Prodrugs of 2-PMPA for healthy tissue protection during PSMA-targeted cancer imaging or radiotherapy

Abstract

To provide a method for preventing or reducing the accumulation of a prostate-specific membrane antigen (PSMA) imaging or therapeutic agent in off-target non-cancer tissues.SOLUTION: The present invention provides a method comprising administering, to a subject being treated with a PSMA-targeted agent, a prodrug of 2-(phosphonomethyl)pentanedioic acid (2-PMPA) in an amount effective to prevent or reduce the binding of the PSMA-targeted agent to off-target non-cancer tissues.SELECTED DRAWING: Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 484,219, filed April 11, 2017. which is incorporated herein by reference in its entirety.

[0002] Federally funded research or development This invention was funded by the National Institutes of Health (NIH) R01 CA161056-0 awarded by the National Cancer Institute (NCI) This invention was made with Government support under the provisions of the Federal Register under US Provisional Patent Application No. 2005 / 0133636. The Government has certain rights in this invention. Summary of the Invention [Problem to be solved by the invention]

[0003] Background Endothelial cells in the angiogenesis of prostate cancer cells, as well as several other solid tumors, It is a specific membrane antigen (PSMA), a membrane tether peptidase PSMA is frequently overexpressed in the prostate (Kasperzyk et al., 2013). Aggressive tumors, metastatic disease, and prognosis in cancer patients It has been shown to correlate with poor prostate cancer outcomes (Perner et al., 2007). For immunization purposes, radiolabeled or cytotoxic drug-conjugated biologics (biologics ogic) and successful efforts have been made to target PSMA with small molecule ligands ( Bouchelouche et al., 2016; Ceci et al., 2017; Haberkorn Berkown et al., 2016; Kratochwil et al., 2016; Maurer et al., 2016) or targeted chemotherapy or radiotherapy (Bouchelo et al., 2016). Uche et al., 2016; Ceci et al., 2017; Haberkorn et al., 2016; Kratochwil et al., 2016; Maurer et al., 201 6; and Pillai et al., 2016), several clinical trials are underway. However, in addition to prostate cancer and proliferative endothelial cells, normal tissues also include the kidney, lacrimal gland, and The highest densities of non-CNS-expressed PSMA are also found in the thyroid and salivary glands. tissues may be areas of interference (for PSMA-expressing cancer imaging) or sites of dose-limiting toxicity. (dose-limiting sites of toxicity) (for PSMA-targeted cancer therapy) (Kratoch wil et al., 2015).

[0004] In an attempt to reduce healthy tissue exposure during PSMA-targeted therapy, A well-tolerated PSMA inhibitor (also called PSMA suppressor) called 2-(phosphonomethyl)pentane The diacid (2-PMPA) directly competes with the shared PSMA binding site in the salivary gland and kidney. Blocking radioligand uptake through direct competitive displacement (Kratochwil et al., 2015; Chatalic et al., 2016) In one study, 177 Co-injection of Lu-PSMA I&T (100MBq) with 2-PMPA (0.01mg) reduced the renal reduced the absorbed dose to the brain by 83% in mice bearing PSMA-expressing human cancer xenografts The combination of 100 mg / kg / day and 100 mg / kg / day reduced nephrotoxicity after 3 months of treatment (Chatalic et al., 2016). Results showed that 2-PMPA also reduced tumor uptake of radiotherapeutic agents by 50%. The researchers also found that the mice who received the radiation therapy alone did not respond to clinical trials and were treated with the radiation therapy. 2-PMPA accelerated tumor growth and significantly reduced overall survival (Chatalic et al., 2016). of 125 Similar results were obtained when paired with I-MIP-1095 ( Kratochwil et al., 2015 ). Previous attempts at mitigating the salivary glands had also failed (Taieb et al., 2018). included co-treatment with 2-PMPA to inhibit PSMA-specific uptake (Kratochwil et al., 2015). These findings are likely due to the high polarity of 2-PMPA as a parent compound, and Most have poor tissue penetration, resulting in little or no penetration into the salivary glands This is consistent with preclinical pharmacokinetic data showing 2-P Although MPA provided an important proof of concept for the shielding approach, cotreatment with this molecule The results suggest that salivary gland / kidney replacement and tumor removal may have significantly improved the therapeutic index of PSMA-targeted therapy. I couldn't get the balance right. [Means for solving the problem]

[0005] Summary In some embodiments, the presently disclosed subject matter provides methods for treating prostate cancer in off-target, non-cancerous tissue. To prevent or reduce accumulation of prostate-specific membrane antigen (PSMA) imaging or therapeutic agents The present invention provides a method of treating a subject with a PSMA-targeted imaging or therapeutic agent. The off-target prodrug of 2-(phosphonomethyl)pentanedioic acid (2-PMPA) was administered to subjects with The agent is administered in an amount effective to prevent or reduce binding of the agent to non-cancerous tissue of the subject. In contrast to 2-PMPA, the 2-PMPA prodrugs of the present disclosure have been shown to inhibit the proliferation and proliferation of healthy, non-cancerous tissues. The tissues showed unexpected preferential distribution, including the kidney and salivary gland, which are resistant to PSMA-targeted drugs. In doing so, the disclosed method provides a method for detecting PSMA targets that represents a site of interference or dose-limiting toxicity. broadening the therapeutic window of therapeutic options, reducing the risk of salivary gland and kidney toxicity, and possibly reducing disease progression. This allows for more treatment cycles to be initiated earlier in the course.

[0006] In certain embodiments, the prodrug of 2-PMPA includes a compound of formula (I) or formula (II): [ka] During the ceremony: Each of R1, R2, R3, and R4 is H, alkyl, Ar, -(CR5R6) n -Ar, -(CR5R6) n -OC(=O)-R7 , -(CR5R6) n -C(=O)-O-R7, -(CR5R6) n -OC(=O)-O-R7, -(CR5R6) n -O-R7, -(CR5R6) n -O-[(CR 5R6) n -O] m -R7, -(CR5R6) n -Ar-OC(=O)-R7, -Ar-C(=O)-O-(CR5R6) n -R7, -(CR5R6) n -NR8R9 , and -(CR5R6) n -C(=O)-NR8R9; where n is 1 to 20. m is an integer from 1 to 20; each R3' and R4' is independently H or alkyl. each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl. each R7 is independently selected from the group consisting of straight chain or branched alkyl; Ar is selected from the group consisting of aryl, substituted aryl, R8 and R9 are each independently an alkyl, heteroaryl, or substituted heteroaryl; The relationships are H or alkyl; and pharma- ceutically acceptable salts thereof.

[0007] In certain embodiments, the compound of formula (I) has the following structure: [ka] It is.

[0008] In another aspect, the presently disclosed subject matter provides a method for treating a patient receiving a PSMA-targeted therapy for cancer. The present invention provides a method for reducing salivary gland damage in a patient receiving a therapeutically effective amount of a prodrug of 2-PMPA. This includes administering a therapeutic dose to a patient.

[0009] In certain embodiments, the salivary gland damage is characterized by dry mouth, thickened saliva, decreased saliva, stomatitis, hoarseness. dysphagia, difficulty swallowing, loss of taste, and combinations thereof. do.

[0010] In yet another aspect, the subject matter of the present disclosure is a method for treating a patient receiving PSMA-targeted therapy for cancer. The present invention provides a method for reducing kidney damage in a patient, comprising administering a therapeutically effective amount of 2-PMPA to the patient. This includes administering a rag to the patient.

[0011] Certain aspects of the presently disclosed subject matter described above may be combined in whole or in part with the presently disclosed subject matter. Other aspects are best described herein below in connection with the accompanying examples and figures. When employed to clarify, these will become apparent as the description proceeds. [Brief description of the drawings]

[0012] Having thus described the subject matter of the present disclosure in general terms, reference will now be made to the accompanying drawings, in which: They are not necessarily drawn to scale and are as follows: [Figure 1] We show that the Tris-POC-2-PMPA prodrug delivered significantly higher 2-PMPA concentrations to the kidneys of nude mice. Compared to an equimolar dose of 2-PMPA, Tris-POC-2-PMPA (5 mg / kg, ip) increased the concentration of 2-PMPA in the kidney by more than 20-fold. [Diagram 2] Figures 2A and 2B show that in contrast to the disclosed prodrugs of 2-PMPA, a similar prodrug of an alternative urea-based PSMA ligand, ZJ-43, did not show increased distribution to mouse kidneys or salivary glands (Figure 2B) compared to administration of the parent ZJ-43 (Figure 2A). [Diagram 3] Figures 3A and 3B show that Tris-POC-2-PMPA administration (Figure 3B) results in significantly increased kidney and salivary gland delivery of 2-PMPA and improved kidney:tumor and saliva:tumor ratios in prostate cancer tumor-bearing mice compared with equimolar 2-PMPA administration (Figure 3A). Concentrations of 2-PMPA were measured in plasma, tumor, salivary gland, and kidney at multiple time points following tail vein administration of either 2-PMPA or Tris-POC-2-PMPA (3 mg / kg or molar equivalent, iv) to NSG mice harboring subcutaneous xenografts of human C4-2 prostate cancer cells. [Figure 4]Figures 4A, 4B, 4C, and 4D show baseline PET imaging (presented as maximum intensity projections) of a non-tumor-bearing mouse 1 hour after injection of 20 MBq of 68Ga-PSMA-617 (Figure 4A) and quantification of renal uptake by mSUV (Figure 4C). The same animal was reimaged another hour after a subsequent injection of Tris-POC-2-PMPA (0.5 mg / kg BW) (Figure 4B). Tracer concentration was then quantified in the kidney by mSUV (Figure 4D). [Diagram 5] Figures 5A, 5B, 5C, and 5D show baseline PET (Figure 5A) and quantification of kidney and tumor uptake by mSUV (Figure 5C) of LNCaP tumor xenograft (left shoulder)-bearing mice 1 hour after injection of 68Ga-PSMA-617. The same animals were reimaged another hour after subsequent injections of different doses of Tris-POC-2-PMPA (or saline as a control) (Figure 5B), and then tumor and kidney uptake was quantified (Figure 5D). [Figure 6] Figures 6A, 6B, 6C, and 6D show the biodistribution of 68Ga-PSMA-617 1 h pi presented as maximum intensity projections in healthy subjects without (Figure 6A, left) or after (Figure 6A, right) pre-dosing with Tris-POC-2-PMPA. Without pre-dosing, renal uptake increases over time, but in contrast, the time-activity curves imply saturation of renal binding by pre-dosing with 0.05 mg / kg BW Tris-POC-2-PMPA 10 min prior to the PET-tracer (Figure 6C). A similar effect was observed for the time-activity curves of the parotid gland (Figure 6D). Coronal thin slices through the kidneys of subjects without (Figure 6B, top) or with (Figure 6B, bottom) premedication indicate saturation of PSMA binding sites physiologically expressed in the proximal tubules, which are conversely located in the renal cortex. Without wishing to be bound by a particular theory, this observation is believed to indicate the proposed mechanism of action for the method of the present disclosure. [Figure 7]Figure 1 shows an interindividual comparison of 68Ga-PSMA-617 biodistribution 1 h pi, presented as maximum intensity projections in prostate cancer patients with Tris-POC-2-PMPA, with or without premedication. When pretreated with Tris-POC-2-PMPA, patients showed similar tracer uptake in the tumor, but uptake in the kidney and salivary gland was significantly reduced. and [Figure 8] The effect of Tris-POC-2-PMPA pretreatment on the biodistribution and absorbed radiation dose to each organ or metastasis following administration of 177Lu-PSMA-617 in prostate cancer patients compared to historical controls who received radiotherapy without Tris-POC-2-PMPA. Based on positive results in diagnostic PET scans, two patients received Tris-POC-2-PMPA (10 mg, iv) 15 min prior to injection with 177Lu-PSMA-617. Compared to historical controls from the same institution (Kratochwil et al., 2016), Tris-POC-2-PMPA pretreatment reduced radiotherapeutic agent uptake in the parotid gland, submandibular gland, and kidney by between 45% and 75%. In contrast, Tris-POC-2-PMPA pretreatment had little to no effect on dose to metastases, with all values ​​falling within the standard deviation of historical controls and, crucially, exceeding absorbed dose values ​​reported to result in therapeutic efficacy (Kratochwil et al., 2016).

[0013] 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) are available upon request and payment of the necessary fee. Provided by the institution upon payment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description The subject matter of this disclosure next follows, in the accompanying drawings, which illustrate some, but not all, embodiments of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described more fully hereinafter with reference to the following figures, in which like numbers refer throughout: The subject matter of the present disclosure may be embodied in many different forms and may be modified in any manner, including, but not limited to, by any of the following embodiments: The present invention should not be construed as being limited to the embodiments described herein; rather, these embodiments should be construed as being This disclosure is provided to satisfy applicable legal requirements. Indeed, the disclosure herein is Numerous modifications and other embodiments of the subject matter will be apparent to those skilled in the art to which the subject matter of this disclosure pertains. One skilled in the art having the benefit of the teachings presented in the foregoing descriptions and the associated drawings will appreciate that It will be appreciated that the presently disclosed subject matter is not limited to the specific embodiments disclosed. It is understood that modifications and other embodiments are within the scope of the appended claims. It should be understood that the intent is to I. 2-PMPA for healthy tissue protection during PSMA-targeted cancer imaging or radiotherapy Prodrug of

[0015] Prostate-specific membrane antigen (PSMA) is a prostate cancer cell that binds to GCPII (glutamic acid carboxypeptidase II) and and FOLH1, which converts N-acetylglutamate (NAAG) to N-acetylglutamate (NAAG). It catalyzes the hydrolysis of folate to non-aspartic acid (NAA) and glutamic acid, and A metallopeptidase that sequentially cleaves the terminal glutamate moiety from liglutamate. One of the most potent, selective, and effective PSMA inhibitors is 2-(phosphonomethyl) However, 2-PMPA has multiple carboxylates. and a highly polar compound with a zinc-binding group, and it has negligible oral have limited availability and poor tissue penetration. In this context, it can be administered intravenously, intraperitoneally, or locally to achieve the desired effect. This fact limits its potential use as a therapeutic agent.

