate cancer. One objective of the present invention is to detect metastatic castration-resistant Low linearity of beta particles for targeted radionuclide therapy of anti-prostate cancer The goal is to develop optimized drugs that use energy transfer irradiation. To this end, we developed a novel PSMA-based 177 Lu-labeled radioligand was synthesized and bound in vitro. The binding affinity and in vivo tumor targeting were evaluated. Radiolabeling of the new ligands was performed using The compounds were synthesized with high (>98%) radiochemical yields and specific activities. Cellular uptake and internalization data shows that all drugs are specifically taken up in PSMA(+)PC3 PIP cells. Selected drugs were subjected to cell viability assays for clonogenesis. Only after incubation for 1 h did PSMA(+)PC3 P cells show significantly higher IFN-γ levels than PSMA(-)PC3 flu cells. A significant decrease in IP cell viability was observed. Selected compounds were administered to primary prostate cancer The in vivo pharmacokinetics and therapeutic effects of clinical drugs in models 177 Lu-PSMA-617 and Beauty 177 Further evaluation was performed in a head-to-head study with Lu-PSMA-I&T. By 72 hours, there was comparable tumor uptake in PSMA-expressing PC3 PIP tumors for the novel agents. These drugs also reduced the amount of 111 MBq ( 3 mCi) intravenously for 8 weeks, and showed efficient tumor regression. 177 Lu Treatment with selected drugs in tumor-bearing mice8 showed a significantly improved survival rate. Nephrotomy of the kidneys was performed in mice after 1 week and 1 year after treatment in tumor-free mice ( 177 Lu-L1, 111 MBq), and no radiation nephropathy was observed.

[0178] 5.2 Background Glutamate carboxypeptidase II [GCPII] or N-acetyl-1-aspartyl-1-glutamate Prostate-specific membrane antigen (PSMA), also known as glutamic acid peptidase I [NAALADase I], is a It is a type II cell surface metalloenzyme and a useful clinical biomarker for prostate cancer. It has been proven to be a 1, 2 Approximately 80% of prostate tumors, as well as other solid tumors, Tumors show strong PSMA expression within newly formed blood vessels, mimicking tumor-associated angiogenesis Lower levels are seen in physiologically normal tissues (e.g., kidney, salivary gland, and small intestine). The differential expression of PSMA in prostate tumors has been of great interest to clinicians and radiochemists. The authors report on a wide range of diagnostic and therapeutic radioisotope imaging applications, including PET, SPECT, nanoparticles, and optical agents. The use of PSMA as a target for delivery of radionuclides has been explored. It is a low molecular weight PET imaging agent of 68 Ga-PSMA-11 3 and 18 F-DCFPyL 4 is prostate cancer The new drug application could revolutionize early diagnosis for men with ovarian cancer and could be submitted for approval by the FDA in the next few years. It is a recently introduced PSMA-based radionuclide therapy agent. 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T 5-11 (Table 6) and halogens 131 I-MIP1095 2, 12, 13 There is a possibility of treating Although it is desirable, more detailed information is needed regarding the safe and effective administration of radionuclides. For example, grade 1-3 hematological toxicity may include xerostomia and Mucositis 13 Along with strong accumulation in the salivary glands causing 131 Reported in I-MIP1095. 22 5 Ac-based LMW agents are also in clinical trials and are being investigated for their efficacy in treating salivary glands. 14 Similar complications have been reported in The long-term nephrotoxicity of PSMA-based radionuclide therapy (these LMW radiotherapies) To address the major safety concerns of current drugs, the data collected in well-designed clinical trials must be collected. Prospective data on this outcome are still lacking.

[0179] Pharmacokinetics of drugs with high tumor / background ratios for safe and effective clinical application The effects of these agents on prostate cancer imaging and treatment (Figure 13) were investigated. The overall biological profile can be determined not only by receptor-specific binding but also by non-specific binding. It is also measured by interactions and is related to molecular weight, charge, hydrophilicity, and metabolic stability. So far, two broad classes of high affinity drugs (K i < 20 nM) Emerging from various studies are: (i) Type I agents. These agents target PSMA-specific tumor uptake. Although it has a high activity and long retention in the body, it is not detected in many PSMA-expressing normal tissues, including the renal cortex and spleen. High uptake 15 Examples include 99m Tc-oxo 16 、 64 Cu-1,4,7-triazacyclonona Nota 17 (Figure 13A) 68 Ga-PSMA-11 18 、 and drugs 68 Ga- / 177 Lu-PSMA -I&T, second generation) (Figure 13B), which have been administered to patients in several clinical trials. It has been given 6、7、19、20 These drugs are the chelates on the original linker / urea construct. These are produced by simply modifying the agent or linker. 21 , affinity for PSMA In recent years, the albumin-bound p-(iodophenyl)butyric acid moiety has been 22-25 Using Several high-affinity radioligands that are highly retained in tumors have been developed, but (ii) Type II agents. These These drugs have high tumor uptake and retention, as well as extensive damage to most normal tissues, including the kidneys and salivary glands. They exhibit rapid clearance from tissues, resulting in high tumor-to-background ratios. Let 16、 17 。 Type II drugs include those developed by the present inventors (Figure 13A). 26 and P.S.M. A-617 5 (Figure 13B). Drug II was recently discovered in a first-in-man study 27 is done A similar pattern of more rapid renal clearance from PSMA-expressing kidneys than from PSMA+ tumors was observed. have been observed, which is consistent with the more disorganized vasculature of the xenografts. This is probably related to faster flow through the organized renal vasculature. 26, 28, 29 .

[0180] The present invention is directed, in part, to targeted immunotherapy for the treatment of metastatic prostate cancer. A novel approach to target PSMA for developing theranostic radiopharmaceutical treatments This includes preclinical evaluation of a series of small molecule compounds. 125 I-iodo-benzoyl Amino)-pentyl]-ureido]-pentanedioic acid ( 125 I-DCIBzL) in human PC xenografts In this study, the 4-haloacetate of Lys-urea-Glu was continuously taken up into the tumor for at least 48 hours. The benzyl derivative was investigated along with other urea-based candidates. The agent was Significant tumor regression was achieved by Gy transfer and short-range (<10 mm) Auger electron irradiation. made 30 DCIBzL is one of the most potent PSMA binders known in the art (K i =0.01 nM ) Furthermore, it emits alpha particles. 211 At-labeled DCIBzL was used in flank tumor models and micrometastases. Both treatments showed significant effects in both the control and control models. 31 Therefore, the metal-based radiation Radiotherapy drugs are fused to linkers and amines to improve the binding affinity and pharmacokinetics of the drugs. Halo-benzyl-ureas derived from the structure of DCIBzL with some rational modification of the chelating agent Several representative compounds were synthesized to evaluate the tumor activity of the drug. The targeting and pharmacokinetic properties of PSMA-based targets were evaluated. - for targeted radionuclide therapy 177 Lu, 212 Pb or 225 Off-target of Ac It is possible to optimise the drug to have reduced effect.

[0181] 5.3 Test Results 5.3.1 Synthesis scheme. As shown in Figure 13, a series of representative compounds were synthesized using high affinity Based on the drug DCIBzL, structure and activity relationships (S All ligands were synthesized for the study. Except for L8 and L14, the 2-amino acids were designed to contain a (Br / I)-benzylLys-urea-Glu targeting moiety. Ligands L1-L4, L7-L9, and L13 were designed to have short and flexible linkers. However, L12 contains a rigid aromatic linker. In contrast, ligands L5, L6 and L14 , similar to previous leads, was designed with a longer linker. 26 Chelating Agents The effect of the chelator DOTA-monoamide as in L1 was examined in ligands L7 and L8. In L9, the assay was performed using the DOTAGA chelator, and in L10, the assay was performed using the chelator L11. Ligands L10 and L11 have a stiffer linker and sharper structure compared to L1 and L9, respectively. To check the effect of DOTA on chelating agents, DOTA-monoamide and DOTAGA chelating agents were used. and designed it to have a rigid cyclohexyl linker like that in PSMA-617. Ligand L13 converts Br-benzyl Lys-urea-Glu into a clinical PET imaging agent. 18 F-DCFPYL By replacing the Br-pyridylLys-urea-Glu with Designed to have 32 Ligand L14 has been recently investigated by several research groups. As if 22-25, 33 on a previously reported PSMA-binding targeting platform The albumin-binding moiety, 4-(p-iodophenyl)butyric acid, was designed to be present in the cytoplasm. The effects of 4-(p-iodophenyl) on the properties of fabrics were investigated.

[0182] All compounds are synthesized using well-established methods for preparing Glu-Lys urea derivatives and related The ligands L1 and L2 were synthesized using solution-phase chemistry based on the linker and chelator conjugation chemistry described above. L2 was synthesized as described in Scheme 2. [ka]

[0183] Scheme 2. a Reagents and conditions: (a) NaBH3CN, MeOH; (b) Boc-5-aminovaleric acid TSTU, DIPEA, DM F or Boc-6-aminohexanoic acid N-hydroxysuccinimide ester, Et3N, DMF, overnight (c) 50% TFA / CH2Cl2; c) 3a or 3c, DOTA-monoamide-NHS, DIPEA, DMSO, room temperature, 3 time; (d) 177 Lu +3 / Lu +3, pH ~4-50.2 NH4OAC, 5 min, 95°C microwave.

[0184] Urea-lysine intermediate di-tert-butyl (((S)-1-(tert-butoxy)-6-((4-iodo / bromophenyl (5-X)-1-oxohexan-2-yl)carbamoyl)-L-glutamic acid, 1a or 1b -Bn)-Lys-urea-Glu (X = Br / I) was synthesized according to the literature method. 34 were synthesized with some modifications. Using these two intermediate compounds, L3, L4, L5, L6, L8, L9, L10, L11 and L12 were also synthesized. Briefly, Boc-5-aminovaleric acid was coupled to 1a and 1b to give 2a and 2c, followed by tert The -But and N-Boc groups were simultaneously removed to give 3a and 3c, respectively, in greater than 90% yield. Compounds 3a and 3c were then reacted with the N-hydroxosuccinimide (NHS)-ester of DOTA-monoamide. The target ligands L1 and L2 were obtained in high yields by reacting with 1,2-dichlorophenyl ether. Ligands L3 and L4 were obtained by It was synthesized as shown in Scheme 3. [ka]

[0185] Scheme 3. a Reagents and conditions: (a) DIPEA, DMF, room temperature, 16 h; (b) TSTU, TEA, DMSO, 4 h; (c) 50% TFA / CH2Cl2; (d) 3b or 3d, DIPEA, DMSO.

[0186] Using the rigid linker p-aminomethylbenzoic acid and DOTA-monoamide NHS ester, A coupling reaction was carried out to obtain compound 4, and the yield was quantified. Compound 4 was then reacted with trimethylamine to obtain Compound 5 was obtained by treatment with TSTU under reduced pressure, followed by tert-butylation with TFA / CH2Cl2. The removal of the aryl group afforded the reactive intermediate 6 in high yield. Ligands L3 and L4 were synthesized by reacting 6 with 3b and Ligands L5 and L6 were obtained in good yields after a simple coupling reaction between 3d and 3e. It was synthesized according to the synthetic route shown in Scheme 4. [ka]

[0187] Scheme 4. a Reagents and conditions: (a) DSS, TEA, DMF; (b) 50% TFA / CH2Cl2; (c) 4, DIPEA, DMSO, 3 hours.

[0188] First, compound 7 was synthesized as previously reported 35 As such, 1a and disuccinimidyl suberate (DS Compound 7 was then treated with 50% TFA / CH2Cl2 to give the t- The butyl group was removed to give compound 8, which was then coupled with Boc-5-aminovaleric acid. After this, the Boc group was removed and coupled with compound 6 to obtain L5. Following the described synthetic route, DOTA-monoamides were synthesized as DOTA-Bn-SCN (L7 and L8) and DOTAGA (L9). Three analogs of L1 were synthesized by replacing the 1-aminopropyl group with 1-aminopropyl group. In contrast, for the chelator DOTAGA, the reaction mixture was first incubated at room temperature for 1 The two ligands L10 and L11 (cyclohexyl) were synthesized by sonication for 1 h, and the coupling reaction was carried out in high yields. Analogs of L1 using the xyl linker were also synthesized as shown in Scheme 5. [ka]

[0189] Scheme 5. a Reagents and conditions: (a)(i) trans-4-(Fmoc-aminomethylcyclohexanecarbamoyl (ii) 20% piperidine / DMF; (c) DOTA-GA anhydride, D IPEA, DMSO, 3 h (c) 50% TFA / CH2Cl2.

[0190] First, the NHS-ester of trans-4-(Fmoc-aminomethylcyclohexanecarboxylic acid) was synthesized in This was synthesized in situ and reacted with 1a to give 10. The Fmoc and tert-butyl groups were subsequently removed to give After coupling with the corresponding chelating agents (DOTAGA and DOTA-monoamide), L10 and L11 were obtained in excellent yields. Ligand L12 was synthesized as shown in Scheme 6. Briefly, According to the method, compound 1a is reacted with intermediate 6, and then the tert-butyl group is removed from Lys-urea-Glu. This afforded L12 in >80% yield. [ka]

[0191] Scheme 6. (a) 6, DIPEA, DMSO; (b) 50% TFA / CH2Cl2.

