α-Methylene and Aminomethyl Lactones and Lactams for Treating Clostridioides difficile Infection (CDI)

Abstract

Provided are compounds, particularly the compounds α-methylene and α-aminomethyl lactones, lactams, iminolactones, and iminolactams, thiolactones, thionolactones, thiolactams, and thionolactams, for treating various infections, including infections caused by Clostridioides difficile; pharmaceutical compositions; and methods for treating these infections.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 306,164, filed February 3, 2022. U.S. Provisional Patent Application No. 63 / 306,164 is incorporated by reference herein in its entirety.

[0002] Technical Field The present disclosure relates to compounds and methods for treating patients with microorganisms, in particular α-methylene and α-aminomethyl lactones, lactams, iminolactones, and iminolactams, thiolactones, thionolactones, thiolactams, and thionolactams for treating infections caused by Clostridioides (formerly known as Clostridium) difficile. [Background technology]

[0003] background This section introduces aspects that may be helpful in making the present disclosure better understood. As such, these statements should be read in this light, and not be understood as admissions about what is or is not prior art.

[0004] The discovery and development of antibiotics transformed medicine, making otherwise fatal bacterial infections treatable. The most common side effects of antibiotic treatment of bacterial infections are diarrhea and colitis [1]. It is widely accepted that antibiotic-induced disruption of the normal intestinal microbiota creates favorable conditions for the growth of toxigenic bacteria, resulting in antibiotic-associated diarrhea (AAD). Nearly 40 years have passed since toxigenic Clostridioides difficile (C. difficile) was identified as the common causative agent of AAD and colitis [2]. Currently, roughly one-third of AAD cases are attributable to C. difficile [3], with an estimated 500,000 cases and approximately 29,000 deaths annually in the United States alone [4].

[0005] Fidaxomicin is the only antibiotic approved by the FDA in the past 40 years to combat Clostridioides difficile infection (CDI) since vancomycin [5-7]. However, recurrence rates for fidaxomicin remain high for infections involving highly virulent strains (24% recurrence rate) and for patients being treated for episodes of recurrent C. difficile-associated diarrhea (20% recurrence rate) [8-11]. One in five CDI patients experience a recurrence of infection, and one in nine patients aged 65 years or older die within 30 days of diagnosis

[12] . Furthermore, mortality associated with CDI is rising, with infections occurring in populations previously considered low risk, such as young adults and healthy adults [8]. Thus, there remains a strong need for the development of selective new antibiotics with improved efficacy to treat CDI with little or no side effects.

[0006] In view of the foregoing, it is an object of the present disclosure to provide new drugs for treating CDI. This and other objects and advantages, as well as features of the present invention, will be apparent from the detailed description provided herein. Summary of the Invention

[0007] overview The present disclosure relates to a compound of formula TIFF2025505612000001.tif43128 and pharma- ceutically acceptable salts thereof: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R is H or alkyl; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together with the N to which they are attached form a ring system.

[0008] The present disclosure also provides a compound of formula (I), comprising the formula The present invention also relates to a compound of TIFF2025505612000002.tif43128 or a pharma- ceutically acceptable salt thereof: During the ceremony, n is 1, 2, 3, or 4; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together with the N to which they are attached form a ring system.

[0009] The present disclosure also provides a compound of formula The present invention also relates to a compound of TIFF2025505612000003.tif60128 or a pharma- ceutically acceptable salt thereof: wherein X is halo.

[0010] The present disclosure also provides a compound of formula The present invention also relates to a compound of formula (I) of the formula: TIFF2025505612000004.tif63165, or a pharma- ceutically acceptable salt thereof.

[0011] The present disclosure also relates to compounds of formula (I): TIFF2025505612000005.tif43128In formula, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

[0012] The present disclosure also provides a compound of formula (I), comprising the formula The present invention also relates to a compound of TIFF2025505612000006.tif43128 or a pharma- ceutically acceptable salt thereof: During the ceremony, n is 1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl.

[0013] The present disclosure also relates to pharmaceutical compositions comprising one or more compounds of any of formulas (I), (II), (III), or (IV) together with one or more pharma- ceutically acceptable diluents, excipients, or carriers. The pharmaceutical compositions may be nanoparticles. The pharmaceutical compositions may also include one or more other antibiotics.

[0014] The present disclosure also relates to a method for treating a patient having an infection, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of Formula (I), (II), (III), or (IV) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. The infection may be caused by Clostridioides difficile.

[0015] The present disclosure also relates to a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a Clostridioides difficile infection in a subject.

[0016] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following detailed description and claims. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows structures of lactones with selectivity for C. diff. [Diagram 2] Figure 2 shows the toxicity analysis of compounds 27, 48, 50, 51, 61, and 85 against human colorectal cells (Caco-2). The percent mammalian viable cells were measured as the mean absorbance ratio (comparing test agent to DMSO) for cytotoxicity analysis of the compounds at 32 μg / mL, 64 μg / mL, and 128 μg / mL against Caco-2 cells using the MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay (tested in triplicate). Dimethylsulfoxide (DMSO) was used as a negative control to determine the baseline value of the cytotoxic effect of each compound. Absorbance values ​​are the average of the minimum of three samples analyzed for each compound. Error bars represent the standard deviation of the absorbance values. Statistical differences (indicated with an asterisk, *) between the values ​​obtained for each compound and those obtained for DMSO (negative control, used as solvent for the compounds) (P<0.05) were determined by two-way ANOVA with post-hoc Dunnett's multiple comparison test. [Diagram 3] Figure 3 shows the sensitivity to CDI using two different protocols, A (antibiotic cocktail) and B (single antibiotic), and shows mice infected with C. difficile and treated with drugs. [Figure 4] FIG. 4 shows a CDI mouse relapse model. [Figure 5A] Figures 5A-5H show results from histological toxicity examination of mouse kidney (5A), liver (5B), lung (5C), spleen (5D), heart (5E), stomach (5F), small intestine (5G), and intestine (5H) tissues. Side-by-side comparisons of treated and control data were performed. All images are at 10x magnification. [Figure 5B] See legend to Figure 5A. [Figure 5C] See legend to Figure 5A. [Figure 5D] See legend to Figure 5A. [Figure 5E] See legend to Figure 5A. [Figure 5F] See legend to Figure 5A. [Figure 5G] See legend to Figure 5A. [Figure 5H] See legend to Figure 5A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description Although the concepts of the present disclosure have been illustrated and described in detail in the description herein, the results in the description should be considered as illustrative and not restrictive in character, with the understanding that only exemplary embodiments have been shown and described, and that all changes and modifications that come within the spirit of the disclosure are desired to be protected.

[0019] The present disclosure relates generally to compounds useful for treating infectious diseases. Pharmaceutical compositions and methods for treating these diseases are within the scope of the present disclosure.

[0020] The present disclosure relates to compounds useful for treating infectious diseases. In an aspect, the present disclosure relates to compounds of the formula or a pharma- ceutically acceptable salt thereof having the formula: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4, and In the general formula, R1, R2, R3, R4, R5, and R6 are the same or different and may be independently hydrogen atoms, halogen atoms, hydroxyl groups, and any other linear, branched, or cyclic aliphatic groups containing any number of carbon (1-30) atoms. These groups may contain one or more heteroatoms, such as oxygen, sulfur, or nitrogen. Representative groups include, but are not limited to, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl (e.g., ortho-substituted, and / or meta-substituted, and / or para-substituted phenyl), heteroaryl, and substituted heteroaryl. Representative substitutions include, but are not limited to, alkoxy, alkylthio, halo, hydroxyl, phenoxy, aryloxy, cyano, isocyano, carbonyl, carboxyl, amino, amido, sulfonyl, substituted heterocyclic, and the like.

[0021] R7 and R8 may independently be a hydrogen atom, a linear, branched, or cyclic aliphatic group, an aryl group, a heteroaryl group, or a substituted aryl group. Alternatively, R7 and R8 together with the N to which they are attached form a ring system, such as aziridine, azetidine, pyrrolidine, or piperidine. These cycles may contain other heteroatoms, such as N, S, or O, to form heterocycles, such as morpholine or thiomorpholine.

[0022] In aspects, the present disclosure relates to methods or processes for extending the clinical usefulness of current antibiotics such as vancomycin and fidaxomicin.

[0023] In an aspect, the disclosure relates to a method of use of a compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating an infectious disease in a subject.

[0024] In aspects, the disclosure relates to pharmaceutical compositions comprising a compound together with one or more pharma- ceutically acceptable diluents, excipients, or carriers.

[0025] In an aspect, the present disclosure provides a compound of formula or a pharma- ceutically acceptable salt thereof having the formula: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R is H or alkyl, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

[0026] In an aspect, the present disclosure provides a compound of formula Compounds of TIFF2025505612000009.tif43128 and pharma- ceutically acceptable salts thereof: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R is H or alkyl; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together form a ring system with the N to which they are attached.