[0016] The subject matter of this disclosure is, in part, the discovery of certain prodrugs of 2-PMPA (see, e.g., Majer et al., 2016). (control) unexpectedly accumulated in the kidneys and salivary glands when administered to animals. Importantly, some of these prodrugs were shown to inhibit the cytotoxicity of prostate cancer xenografts. When administered to mice, it delivered 3 and 4 times more cytotoxicity to the salivary glands and kidneys of rodents, respectively, in contrast to the tumors. The study showed a 57-fold preferential delivery of 2-PMPA to 10-HT2C12. Given this profile, it is undesirable that administration of a prodrug of 2-PMPA may be effective in targeting tumors. These “off-target” non-targeted sites can be eliminated without interfering with the uptake of the radioligand in the tissue. This was thought to prevent subsequent PSMA radioligand binding to cancer tissue. Certain prodrugs are disclosed herein, but are within the skill of those of ordinary skill in the art. ) shows differential accumulation in the kidney and salivary gland. -Other prodrugs of PMPA, and any GCPII inhibitors, may be used according to the methods of the present disclosure. will understand that it may be appropriate to

[0017] The subject matter of the present disclosure demonstrates the efficacy of this approach. In mice, healthy human volunteers, and prostate cancer patients, Administration of the 2-PMPA prodrug prior to administration of the drug increased the radioligand activity in the kidneys and salivary glands. The 2-PMPA protease of the present disclosure successfully displaced the binding of β-lactamase, but preserved tumor uptake. Prodrugs have the properties of PSMA-targeted imaging agents and radiation therapy. Clinically used as a pretreatment agent to improve isomerism and reduce their toxicity. It has the potential to be possible.

[0018] More specifically, the subject matter of the present disclosure alters the tissue distribution of 2-PMPA to non-cancerous tissues and inhibits the proliferation and proliferation of healthy tissues. Novel uses for a class of prodrugs of 2-PMPA to improve organ delivery of 2-PMPA The prodrugs of the present disclosure are preferentially distributed to the kidney, lacrimal gland, and salivary gland, These include off-target binding and mitigation of PSMA-targeted prostate cancer imaging agents and radiotherapy. and represent the site of toxicity.

[0019] Thus, the subject matter of the present disclosure is directed to the detection of inflammatory bowel disease in non-cancerous tissues (e.g., kidney, lacrimal gland, and salivary gland). We provide unexpected findings of PSMA small molecule inhibitors with enhanced accumulation. has been confirmed in humans, demonstrating that the 2-PMPA prodrugs of the present disclosure are useful for PSMA-targeted imaging. (PSMA-targeted imaging) or in combination with radiotherapy, respectively, These results indicate that potential dose-limiting toxicities can be reduced.

[0020] Thus, in some embodiments, the subject matter of the present disclosure provides an off-target Prostate-specific membrane antigen (PSMA) theranostic agents in non-cancerous tissues of The present invention provides a method for preventing or reducing the accumulation of a PSMA serranolytic agent, the method including administering For subjects treated with the stick, 2-(phosphonomethyl)pentanedioic acid (2-PMPA ) prodrug to bind the PSMA theranostic agent to off-target non-cancerous tissues. In such embodiments, the administration of the compound in an amount effective to prevent or reduce In this way, off-target tissues are shielded from the radiotherapeutic agent.

[0021] In some embodiments, the prodrug of 2-PMPA is a PSMA theronostic. tic) agent. By "in combination with" it is meant one or more One or more compounds of the present disclosure may be administered in combination with one or more therapeutic agents, either prior to, simultaneously with, or sequentially therewith. or a combination thereof. is a combination of one or more compounds of the present disclosure and one or more therapeutic agents at the same time (i.e., simultaneously). or at different times (i.e. consecutively, in any order, i.e. before or after on the same or different days) to determine the effect of the combination of both drugs on the cells or subjects. When administered sequentially, the drugs may be administered 1, 5, 10, or 20 minutes apart from each other, as long as this is achieved. The procedure may be performed for 30, 60, 120, 180, 240 minutes or longer. In embodiments, sequentially administered agents are administered 1, 5, 10, 15, 20 or more days apart from each other. When one or more compounds of the present disclosure and one or more therapeutic agents are administered simultaneously, In each case, they each contain either one or more compounds of the present disclosure or one or more therapeutic agents. They can be administered to a cell or to a subject as separate pharmaceutical compositions, or they can be administered as a single or administered to the subject as a single pharmaceutical composition containing both agents. In certain embodiments, the prodrug of 2-PMPA can be administered as a PSMA seronegative. Such a procedure is administered to a subject prior to administration of a contrast agent or imaging agent. In one embodiment, the subject is "pre-treated" with a prodrug of 2-PMPA. The prodrug of PA is administered to a subject simultaneously with a PSMA serotonin or imaging agent. can be.

[0022] In certain embodiments, the off-target tissues consist of kidney, lacrimal gland, and salivary gland. In an organ selected from the group.

[0023] In certain embodiments, the PSMA serotonergic agent is CTT1403, MIP-1095, PSMA-11, PSMA The present invention relates to a method for treating a patient having ordinary skill in the art that uses a medicament for treating a patient having ... The authors further demonstrated that other radiolabeled PSMA serotonergic agents, and indeed any PSMA-targeting agent, can target the binding site. or whether it is a biological or small molecule known in the art. It will be appreciated that any suitable method for use in the disclosed embodiments may be suitable for use in the disclosed methods.

[0024] Exemplary prodrugs of 2-PMPA suitable for use with the methods of the present disclosure include Slusher (Thrasher) et al., PRODRUGS OF PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) IN HIBITOR (prodrug of prostate-specific membrane antigen (PSMA) inhibitor) The present invention is disclosed in CT's patent application publication number WO2016022827A1, which was published on February 11, 2016. which are incorporated herein by reference in their entireties.

[0025] Structures of representative 2-PMPA prodrugs are provided in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0026] In yet another embodiment, fine tuning of the hydrolysis rate is achieved by the following compounds: The combination of POC and methyl-substituted POC can be evaluated as follows: [ka]

[0027] Further directions for 2-PMPA prodrugs include the following approaches, which may be more readily Hydrolyzable phenyl esters; anhydrides, and employing paraoxonase for bioconversion Dioxolone esters that are [ka]

[0028] Additionally, the following dioxolone ester and anhydride prodrugs of 2-PMPA are contemplated: : [ka]

[0029] Further examples of alternative carboxy ester prodrugs of 2-PMPA include: [ka]

[0030] More particularly, in some embodiments, the prodrug of 2-PMPA includes a compound represented by formula (I) or or a compound of formula (II): [ka] During the ceremony: Each of R1, R2, R3, and R4 is H, alkyl, Ar, -(CR5R6) n -Ar, -(CR5R6) n OC(=O)-R7, -(CR5R6) n -C(=O)-O-R7, -(CR5R6) n -OC(=O)-O-R7, -(CR5R6) n -O-R7, -(CR5R6) n -O-[(CR5R 6) n -O] m -R7, -(CR5R6) n -Ar-OC(=O)-R7, -Ar-C(=O)-O-(CR5R6) n -R7, -(CR5R6) n -NR8R9, and -(CR5R6) n -C(=O)-NR8R9; During the ceremony: n is an integer from 1 to 20; m is an integer from 1 to 20; each R3' and R4' is independently H or alkyl; Each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl. Re; Each R7 is independently a straight chain or branched alkyl; Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and Call R8 and R9 are each independently H or alkyl; and Pharmaceutically acceptable salts thereof Includes:

[0031] As further defined herein below, R1-R9 and R3' and The "alkyl" represented by R4' is a C1, C2, C3, C4, C5, C6, C7, or C8 alkyl group. cyclic or branched alkyl, in some embodiments C 1-4 Substituted or unsubstituted alkyl, In some embodiments, C 1-6 Substituted or unsubstituted alkyl, in some embodiments C 1-8 Alki and substituted or unsubstituted alkyl, including but 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, and the like, each of which can contain one or more substitutents. Representative substituents include nt groups include, but are not limited to, alkyl, substituted alkyl, halogen, aryl, Substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkyl These include alkylamino, sulfate, cyano, mercapto, and alkylthio. do.

[0032] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0033] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0034] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0035] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0036] In certain embodiments, the compound of formula (I) is [ka] It is.

[0037] In certain embodiments, the compound of formula (I) is [ka] It is.

[0038] In certain embodiments, the compound of formula (I) is [ka] It is.

[0039] In certain embodiments, the compound of formula (I) is [ka] It is.

[0040] In certain embodiments, the compound of formula (I) is [ka] It is.

[0041] In certain embodiments, the compound of formula (I) is [ka] It is.

[0042] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0043] In certain embodiments, the compound of formula (I) is [ka] It is.

[0044] In certain embodiments, the compound of formula (I) is [ka] It is.

[0045] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0046] In certain embodiments, the compound of formula (I) is [ka] It is.

[0047] In certain embodiments, the compound of formula (I) is [ka] It is.

[0048] In certain embodiments, the compound of formula (I) is [ka] It is.

[0049] In certain embodiments, the compound of formula (I) is [ka] It is.

[0050] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0051] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0052] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0053] In certain embodiments, the compound of formula (I) is [ka] It is.

[0054] In certain embodiments, the compound of formula (I) is: [ka] is selected from the group consisting of:

[0055] In certain embodiments, the compound of formula (II) [ka] It is.

[0056] In certain embodiments, the compound of formula (II) [ka] It is.

[0057] In another embodiment, the subject matter of the present disclosure is a method for treating a patient receiving a PSMA-targeted therapy for cancer. The present invention provides a method for reducing salivary gland damage in a subject, the method comprising administering to the subject a prodrug of 2-PMPA. The method includes administering to a patient a therapeutically effective amount of

[0058] In certain embodiments, the salivary gland damage is characterized by dry mouth, thickened saliva, (also called thickening of the mouth), decreased saliva, stomatitis, hoarseness, and difficulty swallowing (also called "dyscrasia"), taste loss, and combinations thereof. To cause.

[0059] In yet another embodiment, the subject matter of the present disclosure is a method for treating cancer in a patient receiving PSMA-targeted therapy. The present invention provides a method for reducing kidney damage in patients with rheumatoid arthritis, the method comprising administering a prodrug of 2-PMPA to the patient. The method includes administering to the patient a therapeutically effective amount of the compound.

[0060] In certain embodiments, the 2-PMPA profile of the method for reducing salivary gland injury and / or kidney injury is Prodrugs include compounds of formula (I) or (II): [ka] During the ceremony: Each of R1, R2, R3, and R4 is H, alkyl, Ar, -(CR5R6) n -Ar, -(CR5R6) n -OC(=O)-R7 , -(CR5R6) n -C(=O)-O-R7, -(CR5R6) n -OC(=O)-O-R7, -(CR5R6) n -O-R7, -(CR5R6) n -O-[(CR 5R6) n -O] m -R7, -(CR5R6) n -Ar-OC(=O)-R7, -Ar-C(=O)-O-(CR5R6) n -R7, -(CR5R6) n -NR8R9 , and -(CR5R6) n -C(=O)-NR8R9; During the ceremony: n is an integer from 1 to 20; m is an integer from 1 to 20; each R3' and R4' is independently H or alkyl; Each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl. Re; Each R7 is independently a straight chain or branched alkyl; Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and Call R8 and R9 are each independently H or alkyl; and Pharmaceutically acceptable salts thereof Includes:

[0061] In still more particular embodiments, the prodrug of 2-PMPA is: [ka] is selected from the group consisting of:

[0062] In certain embodiments, the PSMA targeted imaging or therapeutic agent is 117Lu-PSMA-617, 131I-MIP-1095, 177Lu-PSMA-I&T, 177Lu-PSMA-R2, 225Ac-PSMA-617, 227Th-PSMA-ADC, CT T1403, CTT1700, 68Ga-PSMA-11, 18F-DCFPyL, CTT1057, 68Ga-PSMA-R2, and 68Ga-PSMA -617.

[0063] In some embodiments, the PSMA-targeted therapeutic is Radiotherapeutic administered in cumulative amounts from GBq to about 100 GBq In certain embodiments, the PSMA targeted radiotherapeutic agent is about 52 GBq to about 100 GBq. is administered in a cumulative amount of

[0064] In some embodiments, the PSMA targeted therapeutic and the 2-PMPA prodrug are at least about 1 In certain embodiments, the PSMA targeted therapeutic agent and and the 2-PMPA prodrug is administered for about 6 to about 15 treatment cycles.

[0065] In certain embodiments, the patient has not previously been treated for cancer. In yet more certain embodiments, the cancer is prostate cancer. II. Drug Composition and Administration

[0066] In another aspect, the present disclosure provides a compound of formula (I) or a compound of formula (II) alone or in combination with The compound may be combined with one or more additional therapeutic agents in a mixture with a pharma- ceutical acceptable excipient. The pharmaceutical composition includes a compound as described above. It will be appreciated that the term "sodium phosphate" includes physiologically acceptable salts.