[0192] Ligand L13 was prepared according to Scheme 7, but with the exception that tumor targeting and drug pharmacokinetics are To investigate the effect of the pharmacophore on Ligand L14 was synthesized according to Scheme 7. First, the NHS-ester of p-(iodophenyl)butyric acid (compound 12) was synthesized and the yield was quantified. This was reported previously using the bifunctional compound 14 35 The reaction with L14 gave a very good result. All synthesized ligands were purified by HPLC and lyophilized to give colorless, hygroscopic solid compounds. The ligands were characterized by standard spectroscopic tools including mass spectrometry and NMR. It was found to be stable at -20°C for at least 6 months. [ka] Scheme 7. a Reagents and conditions: (a) TSTU, DIEA, DMF; (b) 13, DIPEA, DMSO, 2 h.

[0193] All new ligands were synthesized in high yields by incubation at 70°C for 1 h. 177 Radiation at Lu The radiolabeled compound was then purified by HPLC to remove unreacted ligand, and finally In the case of L1 and L2, the radiochemical purity was >99% and the specific activity was >37 MBq / nmol. Rapid and easy microwave assay for related ligands (including L7, L8, L9, L11, L12 and L13) A radiolabeling method using has been developed that can be performed at 40°C, pH ~4, and in 5 minutes with excellent yields (>90%). 177 Lu Labeling agent ( 177 p-Iodobenzyl Lu-L) was newly synthesized by a microwave method. Ligands using urea derivatives (e.g., L4 and L6), long linkers (e.g., L3 and L5) and A number of radiolabeled products have been prepared for ligands using rigid linkers (e.g., L12). All of them were synthesized. 177 Lu-labeled compounds were stable for up to 4 hours at room temperature and up to 24 hours at 4°C, with no significant No significant radiolysis was observed. However, to ensure high stability, the final formulation In this study, we added L-ascorbic acid to the radiolabeled compound and performed the in vivo For the experiments on cellular uptake and internalization, L-ascorbic acid was added. The procedure was carried out immediately without any modification.

[0194] 5.3.2 In Vitro Binding and Cellular Uptake. All new ligands were bound to IgG in the range of 0.03–8 nM. Encirclement K i The stable lutetium analog of L1 (Lu- L1) was synthesized, which showed a 3-fold improvement in binding affinity over L1 (Table 6). When a comparative study of cellular uptake was performed with a 2-hour incubation including Compared with normal PC3 cells, PSMA+ PC3 PIP cells showed approximately 100-fold higher uptake. Cellular uptake and internalization data for selected compounds are shown in Figure 14 and Table 7. Total uptake and internalization of the compounds increased gradually from 1 to 24 hours. . 177 Lu-PSMA-I&T and 177 Both Lu-PSMA-617 and Lu-PSMA-617 induced significantly higher total uptake in PSMA(+) PC3 PIP cells. The results showed that the β-glucosamine complex (α-glucosamine complex) was upregulated by β-glucosamine (α-glucosamine complex) and β-glucosamine complex (α-glucosamine complex) (approximately 60% and 40% of the incubated dose, respectively), whereas 177 L u-L1, 177 Lu-L3 and 177 Lu-L5 showed uptake in the range of 30%. For the above compounds, the percentage of internalization was approximately 18-24% at 1 h and 25-30% at 24 h, consistent with the same results. For all compounds, uptake in PSMA(+)PC3 PIP cells was within the range previously reported. This could be blocked by overtreatment with a known PSMA inhibitor (ZJ43) ( Table 7). 177 Lu-7 and 177The internalization of Lu-8 was also examined up to 24 hours after culture. Modified with bromo-benzyl group 177 Lu-8 was not detected at all time points. 177 Lu- 7 showed nearly >1.5-fold higher internalization. Importantly, the DOTAGA chelator have 177 Lu-9 contains the same chelating agent 177 Comparable cellular uptake and In contrast, the rigid cyclohexyl linker showed low internalization (approximately 70%) (Table 7). When modified, it has a DOTAGA chelator 177 The Lu-10 is 177 Lu-8 and 177 Compared to Lu-9, The DOTA-monoamide-modified mAb showed lower uptake and internalization. 177 Lu-L11 also contains a cyclohexyl linker, 177 Compared to Lu-L1, >1.5 times lower Including 177 It showed lower uptake compared to Lu-10. Furthermore, do 177 Lu-L12 exhibits low uptake compared to most agents from its series. The p-bromopyridyl modified 177 The Lu-13 is 177 Similar cellular uptake and internalization to Lu-1 The migration characteristics of the albumin-bound 4-(p-iodophenyl)-butyric acid were demonstrated. 177 The Lu-14 , showing relatively higher uptake in PSMA(+) PC3 PIP cells at 2 hours.

[0195] [Table 6]

[0196] [Table 7]

[0197] [Table 8]

[0198] 5.3.3 Biodistribution studies. Both PSMA+ PC3 PIP and PSMA- PC3 flu tumors were injected into the upper abdominal cavity. The newly developed 17 7 The tumor uptake and in vivo pharmacokinetics of the Lu compounds were evaluated. The radiotracer dose was ~1.6 7±0.2 MBq (~45±5 μCi) was administered intravenously for all studies presented herein. Based on initial biodistribution studies 24 hours after injection, more details at longer time points up to 72-96 hours Several ligands were selected for biodistribution studies. 177 Lu-7 (Br-benzyl modified (without urea groups attached) and rigid linkers 177 Lu-11 and 177 With the exception of the Lu-12, All compounds were highly uptaken into PSMA(+) tumors at >18% ID / g 24 hours after injection. In male NOD-SCID mice 177 Lu-PSMA-617, 177 Lu-PSMA-I&T, 177 Lu-1, 177 Lu-3 and 17 7 The tissue distribution of Lu-5 is shown in Figures 15 and 16. Mouse body weight and tumor weight is shown in Table 9.

[0199] [Table 9]

[0200] Three hours after injection, 177 Lu-3, 52.6±4.9 %ID / g, and 177 Lu-5 (56.3±18.3) Although significantly higher tumor uptake was observed, 177 Tumor uptake in Lu-1 177 Lu-P SMA-617 and 177 The results were comparable to those of Lu-PSMA-I&T. However, after 24 hours, 177 Lu-3 and 177 Lu- 5, all of which were rapidly cleared due to uptake into PSMA+ PC3 PIP tumors. , 177 Lu-PSMA-617 and 177 In contrast, Lu-PSMA-I&T induced tumor uptake comparable to that of Lu-PSMA-I&T. To, 177 Lu-1 is 177 showed significantly lower tumor uptake compared to Lu-PSMA-617. After 2 hours, we observed no significant differences in tumor uptake of the compounds. All compounds showed low uptake in PC3-flu tumors starting 3 hours after injection. The low binding affinity (<0.3 % ID / g) of the ligand is consistent with its high binding affinity. This indicates that the compound has high specificity.

[0201] The drug was taken up in the tumors at approximately the same rate up to 72 hours after injection, but the drug was not taken up by the normal tissue. Significant changes in tissue uptake were observed. , kidneys and salivary glands and spleen) 177 Lu-PSMA-I&T was significantly higher. The inclusion is 177 In the case of Lu-PSMA-I&T, the rate was 93.39±13.35% ID / g 3 hours after injection. The remaining drugs derived from the drug series showed uptake of <10% ID / g as follows: 177 Lu-PSM A-617 (9.81±6.54% ID / g), 177 Lu-1 (5.17±2.38%ID / g), 177 Lu-3 (7.49 ± 3.21 %ID / g). 1 77 Lu-PSMA-I&T showed rapid renal clearance of 30.39±12.49%ID / g at 24 hours, whereas The drug's renal uptake decreased by approximately three-fold every 24 hours up to 72 hours. 177 Lu -3 and the remaining compounds have a much faster rate of renal clearance (~10-fold greater clearance) , resulting in renal uptake of <0.5 ID / g after 24 hours. 177 Except for Lu-PSMA-I&T, Blood, liver, lungs, stomach, pancreas, spleen, fat, adrenal glands, muscles, small intestine, large intestine, bones and salivary glands Uptake into normal tissues, including the serotonin receptor agonist, was <0.5%ID / g 3 hours after administration. 177 Lu-PSMA-I & Although T was highly taken up in the spleen and salivary glands after 3 hours, it was not significantly increased within 24 hours (these The drug was rapidly cleared into tissues (<1% ID / g) with uptake comparable to that shown by a range of other drugs. Lanced.

[0202] Selected, 177 p-Iodobenzyl analogues of Lu-1 and halobenzyl-modified urea-tert-butyl esters Ligands without a targeting moiety, 177 Lu-L7 and 177 Lu-L14 and bromobenzyl modified Decorated medicines,177 Lu-L8, 177 Lu-L9 and 177 The tissue biodistribution data of Lu-L10 is shown in Figure 17. Drugs 177 The Lu-2 is 177 Compared with Lu-L1, it showed significantly higher tumor uptake 3 hours after injection. Tumor uptake and retention was observed for up to 72 hours. 177 Lu-L7 and 177 Lu-L8 is , modified with DOTA-Bn-SCN chelator, 177 Compared to Lu-L7, 177 Lu-L8 is At all time points, there was significantly higher tumor uptake and retention. This highlights the importance of the bromobenzyl group for tumor retention (55.4±7.2 vs. 25.4 at 2 h) ±7.2 % ID / g; 40.6±7.0 vs 7.0±1.5 % ID / g at 24 h; 27.0±7.0 vs 7.0±3 at 48 h. 3 % ID / g and 24.9±2.3 vs 2.3±0.0 % ID / g). 177 Compared with Lu-PSMA-I&T , which showed much faster renal clearance.

[0203] Has DOTAGA chelating agent 177 Lu-L9: Up to 72 hours after injection 177 Compared with Lu-PSMA-I&T , which showed significantly higher tumor uptake and retention, but much faster renal clearance (24 h Approximately 30-fold higher renal clearance (149.7±32.0% ID / g at 2 hours vs. 5.9±2.7% ID / g at 24 hours) The rigid cyclohexyl linker enhanced cellular uptake compared to L1. ( 177 Lu-L10 and 177 Lu-L11), respectively 177Lu-L9 and 177 Compared to Lu-L1, similar or lower uptake. Drugs with 177 Lu-L13 is 177 It maintains similar tumor uptake as Lu-L1 but at a much faster rate was quickly cleared from normal tissues.

[0204] 177 The biodistribution of Lu-14 was consistent with that reported for albumin binders. The tumor uptake was highest at 24 hours after injection and remained high up to 48 hours. ,First, 177 Lower initial renal uptake (49.49±19.55 % ID / g) compared with Lu-PSMA-I&T. ), but with a 10-fold reduction in activity (93.39 ± 13.35 %ID / g at 24 h vs. 9.55 ± 3.85 at 48 h). Clearance of activity was only approximately three-fold (17.47 ± 4.18 %ID / g at 48 h) compared with 17.5 ± 4.5 %ID / g at 48 h. The drug also had the highest blood uptake in the series. (16.13 ± 2.33 %ID / g at 2 hours after injection, followed by 5.05 ± 0.05 %ID / g at 2 hours and 48 hours Both the spleen and salivary glands showed the highest densities from this series (2.48 ± 0.44 %ID / g). The antibody showed nonspecific uptake.

[0205] 5.3.4 SPECT / CT imaging. 177 Lu-1 and 177 SPECT / CT imaging with Lu-14 was performed to confirm the in vivo pharmacokinetics. As expected from the biodistribution data, 177 SPECT / CT 2 to 192 hours after administration of Lu-1 Imaging revealed high uptake, as expected, in the PSMA+ PC3 PIP tumor (right). However, it was not observed in the PSMA-PC3 flu tumor (left). Consistent with the data, the ligand showed very low uptake in the kidney and all normal tissues. The status of PSMA expression in PSMA(+)PC3 PIP tumors was also examined in imaging experiments. As shown in Figure 18B, compared with the control tumor (no radioactive substance injection), hand, 177 From day 1 to day 12 after treatment with Lu-1 (37 MBq), PSMA(+) staining was observed in PC3 PIP tumors. A significant decrease in color was observed, which may be due in part to downregulation of PSMA expression. The effect of treatment was to increase the number of PSMA binding sites in treated tumors. 177 Lu-1 binds Although low, the relatively low incidence of Higher staining indicates tumor 177 This coincides with the clearance of Lu-1.

[0206] 111 MBq (3 mCi) 177 Lu-PSMA 617, 177 Lu-2, 177 Lu-4 and 177 The group of mice administered Lu-6 ( A comparison of hematological and blood chemistry parameters after 8 weeks (n=3) is shown in Table 10.

