Hybrid amide derivatives of amphotericin B

Abstract

Disclosed are C16 amide derivatives of C2'-epi-amphotericin B (C2'epiAmB) and C16 amide derivatives of amphotericin B (AmB), which are characterized by reduced toxicity and improved clinical efficacy compared to AmB. Also disclosed are pharmaceutical compositions containing either type of C16 amide derivatives and methods of treatment using either type of C16 amide derivatives; and methods of making the C16 amide derivatives of C2'-epi-amphotericin B.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 884,464, filed August 8, 2019, and U.S. Provisional Patent Application No. 62 / 951,753, filed December 20, 2019, the contents of which are incorporated herein by reference in their entireties. GOVERNMENT SUPPORT

[0002] This invention was made with Government support under Grant Nos. GM118185 and AI135812 awarded by the National Institutes of Health. The Government has certain rights in this invention. [Background technology]

[0003] Morbidity and mortality from invasive fungal infections are substantial and are caused primarily by fungal pathogens from two genera: Candida and Aspergillus. Candida species are the fourth most common pathogen isolated in all bloodstream infections. Treatment of invasive candidiasis has a limited success rate (50-70%), and this success is typically only in the healthiest patients. Mortality attributable to invasive candidiasis is substantial (20-30%). The incidence of invasive aspergillosis due to A. fumigatus has increased threefold in the last decade, and its mortality rate has risen by more than 300%. Furthermore, the treatment success rate of current therapies for invasive aspergillosis is low at 40-50%. Invasive aspergillosis is consistently the leading cause of death in immunocompromised patients, but invasive fungal infections (fusariosis, scedosporosis, and mucromycosis) have even higher mortality rates and lack effective treatment options. The current guideline-recommended first-line treatment for invasive aspergillosis as well as most other invasive fungal infections is the triazole antifungal voriconazole. However, pan-triazole resistance in Aspergillus has reached as high as 30% in some geographic regions and in certain high-risk patient populations. In response to this lack of effective treatments, the Infectious Diseases Society of America has highlighted A. fumigatus as one of six pathogens for which a “substantial breakthrough is urgently needed.”

[0004] Amphotericin B (AmB) is a very promising starting point because the drug has potent and dose-dependent fungicidal activity against a broad range of fungal pathogens and has evaded resistance for over half a century. AmB's fungicidal activity, unlike its fungistatic activity, is essential in immunocompromised patients who lack a robust immune system to clear infections. Its broad antifungal activity is especially important in critically ill patients where the pathogen cannot be identified and immediate empirical treatment is required. An international expert panel has mandated that new therapeutic approaches centered around AmB that do not have resistance problems are needed. The problem is that AmB is so toxic that it is limited to use at low doses, which often fail to eradicate the disease.

[0005] We have succeeded in elucidating a new mechanism that could be called a paradigm shift for AmB, which had eluded the scene for half a century. Previous studies reported that AmB binds to sterols, and this binding was thought to primarily drive the formation of membrane permeable pores that kill both fungal and human cells. However, after a decade of atomic-level studies with intensive synthesis of this natural product and state-of-the-art SSNMR experiments, we instead found that AmB kills both fungal and human cells primarily by forming a cytocidal extramembrane sterol sponge. This large aggregate sits on the surface of the lipid bilayer and rapidly extracts membrane sterols, leading to cell death. No membrane permeabilization is required. Based on this new mechanism and increasingly refined structural information, it is proposed that a small molecule-based ligand-selective allosteric effect may enable the selective binding of ergosterol over cholesterol. Guided by this model, the elimination of cholesterol binding and therefore toxicity to mammals was achieved in the form of a new derivative, C2'epiAmB.

[0006] However, C2'epiAmB is limited by its lack of efficacy against many clinically important yeasts and filamentous fungi. AmB derivatives that retain potent, broad-spectrum and resistance-evading fungicidal activity, but without dose-limiting toxicity, would enable new high-dose treatment paradigms with improved clinical efficacy. Summary of the Invention [Means for solving the problem]

[0007] In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, 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, substituted or unsubstituted 5-10 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 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 It is an alkyl.

[0008] In certain embodiments, there is provided a compound of formula (II) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, 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, substituted or unsubstituted 5-10 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 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 It is an alkyl.

[0009] In certain aspects, a pharmaceutical composition is provided that comprises a compound provided herein; and a pharma- ceutically acceptable carrier.

[0010] In certain aspects, methods are provided for treating a fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, thereby treating the fungal infection.

[0011] In certain embodiments, a method is provided for preparing the C16 amide of C2'-epi-amphotericin B according to the transformations depicted in Scheme 1: [ka] In the scheme, 1 is, [ka] represents The base is a tertiary amine (e.g., a trialkylamine [such as EtN]); The peptide coupling reagent is a peptide coupling reagent used in solid phase peptide synthesis (e.g., PyBOP, BOP, HATU, HBTU, DEPBT, DCC, or EDCI); R is H or an amine protecting group (e.g., a carbamate protecting group selected from the group consisting of Fmoc, t-Boc, alloc, and Cbz); 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, substituted or unsubstituted 5-10 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. [Brief description of the drawings]