[0067] In therapeutic and / or diagnostic applications, the compounds of the present disclosure have a wide variety of modes of administration. It can be formulated for systemic and localized administration. The technology and formulations are generally described in Remington: The Science and Practice of Pharmacy. (20 th ed.) Lippincott, Williams & Wilkins (2000) (Remington: The Science and Practice of Pharmacy ( 20th ed.) Lippincott, Williams & Wilkins (2000).

[0068] The compounds according to the present disclosure are effective over a wide dosage range. For each dose, 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and Dosages from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will vary depending on the route of administration, the form in which the compound is administered, and the type of drug being administered. The dosage will depend on the subject being treated, the weight of the subject being treated, and the preferences and experience of the attending physician.

[0069] Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and examples thereof include acetaminophen, ... Examples of the salts include, but are not limited to, acetate, benzenesulfonate, besylate, benzoate, charcoal, etc. Hydrogen tartrate (bicarbonate), hydrogen tartrate (bitartrate), bromide, calcium edetate, calcium Carnsylate, carbonate, citrate, edetate, edisylate, est Glucate, esylate, fumarate, gluceptate, gluconate, glutamate, glutamine Glycollylarsanilate, Hexylresorcinate, Hydraba amine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate Salt, lactobionate, malate, maleate, mandelate, mesylate, muca mucate, napsylate, nitrate, pamoate (embonate), pantothenate , Phosphates / Diphosphates, Polygalacturonates, Salicylates, Stearates, Bases Acetate, succinate, sulfate, tannate, tartrate, or thiocyanate Other pharma- ceutically acceptable salts can be found, for example, in Remington: The Science and Pract. Ice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000). Pharmaceutically acceptable salts include, for example, acetates, benzoates, bromides, carbonates, citrates. , gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, paclitaxel Moates (embonates), phosphates, salicylates, succinates, sulfates, or tartar. Contains acid salts.

[0070] Depending on the particular condition being treated, such agents may be formulated into liquid or solid dosage forms. The agents may be administered, for example, in a manner known to those skilled in the art. As is known in the art, timed- or sustained-low release forms may be used. The technology for preparation and administration is described in Remington:T he Science and Practice of Pharmacy(20 th ed.) Lippincott, Williams & Wilkins (2 Suitable routes include oral, buccal, intra-salivary, By inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral Livery is available by intramuscular, subcutaneous, and intramedullary injection, as well as by intrathecal and direct intraventricular injection. ricular, also called direct intraventricular, intravenous, intra-articular, intra-sternal, synovial Intra-synovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or Other delivery modes may also be included.

[0071] For injection, the agents of the present disclosure may be administered in aqueous solutions, such as Hank's solution, Ringer's solution, or in a physiologically compatible buffer such as physiological saline buffer. For such transmucosal administration, the barrier to be permeated may be Appropriate penetrants are used in the formulation. Such penetrants are generally known in the art. It is knowledge.

[0072] In order to practice the present disclosure, the compounds disclosed herein may be formulated in dosages suitable for systemic administration. The use of pharma- ceutically acceptable inert carriers for the purposes of the present disclosure is within the scope of the present disclosure. and by appropriate manufacturing practices, the compositions of the present disclosure, particularly those formulated as solutions, can be administered parenterally. The compounds may be administered orally, for example, by intravenous injection, etc. The composition can be readily formulated in a suitable dosage form for oral administration using pharma- ceutical acceptable carriers well known in the art. Such carriers can be formulated in a suitable amount to allow the compound of the present disclosure to be administered to the subject being treated. For oral ingestion by a patient (e.g., a tablet, pill, capsule, liquid, It is often formulated as gels, syrups, slurries, suspensions, and the like. Make it possible.

[0073] For nasal or inhalation delivery, the agents of the present disclosure may also be administered in a manner known to those skilled in the art. The formulation may be prepared by known methods, including, but not limited to, solubilizing the agent, diluting it, Or dispersions, for example, saline solutions, preservatives, for example, benzyl alcohol, etc. These may include agents such as absorbents, absorption enhancers, and fluorocarbons.

[0074] Pharmaceutical compositions suitable for use in the present disclosure include those that contain an active ingredient in an amount sufficient to achieve its intended purpose. Determining the effective amount is described in detail, inter alia, in the detailed disclosure provided herein. In light of the teachings herein, this is well within the capabilities of one skilled in the art.

[0075] These pharmaceutical compositions contain suitable pharma- ceutical acceptable compositions containing excipients and auxiliaries in addition to the active ingredient. Acceptable carriers may be included, which are used to prepare pharma- ceutical preparations of the active compounds. Preparations formulated for oral administration include tablets, dragees (sugar-coated tablets, etc.) The formulation may be in the form of a tablet, capsule, or solution.

[0076] Pharmaceutical preparations for oral use may be prepared by combining the active compound with a solid excipient, optionally The resulting mixture is then ground (also called milled) and, if necessary, formed into tablets or dough. By processing the mixture of granules after adding suitable auxiliaries to obtain Rajecore Suitable excipients are in particular bulking agents, such as sugars, etc. , lactose, sucrose, mannitol, or sorbitol; cellulose preparations Products such as corn starch, wheat starch, rice starch, potato starch, gelatin, Gum tragacanth, methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose Sodium dimethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP) If necessary, a disintegrant may be added, for example, cross-linked polyvinylpyrrolidone. Such as lysine, agar, or alginic acid or a salt thereof, e.g., sodium alginate. Such as thorium.

[0077] The dragee cores are provided with a suitable coating. For this purpose, a concentrated sugar solution is used. Optionally, gum arabic, talc, polyvinylpyrrolidone, carbo Carbopol Gel, Polyethylene Glycol (PEG), and / or Titanium Dioxide , lacquer solutions, and suitable organic solvents or solvent mixtures. may be used to label tablets or tablets for identification or to characterize different combinations of doses of active compound. It may also be added to dragee coatings.

[0078] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin (pu capsules). sh-fit capsules, as well as soft, sealed capsules made of gelatin, and plasticizers, e.g. Examples include glycerol or sorbitol. The formulation contains the active ingredient in a filler, such as lactose, a binder, such as starch, etc., and / or lubricants, e.g., talc or malic stearate. Such as magnesium, and optionally, may be included in the mixture along with a stabilizer. In soft capsules, the active compounds are dispersed in a suitable liquid, e.g. fatty oils, liquid paraffin, etc. or liquid polyethylene glycols (PEGs), etc. In addition, a stabilizer may be added. III. Definition

[0079] Although specific terms are employed herein, they are used in a generic and descriptive sense only. and not for purposes of limitation. Unless otherwise specified, all terms used herein are The technical and scientific terms used herein are understood to be understood by those of ordinary skill in the art to which the presently described subject matter pertains. has the same meaning as is commonly understood.

[0080] The following terms relating to compounds of formula (I) are fully understood by those of ordinary skill in the art: Although it is believed to be readily understood, the following definitions are provided to facilitate explanation of the subject matter of this disclosure. These provisions would be apparent to one of ordinary skill in the art upon review of this disclosure. The provisions of this section are intended to supplement and illustrate, not preclude, other provisions.

[0081] The term substituted, whether or not preceded by the term "optionally", and As used herein, substitutent refers to any compound that is suitable for use by those skilled in the art. As recognized by the formula, it is possible to separate a functional group while maintaining the valence of all atoms. This refers to the ability of more than one position in any given structure to be converted to a functional group. may be replaced with more than one substitutent selected from a particular group The substitution moieties may be the same or different at every position. They may also be further substituted (e.g., an aryl group substituent may be freely substituted with another substituent). ), such as, for example, another aryl group, which may further include, for example, one or more (substituted by fluorine at the above position).

[0082] Substituents or linking groups are identified by their conventional chemical formulae, written from left to right In this case, they are chemically identical substitutes that would result from writing the structure from right to left. are equally encompassed, examples being -CH2O- is equivalent to -OCH2-; -C(=O)O- is equivalent to -OC(=O)- -OC(=O)NR- is equivalent to -NRC(=O)O-, and the like;

[0083] When the term "independently selected" is used, the referenced substituent moiety (e.g., an R group) is , e.g., R1, R2, and the like, or variables, e.g. Such as "m" and "n" can be the same or different. For example, R1 and Both R and R can be substituted alkyl, or R can be hydrogen; and and R2 can be substituted alkyl, and the like.

[0084] The terms "a," "an," or "a(n)" as used herein in reference to a group of substitute moieties are For example, if a compound is substituted with "an" alkyl or aryl, When substituted, the compound optionally comprises at least one alkyl and / or at least one aryl group. Each moiety is substituted with one aryl. When a moiety is substituted with an R-substituent, the group may be referred to as "R-substituted." is R-substituted, the moiety is substituted with at least one R-substituted moiety, and and each R substituent moiety is optionally different.

[0085] A named "R" or group generally has that name unless otherwise specified herein. For purposes of illustration, the compounds of the present invention will have structures recognized in the art as corresponding to groups such as those shown in the drawings. For purposes of this disclosure, certain representative "R" groups above are defined below.

[0086] The description of the compounds of the present disclosure is based on principles of chemical bonding known to those skilled in the art. Thus, when a group is substituted with one or more multiple substituent moieties, such Such substitutions are compatible with the principles of chemical bonding and are not inherently unstable and / or environmentally friendly. Under ambient conditions, such as aqueous, neutral, and some known physiological conditions, Given compounds that may be unstable and known to those of ordinary skill in the art, For example, heterocycloalkyl or heteroaryl is selected according to the present invention. and / or a ring heteroatom, according to principles of chemical bonding known to those skilled in the art. This avoids compounds that are inherently unstable.

[0087] As used herein, the term hydrocarbon refers to any chemical group that contains hydrogen and carbon. The hydrocarbons may be substituted or unsubstituted. As will be known to those skilled in the art, As such, any substitutions must be made to satisfy all valencies. can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, Allyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl These include aryl, cyclohexyl, methoxy, diethylamino, and the like. can be.

[0088] The term "alkyl" by itself or as part of another substituent moiety may be used to refer to another Unless otherwise stated, straight-chain (also called unbranched) or branched, acyclic or cyclic hydrocarbons means a group, which may be fully saturated, mono- or polyunsaturated, or a combination thereof; and divalent and polyvalent groups and may have the specified number of carbon atoms (so-called ru, C1-C 10 ("" means 1 to 10 carbons). In certain embodiments, the term "alkyl" The term C 1-20 Linear (so-called "straight chain"), branched or cyclic, saturated or At least partially and in some cases fully unsaturated (so-called alkenyl and and alkynyl) hydrocarbon radicals, which are formed by the removal of a single hydrogen atom, It is derived from a hydrocarbon moiety containing between twenty carbon atoms.

[0089] Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, ethyl, propyl ... propyl, 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, Cyclo propylmethyl, and homologs and isomers thereof.

[0090] "Branched" refers to a lower alkyl group such as methyl, ethyl or propyl. "Lower alkyl" refers to an alkyl group attached to a linear alkyl chain. carbon atoms (so-called C 1-8 alkyl), examples are 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms "Higher alkyl" refers to an alkyl group having from about 10 to about 20 carbon atoms. Examples are aryl groups having 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" refers to, inter alia, C 1-8 Linear alkyl In another embodiment, "alkyl" refers to, inter alia, C 1-8 Reference is made to branched chain alkyls.

[0091] The alkyl group can be optionally substituted with one or more alkyl group substituents ("substituted"). "Alkyl-substituted moieties" ("alkyl-substituted moieties"), which can be the same or different. Such terms include, but are not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, , hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, ara alkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and Optionally, one or more oxygen, sulfur or substituents may be present along the alkyl chain. A substituted or unsubstituted nitrogen atom may be inserted, where the nitrogen substituted moiety is hydrogen, lower alkyl, alkyl (also referred to herein as "alkylaminoalkyl"), or aryl. .

[0092] As such, the term "substituted alkyl" as used herein includes any of the following groups, as defined herein: , alkyl groups, in which one or more atoms or functional groups of the alkyl group are bonded to another atom or functional groups, such as alkyl, substituted alkyl, halogen, aryl, substituted aryl, etc. Alkyl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino Substitutes include but are not limited to sulfato, sulfato, and mercapto.

[0093] The term "heteroalkyl" by itself or in combination with another term, Unless otherwise stated, any stable straight or branched chain or cyclic hydrocarbon group or any and combinations thereof, including at least one carbon atom and the group consisting of O, N, P, Si, and S. and wherein nitrogen, phosphorus, and sulfur are selected from the group consisting of at least one heteroatom selected from the group consisting of The nitrogen heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. (Heteroatom(s), "(group)" is used to indicate that there may be more than one) O, N, P and and S, and Si may be present at any interior position of the heteroalkyl group or at any position where the alkyl group is not part of the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-N H-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH 25 -S(O)-CH3, -CH2-CH2-S(O)2-C H3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH Up to two or three heteroatoms include, for example, -CH2-NH-OCH3 and -CN. and -CH2-O-Si(CH3)3.

[0094] As defined above, heteroalkyl groups, as used herein, include groups that are joined to the remainder of the molecule through a heteroatom. Those groups attached to, for example, -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR, and / or "Heteroalkyl" is defined, followed by a specific A list of heteroalkyl groups follows, such as, for example, -NR'R or others of the type. When used interchangeably, the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. It will be understood that certain heteroalkyl groups may be grouped together in order to add clarity. As such, the term "heteroalkyl" is used herein to refer to a specific heteroalkyl group. , for example, -NR'R'' or others of the like. You shouldn't.