[0207] [Table 10]

[0208] 5.3.5 Radionuclide therapy in cellular and animal models. 177 Lu-1 and 177 48 in Lu-8 The clonal formation efficiency of PSMA(+) PC3 PIP cells after 2 h incubation is shown in Figure 26. The cell viability was measured by incubating the cells for 2 and 24 hours. After 48 hours of incubation, there was no significant loss of colony survival. It was observed that 177 Lu-1 and 177 D0 (37% survival) for Lu-8 was in the same range of 0.3-0.6 μCi / mL. It was.

[0209] NOD / SCID mice (n=10 / group) bearing PSMA+ PC3 PIP tumors were treated with 111 MBq (3 mCi) of ( 177 Lu-PSMA-617, 177 Lu-1, 177 Lu-3 and 177 Lu-5) and the control group (saline administration) A pilot treatment trial was conducted in which a single dose of 100 mg ... The tumor volumes of the mice in the treatment group exceeded five times their initial tumor volumes within 14 days. Mice were euthanized within 4 weeks after injection, primarily due to sudden weight loss and tumor All treatment groups showed significant tumor regression by week 8. The differences between the treatment groups were statistically significant compared to the untreated group by log-rank test (P = .01). 0.002). As shown in Table 8, 177 Lu-3 and 177 Only one mouse in the Lu-PSMA-617 treated group But also at high doses 177 Two mice in Lu-4 reached a tumor volume of >4. After 8 weeks, blood Three mice were selected from each treatment group for detailed analysis and kidney dissection. Selected metabolic and complete blood count data are provided in Table 3, Figures 24 and 25. All animals in the therapy study had normal creatinine (0.3-0.4 mg / dL) and blood urea nitrogen. As shown in Figure 11, 177 Only one mouse in the Lu-PSMA-617-treated group Only sucrose increased the neutrophil count (later to 3.5 ± 3.8 K / ml; control, 2.6 K / ml). In addition, 177 All three mice treated with Lu-PSMA-617 had the same results as the control group and other groups. Platelets were significantly lower compared to the treatment group.

[0210] Pathological examination of an extensive panel of normal tissues by H&E staining showed that the In comparison, there were only modest changes in the treatment group. were primarily identified in the testis and lacrimal gland for all treatment groups (Figure 25). 177 Lu-5 One mouse treated with 177 The most significant changes in all three mice treated with Lu-PSMA-617 were Changes in the kidney were minimal, with no significant tubular changes in all treatment groups. The parotid gland (usually adjacent to the extraorbital lacrimal gland) was clearly spared. Lu-PSMA-617 177 In addition, mild changes were observed in the suborbital lacrimal gland. teeth, 177 Similar changes in the extraorbital lacrimal glands were particularly evident in mice treated with Lu-PSMA-617. showed. 177 One mouse treated with Lu-5 had thymic lymphoma with a morphology similar to NOD / SCI The onset of the disease was usually at about 6 months, consistent with thymic T-lymphoblastic lymphoma, the expected cause of death in D mice. T-lymphoblastic lymphoma is promoted by irradiation and some carcinogens and is associated with NOD Related to endogenous retrovirus / retroelement interactions in the / SCID mouse strain do. 177 In some mice treated with Lu-PSMA-617, tumor cell proliferation was observed in the lungs (<1 mm), as well as in the tumor blood vessels. Tumors and metastases were seen in body cavities and serosal surfaces (carcinomatosis), and blood smears showed no clear The cells were up to 25 μm in size and had very large nuclei (in mice, usually 2–3 The animals have 10 nucleoli and a high rate of mitosis. Degenerative changes in the testes and lacrimal glands indicate that these animals are different from other Treated mice received similar treatment.

[0211] All animals tested had normal creatinine (0.3-0.4 mg / dL) and blood urea nitrogen concentrations. there were.

[0212] 177 Lu-4 and 177 Treatment monitoring for Lu-6 has been completed, but 177 Lu-1 and 177 Lu-PSM A-617 was evaluated for a predefined endpoint (tumor volume of 1800 mm 3 and weight loss >15%) The treatment trial was continued until the results were achieved. 177 Lu-1 and 177 Survival data for Lu-PSMA-617 show. 177 The median survival time for Lu-PSMA-617 was 133 days, compared with 177 234 days for Lu-1 In contrast, this treatment group did not show any changes. The individual tumor volume measurements are shown in FIG. 177 Considering that Lu-1 showed good therapeutic effects, , with increasing doses of 18.5 MBq (0.5 mCi), 37 MBq (1 mCi) and 111 mMBq (3 mCi) (n=5 / group). Growth retardation studies were performed up to 90 days. As shown in FIG. 177 Lu-1 was in all treatment groups. The 0.5 mCi dose of 5 mice treated with 100 mg / kg / day of ... Four of the mice reached a relative volume >5 at 8 weeks post-treatment, whereas only 1 of the mice treated with the 37 MBq dose achieved a relative volume >5 at 8 weeks post-treatment. Only one mouse in the group treated with 37 MBq and 111 MBq showed a similar effect. Mice showed complete tumor regression by 120 days, nearly as fast as that observed in the initial treatment trial. Similar therapeutic effects were observed.

[0213] Using the PC3 PIP flank tumor model, a dose of 111 MBq was administered from 24 to 192 hours after treatment. Using 177 Theranostic (SPECT / CT imaging and treatment) trials of Lu-8 (n= 10) were also conducted. SPECT / CT imaging revealed 177 Profile very similar to Lu-1 (low positive Although the uptake in normal tissues and kidneys was clarified, as expected from the biodistribution data, To, 177 There was a relatively higher background uptake compared to Lu-1. Mice (used for SPECT / CT imaging) died unexpectedly, but after 8 weeks had tumors with relative volumes >5. Only two mice showed tumor growth. The remaining treated mice survived tumor-free for 10 months. and evaluated for toxicity.

[0214] 5.3.6 Discussion A new series of PSMA-based small molecule drugs for the treatment of patients with metastatic prostate cancer 177 Lu label The SAR of theranostic drugs was investigated. 177 Lu is a promising material due to its emission characteristics, manufacturability, and radiation safety. The issue of integrity 131 I and 90 Y, PSMA-targeted and other cancers It is the beta-emitting isotope of choice for therapeutic use. The main reason for this study is the molecular and structural the origin of PSMA, i.e., the PSMA binding site that explains the significant difference in PK between type I and type II There is a need to understand the interaction of PSMA with the targeting moiety Lys-Glu-urea during Understanding this, 177 Lu-PSMA-617 and 177 Compared with Lu-PSMA I&T, radiation-related side effects This will allow us to move on to the search for Type II drugs with less effect. The agent is based on a well-studied, long-linker-based targeting platform. Built on 17, 21, 26, 36-42 From a rigorous synthetic standpoint, compounds that bind to PSMA Radiation Theranostic Agents and Chemical Space for The aim was to expand the scope of this study by developing low molecular weight PSMA-based radionuclide therapy. No other synthetic approach directed toward this goal is known in the art.

[0215] The compounds of the present invention were synthesized using optimized solution phase chemistry. Thus, the method of the present invention comprises: It can be easily adapted to industrial-scale preparations and is more cost-effective than solid-phase peptide synthesis. These radiolabeled therapeutics are expected to be inexpensive and can be easily isolated from the radioactive peaks to produce free ligand. By separating the radioactive materials, we synthesized them with the most specific radioactivity possible. The microwave radiolabeling method rapidly and efficiently produces radioactive markers at a low temperature of 40°C. The cellular uptake and internalization, followed by tissue biodistribution studies, were systematically performed. As a result, several important findings became clear.

[0216] First, by attaching a p-halobenzyl moiety to the PSMA-targeting Glu-Lys-urea This resulted in high tumor uptake and low non-specific binding to normal tissues. R studies have demonstrated that the macrocyclic chelator DOTA-Bn-SCN ( 177 Lu-8) and And DOTAGA( 177 The Lu-9 drug is a DOTA-monoamide chelate with three acetylated arms. Agents (e.g., 177 Lu-1), it was taken up and retained in the tumor at a higher level. These drugs are 177 It exhibits higher plasma binding compared to Lu-1 and 177 Lu-PSMA I&T showed higher initial renal uptake and much faster renal clearance compared to Third, compared to rigid linkers, drugs with p-bromobenzyl moieties have a higher affinity for linear linkers. showed higher tumor uptake and retention with 177 Lu-1 vs. 177 Lu-11, and 177 Lu- 9 pairs 177 This observation was also reflected in cellular uptake studies, 177 Lu-10 / 177 Lu-11 The cyclohexyl linker showed higher intracellular uptake.

[0217] Fourth, as others have recently reported, the attachment of an albumin-binding moiety , by increasing serum half-life 43, 44 , 177 Lu-14 stays in the tumor longer However, as reported elsewhere, these agents have not been shown to be 177 Lu- PSMA-617 or 177 Associated with significantly higher renal retention compared with Lu-PSMA-I&T Given that these agents exhibited distinct characteristics associated with Type I agents, These drugs are 131 I-MIP1095 2, 12, 13 As recognized in 177 Compared to Lu-PSMA-617 , uptake in the salivary and lacrimal glands is expected to be much higher. , and severe abnormalities in normal organs were observed in the lacrimal gland. 177 Lu-PSMA agent substitute organ and Most preclinical studies have shown that the lacrimal gland can be used to Although no studies have been reported on the efficacy of CTT1403 in the treatment of lacrimal glands, the albumin binder CTT1403 has been shown to be highly absorbed into the lacrimal gland. Shown 22 .

[0218] Fifth, renal uptake is low according to autosomal recession studies. 177 Lu-1 showed significant tumor uptake No change, 10-fold renal blockade, but high initial renal uptake 177 Lu-9 showed no significant tumors This suggests that the D-lysine agonist, which is a vasodilator, may be a potential treatment for cancer. Amino acid-based nephroprotectants such as glutamic acid / polyglutamic acid have been shown to be 177 Renal uptake of Lu-PSMA I&T It has been shown that the And it is an important discovery. 45The results of this study showed that uptake in renal proximal tubule cells was partial. In fact, it was confirmed that this was due to PSMA expression. 46 Nephrotoxicity can be 177 Lu-PSMA radionuclide therapy While not a major problem with the law, this blocking strategy 225 PSMA-based alpha particles using Ac-PSMA-617 Salivary gland-related radiation toxicity in neonatal therapy. 47 , and is often obtained with alpha particle-based RPTs. long-term nephrotoxicity 31, 48 It may be helpful for this.

[0219] 5.4 Materials and Methods Solvents and chemicals purchased from commercial sources were of analytical grade or better and were further refined. Diisopropylethylamine (DIEA), triethylamine (TEA) , Lutetium(III) nitrate, N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium Tetrafluoroborate (TSTU), p-aminomethylbenzoic acid, Boc-5-aminovaleric acid, Boc-6- Aminohexanoic acid-N-hydroxysuccinimide and disuccinimidyl suberate DOTA-tris(t-butyl ester)-monoacid (B270) and D OTA-NHS-ester (B280) was purchased from Macrocyclicics, Inc. (Dallas, TX). -Free[ 177 Lu]Cl3 (NEZ307000MC) from PerkinElmer Health Sciences Inc (Shelton, CT, USA) Analytical thin-layer chromatography (TLC) was performed using Aldrich aluminum foil. The experiment was carried out using 0.2 mm silica gel Z19, 329-1 plates and was performed using ultraviolet light (254 nm), I2 and 1 Visualization was performed using a 5% ninhydrin solution in ethanol. Flash chromatography The procedure was performed using silica gel purchased from Bodman (Aston PA), MP SiliTech 32-63 D 60A. All experiments were performed in duplicate or triplicate to ensure reproducibility. HPLC purification of non-radiolabeled compounds was performed using Phenomenex C 18 Luna 10×250 mm 2 Column The analysis was performed on an Agilent 1260 infinity LC system (Santa Clara, CA) using water (0.1% T The column was eluted with 88 / 22 water / CH3CN (0.1% TFA) (A) and CH3CN (0.1% TFA) (B). The mobile phase was 88 / 22 water / CH3CN for 1-5 min, followed by 0 ~88 / 12 water / CH3CN for 5 min and 88 / 22 water / CH3CN for 5-25 min to 44 / 56 water / acetonitrile A gradient HPLC method was used, including a flow rate of 8 mL / min up to 100 µL. 登録商標 500MH z spectrometer 1 H NMR spectra were recorded. Chemical shifts (δ) were determined by the imperfect NMR solvent. Reported in ppm downfield, with reference to the proton resonance resulting from perdeuteration. Low-resolution ESI mass spectra were obtained on a Daltonics Esquire 3000 Plus spectrometer. High-resolution mass spectra were obtained from the Mass Spectrometry and Proteomics Facility at the University of Notre Dame, Notre Dame. Dam, IN, using ESI, by direct injection on a Bruker micrOTOF-II or by Bruker Either LC elution by ultra-high pressure Dionex RSLC using a C18 column coupled with a micrOTOF-Q II The compound, Di-tert-butyl(((S)-6-((4-bromobenzyl)amino)-1-(tert- butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamic acid, 5a, and Di-tert- Butyl(((S)-1-(tert-butoxy)-6-((4-iodobenzyl)amino)-1-oxohexane-2-yl (Carbamoyl)-L-glutamic acid, 5b, was prepared using the method reported below with some modifications. Made 49 C eluted with 70-80% MeOH / HO 18 Column chromatography of the crude product was purified to give 0.90 g (62%) of an oil.