[0012] [Figure 1A] 1 shows the chemical structures of amphotericin B, ergosterol, the major fungal sterol, and cholesterol, the major human sterol. [Figure 1B] A two-step "sterol sponge" model for the cell killing action of AmB is presented. [Figure 2A] 1 depicts the chemical structures and biophysical activities of AmB, AmdeB, C2'deOAmB, and C2'epiAmB. [Figure 2B] FIG. 1 depicts the biophysical activities of AmB, AmdeB, C2'deOAmB, and C2'epiAmB in primary human renal epithelial cells. [Figure 2C]Ergosterol and cholesterol activities of AmB, AmdeB, C2'deOAmB, and C2'epiAmB are shown. [Figure 3A] X-ray crystal structure of N-iodoacyl AmB. [Figure 3B] A proposed structural model of the AmB-Erg complex. A similar model has been proposed for cholesterol. [Figure 4] 1 represents the 11-step synthesis of C2'epiAmB from AmB. [Figure 5A] Sterol binding is shown. The sterol sponge formed in vitro from AmB was titrated with ergosterol and analyzed by UV-Vis spectroscopy. [Figure 5B] Sterol binding is shown. The sterol sponge formed in vitro from AmB was titrated with cholesterol and analyzed by UV-Vis spectroscopy. [Figure 5C] Sterol binding is shown. The sterol sponge formed in vitro from C2'epiAmB was titrated with ergosterol and analyzed by UV-Vis spectroscopy. [Figure 5D] Sterol binding is shown. The sterol sponge formed in vitro from C2'epiAmB was titrated with cholesterol and analyzed by UV-Vis spectroscopy. [Figure 6] 1 depicts toxicity data for AmB-deoxycholate and C2′epiAmB-deoxycholate in mice. [Figure 7] 1 presents toxicity data for AmBisome® in head-to-head comparison with C2'epiAmB as determined by renal genotoxicity biomarkers. [Figure 8A] We show the in vitro antifungal activity of AmB and C2'epiAmB against a broad range of fungal pathogens in a panel of Candida and Aspergillus isolates. [Figure 8B] We show the in vitro antifungal activity of AmB and C2′epiAmB against a broad range of fungal pathogens in a panel of Aspergillus spp. isolates. [Figure 8C] We show the in vitro antifungal activity of AmB and C2'epiAmB against a broad range of fungal pathogens in a panel of clinically relevant invasive molds. [Figure 9] MICs of AmB and C2'epiAmB against C. albicans with ((+)erg) and without ((-)erg) precomplexation with ergosterol are shown. [Figure 10] FIG. 1 depicts the efficacy of AmB and C2′epiAmB in a mouse model of invasive candidiasis. [Figure 11] 1 is a graph showing the cell-killing kinetics of AmB and C16 amide AmB (AmBHEA) against Candida albicans SN250 (C. albicans SN250). [Figure 12] 1 is a scheme showing the rational design of C16 amide C2'epiAmB with both potency and reduced toxicity. [Figure 13A] 1 is a UV-Vis graph showing the binding of AmB to cholesterol. [Figure 13B] 1 is a UV-Vis graph showing the binding of C2'epiAmB to cholesterol. [Figure 13C] FIG. 1 is a UV-Vis graph showing the binding of C16 amide C2′epiAmB (C2′epiAmBHEA; an amide formed from (2-hydroxyethyl)amine and C2′epiAmB) to cholesterol. [Figure 14] 1 shows the use of an AmBisome®-like formulation to enhance the solubility of C2′epiAmB and C16 amide C2′epiAmB. [Figure 15] Studies in mice with AmB, C2'epiAmB, and C16 amide C2'epiAmB (C2'epiAmB-L-His) in an AmBisome®-like formulation are described. [Figure 16]FIG. 1 is a graph showing the effect of the size of the aliphatic ring and aliphatic acyclic chain at the C16 position on activity. [Figure 17] FIG. 1 is a graph showing the effect of polar functional groups at C16 on activity. [Figure 18] 1 is a graph showing the pharmacokinetics of Compound BA compared to Amphotericin B. [Figure 19] FIG. 1 is a graph showing changes in expression of biomarkers of kidney injury by RT-PCR upon treatment with Fungizone, AmBisome, or Sfu-AM220. [Figure 20] FIG. 1 is a graph showing the efficacy of compounds BA, C2′epiAmB and AmBisome as defined by colony forming units (CFU). [Figure 21A] 1 shows in vitro and in vivo safety data for compound BA. [Figure 21B] 1 shows in vitro and in vivo safety data for compound BA. [Figure 21C] 1 shows in vitro and in vivo safety data for compound BA. [Figure 21D] 1 shows in vitro and in vivo safety data for compound BA. [Figure 22] 1 shows in vivo mouse pharmacokinetic data for Compound BA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Amphotericin B (AmB) is a polyene macrolide with a mycosamine adduct, and the complete compound has the following structure: [ka]

[0014] AmB is typically obtained from strains of Streptomyces nodosus. It is currently approved for clinical use in the United States for the treatment of progressive, potentially life-threatening fungal infections, including systemic or deep tissue candidiasis, aspergillosis, cryptococcosis, blastomycosis, coccidioidomycosis, histoplasmosis, and mucormycosis, among others. It is generally formulated for intravenous injection. Amphotericin B is commercially available as Fungizone® (Squibb), Amphocin® (Pfizer), Abelcet® (Enzon), and AmBisome® (Astellas). Due to its undesirable toxic side effects, dosage is generally limited to a maximum of about 1.0 mg / kg / day, with the total cumulative dosage in humans limited to no more than about 3 g.

[0015] AmB kills both fungal and human cells by forming a cytocidal extramembrane sterol sponge. Anderson, TM et al., Nat Chem Biol 2014, 10 (5), 400-6. This large aggregate sits at the surface of the lipid bilayer and rapidly extracts membrane sterols, triggering cell death. Membrane permeabilization is not required. Based on this mechanism, a small molecule-based ligand-selective allosteric effect would allow selective binding of ergosterol over cholesterol, eliminating the mammalian toxicity of AmB (in the form of C2'epiAmB). See Wilcock, BC et al., J Am Chem Soc 2013, 135 (23), 8488-91. The present invention provides a novel method for determining the binding of AmB to the sterol sponge, which is a novel mechanism for determining the binding of AmB to the sterol sponge. D We disclose a novel method for the treatment of rheumatoid arthritis, which provides quantitative and mechanistically based biophysical parameters to guide the rational optimization of the therapeutic index of this clinically important natural product.

[0016] The present invention relates, at least in part, to the inventors' discovery of further derivatives of AmB that also feature an improved therapeutic index compared to AmB. The various derivatives, i.e., the compounds of the present invention, may be semi-synthetic or fully synthetic. One aspect of the present invention is the development of novel synthetic derivatives of AmB that retain the strong binding of ergosterol but do not exhibit detectable binding of cholesterol. The derivatives retain fungicidal activity against many yeasts and molds but do not exhibit detectable mammalian toxicity. This demonstrates that differential binding of ergosterol over cholesterol is possible, providing a non-toxic variant of AmB that maintains desirable antifungal properties. The compounds of the present invention enable new high-dose therapeutic strategies to eradicate life-threatening invasive fungal infections with significantly improved safety profiles.

[0017] The compounds of the present invention and pharmaceutical compositions of the present invention are useful for inhibiting fungal growth. In one embodiment, an effective amount of the compounds of the present invention is contacted with fungi, thereby inhibiting fungal growth. In one embodiment, the compounds of the present invention or pharma- ceutically acceptable salts thereof are added or included in tissue culture medium.

[0018] The compounds of the present invention and pharmaceutical compositions of the present invention are useful for treating fungal infections in subjects. In one embodiment, a therapeutically effective amount of a compound of the present invention or a pharma- ceutical acceptable salt thereof is administered to a subject in need thereof, thereby treating a fungal infection.