[0027] In an aspect, the present disclosure provides a compound of formula The present invention relates to a compound or a pharma- ceutically acceptable salt thereof for treating a patient having an infectious disease, the compound having the formula: During the ceremony, n is 1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

[0028] In an aspect, the present disclosure provides a compound of formula TIFF2025505612000011.tif43128 and pharma- ceutically acceptable salts thereof: During the ceremony, n is 1, 2, 3, or 4; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together form a ring system with the N to which they are attached.

[0029] In an aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) together with one or more carriers, diluents, or excipients. administering to a patient in need of relief from an infection a therapeutically effective amount of one or more compounds of TIFF2025505612000012.tif43128 or a pharma- ceutical acceptable salt thereof; During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; The present invention relates to a method for treating a patient with an infectious disease.

[0030] In an aspect, the disclosure relates to a method for treating a patient having an infection, the method comprising administering a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein the infection is caused by Clostridioides difficile.

[0031] In an aspect, the present disclosure provides a compound of formula (II) together with one or more carriers, diluents, or excipients. administering to a patient in need of relief from an infection a therapeutically effective amount of one or more compounds of formula (I) or a pharma- ceutical acceptable salt thereof; During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7-R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; or R7 and R8 together form a ring system with the N to which they are attached; The present invention relates to a method for treating a patient with an infectious disease.

[0032] In an aspect, the disclosure relates to a method for treating a patient having an infection comprising administering to a patient in need of relief from said infection a therapeutically effective amount of one or more compounds of formula (II) or a pharma- ceutically acceptable salt thereof, together with one or more carriers, diluents, or excipients, wherein said infection is caused by Clostridioides difficile.

[0033] In an aspect, the disclosure provides a method for treating a patient having an infectious disease, comprising administering to the patient a compound of formula (III) together with one or more carriers, diluents, or excipients. TIFF2025505612000014.tif43128 or a pharma- ceutically acceptable salt thereof to a patient in need of relief from said infection, comprising the steps of: During the ceremony, n=1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

[0034] In an aspect, the disclosure relates to a method for treating a patient having an infectious disease, comprising administering to a patient in need of relief from said infection a therapeutically effective amount of one or more compounds of formula (III) or a pharma- ceutically acceptable salt thereof, together with one or more carriers, diluents, or excipients, wherein said infection is caused by Clostridioides difficile.

[0035] In an aspect, the disclosure provides a method for treating a patient having an infectious disease, comprising administering to a patient a compound of formula (IV) together with one or more carriers, diluents, or excipients. TIFF2025505612000015.tif43128 or a pharma- ceutically acceptable salt thereof to a patient in need of relief from said infection, comprising the steps of: During the ceremony, n is 1, 2, 3, or 4; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together form a ring system with the N to which they are attached.

[0036] In an aspect, the disclosure relates to a method for treating a patient having an infection comprising administering to a patient in need of relief from said infection a therapeutically effective amount of one or more compounds of formula (IV) or a pharma- ceutically acceptable salt thereof, together with one or more carriers, diluents, or excipients, wherein said infection is caused by Clostridioides difficile.

[0037] In aspects, the disclosure relates to the use of the above methods to extend the clinical utility of current antibiotics, such as vancomycin and fidaxomicin.

[0038] In an aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: or a pharma- ceutically acceptable salt thereof, wherein X is halo.

[0039] In an aspect, the present disclosure provides a compound of formula The present invention relates to a compound or a pharma- ceutically acceptable salt thereof for treating a patient having an infectious disease, the compound having the formula: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R is H or alkyl, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

[0040] In an aspect, the present disclosure provides a compound of formula The present invention relates to a compound or a pharma- ceutically acceptable salt thereof for treating a patient having an infectious disease, the compound having the formula: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R is H or alkyl; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together form a ring system with the N to which they are attached.

[0041] In an aspect, the present disclosure provides a compound of formula The present invention relates to a compound or a pharma- ceutically acceptable salt thereof for treating a patient having an infectious disease, the compound having the formula: During the ceremony, n is 1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

[0042] In an aspect, the present disclosure provides a compound of formula The present invention relates to a compound or a pharma- ceutically acceptable salt thereof for treating a patient having an infectious disease, the compound having the following structure: During the ceremony, n is 1, 2, 3, or 4; R1, R2, R3, R4, R5, or R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together form a ring system with the N to which they are attached.

[0043] In formula (I), (II), (III) or (IV), X may be O, X may be NH, X may be N(alkyl), X may be -N(Me), or X may be S.

[0044] In formula (I), (II), (III) or (IV), Y may be O, Y may be NH, Y may be N(alkyl), Y may be -N(Me), or Y may be S.

[0045] In formula (I), (II), (III) or (IV), n can be 1, n can be 2, n can be 3, or n can be 4.

[0046] R1 may be hydrogen. R1 may be halogen. R1 may be hydroxyl. R1 may be an optionally substituted alkyl. R1 may be an optionally substituted alkenyl. R1 may be an optionally substituted alkynyl. R1 may be an optionally substituted heteroalkyl. R1 may be an optionally substituted heteroalkenyl. R1 may be an optionally substituted heteroalkynyl. R1 may be an optionally substituted heterocyclyl. R1 may be an optionally substituted cycloalkyl. R1 may be an optionally substituted cycloalkenyl. R1 may be an optionally substituted cycloheteroalkyl. R1 may be an optionally substituted cycloheteroalkenyl. R1 may be an acyl. R1 may be an optionally substituted aryl. R1 may be an optionally substituted heteroaryl. R1 may be an optionally substituted arylalkyl. R1 may be an optionally substituted arylalkenyl. R1 may be an optionally substituted arylalkynyl.

[0047] R2 may be hydrogen. R2 may be halogen. R2 may be hydroxyl. R2 may be an optionally substituted alkyl. R2 may be an optionally substituted alkenyl. R2 may be an optionally substituted alkynyl. R2 may be an optionally substituted heteroalkyl. R2 may be an optionally substituted heteroalkenyl. R2 may be an optionally substituted heteroalkynyl. R2 may be an optionally substituted heterocyclyl. R2 may be an optionally substituted cycloalkyl. R2 may be an optionally substituted cycloalkenyl. R2 may be an optionally substituted cycloheteroalkyl. R2 may be an optionally substituted cycloheteroalkenyl. R2 may be an acyl. R2 may be an optionally substituted aryl. R2 may be an optionally substituted heteroaryl. R2 may be an optionally substituted arylalkyl. R2 may be an optionally substituted arylalkenyl. R2 may be an optionally substituted arylalkynyl.

[0048] R3 may be hydrogen. R3 may be halogen. R3 may be hydroxyl. R3 may be an optionally substituted alkyl. R3 may be an optionally substituted alkenyl. R3 may be an optionally substituted alkynyl. R3 may be an optionally substituted heteroalkyl. R3 may be an optionally substituted heteroalkenyl. R3 may be an optionally substituted heteroalkynyl. R3 may be an optionally substituted heterocyclyl. R3 may be an optionally substituted cycloalkyl. R3 may be an optionally substituted cycloalkenyl. R3 may be an optionally substituted cycloheteroalkyl. R3 may be an optionally substituted cycloheteroalkenyl. R3 may be an acyl. R3 may be an optionally substituted aryl. R3 may be an optionally substituted heteroaryl. R3 may be an optionally substituted arylalkyl. R3 may be an optionally substituted arylalkenyl. R3 may be an optionally substituted arylalkynyl.

[0049] R4 may be hydrogen. R4 may be halogen. R4 may be hydroxyl. R4 may be an optionally substituted alkyl. R4 may be an optionally substituted alkenyl. R4 may be an optionally substituted alkynyl. R4 may be an optionally substituted heteroalkyl. R4 may be an optionally substituted heteroalkenyl. R4 may be an optionally substituted heteroalkynyl. R4 may be an optionally substituted heterocyclyl. R4 may be an optionally substituted cycloalkyl. R4 may be an optionally substituted cycloalkenyl. R4 may be an optionally substituted cycloheteroalkyl. R4 may be an optionally substituted cycloheteroalkenyl. R4 may be an acyl. R4 may be an optionally substituted aryl. R4 may be an optionally substituted heteroaryl. R4 may be an optionally substituted arylalkyl. R4 may be an optionally substituted arylalkenyl. R4 may be an optionally substituted arylalkynyl.

[0050] R5 may be hydrogen. R5 may be halogen. R5 may be hydroxyl. R5 may be an optionally substituted alkyl. R5 may be an optionally substituted alkenyl. R5 may be an optionally substituted alkynyl. R5 may be an optionally substituted heteroalkyl. R5 may be an optionally substituted heteroalkenyl. R5 may be an optionally substituted heteroalkynyl. R5 may be an optionally substituted heterocyclyl. R5 may be an optionally substituted cycloalkyl. R5 may be an optionally substituted cycloalkenyl. R5 may be an optionally substituted cycloheteroalkyl. R5 may be an optionally substituted cycloheteroalkenyl. R5 may be an acyl. R5 may be an optionally substituted aryl. R5 may be an optionally substituted heteroaryl. R5 may be an optionally substituted arylalkyl. R5 may be an optionally substituted arylalkenyl. R5 may be an optionally substituted arylalkynyl.