[0220] 5.4.1 Analytical data of representative compounds Representative compounds of formula (I) are provided in Chart 1. Chart 1: [ka]

[0221] The following compounds are representative of compounds of formula (I): [ka] [ka] [ka]

[0222] Ligands L1 and L2 were synthesized according to standard synthetic routes as shown in Scheme 2. Below, we explain L2 in detail.

[0223] (14S,18S)-9-(4-bromobenzyl)-2,8,16-trioxo-1-(4,7,10-tris(carboxymethyl) (ethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,9,15,17-tetraazaicosane-14, 18,20-Tricarboxylic acid (L1). Boc-5-aminovaleric acid (0.087 g, 0.40 mmol), TSTU (0.121 g, 0 A mixture of 1.40 mmol) and DIPEA (0.103 g, 0.80 mmol) in DMF (1 mL) was stirred at room temperature for 1 h. After dilution with DMF (1 mL), compound 1a (0.264 g, 0.40 mmol) was added dropwise to the reaction mixture. Stir for 4 h, concentrate, and elute with 100% (in 0.1% TFA) C 18 Column Chromatography Purification gave 0.151 g (44%) of an oil as compound 2a. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.95 (s, 1H), 7.40 (d, J = 10 Hz, 1H), 7.34 (d, J= 10 Hz, 1H), 7.24 (s, 1 H), 7.04 (d, J= 5 Hz, 1H), 6.97 (d, J = 10 Hz, 1H), 5.48-5.44 (m, 1H), 4.87-4.83 (m, 1H), 4.48-4.36 (m, 2H), 4.26-4.21 (m, 2H), 3.66-3.63 (m, 1H), 3.12-2.95 (m, 4H), 2.90 (s, 1H), 2.81 (s, 1H), 2.73 (s, 2H), 2.33-2.27 (s, 1H), 2.26-2.23 (m, 3H), 2.00-1.98 (m, 1H), 1.77 (m, 1H), 1.66-1.60 (m, 2H), 1.37 (s, 36H), 1.26-1. 07 (m, 2H); ESMS m / z: 857.3 (M + H) + A cold solution of 2a (0.145 g, 0.17 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated and diluted with 40% acetonitrile. / C eluted with water 18 The product was purified by column chromatography and lyophilized to give a white solid (0.06 mL). Obtained 7 g (67%) as compound 3. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.55 (d, J= 5.0 Hz , 1H), 7.48 (d, J = 5.0 Hz, 1H), 7.19-7.15 (m, 2H), 4.62-4.53 (m, 2H), 4.33-4.27 (m, 2H), 3.40 (s, 1H), 2.98-2.92 (m, 2H), 2.83 (s, 1H), 2.56 (s, 1H), 2.44 (s, 3H), 2.16 (bs, 1H), 1.93-1.84 (m, 2H), 1.74 (s, 2H), 1.67-1.60 (m, 5H), 1.41-1.4 0 (m, 2H); ESMS m / z: 589.1 (M + H) + DOTA-NHS-ester (0.090 g, 0.12 mmol), 3a( The reaction mixture of 1,2-diphenylmethane (0.069 g, 0.08 mmol) and DIPEA (0.102 g, 0.79 mmol) was stirred at room temperature for 3 h. The reaction mixture was concentrated and purified by HPLC to give the desired ligand L1. 1 H NMR (500 MH z, DMSO-d6) δ ppm 12.50 (bs, 5H), 8.38 (bs, 1H), 7.57 (d, J = 5 Hz, 1H), 7.51 ( d, J = 5 Hz, 1H), 7.18-7.12 (m, 2H), 6.55 (bs, 1H), 6.37-6.29 (m, 2H), 4.53 (s, 1H), 4.46 (s, 1H), 4.11-4.04 (m, 3H), 3.80 (bs, 4H), 3.25-2.77 (m, 10H), 2.39-2 .37 (m, 2H), 2.27-2.20 (m, 4H), 1.94-1.92 (m, 1H), 1.72-1.63 (m, 2H), 1.65-1.39 (m, 9H), 1.28-1.22 (m, 4H); HRESI-MS: Calcd. for C 40 H 62 BrNO 15 , 973.3513 [M+H] + , Actual value: 973.3542.

[0224] (14S,18S)-9-(4-iodobenzyl)-2,8,16-trioxo-1-(4,7,10-tris(carboxymethyl) (ethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,9,15,17-tetraazaicosane-14, 18,20-tricarboxylic acid (L2). Compound L3 is prepared from 1b as the starting reactant and 2c and 3c as intermediates. Compound 7c was prepared according to the same procedure as in Scheme 3 by using the starting compound The crude product was prepared using the same procedure as described for 7a, using 5b as a solid. Purify using column chromatography eluting with 10% acetone / CH2Cl2 to obtain a colorless oil. Obtained the substance. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.45 (m, 1H), 7.35 (t, J = 5 Hz, 1H ), 7.29 (m, 1H), 7.21 (m, 1H), 7.15 (d, J = 5 Hz, 1H), 5.70 (m, 1H), 4.58-4.47 ( m, 1H), 4.35-4.27 (m, 2H), 4.09 (m, 1H), 3.40-3.30 (m, 1H), 3.16-3.08 (m, 2H), 2 .80 (s, 2H), 2.41-2.26 (m, 4H), 2.09-2.04 (1H), 1.85-1.80 (m, 1H), 1.75-1.62 (m, 4H), 1.58-1.52 (m, 3H), 1.44 (m, 27H), 1.35 (m, 6H).

[0225] Compound 3c was prepared using 2c as the starting material using the same procedure as described for 3a. The crude product was purified using HPLC. Spectral data for L2: 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.39 (bs, 1H), 7.38 (t, J = 10 Hz, 1H), 7.31 (m, 1H), 7.21-7.18 (m, 2H), 6.36-6.29 (m, 2H), 4.56-4.50 (m, 2H), 4.11-4.01 (m, 3H), 3.82 (s, 3H), 3.59 (s, 4H), 3.19-3.17 (m, 9H), 3.06 (s, 9H), 2.39 (t, J = 5 Hz, 1H), 2.30-2.2 3 (m, 3H), 1.91 (m, 1H), 1.73 (m, 1H), 1.63-1.39 (m, 8H), 1.24 (m, 2H); HRESI-MS : Calcd. for C 40 H 61 IN8O 15 , 1020.3301 [M+H] + .

[0226] (14S,18S)-9-(4-bromobenzyl)-1,8,16-trioxo-1-(4-((2-(4,7,10-tris(calcium) (carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl)phenanthroline 7b was reacted with 7a in the same manner as in 7a. Boc-5-aminovaleric acid was converted to Boc-6-aminohexanoic acid-N-hydroxysuccinimide by the method Prepared by replacing with: Yield 0.115g (46%) of an oil. 1 H NMR (500 MHz, DMSO-d 6) δ ppm 7.41 (d, J= 10 Hz, 1H), 7.35 (d, J = 10 Hz, 1H), 7.04 (d, J = 5 Hz, 1H ), 6.97 (d, J = 10 Hz, 1H), 5.47 (d, J = 10 Hz, 1H), 5.10-5.03 (m, 1H), 4.63-4.5 6 (m, 1H), 4.44 (s, 1H), 4.39 (s, 1H), 4.27-4.22 (m, 2H), 3.29-3.21 (m, 1H), 3.0 7-3.01 (m, 5H), 2.30-2.19 (m, 4H), 2.03-1.98 (m, 1H), 1.80-1.75 (m, 1H), 1.66-1. 58 (m, 7H), 1.49-1.45 (m, 4H), 1.38 (m, 27H), 1.27-1.04 (m, 5H); ESMS m / z: 871.3 (M + H) + Compound 3b was prepared by the same procedure as described for 3a, using 2b as the starting material. The crude product was used directly in the next step without further purification. there was. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.73 (bs, 3H), 7.76 (d, J = 10.0 Hz, 1H), 7.50 (d, J= 10.0 Hz, 1H), 7.18-7.14 (m, 2H), 6.34 (m, 2H), 4.53 (s, 1H), 4.46 ( m, 2H), 3.22-3.17 (m, 2H), 2.82-2.73 (m, 2H), 2.51 (s, 1H), 2.37 (s, 1H), 2.25 ( m, 2H), 1.93 (s, 1H), 1.74-1.71 (m, 1H), 1.64 (s, 1H), 1.55-1.40 (m, 6H), 1.35-1 .33 (m, 1H), 1.25 (s, 4H); ESMS m / z: 603.2 (M + H) + . 4(0.065 g, 0.08 mmol), 3b(0 .047 g, 0.08 mmol) and DIPEA (0.101 g, 0.80 mmol), DMSO (1 ml), medium and chamber Warm it up for 3 minutes and mix it. The reaction mixture was not concentrated and purified by HPLC. 1 H NMR (500 MHz, DMSO -d6) δ ppm 12.65 (brs, 5H), 8.42-8.39 (m, 1H), 7.84-7.81 (m, 2H), 7.56 (d, J = 10.0 Hz, 1H), 7.49 (d, J = 10.0 Hz, 1H), 7.38 (d, J = 5.0 Hz, 2H), 7.17-7.12 (m, 2H), 6.36-6.30 (m, 2H), 4.53 (m, 3H), 4.46 -4.40 (m, 5H), 4.10-3.98 (m, 9H), 3. 63 (bs, 5H), 3.26-3.14 (m, 13H), 2.38 (m, 2H), 2.31-2.20 (m, 3H), 1.93-1.92 (m, 1H), 1.72-1.71 (m, 1H), 1.63-1.41 (m, 8H), 1.34 (m, 1H), 1.25 (brs, 3H); HRESI-M S: Calcd. for C 49 H 71 BrNO 16 , 1120.4197 [M+H] + , Actual value: 1120.4200.

[0227] (14S,18S)-9-(4-iodobenzyl)-1,8,16-trioxo-1-(4-((2-(4,7,10-tris(calcium) (carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl)phenanthroline (nyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylic acid (L4). , replacing Boc-5-aminovaleric acid with Boc-6-aminohexanoic acid-N-hydroxysuccinimide The same procedure as described for 2a can be followed by substituting 1b for 1a as the reactant. Spectral data for 2d prepared accordingly. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.66 (b rs, 1H), 7.61 (d, J = 10 Hz, 1H), 7.55 (d, J = 10 Hz, 1H), 7.15 (brs, 1H), 6.90 (d, J = 5 Hz, 1H), 6.84 (d, J = 10 Hz, 1H), 5.30 (m, 1H), 5.09-5.03 (m, 1H), 4.6 3-4.58 (m, 1H), 4.43 (s, 1H), 4.39-4.35 (m, 1H), 4.26-4.20 (m, 3H), 3.07-3.00 (m , 3H), 2.30-2.22 (m, 5H), 2.00-1.98 (m, 1H), 1.80-1.74 (m, 2H), 1.70-1.64 (m, 3H) ), 1.62-1.61 (m, 2H), 1.38 (s, 36H), 1.32-1.09 (m 3H); ESMS m / z: 917.3 (M + H)+ . 3d spectral data. 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.87 (d, J = 10 Hz, 1 H), 7.72 (d, J = 10 Hz, 1H), 7.66 (d, J = 10 Hz, 1H), 7.30 (d, J = 10 Hz, 1H), 7 .04-6.99 (m, 1H), 4.59-4.51 (m, 1H), 4.32-4.25 (m, 3H), 3.69-3.66 (m, 1H), 3.38- 3.35 (m, 1H), 3.09 (m, 1H), 2.96-2.89 (m, 1H), 2.51-2.45 (m, 1H), 2.43-2.39 (m, 3H), 2.17-2.14 (m, 1H), 1.91-1.72 (m, 2H), 1.71-1.62 (m, 6H), 1.45-1.28 (m, 8H); ESMS m / z: 649.2 (M + H) + Spectral data for L4. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.16 (bs, 4H), 8.41 (m, 4H), 7.82 (t, J = 10.0 Hz, 2H), 7.72 (d, J = 10.0 Hz , 1H), 7.66 (d, J = 10.0 Hz, 1H), 7.37 (d, J = 10.0 Hz, 2H), 7.01 (d, J = 5.0 Hz , 2H), 6.37-6.30 (m, 2H), 4.44-4.39 (m, 8H), 4.11-3.97 (m, 9H), 3.66-3.61 (m, 5H) ), 3.16-3.08 (m, 13H), 2.30 (m, 1H), 2.29-2.20 (m, 2H), 1.94-1.92 (m, 1H), 1.71 (m, 1H), 1.66-1.64 (m, 2H), 1.55-1.47 (m, 8H); HRESI-MS: Calcd. for C 49 H 71 IN9O1 6, 1168.4058 [M+H] + , Actual value: 1168.4045.