[0019] Yeasts are eukaryotic organisms classified in the fungal kingdom. Fungi include larger organisms including yeasts, molds, and mushrooms. Yeasts and molds are clinically relevant as infectious pathogens. Yeasts are usually described as budding fungi. Of particular importance in the context of the present invention are yeast species that can cause infections in mammalian hosts. Such infections most commonly occur in immunocompromised hosts, such as those with compromised barriers to infection (e.g., burn patients) and those with compromised immune systems (e.g., those undergoing chemotherapy or immunosuppressive therapy, those infected with HIV). Pathogenic yeasts include, but are not limited to, various species of the genera Candida and Cryptococcus. Of particular note among the pathogenic yeasts of the Candida genus are C. albicans, C. tropicalis, C. stellatoidea, C. glabrata, C. krusei, C. parapsilosis, C. guilliermondii, C. viswanathii, and C. lusitaniae. The genus Cryptococcus includes, among others, Cryptococcus neoformans. Yeasts can cause infections of mucous membranes, such as infections of the oral cavity, esophagus, and vagina in humans, as well as infections of bone, blood, urogenital tract, and central nervous system, This list is illustrative and in no way limiting.

[0020] Many fungi (other than yeast) can cause infections in mammalian hosts. Such infections occur most commonly in immunocompromised hosts, such as those with compromised barriers to infection (e.g., burn patients) or compromised immune systems (e.g., those undergoing chemotherapy or immunosuppressive therapy, HIV-infected hosts). 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 the above are Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis. Fungi can cause systemic and deep tissue infections in the lungs, bones, blood, genitourinary tract, and central nervous system, to name a few. Some fungi are responsible for skin and nail infections.

[0021] definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified as set forth in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside pages, and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in the following publications: 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.

[0022] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched 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) and the formation and crystallization of chiral salts; alternatively, preferred isomers can be prepared by asymmetric synthesis. See, e.g., 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).

[0023] The present invention further includes the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0024] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , 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 Alkyl is intended to be included.

[0025] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention. In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it is also understood that any of the moieties defined below may be substituted with various substituents, and each definition is intended to include such substituted moieties within the scope as described below. Unless otherwise indicated, the term "substituted" is defined as described below. Furthermore, it is understood that the terms "group" and "radical" may be considered interchangeable as used herein. The articles "a" and "an" may be used herein to refer to one or more (i.e., at least one) of the grammatical object of the article. By way of example, "analog" means one analog or multiple analogs.

[0026] "Alkyl" means the radical of a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, an 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-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10It is alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), i-Pr(-CH(CH3)2), n-Pr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0027] "Alkylene" refers to an alkyl group from which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCH-), pentylene (-CHCHCHCHCH-), hexylene (-CHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., 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)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-)), and the like.

[0028] "Alkenyl" refers to the radical of a straight or branched chain hydrocarbon group 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) ("C 2-20 In certain embodiments, an alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). 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. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0029] "Alkenylene" refers to an alkenyl group from which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. 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, e.g., those 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)-), and the like.

[0030] "Alkynyl" refers to the radical of a straight-chain or branched-chain 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) ("C 2-20 In certain embodiments, alkynyl does not contain a double bond. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 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. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0031] "Alkynylene" refers to a straight chain alkynyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0032] The term "heteroalkyl," as used herein, refers to an alkyl 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) in the parent chain, where the heteroatom or heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the heteroatom or heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group is a saturated group having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms ("heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroalkyl group. 1-10 It is an alkyl.

[0033] The term "heteroalkenyl," as used herein, refers to an alkenyl 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 the heteroatom or heteroatoms are inserted between adjacent carbon atoms in a parent carbon chain and / or the heteroatom or heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having 2-10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-10 In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and two heteroatoms ("heteroC 2-4 In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2-3 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0034] The term "heteroalkynyl" as used herein 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 the heteroatom or heteroatoms are inserted between adjacent carbon atoms in a parent carbon chain and / or the heteroatom or heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group refers to a group having 2-10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-10In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and two heteroatoms ("heteroC 2-4 In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("heteroC 2-3 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0035] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" refer to the divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is provided for a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbons in a linear carbon divalent chain. "Alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" groups may be substituted or unsubstituted with one or more substituents described herein.

[0036] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 π electrons are shared in the ring arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to indicate 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, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0037] In certain embodiments, the aryl group is halo, C 1-8 Alkyl, C 1-8 Haloalkyl, cyano, hydroxy, C 1-8 The alkyl group is substituted with one or more groups selected from alkoxy and amino.

[0038] Representative examples of substituted aryl include: [ka] In the formula, R 56 and R 57 may be hydrogen, and R56 and R 57 At least one of the 1-8 Alkyl, C 1-8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1-8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R 57 and R 56 may combine to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, which optionally contains one or more heteroatoms selected from the group N, O, or S. R 60 and R 61 are each independently hydrogen, C 1-8 Alkyl, C 1-4 Haloalkyl, C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 Aryl, Substituted C 6-10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0039] Other representative aryl groups having a fused heterocyclyl group include: [ka] where each W is C(R 66 )2, NR 66 , O and S; each Y is selected from carbonyl, NR 66, O and S; R 66 are independently hydrogen, C 1-8 Alkyl, C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.

[0040] "Fused aryl" refers to an aryl that shares two of its ring carbons with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0041] "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.

[0042] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 π electrons are shared in the ring arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided within the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring, in such cases the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, and the point of attachment can be at either the aryl or heteroaryl ring, and in such cases the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) can have the point of attachment at either ring, i.e., either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0043] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided within the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided within the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided within the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a 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.

[0044] 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-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolinyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0045] Representative examples of heteroaryls include: [ka] where each Y is carbonyl, N, NR 65 , O and S; R 65 are independently hydrogen, C 1-8 Alkyl, C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.

[0046] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0047] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3-10 Carbocyclyl refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a 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), and the like. Exemplary C 3-8 The carbocyclyl group is the aforementioned C 3-6Examples of carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 The carbocyclyl group is the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the above examples show, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or includes fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in which case the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 It is a carbocyclyl.

[0048] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). C 5-6 Examples of carbocyclyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of carbocyclyl groups include the above-mentioned C 5-6 Examples include carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of carbocyclyl groups include the above-mentioned C 3-6 Carbocyclyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 It is a carbocyclyl.