[0095] "Cyclic" and "cycloalkyl" refer to alkyl groups having from about 3 to about 10 carbon atoms, e.g., 3, 4, 5, It refers to a non-aromatic monocyclic or polycyclic ring system of 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can optionally be partially unsaturated. Optionally, alkyl group substituted moieties, oxo, and / or alkylene, as defined herein. Optionally, one or more oxygen, sulfur or aryl groups may be substituted along the cyclic alkyl chain. or a substituted or unsubstituted nitrogen atom, where the nitrogen-substituting moiety is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and Polycyclic cycloalkyl rings include adamantyl, octahy Dronaphthyl, decalin, camphor, camphane, and noradamantyl, and abbreviated Synthetic ring systems, such as dihydro- and tetrahydronaphthalenes, and the like. What is included.

[0096] As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group as defined above. References to alkyl groups also refer to the parent molecular moiety through the alkyl group defined above. Examples of cycloalkylalkyl groups are cyclopropylmethyl and cyclopentylmethyl. Contains ethyl ethyl.

[0097] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a non-aromatic ring system, Saturated or partially unsaturated ring systems, such as 3- to 10-membered substituted or unsubstituted cycloalkyl Ring systems and the like refer to ring systems that contain one or more heteroatoms, which may be the same or can be different, and nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and may optionally contain one or more double bonds.

[0098] The cycloheteroalkyl ring may optionally be joined to other cycloheteroalkyl rings and / or non-aromatic rings. The heterocycle may be fused to or otherwise attached to an aromatic hydrocarbon ring. having from one to three heteroatoms independently selected from hydrogen, sulfur, and nitrogen; wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms Atoms may be optionally quaternized. In certain embodiments, the term heterocycle refers to a non-aromatic ring. Refers to 5-, 6-, or 7-membered ring or polycyclic groups in which at least one ring atom is O, S, and N, where the nitrogen and sulfur heteroatoms are optionally oxidized. substituted), including but not limited to bi- or tricyclic groups, and containing oxygen, sulfur, and nitrogen and wherein: (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 2 double bonds; and each seven-membered ring has zero to three double bonds; and (ii) the nitrogen and sulfur heteroatoms are (iii) the nitrogen heteroatom may be optionally quaternized, and (iv) Any of the above heterocycles may be fused to an aryl or heteroaryl ring. Heteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, Imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, isopropyl Endolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrazolium tetrahydrofuranyl, and the like.

[0099] The terms "cycloalkyl" and "heterocycloalkyl" are by themselves also defined as or in combination with other terms, unless otherwise stated, "alkyl" and "heteroaryl" are used interchangeably. In addition, each of the heterocycloalkyl groups represents a cyclic version of the heterocycloalkyl group. A heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of alkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexyl, xenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl). , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl , tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and others of the same type The terms "cycloalkylene" and "heterocycloalkylene" are used interchangeably. The terms cycloalkyl and heterocycloalkyl refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively. .

[0100] An unsaturated alkyl group is one that has one or more double or triple bonds. Examples of alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl. , 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and and 3-propynyl, 3-butynyl, and the higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are termed "homoalkyl."

[0101] More specifically, the term "alkenyl" as used herein means an alkyl group selected from the group consisting of a single hydrogen atom. C having at least one carbon-carbon double bond by removal of 1-20 Including linear or branched chains It refers to a univalent group derived from a branched hydrocarbon moiety. Alkenyl groups include, for example, , ethenyl (also known as vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, Includes pentenyl, hexenyl, octenyl, and butadienyl.

[0102] As used herein, the term "cycloalkenyl" refers to an alkenyl group that is an alkenyl group having at least one carbon-carbon divalent Examples of cycloalkenyl groups include cyclopropenyl, Cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclo Cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl Includes:

[0103] As used herein, the term "alkynyl" refers to a group containing at least one carbon-carbon triple bond. Straight or branched chain of the designed number of carbon atoms 1-20 Refers to a monovalent radical derived from a hydrocarbon Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, aryl, pentynyl, hexynyl, heptynyl, and allenyl groups, and the like; These include:

[0104] The term "alkylene", by itself or as part of another substituent, refers to any group having from 1 to about 20 alkyl groups. Carbon atoms in, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1 Straight or branched bicyclic groups derived from alkyl groups having 8, 19, or 20 carbon atoms. The alkylene group may be linear, branched or cyclic. The alkylene group may also be optionally unsaturated and / or contain one or more "alkyl" groups. Optionally, along the alkylene group, one or more Oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl"). "), where the nitrogen-substituted moiety is an alkyl as described above. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-);Cyclohexylene (-C6H 10 -);-CH=CH-CH=CH-;-CH=CH-CH2-;-CH2CH2CH 2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r - in which each of q and r is independently from 0 to about 20, examples being 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 water. alkyl or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). The alkylene group can have from about 2 to about 3 carbon atoms. and can have 6-20 carbons. Typically, alkyl (or alkenyl) groups are The alkylene groups have from 1 to 24 carbon atoms, and these groups may be used in some embodiments of the present disclosure. "Lower alkyl" or "lower alkylene" refers to a group having 10 or fewer carbon atoms in the form of a cyclic alkyl group. A shorter chain alkyl or alkylene group, usually having eight or fewer carbon atoms. .

[0105] The term "heteroalkylene" by itself or as part of another substituent moiety includes means a divalent group derived from heteroalkyl, including but not limited to, -CH2-CH2-SC Examples of heteroalkylene groups include -H-CH- and -CH-S-CH-CH-NH-CH-. In addition, heteroatoms can also occupy either or both of the chain ends (e.g., alkyl groups, alkyl groups, alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like (and other similar types). In addition, for alkylene and heteroalkylene linking groups: No orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0106] The term "aryl" refers to groups fused or covalently linked together, unless otherwise stated. aromatic rings which may be monocyclic or polycyclic (e.g., 1 to 3 rings, etc.) The term "heteroaryl" refers to a hydrocarbon substituent selected from N, O, and S. A ring containing from one to four heteroatoms (in each separate ring in the case of multiple rings). refers to an aryl group (or ring) in which the nitrogen and sulfur atoms are optionally oxidized, and The nitrogen atom is optionally quaternized. Heteroaryl groups are separated through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include , phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl aryl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-Oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4 -Isoxazolyl, 5-Isoxazolyl, 2-Thiazolyl, 4-Thiazolyl, 5-Thiazolyl , 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl , 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl The aryl and heteroaryl groups mentioned above include aryl, 3-quinolyl, and 6-quinolyl. Each substituent on the ring system is selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene" are defined as aryl and heteroaryl, respectively. This refers to the bivalent form of

[0107] For the sake of brevity, the term "aryl" includes the following when used in combination with other terms (e.g. is aryloxo, arylthioxo, arylalkyl), aryl as defined above Thus, the terms "arylalkyl" and "heteroaryl" are used interchangeably. The term "heteroarylalkyl" refers to an aryl or heteroaryl group attached to an alkyl group. Those groups attached (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and and the like) are carbon atoms (e.g., methylene groups) are oxygen atoms, Those alkyl groups which are replaced by (e.g., phenoxymethyl, 2-pyridyl (e.g., 3-(1-naphthyloxy)propyl, 3-(1-naphthyloxy)propyl, and the like) However, the term "haloaryl" as used herein is intended to include The term is meant to cover only aryl that are substituted with one or more halogen.

[0108] Heteroalkyl, heterocycloalkyl, or heteroaryl may have a specific number of members. (e.g., "3- to 7-membered"), the term "member" refers to a carbon or heteroatom. mentions.

[0109] Further, generally, the formula: [ka] As used herein, structures represented by the formula: Aliphatic and non-aliphatic, including 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, and the like. and / or aromatic cyclic compounds, including saturated, partially saturated, and unsaturated ring structures. The structures include substituent moieties R groups, where the R groups may be present or absent, and When present, one or more R groups are each substituted at one or more available carbon atoms of the ring structure. The presence or absence of an R group and the number of R groups is determined by the value of the variable "n", which is It is usually an integer having a value ranging from 0 to the number of carbon atoms in the ring available for substitution. When there is more than one R group, they are substituted at available carbons in the ring structure rather than at another R group. For example, in the above structure where n is 0 to 2, a group of compounds may include, but is not limited to, , the following: [ka] and others of the same kind, including, but not limited to:

[0110] The dashed lines representing bonds in cyclic ring structures indicate that The term "cyclic ring" refers to the possibility of either the presence or absence of a bond. The dashed lines representing bonds in the structures indicate whether the ring structure is saturated, partially saturated, or unsaturated. It indicates that the ring structure is selected from the group consisting of saturated ring structures.

[0111] JPEG2025028897000047.jpg842 shows the attachment point of the moiety to the rest of the molecule.

[0112] When a named atom of an aromatic or heteroaromatic ring is defined as "absent" , the named atom is replaced by a direct bond.

[0113] Each of the above terms (examples include "alkyl," "heteroalkyl," "cycloalkyl," and and "heterocycloalkyl", "aryl", "heteroaryl", "phosphonate" ", "sulfonate" and their divalent derivatives) refer to the substitution and non-substitution of the indicated radical. Optional substitution moieties for each type of radical are provided below. Provide.

[0114] Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent substituted Conductive groups (alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, Cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkene Substituent moieties for aryl (including groups often referred to as -nyl) include, but are not limited to, the following: R', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R' , -CO2R', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR ', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN and -NO2 The number of m' is one or more of a variety of groups selected from the group consisting of the numbers ranging from zero to (2m'+1). where m' is the total number of carbon atoms in such group. R′ and R′″ are each independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, Unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl , an alkoxy or thioalkoxy group, or an arylalkyl group, As used, an "alkoxy" group refers to an alkyl group attached to the remainder of the molecule through a divalent oxygen. When a compound of the present disclosure includes more than one R group, for example, each R group can be selected from each R', As with the R'', R''' and R'''' groups, when more than one of these groups is present, they are selected independently. When R' and R'' are attached to the same nitrogen atom, they may be 4-, 5-, 6-, or 7-membered. It can be combined with a nitrogen atom to form a ring. For example, -NR'R'' is It is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion, one skilled in the art will appreciate that the term "alkyl" can be used to refer to any group other than a hydrogen group. Groups containing bonded carbon atoms, such as haloalkyl (e.g., -CF3 and -CH2CF3) and a Sil (examples include -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like) will be understood to mean including such things as:

[0115] Similar to the substitution moieties described above for the alkyl group, aryl and heteroaryl Exemplary substitution moieties for the groups (as well as their divalent derivatives) are various and For example: halogen, -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''R''')=NR'''', -NR-C(NR'R'')=NR'''-S(O)R', -S(O)2R', -S(O)2 NR'R'', -NRSO2R', -CN and -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxo, and fluoro(C1-C4)alkyl, from zero to open valences in the aromatic ring system. n valences); and and R'''' are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted The compounds of the present disclosure may be independently selected from substituted aryl and substituted or unsubstituted heteroaryl. When a compound contains more than one R group, for example, each R group may be independently selected from each of R', R'', R''', and R''. As with the " 1 - 3 " group, when more than one of these groups is present, they are selected independently.

[0116] Two substitution moieties at adjacent atoms of an aryl or heteroaryl ring are optionally represented by the formula -TC(O)-( CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'- or is a single bond, and q is an integer from 0 to 3. Alternatively, aryl or hexyl Two substitution moieties at adjacent atoms of the heteroaryl ring are optionally represented by the formula -A-(CH2) r -B- substitution A and B may be independently substituted with -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.

[0117] One of the single bonds of the new ring so formed may optionally be replaced by a double bond. Alternatively, two substitution moieties at adjacent atoms of an aryl or heteroaryl ring may be Optionally, the formula (CRR') s -X'-(C''R'') d -, where s and d are independently an integer from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or is -S(O)2NR'-. The substituents R, R', R'' and R'' may independently be hydrogen, substituted or unsubstituted. substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0118] As used herein, the term "acyl" refers to a group in which the -OH of a carboxyl group is substituted with another moiety. Refers to organic acid groups that are substituted and have the general formula RC(=O)--, where R is as defined herein. As such, alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic. As such, the term "acyl" specifically refers to an aryl acyl group. Acyl groups include, for example, acetylfuran and phenacyl groups. Particular examples of groups include acetyl and benzoyl.

[0119] The terms "alkoxyl" or "alkoxy" are used interchangeably herein and refer to the parent molecule. Saturated (so-called alkyl-O-) or unsaturated moieties attached through oxygen atoms (alkenyl-O- and alkynyl-O-) groups, where "alkyl", The terms "alkenyl" and "alkynyl" are as defined above, and 1-20 of and may include linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including For example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, se c-butoxyl, t-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl This includes, but is not limited to, tethers, cables, and the like.

[0120] As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl ether. For example, methoxyethyl or ethoxymethyl groups.

[0121] "Aryloxyl" refers to an aryl-O- group in which the aryl group is as previously described As used herein, the term "aryloxyl" refers to phenyl, phenyl, phenyloxyl ... Oxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxy. Mention may be made of xyl-substituted phenyloxyl or hexyloxyl.