[0228] (21S,25S)-16-(4-bromobenzyl)-1,8,15,23-tetraoxo-1-(4-((2-(4,7,10-tris( (Carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl Phenyl)-2,7,16,22,24-pentaazaheptacosane-21,25,27-tricarboxylic acid (L5). The compound L5 was prepared according to a multi-step organic synthesis method as shown in Scheme 4. 1a (0.190 g, 0 A solution of Et3N (0.029 g, 0.29 mmol) and DMF (1 mL) was added to dissolve in DMF (1 mL). The reaction mixture was added dropwise to a stirred solution of phenylimidyl suberate (0.223 g, 0.61 mmol). Stir overnight, concentrate, and run on flash column chromatography eluting with 30% acetonitrile / CH2Cl2. Purification by chromatography gave 0.120 g (46%) of an oil. ESMS m / z: 911.3 (M + H) + Compound 8 was prepared using the same method as described for 10. The crude product was purified as 40 Purify by column chromatography eluting with ~60% acetonitrile / CH2Cl2 and obtain 0.09 Yield: 0 g (40%) of an oil. 1 H NMR (500 MHz, CDCDMSO-d6) δ ppm 7.70 (brs, 1H), 7. 62 (d, J = 5.0 Hz, 1H), 7.55 (d, J= 10.0 Hz, 1H), 6.91 (d, J = 5.0 Hz, 1H), 6.85 (d, J = 5.0 Hz, 1H), 5.41 (d, J = 5.0 Hz, 1H), 5.33 (d, J = 10.0 Hz, 1H), 5.09- 5.02 (m, 1H), 4.45-4.35 (m, 2H), 4.25-4.19 (m, 3H), 3.41-3.34 (m, 1H), 3.12-3.05 (m, 2H), 2.57-2.50 (m, 2H), 2.31-2.18 (m, 5H), 1.97 (m, 1H), 1.86-1.77 (m, 3H), 1.71-1.63 (m, 5H), 1.57-1.46 (m, 5H), 1.37 (m, 27 H); ESMS m / z: 957.2 (M + H) + Compound 12 was prepared using the same method as described for 3a. The crude product was obtained in 40-50% yield. Purify by C-18 column chromatography eluting with acetonitrile / water to obtain a concentration of 0.057 Yield: 1.0 g (58%) of product. ESMS m / z: 743.2 (M + H) + Compound L6 was synthesized by the synthesis of compound L6 as a starting material. The reaction mixture was prepared using the same procedure as described for L1 using 1a and 12. It was concentrated and purified by HPLC. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.97 (brs, 1H), 8.43 (t, J = 5.0 Hz, 1H), 7.83 (d, J= 10.0 Hz, 2H), 7.78-7.73 (m, 1H), 7.56 (d, J= 10 .0 Hz, 1H), 7.50 (d, J = 10.0 Hz, 2H), 7.38 (d, J = 10.0 Hz, 2H), 7.17-7.14 (m, 2H), 6.36-6.30 (m, 2H), 4.52-4.39 (m, 8H), 4.09-4.00 (m, 6H), 3.65-3.60 (m, 5H), 3.26-3.08 (m, 11H), 3.07-3.04 (m, 3H), 2.36-2.33 (m, 1H), 2.27-2.22 (m, 2H), 2. 06-2.01 (m, 2H), 1.93-1.92 (m, 1H), 1.73-1.64 (m, 2H), 1.51-1.43 (m, 11H), 1.26- 1.19 (m, 6H); HRESI-MS: Calcd. for C 55 H 82 BrN 10 O 17 , 1233.5037 [M+H] + , Actual value: 1 233.5029.

[0229] (21S,25S)-16-(4-iodobenzyl)-1,8,15,23-tetraoxo-1(4-((2-(4,7,10-tris( Carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl) Phenyl)-2,7,16,22,24-pentaazaheptacosane-21,25,27-tricarboxylic acid (L6). Compound Compound L7 was prepared using the same method as described for L5. The crude product was purified by HPLC. Made. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.97 (brs, 1H), 8.43 (t, J = 5.0 Hz, 1H ), 7.83 (d, J= 10.0 Hz, 2H), 7.78-7.72 (m, 2H), 7.67 (d, J= 5, 1H), 7.55 (bs, 1H ), 7.39 (d, J = 10.0 Hz, 2H), 7.03-6.99 (m, 2H), 6.36-6.30 (m, 2H), 4.52-4.39 (m , 4H), 4.11-4.00 (m, 6H), 3.64 (m, 4H), 3.26-3.04 (m, 14H), 2.35-2.33 (m, 1H), 2 .27-2.22 (m, 3H), 2.20-2.01 (m, 2H), 1.93-1.92 (m, 1H), 1.73-1.62 (m, 2H), 1.51- 1.43 (m, 11H), 1.26-1.19 (m, 6H); HRESI-MS: Calcd. for C 55 H 82 IN 10 O 17 , 1281.4899 [M+H] + , Actual value: 1281.4889.

[0230] (13S,17S)-8-(4-bromobenzyl)-7,15-dioxo-1-((4-((1,4,7,10-tetrakis(calcium) 1,4,7,10-tetraazacyclododecan-2-ylmethylphenylamino -Thioxo-2,8,14,16-tetraazanonadecane-13,17,19-tricarboxylic acid (L8). p-SCN-Bn-D OTA (12.2 mg, 17.7 μmol) was dissolved in 5a (12.2 mg) and DIPE in DMSO (130 μL) equilibrated to 40 °C. The reaction mixture was stirred at 40° C. for 4 h and then cooled to 4° C. The reaction mixture was purified by reverse phase HPLC (20% ACN for 5 min, then 20 ~40% for 19 minutes). t Approximately 12 minutes. The purified fractions were combined and purified by rotary evaporation. The volume was reduced by filtration and then freeze-dried. ESI-MS: 1138.37[M+H] + , Actual value: 1138.5. Compound 1 was further purified by HPLC using a gradient method. The HPLC method used a mobile phase of 88% water (0.1% TFA) and 22% CH3CN (0.1% TFA) for 1-5 min, followed by 88% water (containing 0.1% TFA) for 0-5 min. ) and 12% CH3CN (0.1% TFA), and 88% water to 44% water and 12% acetonitrile for 5–25 min. The gradient included 56% acetonitrile at a flow rate of 8 mL / min.

[0231] (13S,17S)-7,15-dioxo-1-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10 -Tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1-thioxo-2,8,14,16-tetra (L7) p-SCN-Bn-DOTA (8.0 mg, 11.6 umol ) was added to a stirred solution of 5a and DIPEA (10.1 uL, 58 umol) in DMSO (150 uL) equilibrated to 40 °C. The reaction mixture was stirred at 40° C. for 4 hours, then cooled to room temperature, diluted with water, and finally The mixture was purified by two-phase HPLC (hold 12% ACN for 5 min, then 12-32% for 20 min). Rt approx. 12 min. The purified fractions were combined, evaporated to a reduced volume, and then lyophilized. M / Z calcd, 970 .41. M / Z actual value, 970.4.. ESI-MS: 970.05[M+H] + , Actual value: 970.1.

[0232] (3S,7S)-12-(4-bromobenzyl)-5,13,19-trioxo-22-(4,7,10-tris(carboxy) Methyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,18-tetraazadocosane-1 ,3,7,22-tetracarboxylic acid (L9). DOTA-GA anhydride (0.087 g, 0.19 mmol), 8a (0.075 g, 0.1 A suspension of 0.3 mmol) and DIPEA (0.066 g, 0.51 mmol) was sonicated at room temperature for 1 h and then sonicated for another 2 h. The reaction mixture was concentrated and purified by HPLC. ESMS m / z: 1047.2 (M + H) + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.66 (bs, 4H), 7.86-7.82 (m, 1H), 7.56 (d , J = 10 Hz, 1H), 7.50 (d, J = 10 Hz, 1H), 7.15 (m, 2H), 6.34-6.29 (m, 2H), 4.52 (s, 1H), 4.45 (s, 2H), 4.12-4.04 (m, 5H), 3.50 (m, 4H), 3.29 (m, 3H), 3.19 (m, 3H), 3.07-2.90 (m, 8H), 2.38 (m, 3H), 2.25 (m, 3H), 1.94-1.90 (m, 3H), 1.71 (m, 2H), 1.53-1.43 (m, 6H), 1.42 (m, 1H), 1.41-1.23 (m, 3H); ESMS m / z: 1047.2 (M + H ) + .HRESI-MS: Calcd. for C 43 H 65 BrNO 17, 1047.3714 [M+H] + , Actual value: 1045.3705.

[0233] (((1S)-5-((1R,4r)-N-(4-bromobenzyl)-4-((4-carboxy-4-(4,7,10-tris(calcium) 1,4,7,10-tetraazacyclododecan-1-yl butanamide methyl L-hexane-1-carboxamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid (L 11) (VK03-51). trans-4-(Fmoc-aminomethylcyclohexanecarboxylic acid) (0.069 g, 0.18 A mixture of TSTU (0.055 g, 0.18 mmol) and DIPEA (0.064 g, 0.50 mmol) was dissolved in DMF (1 mL After dilution with DMF (1 mL), compound 5a (0.110 g, 0.17 mmol) was added to the reaction mixture. The reaction mixture was stirred for 4 h, concentrated, and then loaded onto silica gel eluted with 2% MeOH / CH2Cl2. Purification by gel chromatography gave 0.90 g (52.94%) of an oily product. 1 H NMR ( 500 MHz, CDCl3) δ ppm 8.02 (s, 1H), 7.78 (d, J = 5.0 Hz, 3H), 7.60 (d, J = 10.0 Hz, 3H), 7.41 (t, J = 10.0 Hz, 4H), 7.33 (d, J = 10.0 Hz, 3H), 7.08 (m, 1H), 4. 79 (m, 1H), 4.46 (m, 3H), 4.22 (m, 3H), 3.15 (m, 1H), 3.08 (m, 2H), 2.81 (s, 1H) , 2.59 (t, J = 10.0 Hz, 1H), 2.32 (m, 1H), 2.20 (s, 2H), 2.08 (m, 1H), 1.85 (m, 4H), 1.60-1.44 (m, 27H), 1.26 (s, 1H), 1.05-0.88 (m, 3H). Then the oily product was dissolved in 20% piperidine / DMF and stirred at room temperature under N2 for 3 h. The reaction mixture was concentrated and Chromatography using 10% MeOH / CH2Cl2 as eluent afforded 0.030 g of product ( Yield=42.8%). ESMS m / z: 795.2 (M + H) + The product (0.030 g, 0.04 mmol) was dissolved in DO To a suspension of TA-GA anhydride (0.028 g, 0.05 mmol in 1 ml) and DIPEA (0.024 g, 0.18 mmol) The reaction mixture was concentrated, sonicated at room temperature for 1 h, and then stirred at room temperature for 2 h. The product was purified on a Sep-Pak column using 70-80% ACN / H2O as the eluent. ESMS m / z: 125 3.4(M+H) + .

[0234] (((S)-5-(N-(4-bromobenzyl)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10- Tetraazacyclododecan-1-yl)acetamido)methyl)benzamido)-1-carboxype (N-butyl)carbamoyl-L-glutamic acid (L12). L1 was synthesized following a multi-step organic synthesis as described in Scheme 2. DOTA-tBu-ES To the solution of ter, 1 (0.4 g, 0.5 mmol in 7 ml DMF) was added p-aminomethylbenzoic acid (0.076 g, 0.5 mmol). (mmol) was added and the solution was stirred at room temperature overnight. The resulting solution was evaporated under high vacuum. The solid residue was dissolved in 20 / 80 acetonitrile / water and 18 The product was purified using a SepPak column. The product was eluted with 60 / 40, 50 / 50 and 40 / 60 acetonitrile / water fractions. The extracts were combined, evaporated, and then freeze-dried to give a colorless solid. Yield: 0.36 g (80%). SMS m / z: 706.5(M+H) +A solution of compound 2 (0.2 g, 0.29 mmol in DMF) was added to TSTU (0.1 g, 0.34 mmol). (0.5 mmol) and DMAP (0.17 g, 0.1 mmol) were added and stirred at room temperature overnight. The solution was then subjected to high vacuum The solid residue was dissolved in 20 / 80 acetonitrile / water and 18 Purification with SepPak columns The product, compound 3, was eluted in 50 / 50 and 40 / 60 acetonitrile / water fractions and frozen. Drying gave a colorless solid. Yield: 0.23 g, 90%. ESMS m / z: 802.96 (M + H). + . compound 3 (0.2 g, 0.23 mmol) was dissolved in ice-cold TFA / CH2Cl2 (1:1) and stirred for 18 h overnight. Concentrate the mixture and elute with 50-60% acetonitrile / water. 18 Column Chromatography and gave 4 in good yield (0.16 g, ca. 60%) after lyophilization. 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.03 (bs, 1H), 8.09 (d, J = 10.0 Hz, 2H), 7.93 (d, J= 10.0 Hz, 1H), 7.59 (d, J = 5.0 Hz, 3H), 7.43 (d, J = 10.0 Hz, 1H), 4.49 (m, 3H), 4.04-3.9 9 (m, 6H), 3.66 (m, 5H), 2.91 (s, 6H), 2.09 (s, 1H), 1.54 (s, 3H), 1.23 (s, 1H); ESMS m / z: 635.3 (M + H) + Compound 6 was prepared by dissolving 4 (0.200 g, 0.36 mmol) and 5a in DMSO (1 mL). 4 9(0.050 g, 0.16 mmol), followed by DIPEA (0.406 g, 3.65 mmol). l) was added and the reaction mixture was stirred at room temperature overnight. The crude product was concentrated and further purified. A cold solution of 50% TFA / CH2Cl2 (2 ml) was added to 6 (0.050 g, 0.04 mmol), and the mixture was used without further purification. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by HPLC to give the final product in good yield. The product L1 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.80 (brs, 3H), 8.94 (s, 1H), 7. 56 (m, 3H), 7.38-7.34 (m, 4H), 7.15 (m, 1H), 6.35 (d, J = 10 Hz, 2H), 4.64 (m, 4 H), 4.43-4.39 (m, 5H), 4.13-3.99 (m, 7H), 3.63 (bs, 4H), 3.14 (m, 9H), 2.37-2.18 (m, 2H), 1.95-1.89 (m, 1H), 1.74-1.68 (m, 1H), 1.55-1.49 (m, 3H), 1.39-1.30 (m, 2H), 1.05 (m, 1H); HRESI-MS: Calcd. for C 43 H 60 BrNO 15 , 1007.3356 [M+H] + , Actual measurement Value: 1007.3367.