[0049] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl"), or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0050] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 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 one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. 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 pyrrolyl-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 (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0052] Particular examples of heterocyclyl groups are shown in the following illustrative examples: [ka] where each W is CR 67 , C(R 67 )2, NR 67 , O and S; each Y is selected from NR 67 , O and S; R 67 are independently hydrogen, C 1-8 Alkyl, C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, carbocyclyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. Substituents include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0053] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl (e.g., heteroalkyl), carbocyclyl (e.g., heterocyclyl), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheteroalkenyl), having 1 to 5, especially 1 to 3, heteroatoms.

[0054] "Acyl" is the radical -C(O)R 20 where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to any group consisting of R 20 is an acyl group, where the aryl group is not hydrogen. Representative acyl groups include 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 (C 6-10 Aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C 3-10 carbocyclyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R is a C substituted with halo or hydroxy. 1-8 Alkyl; or C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an 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 substituted with haloalkoxy or hydroxy.

[0055] "Acylamino" is the radical -NR 22 C(O)R 23 Here, R 22 and R 23 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein; 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. Certain exemplary "acylamino" groups are -NR 24 C(O)-C 1-8 Alkyl, -NR 24 C(O)-(CH2) t (C 6-10 Aryl), -NR 24 C(O)-(CH2) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH2) t (C 3-10 carbocyclyl), and -NR 24 C(O)-(CH2) t (4-10 membered heterocyclyl) (wherein t is an integer of 0 to 4; each R 24 are independently H or C 1-8 In certain embodiments, R 25 is H or C substituted with halo or hydroxy 1-8 Alkyl;C 3-10Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an 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; R 26 is H or C substituted with halo or hydroxy 1-8 Alkyl;C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an 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 hydroxyl; 25 and R 26 At least one of the is other than H.

[0056] "Acyloxy" is the group -OC(O)R 27 where R 27 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 is a halo or hydroxy substituted C 1-8 Alkyl;C 3-10Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an 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.

[0057] "Alkoxy" is -OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., alkoxy having 1 to 6 carbon atoms. More particular alkoxy groups have 1 to 4 carbon atoms.

[0058] In certain embodiments, R 29 is amino, substituted amino, C 6-10 Aryl, aryloxy, carboxyl, cyano, C 3-10 A group having one or more substituents selected from the group consisting of carbocyclyl, 3-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example 1-5 substituents, particularly 1-3 substituents, and particularly 1 substituent. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C 6-10Aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t C 3-10 carbocyclyl), and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, carbocyclyl or heterocyclyl groups present are themselves 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 It may be substituted by haloalkoxy or hydroxy. Particular exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0059] "Amino" refers to the radical -NH2.

[0060] "Substituted amino" refers to a 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C 1-8 Alkyl, C 3-8 Alkenyl, C 3-8 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3-10 carbocyclyl; or halo or hydroxy substituted C 1-8 Alkyl; halo or hydroxy substituted C 3-8Alkenyl; C substituted with halo or hydroxy 3-8 Alkynyl, or -(CH2) t (C 6-10 Aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C 3-10 carbocyclyl), or -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is an 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 or both R groups together form an alkylene group.

[0061] Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C 1-8 Alkyl, -NR 39 -(CH2) t (C 6-10 Aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C 3-10 carbocyclyl), and -NR 39 -(CH2) t (4-10 membered heterocyclyl), in which t is an integer of 0 to 4, for example 1 or 2, and each R 39 are independently H or C 1-8 any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, carbocyclyl, or heterocyclyl group present may itself be 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 It may be substituted by haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0062] "Azide" refers to the radical -N3.

[0063] "Carbamoyl" or "amide" refers to the radical -C(O)NH2.

[0064] A "substituted carbamoyl" or "substituted amide" is a group -C(O)N(R 62 ) 2, wherein each R 62 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 62 At least one of R is not hydrogen. 62 , H, C 1-8 Alkyl, C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 aryl, aralkyl, 5- to 10-membered heteroaryl, and heteroaralkyl; or C substituted with halo or hydroxy. 1-8 Alkyl; or C 3-10 Carbocyclyl, 4-10 membered heterocyclyl, C 6-10 Aryl, aralkyl, 5- to 10-membered heteroaryl, or heteroaralkyl (each of which is an 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 haloalkoxy or hydroxy; provided that at least one R 62 is other than H.

[0065] Exemplary "substituted carbamoyl" groups include, but are not limited to, -C(O)NR 64 -C 1-8 Alkyl, -C(O)NR 64 -(CH2) t (C 6-10 Aryl), -C(O)N 64 -(CH2) t (5-10 membered heteroaryl), -C(O)NR 64 -(CH2) t (C 3-10 carbocyclyl), and -C(O)NR 64 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and each R 64 are independently H or C 1-8 alkyl, and any aryl, heteroaryl, carbocyclyl or heterocyclyl groups present are themselves 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 It may be substituted by haloalkoxy or hydroxy.

[0066] "Carboxy" refers to the radical -C(O)OH.

[0067] "Cyano" refers to the radical -CN.

[0068] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0069] "Hydroxy" refers to the radical -OH.

[0070] "Nitro" refers to the radical -NO2.

[0071] "Carbocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with 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.

[0072] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0073] "Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple fused rings with at least one, and especially one or two, sites of olefinic unsaturation, including fused and bridged ring systems. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[0074] "Fused cycloalkenyl" refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring, and having olefinic unsaturation arranged in such a way as to confer aromaticity to the cycloalkenyl ring.

[0075] "Ethylene" refers to a substituted or unsubstituted --(CC)--.

[0076] "Ethenyl" refers to a substituted or unsubstituted -(C=C)-.

[0077] "Ethynyl" is Points to TIFF0007636004000010.tif16115.

[0078] A "nitrogen-containing heterocyclyl" group refers to a 4-7 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-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0079] "Thioketo" refers to the =S group.

[0080] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon substitution provides for a stable compound (e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents can be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that result in the formation of a stable compound. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0081] 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 , -COH, -CHO, -C(OR cc )2, -CO2R aa , -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)(R aa)2, -OP(=O)(ORCC)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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; Or, the two geminal hydrogens on the carbon atom can be substituted with the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced by; R aa Each instance of 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa and wherein the groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R bb Each instance 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bband wherein the groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc and wherein the groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R dd Each example is independently a 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 )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -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 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd the substituents together may form =O or =S; R ee Each instance of 1-6 Alkyl, C 1-6Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R ff Each instance of is independently hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff and wherein the groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R gg Each example is independently a 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, -SC1-6 Alkyl, -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(=O)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 1-6Alkyl), -C(=S)SC 1-6 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 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents together may form =O or =S; where X - is the counter ion.

