Formulation of Amphotericin B Hybrid Amide Derivatives in DSGPEG2K Micelles

Abstract

A composition comprising a lipid polymer excipient and AmB or an AmB derivative is disclosed. The lipid polymer excipient can form micelles when formulated with AmB or an AmB derivative, solubilizing and stabilizing the drug. Also disclosed is a method of treating fungal infections using this composition.

Description

Cross - reference to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 355,345, filed on June 24, 2022. Government support

[0002] This invention was made with government support under Grant No. R01 AI135812, approved by the National Institutes of Health. The U.S. government has certain rights in this invention.

Technical Field

[0003] The present disclosure provides compositions of amphotericin B and its derivatives with improved solution stability and plasma compatibility, as well as methods of using such formulations. More particularly, the present disclosure relates to micellar formulations comprising amphotericin B or its derivative and a block copolymer that not only stabilizes the pharmaceutical active ingredient but unexpectedly improves the potency of the compound and extends its half - life.

Background Art

[0004] The morbidity and mortality rates of invasive fungal infections are considerable, which are mainly caused by fungal pathogens of two genera, Candida and Aspergillus. Candida species are the fourth most common pathogens isolated in any bloodstream infection. The success rate of treating invasive candidiasis is limited (50 - 70%), which typically only applies to extremely healthy patients. The mortality rate that can be caused by invasive candidiasis is considerable (20 - 30%). The incidence of invasive aspergillosis caused by Aspergillus fumigatus has tripled in the past decade, and its mortality rate has increased by more than 300%. Furthermore, the success rate of the current treatment for invasive aspergillosis is as low as 40 - 50%. Invasive aspergillosis continues to be a major cause of death in immunocompromised patients, and invasive mold infections (fusariosis, scedosporiosis, and mucormycosis) have even higher mortality rates and no effective treatment options. The first-choice therapeutic agent recommended in current guidelines for invasive aspergillosis and most other invasive mold infections is voriconazole, a triazole antifungal drug. However, the pan-triazole resistance of Aspergillus is up to 30% in some places and in certain high-risk patient groups. The Infectious Diseases Society of America recognized the lack of such effective treatment methods and emphasized Aspergillus fumigatus as one of only six pathogens for which a "substantive breakthrough is urgently needed".

[0005] Amphotericin B (AmB) is a very promising starting point. This is because this drug has potent and dose-dependent fungicidal activity against a wide range of fungal pathogens and has avoided resistance for half a century. In contrast to its antifungal activity, the fungicidal activity of AmB is important in immunocompromised patients who have lost a robust immune system to assist in the eradication of the infection. When the identity of the pathogen is unknown and immediate empirical treatment is required, broad antifungal activity is particularly important in critically ill patients. The International Expert Committee recently directed that new treatment approaches centered on AmB without the problem of resistance are needed. The problem is that because AmB has strong toxicity, its use is limited to low-dose protocols and often fails to eradicate the disease.

[0006] An understanding of the mechanism of AmB, which represents a new paradigm shift in this field and has not been elucidated for half a century, has been achieved. Previous studies have reported that AmB binds to sterols, which was thought to mainly promote the formation of membrane-permeable pores and kill both fungal and human cells. Through a decade-long, thorough investigation at the atomic level enabled by the synthesis of this natural product and experiments using state-of-the-art SSNMR, it has been discovered that AmB kills both fungal and human cells mainly by forming a cytotoxic extracellular sterol sponge. This huge aggregate lands on the surface of the lipid bilayer and rapidly extracts membrane sterols, which causes cell death. Membrane permeabilization is unnecessary. Based on this new mechanism and increasingly refined structural information, it has been proposed that selective binding of ergosterol over cholesterol can be enabled by a small molecule-based ligand-selective allosteric effect. From this model, it was found that a new derivative, C2’epiAmB, eliminates cholesterol binding and thus toxicity in mammals. Summary of the Invention Problems to be Solved by the Invention

[0007] However, the limitation of C2’epiAmB is that it is ineffective against a large number of clinically important yeasts and molds. Other AmB derivatives have problems such as low plasma compatibility and solution stability. Therefore, there remains a need to develop formulations of AmB derivatives that retain potent and broad-spectrum resistance-evading antifungal activity, minimize dose-limiting toxicity, and improve the plasma compatibility and solution stability of these important compounds.

Means for Solving the Problems

[0008] In certain embodiments, the present invention provides a composition comprising the following (i) and (ii): (i) a lipid polymer excipient having the structure of formula (X):

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0009] In certain embodiments, this compound is

Chemical formula

[0010] Also provided herein is a method for treating a fungal infection, the method comprising administering to a subject in need of treatment for a fungal infection a therapeutically effective amount of the composition of the present invention.

[0011] In another aspect, the present invention provides the use of the composition of the present invention in the manufacture of a medicament for treating a fungal infection.

[0012] The present invention also provides a composition for use in treating a fungal infection.

Brief Description of the Drawings

[0013]

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Mode for Carrying Out the Invention

[0014] The present invention is based on the discovery of micellar formulations of amphotericin B and its derivatives that provide improved solution stability and plasma concentration of the antifungal payload. The inventors have surprisingly discovered that this formulation unexpectedly improves the efficacy of the amphotericin derivative and also extends its half-life in vivo.

[0015] Amphotericin B (AmB) is a polyene macrolide with a mycosamine adduct, and the complete compound has the following structure.

Chemical formula

[0016] AmB is generally obtained from strains of Streptomyces nodosus. AmB is currently approved in the United States for clinical use in the treatment of progressive and potentially life-threatening fungal infections, including infections such as systemic or deep tissue candidiasis, aspergillosis, cryptococcosis, blastomycosis, coccidioidomycosis, histoplasmosis, and mucormycosis. AmB is generally formulated for intravenous injection. Amphotericin B is commercially available, for example, as Fungizone® (Squibb), Amphocin® (Pfizer), Abelcet® (Enzon), and Ambisome® (Astellas Pharma Inc.). Due to its undesirable toxic side effects, dosing is generally limited to a maximum of about 1.0 mg / kg / day, and the total cumulative dose should not exceed about 3 g in humans.

[0017] AmB kills both fungal and human cells by forming cytotoxic extracellular sterol sponges. Anderson, T. M. et al., Nat Chem Biol 2014, 10 (5), 400-6. These large aggregates land on the surface of the lipid bilayer and rapidly extract membrane sterols, which causes cell death. Membrane permeabilization is not required. Based on this mechanism, selective binding of ergosterol over cholesterol is enabled by a small molecule-based ligand-selective allosteric effect, eliminating the toxicity of AmB in mammals (in the form of C2’epiAmB). See Wilcock, B. C. et al., J Am Chem Soc 2013, 135 (23), 8488-91. The present invention discloses the K D for the binding of both ergosterol and cholesterol to the AmB sterol sponge, which provides quantitative, mechanism-based biophysical parameters that lead to a rational optimization of the therapeutic index of this clinically important natural product.

[0018] Further derivatives of AmB have been identified and shown to have an improved therapeutic index compared to AmB. Such derivatives of AmB retain a strong binding to ergosterol but show no detectable binding to cholesterol, retain fungicidal efficacy against many yeasts and molds, but show no detectable toxicity in mammals. This demonstrates that differential binding of ergosterol over cholesterol is possible, providing a non-toxic variant of AmB with desirable antifungal properties preserved.

[0019] Such AmB derivatives have a significantly improved safety profile and have the therapeutic potential to eradicate life-threatening invasive fungal infections, but there are challenges with regard to drug administration, particularly intravenous administration, due to their low plasma compatibility and low solution stability.

[0020] Accordingly, the present invention is based in part on the discovery of formulations of novel AmB derivatives that are (1) effective against fungal pathogens, (2) minimally toxic in mammals, (3) plasma compatible, and (4) stable in solution.

[0021] The compositions of the present invention are useful for inhibiting the growth of fungi. In one embodiment, the growth of fungi is inhibited by contacting the fungi with an effective amount of the composition of the present invention. In one embodiment, the composition of the present invention is added to or contained in a tissue culture medium.

[0022] The compositions of the present invention are useful for treating fungal infections in a subject. In one embodiment, a fungal infection is treated by administering a therapeutically effective amount of the composition of the present invention to a subject in need of treatment for the fungal infection.

[0023] Yeasts are eukaryotes classified in the fungal kingdom. Fungi include yeasts, molds, and larger organisms such as mushrooms. Yeasts and molds are clinically important as infectious agents. Yeasts are typically described as the budding form of fungi. Of particular importance in the context of the present invention are yeast species that can cause infections in mammalian hosts. Such infections generally occur in immunocompromised hosts, including hosts in whom the barriers to infection are compromised (e.g., burn victims), as well as hosts with a compromised immune system (e.g., hosts receiving chemotherapy or immunosuppressive therapy, and hosts infected with HIV). Pathogenic yeasts include, but are not limited to, various species of the genus Candida and various species of the genus Cryptococcus. Among the pathogenic yeasts of the genus Candida, of particular note are Candida albicans, Candida tropicalis (C. tropicalis), Candida stellatoidea (C. stellatoidea), Candida glabrata (C. glabrata), Candida krusei (C. krusei), Candida parapsilosis (C. parapsilosis), Candida guilliermondii (C. guilliermondii), Candida viswanathii (C. viswanathii), and Candida lusitaniae (C. lusitaniae). The genus Cryptococcus specifically includes Cryptococcus neoformans (Cryptococcus neoformans). Yeasts can cause infections of the mucous membranes, such as infections of the human oral cavity, esophagus, and vagina, as well as infections of the bone, blood, urogenital tract, and central nervous system. This list is illustrative and in no way limiting.

[0024] A number of fungi (other than yeast) can cause infections in mammalian hosts. Such infections generally occur in immunocompromised hosts, including hosts in whom the barriers to infection are impaired (e.g., burn victims), as well as hosts in whom the immune system is impaired (e.g., hosts receiving chemotherapy or immunosuppressive therapy, and hosts infected with HIV). Pathogenic fungi (other than yeast) include, but are not limited to, species of the genera Aspergillus, Rhizopus, Mucor, Histoplasma, Coccidioides, Blastomyces, Trichophyton, Microsporum, and Epidermophyton. Of particular note among these are Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis. Fungi can cause systemic and deep tissue infections of, for example, the lung, bone, blood, urogenital tract, and central nervous system. Some fungi are the cause of skin and nail infections.

[0025] The composition of the present invention In certain aspects, the present invention provides a composition comprising (i) and (ii) below: (i) a lipid polymer excipient having the structure of formula (X): [Chem. formula] [wherein, n is independently selected from 0 to 10; m is selected from 10 to 60]; (ii) a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof: [Chem. formula] [Chemical formula] Compound having the structure of formula (I): [Chemical formula] and Compound having the structure of formula (II): [Chemical formula] [In the formula, R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-10 carbocyclic, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; or R 1 and R 2 together with the nitrogen to which they are attached form a substituted or unsubstituted 3- to 10-membered heterocyclyl; R 3 is -NR 5 R 6 substituted or unsubstituted amino, substituted or unsubstituted urea, substituted or unsubstituted carbamate, or substituted or unsubstituted guanidinyl; R 4 is hydrogen, or substituted or unsubstituted C 1-6 alkyl; R 5 and R 6 are independently hydrogen, C(O)OR f substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-10 carbocyclic, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C5-10 Aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R 5 and R 6 together with the nitrogen to which they are attached form a substituted or unsubstituted 3- to 10-membered heterocyclyl; R f is selected from the group consisting of 2-alken-1-yl, tert-butyl, benzyl, and fluorenylmethyl.

[0026] In certain embodiments, the compound is AmB.

[0027] In certain embodiments, the compound is C2’epiAmB.

[0028] In certain embodiments, the compound is a compound having the structure of formula (I).

[0029] In certain embodiments, the compound is a compound having the structure of formula (II).

[0030] In certain embodiments, the compound is a compound having the structure of formula (I) or formula (II); R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-10 carbocyclyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl.