[0051] R6 may be hydrogen. R6 may be halogen. R6 may be hydroxyl. R6 may be an optionally substituted alkyl. R6 may be an optionally substituted alkenyl. R6 may be an optionally substituted alkynyl. R6 may be an optionally substituted heteroalkyl. R6 may be an optionally substituted heteroalkenyl. R6 may be an optionally substituted heteroalkynyl. R6 may be an optionally substituted heterocyclyl. R6 may be an optionally substituted cycloalkyl. R6 may be an optionally substituted cycloalkenyl. R6 may be an optionally substituted cycloheteroalkyl. R6 may be an optionally substituted cycloheteroalkenyl. R6 may be an acyl. R6 may be an optionally substituted aryl. R6 may be an optionally substituted heteroaryl. R6 may be an optionally substituted arylalkyl. R6 may be an optionally substituted arylalkenyl. R6 may be an optionally substituted arylalkynyl.

[0052] R7 may be hydrogen. R7 may be an optionally substituted alkyl. R7 may be an optionally substituted alkenyl. R7 may be an optionally substituted alkynyl. R7 may be an optionally substituted heteroalkyl. R7 may be an optionally substituted heteroalkenyl. R7 may be an optionally substituted heteroalkynyl. R7 may be an optionally substituted heterocyclyl. R7 may be an optionally substituted cycloalkyl. R7 may be an optionally substituted cycloalkenyl. R7 may be an optionally substituted cycloheteroalkyl. R7 may be an optionally substituted cycloheteroalkenyl. R7 may be an acyl. R7 may be an optionally substituted aryl. R7 may be an optionally substituted heteroaryl. R7 may be an optionally substituted arylalkyl. R7 may be an optionally substituted arylalkenyl. R7 may be an optionally substituted arylalkynyl.

[0053] R8 may be hydrogen. R8 may be an optionally substituted alkyl. R8 may be an optionally substituted alkenyl. R8 may be an optionally substituted alkynyl. R8 may be an optionally substituted heteroalkyl. R8 may be an optionally substituted heteroalkenyl. R8 may be an optionally substituted heteroalkynyl. R8 may be an optionally substituted heterocyclyl. R8 may be an optionally substituted cycloalkyl. R8 may be an optionally substituted cycloalkenyl. R8 may be an optionally substituted cycloheteroalkyl. R8 may be an optionally substituted cycloheteroalkenyl. R8 may be an acyl. R8 may be an optionally substituted aryl. R8 may be an optionally substituted heteroaryl. R8 may be an optionally substituted arylalkyl. R8 may be an optionally substituted arylalkenyl. R8 may be an optionally substituted arylalkynyl.

[0054] R7 and R8 together may form a ring system with the N to which they are attached. The ring system may contain one or more additional heteroatoms. The ring system may be a monocyclic, bicyclic, or polycyclic ring system. The ring system may be substituted or unsubstituted. The ring system may be a 3-12 membered ring system.

[0055] In an aspect, the present disclosure provides a compound of formula or a pharma- ceutically acceptable salt thereof having the formula: wherein X is halo.

[0056] In an aspect, the present disclosure provides a compound of formula The present invention relates to a compound or a pharma- ceutically acceptable salt thereof for treating a patient having an infectious disease, the compound having the formula: wherein X is halo.

[0057] In an embodiment, the infection is caused by Clostridioides difficile.

[0058] In an aspect, the present disclosure provides a method for producing a method for treating a cancer cell comprising: TIFF2025505612000023.tif63167 or a pharma- ceutically acceptable salt thereof.

[0059] In an aspect, the present disclosure provides a compound of formula The present invention relates to a compound or a pharma- ceutically acceptable salt thereof for treating a patient having an infectious disease, the compound having the formula: wherein X is halo.

[0060] In some embodiments, the infection is caused by Clostridioides difficile.

[0061] In aspects, the present disclosure relates to pharmaceutical compositions comprising one or more compounds together with one or more pharma- ceutically acceptable diluents, excipients, or carriers.

[0062] In aspects, the disclosure relates to pharmaceutical compositions comprising one or more compounds of Formula (I), (II), (III), or (IV) together with one or more diluents, excipients, or carriers.

[0063] In aspects, the present disclosure relates to pharmaceutical compositions comprising nanoparticles of one or more compounds of Formula (I), (II), (III), or (IV), together with one or more diluents, excipients, or carriers.

[0064] In an aspect, the disclosure relates to the use of one or more compounds, or pharma- ceutically acceptable salts thereof, in the manufacture of a medicament for treating Clostridioides difficile infection in a subject.

[0065] In an aspect, the disclosure relates to a method of use of a compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating an infectious disease in a subject.

[0066] As used herein, the following terms and phrases shall have the meanings set forth below: Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0067] The term "about" can allow for some variation in value or range of a stated value, for example, within 10%, within 5%, or within 1%, or within a stated limit of a range. The term "substantially" can allow for some variation in value or range of a stated value, for example, within 90%, within 95%, within 99%, within 99.5%, within 99.9%, within 99.99%, or within 99.999%, or more, or within a stated limit of a range.

[0068] The words "a," "an," or "the" are used to include one or more unless the context clearly indicates otherwise. The word "or" is used to refer to a non-exclusive "or" unless otherwise specified.

[0069] Any phraseology or terminology used herein and not specifically defined is for purposes of description only and not limitation. Any use of section headings is intended to aid in the reading of the document and should not be construed as limiting. Additionally, information associated with a section heading may be located either within or outside of that particular section.

[0070] All publications, patents, and patent documents referred to in this document are incorporated herein by reference in their entirety, as if each were incorporated by reference. In the unlikely event of a conflict in usage between this document and a document so incorporated by reference, the usage in the incorporated references should be considered complementary to the usage in this document. In the event of any irreconcilable conflict, the usage in this document shall take precedence.

[0071] The term "substituted" refers to a functional group in which one or more hydrogen atoms contained in the functional group are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" refers to a group that can be on a molecule or is substituted on a molecule. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxylate esters; sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, azides, hydroxylamines, cyanos, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms in various other groups. "Substituted" or "substituted with" is understood to include the implicit proviso that such substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like, subject to the permissible valences of the substituted atom and substituents. The term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. Heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds that satisfy the valences of the heteroatom.Substituents may include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aryl, or an aromatic or heteroaromatic moiety. Substituents on a substituted alkyl are C. 1~6 Alkyl, C 3~6 The substituents on the substituted alkyl may be selected from cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. The substituents on the substituted alkyl may be selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that the substituents themselves may be substituted, if appropriate. Unless specifically stated as "unsubstituted," reference to a chemical moiety includes substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0072] The term "substituted" refers to the following groups: halogen (e.g., F, Cl, Br, and I), R, OR, ROH (e.g., CHOH), OC(O)N(R), CN, NO, NO, ONO, azido, CF, OCF, methylenedioxy, ethylenedioxy, (C-C 20 )heteroaryl, N(R)2, Si(R)3, SR, SOR, SO2R, SO2N(R)2, SO3R, P(O)(OR)2, OP(O)(OR)2, C(O)R, C(O)C(O )R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, C(O)N(R)OH, OC(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2It also refers to a group substituted with one or more groups, including, but not limited to, N(R)N(R), N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R), N(R)SOR, N(R)SON(R), N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R), N(R)C(S)N(R), N(COR)COR, N(OR)R, C(=NH)N(R), C(O)N(OR)R, or C(=NOR)R. 20 ) Alkyl, (C6-C 20 ) an aryl, heterocyclyl or polyalkylene oxide group, for example of the formula -(CH2CH2O) f -R-OR, -(CH2CH2CH2O) g -R-OR, or -(CH2CH2O) f (CH2CH2CH2O) gand each of f and g is independently an integer from 1 to 50 (e.g., 1 to 3, 1 to 5, 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 2 to 5, 2 to 10, 2 to 20, 2 to 30, 2 to 40, 2 to 50, 3 to 10, 3 to 20, 3 to 40, 3 to 50, 5 to 10, 5 to 20, 5 to 30, 5 to 40, 5 to 50, and any other range therebetween). "Substituted" also includes groups substituted with one or more groups, including, but not limited to, the following groups: fluoro, chloro, bromo, iodo, amino, amido, alkyl, hydroxy, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino, and dialkylamido. When there are two or more adjacent substituents, the substituents may be linked to form a carbocyclic or heterocyclic ring. Such adjacent groups may have a vicinal or geminal relationship and may be adjacent on the ring, for example, in an ortho configuration. Each instance of "substituted" is understood to be independent. For example, a substituted aryl may be substituted with bromo and a substituted heterocyclic ring on the same compound may be substituted with alkyl. It is contemplated that the substituted group may be substituted with one or more non-fluoro groups. As another example, the substituted group may be substituted with one or more non-cyano groups. As another example, the substituted group may be substituted with one or more groups other than haloalkyl. As yet another example, the substituted group may be substituted with one or more groups other than tert-butyl. As yet a further example, the substituted group may be substituted with one or more groups other than trifluoromethyl.As still further examples, a substituted group may be substituted with one or more groups other than nitro, other than methyl, other than methoxymethyl, other than dialkylaminosulfonyl, other than bromo, other than chloro, other than amido, other than halo, other than benzodioxepinyl, other than polycyclic heterocyclyl, other than polycyclic substituted aryl, other than methoxycarbonyl, other than alkoxycarbonyl, other than thiophenyl, or other than nitrophenyl, or with groups satisfying any combination of such descriptions. Additionally, "substituted" is also understood to include fluoro, cyano, haloalkyl, tert-butyl, trifluoromethyl, nitro, methyl, methoxymethyl, dialkylaminosulfonyl, bromo, chloro, amido, halo, benzodioxepinyl, polycyclic heterocyclyl, polycyclic substituted aryl, methoxycarbonyl, alkoxycarbonyl, thiophenyl, and nitrophenyl groups.