[0082] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 2- Included are sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0083] Nitrogen atoms may be substituted or unsubstituted where valence permits, and include 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl; or two R cc and wherein the groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc , and R dd is as defined above.

[0084] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0085] Other definitions "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of a federal or state government or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, or more specifically, in humans.

[0086] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharma- ceutically acceptable and possess 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) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with 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-methylsulfonic acid, ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, where the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0087] "Pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66 (1):1-79 (January 77)).

[0088] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

[0089] "Pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to produce a parent molecule of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR and -CH2OR radicals, where R is independently selected for each occurrence from alkyl, trialkylsilyl, carbocyclic aryl, or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

[0090] "Prodrug" refers to a compound that contains a derivative of the compound of the present invention that has a cleavable group and becomes a compound of the present invention that is pharmacologic in vivo by solvolysis or under physiological conditions. Such examples include, but are not limited to, choline ester derivatives, etc., and N-alkylmorpholine esters, etc. Other derivatives of the compounds of the present invention have activity in both their acid form and acid derivative form, but often provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms in the acid-sensitive form (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acid groups pendant on the compounds of the present invention are specific prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or (alkoxycarbonyl)oxy)alkyl esters. 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 It is an aryl alkyl ester.

[0091] "Solvate" refers to a form of a compound associated with a solvent or water (also called a "hydrate"), usually by solvolysis. This physical association involves hydrogen bonding. Common solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form, solvated or hydrated. Suitable solvates include pharma- ceutically acceptable solvates, such as hydrates, including both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate is isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0092] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, toddlers, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain aspects, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0093] "Effective amount" means an amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. "Effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. "Therapeutically effective amount" refers to an amount effective for therapeutic treatment. "Prophylactically effective amount" refers to an amount effective for prophylactic treatment.

[0094] "Preventing" or "prevention" or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., not developing at least one clinical symptom of the disease in a subject who has not yet been exposed to a disease-causing agent or who is susceptible to the disease prior to the onset of the disease).

[0095] "Prophylaxis" is related to "prevention" and refers to measures or procedures aimed at preventing, rather than treating or curing, a disease. Non-limiting examples of preventive measures may include the administration of a vaccine; the administration of low molecular weight heparin to hospitalized patients who are at risk of thrombosis due to immobility; and the administration of antimalarial drugs such as chloroquine prior to visiting areas where malaria is endemic or at high risk of contracting malaria.

[0096] "Treating" or "treatment" or "therapeutic treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., halting the disease or reducing at least one sign, degree or severity of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0097] As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can contain, for example, deuterium ( 2 H or D), carbon 13 ( 13 C), nitrogen 15( 15In compounds with such isotopic substitutions, the following atoms may vary, if present: any hydrogen may be replaced by any other hydrogen; 2 H / D, any carbon may be 13 C or any nitrogen 15 It will be understood that the presence and location of such atoms may be determined within the skill of one of ordinary skill in the art. Similarly, the present invention includes the preparation of isotopic variants using radioactive isotopes, for example, when the resulting compounds may be used in drug and / or substrate tissue distribution studies. The radioactive isotope tritium ( 3 H) and carbon-14 ( 14 C) is particularly useful for this purpose in view of its ease of incorporation and ease of detection. 11 C. 18 F, 15 O. 13 Compounds can also be prepared substituted with positron emitting isotopes, such as N, which are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. All isotopic variants of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0098] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0099] Stereoisomers that are not mirror images of one another are called "diastereomers" and those that are non-superimposable mirror images of each other are called "enantiomers". If a compound has an asymmetric center and, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0100] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, differing in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium by the movement of electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomers can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0101] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0102] As used herein, unless otherwise indicated, the term "enantiomerically pure R compounds" refers to at least about 95% by weight R-compounds and up to about 5% by weight S-compounds, at least about 99% by weight R-compounds and up to about 1% by weight S-compounds, or at least about 99.9% by weight R-compounds and up to about 0.1% by weight S-compounds. In certain embodiments, the weights are based on the total weight of the compounds.

[0103] As used herein, unless otherwise indicated, the term "enantiomerically pure S-compounds" or "S-compounds" refers to at least about 95% by weight S-compounds and up to about 5% by weight R-compounds, at least about 99% by weight S-compounds and up to about 1% by weight R-compounds, or at least about 99.9% by weight S-compounds and up to about 0.1% by weight R-compounds. In certain embodiments, the weights are based on the total weight of the compounds.

[0104] In the compositions provided herein, the enantiomerically pure compound, or its pharma- ceutically acceptable salt, solvate, hydrate or prodrug, may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound may comprise, for example, about 90% of excipients and about 10% of an enantiomerically pure R compound. In some embodiments, the enantiomerically pure R compound in such a composition may comprise, 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 comprising an enantiomerically pure S-compound may comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure S compound. In some embodiments, the enantiomerically pure S compound in such a composition may comprise, 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 some embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0105] The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0106] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, of the same. The methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art.

[0107] Those skilled in the art of organic synthesis will recognize that the maximum number of heteroatoms in a chemically feasible and stable heterocyclic ring, whether it is aromatic or non-aromatic, depends on the ring size, the degree of unsaturation, and the valence of the heteroatoms. In general, a heterocyclic ring can have from 1 to 4 heteroatoms, so long as the heteroaromatic ring is chemically feasible and stable.

[0108] Compounds of the Invention In certain embodiments, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, 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, substituted or unsubstituted 5-10 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 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 It is an alkyl.

[0109] In certain embodiments, 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 It is aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0110] In certain embodiments, R 1 and R 2 are independently hydrogen, unsubstituted C 1-6 Alkyl, alkoxy C 1-6 Alkyl, haloC 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 It is a carbocyclyl, an unsubstituted 3- to 10-membered heterocyclyl, or a hydroxyl 3- to 10-membered heterocyclyl.

[0111] In certain embodiments, R 1 and R 2 At least one of the groups is hydrogen.

[0112] In certain embodiments, R 1 and R 2 At least one of R is hydrogen, and 1 and R 2 Neither of these are hydrogen.

[0113] In certain embodiments, R 1 and R 2 together with the nitrogen to which they are attached form a substituted or unsubstituted 3- to 10-membered heterocyclyl.

[0114] In certain embodiments, R 1 and R 2 together with the nitrogen to which they are attached form an unsubstituted 3- to 10-membered heterocyclyl, amino 3- to 10-membered heterocyclyl, hydroxyl 3- to 10-membered heterocyclyl, or heterocyclyl 3- to 10-membered heterocyclyl.