[0122] "Aralkyl" refers to an aryl-alkyl- group, where the aryl and alkyl are As previously described, and includes substituted aryl and substituted alkyl. Alkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0123] "Aralkyloxyl" refers to an aralkyl-O- group, where the aralkyl group is as defined above. An exemplary aralkyloxyl group is benzyloxyl.

[0124] "Alkoxycarbonyl" refers to an alkyl-O-CO- group. The alkoxy group includes methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and and t-butyloxycarbonyl.

[0125] "Aryloxycarbonyl" refers to an aryl-O-CO- group. The oxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

[0126] "Aralkoxycarbonyl" refers to an aralkyl-O-CO- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

[0127] "Carbamoyl" refers to an amide group of the formula -CONH2. "Alkylcarbamoyl" refers to an amide group of the formula -CONH2. Refers to the group RN-CO-, where one of R and R' is hydrogen and the other of R and R' is Alkyl and / or substituted alkyl as described above. "Dialkylcarbamoyl" refers to the group R'RN-CO-, where each R and R', independently, is an alkyl group as defined above. and / or substituted alkyl.

[0128] The term carbonyldioxyl as used herein refers to a carbonate group of formula -O-CO-OR. .

[0129] "Acyloxyl" refers to an acyl-O- group, where acyl is as previously described.

[0130] The term "amino" refers to the -NH2 group and also refers to the addition of one or more hydrogen radicals to an organic group. The method known in the art is derived from ammonia by replacing it with dicarbaromatic salts. Certain nitrogen-containing groups are also referred to. For example, the terms "acylamino" and "alkylamino" refer to certain N-substituted organic radicals with acyl and alkyl substituents, respectively .

[0131] As used herein, "aminoalkyl" refers to an amino group that is covalently attached to an alkylene linker. More specifically, the terms alkylamino, dialkylamino, and trialkylamino are attached to the parent molecular moiety through a nitrogen atom and are as defined above. The term alkylamino refers to one, two, or three alkyl groups, each of which is defined as refers to a group having the structure -NHR', where R' is an alkyl group as defined above; In contrast, the term dialkylamino refers to a group having the structure -NR'R'', where R' and R " are each independently selected from the group consisting of alkyl groups. The term trialkylamino includes Refers to a group having the structure -NR'R''R''', where R', R'', and R''' are each independently Additionally, R', R'', and / or R''' are collectively selected from the group consisting of alkyl groups. Then, optionally -(CH2) k -, where k is an integer from 2 to 6. Examples include, but are not limited to However, methylamino, dimethylamino, ethylamino, diethylamino, diethylamino nocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino and propylamino.

[0132] 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, substituted or unsubstituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Heteroaryl is selected from the group consisting of aryl, hetero ...

[0133] The terms alkylthioether and thioalkoxyl refer to the thioether moiety which is linked to the parent molecular moiety through the sulfur atom. The tee is attached to a saturated (so-called alkyl-S-) or unsaturated (so-called alkenyl- Examples of thioalkoxy moieties include alkynyl-S- and alkynyl-S- groups. However, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio , and others of the same type.

[0134] "Acylamino" refers to an acyl-NH- group, where acyl is as previously defined. "Aroylamino" refers to an aroyl-NH- group in which the aroyl is as previously described.

[0135] The term "carbonyl" refers to the group --(C.dbd.O)--.

[0136] The term "carboxyl" refers to a -COOH group. Such groups are also referred to herein as " These are also called "carboxylic acid" moieties.

[0137] As used herein, the terms "halo," "halide," or "halogen" refer to fluoro. In addition, terms such as "haloalkyl" and "haloalkyl" refer to chloro, bromo, and iodo groups. and the like, "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, trifluoromethyl. , 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and similar This means that it includes things like:

[0138] The term "hydroxyl" refers to an --OH group.

[0139] The term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0140] The term "mercapto" refers to a -SH group.

[0141] As used herein, the term "oxo" refers to an oxygen atom that is double bonded to a carbon atom or another element. It means atom.

[0142] The term "nitro" refers to the -NO2 group.

[0143] The term "thio" refers to the compounds previously described herein in which a carbon or oxygen atom is replaced by a sulfur atom.

[0144] The term "sulfate" refers to the -SO4 group.

[0145] As used herein, the term thiohydroxyl or thiol refers to --SH.

[0146] The term ureido refers to a urea group of the formula -NH-CO-NH2.

[0147] Unless expressly defined otherwise, as used herein, "substituents" include any of the groups defined herein. The functional group may be selected from one or more of the following moieties: (A) -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, unsubstituted alkyl, unsubstituted Heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl , unsubstituted heteroaryl, and (B) Alkyl, heterocyclic, or aryl substituted with at least one substituent selected from the following: Cycloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl : (i) oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted Heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl , unsubstituted heteroaryl, and (ii) an alkyl, heterocyclic or aryl group substituted with at least one substituent selected from the following: Cycloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl (a) Oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted Heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl , unsubstituted heteroaryl, and (b) Oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted Alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl at least one substituted moiety selected from , unsubstituted aryl, and unsubstituted heteroaryl; substituted by alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl, or heteroaryl.

[0148] As used herein, the term "lower substituent" or "lower s "Substituent group" refers to any group selected from the substituents listed above. wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl. Each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl. and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5-C7 cycloalkyl. and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5- to 7-membered heterocycloalkyl. It is a cycloalkyl.

[0149] As used herein, a "size-limited substitution moiety" or "size-limited substituent" refers to a "substituent" that is means a group selected from all of the substituents described above, where each substituted or unsubstituted Alkyl is substituted or unsubstituted C1-C 20 alkyl, and each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl alkyl is a substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heteroaryl is The cycloalkyl is a substituted or unsubstituted 4- to 8-membered heterocycloalkyl.

[0150] Throughout this specification and the claims, any chemical formula or name given includes all tautomeric forms. isomers, homologues, and optical and stereoisomers, as well as mixtures of such isomers is included in the racemic mixture.

[0151] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, With respect to absolute stereochemistry, as (R)- or (S)-, or with respect to amino acids as (D)- or The stereoisomeric form that may be defined as (L)-, and the individual isomers, are encompassed within the scope of this disclosure. The compounds of the present disclosure are too unstable to be synthesized and / or isolated by the present technology. The present disclosure does not include those compounds known in the art in racemic and optically pure forms. This means that compounds containing optically active (R)- and (S)-, or (D)- and (L)-isotopic compounds are included. The isomers may be prepared using chiral synthons or chiral reagents, or may be prepared using conventional techniques. The compounds described herein may be decomposed through olefinic bonds or other geometric asymmetries. When a compound contains a core, and unless otherwise specified, the compound may include both E and Z geometric isomers. It is intended that the term "consultant" be included.

[0152] Unless otherwise stated, structures depicted herein also represent all stereochemical forms of the structure; That is, it is also meant to include the R and S configurations for each asymmetric center. , single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds. is within the scope of this disclosure.

[0153] Certain compounds of this disclosure may exist in tautomeric forms and all such tautomeric forms of the compounds are It will be apparent to one skilled in the art that various gender types are within the scope of the present disclosure. The term "tautomerism" as used herein refers to the process by which a compound exists in equilibrium and easily changes from one isomer to another. It refers to one of two or more structural isomers that are interchangeable without any conversion.

[0154] Unless otherwise stated, structures depicted herein may also contain one or more isotopic enrichments. It also includes compounds which differ only in the presence of (fully enriched) atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C- or 14 C-enriched carbon Compounds having this structure except for the substitution of carbons are within the scope of this disclosure.

[0155] The compounds of the present disclosure may also contain unnatural proportions at one or more of the atoms that constitute such compounds. Atomic isotopes may be included. For example, the compounds may contain radioisotopes, e.g. For example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C) etc. All isotopic variations of the compounds of the present disclosure may be radioactive. Regardless of whether or not the above is true, it is within the scope of this disclosure.

[0156] As used herein, the term "monomer" refers to a molecule that can undergo polymerization; This provides the building blocks for the essential structure of macromolecules or polymers.

[0157] A "polymer" is a molecule of high relative molecular mass, the structure of which is essentially a product of a lower relative molecular mass. A monomer may contain multiple repeats of a unit derived from a molecule of a monomer.

[0158] As used herein, "oligomer" refers to, for example, a compound that contains a potentially unlimited number of monomers. In contrast to polymers that can be made from a single monomer unit, dimers, trimers, and tetramers are A monomer is a non-limiting example of an oligomer.

[0159] The compounds of the present disclosure may exist as salts. The present disclosure includes such salts. Examples of suitable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, malate, etc. Leylate, acetate, citrate, fumarate, tartrate (e.g. (+)-tartrate, (-)-tartrate) tartrates or mixtures thereof, including racemic mixtures, succinates, benzoates and amino acids; For example, salts with glutamic acid and the like are included. These salts are not intended to be used in the present technology. In addition, base addition salts, e.g., sodium , potassium, calcium, ammonium, organic amino, or magnesium salts, or the like When the compounds of the present disclosure contain relatively basic functional groups, the salts of the above-mentioned compounds are also included. , acid addition salts are prepared by converting the neutral form of such compounds into salts, either neat or in a suitable inert solvent. Either of the above can be achieved by contacting the compound with a sufficient amount of the desired acid. Examples of possible acid addition salts include those of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, and the like. rbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogen phosphoric acid (dihydrogenphosphoric acid), sulfuric acid, monohydrogensulfuric acid, iodine Derived from inorganic acids such as hydrochloric acid, or phosphorous acid and the like. As well as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, Succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-Tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and similar. Also included are salts derived from organic acids such as aryl, aryl, arylsulfates, etc. Also included are salts of amino acids, e.g. Such as phosphates and the like, and glucuronic acid or galactosyl Also included are salts of organic acids such as turonic acid and the like. The compounds are salts that allow the compounds to be converted into either base addition salts or acid addition salts. It contains both basic and acidic functional groups.

[0160] The neutral forms of the compounds can be prepared by contacting the salts with a base or acid and reacting in a customary manner. The parent compound can be regenerated by isolating it in a 200 mL flask. The parent form of the compound may be regenerated by isolating it in a 20 mL flask. The various salt forms differ in properties, such as solubility in polar solvents. do.

[0161] Certain compounds of the present disclosure may be used in unsolvated as well as solvated forms, including hydrated forms. In most cases, the solvated forms are equivalent to the unsolvated forms and are described in the present disclosure. Certain compounds of the present disclosure may be present in multiple crystalline or amorphous forms. For the most part, all physical forms are suitable for the uses contemplated by this disclosure. Equivalents are intended to be within the scope of this disclosure.

[0162] The term "pharmaceutically acceptable salt" refers to a salt of a particular substituent found in the compounds described herein. Active compounds that can be prepared with relatively non-toxic acids or bases depending on the converting moiety When compounds of the present disclosure contain relatively acidic functional groups, the The neutral form of such a compound can be sufficiently A base addition salt can be obtained by contacting the compound with an appropriate amount of the desired base. Examples of acceptable base addition salts include sodium, potassium, calcium, ammonium, Organic amino or magnesium salts or similar salts. When a compound contains a relatively basic functional group, the neutral form of such a compound may be referred to as neat or as a suitable unsaturated form. Acid addition by contacting the compound with a sufficient amount of the desired acid in either an active solvent or Examples of pharma- ceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, and the like. , Carbonic acid, Monohydrogen carbonate, Phosphoric acid, Monohydrogen phosphate, Dihydrogen phosphate, Sulfuric acid, Monohydrogen sulfate, Iodide Derived from inorganic acids such as hydroacid, phosphorous acid, and the like; As well as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, Suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolyls Such as sulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts derived from relatively non-toxic organic acids, such as salts of amino acids, e.g. Such as alginate, and glucuronic acid or galacturic acid and others Also included are salts of organic acids such as those of the same type (see, for example, Berge et al., "Pharm aceutical Salts,” Journal of Pharmaceutical Science ence (Journal of Pharmaceutical Sciences), 1977, 66, 1-19. Certain specific compounds of the present disclosure may be converted into either a base or acid addition salt. The compound contains both basic and acidic functional groups that allow it to be bound to the acid.

[0163] In addition to salt forms, the present disclosure provides compounds in prodrug form. A prodrug of a compound undergoes a chemical change under physiological conditions to provide a compound of the disclosure. Furthermore, prodrugs are compounds that can be easily synthesized in an ex vivo environment. The compounds of the present disclosure can be converted to compounds of the present disclosure by chemical or biochemical methods. The drug is placed in a transdermal patch reservoir along with a suitable enzyme or chemical reagent. can be slowly converted to the compounds of the present disclosure.

[0164] The term "protecting group" refers to a group that protects some or all of the reactive moieties of a compound. Such moieties participate in chemical reactions until the blocking and protecting groups are removed. Chemical moieties that prevent ), Protective Groups in Organic Synthesis, 3rd ed. 3rd Edition, John Wiley & Sons (1999) and When different protecting groups are employed, each ( It may be advantageous for different (different) protecting groups to be removable by different means. Protective groups that are cleaved under different reaction conditions allow for differential removal of such protecting groups. For example, protecting groups are removable by acid, base, and hydrogenolysis. trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl, etc. The Cbz group is acid labile and can be removed by hydrogenolysis, and the base labile Cbz group is base labile. In the presence of an amino group protected by the unstable Fmoc group, carboxy and hydroxy groups It can be used to protect reactive moieties. Carboxylic acid and hydroxy reactive moieties. Yeti is a cationically stable ... or by carbamates that are both acid and base stable but hydrolytically removable. In the presence of a blocked amine, a base labile group such as, without limitation, methyl It can be blocked by such things as ethyl, ethyl, and acetyl.