[0235] (14S,18S)-9-((6-bromopyridin-3-yl)methyl)-2,8,16-trioxo-1-(4,7,10-tri (carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,9,15,17-tetra Azaicosane-14,18,20-tricarboxylic acid (L13) (VK02-112).1 H NMR (500 MHz, DMSO-d6) δ ppm 7.21 (m, 1H), 7.13 (m, 2H), 6.12 (bs, 1H), 5.90 (bs, 1H), 4.29 (s, 1H), 4 .19-4.15 (m, 2H), 3.26 (m, 1H), 2.93 (m, 2H), 2.34-2.23 (m, 3H), 2.07-2.02 (m, 1 H), 1.82-1.76 (m, 1H), 1.70-1.64 (m, 3H), 1.56-1.53 ​​(m, 1H), 1.43-1.37 (m, 27H), 1.27 (d, J = 5 Hz, 2H); ESMS m / z: 657.2 (M + H) + The product was purified by C-18 Sep-Pak column. The mixture was purified using 70-90% ACN / HO. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.25 (s, 1H), 7.49 (m, 1H), 7.43 (m, 1H), 5.95 (m, 1H), 5.36 (m, 1H), 4.80 (s, 1H), 4.51 (m, 2H), 4.36-4.33 (m, 3H), 3.24-3.09 (m, 5H), 2.40-2.29 (m, 6H), 2.10-2.05 (m, 2H), 1.85-1.76 (m, 3H), 1.72-1.66 (m, 3H), 1.60-1.36 (m, 36H); ESMS m / z: 856.3 (M + H) + The product was purified on silica gel using 3% MeOH / CH2Cl2 as eluent. Yield 17. The 4% product was purified on a C-18 Sep-Pak column using 50-60% ACN / H2O. Yield 82.6%. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 7.80 (m, 1H), 7.26-7.13 (m, 1H), 6.41-6.36 (m, 1H), 4.48 (dd, J = 2.0, 1.5 Hz, 1H), 4.11 (m, 2H), 3.23 (m, 1H), 2 .79 (bs, 2H), 2.42 (s, 1H), 2.33-2.21 (m, 3H), 1.94 (m, 1H), 1.75-1.65 (m, 2H), 1.57-1.42 (m, 6H), 1.28-1.23 (m, 3H), 1.10 (dd, J = 5, 2.5, 1.5 Hz, 1H); ESMS m / z: 588.2 (M + H) + .

[0236] (3S,7S,26S,29R)-38-(4-iodophenyl)-5,13,20,28,35-pentaoxo-29-(2-(4,7,10 -Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamide -4,6,12,21,27,34-Hexaazaoctatriacontane-1,3,7,26-tetracarboxylic acid (L14) (S R-IX-14 A).

[0237] 5.4.2 Radiolabeling and serum stability. For each radiolabeling reaction: In 200 mM NaOAc (pH 4-5), mCi 177 Approximately 1 nmol of radioactive ligand per Lu was incubated at 95°C for 5 min. The reaction solution was diluted with 300 μL of water. The composition was determined by injecting 20-40 μL aliquots of the solution onto the HPLC. The radiolabeled product [ 177Lu]X was obtained in approximately 98% radiochemical yield. All radiolabeled compounds were purified using Phenomenex C 18 Luna 1 0×250 mm 2 The product was purified using a column and the Agilent Prostar System (Palo Alto, CA). These were measured using a Varian ProStar 325 UV-Vis variable wavelength detector and a Bioscan (Poway, CA) flow cytometer. Counting in-line radioactivity detector, all controlled by Galaxie software The flow rate was controlled at 1:1 with water (0.1% TFA) (A) and CH3CN (0.1% TFA) (B) as the elution solvent. To ensure uniform purity, an isocratic solution was used for the radiation. The specific radioactivity was measured by preparative HPLC purification. The radioactivity eluting at the retention time of the product and the area under the curve for UV absorption are The purity of the test compound was calculated as the ratio of the mass of the corresponding sample to the mass of the corresponding sample. The purity was determined by analytical HPLC to be > 95%.

[0238] The HPLC method and HPLC chromatograms of the radiolabeled compounds were obtained (data not shown). The specific activity of the compound was >37 MBq / nmol (n>12). The eluate was neutralized with 1 M Na2CO3 solution and the volume of the eluate was reduced by drying under vacuum. The fraction was diluted with saline and 2 μl of ascorbic acid (200 mg / mL) to evaluate the biodistribution and imaging of the cells. For all biological studies, including feeding and treatment studies, the desired radioactivity concentration was achieved. The yield of radiolabeled material was also improved by adding 10 mM diethylenetriaminepentaacetic acid (DTPA) to the mobile phase. The samples were evaluated using silica gel instant TLC (ITLC). The diluted samples were spotted onto ITLC silica gel strips and chromatographed. After the migration to the solvent front was complete, the ITLC sample stream was The lip was dried, cut in half, and measured using a Wallac Wizard γ counter (PerkinElmer, Radiolabel yields were determined by counting in a 30-well plate (Boston, MA). Radiochemical purity was determined using a high-speed It was evaluated by liquid chromatography (HPLC) analysis.

[0239] 5.4.3 Cell lines. Androgen-independent cell lines derived from advanced androgen-independent bone metastases. We used sublines of the PC3 human prostate cancer cell line, which express high levels of PSMA. PSMA positive (+) PC3 PIP] or have been modified to express the target [PSMA- Negative (-) PC3 flu]. They were examined by Dr. Warren Heston (Cleveland Clinic) The cells were kindly provided by the University of California, San Diego, Calif. Cells were cultured in 10% fetal bovine serum (FBS) (Sigma-Aldrich, St. Louis, MO, USA) for 1 h at 37 °C. MO) and 1% penicillin-streptomycin (Corning Cellgro, Manassas, VA). PSMA+ PC3 PIP cells were grown in RPMI 1640 medium (Corning Cellgro, Manassas, VA). The cells were grown in the presence of 20 μg / mL puromycin to maintain PSMA expression. All cultures were maintained in a humidified incubator at 37.0°C in an atmosphere containing 5% carbon dioxide (CO2). did.

[0240] 5.4.4 Cellular uptake and internalization measurements. Cellular uptake studies were performed according to previously reported methods. I did the same thing. 50 Cells (1 million) were cultured in growth medium in 6-well plates at 37 kBq / The cells were incubated with 1 μCi / mL of each radiolabeled agent. Specific cellular uptake was measured. To determine cell uptake, cells were preblocked with ZJ43 at a final concentration of 10 μM. Terminated by washing with cold PBS. Incubate at 37°C for 20 and 60 min. Afterwards, the cells were washed with binding buffer and trypsinized using a non-enzymatic buffer. The activity relative to the cells was measured using a gamma spectrometer (1282 Compugamma CS; Pharmacia / LKB Nuclear For the internalization assay, cells were incubated with a non-enzymatic buffer. Aliquots of 1 million cells per tube were then prepared using 37 mL of PBS. Incubated with kBq (1 μCi) of each radiolabeled agent for 1, 2, 4 and 24 hours at 37°C. Receptor endocytosis was considered to be minimal at 4°C, so we performed incubation at 37°C. Internalization assays were performed using only the incubated cells. The medium was removed and the cells were washed once with binding buffer followed by mild acid buffer at 4°C for 5 min. The cells were then washed with the acidic buffer (50 mM glycine, 150 mM NaCl [pH 3.0]). The filaments were harvested and the cells were washed twice with binding buffer. The pooled washes (containing filaments bound to the cell surface) were Combined 177 Lu-labeled agent) and cell pellet (internalized 177 (Contains Lu labeling agent) The cells were counted in an automated gamma counter along with standards. All radioactivity values ​​were expressed per million cells. The results were converted to a percentage of the incubated dose (%ID). Experiments were performed in triplicate. The data were analyzed by linear regression using PRIZM software. Made it fit.

[0241] 5.4.5 Biodistribution. Mice were administered 1.11–1.85 MBq (30–50 μCi) of 150 μL of saline (n = 4). 177 Lu-X Tail The mice were injected intravenously. 10, 30, 60, and 120 minutes after the injection, the mice were decubitused. The animals were sacrificed by mortar and their blood was immediately collected by cardiac puncture. , pancreas, spleen, adipose tissue, kidney, muscle, small and large intestine, bladder, PSMA(+)PC3 PIP and PSMA(- ) PC3 flu tumors were harvested. Each organ was weighed, and tissue radioactivity was measured using an automatic gamma counter (1282 The measurements were performed using a Compugamma CS (Pharmacia / LKBNuclear, Inc., Mt. Waverly, Vic. Australia). The percentage of injected dose per gram of tissue (% ID / g) was calculated using the standard dilution of the first dose. The results were calculated by comparison with the standard deviations from the original values. All measurements were corrected for decay.

[0242] 5.4.6 In vivo blood plasma protein binding and metabolism in mice (n=2 / group). 17 7 Lu-1 and 177 Inject Lu-9 radiotracer (3.7 mBq in 150 μL saline) intravenously into the tail vein. The mice were sacrificed 2 hours after administration. Blood was then transferred to heparinized tubes. The plasma samples (50 μL) were collected in a 10-mL flask and centrifuged (5 min, 1700 g) to isolate plasma. The mixture was transferred to an ultrafiltration device [Centrifree ultrafiltration device (Millipore Sigma, USA)]. The protein was isolated by centrifugation. Samples of the filtrate and protein fraction were then purified using Gamma Cow. Additionally, ITLC was performed to assess the stability of the radiotracer in the aqueous blood fraction. Evaluated.

[0243] 5.4.7 SPECT / CT imaging of small animals. 177 Lu-1 and 177 Lu-14) was administered to the same PSMA(+)PC3 PIP and PSMA(-)PC3 flu tumors used in the biodistribution study. Imaging was performed using models (n=2) with xenografts of both the RA and RA. SPECT-CT imaging for the purpose of this study was performed using mice bearing only PSMA(+) PC3 PIP tumors. Before and during the injection of the radiopharmaceutical, 1% isoflurane gas (oxygen) flowing at 0.6 L / min was administered. Mice were anesthetized using IV catheter.

[0244] Mice were administered approximately 37 MBq (1 mCi) or 111 MBq (3 mCi, for therapeutic research) 177 Lu-X was injected via the tail vein. The radiopharmaceutical was taken up for 2 hours. After incubating the mouse in the anesthetic chamber, the flow rate of the anesthetic agent was increased to 0.8 L / min while the anesthetized mouse was placed in the scanner gun. The mouse was placed on a tray and secured in place with medical tape. The mouse was then covered with several layers of Chux disposable pads. Mice were kept warm by illumination with a dissecting lamp during scanning. Single-pinhole median-energy (PHME) collimator with a diameter of 1.0 mm meter, 64 projection angles with stepwise rotation to a full 360°, 45 s SPECT imaging was performed at 1000 x 1000 increments. The radius of rotation was set to 6.5 cm. This provided a 7.5 cm field of view covering the mouse's body from head to bladder. Prior to scintigraphy, a CT scan was performed for both anatomical registration and attenuation correction. A total of 512 projections were scanned in 2 minutes covering a full 360° rotation. The images were acquired in continuous rotation mode for 100 s. The commercially available software was obtained from the vendor (GammaMedica). The data were reconstructed and merged using the AMIDE software. Analyzed.