[0073] "Alkyl" refers to a fully saturated, cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if not specified. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. Straight or branched chain alkyl refers to any group that is not bound to its backbone (e.g., C1-C for straight chain). 30 , for branched chains, C3 to C 30 ) may have up to 30 carbon atoms, or may have up to 20. An alkyl group may be substituted or unsubstituted.

[0074] The term "alkylene" refers to an alkyl group having a specified number of carbons, e.g., 2-12 carbon atoms, containing two points of attachment on its longest carbon chain to the remainder of the compound. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and the like. An alkylene group may be a cyclic or acyclic, branched or unbranched carbon chain moiety, and may be substituted with one or more substituents. For example, an alkylene-aryl may be benzyl.

[0075] "Cycloalkyl" means mono- or bicyclic, or bridged, or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. In various aspects, cycloalkyls have from 3 to 10 carbon atoms in their ring structure, or from 3 to 6 carbons in the ring structure. Cycloalkyl groups can be substituted or unsubstituted. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups can have from 3 to about 8 to 12 ring members, whereas in other embodiments, the number of ring carbon atoms can be 3 to 4, 5, 6, or 7. In some embodiments, cycloalkyl groups can have from 3 to 6 carbon atoms (C3-C6). Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as, but not limited to, decalinyl.

[0076] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein refers to an alkyl group as defined above, but having 1-10 carbons, or 1-6 carbon atoms in its backbone structure, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Substituents referred to herein as alkyl may also be lower alkyl.

[0077] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched, unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limit on the number of carbon atoms is specified, and having one or more double bonds in the moiety. Alkenyls of 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, docenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl in their various isomeric forms, where the unsaturated bond may be located anywhere in the moiety and may have either the (Z) or (E) configuration about the double bond.

[0078] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl, but which has one or more triple bonds.

[0079] The term "acyl" refers to a group containing a carbonyl moiety and bonded through the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which may be part of a substituted or unsubstituted alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group, and the like. In the special case where the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as this term is defined herein. An acyl group may contain 0 to about 12-40, 6-10, 1-5, or 2-5 additional carbon atoms bonded to the carbonyl group. Acryloyl is an example of an acyl group. Acyl groups may also contain heteroatoms within the meaning herein. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups, and the like. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is the trifluoroacetyl group.

[0080] The term "aryl" includes 3- to 12-membered, substituted or unsubstituted, monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms are heteroatoms (i.e., heteroaryl). In various aspects, aryl groups include 5- to 12-membered, or 6- to 10-membered rings. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are shared between two adjacent rings, where at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered, 5- to 12-membered, or 5- to 10-membered rings, where the ring structure includes 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl may be monocyclic, bicyclic, or polycyclic. Each instance of an aryl group may be independently substituted, i.e., unsubstituted ("unsubstituted aryl"), or substituted with one or more substituents; for example, with 1-5 substituents, 1-4 substituents, 1-3 substituents, 1-2 substituents, or only one substituent ("substituted aryl"). The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. For example, an aryl group may be an unsubstituted C5-C 12 It may be aryl, and the aryl group is a substituted C5-C10 It may be aryl. Aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups have from about 6 to about 14 carbons (C6 to C8) in the ring portion of the group. 14 ) or 6 to 10 carbon atoms (C6 to C 10 ). Aryl groups can be unsubstituted or substituted as defined herein. Representative substituted aryl groups can be mono-substituted, poly-substituted, and include, but are not limited to, di-, tri-, tetra-, penta-, or hexa-substituted phenyl, or di- to octa-substituted naphthyl groups, which may be substituted with carbon or non-carbon groups, such as those enumerated herein.

[0081] The terms "aralkyl" and "arylalkyl" refer to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0082] The terms "heterocyclyl" and "heterocyclic group" refer to 3- to 12-membered ring structures, 5- to 12-membered rings, or 5- to 10-membered rings whose ring structures contain one to four heteroatoms. The heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. The heterocycles can be saturated or unsaturated. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocycle may be optionally substituted at one or more positions with such substituents as described above, for example, halogen, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0083] Heteroaryl rings are an embodiment of heterocyclyl groups. The phrase "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, and benzimidazolinyl groups. For example, heterocyclyl groups include: TIFF2025505612000025.tif52152, where X 5 H, (C1~C 20 ) Alkyl, (C6-C 20 ) aryl, or an amine protecting group (e.g., t-butyloxycarbonyl group), and the heterocyclyl group may be substituted or unsubstituted. Nitrogen-containing heterocyclyl groups are heterocyclyl groups that contain a nitrogen atom as an atom in the ring. In some embodiments, the heterocyclyl is a heterocyclyl other than thiophene or substituted thiophene. In some embodiments, the heterocyclyl is a heterocyclyl other than furan or substituted furan.

[0084] Heteroaryl rings are an embodiment of heterocyclyl groups. The phrase "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triadiolyl, tetrazolyl, benzoxazolinyl, benzthiazolinyl, and benzimidazolinyl groups.

[0085] The term "heterocyclylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, and indol-2-ylpropyl.

[0086] The term "heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen or bond of the alkyl group is replaced with a bond with a heteroaryl group, as defined herein.

[0087] The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group may further contain double or triple bonds and may also contain heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group within the context in which two adjacent atoms of the structure are substituted.

[0088] The term "amine" refers to primary, secondary, and tertiary amines, for example, having the formula N(group)3, where each group can be independently H or non-H, such as alkyl, aryl, etc. Amines include R-NH2, e.g., alkylamines, arylamines, alkylarylamines; R2NH, where each R is independently selected. For example, dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and R3N, where each R is independently selected. For example, including but not limited to, trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" also includes ammonium ions as used herein.

[0089] The term "amino group" refers to -NH2, -NHR, -NR2, or -NR3 + and -NR3, which cannot be protonated. + where each R is independently selected. Thus, any compound substituted with an amino group can be considered an amine. An "amino group" can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups. The term "halo," "halide," or "halogen" refers to halogen, including, but not limited to, fluoro, chloro, bromo, iodo, and the like, in radioactive and non-radioactive forms. Halo may be selected from the group consisting of fluoro, chloro, and bromo.

[0090] The term "haloalkyl" includes mono-haloalkyl groups, poly-haloalkyl groups where all halo atoms may be the same or different, and per-haloalkyl groups in which all hydrogen atoms are replaced by halogen atoms such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, -CF(CH3)2, and the like.

[0091] The term "optionally substituted" or "optional substituents" means that the group in question is unsubstituted or substituted with one or more of the specified substituents. When the group in question is substituted with multiple substituents, the substituents may be the same or different. The terms "independently," "independently is," and "independently selected from" mean that the groups in question may be the same or different. Some terms defined herein may occur more than once in the structures, and when so occurring, each term shall be defined independently of the other terms.

[0092] The term "nitro" means -NO2. The term "halogen" designates -F, -Cl, -Br, or -I. The term "sulfhydryl" means -SH. The term "hydroxyl" means -OH. The term "sulfonyl" means -SO2-. The term "azido" means -N3. The term "cyano" means -CN. The term "isocyanato" means -NCO. The term "thiocyanato" means -SCN. The term "isothiocyanato" means -NCS. The term "cyanato" means -OCN.

[0093] The compounds may contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. In one embodiment, the compounds are not limited to any particular stereochemical requirement, and the compounds, as well as compositions, methods, uses, and medicaments comprising the compounds, may be optically pure or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. Such stereoisomeric mixtures may contain only one stereochemical configuration at one or more chiral centers, whereas they may contain mixtures of stereochemical configurations at one or more other chiral centers.

[0094] Similarly, the compounds may include cis, trans isomers, diastereomers, enantiomers, and geometric centers such as E and Z double bonds. In another embodiment, the compounds are not limited to any particular geometric isomeric requirement, and the compounds, and compositions, methods, uses, and medicaments comprising the compounds, may be pure or any of a variety of geometric isomeric mixtures. Such geometric isomeric mixtures may include only one configuration at one or more double bonds and chiral carbons, whereas they may include a mixture of geometries at one or more other double bonds and chiral carbons.