[0165] Carboxylic acid and hydroxy reactive moieties also provide hydrolytically removable protecting groups. The aryl group may be blocked by a group such as a benzyl group, while the acid and hydrogen Amine groups that can be attached can be substituted with base labile groups such as Fmoc. Carboxylic acid reactive moieties can be blocked by oxidatively removable protecting groups, e.g. , 2,4-dimethoxybenzyl, etc., while Any remaining amino groups can be blocked with fluoride-labile silyl carbamates.

[0166] Allyl blocking groups (also called allyl protecting groups) are functionalized in the presence of acid- and base-protecting groups. It is useful because the former is stable and can be subsequently removed by metal or pyrolytic acid catalysts. For example, allyl-blocked carboxylic acids are acid-unstable. In the presence of a suitable t-butyl carbamate or base-labile acetate protecting group, palladium is The protecting group can be removed by a fluorine(O)-catalyzed reaction. Yet another form of protecting group is a resin. To the extent that a residue is attached to the resin, that functional group is Once released from the resin, the functional group is blocked and cannot react. It is possible.

[0167] Exemplary blocking / protecting groups include, but are not limited to, the following moieties: : [ka]

[0168] The subjects treated by the methods of the present disclosure, in many embodiments thereof, desirably Although the present invention is directed to human subjects, the methods described herein are valid for all vertebrate species and include is intended to be included in the term "subject." for medical purposes, e.g., to treat an existing condition or disease or to prevent the onset of a condition or disease. For human subjects, or for medical, veterinary, or other uses, such as preventive treatments to prevent disease. The present invention may include animal subjects for purposes or development purposes. Suitable animal subjects include mammals. Animals, including but not limited to primates, such as humans, monkeys, apes, and the like etc.; bovines, e.g. cattle, male Cattle (oxen), and the like; sheep-like (ovines), e.g., Sheep and the like; caprines, e.g. goats and the like; porcines, e.g., brook pigs, hogs, and the like; horses (eq uines, examples being horses, donkeys, zebras, and the like; cats Felines, including wild and domestic cats; dog-like canines, including dogs; lagomorphs, rabbits rabbit, hare, and the like; and Including but not limited to rodents, mice, rats, and the like. The animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Additionally, a "subject" includes a patient who is afflicted with or suspected of being afflicted with a condition or disease. Therefore, the terms "subject" and "patient" are used herein. Let's use them interchangeably.

[0169] Generally, an "effective amount" of an active agent or drug delivery device is one that satisfies a desired biological response. This refers to the amount of information required to derive an answer that would be recognized by a person of ordinary skill in the art. As will be appreciated, an effective amount of a drug or device is one that achieves a desired biological endpoint. The composition of the encapsulation matrix, the target tissue, and other related The amount of oxygen that can be absorbed may vary depending on factors such as the type of oxygen that can be absorbed, the amount of oxygen that can be absorbed, and the like.

[0170] In keeping with longstanding patent law convention, "a," "an," and "the" The term "one or more" as used in this application, including the claims, means "one or more Therefore, for example, where the context clearly indicates the opposite (e.g. A reference to "a subject," unless "is plural," and so on. contains multiple targets.

[0171] Throughout this specification and claims, the words "comprise" and "have as a component" are used interchangeably. ", "comprises" and "comprising" The term "having as a component, etc." is used where the context otherwise requires. Similarly, "include" is used in a non-exclusive sense. The term "including as a part, etc." and its grammatical variations refer to an item in a list. The enumeration lists other similar apps that can replace or add to the listed items. The list is intended to be non-limiting so as not to exclude items.

[0172] For purposes of this specification and the appended claims, unless otherwise indicated, amounts, Size, dimension, proportion, shape, formula, parameter, percentage, parameter, quantity All numerical values, characteristics, and other numerical values ​​used in this specification and claims are The numbers may differ in color from those shown unless the term "about" explicitly appears with the value, amount, or range. All such expressions should be understood to be modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the following specification and appended claims The numerical parameters expressed in the above are not, and need not be, precise, but are subject to tolerances, Conversion factors, rounding, measurement errors and the like, and the subject matter currently disclosed Depending on the desired properties sought to be obtained by may be approximated and / or larger or smaller as necessary to reflect other factors. For example, when referring to a value, the term "about" may mean some amount from the specified amount. In some embodiments, the range is ±100%, in some embodiments, ±50%, and in some embodiments, ±2 0%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments In some embodiments, ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1%. It can be meant to encompass variations that are in the disclosed method. or employing the disclosed compositions.

[0173] Further, when used in conjunction with one or more numbers or numerical ranges, the term "about" All such numbers are referred to and expressed inclusively in ranges. It should be understood that the range is modified by expanding the upper and lower boundaries of the numerical values. Enumerations of numeric ranges by endpoint include all numbers within the range, for example, all Integers and fractions thereof (e.g., the enumeration 1 to 5 includes 1, 2, 3, 4, and 5, and so on) These include fractions, examples include 1.5, 2.25, 3.75, 4.1, and the like. and any range therein. EXAMPLES

[0174] The following examples are provided to illustrate, by way of example, the practice of exemplary embodiments of the presently disclosed subject matter. It is included to provide guidance to those skilled in the art and to those of ordinary skill in the art. In light of Bell, the skilled artisan will appreciate that the following examples are intended to be illustrative only, and that the vast majority of Variations, modifications, and alternatives may be employed without departing from the scope of the subject matter of this disclosure. It can be appreciated that the following synthetic descriptions and specific The examples are intended for illustrative purposes only and are not intended to be limiting for making compounds of the present disclosure by other methods. and should not be construed as limiting in any way whatsoever the nature and scope of the disclosure.

[0175] Example 1

[0176] method

[0177] 2-PMPA prodrug versus placebo in nude mice or C4-2 prostate cancer tumor-bearing NSG mice Comparative tissue distribution of equimolar 2-PMPA.

[0178] Nude mice were anesthetized with isoflurane for a short period and perfused with saline, prior to injection of 2-PMPA or Either the prodrug LTP-144 or Tris-POC-2-PMPA (compound 10 in Table 1) (5 mg / kg or molar equivalent, ip (intraperitoneal)) and sacrificed 30 min later. The LC / MS-MS-based bioanalysis was performed as described above. Using a 2-PMPA ELISA kit (Majer et al., 2016), each tissue sample was evaluated for 2-PMPA concentration. Prodrug of the enzyme-based PSMA ligand ZJ-43 (promoiety similar to Tris-POC-2-PMPA) Modifications) were tested using similar methods.

[0179] To generate the C4-2 in vivo model, 6 LNCaP-C4-2 cells were cultured in male NSG mice. The tumor was injected subcutaneously into the flank. 3 When the tumor grows to a size that is too large, it is excised and aseptically The tissue was cut into 2-mm x 2-mm pieces and frozen back viably. ) (5% DMSO / 95% FBS). Tumors were not passaged from mouse to mouse more than four times. For the experiment, two vials of viable frozen explants were thawed at 37° C. Tumor explants The cells were washed in RPMI without FCS and then injected into subcutaneous pockets in male NSG mice. Surgically implanted. Tumors 600-800mm 3 When the tumor reached 100 μg / mL, the mouse was euthanized and the tumor was aseptically cultured. The tumors were excised and cut into 2-mm x 2-mm pieces before being reimplanted into 40 mice. 0-700mm 3Pharmacokinetic studies were performed when the dose reached 10 mg / kg iv. A dose of Tris-POC-2-PMPA (7.62 mg / kg, iv) was administered in a vehicle (5% EtOH / 10% Tween 80 / 85% 50 mM NaCl solution). After dissolving in 0.25, 0.5, 1, 3 M HEPES, the mixture was injected via the tail vein. Mice were euthanized under isoflurane anesthesia after 6 h or 10 min (n=3 / group). Blood was collected by puncture into EDTA-lined tubes and centrifuged to separate plasma. The salivary glands, kidneys, and tumors were harvested and dried. All tissues were stored at -80°C prior to bioanalysis.

[0180] Displacement study in non-tumor-bearing NMRI mice

[0181] 68 Ga-PSMA-617 was synthesized as previously described (Afshar-Oromieh Olomie et al., 2015). The specific activity (0. 2-20MBq tagged to 0.8μg precursor peptide 68 Ga) was used in clinical applications. (Afshar-Oromieh et al., 2015). Three non-tumor-bearing NMRI mice were treated with the tail vein 20MBq via 68 One hour after injection, specific tracers of PSMA were detected in the kidney. Mice were placed in a dedicated renal calyx for a period of time sufficient for binding of the tracer and removal of unbound tracer from the renal calyx. The images were taken using a PET scanner (Siemens, Inveon) and the kidneys were Immediately after the baseline scan, the uptake in the liver was quantified (baseline scan). All samples were dosed with 16 μg of Tris-POC-2-PMPA (0.5 mg / kg*32.1 g body weight (BW)) in 0 μL of saline. Mice) were injected via the tail vein. Another hour later, the so-called PET tracer injection After 2 hours, per animal PET 68 Ga-PSMA-617 renal uptake was reassessed (replacement scan) .

[0182] Replacement studies in nude mice bearing LNCaP tumor xenografts

[0183] 5*10 6 LNCaP cells (BD Biosciences) were cultured in nude mice (n=3). The tumors were implanted behind the left shoulder of the mice; they reached a diameter of approximately 1 cm 8-12 weeks after inoculation. and the baseline uptake of the radiopharmaceutical in the tumor is 68 Ga-PSMA-617 (0.4 μg PSMA-61 10-40 MBq tagged with 7 precursors 68 One hour after injection of Ga, the animals were scanned using PET (Siemens, Immediately after the baseline scan, animals were given 100 μg saline. In the control group, 0.5mg / kgBW or 0.05mg / kgBW Tris-POC-2-PMPA was used. Saline was injected. Another hour later, so-called 2 hours after the injection of the PET tracer, the kidney and in tumors 68 Uptake of Ga-PSMA-617 was reassessed for every second animal PET (replacement sequence). Can).

[0184] With and without pre-dosing of Tris-POC-2-PMPA 68Ga-PSMA-617 Kidney and salivary gland uptake in healthy human subjects investigated using

[0185] In advance 68 0.1, 1, 2, and 3 h after Ga-PSMA-617 injection (Afshar-Oromieh et al., 2015). Relevant tumor negative data were collected from a pair of patients (Siemens, mCT) imaged at 0 and 4 hours. One subject without a blood clot (<5 mL) was randomly selected to receive a physiologic evaluation of the kidneys and salivary glands during the study. We chose to quantify spontaneous tracer uptake. ent), one healthy volunteer was given 5 mg (0.01 mg) of The rats were then injected with a Tris-POC-2-PMPA solution (0.05 mg / kg BW) in 2.5 mL of 30% ethanol. Degree, 68 PET scans were performed at 0.1, 1, 2, 3, and 4 hours after injection of Ga-PSMA-617 (S iemens, mCT) and time-dependent tracer uptake in the kidneys and salivary glands. The results were quantified according to SUVmax (maximum standardized uptake value).

[0186] With and without premedication with Tris-POC-2-PMPA 68 Prostate examined with Ga-PSMA-617 Tumor, kidney, and salivary gland uptake in patients with adenocarcinoma

[0187] One patient underwent PET imaging 1 hour after injection of 68Ga-PSMA-617 to determine tumor, kidney and Tracer uptake in the peritoneal and salivary glands was quantified according to SUVmax. The sent was imaged using the same protocol, but with 10 mg PET-tracer 15 min prior to application. Pretreated with (0.1mg / kgBW) Tris-POC-2-PMPA solution (in 2.5mL of 30% ethanol) did.

[0188] With and without Tris-POC-2-PMPA premedication 177 Treatment with Lu-PSMA-617 and Tumor, kidney and salivary gland uptake in imaged prostate cancer patients

[0189] 177 Lu-PSMA-617 complies with the revised Declaration of Helsinki, paragraph 37, "Unproven Interventions In accordance with the Guidelines for Unproven Interventions in Clinical Practice, and all Priority of approved procedures (without contraindications) and nuclear medicine physicians and urology or oncology "Confirmation of the indication" by both a clinical and external expert In accordance with the German regulations on "compassionate use", All patients were treated with PSMA imaging. No systematic payroll was performed, except that participants had to present a PSMA-positive tumor phenotype based on their No treatment selection was performed. All patients were informed of the experimental nature of this treatment. All subjects were informed of the study and provided written informed consent. The Society approved this retrospective study. Two patients 177 Lu -Pretreatment with Tris-POC-2-PMPA before administration of PSMA-617. Then, gamma imaging The study was performed over several hours and radiation dosimetry was performed on healthy organs and metastatic lesions. The estimated values ​​of β-aminobutyric acid (β-aminobutyric acid) and β-aminobutyric acid (β-aminobutyric acid) were calculated and compared with the historical control group that did not receive Tris-POC-2-PMPA pretreatment. The dosimetry data from historical controls presented here were compared with those previously reported. The data were derived from patients treated at our center under the same protocol as that used in the study (J Nucl Med.(Journal of Nuclear Medicine) 2016 Aug;57(8):117 0-6.) All dosimetry was performed as previously described in that report (JN ucl Med., 2016 Aug;57(8):1170-6. ).