[0245] 5.4.8 Radiopharmaceutical treatment of tumors. 177 Lu-L1, 177 Lu-L3, 177 Lu-L5 and 177 Lu-PS To examine the therapeutic effect of a single intravenous administration of MA-617 compared with saline. To investigate the antitumor effect of PIP on the PC3 flank tumor growth delay model, This was a head-to-head comparison study in which tumor-bearing mice and The same batch was used for radioactivity. The thickness is about 60 to 85 mm. 3 The study was initiated when the tumor volume was 100 mg / kg / day (Table 8). The mice were monitored for 8 weeks to monitor for tumor growth retardation. Tumor volumes were monitored every 3 days throughout the study. Criteria for points were body weight loss >= 15% and tumor volume > 1800 mm 3 , active ulceration of the tumor After 8 weeks, three mice from each group were subjected to detailed autopsy. The specimens were subjected to biopsy and blood analysis. 177 Lu-1 and 177 The group of mice that received Lu-PSMA-617 showed Monitoring continued until the end of the study. These definitions were also used in the Kaplan-Meier analysis. The probability of reaching five times the initial tumor volume was determined using Kaplan-Meier curves and scaled logarithmically. Comparisons were made using the rank test. V = width 2 The formula was used to calculate tumor volume: x length / 2. Later 177 The toxicity in healthy CD-1 (n = 3) mice receiving 111 MBq of Lu was examined using a 1:1 ratio. Pathological examinations at the Johns Hopkins Pathology Core Facility (serum metabolic panel, blood counts, and kidney The animals were evaluated by complete necropsy including detailed histopathology of the salivary and lacrimal glands.

[0246] 5.4.9 Data analysis. Data are expressed as mean ± standard deviation (SD). Prism software Statistical significance was determined using software (GraphPAD, San Diego, California). Significance was calculated using paired t-test. P values ​​<0.05 were considered significant.

[0247] 5.5 References 1. Kiess, A. P.; Banerjee, S. R.; Mease, R. C.; Rowe, S. P.; Rao, A.; Foss, C. A.; Chen, Y.; Yang, X.; Cho, S. Y.; Nimmagadda, S.; Pomper, M. G. Prostate-spec ific membrane antigen as a target for cancer imaging and therapy. Quarterly jour nal of nuclear medicine and molecular imaging 2015, 59, 241-68. 2. Haberkorn, U.; Eder, M.; Kopka, K.; Babich, J. W.; Eisenhut, M. New Strateg ies in Prostate Cancer: Prostate-Specific Membrane Antigen (PSMA) Ligands for Di agnosis and Therapy. Clinical cancer research 2016, 22, 9-15. 3. Sterzing, F.; Kratochwil, C.; Fiedler, H.; Katayama, S.; Habl, G.; Kopka, K .; Afshar-Oromieh, A.; Debus, J.; Haberkorn, U.; Giesel, F. L. (68)Ga-PSMA-11 PE T / CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging 2016, 43, 34-41. 4. Rowe, S. P.; Macura, K. J.; Ciarallo, A.; Mena, E.; Blackford, A.; Nadal, R .; Antonarakis, E. S.; Eisenberger, M. A.; Carducci, M. A.; Ross, A. E.; Kantoff , P. W.; Holt, D. P.; Dannals, R. F.; Mease, R. C.; Pomper, M. G.; Cho, S. Y. Co mparison of Prostate-Specific Membrane Antigen-Based 18F-DCFBC PET / CT to Convent ional Imaging Modalities for Detection of Hormone-Naive and Castration-Resistant Metastatic Prostate Cancer. Journal of nuclear medicine 2016, 57, 46-53. 5. Benesova, M.; Schafer, M.; Bauder-Wust, U.; Afshar-Oromieh, A.; Kratochwil, C.; Mier, W.; Haberkorn, U.; Kopka, K.; Eder, M. Preclinical Evaluation of a Ta ilor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imagin g and Endoradiotherapy of Prostate Cancer. Journal of Nuclear Medicine 2015, 56, 914-20. 6. Herrmann, K.; Bluemel, C.; Weineisen, M.; Schottelius, M.; Wester, H. J.; C zernin, J.; Eberlein, U.; Beykan, S.; Lapa, C.; Riedmiller, H.; Krebs, M.; Kropf , S.; Schirbel, A.; Buck, A. K.; Lassmann, M. Biodistribution and radiation dosi metry for a probe targeting prostate-specific membrane antigen for imaging and t herapy. Journal of nuclear medicine 2015, 56, 855-61. 7. Weineisen, M.; Schottelius, M.; Simecek, J.; Baum, R. P.; Yildiz, A.; Beyka n, S.; Kulkarni, H. R.; Lassmann, M.; Klette, I.; Eiber, M.; Schwaiger, M.; West er, H. J. 68Ga- and 177Lu-labeled PSMA I&T: Optimization of a PSMA targeted ther anostic concept and first proof of concept human studies. Journal of nuclear med icine 2015, 56, 1169-76. 8. Kratochwil, C.; Giesel, F. L.; Eder, M.; Afshar-Oromieh, A.; Benesova, M.; Mier, W.; Kopka, K.; Haberkorn, U. [(1)(7)(7)Lu]Lutetium-labelled PSMA ligand-in duced remission in a patient with metastatic prostate cancer. Eur J Nucl Med Mol Imaging 2015, 42, 987-8. 9. Afshar-Oromieh, A.; Hetzheim, H.; Kratochwil, C.; Benesova, M.; Eder, M.; N eels, O. C.; Eisenhut, M.; Kubler, W.; Holland-Letz, T.; Giesel, F. L.; Mier, W. ; Kopka, K.; Haberkorn, U. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET / CT: Biodistribution in Humans, Radiation Dosimetry, a nd First Evaluation of Tumor Lesions. Journal of Nuclear Medicine 2015, 56, 1697 -1705. 10. Soydal, C.; Ozkan, E.; Akyurek, S.; Kucuk, N. O. Marked Response to 177Lu Prostate-Specific Membrane Antigen Treatment in Patient With Metastatic Prostate Cancer. Clinical nuclear medicine 2016, 41, 159-60. 11. Baum R.P., K., H.R.,Schuchardt C., Singh A., Weineisen M., Wiessalla S., S chottelius M., Mueller D., Klette I., Wester H.-J. Lutetium-177 PSMA Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy . Journal of nuclear medicine 2016, In Press. 12. Hillier, S.; Rubino, K.; Maresca, K.; Marquis, J.; Tesson, M.; Zimmerman, C.; Eckelman, W.; Mairs, R.; Joyal, J.; Babich, J. [131I]MIP-1466, a small molec ule prostate-specific membrane antigen (PSMA) inhibitor for targeted radiotherap y of prostate cancer (PCa). Journal of nuclear medicine meeting abstract 2012, 53, 170. 13. Zechmann, C. M.; Afshar-Oromieh, A.; Armor, T.; Stubbs, J. B.; Mier, W.; H adaschik, B.; Joyal, J.; Kopka, K.; Debus, J.; Babich, J. W.; Haberkorn, U. Radi ation dosimetry and first therapy results with a (124)I / (131)I-labeled small mo lecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging 2014, 41, 1280-92. 14. Haberkorn, U.; Afshar-Oromieh, A.; Giesel, F.; Kopka, K.; Eder, M.; Babich , J.; Kratochwil, C. P8.01PSMA ligands for diagnosis and therapy of prostate can cer. Annals of Oncology 2015, 26, ii33. 15. Trover, J. K.; Beckett, M. L.; Wright, G. L. Detection and characterizatio n of the prostate-specific membrane antigen (PSMA) in tissue extracts and body f luids. International Journal of Cancer 1995, 62, 552-558. 16. Ray Banerjee, S.; Pullambhatla, M.; Foss, C. A.; Falk, A.; Byun, Y.; Nimma gadda, S.; Mease, R. C.; Pomper, M. G. Effect of chelators on the pharmacokineti cs of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA). Journal of medicinal chemistry 2013, 56, 6108-21. 17. Banerjee, S. R.; Pullambhatla, M.; Foss, C. A.; Nimmagadda, S.; Ferdani, R .; Anderson, C. J.; Mease, R. C.; Pomper, M. G. (6)(4)Cu-labeled inhibitors of p rostate-specific membrane antigen for PET imaging of prostate cancer. Journal of medicinal chemistry 2014, 57, 2657-69. 18. Eder, M.; Schaefer, M.; Bauder-Wuest, U.; Hull, W.-E.; Waengler, C.; Mier, W.; Haberkorn, U.; Eisenhut, M. 68Ga-Complex Lipophilicity and the Targeting Pr operty of a Urea-Based PSMA Inhibitor for PET Imaging. Bioconjugate Chemistry 20 12, 23, 688-697. 19. Afshar-Oromieh, A.; Haberkorn, U.; Schlemmer, H. P.; Fenchel, M.; Eder, M. ; Eisenhut, M.; Hadaschik, B. A.; Kopp-Schneider, A.; Rothke, M. Comparison of P ET / CT and PET / MRI hybrid systems using a 68Ga-labelled PSMA ligand for the diagn osis of recurrent prostate cancer: initial experience. Eur J Nucl Med Mol Imagin g 2014, 41, 887-97. 20. Afshar-Oromieh, A.; Avtzi, E.; Giesel, F.; Holland-Letz, T.; Linhart, H.; Eder, M.; Eisenhut, M.; Boxler, S.; Hadaschik, B.; Kratochwil, C.; Weichert, W.; Kopka, K.; Debus, J.; Haberkorn, U. The diagnostic value of PET / CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate ca ncer. European Journal of Nuclear Medicine and Molecular Imaging 2015, 42, 197-2 09. 21. Banerjee, S. R.; Foss, C. A.; Castanares, M.; Mease, R. C.; Byun, Y.; Fox, J. J.; Hilton, J.; Lupold, S. E.; Kozikowski, A. P.; Pomper, M. G. Synthesis an d evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-s pecific membrane antigen (PSMA). Journal of medicinal chemistry 2008, 51, 4504-1 7. 22. Choy, C. J.; Ling, X.; Geruntho, J. J.; Beyer, S. K.; Latoche, J. D.; Lang ton-Webster, B.; Anderson, C. J.; Berkman, C. E. (177)Lu-Labeled Phosphoramidate -Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and T herapeutic Efficacy in Prostate Tumor-Bearing Mice. Theranostics 2017, 7, 1928-1 939. 23. Benesova, M.; Umbricht, C. A.; Schibli, R.; Muller, C. Albumin-Binding PSM A Ligands: Optimization of the Tissue Distribution Profile. Mol Pharm 2018, 15, 934-946. 24. Umbricht, C. A.; Benesova, M.; Schibli, R.; Muller, C. Preclinical Develop ment of Novel PSMA-Targeting Radioligands: Modulation of Albumin-Binding Propert ies To Improve Prostate Cancer Therapy. Mol Pharm 2018. 25. Kelly, J.; Amor-Coarasa, A.; Ponnala, S.; Nikolopoulou, A.; Williams, C., Jr.; Schlyer, D.; Zhao, Y.; Kim, D.; Babich, J. W. Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors. Eur J Nucl Med Mol Imaging 2018. 26. Banerjee, S. R.; Foss, C. A.; Pullambhatla, M.; Wang, Y.; Srinivasan, S.; Hobbs, R. F.; Baidoo, K. E.; Brechbiel, M. W.; Nimmagadda, S.; Mease, R. C.; Sgo uros, G.; Pomper, M. G. Preclinical evaluation of 86Y-labeled inhibitors of pros tate-specific membrane antigen for dosimetry estimates. Journal of nuclear medic ine 2015, 56, 628-34. 27. Kulkarni, H. R.; Singh, A.; Schuchardt, C.; Niepsch, K.; Sayeg, M.; Leshch , Y.; Wester, H. J.; Baum, R. P. PSMA-Based Radioligand Therapy for Metastatic C astration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013. Journa l of nuclear medicine 2016, 57, 97s-104s. 28. Hillier, S. M.; Kern, A. M.; Maresca, K. P.; Marquis, J. C.; Eckelman, W. C.; Joyal, J. L.; Babich, J. W. 123I-MIP-1072, a small-molecule inhibitor of pro state-specific membrane antigen, is effective at monitoring tumor response to ta xane therapy. Journal of nuclear medicine 2011, 52, 1087-93. 29. Chen, Y.; Pullambhatla, M.; Foss, C. A.; Byun, Y.; Nimmagadda, S.; Sentham izhchelvan, S.; Sgouros, G.; Mease, R. C.; Pomper, M. G. 2-(3-{1-Carboxy-5-[(6-[ 18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pen tanedioic acid, [18F] DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clinical cancer rese arch 2011, 17, 7645-53. 30. Chen, Y.; Foss, C. A.; Byun, Y.; Nimmagadda, S.; Pullambahatla, M.; Fox, J . J.; Castanares, M.; Lupold, S. E.; Babich, J. W.; Mease, R. C.; Pomper, M. G. Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imagin g Agents for Prostate Cancer. Journal of Medicinal Chemistry 2008, 51, 7933-7943 . 31. Kiess, A. P.; Minn, I.; Vaidyanathan, G.; Hobbs, R. F.; Josefsson, A.; She n, C.; Brummet, M.; Chen, Y.; Choi, J.; Koumarianou, E.; Baidoo, K.; Brechbiel, M. W.; Mease, R. C.; Sgouros, G.; Zalutsky, M. R.; Pomper, M. G. (2S)-2-(3-(1-Ca rboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targe ted alpha-Particle Radiopharmaceutical Therapy. Journal of nuclear medicine 2016 , 57, 1569-1575. 32. Szabo, Z.; Mena, E.; Rowe, S.; Plyku, D.; Nidal, R.; Eisenberger, M.; Anto narakis, E.; Fan, H.; Dannals, R.; Chen, Y.; Mease, R.; Vranesic, M.; Bhatnagar, A.; Sgouros, G.; Cho, S.; Pomper, M. Initial Evaluation of [18F]DCFPyL for Pros tate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer. M olecular Imaging and Biology 2015, 1-10. 33. Muller, C.; Struthers, H.; Winiger, C.; Zhernosekov, K.; Schibli, R. DOTA conjugate with an albumin-binding entity enables the first folic acid-targeted 1 77Lu-radionuclide tumor therapy in mice. J Nucl Med 2013, 54, 124-31. 34. Tykvart, J.; Schimer, J.; Barinkova, J.; Pachl, P.; Postova-Slavetinska, L .; Majer, P.; Konvalinka, J.; Sacha, P. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targ eting and delivery. Bioorganic & medicinal chemistry 2014, 22, 4099-108. 35. Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Foss, C. A.; Green, G.; Fox, J. J.; Lupold, S. E.; Mease, R. C.; Pomper, M. G. Sequential SPE CT and optical imaging of experimental models of prostate cancer with a dual mod ality inhibitor of the prostate-specific membrane antigen. Angewandte Chemie Int ernational Edition 2011, 50, 9167-70. 36. Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Green, G.; Fo x, J. J.; Horti, A.; Mease, R. C.; Pomper, M. G. 68Ga-labeled inhibitors of pros tate-specific membrane antigen (PSMA) for imaging prostate cancer. Journal of me dicinal chemistry 2010, 53, 5333-41. 37. Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Foss, C. A.; Green, G.; Fox, J. J.; Lupold, S. E.; Mease, R. C.; Pomper, M. G. Sequential SPE CT and Optical Imaging of Experimental Models of Prostate Cancer with a Dual Mod ality Inhibitor of the Prostate-Specific Membrane Antigen. Angewandte Chemie 201 1, 50, 9167-70. 38. Banerjee, S. R.; Pullambhatla, M.; Shallal, H.; Lisok, A.; Mease, R. C.; P omper, M. G. A modular strategy to prepare multivalent inhibitors of prostate-sp ecific membrane antigen (PSMA). Oncotarget 2011, 2, 1244-53. 39. Chen, Y.; Dhara, S.; Banerjee, S. R.; Byun, Y.; Pullambhatla, M.; Mease, R . C.; Pomper, M. G. A low molecular weight PSMA-based fluorescent imaging agent for cancer. Biochemical and biophysical research communications 2009, 390, 624-9 . 40. Chen, Y.; Pullambhatla, M.; Banerjee, S. R.; Byun, Y.; Stathis, M.; Rojas, C.; Slusher, B. S.; Mease, R. C.; Pomper, M. G. Synthesis and biological evalua tion of low molecular weight fluorescent imaging agents for the prostate-specifi c membrane antigen. Bioconjug Chem 2012, 23, 2377-85. 41. Ray Banerjee, S.; Pullambhatla, M.; Foss, C. A.; Falk, A.; Byun, Y.; Nimma gadda, S.; Mease, R. C.; Pomper, M. G. Effect of chelators on the pharmacokineti cs of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA). J Med Chem 2013, 56, 6108-21. 42. Shallal, H. M.; Minn, I.; Banerjee, S. R.; Lisok, A.; Mease, R. C.; Pomper , M. G. Heterobivalent agents targeting PSMA and integrin-alphavbeta3. Bioconjug Chem 2014, 25, 393-405. 43. Dennis, M. S.; Jin, H.; Dugger, D.; Yang, R.; McFarland, L.; Ogasawara, A. ; Williams, S.; Cole, M. J.; Ross, S.; Schwall, R. Imaging tumors with an albumi n-binding Fab, a novel tumor-targeting agent. Cancer research 2007, 67, 254-61. 44. Dennis, M. S.; Zhang, M.; Meng, Y. G.; Kadkhodayan, M.; Kirchhofer, D.; Co mbs, D.; Damico, L. A. Albumin binding as a general strategy for improving the p harmacokinetics of proteins. The Journal of biological chemistry 2002, 277, 3503 5-43. 45. Chatalic, K. L.; Heskamp, S.; Konijnenberg, M.; Molkenboer-Kuenen, J. D.; Franssen, G. M.; Clahsen-van Groningen, M. C.; Schottelius, M.; Wester, H. J.; v an Weerden, W. M.; Boerman, O. C.; de Jong, M. Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targe ted Theranostic Agent. Theranostics 2016, 6, 849-61. 46. Chang, S. S. Overview of Prostate-Specific Membrane Antigen. Reviews in Ur ology 2004, 6, S13-S18. 47. Kratochwil, C.; Bruchertseifer, F.; Rathke, H.; Bronzel, M.; Apostolidis, C.; Weichert, W.; Haberkorn, U.; Giesel, F. L.; Morgenstern, A. Targeted Alpha T herapy of mCRPC with 225Actinium-PSMA-617: Dosimetry estimate and empirical dose finding. Journal of Nuclear Medicine 2017. 48. Song, H.; Hobbs, R. F.; Vajravelu, R.; Huso, D. L.; Esaias, C.; Apostolidi S, C.; Morgenstern, A.; Sgouros, G. Radioimmunotherapy of breast cancer metastases es with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. Can Cer Res 2009, 69, 8941-8. 49. Tykvart, J.; Schimer, J.; Barinkova, J.; Pachl, P.; Postova-Slavetinska, L .; Majer, P.; Konvalinka, J.; Sacha, P. Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targ eting and delivery. Bioorganic & Medicinal Chemistry 2014, 22, 4099-4108. 50. Ray Banerjee, S.; Chen, Z.; Pullambhatla, M.; Lisok, A.; Chen, J.; Mease, RC; Pomper, MG Preclinical Comparative Study of (68)Ga-Labeled DOTA, NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA. Bioconjugate chemistry 20 16, 27, 1447-55.