[0115] In certain embodiments, R 3 Ha-NR 5 R 6 where: 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 5-10 membered heteroaryl; f is selected from the group consisting of 2-alken-1-yl, tert-butyl, benzyl, and fluorenylmethyl; 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.

[0116] In certain 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 It is aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0117] In certain embodiments, R 5 and R 6 are independently hydrogen or C(O)OR f It is.

[0118] In certain embodiments, R f is fluorenylmethyl.

[0119] In certain embodiments, R 5 and R 6 At least one of the groups is hydrogen.

[0120] In certain embodiments, R 5 and R 6 are both hydrogen.

[0121] In certain embodiments, R 4 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 2-6 It is alkenyl.

[0122] In certain embodiments, R 4 is hydrogen, haloC 1-6 Alkyl or unsubstituted C 2-6 It is alkenyl.

[0123] In certain embodiments, R 4 is hydrogen.

[0124] In certain embodiments, there is provided a compound of formula (II) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, 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, substituted or unsubstituted 5-10 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 a substituted or unsubstituted amino, a substituted or unsubstituted urea, a substituted or unsubstituted carbamate, or a substituted or unsubstituted guanidinyl; R4 is hydrogen or substituted or unsubstituted C 1-6 It is an alkyl.

[0125] In certain embodiments, 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 It is aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0126] In certain embodiments, R 1 and R 2 are independently hydrogen, unsubstituted C 1-6 Alkyl, Hydroxyl C 1-6 Alkyl, Amino C 1-6 Alkyl, unsubstituted C 3-10 It is a carbocyclyl.

[0127] In certain embodiments, R 1 and R 2 At least one of the groups is hydrogen.

[0128] In certain embodiments, R 1 and R 2 At least one of R is hydrogen, and 1 and R 2 Neither of these are hydrogen.

[0129] In certain embodiments, R 3 Ha-NR 5 R 6 where: R 5 and R 6 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C2-6 Alkynyl, substituted or unsubstituted C 3-10 Carbocyclyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, or a substituted or unsubstituted 5-10 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.

[0130] In certain 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 5-10 membered heteroaryl; R f is selected from the group consisting of 2-alkene-1-yl, tert-butyl, benzyl and fluorenylmethyl.

[0131] In certain embodiments, R 5 and R 6 are independently hydrogen or C(O)OR f It is.

[0132] In certain embodiments, R f is fluorenylmethyl.

[0133] In certain embodiments, R 5 and R 6 At least one of the groups is hydrogen.

[0134] In certain embodiments, R 5 and R 6 are both hydrogen.

[0135] In certain embodiments, R 4 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 2-6 It is alkenyl.

[0136] In certain embodiments, R 4 is hydrogen, haloC 1-6 Alkyl or unsubstituted C 2-6 It is alkenyl.

[0137] In certain embodiments, R 4 is hydrogen.

[0138] In certain embodiments, a compound selected from the group consisting of: [ka] [ka] [ka] [ka]

[0139] In certain embodiments, a compound selected from the group consisting of: [ka] [ka] [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0140] In certain aspects, a pharmaceutical composition is provided that comprises a compound provided herein; and a pharma- ceutically acceptable carrier.

[0141] In certain embodiments, the pharmaceutical composition is in an intravenous dosage form.

[0142] In certain embodiments, the pharmaceutical composition is in an oral dosage form.

[0143] In certain aspects, a method of treating a fungal infection is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, thereby treating the fungal infection.

[0144] In certain embodiments, the compound is administered intravenously.

[0145] In certain embodiments, the compound is administered orally.

[0146] In certain embodiments, a method is provided for preparing the C16 amide of C2'-epi-amphotericin B according to the transformations depicted in Scheme 1: [ka] In the scheme, 1 is, [ka] represents; The base is a tertiary amine (e.g., a trialkylamine [such as EtN]); The peptide coupling reagent is a peptide coupling reagent used in solid phase peptide synthesis (e.g., PyBOP, BOP, HATU, HBTU, DEPBT, DCC, or EDCI); R is H or an amine protecting group (e.g., a carbamate protecting group selected from the group consisting of Fmoc, t-Boc, alloc, and Cbz); 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, substituted or unsubstituted 5-10 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.

[0147] In certain embodiments, R is H.

[0148] In certain embodiments, R is a carbamate protecting group selected from the group consisting of Fmoc, t-Boc, alloc, and Cbz.

[0149] In certain embodiments, the base is a trialkylamine.

[0150] In certain embodiments, the base is Et3N.

[0151] In certain embodiments, the peptide coupling reagent is PyBOP, BOP, HATU, HBTU, DEPBT, DCC, or EDCI.

[0152] Pharmaceutical Compositions The present invention also provides pharmaceutical compositions and methods for preparing the same.

[0153] One aspect of the present invention is a pharmaceutical composition comprising the compound of the present invention; and a pharmaceutically acceptable carrier. In one embodiment, the present invention is a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to 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 that is combined with an active ingredient to facilitate application. The components of the pharmaceutical composition can also be mixed with the compound of the present invention and with each other in such a manner that there is no interaction that would substantially impair the desired pharmaceutical efficacy.

[0154] In certain embodiments, the pharmaceutical composition is in an intravenous dosage form.

[0155] In certain embodiments, the pharmaceutical composition is in an oral dosage form.

[0156] In certain embodiments, the pharmaceutical composition is a lyophilized preparation of the liposomally intercalated or liposomally encapsulated active compound.

[0157] In certain embodiments, the pharmaceutical composition is a lipid complex of the compound in aqueous suspension.

[0158] The foregoing embodiments of pharmaceutical compositions of the present invention are meant to be illustrative and not limiting.

[0159] A method for preparing such a pharmaceutical composition is also provided, which comprises placing a compound of the invention, or a pharma- ceutically acceptable salt thereof, in a pharma- ceutically acceptable carrier.

[0160] Methods of the Invention The compounds of the present invention are useful for inhibiting the growth of fungi and yeast, particularly including fungi and yeast that are clinically important as pathogens. Advantageously, the compounds of the present invention have an improved therapeutic index compared to AmB, thereby providing an agent with improved efficacy and reduced toxicity compared to AmB. The compounds of the present invention are useful in methods for treating fungal and yeast infections, particularly including systemic fungal and yeast infections. The compounds of the present invention are also useful in the manufacture of medicaments for treating fungal and yeast infections, particularly including systemic fungal and yeast infections. The present invention further provides the use of the compounds of the present invention for the treatment of fungal and yeast infections, particularly including systemic fungal and yeast infections.