[0190] Example 2

[0191] result

[0192] First, the prodrug Tris-POC-2-PMPA was shown to be effective in pharmacokinetic / tissue distribution studies in mice. It was shown to deliver high levels of 2-PMPA to the kidney. In mice bearing the IL-1 gene, Tris-POC-2-PMPA inhibited the proliferation and proliferation of prostate cancer xenografts, respectively. demonstrated 3- and 57-fold preferential delivery of 2-PMPA to the salivary glands and kidneys of rodents. s-POC-2-PMPA is a PSMA-targeted PET tracer in normal mice 68 Ga-PSMA-6 It was shown to significantly reduce renal uptake of 17 in prostate cancer tumor-bearing mice. When tested, Tris-POC-2-PMPA 68 Selectively reduce renal uptake of Ga-PSMA-617 In a pilot study in healthy males, Tr Pretreatment with is-POC-2-PMPA was performed in the same manner as in mice. More later 68 Ga-PSMA-617 binding to kidney and salivary gland was displaced by approximately 65% Intra-individual comparisons in prostate cancer patients demonstrated that prior administration of Tris-POC-2-PMPA reduced renal After the 68 Ga-PSMA-617 binding to the retina by >75% and to the salivary glands by >35%. The tumor uptake of the tracer was largely avoided. About radiation therapy 177 Before injection of Lu-PSMA-617, two prostate cancer patients were Tris-POC-2-PMPA reduced the dose to both the salivary glands (72% dose reduction) and kidneys (45% dose reduction). reduced radiation exposure in prostate cancer tumors compared with historical controls Together, these data suggest that Tris-POC-2-PMPA or its analogs may be effective in treating rhesus malabsorption and rhesus malabsorption. Such prodrugs are released from radioligand binding to healthy organs (e.g., kidneys, lacrimal glands, and saliva). While selectively protecting the tumor gland, PSMA-targeted imaging or radiation This suggests that it does not interfere with tumor uptake of the radioligand during therapy.

[0193] Comparative tissue distribution of 2-PMPA prodrug versus equimolar 2-PMPA in nude mice.

[0194] Compared with equimolar doses of 2-PMPA, LTP144 and Tris-POC-2-PMPA suppressed 2-PMP expression in the kidney. Tris-POC-2-PMPA showed the most favorable distribution, resulting in significantly increased concentrations of A in the kidney. The delivery of 2-PMPA to the brain was increased by more than 20% (Figure 1). In contrast to the ZJ-43 ligand, a similar prodrug of an alternative urea-based PSMA ligand, ZJ-43, Parental administration of 43 (Figure 2A) did not show increased distribution to mouse kidney or salivary gland. (Figure 2B).

[0195] Tris-POC-2-PMPA (compound 10 in Table 1) delivered 2-PMPA to mouse salivary glands and kidneys to inhibit prostate cancer. Send preferentially compared to xenografts.

[0196] Concentrations of 2-PMPA in plasma, tumors, salivary glands, and kidneys were determined using 2-PMPA or Tris-POC of either -2-PMPA (3 mg / kg or molar equivalent, iv) in human C4-2 prostate cancer cells subcutaneously. were measured at multiple time points after tail vein administration into xenograft-bearing NSG mice (Figure 3A and Figure 3B TRIS-POC-2-PMPA treatment reduced 2-PMPA salivary gland and kidney exposure by 17.5 h*nmol / g and 374 h*nmol / g, respectively. h*nmol / g, yielding 3-fold and 57-fold more than those observed in the tumors (Figure 3B). When -PMPA was administered directly (Figure 3A), the exposure to the salivary gland and kidney was 1.76 h*nmol / g and 94. At 8h*nmol / g, these were 10- and 4-fold lower than those achieved by TRIS-POC-2-PMPA delivery. Therefore, TRIS-POC-2-PMPA was associated with a saliva:tumor and kidney:tumor 2-PMPA concentration ratio of 0.01 to 0.01. gave a significant improvement.

[0197] Replacement studies in non-tumor-bearing NMRI mice

[0198] The mean renal uptake in the baseline scan was 3.4 mSUV (Figure 4A). In the scan (Figure 4B), radioactivity was almost entirely removed from the kidney due to residual uptake of 0.3 mSUV. was replaced by (<10% of baseline uptake).

[0199] Replacement studies in nude mice bearing LNCaP tumor xenografts

[0200] In baseline scans, mean tumor uptake was mSUV1.02 and mean kidney uptake was The mSUV was 2.36 (Fig. 5A). In the displacement scan (Fig. 5B), the tumor uptake was almost The mean mSUV for the two premedicated animals was almost unchanged. However, this was significantly lower than in animals that received only saline to stimulate diuresis (mSUV 0.84). The renal uptake after Tris-POC-2-PMPA injection was substituted with mSUV 0.24. , which was 50% lower than with forced diuresis (control: mSUV 0.47).

[0201] With and without premedication with Tris-POC-2-PMPA 68 Health examined using Ga-PSMA-617 Kidney and salivary gland uptake in healthy human subjects

[0202] Physiological changes in control patients without prior administration of Tris-POC-2-PMPA 68 Ga-PS Biodistribution of MA-617 (Fig. 6A, left; maximum intensity projection 1 h pi) as well as in the kidney (Fig. 6C) and ear. Its typical pharmacokinetics in the subcutaneous gland (Figure 6D) was consistent with previous publications (Afshar-Oromieh et al., 2015 ) and can be considered representative. Concentrations are found in the kidneys and salivary glands and increase over time. Thin slices of the kidney (Figure 6B, top) demonstrated strong tracer uptake in the renal cortex, so-called This corresponds to PSMA expression in the proximal convoluted tubule reported in histopathological examination.

[0203] In volunteers premedicated with Tris-POC-2-PMPA 68 In vivo distribution of Ga-PSMA-617 The plot (Fig. 6A, right; maximum intensity projection 1 h pi) shows significant no-accretion of the tracer over time. Coronal thin slices through the kidney (Fig. 6B, bottom) revealed a marked decrease in renal uptake. Demonstrating uniform contrast throughout the parenchyma, but tracer accumulation observed in the calyx clearance through the entire nephron is implied.

[0204] The highest uptake in the renal parenchyma was observed for Tris-POC-2-PMPA compared to the representative control. The effect was only 65% ​​in premedicated volunteers (SUVmax 16.5 vs. 47.5). The results were very similar for Tris-POC-2-PMPA premedicated volunteers (SUVmax 13.5 vs. 41.2). The observed tracer uptake was consistent with the mean kidney uptake published by Afshar-Oromieh et al., 2015. / The uptake of the parotid gland was reduced by more than one standard deviation, and therefore the results were not observed by chance. The probability of this occurring is <5%.

[0205] With and without premedication with Tris-POC-2-PMPA 68 Prostate examined with Ga-PSMA-617 Tumor, kidney, and salivary gland uptake in patients with adenocarcinoma

[0206] Avid uptake of PSMA radioligand was observed in the metastases (SUVmax 3.6-12.5), ears, and in the submandibular gland (SUVmax 18.2), submandibular gland (SUVmax 23.1), and kidney (SUVmax 35.4). , 68 PET scans were performed one hour after administration of Ga-PSMA-617 in the first patient. This was confirmed (Figure 7, upper left). 68 Inject Ga-PSMA-61715 When administered 10 min before the injection, Tris-POC-2-PMPA (10 mg, iv) reduced the uptake of the radioligand. The parotid gland (SUVmax 10.6), submandibular gland (SUVmax 14.6), and kidney (SUVmax 8.5) were significantly higher in the 10-fold increase. However, there was no clear effect on metastasis (SUVmax 3.9-8.8) (Figure 7, upper right). Quantification as percent change within subjects revealed that Tris-POC-2-PMPA inhibits the secretion of phospholipids in the salivary gland and kidney. After pretreatment with TRIS-POC-2-PMPA, the uptake of , an average of only 3% change was observed in metastases, and in some lesions 68 Uptake of Ga-PSMA-617 An increase was actually observed.

[0207] TRIS-POC-2-PMPA pretreatment improves salivary gland and kidney function in patients with mCRPC 177 Lu-PS It attenuated MA-617 uptake but not metastasis.

[0208] Based on positive diagnostic PET scan results, two mCRPC patients were subsequently 177 L TRIS-POC-2-PMPA (10 mg, iv) was administered 15 min prior to the injection of u-PSMA-617 (Figure 8, top). Representative patient, with the diagnostic scan on the left and the therapeutic scan on the right separated by lines; (summary data) compared with historical controls from the same centers (Kratochwil et al. , 2016), TRIS-POC-2-PMPA pretreatment was associated with increased radiation therapy in the parotid, submandibular, and kidneys. The absorbed doses were 0.24, 0.5, and 0.6 for Patient 1, respectively. and 0.38 Gy / GBq for patient 1, and 0.46, 0.44, and 0.43 Gy / GBq for patient 2, respectively. All of these values ​​are within the standard deviation of the historical controls. and 76%, 67%, and 48% for the parotid, submandibular, and kidneys, respectively. In contrast, pretreatment with TRIS-POC-2-PMPA reduced the radiation dose to metastases. Patient 1 received an average of 8.03 Gy / GBq. Patient 1 had a mean dose of 13.15 Gy / GBq, and Patient 2 had a mean dose of 13.15 Gy / GBq. These values ​​were both Both were within the standard deviation of historical controls and, importantly, demonstrated therapeutic efficacy. The absorbed dose values ​​reported for this dose range are at or above those reported in Kratochwil et al., 2016. .

[0209] Although not dose limiting, TRIS-POC-2-PMPA was administered without any clear effect on spleen dose. 177 Lu-PSM TRIS-POC-2-PMPA also appeared to moderately reduce hepatic exposure to A-617. One recent report showed that the tear gland 177 Critical threshold after Lu-PSMA-617 therapy predicted that the cerebrospinal fluid would be the first organ to receive a mean effective dose of 2.82 Gy / GBq (Hohberg This value was reported in another recent study (Scarpa et al., 2017). similar to those reported and the values ​​obtained in the historical controls presented here. Compared to these mean control values, pretreatment with TRIS-POC-2-PMPA increased the mean This resulted in a 5.0% reduction in dose to the lacrimal gland.

[0210] Historical control patients used as direct comparators in this study The healthy organ dosimetry estimates for the patient are either therapeutic or subtherapeutic. Concentration 177 Median values ​​previously reported for other mCRPC patients receiving Lu-PSMA-617 It is important to note that the 1990s is very close to the 1990s (Kratochwil et al., 2016; Hohberg et al., 2016; Scarpa et al., 2017; Delker et al., 2016; Fendler Kabasakal et al., 2015; Kabasakal et al., 2017; Yadav et al. In the presently disclosed subject matter, the control was a mean dose of 1.44 Gy / GBq to the salivary glands. absorbed dose to the kidneys of 0.78 Gy / GBq (reported range: 0.5 3-0.99 Gy / GBq), and 0.03 Gy / GBq to red bone marrow (reported range: 0.01-0.05 Gy / GBq). and can therefore be considered representative. References

[0211] All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety. All publications, particulars, references herein are indicative of the level of skill of those skilled in the art to which the subject matter of the disclosure pertains. Patent applications, patents, and other references are hereby incorporated by reference as if each individual publication, patent application, patent, and other references are specifically and individually indicated to be incorporated by reference. No. 60 / 313,933, filed on Oct. 23, 2007. These and other related patent applications, patents, and related applications are hereby incorporated by reference to the same extent as if each application was filed on Oct. 23, 2007. and other references are referred to herein, although such references are not intended to be limiting unless expressly stated in any of these documents. does not constitute an admission that the invention forms part of the common general knowledge in the art. It will be understood that in the event of a conflict between this specification and any incorporated references, In this case, the specification (including any amendments thereto, which may be based on the incorporated references) The accepted meaning of terms in standards should be controlled by the Standard abbreviations for various terms are used herein unless otherwise noted.