[0248] References All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. All publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which the disclosure pertains. Products, patent applications, patents, and other references (e.g., websites, databases, etc.) Each publication, patent application, patent, and other reference is specifically and individually indicated to be incorporated by reference. and to the extent that it is indicated that the disclosure is incorporated herein by reference in its entirety. Numerous patent applications, patents and other references are referenced herein, including, but not limited to, the following: Such references are based on the common general knowledge in the art. It is understood that this specification and any incorporated references are not intended to be a part of the present application. In the event of a conflict between the cited documents, the present specification, including any amendments thereto, shall be deemed to be incorporated by reference. The disclosures contained herein (which may be based on references contained herein) shall take precedence unless otherwise indicated. Unless otherwise specified, standard, art-accepted meanings of terms are used. Use standard abbreviations for important terms.

[0249] International PCT Patent Application No. PCT / US2008 / 007947 to Pomper, MG, Ra y, S., Mease, RC, Foss, C. for Labeled inhibitors of prostate specific membrane e antigen (PSMA), biological evaluation, and use as imaging agents, published 20 08 / 12 / 31 (WO 2009 / 002529 A2); International PCT Patent Application No. PCT / US2008 / 013158 to Chandran SS, R ay S., Denmeade S.R., Pomper M.G., Mease R.C. for Prostate specific membrane ant igen targeted nanoparticles for therapy of prostate cancer, published 2009 / 06 / 04 (WO 2009070302 A1); International PCT Patent Application Publication No. PCT / US2010 / 028020 to Pomp er M.G., Mease R.C.; Ray S., Chen Y. for PSMA-targeting compounds and uses ther eof, published 2010 / 09 / 23 (WO 2010108125 A2); Banerjee, S. R., Foss, C. A., Pullambhatla, M., Wang, Y., Srinivasan, S., Hobb s, R. F., Baidoo, K. E., Brechbiel, M. W., Nimmagadda, S., Mease, R. C., Sgouros , G., and Pomper, M. G. (2015) Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates. Journal of nuclea r medicine 56, 628-34; Banerjee, S. R., Pullambhatla, M., Byun, Y., Nimmagadda, S., Green, G., Fox, J . J., Horti, A., Mease, R. C., and Pomper, M. G. (2010) 68Ga-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer. J Med Chem 53, 5333-5341; Banerjee, S. R., Pullambhatla, M., Byun, Y., Nimmagadda, S., Foss, C. A., Gree n, G., Fox, J. J., Lupold, S. E., Mease, R. C., and Pomper, M. G. (2011) Sequent ial SPECT and optical imaging of experimental models of prostate cancer with a d ual modality inhibitor of the prostate-specific membrane antigen. Angewandte Che mie International Edition 50, 9167-9170; Banerjee, S. R., Pullambhatla, M., Shallal, H., Lisok, A., Mease, R. C., and Pom per, M. G. (2011) A modular strategy to prepare multivalent inhibitors of prosta te-specific membrane antigen (PSMA). Oncotarget 2, 1244-1253; Ray Banerjee, S., Pullambhatla, M., Foss, C. A., Falk, A., Byun, Y., Nimmagadd a, S., Mease, R. C., and Pomper, M. G. (2013) Effect of chelators on the pharmac okinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane a ntigen (PSMA). J Med Chem 56, 6108-6121; Banerjee, S. R., Pullambhatla, M., Foss, C. A., Nimmagadda, S., Ferdani, R., A nderson, C. J., Mease, R. C., and Pomper, M. G. (2014) (6)(4)Cu-labeled inhibito rs of prostate-specific membrane antigen for PET imaging of prostate cancer. J M ed Chem 57, 2657-2669; Ray Banerjee, S., Chen, Z., Pullambhatla, M., Lisok, A., Chen, J., Mease, R. C ., and Pomper, M. G. (2016) Preclinical Comparative Study of (68)Ga-Labeled DOTA , NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA. Bioconjug Chem 27, 1447-1455; Benesova, M., Schafer, M., Bauder-Wust, U., Afshar-Oromieh, A., Kratochwil, C. , Mier, W., Haberkorn, U., Kopka, K., and Eder, M. (2015) Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety fo r Imaging and Endoradiotherapy of Prostate Cancer. Journal of nuclear medicine 5 6, 914-20; Tykvart, J., Schimer, J., Jancarik, A., Barinkova, J., Navratil, V., Starkova, J., Sramkova, K., Konvalinka, J., Majer, P., and Sacha, P. (2015) Design of Hig hly Potent Urea-Based, Exosite-Binding Inhibitors Selective for Glutamate Carbox ypeptidase II. Journal of medicinal chemistry 58, 4357-63; Weineisen, M., Simecek, J., Schottelius, M., Schwaiger, M., and Wester, H.-J. (2014) Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands fo r functional imaging and endoradiotherapy of prostate cancer. EJNMMI Res 4, 1-15 .

[0250] The foregoing subject matter has been described in some detail by way of illustration and examples for clarity of understanding. However, it will be apparent to those skilled in the art that modifications and variations 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; 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; And; L is for C 1 -C 6 Alkylene and C 3 -C 6 From the group consisting of cycloalkylene and arylene is a linker selected from the group consisting of 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 where 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 a radioactive metal; and pharma- ceutically 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: 【Chemistry 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, 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, 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, 47 Sc and 166 The compound of claim 4, wherein the compound is selected from the group consisting of Ho.

6. The compound of formula (I) is 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 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; 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; And; L is for C 1 -C 6 Alkylene and C 3 -C 6 From the group consisting of cycloalkylene and arylene is a linker selected from the group consisting of 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 where 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 radiometal-containing chelating agent suitable for radiotherapy; and pharma- ceutically acceptable salts thereof.

23. 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; The method of claim 7, wherein the compound is selected from the group consisting of:

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

10. The radioactive metal is selected from the group consisting of: 90 Y, 177 Lu, 211 At, 111 In, 153 Sm, 186 Re, 188 Re, 67 Cu, 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】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemical 27】 The method of claim 7, wherein the compound is 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, prostate tumor or cells, lung tumor or cells, kidney tumor or cells, glioblastoma, pancreatic tumor or cells cyst, bladder tumor or cell, sarcoma, melanoma, breast tumor or cell, colon tumor or cell, reproductive cells, pheochromocytoma, esophageal tumor or cells, gastric tumor or cells, and combinations thereof. The method of claim 7, wherein the compound is selected from the group consisting of:

13. 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 isolated in vitro, in vivo or ex vivo. The method of claim 7, wherein

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

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

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

18. The compound of formula (I) is 【Chemistry 28】 Where: X is H or 4-benzylbromine; and M is 177 Lu, 225 Ac, 213 Bi, and 203 Pb, 2. The compound of claim 1 selected from the group consisting of:

19. The compound of formula (I) is 【Chemical 29】 Where: X is H or 4-benzylbromine; and M is 177 Lu, 225 Ac, 213 Bi, and 203 Pb, The method of claim 7, wherein the compound is selected from the group consisting of:

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