[0095] The terms "salt" and "pharmaceutically acceptable salt" refer to derivatives of a parent compound, which are modified to produce acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups, such as amines; and alkali or organic salts of acidic groups, such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; as well as those prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

[0096] Pharmaceutically acceptable salts can be synthesized from parent compounds that contain basic or acidic moieties by conventional chemical methods.In some cases, such salts can be prepared by reacting the free acid or free base forms of these compounds with stoichiometric amounts of suitable bases or acids in water or organic solvents, or in a mixture of the two.Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.Lists of suitable salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is incorporated herein by reference for its disclosure regarding the same.

[0097] The term "solvate" means a compound or a salt thereof that further contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0098] The term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound of the present disclosure. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound that contain a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Specific prodrugs of compounds with a carboxyl functional group are the lower alkyl esters of the carboxylic acid. Carboxylic acid esters are conveniently formed by esterifying any carboxylic acid moiety present in the compound. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley), and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH), both of which are incorporated herein by reference for their disclosures relating to the same.

[0099] Furthermore, in each of the above and following embodiments, the formula should be understood to include and represent all pharma- ceutically acceptable salts of the compound, as well as any and all hydrates and / or solvates of the compound or its salts. It should be recognized that certain functional groups, such as hydroxy, amino, and similar groups, form complexes and / or coordination compounds with water and / or various solvents in the various physical forms of the compound. Thus, the above formula should be understood to include and represent these various hydrates and / or solvates. In each of the above and following embodiments, the formula should also be understood to include and represent each possible isomer, e.g., stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the above and following embodiments, the formula should also be understood to include and represent any and all crystalline, partially crystalline, and non-crystalline and / or amorphous forms of the compound.

[0100] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting any of the present compositions or their components. Each carrier must be "acceptable" in the sense of being compatible with the present composition and its components, and not harmful to the patient. Some examples of materials which can serve as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and the like. (10) soybean oil; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0101] The term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds. These salts can be prepared during the final isolation and purification of the compounds, or in situ by separately reacting the purified compounds in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, and the like (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19, the disclosure of which is incorporated herein by reference regarding the same).

[0102] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and therefore can form pharma-ceutically acceptable salts with pharma-ceutically acceptable bases. The term "pharma-ceutically acceptable salts" refers in these cases to the relatively non-toxic inorganic and organic base addition salts of the compounds. These salts can also be prepared during the final isolation and purification of the compounds, or in situ by separately reacting the purified compounds in their free acid form with a suitable base, for example, a hydroxide, carbonate, or bicarbonate of a pharma-ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0103] A "therapeutically effective amount" (or "effective amount") of a compound for use in treatment refers to an amount of said compound in a preparation that, when administered (to a mammal, preferably a human) as part of a desired dosing regimen, reduces symptoms, ameliorates a condition, or delays the onset of a disease state, for example, at a reasonable benefit / risk ratio applicable to any medical treatment, according to clinically accepted standards for the disorder or condition to be treated, or for cosmetic purposes. In particular, therapeutic agents, including but not limited to the compounds of the present invention, may be provided in particles. Particles, as used herein, refer to nanoparticles or microparticles (or in some cases even larger particles) that may consist entirely or partially of the compounds of the present invention or other therapeutic agents described herein. The particles may contain the therapeutic agent in a core surrounded by a coating, including but not limited to an enteric coating. The therapeutic agent may also be dispersed throughout the particle. The therapeutic agent may also be adsorbed within the particle. The particles may be of any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic agent, the particles may contain any material routinely used in the pharmaceutical and medical arts, including, but not limited to, erodible, non-erodible, biodegradable, or non-biodegradable materials or combinations thereof.The particles may be microcapsules that contain the compounds of the present invention in solution or in a semi-solid state.The particles may be particles of virtually any shape.

[0104] The term "administering" includes all means of introducing the compounds and compositions into a patient, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, etc. The compounds and compositions may be administered in unit dosage forms and / or formulations containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants, and vehicles.

[0105] Exemplary formats for oral administration include tablets, capsules, elixirs, syrups, etc. Exemplary routes for parenteral administration include intravenous, intraarterial, intraperitoneal, epidural, intraurethral, ​​intrasternal, intramuscular, and subcutaneous routes, as well as any other parenteral administration route recognized in the art.

[0106] Exemplary means of parenteral administration include needle (including microneedle) injectors, needle-free injectors and injection techniques, as well as any other means of parenteral administration recognized in the art. Parenteral formulations are typically aqueous solutions that may contain excipients, such as salts, carbohydrates, and buffers (preferably at a pH ranging from about 3 to about 9), but for some applications may be more appropriately formulated as sterile non-aqueous solutions or as dry forms used with a suitable vehicle, such as sterile, pyrogen-free water. Preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. Parenteral administration of a compound is illustratively performed in the form of a saline solution or with the compound incorporated into liposomes. If the compound does not have sufficient solubility to be dissolved, a solubilizing agent, such as ethanol, can be applied.

[0107] The dosage of each compound depends on several factors, including the method of administration, the condition to be treated, the severity of the condition, whether the condition is being treated or prevented, and the age, weight, and health of the person to be treated. In addition, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic agent) information about a particular patient may affect the dosage used.

[0108] In said method, the individual components of the co-administration or combination can be administered by any suitable means, contemporaneously, simultaneously, sequentially (in either order), separately, or in one pharmaceutical formulation. When the co-administered compounds or compositions are administered in separate dosage forms, the number of dosages administered per day for each compound can be the same or different. The compounds or compositions can be administered via the same or different routes of administration. The compounds or compositions can be administered according to a simultaneous or alternating regimen, can be administered at the same or different times during therapy, and can be administered simultaneously in divided or single dose form.

[0109] The term "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that induces a biological or therapeutic response in a tissue system, animal, or human, as desired by a researcher, veterinarian, physician, or other clinician, including the alleviation of symptoms of the disease or disorder being treated. In one aspect, a therapeutically effective amount is an amount that can treat or alleviate symptoms of a disease or disorder with a reasonable benefit / risk ratio applicable to any medical treatment. However, the total daily usage of the compounds and compositions can be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient depends on a variety of factors, including the disorder and severity of the disorder being treated; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the administration time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used; and similar factors well known to a researcher, veterinarian, physician, or other clinician of ordinary skill.

[0110] A wide range of acceptable dosages is contemplated, including doses falling within the range of about 1 μg / kg to about 1 g / kg, depending on the route of administration. Doses may be single or divided and may be administered according to a wide variety of protocols, including qd (once a day), bid (twice a day), tid (three times a day), or every other day, weekly, monthly, quarterly, etc. In each of these cases, the therapeutically effective amounts described herein correspond to the instance of administration, or alternatively, correspond to the total amount daily, weekly, monthly, or quarterly as determined by the dosing protocol.

[0111] In addition to the exemplary dosages and dosing protocols described herein, it should be understood that the effective amount of any one or mixture of the compounds can be determined by the attending diagnostician or physician using known techniques and / or by observing results obtained in similar situations. In determining the effective amount or dose, numerous factors are taken into account by the attending diagnostician or physician, including, but not limited to, the species of mammal, including humans, its size, age, and general health, the specific disease or disorder involved, the extent or complications or severity of the disease or disorder, the response of the individual patient, the specific compound administered, the method of administration, the bioavailability characteristics of the administered preparation, the selected dosing schedule, the use of concomitant drugs, and other relevant circumstances.

[0112] The term "patient" includes humans and non-human animals, such as companion animals (such as dogs and cats) and livestock animals. Livestock animals are animals that are kept for food production. The patient to be treated is preferably a mammal, in particular a human. EXAMPLES

[0113] The procedure for the preparation of AAMGBL (α-aminomethyl-γ-butyrolactone) is described in Scheme 1.

[0114] A series of γ-hydroxy-α-methylene esters of general structure V were prepared according to published procedures [21-25]. These were converted to the corresponding α-aminomethyl-γ-butyrolactones AMGBL (general structure VII) as previously described. Molecules of formula VII were converted to the corresponding α-aminomethyl lactones (general structure VI) as described by others [16, 17] and by the present inventors

[26] . Molecules of formula I were directly converted to molecules VI as described by the present inventors

[27] .

[0115] The synthesis is shown in Scheme 1. TIFF2025505612000026.tif72128

[0116] An alternative purification process for obtaining AAMGBL with extremely high purity is provided herein. In the present invention, α-aminomethyl lactone (general structural formula III) prepared from the molecules of formulas I and II was converted to the corresponding fumarate salt, separated from other impurities, and purified by adding a base (NaOH).

[0117] Aminolactones can also be purified by precipitation with an organic or inorganic acid (e.g., HCl, HBr) or an organic or inorganic salt (e.g., ammonium chloride or ammonium bromide) or salt of an organic acid (e.g., oxalic acid, maleic acid, etc.) and treatment with a base (e.g., LiOH, NaOH, or KOH).