[0031] In certain embodiments, the compound is a compound having the structure of formula (I) or formula (II); R 1 and R 2 are independently hydrogen, unsubstituted C 1-6 alkyl, hydroxyl C 1-6 alkyl, alkoxy C 1-6Alkyl, halo C 1-6 Alkyl, amino C 1-6 Alkyl, heterocyclyl C 1-6 Alkyl, unsubstituted C 2-6 Alkynyl, unsubstituted C 3-10 Carbocyclyl, amino C 3-10 Is a carbocyclyl, unsubstituted 3- to 10-membered heterocyclyl, or hydroxyl 3- to 10-membered heterocyclyl.

[0032] In certain embodiments, this compound is a compound having the structure of formula (I) or formula (II); R 1 And R 2 At least one of which is hydrogen.

[0033] In certain embodiments, this compound is a compound having the structure of formula (I) or formula (II); R 1 And R 2 Neither will both be hydrogen.

[0034] In certain embodiments, this compound is a compound having the structure of formula (I) or formula (II); R 1 And R 2 Together with the nitrogen to which they are attached, form a substituted or unsubstituted 3- to 10-membered heterocyclyl.

[0035] In certain embodiments, this compound is a compound having the structure of formula (I) or formula (II); R 3 Is -NR 5 R 6 And; R 5 And R 6 Are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 Carbocyclyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 5-10is aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R 5 and R 6 together with the nitrogen to which they are attached form a substituted or unsubstituted 3- to 10-membered heterocyclyl; R f is selected from the group consisting of 2-alken-1-yl, tert-butyl, benzyl, and fluorenylmethyl.

[0036] In certain such embodiments, R 5 and R 6 are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-10 carbocyclyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl.

[0037] In further such embodiments, R 5 and R 6 are independently hydrogen or C(O)OR f , and optionally, R f is fluorenylmethyl. In certain such embodiments, at least one of R 5 and R 6 is hydrogen; preferably, R 5 and R 6 are both hydrogen.

[0038] In certain embodiments, this compound is a compound having the structure of formula (I) or formula (II); R 4 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 2-6 alkenyl. In certain such embodiments, R 4 is hydrogen, halo C 1-6 alkyl, or unsubstituted C2-6 It is alkenyl. In certain preferred embodiments, R 4 is hydrogen.

[0039] In certain embodiments, this compound is selected from the group consisting of:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0040] Alternatively, this compound is selected from the group consisting of:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

[0041] In a further embodiment, this compound is selected from the group consisting of:

Chem.

[0042] For example, in some embodiments, this compound is

Chem.

[0043] Alternatively, this compound may be

Chem.

[0044] In certain embodiments, this compound is in the form of a pharmaceutically acceptable salt. For example, in certain preferred embodiments, this compound is

Chem.

[0045] In other such embodiments, this compound is

Chem.

[0046] These and other amphotericin B derivatives, as well as synthetic routes and experimental procedures for preparing these compounds, are disclosed, for example, in International Publication No. WO 2015 / 175875, International Publication No. WO 2021 / 026520, and International Publication No. WO 2022 / 035752, and these publications are incorporated herein by reference.

[0047] In certain embodiments, n is independently selected from 1 to 9, 2 to 8, 3 to 7, or 4 to 6, respectively. In certain preferred embodiments, n is 5, respectively.

[0048] In certain embodiments, m is selected from 20 to 60, 30 to 50, or 40 to 50. In certain preferred embodiments, m is 44.

[0049] In certain embodiments, the lipid polymer excipient forms micelles in an aqueous solution.

[0050] In certain embodiments, the composition further comprises an agent for controlling plasma osmotic pressure.

[0051] In certain embodiments, the composition further comprises an agent for controlling pH.

[0052] In certain embodiments, the composition further comprises an agent for controlling oxidation.

[0053] In certain embodiments, the molar ratio of the lipid polymer excipient to the compound is from about 1:1 to about 10:1, from about 1:1 to about 5:1, from about 2:1 to about 4:1, or about 3:1.

[0054] In certain embodiments, the lipid polymer excipient is distearoyl-rac-glycerol-polyethylene glycol-2000 (referred to herein as DSG-PEG-2000). In other embodiments, the lipid polymer excipient is 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol-2000 (alternatively DMG-PEG-2000, or for certain positional isomers referred to as 1,2-DMG-PEG-2000). In certain embodiments, DMG-PEG-2000 is a mixture of two positional isomers, namely 1,2-DMG-PEG-2000 and 1,3-DMG-PEG-2000).

[0055] In certain embodiments, this composition is: (i) a lipid polymer excipient having the structure of formula (X) [Chemical formula] [wherein n is 5; m is 44] ; and (ii) the following: [Chemical formula] a compound represented by comprising, consisting essentially of, or consisting of these, and the molar ratio of the lipid polymer excipient to the compound is about 3:1.

[0056] In certain embodiments, the antifungal efficacy of this composition is higher than that of the compound alone.

[0057] In certain embodiments, the in vitro antifungal efficacy of this composition is higher than that of the compound alone in vitro.

[0058] In a further embodiment, the in vivo antifungal efficacy of this composition is higher than that of the compound alone in vivo.

[0059] In certain embodiments, the in vivo half-life of this composition is longer than the in vivo half-life of the compound alone.

[0060] In certain embodiments, this composition is a sustained-release composition.

[0061] In certain embodiments, this composition is an intravenous dosage form.

[0062] In certain embodiments, this composition further comprises a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic component combined with the active ingredient to facilitate administration. The components of the composition can also be mixed so that no interactions occur that substantially impair the desired pharmaceutical efficacy.

[0063] The above embodiments of the pharmaceutical composition of the present invention are intended to be illustrative and not limiting.

[0064] Also provided is a method of making such a pharmaceutical composition. This method includes incorporating a compound of the present invention or a pharmaceutically acceptable salt thereof into a pharmaceutically acceptable carrier.

[0065] The method of the present invention The present invention provides a method of treating a fungal infection, which includes treating a fungal infection by administering a therapeutically effective amount of the composition of the present invention to a subject in need of treatment for the fungal infection. In certain such embodiments, this composition is administered intravenously.

[0066] In certain embodiments, the subject is a mammal; or a primate, dog, cat, or cow; or a human; or a human.

[0067] The present invention also provides the use of the composition of the present invention in the manufacture of a medicament for treating fungal infections. In certain such embodiments, the medicament is in an intravenous dosage form.

[0068] The present invention also provides a composition for use in the treatment of fungal infections.

[0069] In certain embodiments, administration of this composition delivers a dose of 0.01 mg to 10 mg of a compound (such as AmB, C2’epiAmB, a compound of formula (I), or a compound of formula (II)).

[0070] For example, in certain embodiments where the composition is a sustained release composition, administration of this composition delivers a daily dose of 0.01 mg to 10 mg of the compound.

[0071] For example, in certain embodiments where the composition is a sustained release composition, the composition is administered once every 6 months, once every 5 months, once every 4 months, once every 3 months, once every 2 months, once a month, twice a month, once every two weeks, once a week, twice a week, or three times a week.

[0072] In certain embodiments, the composition is in an intravenous dosage form.

[0073] The composition of the present invention is particularly useful for inhibiting the growth of fungi and yeasts, including fungi and yeasts that are clinically important as pathogens. The composition of the present invention is particularly useful in methods for treating fungal and yeast infections, including systemic fungal and yeast infections.

[0074] In certain embodiments, the composition is administered intravenously.

[0075] Definitions Hereinafter, the definitions of functional groups and chemical terms will be described in more detail. Chemical elements are described in Handbook of Chemistry and Physics, 75 thIdentified according to the CAS-formatted periodic table on the front and back covers of the Ed., and the specific functional groups are defined as a whole as described therein. Further, the general principles of organic chemistry, as well as specific functional substructures and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0076] The compounds described herein can contain one or more chiral centers and can exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC), as well as the formation and crystallization of chiral salts; or can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0077] The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0078] When ranges of values are recited, it is intended that the invention include each intervening value and subrange within the recited range. For example, "C" 1-6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 ,"C 1-5 ,"C 1-4 ,"C 1-3 ,"C 1-2 ,"C 2-6 ,"C2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 is intended to include alkyl.

[0079] The following terms are intended to have the meanings presented below and are useful in understanding the description and scope of the present invention. When describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, when the following terms are present, they are intended to have the following meanings unless otherwise indicated. Also, as described herein, any of the substructures defined below may be substituted with various substituents, and each definition is intended to include such substituted substructures within the scope described below. Unless otherwise specified, the terms "substituted, substitution" shall be defined as described below. Further, it should be understood that the terms "group" and "radical" may be considered interchangeable when used herein. The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an analogue" means one analogue or more than one analogue.

[0080] "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C1-9 "alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl"). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each example of the alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1-10It is alkyl. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), i-Pr (-CH(CH3)2), n-Pr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0081] "Alkylene" refers to an alkyl group, with two hydrogens removed to form a divalent radical, which may or may not be substituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0082] "Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group (referred to as "C 2-20 alkenyl") having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). In certain embodiments, alkenyl contains no triple bonds at all. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (referred to as "C 2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (referred to as "C 2-9"(alkenyl). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 alkenyl). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 alkenyl). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 alkenyl). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 alkenyl). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 alkenyl). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (as in 2-butenyl) or terminal (as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. C 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 alkenyl groups, and pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like. Unless otherwise specified, each example of the alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2-10 alkenyl.

[0083] "Alkenylene" refers to an alkenyl group from which two hydrogens have been removed to form a divalent radical, which may or may not be substituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-), and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0084] "Alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ( 2-20 "Calkynyl"). In certain embodiments, alkynyl contains no double bonds at all. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ( 2-10 "Calkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ( 2-9 "Calkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ( 2-8 "Calkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ( 2-7 "Calkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ( 2-6 "Calkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ( 2-5"(alkynyl)". In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 alkynyl)". In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 alkynyl)". In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be internal (as in the case of 2-butynyl) or terminal (as in the case of 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. C 2-6 Examples of alkenyl groups include the C 2-4 alkynyl groups described above, and pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each example of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2-10 alkynyl.

[0085] "Alkynylene" refers to a straight-chain alkynyl group, optionally substituted or unsubstituted, from which two hydrogens have been removed to form a divalent radical. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0086] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, further containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, where the one or more heteroatoms are inserted between adjacent carbon atoms in the main carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., at the point of attachment. In certain embodiments, the heteroalkyl group is a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (a "heteroC 1-10 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (a "heteroC 1-9 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (a "heteroC 1-8 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (a "heteroC 1-7 alkyl"). In some embodiments, the heteroalkyl group is a group having from 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (a "heteroC 1-6 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 5 carbon atoms and 1 or 2 heteroatoms (a "heteroC 1-5 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 4 carbon atoms and / or 2 heteroatoms (a "heteroC 1-4 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 3 carbon atoms and 1 heteroatom (a "heteroC 1-3 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 2 carbon atoms and 1 heteroatom (a "heteroC 1-2is an “alkyl”). In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“heteroC1 alkyl”). In some embodiments, the heteroalkyl group is a group having 2 to 6 carbon atoms and one or two heteroatoms (“heteroC 2-6 alkyl”). Unless otherwise specified, each example of the heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In certain embodiments, the heteroalkyl group is unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is substituted heteroC 1-10 alkyl.

[0087] As used herein, the term “heteroalkenyl” is an alkenyl group as defined herein that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), and this one or more heteroatoms are inserted between adjacent carbon atoms in the main carbon chain and / or this one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., at the point of attachment. In certain embodiments, the heteroalkenyl group is a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-10 alkenyl”). In some embodiments, the heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 alkenyl”). In some embodiments, the heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8"(alkenyl)". In some embodiments, the heteroalkenyl group has from 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7 "(alkenyl)". In some embodiments, the heteroalkenyl group has from 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 "(alkenyl)". In some embodiments, the heteroalkenyl group has from 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-5 "(alkenyl)". In some embodiments, the heteroalkenyl group has from 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-4 "(alkenyl)". In some embodiments, the heteroalkenyl group has from 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("heteroC 2-3 "(alkenyl)". In some embodiments, the heteroalkenyl group has from 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-6 "(alkenyl)". Unless otherwise specified, each example of the heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, the heteroalkenyl group is unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is substituted heteroC 2-10 alkenyl.