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Journal of nuclear medicine e: official publication, Society of Nuclear Medicine 57, 1170-1176 (2016). Kratochwil C. et al. Targeted Alpha Therapy of mCRPC with (225)Actinium-PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control.(( 225) Targeted alpha therapy for mCRPC using actinium-PSMA-617: Swimmer plot analysis Analysis suggests efficacy regarding duration of tumor control.) Journal of Nuclear Medicine e: official publication, Society of Nuclear Medicine, (2018). Kratochwil C. et al. Targeted Alpha Therapy of mCRPC with 225Actinium-PSMA-617: Do simetry estimate and empirical dose finding. (mC using 225 actinium-PSMA-617) Targeted alpha therapy for RPC: dosimetry estimates and empirical dosimetry findings. Journal of nucle ar medicine: official publication, Society of Nuclear Medicine, (2017). Kratochwil C. et al. 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Current status of prostate-specific membrane antigen targeting in nuclear medicine: diagnosis of prostate cancer and clinical interpretation of chelating agents containing prostate-specific membrane antigen ligands for treatment.)Seminars i n nuclear medicine 46, 405-418 (2016). Kwekkeboom D., Perspective on 177Lu-PSMA Therapy for Metastatic 17. Metastatic Castration-Resistant Prostate Cancer. 7Lu-PSMA treatment prospects. )Journal of nuclear medicine: official publication, Societ y of Nuclear Medicine 57, 1002-1003 (2016). Liu H. et al., Constitutive and antibody-induced internalization of prosta Constitutive and antibody-induced internalization of prostate-specific membrane antigen. line. )Cancer research 58, 4055-4060 (1998). Lutje S. et al., PSMA Ligands for Radionuclide Imaging and Therapy o f Prostate Cancer: Clinical Status. PSMA ligands for treatment: clinical status. Theranostics 5, 1388-1401 (2015). 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Morris MJ et al., Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results Radiation-free survival as a response biomarker in metastatic castration-resistant prostate cancer :COU-AA-302 results. )Journal of clinical oncology : official journal of the Ameri can Society of Clinical Oncology 33, 1356-1363 (2015). Nedelcovych M. et al., Enhanced Brain Delivery of 2-(Phosphonome thyl)pentanedioic Acid Following Intranasal Administration of Its gamma-Substitu ted Ester Prodrugs. (Gamma-Substituted Ester Prodrugs of 2-(Phosphonomethyl)pentanedioic Acid) Enhanced brain delivery of 2-(phosphonomethyl)pentanedioic acid following intranasal administration of Rag.) Molecula r pharmaceutics 14, 3248-3257 (2017). O'Keefe DS, DJ Bacich, WD Heston, Comparative analysis of prostate-specific membrane antigen (PSMA) versus a prostate-specific Prostate-specific membrane antigen-like gene. Comparative analysis of genes.)The Prostate 58, 200-210 (2004). Omlin A. et al., Improved survival in a cohort of trial participants with h metastatic castration-resistant prostate cancer demonstrates the need for upda ted prognostic nomograms. (A cohort of study participants with metastatic castration-resistant prostate cancer) The improved survival in patients with bronchitis indicates the need for updated prognostic nomograms. logy 64, 300-306 (2013). Parker, C. et al., Alpha emitter radium-223 and survival in metastatic protoplasts. Alpha-emitter radium-223 and survival in metastatic prostate cancer. . )The New England journal of medicine 369, 213-223 (2013). Perner S, Hofer MD, Kim R, et al., Prostate-specific membrane a Antigen expression as a predictor of prostate cancer progression. Prostate-specific membrane antigen expression as a predictor of prostate cancer. Hum Pathol )2007;38:696-701. Petrylak DP et al., Docetaxel and estramustine compared with mitoxa ntrone and prednisone for advanced refractory prostate cancer. Docetaxel and estramustine versus mitoxantrone and prednisolone for adenocarcinoma Compare with Nisone.)The New England journal of medicine 351, 1513-1520 (2004). Pillai MR, Nanabala R, Joy A, Sasikumar A, Russ Knapp FF. Radiolabeled enzyme inhibitors and binding agents s targeting PSMA: Effective theranostic tools for imaging and therapy of prostat Radiolabeled enzyme inhibitors and binders targeting PSMA: a potential treatment for prostate cancer. An effective theranostic tool for imaging and therapy. Nuclear Medicine and Biology 2016; 43:692-720. Rahbar K. et al., German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. German multicenter study investigating u-PSMA-617 radioligand therapy.)Journal of Nucle ar medicine: official publication, Society of Nuclear Medicine 58, 85-90 (2017) . Rahbar K., H. Ahmadzadehfar, M. Boegemann, (177)Lu-PSMA-617 radioligand therapy in mCRPC: ready for phase III trial?(mCRP (177)Lu-PSMA-617 radioligand therapy in C: Are we ready for a Phase III trial? )European journal of nuclear medicine and molecular imaging 45, 513-514 (2018). Ramadan WH, WK Kabbara, HS Al Basiouni Al Masri (Al-Bassioni Al-Masri), Enzalutamide for patients with metastatic cast For patients with metastatic castration-resistant prostate cancer. Enzalutamide is an effective treatment for cancer. OncoTargets and therapy 8, 871-876 (2015). Ristau BT, DS O'Keefe, DJ Bacich, The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of res earch. (Prostate-specific membrane antigen: lessons learned from 20 years of research and current clinical implications.) Ur Oncology 32, 272-279 (2014). Saad F. et al., The 2015 CUA-CUOG Guidelines for the management of castrat For the management of castration-resistant prostate cancer (CRPC). 2015 CUA-CUOG Guidelines. Canadian Urological Association journal = Journal de l'Association des urologues du Canada 9, 90-96 (2015). Scarpa L. et al., The (68)Ga / (177)Lu theragnostic concept in PSMA targeting of cast ration-resistant prostate cancer: correlation of SUVmax values ​​and absorbed dose (68)Ga / (177)Lu diagnostics for PSMA targeting in castration-resistant prostate cancer Concept of Radiography: Correlation between SUVmax and absorbed dose estimates.)European journal of nuclear medicine cine and molecular imaging 44, 788-800 (2017). Schwarzenboeck SM et al., PSMA Ligands for PET Imaging of Prostate Cancer. (PSMA Ligands for PET Imaging of Prostate Cancer) Journal of nuclear medicine : official publication, Society of Nuclear Medicine 58, 1545-155 2 (2017). Silver DA, I. Pellicer, W. R. Fair, W. D. Heston, C. 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[0213] The subject matter of the preceding paragraphs has been described in some detail by way of illustration and example for purposes of clarity of understanding. However, it will be understood that certain variations and modifications can be practiced within the scope of the appended claims. will be understood by those skilled in the art.

Claims

1. Prostate-specific membrane antigen (PSMA)-targeted imaging in off-target non-cancerous tissues or a method for preventing or reducing exposure to a therapeutic agent, comprising administering to said therapeutic agent a 2-(phosphonomethyl) A prodrug of 2-pentanedioic acid (2-PMPA) was administered to subjects treated with PSMA-targeting agents. Effective in preventing or reducing binding of PSMA-targeting drugs to target non-cancerous tissues The method of claim 1, further comprising administering in an amount

2. Prodrugs of 2-PMPA include compounds of formula (I) or formula (II): 【Chemistry 1】 During the ceremony: Each R 1 , R 2 , R 3 , and R 4 is H, alkyl, Ar, -(CR 5 R 6 ) n -Ar, -(CR 5 R 6 ) n -OC(=O)-R 7 、-(CR 5 R 6 ) n -C(=O)-O-R 7 、-(CR 5 R 6 ) n -O-C(=O)-O-R 7 、-(CR 5 R 6 ) n -O-R 7 、-(CR 5 R 6 ) n -O-[(CR 5 R 6 ) n -O] m -R 7 、-(CR 5 R 6 ) n -Ar-O-C(=O)-R 7 、-Ar-C(=O)-O-(CR 5 R 6 ) n -R 7 、-(CR 5 R 6 ) n -NR 8 R 9 , and -(CR 5 R 6 ) n -C(=O)-NR 8 R 9 independently selected from the group consisting of: During the ceremony: n is an integer from 1 to 20; m is an integer from 1 to 20; Each R 3 ' and R 4 ' is independently H or alkyl; Each R 5 and R 6 is independently selected from the group consisting of H, alkyl, and alkylaryl. R; Each R 7 is independently straight chain or branched alkyl; Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Call R 8 and R 9 are each independently H or alkyl; and Pharmaceutically acceptable salts thereof 2. The method of claim 1, comprising:

3. The compound of formula (I) is as follows: 【Chemistry 2】 The method of claim 2, wherein the compound is selected from the group consisting of:

4. The compound of formula (I) is as follows: 【Chemistry 3】 The method of claim 2, wherein the compound is selected from the group consisting of:

5. The compound of formula (I) is as follows: 【Chemistry 4】 The method of claim 2, wherein the compound is selected from the group consisting of:

6. The compound of formula (I) is as follows: 【Chemistry 5】 The method of claim 2, wherein the compound is selected from the group consisting of:

7. The compound of formula (I) 【Chemistry 6】 The method of claim 2,

8. The compound of formula (I) 【Chemistry 7】 The method of claim 2,

9. The compound of formula (I) 【Chemistry 8】 The method of claim 2,

10. The compound of formula (I) 【Chemistry 9】 The method of claim 2,

11. The compound of formula (I) 【Chemistry 10】 The method of claim 2,

12. The compound of formula (I) 【Chemistry 11】 The method of claim 2,

13. The compound of formula (I) is as follows: 【Chemistry 12】 The method of claim 2, wherein the compound is selected from the group consisting of:

14. The compound of formula (I) 【Chemistry 13】 The method of claim 2,

15. The compound of formula (I) 【Chemistry 14】 The method of claim 2,

16. The compound of formula (I) 【Chemistry 15】 The method of claim 2,

17. The compound of formula (I) is as follows: 【Chemistry 16】 The method of claim 2, wherein the compound is selected from the group consisting of:

18. The compound of formula (I) 【Chemistry 17】 The method of claim 2,

19. The compound of formula (I) 【Chemistry 18】 The method of claim 2,

20. The compound of formula (I) 【Chemistry 19】 The method of claim 2,

21. The compound of formula (I) 【Chemistry 20】 The method of claim 2,

22. The compound of formula (I) is as follows: 【Chemistry 21】 The method of claim 2, wherein the compound is selected from the group consisting of:

23. The compound of formula (I) is as follows: 【Chemical 22】 The method of claim 2, wherein the compound is selected from the group consisting of:

24. The compound of formula (I) is as follows: 【Chemistry 23】 The method of claim 2, wherein the compound is selected from the group consisting of:

25. The compound of formula (I) 【Chemistry 24】 The method of claim 2,

26. The compound of formula (I) is as follows: 【Chemistry 25】 The method of claim 2, wherein the compound is selected from the group consisting of:

27. The compound of formula (II) 【Chemistry 26】 The method of claim 2,

28. The compound of formula (II) 【Chemistry 27】 The method of claim 2,

29. Prodrugs of 2-PMPA may be administered in combination with PSMA-targeted imaging or therapeutic agents. The method of claim 1 .

30. Prodrugs of 2-PMPA are useful for administering PSMA-targeted imaging or therapeutic agents prior to their administration.

30. The method of claim 29 administered to an elephant.

31. Prodrugs of 2-PMPA can be administered to subjects simultaneously with PSMA-targeted imaging or therapeutic agents.

30. The method of claim 29, wherein the method is performed by

32. The off-target tissue is in an organ selected from the group consisting of kidney, lacrimal gland, and salivary gland.

2. The method of claim 1.

33. PSMA-targeted imaging or therapeutic agents include PSMA-11, PSMA-617, and PSMA I&T. The method of claim 1, wherein the compound is selected from the group consisting of:

34. To reduce salivary gland damage in patients receiving PSMA-targeted therapy for cancer or administering to the patient a therapeutically effective amount of a prodrug of 2-PMPA.

35. Salivary gland damage may include dry mouth, thickened saliva, decreased saliva, stomatitis, hoarseness, difficulty swallowing, and loss of taste.

35. The method of claim 34, which causes a side effect selected from the group consisting of:

36. Reducing kidney damage in patients receiving PSMA-targeted therapy for cancer administering to the patient a therapeutically effective amount of a prodrug of 2-PMPA.

37. Prodrugs of 2-PMPA include compounds of formula (I) or formula (II): 【Chemistry 28】 During the ceremony: Each R 1 , R 2 , R 3 , and R 4 is H, alkyl, Ar, -(CR 5 R 6 ) n -Ar, -(CR 5 R 6 ) n -OC(=O)-R 7 、-(CR 5 R 6 ) n -C(=O)-O-R 7 、-(CR 5 R 6 ) n -O-C(=O)-O-R 7 、-(CR 5 R 6 ) n -O-R 7 、-(CR 5 R 6 ) n -O-[(CR 5 R 6 ) n -O] m -R 7 、-(CR 5 R 6 ) n -Ar-O-C(=O)-R 7 、-Ar-C(=O)-O-(CR 5 R 6 ) n -R 7 、-(CR 5 R 6 ) n -NR 8 R 9 , and -(CR 5 R 6 ) n -C(=O)-NR 8 R 9 independently selected from the group consisting of: During the ceremony: n is an integer from 1 to 20; m is an integer from 1 to 20; Each R 3 ' and R 4 ' is independently H or alkyl; Each R 5 and R 6 is independently selected from the group consisting of H, alkyl, and alkylaryl. R; Each R 7 is independently straight chain or branched alkyl; Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Call R 8 and R 9 are each independently H or alkyl; and Pharmaceutically acceptable salts thereof 37. The method of any one of claims 34-36, comprising:

38. Prodrugs of 2-PMPA include the following: 【Chemical 29】 38. The method of any one of claims 34-37, selected from the group consisting of:

39. PSMA-targeted imaging or therapeutic agents include 117Lu-PSMA-617, 131I-MIP-1095, 177Lu -PSMA-I&T, 177Lu-PSMA-R2, 225Ac-PSMA-617, 227Th-PSMA-ADC, CTT1403, CTT1700, 68Ga - selected from the group consisting of PSMA-11, 18F-DCFPyL, CTT1057, 68Ga-PSMA-R2, and 68Ga-PSMA-617 39. The method of any one of claims 34-38, wherein

40. The PSMA targeted therapeutic agent is administered in a cumulative amount of from about 3 GBq to about 100 GBq of radiation therapy.

40. The method of any one of claims 34-39, wherein the substance is a therapeutic agent.

41. The PSMA targeted radiotherapeutic agent is administered in a cumulative amount of about 52 GBq to about 100 GBq.

41. The method of claim 40.

42. The PSMA targeted therapeutic and the 2-PMPA prodrug are administered for about 1 to about 15 treatment cycles.

42. The method of any one of claims 34-41, wherein the method is performed using

43. The PSMA targeted therapeutic and the 2-PMPA prodrug are administered for about 6 to about 15 treatment cycles. The method of claim 42, wherein the method is performed by

44. Any of claims 34-43, wherein the patient has not previously been treated for cancer. A method of one term.

45. 45. The method of any one of claims 34-44, wherein the cancer is prostate cancer.

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