[0118] This purification process enabled the one-pot direct synthesis of α-aminomethyl-γ-butyrolactone (AAMGBL) from the carbonyl. A representative one-pot synthesis and purification of (cis)-5-(4-(benzyloxy)-3-methoxyphenyl)-4-(2-bromophenyl)-3-(piperidin-1-ylmethyl)dihydrofuran-2(3H)-one is shown in Scheme 2. TIFF2025505612000027.tif148149

[0119] Representative procedures for the synthesis of compounds of Formulas V, VI, and VII are set forth below.

[0120] 1. General procedure for the preparation of cis-γ-hydroxyesters (compound formula V)

[21] TIFF2025505612000028.tif26128

[0121] To a solution of alkyl bromomethacrylate (1.0 eq) in a mixture of tetrahydrofuran (THF) and water was added the appropriate aldehyde or ketone (1.5 eq). The solution was stirred rapidly at room temperature while indium powder (1.2 eq) was added in one portion. The suspension was stirred until the reaction was complete as judged by thin layer chromatography (TLC) analysis. The mixture was partitioned between water and ethyl acetate and the organic layer was removed. The crude product was extracted one more time from the aqueous layer with ethyl acetate. The combined organic layers were washed with water, then with saturated brine, and then dried over sodium sulfate (Na2SO4). After filtration, the product was purified by flash column chromatography to obtain the desired cis-γ-hydroxy ester.

[0122] 2. General Procedure for the Preparation of Trans-Lactones (Formula VII) (i) General procedure for the preparation of boronates

[22] TIFF2025505612000029.tif25128

[0123] A mixture of CuCl (1.3 equiv.) and LiCl (1.3 equiv.) in dimethylformamide (DMF) was stirred at 25°C under N2 for 1 h, and pinacol diboronate (1.3 equiv.) dissolved in DMF was added to the reaction mixture. Potassium acetate (KOAc) (1.3 equiv.) was added to the reaction mixture, followed by allylic acetate (1.0 equiv.) dissolved in DMF. The reaction mixture was further stirred for 3-5 h. The reaction mixture was then quenched with water and extracted with ether. The combined organic layers were dried over magnesium sulfate (MgSO4), concentrated under reduced pressure, and purified by column chromatography to obtain crotylboronate. TIFF2025505612000030.tif26128

[0124] (ii) General procedure for the preparation of trans-lactones

[23] Crotyl boronate (1 eq.) was dissolved in toluene and the aldehyde (1.2 eq.) was added. 11 The reaction mixture was refluxed for 8-12 hours until completion was monitored by B NMR spectroscopy. The reaction mixture was then cooled to room temperature and 20% indium triflate [In(OTf)3] was added along with 20% aldehyde and stirred for 2-4 hours. The mixture was washed with water and the product was extracted with ether (3X5 mL). The combined organic layers were washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the trans-lactone.

[0125] 3. Alternative procedure for the preparation of the trans-lactone (compound formula VII)

[24] TIFF2025505612000031.tif27128

[0126] Triethylamine (1.1 equiv.) was added to a solution of the γ-hydroxyester (1.0 equiv.) in dichloromethane (DCM). Methanesulfonyl chloride (1.1 equiv.) was added dropwise and the reaction mixture was stirred until judged complete by TLC analysis. The reaction mixture was quenched with saturated aqueous ammonium sulfate and then extracted with DCM. The combined organic layers were concentrated under reduced pressure and the product was purified by column chromatography to obtain the trans-lactone.

[0127] 4. General procedure for the preparation of cis-lactone (compound formula VII)

[25] TIFF2025505612000032.tif27128

[0128] Crotyl boronate (1 eq.) was dissolved in toluene and the aldehyde (1.2 eq.) was added. 11 The reaction mixture was refluxed for 8-12 h until completion was monitored by B NMR spectroscopy. The reaction mixture was then cooled to room temperature and 20% p-TSA was added along with 20% aldehyde and stirred for 4-5 h. The mixture was washed with water and the product was extracted with ether. The combined organic layers were washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the trans-lactone.

[0129] 5. Alternative procedure for the preparation of cis-lactones

[20] TIFF2025505612000033.tif27128

[0130] To a solution of the cis-γ-hydroxyester (1.0 equiv.) in DCM was added p-toluenesulfonic acid (0.1 equiv.). The solution was stirred until judged complete by TLC analysis. After partitioning between water and dichloromethane, the organic layer was dried over Na2SO4. The crude product was purified by column chromatography to give the desired cis-lactone.

[0131] 6. General procedure for aminolactones by conjugate addition to VII (compound of formula VI)

[26] TIFF2025505612000034.tif29128

[0132] To a solution of cis-α-methylene lactone (1.0 equiv.) in DCM was added N,N-dialkylamine (3.0 equiv.) in one portion at room temperature. The solution was stirred rapidly until completion as judged by TLC analysis. The crude mixture was directly concentrated under reduced pressure to remove the solvent and excess amine. When deemed necessary, the crude reaction mixture was purified by flash column chromatography with amine addition to obtain the desired amino lactone.

[0133] 7. General procedure for aminolactonization. Direct synthesis of aminolactones (formula VI) from γ-hydroxyesters (formula V)

[27] TIFF2025505612000035.tif31128

[0134] To a solution of the cis-γ-hydroxy ester (1.0 equiv.) in dichloromethane was added N,N-dialkylamine (3.0 equiv.) in one portion at room temperature. The solution was stirred rapidly until completion as judged by TLC analysis. The crude mixture was directly concentrated under reduced pressure to remove the solvent and excess amine. When deemed necessary, the crude reaction mixture was purified by flash column chromatography with amine addition to obtain the desired amino lactone.

[0135] One-pot synthesis and purification of AAMGBL via fumarate formation (i) Barbier reaction of 4-(benzyloxy)-3-methoxybenzaldehyde (benzylvanillin) TIFF2025505612000036.tif30149

[0136] To a round bottom flask equipped with a magnetic stir bar was added 1.0 equivalent of allylic bromide. This material was suspended in deionized water to a 1.0 M suspension. Then, with vigorous stirring, 1.5 volume equivalents of THF (relative to H2O) were added, followed by 1.5 equivalents of electrophile (aldehyde or ketone) and 1.3 equivalents of indium powder. The reaction mixture was stirred at room temperature for 2-12 hours (the reaction was followed by TLC) and then partitioned between EtOAc and deionized water. After separating the organic layer, the aqueous layer was extracted with multiple portions of ethyl acetate (if necessary). The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated.

[0137] (ii) Aminolactonization of hydroxyesters (Diastereoselective Synthesis of α-(Aminomethyl)-γ-Butyrolactones via a Catalyst-free Aminolactonization. Ramachandran, PV; Nicponski, DR Chem. Commun. 2014, 50, 15216-15219) TIFF2025505612000037.tif28131

[0138] The concentrated crude reaction mixture from the previous Barbier reaction was dissolved in absolute ethanol to make a 0.1 M solution for the first equivalent of allyl bromide used. To this solution was added 2.0 equivalents of piperidine and the mixture was stirred at room temperature until the reaction was complete by TLC. Volatiles were evaporated from the reaction and the mixture was dissolved in diethyl ether to make a 0.1 M solution for the first equivalent of allyl bromide used.

[0139] (iii) Preparation of fumarate salts of aminolactones and recovery of aminolactones (Diastereoselective Synthesis of α-(Aminomethyl)-γ-Butyrolactones via a Catalyst-free Aminolactonization. Ramachandran, PV; Nicponski, DR Chem. Commun. 2014, 50, 15216-15219) TIFF2025505612000038.tif47154

[0140] Add fumaric acid (2 equivalents) to the above solution and stir the mixture vigorously for 30-60 minutes. During this time the solution becomes cloudy and white as the fumarate salt precipitates out of solution. The suspension is then centrifuged and the supernatant is decanted. The remaining solid is resuspended in additional diethyl ether and the centrifugation, decantation process is repeated three additional times. After the final decantation of the supernatant, dissolve the solid in water. Add 3M NaOH dropwise to the above solution until no more solid precipitates from the aqueous solution. Once the pure amino lactone is obtained, extract the solid from the aqueous mixture using three portions of diethyl ether and combine the organic extracts, wash with saturated brine, dry with sodium sulfate, filter and concentrate under reduced pressure.

[0141] Bioassay Methods are provided for controlling the growth of Clostridioides difficile bacterial cells by arresting the cell cycle or by inducing cell death. The methods involve treating the cells with a compound having the general structural formula I, II, or III, or an organic or inorganic salt, solvate, or hydrate thereof. The cells may be cancer cells or any other cells with abnormal growth. Although the focus was on Clostridioides difficile bacterial cells, the efficacy of lactones and aminolactones against other bacterial cells, such as Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, and fungal cells, such as Candida albicans, was also examined.