[0088] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where one or more of these heteroatoms are inserted between adjacent carbon atoms within the main carbon chain and / or one or more of these heteroatoms are inserted between a carbon atom and the parent molecule, i.e., at the point of attachment. In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("hetero C 2-10 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("hetero C 2-9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("hetero C 2-8 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("hetero C 2-7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("hetero C 2-6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("hetero C 2-5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("hetero C 2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("hetero C 2-3"(alkynyl)". In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or two heteroatoms ("heteroC 2-6 alkynyl)". Unless otherwise specified, each instance of the heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). In certain embodiments, the heteroalkynyl group is unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is substituted heteroC 2-10 alkynyl.

[0089] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" each refer to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. For a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", or "heteroalkynylene" group, when a range or number of carbons is provided, this range or number is understood to refer to the range or number of carbons in the straight-chain carbon divalent chain. The "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" groups may or may not be substituted with one or more substituents described herein.

[0090] "Aryl" has 6 to 14 ring carbon atoms provided within an aromatic ring system, has no heteroatoms, and is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n + 2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) radical ("C 6-14refers to "aryl". In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 aryl"; e.g., anthracyl). "Aryl" also includes a ring system in which the aryl ring defined above is fused to one or more carbocyclic or heterocyclic groups and the radical or point of attachment is on the aryl ring. In such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each example of the aryl group is independently optionally substituted, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C 6-14 aryl. In certain embodiments, the aryl group is substituted C 6-14 aryl.

[0091] In certain embodiments, the aryl group is halo, C 1-8 alkyl, C 1-8 haloalkyl, cyano, hydroxy, C 1-8It is substituted with one or more of the groups selected from alkoxy and amino.

[0092] Examples of representative substituted aryls include the following:

Chemical formula

[0093] Other representative aryl groups having a fused heterocyclyl group include the following:

Chemical formula

[0094] "Fused aryl" refers to an aryl in which two of its ring carbons are shared with a second aryl or heteroaryl ring, or with a carbocyclyl or heterocyclyl ring.

[0095] "Aralkyl" is a subset of alkyl and aryl as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0096] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms provided within an aromatic ring system, with each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, provided the valence allows. A bicyclic heteroaryl ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, with the point of attachment on the heteroaryl ring, and in such cases, the ring member count continues to refer to the ring member count within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused to one or more aryl groups, with the point of attachment on the aryl or heteroaryl ring, and in such cases, the ring member count refers to the ring member count within the fused (aryl / heteroaryl) ring system. In a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl).

[0097] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system (a "5- to 10-membered heteroaryl") having ring carbon atoms provided within the aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system (a "5- to 8-membered heteroaryl") having ring carbon atoms provided within the aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system (a "5- to 6-membered heteroaryl") having ring carbon atoms provided within the aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0098] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0099] Examples of representative heteroaryls include the following:

Chemical Structure

[0100] "Heteroaralkyl" is a subset of alkyl and aryl as defined herein and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0101] "Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms within a non-aromatic ring system ("C 3-10 carbocyclyl") and having no heteroatoms. In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl"). Exemplary C 3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3-8 carbocyclyl groups include, but are not limited to, the above-mentioned C 3-6A carbocyclic group, and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. may be mentioned. Exemplary C 3-10 Examples of the carbocyclic group include, but are not limited to, the above-mentioned C 3-8 carbocyclic group, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), etc. may be mentioned. As shown by the above examples, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic"), or includes a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic carbocyclic"), and may be saturated or partially unsaturated. "Carbocyclic" also includes a ring system in which the carbocyclic ring defined above is fused with one or more aryl or heteroaryl groups and the bonding point is on the carbocyclic ring. In such cases, the number of carbons still refers to the number of carbons within the carbocyclic ring system. Unless otherwise specified, each example of the carbocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclic group is unsubstituted C 3-10 carbocyclic. In certain embodiments, the carbocyclic group is substituted C 3-10 carbocyclic.

[0102] In some embodiments, "carbocyclic" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3-10("carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 "carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 "carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 "carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 "carbocyclyl"). C 5-6 Examples of the carbocyclyl group include cyclopentyl (C5) and cyclohexyl (C5). C 3-6 Examples of the carbocyclyl group include the above-mentioned C 5-6 carbocyclyl group, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of the carbocyclyl group include the above-mentioned C 3-6 carbocyclyl group, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of the carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is unsubstituted C 3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is substituted C 3-10 carbocyclyl.

[0103] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system (a "3- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, with each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In a heterocyclyl containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence permits. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl"), or a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. A bicyclic heterocyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" includes a ring system in which the heterocyclyl ring defined above is fused to one or more carbocyclic groups and the point of attachment is on the carbocyclic or heterocyclyl ring, or a ring system in which the heterocyclyl ring defined above is fused to one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring. In such cases, the ring member count continues to refer to the ring member count within the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., either unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0104] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system (a "5- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, with each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system (a "5- to 8-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, with each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system (a "5- to 6-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, with each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0105] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiirenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0106] Specific examples of the heterocyclyl group are shown in the following exemplary examples:

Chemical formula

[0107] The term "hetero," as used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. "Hetero" is applicable to any of the aforementioned hydrocarbon groups having from 1 to 5, particularly 1 to 3 heteroatoms, such as alkyl (e.g., heteroalkyl), carbocyclic (e.g., heterocyclic), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheteroalkenyl).

[0108] "Acyl" refers to the radical -C(O)R 20 wherein R 20 is hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl as defined herein. "Alkanoyl" is an acyl group wherein R 20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C 1-8 alkyl, -C(O)-(CH2) t (C6- 10 aryl), -C(O)-(CH2) t (5- to 10-membered heteroaryl), -C(O)-(CH2) t (C 3-10 carbocyclic), and -C(O)-(CH2) t (4- to 10-membered heterocyclic), where t is an integer from 0 to 4. In certain embodiments, R is C 1-8 alkyl substituted with halo or hydroxy; or each of unsubstituted C 1-4 alkyl, halo, unsubstituted C 1-4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1-4Hydroxyalkyl, or unsubstituted C 1-4 C substituted with haloalkoxy or hydroxy 3-10 Carbocyclic, 4- to 10-membered heterocyclic, C6- 10 Aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl.

[0109] "Acylamino" refers to the radical -NR 22 C(O)R 23 where each R 22 and each R 23 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 22 is an amino protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. Specific exemplary "acylamino" groups are -NR 24 C(O)-C 1-8 alkyl, -NR 24 C(O)-(CH2) t (C6- 10 aryl), -NR 24 C(O)-(CH2) t (5- to 10-membered heteroaryl), -NR 24 C(O)-(CH 2)t (C 3-10 carbocyclic), and -NR 24 C(O)-(CH2) t (4- to 10-membered heterocyclic), where t is an integer from 0 to 4, and each R 24 is independently H or C 1-8 alkyl. In certain embodiments, R 25 is H, halo, or C 1-8 alkyl substituted with hydroxy; each unsubstituted C1-4 Alkyl, halo, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, or unsubstituted C 1-4 C substituted with haloalkoxy or hydroxy 3-10 Carbocyclic, 4- to 10-membered heterocyclic, C6- 10 Aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl; R 26 Is H, C substituted with halo or hydroxy 1-8 Alkyl; each unsubstituted C 1-4 Alkyl, halo, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, or unsubstituted C 1-4 C substituted with haloalkoxy or hydroxyl 3-10 Carbocyclic, 4- to 10-membered heterocyclic, C6- 10 Aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl; provided that R 25 And R 26 At least one of which is other than H.

[0110] "Acyloxy" refers to the radical -OC(O)R 27 Where R 27 Is hydrogen, substituted or unsubstituted alkyl as defined herein, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 Is C substituted with halo or hydroxy 1-8 Alkyl; each unsubstituted C 1-4 Alkyl, halo, unsubstituted C1-4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1-4 hydroxyalkyl, or unsubstituted C 1-4 C substituted with haloalkoxy or hydroxy 3-10 carbocyclic, 4- to 10-membered heterocyclic, C6- 10 aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl.

[0111] "Alkoxy" refers to the group -OR 29 wherein R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy, i.e., those having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0112] In certain embodiments, R 29 is amino, substituted amino, C6- 10 aryl, aryloxy, carboxyl, cyano, C 3-10 carbocyclic, 3- to 10-membered heterocyclic, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, and is a group having one or more substituents selected from the group consisting of, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6- 10 aryl), -O-(CH2) t(5 to 10-membered heteroaryl), -O-(CH2) t (C 3-10 (carbocyclic), and -O-(CH2) t (4 to 10-membered heterocyclic) are included, where t is an integer from 0 to 4, and any aryl, heteroaryl, carbocyclic, or heterocyclic group present is, by itself, unsubstituted C 1-4 alkyl, halo, unsubstituted C 1-4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1-4 hydroxyalkyl, or unsubstituted C 1-4 haloalkoxy or hydroxy may be substituted. Specific exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0113] "Amino" refers to the radical -NH2.

[0114] "Substituted amino" refers to an amino group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, and at least one of R 38 is not hydrogen. In certain embodiments, each R 38 is independently hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C6- 10 aryl, 5 to 10-membered heteroaryl, 4 to 10-membered heterocyclic, or C 3-10 (carbocyclic); or C 1-8 alkyl substituted with halo or hydroxy; C 3-8 alkenyl substituted with halo or hydroxy; C 3-8alkynyl, or t is an integer from 0 to 8, each being unsubstituted C 1-4 alkyl, halo, unsubstituted C 1-4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1-4 hydroxyalkyl, or unsubstituted C 1-4 substituted with haloalkoxy or hydroxy, -(CH2) t (C6- 10 aryl), -(CH2) t (5- to 10-membered heteroaryl), -(CH2) t (C 3-10 carbocyclic), or -(CH2) t (4- to 10-membered heterocyclic); or both R groups are bonded to form an alkylene group.

[0115] Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C 1-8 alkyl, -NR 39 -(CH2) t (C6- 10 aryl), -NR 39 -(CH2) t (5- to 10-membered heteroaryl), -NR 39 -(CH2) t (C 3-10 carbocyclic), and -NR 39 -(CH2) t (4- to 10-membered heterocyclic), where t is an integer from 0 to 4, such as 1 or 2, and each R 39 is independently H or C 1-8 alkyl; any alkyl group present may itself be substituted with halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, carbocyclic, or heterocyclic group present may itself be unsubstituted C 1-4 alkyl, halo, unsubstituted C 1-4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1-4 hydroxyalkyl, or unsubstituted C 1-4It may be substituted with haloalkoxy or hydroxy. To avoid ambiguity, the term "substituted amino" includes alkylamino groups, substituted alkylamino groups, alkylarylamino groups, substituted alkylarylamino groups, arylamino groups, substituted arylamino groups, dialkylamino groups, and substituted dialkylamino groups as defined below. Substituted amino includes both mono-substituted amino groups and di-substituted amino groups.

[0116] "Azido" refers to the radical -N3.

[0117] "Carbamoyl" or "amido" refers to the radical -C(O)NH2.

[0118] "Substituted carbamoyl" or "substituted amido" refers to the radical -C(O)N(R 62 )2, where each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, and one of R 62 is not hydrogen. In certain embodiments, R 62 is H, C 1-8 alkyl, C 3-10 carbocyclic, 4- to 10-membered heterocyclic, C6- 10 aryl, aralkyl, 5- to 10-membered heteroaryl, and heteroaralkyl; or C 1-8 alkyl substituted with halo or hydroxy; or C 1-4 alkyl, halo, unsubstituted C 1-4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1-4 hydroxyalkyl, or C 1-4 carbocyclic, 4- to 10-membered heterocyclic, C6- 3-10 substituted with haloalkoxy or hydroxy; or C10 Selected from aryl, aralkyl, 5- to 10-membered heteroaryl, or heteroaralkyl; provided that at least one R 62 is other than H.