[0161] One aspect of the invention is a method of treating a fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, thereby treating the fungal infection.

[0162] As used herein, "inhibit" or "inhibition" means to reduce by an objectively measurable amount or extent compared to a control. In one embodiment, inhibit or inhibit means to reduce by at least a statistically significant amount compared to a control. In one embodiment, inhibit or inhibit means to reduce by at least 5 percent compared to a control. In various individual embodiments, inhibit or inhibit means to reduce by at least 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, or 95 percent (%) compared to a control.

[0163] As used herein, the terms "treat" and "treating" refer to performing an intervention that results in: (a) preventing a condition or disease from occurring in a subject who may be at risk for developing or predisposed to having the condition or disease, but has not yet been diagnosed as having it; (b) inhibiting the condition or disease, e.g., slowing or halting its onset; or (c) alleviating or ameliorating the condition or disease, e.g., causing regression of the condition or disease. In one embodiment, the terms "treat" and "treatment" refer to performing an intervention that results in: (a) inhibiting the condition or disease, e.g., slowing or halting its onset; or (b) alleviating or ameliorating the condition or disease, e.g., causing regression of the condition or disease. For example, in one embodiment, the terms "treat" and "treatment" refer to performing an intervention that results in: (a) inhibiting the condition or disease, e.g., slowing or halting its onset; or (b) alleviating or ameliorating the fungal infection, e.g., causing regression of the fungal infection.

[0164] As used herein, "fungal infection" refers to an infection of a subject with a fungus as defined herein. In one embodiment, the term "fungal infection" includes a yeast infection. As used herein, "yeast infection" refers to an infection of a subject with a yeast as defined herein.

[0165] As used herein, "subject" refers to a living mammal. In various embodiments, the subject is a non-human mammal, including, but not limited to, a mouse, a rat, a hamster, a guinea pig, a rabbit, a sheep, a goat, a cat, a dog, a pig, a horse, a cow, or a non-human primate. In one embodiment, the subject is a human.

[0166] As used herein, "subject with fungal infection" refers to a subject that shows at least one objective symptom of fungal infection.In one embodiment, the subject with fungal infection is a subject that has been diagnosed with fungal infection and is in need of treatment.The method of diagnosing fungal infection is well known and does not need to be described in detail here.

[0167] As used herein, "subject with yeast infection" refers to a subject that shows at least one objective symptom of yeast infection.In one embodiment, a subject with yeast infection is a subject that is diagnosed with yeast infection and needs treatment.Methods for diagnosing yeast infection are well known and need not be described in detail here.

[0168] In certain embodiments, the compound is administered intravenously.

[0169] In certain embodiments, the compound is administered orally.

[0170] In certain embodiments, the compound is administered systemically.

[0171] In certain embodiments, the compound is administered parenterally.

[0172] In some embodiments, the compound is administered intraperitoneally.

[0173] In certain embodiments, the compound is administered enterally.

[0174] In certain embodiments, the compound is administered intraocularly.

[0175] In certain embodiments, the compound is administered locally.

[0176] Additional routes of administration of the compounds of the invention are also contemplated by the present invention, including, but not limited to, intravesical (bladder), pulmonary, and intrathecal.

[0177] As used herein, the phrase "effective amount" refers to any amount sufficient to achieve a desired biological effect.

[0178] As used herein, the phrase "therapeutically effective amount" refers to an amount sufficient to achieve the desired therapeutic effect, for example, an amount sufficient to treat a fungal or yeast infection.

[0179] For any compound described herein, a therapeutically effective amount can generally be initially determined from in vitro studies, animal models, or both in vitro studies and animal models. In vitro methods are well known and include methods such as minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), concentration at which growth is inhibited by 50% (IC 50 ), and the concentration at which proliferation is inhibited by 90% (IC 90 Therapeutically effective amounts may include determining the amount of the compound of the present invention that is administered to the patient, such as the amount of the compound administered to the patient. The therapeutically effective amount may also be determined from human data of the compound of the present invention that has been tested in humans, as well as human data of compounds known to exhibit similar pharmacological activity, such as other related active substances (e.g., AmB). Higher doses may be required for parenteral administration. The applied dose may be adjusted based on the relative bioavailability and potency of the administered compound. It is within the ability of the ordinary skilled artisan to adjust the dose to achieve maximum efficacy based on the methods described herein as well as other methods well known in the art.

[0180] For any compound described herein, the therapeutically effective amount for use in human subjects can be determined first from in vitro studies, animal models, or both in vitro studies and animal models. The therapeutically effective amount for use in human subjects can also be determined from human data of the compound of the present invention tested in humans, as well as human data of compounds known to exhibit similar pharmacological activity, such as other related active agents (e.g., AmB). Parenteral administration may require higher doses. The applied doses can be adjusted based on the relative bioavailability and efficacy of the administered compounds. It is within the capabilities of the ordinary skilled artisan to adjust the dose to achieve maximum efficacy based on the above methods and other methods known in the art.

[0181] Dosage and Formulation The compound of the present invention can be combined with other therapeutic agents.The compound of the present invention and other therapeutic agents can be administered simultaneously or sequentially.When other therapeutic agents are administered simultaneously, they can be administered in the same or separate formulations, but they are administered substantially simultaneously.When the administration of other therapeutic agents and the compound of the present invention is separated in time, the other therapeutic agents are administered sequentially with each other and with the compound of the present invention.The time interval between the administration of these compounds can be several minutes or longer.

[0182] Examples of other therapeutic agents include other antifungal agents, including AmB, as well as other antibiotics, antivirals, anti-inflammatory agents, immunosuppressants, and anti-cancer agents.

[0183] As stated above, "effective amount" refers to any amount sufficient to achieve a desired biological effect. By selecting from a variety of active compounds and weighing factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and preferred mode of administration, in combination with the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that does not cause substantial undesirable toxicity, yet is effective in treating a particular subject. The effective amount for any particular application may 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. Those skilled in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. In general, it is preferred to use the maximum dose, i.e., the highest safe dose 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 patient's peak or sustained plasma levels of the drug. "Dose" and "dosage" are used interchangeably herein.

[0184] In general, the daily oral dose of the active compound will be about 0.01 milligram (mg) / kg / day to 1000 mg / kg / day for human subjects. Oral doses ranging from 0.5 to 50 mg / kg, administered once or several times per day, are expected to produce the desired results. Dosages can be appropriately adjusted to achieve the desired drug levels depending on the mode of administration, such as local or systemic. For example, intravenous administration is expected to be one to several orders of magnitude lower per day. If the response in the subject is inadequate at such doses, even higher doses (or higher effective doses via a different, more localized route of delivery) can be used, as tolerated by the patient. Multiple administrations per day are contemplated to achieve adequate systemic levels of the compound.