[0142] method: The minimum inhibitory concentrations (MICs) of the compounds and the control drugs, linezolid (antibiotic), vancomycin (antibiotic), 5-fluorocytosine (5-FC, antifungal drug), and fluconazole (antifungal drug), were determined using broth microdilution methods according to guidelines outlined by the Clinical and Laboratory Standards Institute (CLSI) for clinically relevant bacterial (Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus faecalis (VRE), Vancomycin-resistant Enterococcus faecium (VRE), Clostridioides difficile, and Escherichia coli) and fungal (Candida albicans) strains [28, 29]. A solution equivalent to a 0.5 McFarland standard was prepared from each strain, with approximately 5 × 10 5Bacterial inocula of CFU / mL were diluted in cation-adjusted Mueller-Hinton broth (for S. aureus and E. coli), tryptone soy broth (for E. faecalis), or brain heart infusion broth (for E. faecium). C. difficile strains were cultured in brain heart infusion broth supplemented with hemin and vitamin K. C. albicans was cultured at approximately 1.5 × 10 3 The compounds were diluted in RPMI medium supplemented with 3-(N-morpholino)propanesulfonic acid to a fungal concentration of CFU / mL. Compounds and control drugs were added to the first row of a 96-well plate and diluted (to a concentration gradient of 128 to 1 μg / mL) in the medium containing the bacteria. Plates were then incubated aerobically at 37°C for at least 18 hours for MRSA, VRE, and E. coli strains. C. albicans was incubated aerobically at 37°C for 24 hours. Plates containing C. difficile were incubated anaerobically at 37°C for 48 hours. Partial MIC results reported in Table 1 are the lowest concentrations at which the compound / drug completely inhibited visual bacterial / fungal growth.

[0143] result: Preliminary whole-cell screening assays demonstrated a discernible relationship between substitution pattern and antibacterial activity for a series of racemic cis-β,γ-disubstituted-α-methylene- and -aminomethyl-γ-butyrolactones. The assays revealed that (i) more than half of the 120 lactones were inactive against all bacterial strains assayed, and (ii) few of these molecules were active against all Gram-positive bacterial cells with different degrees of bacteriostatic potential, with six of these molecules (27, 48, 50, 51, 61, and 85; see Figure 1 for detailed structures) exhibiting highly selective antibacterial activity against C. difficile (Table 1). Of these, piperidinomethyl lactone 27 exhibited highly potent activity against various pathogenic strains of C. difficile similar to vancomycin.

[0144] Table 1. Minimum inhibitory concentrations (MICs in μg / mL) of lactones and control drugs screened against bacterial strains. TIFF2025505612000039.tif70136

[0145] Assays for clinical strains of C. difficile Lactones 27, 48, 50, 51, 61, and 85 did not inhibit test strains of MRSA and E. faecium and were therefore further tested against C. difficile clinical strains to assess their selective activity against C. difficile. Given that these compounds were inactive against MRSA, VRE, and C. albicans and showed moderate antibacterial activity against C. difficile BAA-1870, activity against additional strains of C. difficile was examined.

[0146] The antibacterial activity of compounds 48, 50, 51, 61, and 85 against a panel of Clostridioides difficile strains was evaluated. Bacterial solutions equivalent to a 0.5 McFarland standard were prepared and diluted in brain heart infusion broth supplemented with hemin and vitamin K. Compounds and control drugs were added to the first row of a 96-well plate and serially diluted (to give a concentration gradient of 128 to 1 μg / mL) in medium containing the bacteria. Plates were then incubated anaerobically at 37 °C for 48 h. The MICs reported in Tables 2 and 3 are the lowest concentrations of the compounds and control drugs that completely inhibited visual bacterial growth.

[0147] Screening of lactones against highly virulent C. difficile strains:

[0148] Screening of lactones against normal human intestinal microflora: The activity of selected lactones against the human gut microbiota was also investigated. The microbiota interferes with the ability of C. difficile to colonize the gastrointestinal tract and subsequently cause infection. Many antibiotics inhibit / kill the endogenous microflora, which allows enhanced colonization and infection by C. difficile. Three different bacterial species present in the gut microflora were used in this experiment; Bifidobacterium (anaerobic gram-positive bacteria), Bacteroides (anaerobic gram-negative bacteria), and Lactobacillus (microaerophilic gram-positive bacteria). An ideal compound / drug would have selective antibacterial activity against C. difficile such that damage / killing of the resident microflora present in the GI tract (which would exacerbate the infection caused by C. difficile) does not occur.

[0149] Table 2. Minimum inhibitory concentrations (MICs in μg / mL) of compounds and control drugs against highly pathogenic Clostridioides difficile strains. TIFF2025505612000040.tif88150

[0150] Table 3. Minimum inhibitory concentrations (MICs in μg / mL) of compounds and control drugs against clinically important Clostridioides difficile strains. TIFF2025505612000041.tif75147Vanc=vancomycin, Met=metronidazole, Fid=fidaxomicin

[0151] Table 4. Minimum inhibitory concentrations (MICs in μg / mL) of compounds and control drugs against normal human intestinal microflora. TIFF2025505612000042.tif240162 * Ba = Bacteroides spp. ** Bi=Bifidobacterium. Vanc=vancomycin, Met=metronidazole, Fid=fidaxomicin

[0152] First, Bifidobacterium and Bacteroides were grown anaerobically on brain heart infusion supplemented (BHIS) agar (brain heart infusion agar with added hemin, vitamin K, and L-cysteine) at 37°C for 48 hours. Lactobacillus was cultured on MRS agar and incubated at 37°C for 48 hours in the presence of 5% CO2. Each bacterium was suspended in phosphate buffered saline (PBS) to a 0.5 McFarland standard and then diluted to approximately 5x10 5 The bacterial inoculum was diluted in brain heart infusion broth (for Bifidobacterium and Bacteroides) or MRS broth (for Lactobacillus) to obtain CFU / mL. The bacteria were then inoculated into 96-well plates containing serial dilutions of the compounds and incubated for 48 hours. The MIC reported in Table 4 is the lowest concentration of compound / control drug that inhibited visual bacterial growth.

[0153] It is quite noteworthy that none of the selected lactones tested inhibit any bacteria of the normal intestinal microflora, which is very important and advantageous for their development as potential drugs for use against C. difficile. In contrast, all three control drugs tested had adverse effects on certain bacterial species (e.g., metronidazole inhibited the growth of Bacteroides and Bifidobacterium species).

[0154] In vivo safety profile and toxicity Any possible toxicity of aminomethyl lactone 27 was evaluated at oral doses higher than the expected doses used for antibacterial efficacy. The maximum tolerated dose (MTD) in mice was calculated and was expected to be several times higher than the therapeutic dose. The MTD is the dose that does not cause death, more than 10% weight loss, clinical signs of toxicity, and does not cause significant changes in renal and / or hepatic function in survivors. Since 10 mg / kg was found to be non-toxic in mice in our initial mouse model studies, we selected 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, 200 mg / kg, and 400 mg / kg doses of 27, each given once to one mouse, and the mice were observed daily for weight gain, clinical signs of abnormality, and renal and hepatic function over a period of 14 days.

[0155] At the end of the study, all animals appeared healthy and with good body weight. The animals were then euthanized and major organ (heart, liver, lung, kidney, spleen, and intestine) tissues were collected for histological examination of toxicity. The assessors were blinded to the treatment status of each mouse at the time of examination. Overall, the tissues examined appeared to be within normal histological limits. Images from the histology are shown in Figure 5. Overall, 27 appeared to be non-toxic to mice.

[0156] Antibiotic-induced C. difficile-associated diarrhea mouse model To establish the feasibility of using this new class of antibiotic orally against C. difficile infection, preliminary in vivo experiments were performed in two mouse models of antibiotic-induced C. difficile-associated diarrhea and two relapse models.

[0157] experiment: Groups of 12-week-old female C57BL / 6 mice were sensitized to CDI using two different protocols [32,33]. A- Mice were given an antibiotic cocktail containing gentamicin (0.035 mg / mL), kanamycin (0.4 mg / ml), metronidazole (0.215 mg / mL), colistin (850 U / mL), and vancomycin (0.045 mg / mL) in their drinking water for 5 days. Mice were then treated with clindamycin (10 mg / kg) 2 days after withdrawal of the antibiotic cocktail. One day after clindamycin treatment, 1.9x10 of C. difficile ATCC 43255

[32] were inoculated. 6 Mice were orally infected with CFU spore suspension. Two hours after infection, animals were divided into groups (n = 10) and groups were given vehicle (sterile water), compound 27 (10 mg / kg), or vancomycin (10 mg / kg) by oral gavage daily for 5 days. B-In the second protocol, mice were sensitized to CDI for 10 days with cefoperazone (1.5 mg / mL) in drinking water. Mice were then switched to normal water for 2 days, after which they were injected intraperitoneally with clindamycin (10 mg / kg)

[38] . One day after clindamycin treatment, mice were infected and treated as group A above. As shown in Figure 3A and B, aminomethyllactone 27 showed 100% protection at 10 mg / kg, the same as vancomycin, in the two mouse models used.