[0119] Exemplary "substituted carbamoyl" groups include, but are not limited to, -C(O)NR 64 -C 1-8 alkyl, -C(O)NR 64 -(CH2) t (C6- 10 aryl), -C(O)N 64 -(CH2) t (5- to 10-membered heteroaryl), -C(O)NR 64 -(CH2) t (C 3-10 carbocyclic), and -C(O)NR 64 -(CH2) t (4- to 10-membered heterocyclic), where t is an integer from 0 to 4, and each R 64 independently represents H or C 1-8 alkyl, and any aryl, heteroaryl, carbocyclic, or heterocyclic group present may itself be unsubstituted C 1-4 alkyl, halo, unsubstituted C 1-4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1-4 hydroxyalkyl, or unsubstituted C 1-4 alkyl substituted with haloalkoxy or hydroxy.

[0120] "Carboxy" refers to the radical -C(O)OH.

[0121] "Cyano" refers to the radical -CN.

[0122] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is fluoro or chloro.

[0123] "Hydroxy" refers to the radical -OH.

[0124] "Nitro" refers to the radical -NO2.

[0125] "Carbocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted by a carbocyclyl group. Typical carbocyclylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0126] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted by a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, and morpholinylethyl.

[0127] "Cycloalkenyl" refers to a substituted or unsubstituted carbocyclyl group having 3 to 10 carbon atoms, having a single ring, or a plurality of condensed rings including a fused ring system and a bridged ring system, and having at least one, particularly 1 to 2 olefinic unsaturated sites. Examples of such cycloalkenyl groups include monocyclic structures such as cyclohexenyl, cyclopentenyl, and cyclopropenyl.

[0128] "Fused cycloalkenyl" refers to a cycloalkenyl in which two of its ring carbon atoms are common to a second aliphatic or aromatic ring, and its olefinic unsaturation is arranged to impart aromaticity to the cycloalkenyl ring.

[0129] "Ethylene" refers to substituted or unsubstituted -(C-C)-.

[0130] "Ethenyl" refers to substituted or unsubstituted -(C=C)-.

[0131] "Ethynyl" refers to -(C≡C)-.

[0132] The term "nitrogen-containing heterocyclyl" group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0133] "Thioketo" refers to the group =S.

[0134] The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). Generally, the terms "substituted, substitution" mean that, whether or not the term "optionally" is prefixed, at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that results in a stable compound (e.g., a compound that does not spontaneously change by rearrangement, cyclization, elimination, or other reaction) upon substitution. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when two or more positions within a given structure are substituted, the substituents are the same or different with respect to each position. The terms "substituted, substitution" are intended to include substitution with any acceptable substituent of an organic compound, any of the substituents described herein that results in the formation of a stable compound. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable substructure.

[0135] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )-TXk-N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2Raa 、 -OC(=O)R aa 、 -OCO₂R aa 、 -C(=O)N(R bb )₂、 -OC(=O)N(R bb )₂、 -NR bb C(=O)R aa 、 -NR bb CO₂R aa 、 -NR bb C(=O)N(R bb )₂、 -C(=NR bb )R aa 、 -C(=NR bb )OR aa 、 -OC(=NR bb )R aa 、 -OC(=NR bb )OR aa 、 -C(=NR bb )N(R bb )₂、 -OC(=NR bb )N(R bb )₂、 -NR bb C(=NR bb )N(R bb )₂、 -C(=O)NR bb SO₂R aa 、 -NR bb SO₂R aa 、 -SO₂N(R bb )₂、 -SO₂R aa 、 -SO₂OR aa 、 -OSO₂R aa 、 -S(=O)R aa 、 -OS(=O)R aa 、 -Si(R aa )₃、 -OSi(R aa )₃、 -C(=S)N(R bb )₂、 -C(=O)SR aa 、 -C(=S)SR aa 、 -SC(=S)SR aa 、 -SC(=O)SR aa 、 -OC(=O)SR aa 、 -SC(=O)OR aa 、 -SC(=O)R aa 、 -P(=O)₂R aa 、 -OP(=O)₂R aa 、 -P(=O)(R aa )₂、 -OP(=O)(Raa ) 2, -OP(=O)(OR cc ) 2, -P(=O)2N(R bb ) 2, -OP(=O)2N(R bb ) 2, -P(=O)(NR bb ) 2, -OP(=O)(NR bb ) 2, -NR bb P(=O)(OR cc ) 2, -NR bb P(=O)(NR bb ) 2, -P(R cc ) 2, -P(R cc ) 3, -OP(R cc ) 2, -OP(R cc ) 3, -B(R aa ) 2, -B(OR cc ) 2, -BR aa (OR cc )、C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic, 3 - 14 membered heterocyclic, C 6-14 Aryl, and 5 - 14 membered heteroaryl are included, where alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; Or two geminal hydrogens on a carbon atom are replaced by the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)0R aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc ; R aa Each example of is independently, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10Carbocyclic, 3- to 14-membered heterocyclic, C 6-14 Aryl, and 5- to 14-membered heteroaryl, or two R aa Groups are joined to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R dd Groups; R bb Each example of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic, 3- to 14-membered heterocyclic, C 6-14 Aryl, and 5- to 14-membered heteroaryl, or two R bbThe groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; Each instance of R cc is independently selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; Each instance of R dd is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff ),2, -N(R ff ),2, -N(R ff ),3 + X - , -N(OR ee ),R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff ),2, -OC(=O)N(R ff ),2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff)2, -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ), -OC(=NR ff )N(R ff ), -NR ff C(=NR ff )N(R ff ), -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic, 3 - 10 membered heterocyclic, C6 - 10 aryl, 5 - 10 membered heteroaryl, and are each independently selected from, where alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can combine to form =O or =S; R ee each example of which is independently, C 1-6 alkyl, C 1-6 perhaloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, C6 - 10 Selected from aryl, 3 - to 10 - membered heterocyclic, and 3 - to 10 - membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; R ff each example of which is independently selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic, 3 - to 10 - membered heterocyclic, C 6-10 aryl, and 5 - to 10 - membered heteroaryl, or two R ff groups are joined to form a 3 - to 14 - membered heterocyclic or 5 - to 14 - membered heteroaryl ring, wherein alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; R gg each example of which is independently halogen, - CN, - NO2, - N3, - SO2H, - SO3H, - OH, - OC 1-6 alkyl, - ON(C 1-6 alkyl)2, - N(C 1-6 alkyl)2, - N(C 1-6 alkyl)2 + X - , - NH(C 1-6 alkyl)2 + X - , - NH2(C 1-6 alkyl) + X - , - NH3 + X - , - N(OC 1-6 alkyl)(C 1-6 alkyl), - N(OH)(C 1-6 alkyl), - NH(OH), - SH, - SC 1-6Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=0)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3 - C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, C6 - 10 Aryl, 3 - to 10 - membered heterocyclic, 5 - to 10 - membered heteroaryl; or two geminal R gg Substituents can combine to form =O or =S; where X - is a counterion.

[0136] "Counterion" or "anionic counterion" is a negatively charged group that binds to a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HSO4 - , SO4 2- , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p - toluenesulfonate, benzenesulfonate, 10 - camphorsulfonate, naphthalene - 2 - sulfonate, naphthalene - 1 - sulfonate - 5 - sulfonate, ethane - 1 - sulfonate - 2 - sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0137] The nitrogen atom may be substituted or unsubstituted as long as the valence permits, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )0R aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclic, 3- to 14-membered heterocyclic, C6- 14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups bonded to the nitrogen atom are bonded to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and where R aa , R bb , R cc , and R dd are as defined above.

[0138] These exemplary substituents, as well as other exemplary substituents, are described in more detail in the detailed description of the invention, the examples, and the claims. The present invention is not intended to be limited in any way by the exemplary list of substituents described above.

[0139] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a State government or corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals, and more particularly in humans.

[0140] "Pharmaceutically acceptable salt" refers to salts of a compound that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc., acid addition salts; or (2) when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or salts formed when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. The salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. are included.

[0141] "Pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc. (see, for example, Berge, et al., J. Pharm. Sci. 66 (1):1-79 (January 77)).

[0142] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier used in the administration of the compounds of the present invention.

[0143] "Pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to become the parent compound of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR, and -CH2OR radicals, where each R is independently selected from alkyl, trialkylsilyl, carbocyclic aryl, or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy, or alkoxy. Specific representative examples of metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

[0144] "Prodrug" refers to a compound having a cleavable group and becoming a compound of the present invention having pharmaceutical activity in vivo by solvolysis or under physiological conditions, and also includes derivatives of the compound of the present invention. Examples of such include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compound of the present invention are active in both the acid form and the acid derivative form, but in the acid-sensitive form, advantages regarding solubility, tissue compatibility, or delayed release in mammals are often provided (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include, for example, esters prepared by reaction of a parent acid with a suitable alcohol, or amides prepared by reaction of a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides, which are acid derivatives known to those skilled in the art. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups that are pendant groups of the compound of the present invention are specific prodrugs. In some cases, double ester type prodrugs such as (acyloxy)alkyl esters or (alkoxycarbonyl)oxy)alkyl esters are desirable. In particular, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 7-12 substituted aryl, and C 7-12 arylalkyl esters.

[0145] "Solvate" usually refers to a form of a compound combined with a solvent or water, usually by a solvation reaction (also called "hydrate"). This physical bond includes hydrogen bonds. Conventional solvents include water, ethanol, acetic acid, etc. The compounds of the present invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain examples, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0146] As used herein, "subject" refers to a living mammal. In various embodiments, the subject is a non-human mammal including, but not limited to, mice, rats, hamsters, guinea pigs, rabbits, sheep, goats, cats, dogs, pigs, horses, cows, or non-human primates. In one embodiment, the subject is a human.

[0147] As used herein, "subject having a fungal infection" refers to a subject presenting at least one objective sign of a fungal infection. In one embodiment, a subject having a fungal infection is a subject diagnosed with a fungal infection and in need of treatment thereof. Since methods for diagnosing fungal infections are known, they need not be described in detail herein.

[0148] As used herein, "subject having a yeast infection" refers to a subject presenting at least one objective sign of a yeast infection. In one embodiment, a subject having a yeast infection is a subject diagnosed with and in need of treatment for a yeast infection. Since methods for diagnosing yeast infections are known, they need not be described in detail herein.

[0149] As used herein, the phrase "effective amount" refers to any amount sufficient to achieve a desired biological effect.

[0150] As used herein, the phrase "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic effect, e.g., to treat a fungal or yeast infection.

[0151] For any compound described herein, a therapeutically effective amount can generally be determined first from in vitro studies, animal models, or both in vitro studies and animal models. In vitro methods are known and can include determinations such as minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), concentration inhibiting 50 percent growth (IC 50 ), concentration inhibiting 90 percent growth (IC 90 ), etc. A therapeutically effective amount can also be determined from human data regarding the compounds of the invention tested in humans and regarding compounds known to exhibit equivalent pharmacological activity, such as other active agents (e.g., AmB) related thereto. For parenteral administration, the required dose may be higher. The dose applied can be adjusted based on the relative bioavailability and efficacy of the compound administered. Adjusting the dose to achieve maximum effectiveness based on the methods described herein and other methods is known in the art and within the capabilities of one of ordinary skill.

[0152] For any compound described herein, a therapeutically effective amount for use in a human subject can be determined first from in vitro studies, animal models, or both in vitro studies and animal models. A therapeutically effective amount for use in a human subject can also be determined from human data regarding the compounds of the invention tested in humans and regarding compounds known to exhibit comparable pharmacological activity, such as other active agents (e.g., AmB) related thereto. For parenteral administration, the required dose may be higher. The dose applied can be adjusted based on the relative bioavailability and efficacy of the compound administered. Adjusting the dose to achieve the highest effectiveness based on the methods described above and other methods is known in the art and within the capabilities of a person of ordinary skill.

[0153] As used herein, "inhibit" or "inhibiting" means reducing by an objectively measurable amount or degree as compared to a control. In one embodiment, "inhibit" or "inhibiting" means reducing by at least a statistically significant amount as compared to a control. In one embodiment, "inhibit" or "inhibiting" means reducing by at least 5 percent as compared to a control. In various individual embodiments, "inhibit" or "inhibiting" means reducing by at least 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, or 95 percent (%) as compared to a control.

[0154] "Treating" or "treatment" or "therapeutic treatment" for a disease or disorder, in one embodiment, refers to an improvement of the disease or disorder (i.e., a halt in the progression of the disease, or a reduction in the signs, degree, or severity of at least one of the clinical symptoms of the disease). In another embodiment, "treating" or "treatment" refers to an improvement in at least one physical parameter that may or may not be recognizable to the subject. In yet another embodiment, "treating" or "treatment" refers to a physical regulation (e.g., stabilization of recognizable symptoms), a physiological regulation (e.g., stabilization of physical parameters), or both of the disease or disorder. In a further embodiment, "treating" or "treatment" refers to slowing the progression of the disease. For example, in one embodiment, the terms "treating" and "treat" refer to (a) inhibiting a fungal infection, e.g., delaying or preventing its onset; or (b) reducing or improving a fungal infection, e.g., performing an intervention that results in regression of the fungal infection.

[0155] "Preventing" or "prevention" or "prophylactic treatment" refers to a reduction in the risk of acquisition or onset of a disease or disorder (i.e., in a subject who has not yet been exposed to the causative agent of the disease or is susceptible to the disease, preventing at least one of the clinical symptoms of the disease from occurring prior to the onset of the disease).

[0156] It should also be understood that compounds having the same molecular formula but different properties or the bonding of their atoms or the spatial arrangement of their atoms are called "isomers". Isomers with different spatial arrangements of their atoms are called "stereoisomers".

[0157] Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images and cannot be superimposed on each other are called "enantiomers". If a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the Cahn and Prelog R and S assignments or by the way the molecule rotates the plane of polarization and are designated as dextrorotatory or levorotatory (i.e., as the (+) isomer or (-) isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal ratios is called a "racemic mixture".

[0158] "Tautomers" are interconvertible forms of a particular compound structure and refer to compounds with different displacements of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium by the movement of their electrons and atoms (usually H). For example, enol and ketone are tautomers because they are rapidly interconverted when treated with an acid or a base. Another example of tautomers is the acyl and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or a base. Tautomeric forms can be relevant to the acquisition of the optimal chemical reactivity and biological activity of the compound of interest.

[0159] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., the enantiomeric excess is substantially zero). In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and thus the enantiomeric excess of the "R" form is substantially zero. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0160] As used herein, unless otherwise indicated, the term "enantiomerically pure R-compound" means at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, or at least about 99.9% by weight R-compound and at most about 0.1% by weight S-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0161] As used herein, unless otherwise indicated, the term "enantiomerically pure S-compound" or "S-compound" means at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound, or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0162] In the compositions provided herein, an enantiomerically pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, can be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound can contain, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition can contain, for example, at least about 95% by weight of the R compound and up to about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound can contain, for example, about 90% excipient and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can contain, for example, at least about 95% by weight of the S compound and up to about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated without or with little excipient or carrier.

[0163] The compounds of the invention may have one or more chiral centers and thus such compounds can be produced as individual (R) or (S) stereoisomers, or mixtures thereof.

[0164] Unless otherwise indicated, the description or naming of a particular compound in this specification and the claims is intended to include both the individual enantiomers and mixtures thereof, racemates, etc. Methods for the determination of stereochemical structure and the separation of stereoisomers are known in the art.

[0165] The terms "conjoint administration" and "administered conjointly" refer to any mode of administration of two or more different therapeutic compounds such that a second compound is administered while a previously administered therapeutic compound is still active in the body (e.g., the two compounds are simultaneously active in the body of a patient, which may include a synergistic effect of the two compounds). For example, a plurality of different therapeutic compounds can be administered simultaneously or sequentially, either as a single formulation or as separate formulations. In certain embodiments, a plurality of different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or 1 week of each other. Thus, an individual undergoing such treatment can benefit from the combined effects of a plurality of different therapeutic compounds.

[0166] As used herein, "fungal infection" refers to an infection in or of a subject by a fungus as defined herein. In one embodiment, the term "fungal infection" includes yeast infections. As used herein, "yeast infection" refers to an infection in or of a subject by a yeast as defined herein.

[0167] As used herein, "active ingredient", "therapeutically active ingredient", "active agent", "drug", or "drug substance" means the active ingredient of a pharmaceutical product, also known as an active pharmaceutical ingredient (API).

[0168] As used herein, "drug loading" refers to the percentage by mass of one or more active ingredients in the mass of the entire formulation.

[0169] The term "about" refers to the variation in numerical values commonly encountered by those skilled in the art in the field of inhalation formulations and includes variations of plus or minus 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the recited numerical value.

[0170] Throughout this specification and in the following claims, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", are to be understood as implying the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0171] Unless otherwise specified or apparent from the context, numerical ranges include both endpoints and any value between them.

[0172] Packaged pharmaceutical product In a further aspect, provided herein is a packaged pharmaceutical product comprising a composition of the invention.

[0173] In certain embodiments, the composition is a sustained-release composition.

[0174] In certain embodiments, the composition is an intravenous formulation.

[0175] As described above, the term "effective amount" refers to any amount sufficient to achieve the desired biological effect. In combination with the teachings provided herein, by making selections from various active compounds and weighting factors such as potency, relative bioavailability, patient body weight, severity of side effects, and preferred dosage forms, an effective prophylactic or therapeutic treatment regimen can be planned that does not substantially cause undesirable toxicity and yet is still effective for the treatment of a particular subject. The effective amount for any particular application can vary depending on factors such as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agents without undue experimentation. Generally, it is preferred to use the maximum dosage, i.e., the highest dosage within a safe range according to any medical judgment. Multiple administrations per day may be contemplated to achieve an appropriate systemic level of the compound. The appropriate systemic level can be determined, for example, by measuring the peak or steady-state plasma level of the drug in the patient. The terms "dose" and "dosage" are used interchangeably herein.

[0176] In some embodiments, intravenous administration of the compounds of the invention may typically be from 0.1 mg / kg / day to 20 mg / kg / day. Thus, the intravenous dosage may be equivalent to the maximum tolerated dose of AmB, or advantageously exceed it. The intravenous dosage may be equivalent to the maximum daily tolerated dose of AmB, or advantageously exceed it. The intravenous dosage may be equivalent to the cumulative maximum tolerated dose of AmB, or advantageously exceed it.

[0177] Also, the intravenous dosage may be equivalent to the maximum recommended dose of AmB, or advantageously exceed it. Also, the intravenous dosage may be equivalent to the maximum daily recommended dose of AmB, or advantageously exceed it. Also, the intravenous dosage may be equivalent to the cumulative maximum recommended dose of AmB, or advantageously exceed it.

[0178] For any compound described herein, a therapeutically effective amount can first be determined from animal models. A therapeutically effective dosage can also be determined from human data regarding the compounds of the invention tested in humans and regarding compounds known to exhibit comparable pharmacological activity, such as other active agents related thereto. In the case of parenteral administration, the required dosage may be higher. The dosage applied can be adjusted based on the relative bioavailability and efficacy of the compound administered. Adjusting the dosage to achieve the highest effectiveness based on the methods described above and other methods is known in the art and within the capabilities of a person of ordinary skill.

[0179] The formulations of the invention are administered as pharmaceutically acceptable solutions which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0180] Amphotericin B is commercially available in a number of formulations, including deoxycholate-based (sometimes called desoxycholate-based) formulations and lipid-based formulations, including liposomal formulations.

[0181] In the case of intravenous administration, the pharmaceutical active ingredient can be stabilized within micelles. In certain embodiments, the micelles are formed from block copolymers. In further embodiments, the micelles are formed from multiple components (e.g., block copolymers and deoxycholate compounds) and may be referred to as "mixed micelles".

[0182] When systemic delivery is desired, the compound may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be provided in unit dosage forms, for example, in ampoules or multi-dose containers, with preservatives added. Alternatively, the injectable formulation may be formulated for sustained or controlled release. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. Examples of stabilizers include compounds that can form micelles.

[0183] Examples of pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Further, a suspension of the active compound may be prepared as a suitable oily injectable suspension. Suitable lipophilic solvents or vehicles include fats such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may contain suitable stabilizers or agents that enhance the solubility of the compound to enable the preparation of highly concentrated solutions or improve the half-life of the compound in solution.

[0184] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0185] In addition to the above-described formulations, the compound may be formulated as a depot formulation. Such long-acting formulations can be formulated using suitable polymeric materials, or using hydrophobic materials (e.g., as an emulsion in an acceptable oil), or using ion exchange resins, or as a slightly insoluble derivative, for example, as a slightly insoluble salt.

[0186] The pharmaceutical composition may include a suitable solid or gel-phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0187] Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous inhalation solutions or physiological saline solutions, microencapsulated forms, co-crystallized forms, forms coated on fine gold particles, forms encapsulated within liposomes, atomized forms, aerosols, pellets for subcutaneous implantation, or forms dried on sharp objects for entry into the skin by abrasion. The pharmaceutical composition also includes granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations for long-term release of the active compound, and for these preparations, as described above, excipients, as well as additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavors, sweeteners, or solubilizers are used in the conventional manner. The pharmaceutical composition is suitable for use in various drug delivery systems. For a concise report on methods of drug delivery, see Langer R, Science 249:1527-33 (1990) (incorporated herein by reference).

[0188] The compounds of the present invention, and optionally other therapeutic agents, may be administered as such (as they are) or in the form of pharmaceutically acceptable salts. When used in medicine, the salts must be pharmaceutically acceptable, but pharmaceutically unacceptable salts may be used to prepare their pharmaceutically acceptable salts. Such salts include, but are not limited to, salts prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts can also be prepared as alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, or calcium salts of carboxylic acid groups.

[0189] Suitable buffers include: acetic acid and salts (1-2 w / v%); citric acid and salts (1-3 w / v%); boric acid and salts (0.5-2.5 w / v%); and phosphoric acid and salts (0.8-2 w / v%). Suitable preservatives include benzalkonium chloride (0.003-0.03 w / v%); chlorobutanol (0.3-0.9 w / v%); parabens (0.01-0.25 w / v%); and thimerosal (0.004-0.02 w / v%).

[0190] The pharmaceutical composition of the present invention comprises an effective amount of the compound of the present invention and, optionally, at least one additional therapeutic agent contained in a pharmaceutically acceptable carrier.

[0191] Without being limiting, specifically, one or more therapeutic agents, including the compounds of the present invention, can be provided in particulate form. As used herein, the term "particle" means nanoparticles or microparticles (or, in some cases, even larger particles) that may wholly or in part consist of a compound of the present invention or one or more other therapeutic agents described herein. The particles may contain one or more therapeutic agents within a core surrounded by a coating, including but not limited to an enteric coating. The one or more therapeutic agents may be dispersed throughout the particle. The one or more therapeutic agents may be adsorbed to the particle. The particles may exhibit any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and combinations thereof. In addition to one or more therapeutic agents, the particles may contain any material conventionally used in the fields of pharmacy and medicine, including but not limited to erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules encapsulating a compound of the present invention in solution or semi-solid form. The particles may be of substantially any shape.