[0158] Continuous treatment with 27 and comparison with vancomycin For mouse relapse, two models were used to test the efficacy of aminomethyl lactone 27 in preventing relapse after vancomycin treatment. The two models used were A - the model of Chen et al.

[32] and B - a more aggressive protocol developed using an improved antibiotic cocktail of Chen et al. (giving three times the dose of antibiotics). Briefly, groups of 12-week-old female C57BL / 6 mice were susceptible to CDI by giving either the antibiotic cocktail in the drinking water or a three times dose of the antibiotic cocktail for 5 days. The mice were then treated with clindamycin (10 mg / kg) 2 days after withdrawal of the antibiotic cocktail. One day after clindamycin treatment, the mice were challenged with 1.9x10 of C. difficile ATCC 43255

[32] . 6 Animals were orally infected with a CFU spore suspension. Two hours after infection, animals were divided into groups (n=10) and groups were given compound 27 (10 mg / kg) or vancomycin (10 mg / kg) by oral gavage daily for 5 days. Treatment was stopped on day 5, and mice were monitored for an additional 23 days. Mice treated with compound 27 or vancomycin showed no signs of disease during therapy. However, from day 9 onwards (4 days after vancomycin was discontinued), vancomycin-treated mice developed CDI. By day 11, only 60% of vancomycin-treated mice survived with the original protocol (1x antibiotics) and 0% with the aggressive antibiotic protocol (3x antibiotics). Oral treatment with an identical dose of compound 27 resulted in 100% survival of mice with no recurrences over 28 days (Figure 4). Symptomatic recurrences of CDI occur in approximately 20% of patients and are difficult to treat [34-38]. In addition to subsequent prolonged shedding and transmission of C. difficile, one in five CDI patients experienced recurrent infection and died within 30 days of diagnosis.

[12] Compound 27 could reduce recurrence and potentially extend the clinical utility of current antibiotics (vancomycin and fidaxomicin).

[0159] In vitro cytotoxicity analysis of lactones against Caco-2 cells In vitro toxicity studies were designed to evaluate the potential toxicity of synthesized α-methylene γ-butyrolactone (AMGBL) and α-aminomethyl γ-butyrolactone (AAGBL) with the goal of providing critical information regarding non-toxic doses to be used in future animal studies. Caco-2 cells, an immortalized human colorectal adenocarcinoma cell line primarily used as a model of the intestinal epithelial barrier, were selected due to their presence in the gastrointestinal tract (GIT) [30,31].

[0160] method: To ascertain potential toxic effects on mammalian cells in vitro, compounds (at concentrations of 32 μg / mL, 64 μg / mL, and 128 μg / mL) were assayed against human colorectal (Caco-2) cell lines. Briefly, cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 20% fetal bovine serum (FBS), non-essential amino acids (1X), and penicillin-streptomycin at 37°C with CO2 (5%). Control cells received only DMSO at a concentration equal to that in the drug-treated cell samples. Cells were incubated with compounds (in triplicate) in 96-well plates for 2 hours at 37°C with CO2 (5%). The assay reagent MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (Promega, Madison, WI, USA) was then added and the plates were incubated for 4 h. Absorbance readings (at OD490) were measured using a kinetic microplate reader (Molecular Devices, Sunnyvale, CA, USA). The amount of viable cells after treatment with each compound was expressed as a percentage of the viability of DMSO-treated control cells (mean ± standard deviation of triplicate wells). Toxicity data were analyzed by two-way ANOVA with post hoc Dunnett's multiple comparison test (P < 0.05) using GraphPad Prism 6.0 (GraphPad Software, La Jolla, CA) (Figure 2).

[0161] Figure 2 shows the toxicity analysis of compounds 27, 48, 50, 51, 61, and 85 against human colorectal cells (Caco-2). For the cytotoxicity analysis of the compounds at 32 μg / mL, 64 μg / mL, and 128 μg / mL against Caco-2 cells using MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (tested in triplicate), percent mammalian viable cells were measured as the mean absorbance ratio (comparing test agent to DMSO). Dimethylsulfoxide (DMSO) was used as a negative control to determine the baseline value of the cytotoxic effect of each compound. Absorbance values ​​are the average of the minimum of three samples analyzed for each compound. Error bars represent the standard deviation of the absorbance values. Statistical differences (indicated with an asterisk, *) between the values ​​obtained for each compound and those obtained for DMSO (negative control, used as solvent for the compounds) (P<0.05) were determined by two-way ANOVA with post-hoc Dunnett's multiple comparison test.

[0162] result: Compounds 27, 48, and 51 were non-toxic to Caco-2 cells up to a concentration of 128 μg / mL. Compounds 61 and 85 were found to be toxic to Caco-2 cells at 128 μg / mL. Compound 50 was non-toxic to Caco-2 cells up to a concentration of 32 μg / mL.

[0163] Those skilled in the art will recognize that numerous variations can be made to the specific implementations described above, and implementations should not be limited to the specific limitations described. Other implementations may be possible.

[0164] It is intended that the scope of the present methods and compositions be defined by the following claims. However, it should be understood that the present disclosure may be practiced otherwise than as specifically described and illustrated without departing from its spirit or scope. It should be understood by those skilled in the art that various alternatives to the embodiments described herein may be employed in the practice of the following claims without departing from the spirit or scope thereof as defined in the claims.

[0165] References: TIFF2025505612000043.tif216166TIFF2025505612000044.tif225166TIFF2025505612000045.tif172166

[0166] Numbered Aspects Aspect 1 relates to: formula A compound having the formula: TIFF2025505612000046.tif43128 or a pharma- ceutically acceptable salt thereof: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R is H or alkyl; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together with the N to which they are attached form a ring system. Aspect 2 relates to: formula The compound of embodiment 1, which is a compound of TIFF2025505612000047.tif43128 or a pharma- ceutically acceptable salt thereof: During the ceremony, n is 1, 2, 3, or 4; R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R7 and R8 are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted, or R7 and R8 together with the N to which they are attached form a ring system. Aspect 3 relates to: formula The compound of embodiment 1, which is a compound of TIFF2025505612000048.tif60128 or a pharma- ceutically acceptable salt thereof: wherein X is halo. Aspect 4 relates to: formula The compound of embodiment 1, which is a compound of TIFF2025505612000049.tif63165 or a pharma- ceutically acceptable salt thereof. Aspect 5 relates to: formula Compound in TIFF2025505612000050.tif43128: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted. Aspect 6 relates to the following: formula The compound of embodiment 5, which is a compound of TIFF2025505612000051.tif43128 or a pharma- ceutically acceptable salt thereof: During the ceremony, n is 1, 2, 3, or 4, and R1, R2, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl. Aspect 7 relates to the following: A pharmaceutical composition comprising one or more compounds of any of embodiments 1-6, together with one or more pharma- ceutically acceptable diluents, excipients, or carriers. Aspect 8 relates to the following: The pharmaceutical composition of embodiment 7, which is a nanoparticle. Aspect 9 relates to: The pharmaceutical composition of embodiment 7 or 8, further comprising one or more other antibiotics. Aspect 10 relates to: A method for treating a patient having an infectious disease, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds of embodiments 1-6 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 7-9. Aspect 11 relates to: The method of embodiment 10, wherein said infection is caused by Clostridioides difficile. Aspect 12 relates to: Use of a compound according to any one of items 1 to 6, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating Clostridioides difficile infection in a subject.

Claims

1. formula or a pharma- ceutically acceptable salt thereof: During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4; R is H or alkyl; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R 7 and R 8 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; or R 7 and R 8 form a ring system together with the N to which they are attached.

2. formula or a pharma- ceutically acceptable salt thereof. During the ceremony, n is 1, 2, 3, or 4; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and R 7 and R 8 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; or R 7 and R 8 form a ring system together with the N to which they are attached.

3. formula or a pharma- ceutically acceptable salt thereof. wherein X is halo.

4. formula or a pharma- ceutically acceptable salt thereof.

5. Compounds of formula (I): During the ceremony, X is O, NH, NR, or S; Y is O, NH, NR, or S; n is 1, 2, 3, or 4, and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted.

6. formula or a pharma- ceutically acceptable salt thereof. During the ceremony, n is 1, 2, 3, or 4, and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is independently hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, acyl, aryl, heteroaryl, arylalkyl, arylalkenyl, or arylalkynyl.

7. 10. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 together with one or more pharma- ceutically acceptable diluents, excipients or carriers.

8. 8. The pharmaceutical composition of claim 7, which is a nanoparticle.

9. 9. The pharmaceutical composition of claim 7 or 8, further comprising one or more other antibiotics.

10. 10. A method for treating a patient having an infectious disease, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 7 to 9.

11. 11. The method of claim 10, wherein the infection is caused by Clostridioides difficile.

12. 13. Use of a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a Clostridioides difficile infection in a subject.

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