[0192] Both non-biodegradable polymer materials and biodegradable polymer materials can be used in the production of particles for the delivery of one or more therapeutic agents. Such polymers may be natural polymers or synthetic polymers. The polymer is selected based on the period during which release is desired. Of particular interest as bioadhesive polymers are the bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7 (the teachings of this document are incorporated herein by reference). This includes polyhyaluronic acid, casein, gelatin, gluten, polyanhydrides, polyacrylic acid, alginic acid, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0193] Therapeutic agents such as the compounds described herein can be provided as micelle formulations. The micelle formulations can be prepared using standard techniques for completely mixing or combining a polymer component (e.g., a lipid polymer excipient) and a pharmaceutically active ingredient. Mechanical mixing procedures can also be used to achieve complete mixing of the components of the composition.

[0194] An injection device such as a syringe can be prepared to encapsulate the micelle formulation by using any technique for placing the composition into the injection device so that the composition can be injected by the device. For example, the composition of the present invention can be placed into the barrel of a syringe by mechanical means or extrusion.

[0195] The compositions of the present invention can be stored for a significant period of time. In certain embodiments, the compositions can be stored at room temperature or at a temperature below room temperature.

[0196] The composition of the present invention can be placed in a sterile container for later use as a pharmaceutical preparation. Such a container may preferably be a sealed vial having sufficient space for later addition of an aqueous physiologically acceptable carrier. In this way, the composition of the present invention can be used to produce a drug containing micelles in the above-mentioned container after the introduction of an aqueous carrier. The dissolution of the composition in the carrier with concomitant simultaneous formation of micelles may be accelerated by agitation (e.g., shaking) or may occur over a long period without agitation.

[0197] The method of administering the composition according to the present invention can be carried out according to methods known in the art. Methodologies for injecting such a composition or solution into a selected site within a patient's body can be selected and carried out by a medical professional.

[0198] In certain embodiments, the lipid polymer excipient in the composition of the present invention is a biocompatible micelle-forming polymer. Exemplary biocompatible micelle-forming polymers include polymers known in the art such as those described in WO 01 / 87345. In certain embodiments, one or more micelle-forming polymers in the composition of the present invention are diblock copolymers suitable for micelle formation as taught in the art or as specifically described herein. a diblock copolymer suitable for micelle formation.

[0199] The hydrophobic portion of such a diblock copolymer may include one or more hydrophobic polymers such as polyesters, polyanhydrides, polyglycolic acid, polybutrylactones, polyhydroxybutyric acid, polylactic acid, and polylacaprolactone. The hydrophobic portion of the copolymer may include one or more different hydrophobic polymers in a random or block orientation. In certain embodiments, the molecular weight of the hydrophobic portion of the copolymer is from about 200 to about 5000.

[0200] The molecular weight of the hydrophobic portion of the micelle-forming copolymer that can be used in the present invention is greater than about 750 and up to about 8000. In some embodiments, the molecular weight is in the range of about 1000 or 2000 to 3000 or 5000. In some embodiments, the hydrophobic portion of the micelle-forming copolymer is polyethylene glycol.

[0201] The weight ratio of the hydrophobic component to the hydrophilic component of the micelle-forming polymer used in the present invention can be adjusted to provide the desired chemical properties, manufacture, and control. For injection, the amount of the lipid polymer excipient is preferably an amount such that the resulting mixture or matrix is injectable, as defined herein. The amount of the pharmaceutically active ingredient contained in the composition is an amount that can provide the desired amount of drug-loaded micelles, and preferably does not exceed an amount that can be sufficiently dispersed in the micelle-forming composition.

[0202] In certain embodiments, the drug-loaded micelles in the composition of the present invention are lyophilized after preparation and stored in a dry state. The dry micelles can be reconstituted in a pharmaceutically acceptable carrier such as sterile saline or sterile dextrose solution, e.g., 5% dextrose, and after being fully hydrated, can be filter sterilized (optionally through a 0.22 μm filter) prior to administration.

[0203] One or more therapeutic agents can be included in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the mode and profile of drug release from the formulation are controlled. This refers to immediate release formulations and non-immediate release formulations, and non-immediate release formulations include, but are not limited to, sustained release formulations and delayed release formulations. The term "sustained release" (which may also be referred to as "extended release") refers, in its conventional meaning, to a drug formulation that provides for the gradual release of a drug over an extended period of time and, although not essential, preferably results in a substantially constant drug blood level over an extended period of time. The term "delayed release" refers, in its conventional meaning, to a drug formulation in which there is a time delay between the administration of the formulation and the release of the drug from the formulation. "Delayed release" may or may not be accompanied by the gradual release of the drug over an extended period of time, and thus may or may not be "sustained release".

[0204] The use of long-term sustained release implants may be particularly suitable for the treatment of chronic conditions. As used herein, "long-term" release means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, preferably 30 to 60 days. Long-term sustained release implants are known to those of ordinary skill in the art and include some of the release systems described above.

Examples

[0205] Although the present invention has been described in detail, it will be more clearly understood by reference to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the present invention.

[0206] The amphotericin B derivatives used in the compositions of the present invention, as well as the synthetic routes and experimental procedures for preparing these compounds, are disclosed, for example, in WO 2015 / 175875, WO 2021 / 026520, and WO 2022 / 035752, which are incorporated herein by reference.

[0207] Example 1: Stability and Plasma Compatibility of AM-2-19

Chemical formula

[0208] AM-2-19 (and its acetate, AM-2-19-OAc) is a potent antifungal compound that exhibits excellent efficacy against a number of fungal pathogens, has a long half-life, and reduces nephrotoxicity compared to AmB and other AmB derivatives. However, AM-2-19 has problems with low plasma compatibility and solution stability.

[0209] The in vitro plasma compatibility of AM-2-19 in human plasma is shown below:

Table 1

[0210] As shown in Figure 1, AM-2-19 lacks solution stability in IV-compatible solvents such as 5% dextrose in water (D5W).

[0211] To improve the plasma compatibility and solution stability of this promising antifungal compound, the following experiments were conducted.

[0212] Example 2: Stability and Plasma Compatibility of Micelle Formulations Multiple micelle formulations of AM-2-19 OAc were prepared and tested according to the following protocol: · Mix 0.5 mL of the formulation solution (2.5 mg / mL) with 0.5 mL of plasma (ITR protocol) · Visually inspect the solution ·Centrifuge at 1600 g and check for the presence of pellets. ·Centrifuge at 5000 g and check for the presence of pellets. ·Centrifuge at 20000 g and check for the presence of pellets. ·Negative controls: D5W, physiological saline, and AM-2-19-OAc in water ·Positive controls: D5W, physiological saline, and water only

[0213] Plasma incompatibility is indicated by the turbidity of the mixture when the micelle formulation is mixed with plasma. Furthermore, the presence of pellets after centrifugation of the plasma-micelle formulation mixture indicates plasma incompatibility.

[0214] The results are shown below.

Table 2

Table 3

[0215] The formulations of AM-2-19-OAc and DSG-PEG-2000 showed plasma compatibility in D5W, physiological saline, and water, while the formulations of AM-2-19-OAc alone did not show plasma compatibility.

[0216] Images of the AM-2-19-OAc and DSG-PEG-2000 formulations (i.e., Experiments 2, 3, and 4) after addition of plasma are shown in Figure 2A, and images of the negative control formulations (i.e., Experiments 23, 24, and 25) after addition of plasma are shown in Figure 2B.

[0217] Example 3: Preparation of AM-2-19-FB (free base) in 30 mM acetate, pH 5, in D5W, in DSG-PEG2000 As shown in Example 1, the concentration of AM-2-19-OAc varies over time in a D5W solution. Furthermore, the solution of AM-2-19-OAc in D5W is not compatible with plasma, which hinders the intravenous formulation of the compound.

[0218] The inventors hypothesized that this concentration variation might be caused by aggregation and / or adsorption to glass. Similarly, aggregation promoted by the pH and amphiphilicity of the compound might have led to plasma incompatibility.

[0219] The inventors surprisingly discovered that micelle stabilization of the amphotericin derivative not only significantly improves stability and plasma compatibility, but also remarkably improves efficacy and half-life as detailed below.

[0220] Note: The molar ratio of AM-2-19-FB:DSG-PEG2000 is fixed at 1:3.

[0221] Step 1. Preparation of placebo formulation (30 mM acetic acid in D5W, pH 5, DSG-PEG2000) · Prepare 30 mM acetate in D5W using glacial acetic acid in a beaker · Adjust the pH using 10N NaOH · Transfer to a volumetric flask and add D5W to the appropriate volume · Recheck the pH (typically no change) · Bubble nitrogen through the solution for 5 - 15 minutes depending on the volume being prepared · Weigh DSG-PEG2000 and place it in a vial · Weigh the required amount of 30 mM acetate in D5W, pH 5 and add it to the vial containing DSG-PEG2000 · Sonicate for 5 minutes · Add a stir bar and stir until completely dissolved

[0222] Step 2. Preparation of AM-2-19-FB formulation · Weigh AM-2-19-FB and place it in a vial · Weigh the required amount of the placebo formulation prepared in Step 1 and add it to the above vial · Vortex for 10 seconds · Add a stir bar and heat at 50 °C with rapid stirring for 30 minutes ·Cool to room temperature on ice ·Filter with a 0.22 μm PVDF syringe filter

[0223] By continuously diluting the above-mentioned formulation using D5W as a diluent, a lower concentration of AM-2-19-FB can be prepared.

[0224]

Table 4

[0225] Example 4: Preparation of a dosing solution of AM-2-19-OAc A dosing solution was prepared using a micellar solution vehicle of 5% dextrose aqueous solution (D5W) containing distearoyl-rac-glycerol PEG 2000 (DSG-PEG 2000). DSG-PEG 2000 is a PEGylated lipid polymer excipient that forms mixed micelles when formulating AM-2-19 and functions to solubilize and stabilize the drug.

[0226] Premise: ·Dose levels: 0.3, 1.0, 3.0, and 7.0 mg / kg ·Dog body weight - 10 kg ·Dose volume - 1 mL / kg (IV bolus) ·Concentration - 0.3, 1.0, 3.0, and 7.0 mg / mL AM-2-19 free base ·Bolus injection - Administer 10 mL to each animal ·Sterile filtration is required for this study

[0227] Drug: ·AM-2-19 acetate (molecular weight: 1057.24 g / mol). Note that the molecular weight of the AM-2-19 free base is 997.19 g / mol. ·The purity and correction factor of AM-2-19 acetate are provided in the Certificate of Analysis.

[0228] Vehicle components: ·For dextrose 5% (D5W) USP, a commercially available product needs to be purchased. This is also called D-glucose 5% (w / w). ·Distearoyl-rac-glycerol PEG 2000 (DSG-PEG 2000) (molecular weight 2621.4 g / mol).

[0229] Note that the average concentration of the vehicle over the range of DSG-PEG 2000 concentrations used in this study is 1.026 g / mL

[0230] Preparation of dosage formulations For the amounts of drug (AM-2-19 free base) and DSG-PEG 2000 for the preparation of the vehicle and dosage solutions, please refer to the following table. Since the drug is provided as acetate, the amount of acetate to be weighed must be calculated using the correction factor provided in the CoA. A procedure for preparing a stock solution of the highest drug concentration that will be filter sterilized later is described. Lower concentration solutions are prepared by diluting this high concentration solution (in D5W / glucose 5% (w / w)).

[0231] If necessary, a vehicle solution (DSG-PEG 2000 in D5W) can be prepared in advance, filtered through a 0.22 μm filter, and stored in a refrigerator (2 - 8°C) while not in use. The vehicle solution is stable for 7 days.

[0232] Dosage solutions must be freshly prepared daily. The stability of the dosage solution is such that preparation and dosing need to be done within 6 hours.

[0233] The following are instructions for preparing 100.0 mL of vehicle formulation. The volume can be increased up to a maximum of 750 mL (the limit based on the inventors' experience) as needed.

[0234] 4A. Preparation of Vehicle (55.20 mg / mL of DSG-PEG 2000, 100 mL) a. Pipette (or weigh) exactly 100.0 mL of D5W and place it in a suitable glass container. b. Insert a stir bar into the container and start stirring the D5W. c. Weigh exactly 5.52 g of DSG-PEG 2000 and transfer it into the D5W. Adding the DSG-PEG 2000 in multiple portions may help prevent aggregation / lumping. d. Sonicate for 5 minutes at room temperature to facilitate dissolution of DSG-PEG 2000. e. Stir the solution on a stir plate at room temperature for at least 15 minutes to ensure complete dissolution of DSG-PEG 2000. f. If necessary, sonicate the vehicle for an additional 5 minutes and then stir for more than 15 minutes until DSG-PEG 2000 is completely dissolved. The resulting micelle solution should be clear. g. Measure and record the final pH. h. If preparing the DSG-PEG 2000 solution for use on the same day, skip steps i and j. i. Filter the DSG-PEG 2000 solution through a 0.22 μm filter. If necessary, a Millex GV filter (e.g., 33 mm) of the same Durapore PVDF membrane but larger than that specified above can also be used. j. Prepared in this way, the vehicle solution can be pre-prepared and stored in a refrigerator (2 - 8°C) for 7 days.

[0235] 4B. Preparation of Dosage Solution The dosage formulation is freshly prepared on the day of dosing. First, a stock solution with the highest achievable drug concentration (7.0 mg / mL) is prepared and sterile filtered. Lower concentration dosing solutions are then prepared by subsequent dilution using D5W as the diluent. The dosage formulation, which is the test item, is prepared using clean techniques under a laminar flow hood. These formulations are photosensitive. Therefore, protect all containers from light during preparation.

[0236] Preparation of stock solution (7.0 mg / mL dosing solution, 60.0 mL) k. Accurately weigh 420.0 mg of the test item (AM-2-19) and place it in a suitable glass container (Note: Use the correction factor provided in the CoA to calculate the amount of AM-2-19 acetate to be weighed. Since AM-2-19 acetate is fluffy, electrostatic reduction may be required). l. Add exactly 60.0 mL of vehicle solution (room temperature) and dissolve the drug. m. Place the container in a water bath on a heated magnetic stirrer plate, cover the container, and start stirring while keeping the cover on to minimize evaporation. n. Insert a thermometer into the water bath and heat the water until a temperature of 50 ± 2 °C is reached while constantly monitoring the temperature. o. Once the water bath reaches a temperature of 50 ± 2 °C, continue stirring the formulation for an additional 30 minutes. Monitor the temperature and use ice or cold water as necessary to maintain the water bath temperature at 50 ± 2 °C. p. Remove the flask containing the dosage formulation from the water bath and cool the solution to room temperature by placing the container in an ice bath while occasionally shaking the flask, or by placing the container in a fume hood. q. After returning the dosage formulation solution to room temperature (15 - 30 °C), filter it through a 0.22 μm PVDF syringe filter (33 mm membrane size) and discard the first 2 mL. Filtration is not required if the solution concentration is lower, and it is necessary to prepare it under a laminar flow hood using clean techniques.

[0237] The dilutions recommended for preparing 35.0 mL of a lower concentration dosing solution are shown in the following table. For example, to prepare a dosing solution of 3.0 mg / mL, the 7.0 mg / mL stock solution created in Steps 2.a - 2.g above is diluted 1:2.33 with D5W (15.0 mL of stock + 20.0 mL of D5W). [Table 5]

[0238] The elapsed time between the preparation and administration of the dosing solution must be less than 6 hours.

[0239] Example 5: Characterization of AM - 2 - 19 - OAc - DSG - PEG - 2000 Formulation The structures of AM - 2 - 19 - OAc and DSG - PEG - 2000 are shown in Figure 3. As shown below, the size of the micelles was characterized by dynamic light scattering (DLS) which demonstrated the stability of the micelles over time. [Table 6]

[0240] As shown in Figure 4, there were no significant changes in the UV spectrum over time, which indicates the stability of the DSG - PEG 2000 micelle formulation of AM - 2 - 19 - OAc. In fact, more than 98% of the initial concentration was retained at the 24 - hour time point.

[0241] Example 6: Aqueous Stability of AM - 2 - 19 - OAc Compared to AM - 2 - 19 - OAc - DSG - PEG - 2000 The aqueous solution stability of the AM-2-19-OAc stock solution and the AM-2-19-OAc-DSG-PEG-2000 stock solution in D5W was evaluated at 2.5 mg / mL. The AM-2-19-OAc-DSG-PEG-2000 stock solution was prepared by adding AM-2-19-OAc to a solution of DSG-PEG 2000 in D5W to prepare a 1:3 (drug: excipient) composition, which was stirred at 50 °C for 30 minutes to form a micelle formulation.

[0242] To measure the solution stability of each solution, aliquots were carefully taken from the top of each stock solution at predetermined time points and diluted 500-fold with methanol for UV measurement. In the AM-2-19-OAc stock solution, a concentration loss of more than 10% was recorded at 6 hours (Figure 5A). In contrast, the AM-2-19-OAc-DSG-PEG-2000 stock solution remained stable and substantially no concentration loss was observed after 6 hours at room temperature (Figure 5B).

[0243] Example 7: Solution behavior of AM-2-19-OAc-DSG-PEG-2000 The solution behavior of AM-2-19-OAc-DSG-PEG-2000 was evaluated using UV-Vis and NMR techniques. The UV pattern of the AM-2-19-OAc solution was concentration-dependent, and it was found that the monomer-like UV pattern at low concentrations shifted to an aggregate-like pattern with an absorption peak at 410 nm at high concentrations (Figures 6A and 6B). In AM-2-19-OAc-DSG-PEG-2000, such a concentration-dependent change in UV was not observed, and a sharp absorption peak appeared at 415 nm, which was assumed to be derived from the drug encapsulated in the micelles (Figures 6C and 6D).

[0244] To further understand the encapsulation phenomenon, solutions of AM-2-19-OAc, AM-2-19-OAc-DSG-PEG-2000, and DSG-PEG-2000 were prepared in deuterated D5W and at various temperatures 1It was investigated by 1H-NMR. In the DSG-PEG-2000 control, no characteristic peaks were observed up to 35 °C. However, at about 40 °C, a distinct peak appeared, which is thought to be due to micelle phase transition (Figure 7). See Otten, D. et al. Biophysical Journal, 1995, 68 (2), 584-597. When the same experiment was carried out with AM-2-19-OAc-DSG-PEG-2000, no characteristic peaks of AM-2-19 were observed at 25 - 36 °C (Figure 7). However, at about 40 °C corresponding to micelle phase transition, the polyene signal of AM-2-19 began to appear in line with the more rapid relaxation of the encapsulated drug molecules during the phase transition of DSG-PEG-2000 (Figure 7). In the absence of DSG-PEG 2000 micelles, the polyene signal of AM-2-19 can be confirmed at 25 °C (Figure 7). These results suggest that the majority of the drug molecules are encapsulated in AM-2-19-OAc-DSG-PEG-2000.

[0245] Example 8: Broad-spectrum antifungal activity of AM-2-19-OAc-DSG-PEG-2000 formulations The AM-2-19-OAc-DSG-PEG-2000 formulation was tested against various fungal strains and compared with AmB, AM-2-19-OAc (in vehicle), and DSG-PEG-2000 micelles (without API). The results are shown in the following table. [Table 7]

[0246] Surprisingly, DSG-PEG-2000 increases the potency of AM-2-19-OAc in vitro.

[0247] Furthermore, DSG-PEG-2000 extends the half-life of AM-2-19-OAc compared to the half-life of AM-2-19-OAc without micelle formulation (see Figure 8).

[0248] Also, the micelle formulation provided favorable tissue distribution data in mice (see Figure 9).

[0249] Example 9: AM-2-19-OAc-DSG-PEG-2000 retains a characteristic UV pattern in RPMI To investigate the structure of AM-2-19-OAc-DSG-PEG-2000 under biologically relevant conditions, 320 μM stock solutions of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 were diluted with RPMI 1640 (pH = 7) to mimic the in vitro antifungal efficacy evaluation conditions. The characteristic 415 nm UV peak of micellar AM-2-19-OAc-DSG-PEG-2000 was retained at concentrations of 2 μM and above, but the characteristic 410 nm UV peak of AM-2-19-OAc was not observed in the diluted samples (Figures 10A - 10D). The retention of the micellar structure at these concentrations is consistent with the improved MIC of AM-2-19-OAc-DSG-PEG-2000 against fungal isolates compared to AM-2-19-OAc.

[0250] Example 10: AM-2-19 in AM-2-19-OAc-DSG-PEG-2000 binds to plasma proteins The effects of plasma dilution and albumin titration on AM-2-19-OAc-DSG-PEG-2000 were investigated. This mimics the fate of drug molecules after IV dosing or infusion. The UV patterns of the stock solutions of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 contained peaks characteristic of 410 nm and 415 nm, respectively (Figures 11A and 11B). However, upon dilution with plasma, the UV patterns of both the AM-2-19-OAc solution and the AM-2-19-OAc-DSG-PEG-2000 solution exhibited a peak characteristic of 418 nm, indicating that AM-2-19 is bound to plasma proteins (Figures 11C and 11D).

[0251] Similar peaks were also observed when any of these solutions were titrated with human serum albumin (Figure 11C and 11D). See Xie, M. et al. Biochim Biophys Acta. 2006, 1760(8), 1184-91.

[0252] Any of these solutions were titrated with albumin, and the UV spectra of the resulting solutions were measured at various ratios of AM-2-19 to albumin (Figure 12A - 12D). The shift in the UV pattern of each solution begins to appear at a ratio of 1:0.8. For the titration of AM-2-19-OAc, a broad peak transition from 410 nm to 418 nm was recorded at a ratio of 1:1 (Figure 12A and 12B), while for AM-2-19-OAc-DSG-PEG-2000, a sharp hypsochromic shift from 415 nm to 418 nm was obtained at a ratio of 1:1 (Figure 12C and 12D), suggesting that AM-2-19-OAc-DSG-PEG-2000 efficiently transfers AM-2-19 to albumin.

[0253] These data indicate that AM-2-19-OAc-DSG-PEG-2000 provides improved aqueous stability and plasma compatibility, and retains the micellar structure at biologically relevant concentrations without interfering with binding to plasma proteins.

[0254] Example 11: Analysis of Toxic Biomarkers A panel of AM-2-19-OAc formulations, other AmB formulations, and control formulations were evaluated for toxicity.

[0255] As shown in Figure 13, AM-2-19-OAc-DSG-PEG-2000 does not increase common toxic biomarkers.

[0256] Figure 14 shows that AM-2-19-OAc-DSG-PEG-2000 maintains the loss of toxicity in vitro.

[0257] Figure 15 shows a series of histopathology charts demonstrating that the AM-2-19-OAc-DSG-PEG-2000 formulation does not cause kidney injury in mice, rats, or dogs.

[0258] Example 12: Toxicokinetics The toxicokinetics and tolerance of a single dose of AM-2-19-OAc-DSG-PEG-2000 in rats were studied. The following table shows an overview of the experimental setup. [Table 8]

[0259] The toxicity biomarkers are shown in Figure 16.

[0260] In addition, AM-2-19-OAc-DSG-PEG-2000 was evaluated in dogs over a 2-week period and multiple dosing schedules. In the dosing protocol, all dogs survived at all doses, and no clinical findings or signs of distress were observed in any dog. Also, there was no change in the food intake of any dog.

[0261] The results of dosing regimen A (administered every other day) are shown in Figure 17.

[0262] The results of dosing regimen B (administered every 4 days) are shown in Figure 18.

[0263] The results of dosing regimen C (administered once a week) are shown in Figure 19.

[0264] Example 13: Efficacy of the micelle formulation AM-2-19-OAc-DSG-PEG-2000 is a highly potent antifungal agent against a series of fungal infections, including drug-resistant and refractory strains, and fungi such as Aspergillus terreus which is difficult to treat even without drug resistance. As shown in Figure 20, AM-2-19-OAc-DSG-PEG-2000 shows a lower minimum inhibitory concentration (MIC) compared to the amphotericin B liposomal formulation AmBisome against a number of yeast and mold strains including drug-resistant Candida albicans ATCC90028. As shown in Figure 21, AM-2-19-OAc-DSG-PEG-2000 dramatically reduces fungal burden in kidney and lung tissues compared to the control and AmBisome in various fungal strains. In Figure 21, "Pre" represents the fungal burden at the time point of t (time) = 0.

[0265] Example 14: Application of the micelle formulation platform to further AmB derivatives The surprising benefit of the DSG-PEG 2000 micelle formulation is not limited to AM-2-19-OAc. Other derivatives of amphotericin B, including AmB amides and C2’ epi amides having the structures shown below, were formulated using DSG-PEG 2000.

Chemical formula

[0266] To investigate these compounds, only 2 mg of the compound was weighed and placed in a clean 7 mL glass vial. Next, 3 equivalents of DSG-PEG 2000 (DP2K) were weighed and placed in another 7 mL glass vial.

[0267] 1 mL of D5W was added to the second vial and sonicated for 15 minutes to prepare a clear solution of DP2K, which was filtered through a 0.22 μm syringe filter for the C2’ epi compound. The solution in the first vial containing the compound (as acetate) was transferred to this DP2K solution and stirred at 50 °C for 30 minutes to create a clear yellow solution. Next, this solution was cooled to room temperature.

[0268] As shown in Figure 22 and the following table, the DSG-PEG 2000 micelle formulation also significantly improved the solution stability of AM-290-2, AM-243-2, C2’epiMA, and C2’epiC5. Figure 22 shows the UV spectrum of a sample at a target concentration of 2 mg / mL. Samples at different time points were prepared by diluting 10 μl aliquots with 990 μl of MeOH (100-fold dilution). As shown, there were no significant changes in the UV spectrum over time, indicating the stability of the DSG-PEG 2000 micelle formulation of the AmB derivatives.

[0269] [Table 9]

[0270] Incorporation by reference All patents and published patent applications mentioned in the above description are hereby incorporated by reference in their entirety into this application.

[0271] Equivalents For the purpose of clear understanding, the present invention has been described in some detail by way of illustration and example. However, the present invention can be practiced by modifying or varying the invention within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the present invention or any of its specific embodiments, and it is intended that such modifications or variations be encompassed by the appended claims, which will be apparent to those skilled in the art.

Claims

1. A composition comprising: (i) a lipid polymer excipient having the structure of formula (X): 【Chemical 1】 [wherein, n is independently selected from 0 to 10; m is selected from 10 to 60]; and (ii) a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof: 【Chemical Formula 2】 [Chemical Formula 3] A compound having the structure of formula (I): 【Chemical Formula 4】 and A compound having the structure of formula (II): 【Chemical Formula 5】 [wherein, R １ and R ２ each independently is hydrogen, substituted or unsubstituted C １－６ alkyl, substituted or unsubstituted C ２－６ alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted C ３－１０ carbocyclic, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C ５－１０ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; or R １ and R ２ together with the nitrogen to which they are attached form a substituted or unsubstituted 3- to 10-membered heterocyclyl; R ３ is -NR ５ R ６ , a substituted or unsubstituted amino, a substituted or unsubstituted urea, a substituted or unsubstituted carbamate, or a substituted or unsubstituted guanidinyl; R ４ is hydrogen, or substituted or unsubstituted C １－６ alkyl; R ５ and R ６ are independently hydrogen, C(O)OR ｆ , substituted or unsubstituted C １－６ alkyl, substituted or unsubstituted C ２－６ alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted C ３－１０ carbocyclic, substituted or unsubstituted 3- to 10-membered heterocyclic, substituted or unsubstituted C ５－１０ aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R ５ and R ６ together with the nitrogen to which they are attached form a substituted or unsubstituted 3- to 10-membered heterocyclyl; R ｆ is selected from the group consisting of 2-alken-1-yl, tert-butyl, benzyl, and fluorenylmethyl] comprising, a composition.

2. The composition according to claim 1, wherein the compound is AmB.

3. The composition according to claim 1, wherein the compound is C2’ epiAmB.

4. The composition according to claim 1, wherein the compound is a compound having the structure of formula (I).

5. The composition according to claim 1, wherein the compound is a compound having the structure of formula (II).

6. The compound is a compound having the structure of formula (I) or formula (II), R １ and R ２ each independently is hydrogen, substituted or unsubstituted C １－６ alkyl, substituted or unsubstituted C ２－６ alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted C ３－１０ carbocyclic, substituted or unsubstituted 3- to 10-membered heterocyclic, substituted or unsubstituted C ５－１０ aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, the composition according to claim 1.

7. The compound is a compound having the structure of formula (I) or formula (II), R １ and R ２ are independently hydrogen, unsubstituted C １－６ alkyl, hydroxyl C １－６ alkyl, alkoxy C １－６ alkyl, halo C １－６ alkyl, amino C １－６ alkyl, heterocyclyl C １－６ alkyl, unsubstituted C ２－６ alkynyl, unsubstituted C ３－１０ carbocyclyl, amino C ３－１０ carbocyclyl, unsubstituted 3- to 10-membered heterocyclyl, or hydroxyl 3- to 10-membered heterocyclyl, the composition according to claim 1 or 6.

8. The compound is a compound having the structure of formula (I) or formula (II), R １ and R ２ The composition according to any one of claims 1, 6, and 7, wherein at least one of them is hydrogen.

9. The compound is a compound having the structure of formula (I) or formula (II), R １ and R ２ both do not become hydrogen, the composition according to any one of claims 1 and 6 to 8.

10. The compound is a compound having the structure of formula (I) or formula (II), R １ and R ２ The composition according to any one of claims 1, 6, and 7, which together with the nitrogen to which they are attached forms a substituted or unsubstituted 3- to 10-membered heterocyclyl.

11. The compound is a compound having the structure of formula (I) or formula (II), R ３ is -NR ５ R ６ and; R ５ and R ６ are independently hydrogen, C(O)OR ｆ , substituted or unsubstituted C １－６ alkyl, substituted or unsubstituted C ２－６ alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted C ３－１０ carbocyclic, substituted or unsubstituted 3- to 10-membered heterocyclic, substituted or unsubstituted C ５－１０ aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R ５ and R ６ together with the nitrogen to which they are attached form a substituted or unsubstituted 3- to 10-membered heterocyclyl; R ｆ is the composition according to any one of claims 1 and 6 to 10, selected from the group consisting of 2-alken-1-yl, tert-butyl, benzyl, and fluorenylmethyl.

12. R ５ and R ６ are independently hydrogen, C(O)OR ｆ , substituted or unsubstituted C １－６ alkyl, substituted or unsubstituted C ２－６ alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted C ３－１０ carbocyclic, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C ５－１０ aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, the composition according to claim 11.

13. R ５ and R ６ are independently hydrogen or C(O)OR ｆ and optionally, R ｆ is fluorenylmethyl, the composition according to claim 12.

14. R ５ and R ６ The composition according to claim 11, wherein at least one of them is hydrogen.

15. R ５ and R ６ are both hydrogen, the composition according to claim 11.

16. The compound is a compound having the structure of formula (I) or formula (II), R ４ is hydrogen, a substituted or unsubstituted C １－６ alkyl, or a substituted or unsubstituted C ２－６ alkenyl, and the composition according to any one of claims 1 and 6 to 15.

17. R ４ is hydrogen, halo C １－６ alkyl, or unsubstituted C ２－６ alkenyl, the composition according to claim 16.

18. R ４ The composition according to claim 17, wherein R is hydrogen.

19. The compound is 【Chemical Formula 6】 【Chemical 7】 【Chemical 8】 【Chemical Formula 9】 【Chemical 10】 selected from the group consisting of, the composition according to claim 1.

20. The compound is 【Chemical 11】 【Chemical 12】 【Chemical 13】 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemical 24】 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical 29】 【Chemical Formula 30】 【Chemical 31】 【Chemical Formula 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 【Chemical Formula 40】 【Chemical 41】 selected from the group consisting of, the composition according to claim 1.

21. The compound is 【Chemical 42】 selected from the group consisting of, the composition according to claim 1.

22. The compound is 【Chemical 43】 the composition according to claim 21.

23. The compound is 【Chemical 44】 the composition according to claim 21.

24. The composition according to any one of claims 1 to 23, wherein the compound is in the form of a pharmaceutically acceptable salt.

25. The compound is 【Chemical 45】 the composition according to claim 1.

26. The compound is 【Chemical 46】 the composition according to claim 1.

27. The composition according to any one of claims 1 to 26, wherein n is independently selected from 1 to 9.

28. The composition according to any one of claims 1 to 26, wherein n is independently selected from 2 to 8 respectively.

29. The composition according to any one of claims 1 to 26, wherein n is independently selected from 3 to 7 respectively.

30. The composition according to any one of claims 1 to 26, wherein n is independently selected from 4 to 6 respectively.

31. The composition according to any one of claims 1 to 26, wherein n is 5 respectively.

32. The composition according to any one of claims 1 to 31, wherein m is selected from 20 to 60.

33. The composition according to any one of claims 1 to 31, wherein m is selected from 30 to 50.

34. The composition according to any one of claims 1 to 31, wherein m is selected from 40 to 50.

35. The composition according to any one of claims 1 to 31, wherein m is 44.

36. The composition according to any one of claims 1 to 35, wherein the lipid polymer excipient forms micelles in an aqueous solution.

37. The composition according to any one of claims 1 to 36, further comprising an agent for controlling plasma osmotic pressure.

38. The composition according to any one of claims 1 to 37, further comprising an agent for controlling pH.

39. The composition according to any one of claims 1 to 38, further comprising an agent for controlling oxidation.

40. The composition according to any one of claims 1 to 39, wherein the molar ratio of the lipid polymer excipient to the compound is about 1:1 to about 10:

1.

41. The composition according to any one of claims 1 to 39, wherein the molar ratio of the lipid polymer excipient to the compound is about 1:1 to about 5:

1.

42. The composition according to any one of claims 1 to 39, wherein the molar ratio of the lipid polymer excipient to the compound is about 2:1 to about 4:

1.

43. The composition according to any one of claims 1 to 39, wherein the molar ratio of the lipid polymer excipient to the compound is about 3:

1.

44. (i) A lipid polymer excipient having the structure of formula (X): 【Chemical 47】 [wherein, n is 5; m is 44] and (ii) The following: 【Chemical 48】 A compound represented by The composition according to claim 1, comprising, consisting essentially of, or consisting of these, wherein the molar ratio of the lipid polymer excipient to the compound is about 3:

1.

45. The composition according to any one of claims 1 to 44, wherein the antifungal efficacy of the composition is higher than the antifungal efficacy of the compound alone.

46. The composition according to claim 45, wherein the in vitro antifungal efficacy of the composition is higher than the in vitro antifungal efficacy of the compound alone.

47. The composition according to claim 45, wherein the in vivo antifungal efficacy of the composition is higher than the in vivo antifungal efficacy of the compound alone.

48. The composition according to any one of claims 1 to 47, wherein the in vivo half-life of the composition is longer than the in vivo half-life of the compound alone.

49. The composition according to any one of claims 1 to 48, wherein the composition is a sustained-release composition.

50. The composition according to any one of claims 1 to 49, wherein the composition is in an intravenous dosage form.

51. A method for treating a fungal infection, comprising treating the fungal infection by administering to a subject in need of treatment for the fungal infection a therapeutically effective amount of the composition according to any one of claims 1 to 50.

52. The method according to claim 51, wherein the composition is administered intravenously.

53. The method according to claim 51 or 52, wherein the subject is a mammal; or a primate, dog, cat, or cow; or a human; or a human.

54. Use of the composition according to any one of claims 1 to 50 in the manufacture of a medicament for treating a fungal infection.

55. The use according to claim 54, wherein the medicament is in an intravenous dosage form.

56. The composition according to any one of claims 1 to 50 for use in the treatment of a fungal infection.

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