[0185] In one embodiment, intravenous administration of the compound of the present invention can typically be 0.1 mg / kg / day to 20 mg / kg / day. Thus, intravenous administration can be similar to or advantageously exceed the maximal tolerated dose of AmB. Intravenous administration can also be similar to or advantageously exceed the daily maximal tolerated dose of AmB. Intravenous administration can also be similar to or advantageously exceed the cumulative maximal tolerated dose of AmB.

[0186] Intravenous dosing may also be similar to or advantageously exceed the maximum recommended dose of AmB. Intravenous dosing may also be similar to or advantageously exceed the maximum recommended daily dose of AmB. Intravenous dosing may also be similar to or advantageously exceed the maximum recommended cumulative dose of AmB.

[0187] For any compound described herein, the therapeutically effective amount can be determined from animal models first. The therapeutically effective dose can also be determined from the human data of the compound of the present invention tested in humans, as well as the human data of compounds known to exhibit similar pharmacological activity, such as other related active substances. Parenteral administration may require higher doses. The applied dose can be adjusted based on the relative bioavailability and efficacy of the administered compound. It is within the ability of a person skilled in the art to adjust the dose to achieve maximum efficacy based on the above methods and other methods well known in the art.

[0188] The formulations of the present invention are administered in pharma- ceutically acceptable solutions, which may ordinarily contain pharma- ceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0189] Amphotericin B is commercially available in many formulations, including deoxycholate-based (sometimes referred to as deoxycholate-based) and lipid-based (including liposomal) formulations. The amphotericin B derivative compounds of the present invention may similarly be formulated, for example, but not limited to, deoxycholate-based and lipid-based (including liposomal) formulations.

[0190] For use in treatment, an effective amount of the compound of the present invention can be administered to a subject by any mode that delivers the compound of the present invention to the desired surface.The administration of the pharmaceutical composition of the present invention can be achieved by any means known to those skilled in the art.The administration route includes, but is not limited to, oral, intravenous, intramuscular, intraperitoneal, subcutaneous, direct injection (e.g., into tumor or abscess), mucosal, pulmonary (e.g., inhalation), and topical.

[0191] For intravenous and other parenteral administration routes, the compounds of the present invention can generally be formulated in the same manner as AmB.For example, the compounds of the present invention can be formulated as lyophilized preparations using deoxycholic acid, as lyophilized preparations of liposome-entrapped or encapsulated active compounds, as lipid complexes in aqueous suspension, or as cholesteryl sulfate complexes.Lyophilized preparations are generally reconstituted in suitable aqueous solutions, such as sterile water or saline, immediately before administration.

[0192] For oral administration, the compounds (i.e., the compounds of the present invention and other therapeutic agents) can be easily formulated by combining the active compounds with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by the subject. Pharmaceutical preparations for oral use can be obtained as solid excipients, and optionally the resulting mixture is milled, and the mixture of granules is processed to obtain tablets or dragee cores, after adding suitable auxiliaries as necessary. Suitable excipients are, in particular, fillers, such as sugars, for example, lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If necessary, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate). Optionally, the oral formulations may also be formulated in saline or buffers, such as EDTA for neutralizing internal acid conditions, or may be administered without a carrier.

[0193] Oral dosage forms of one or more of the above components are also specifically contemplated. One or more of the components may be chemically modified so that oral delivery of the derivatives is effective. In general, the contemplated chemical modifications are the attachment of at least one moiety to the component molecule itself, said moiety allowing for (a) inhibition of acid hydrolysis; and (b) uptake from the stomach or intestine into the bloodstream. Increasing the overall stability of the component(s) and increasing circulation time in the body is also desirable. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4: 185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane.As noted above, preferred for pharmaceutical applications are polyethylene glycol moieties.

[0194] For the component (or derivative), the location of release may be the stomach, the small intestine (the duodenum, jejunum, or ileum), or the large intestine. Those skilled in the art have available formulations that do not dissolve in the stomach but release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment by protecting the compound (or derivative) of the present invention or by releasing the biologically active material beyond the stomach environment, such as in the intestine.

[0195] To ensure complete gastric resistance, a coating impermeable to at least pH 5.0 is essential. Examples of the more common inactive ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (or cellulose acetate phthalate) (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be used as mixed films.

[0196] A coating or mixture of coatings may also be used on tablets that are not intended for protection from the stomach. This includes sugar coatings, or coatings that make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) to deliver dry therapeutics (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material for cachets may be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet triturates, moist massing techniques may be used.

[0197] The therapeutic agent may be included in the formulation as fine multiparticulates in the form of granules or pellets with a particle size of about 1 mm. Also, formulations of the material for capsule administration may be as a powder, as lightly compressed plugs, or as tablets. The therapeutic agent may be prepared by compression.

[0198] Colorants and flavoring agents may all be included. For example, the compounds (or derivatives) of the present invention may be formulated (such as by liposome or microsphere encapsulation) and then further included in an edible product, such as a refrigerated beverage, that includes colorants and flavoring agents.

[0199] The amount of therapeutic agent may be diluted or increased with inert materials. These diluents may include carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts, such as calcium triphosphate, magnesium carbonate, and sodium chloride, may also be used as fillers. Commercially available diluents include Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[0200] Disintegrants may be included in the formulation of the therapeutic agent in solid dosage form. Materials used as disintegrants include, but are not limited to, starch, such as Explotab, a commercial disintegrant based on starch. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid-type carboxymethylcellulose, natural sponge, and bentonite can all be used. Another form of disintegrant is the insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders, and these can include powdered gums such as agar, Karaya, or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0201] Binders can be used to hold the therapeutic agent together to form a hard tablet and can include materials derived from natural products such as acacia, tragacanth, starch and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solutions to granulate the therapeutic agent.

[0202] Anti-frictional agents can be included in the formulation of the therapeutic agent to prevent adhesion during the formulation process. Lubricants can be used as a layer between the therapeutic agent and the die wall, and include, but are not limited to, stearic acid with magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants can also be used, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000 and 6000.

[0203] Glidants may also be added which can improve the flow properties of the drug during formulation and aid in rearrangement during compression. Glidants can include starch, talc, pyrogenic silica, and hydrated aluminosilicates.

[0204] Surfactants may be added as wetting agents to aid in the dissolution of the therapeutic agent into the aqueous environment. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents may also be used and may include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose. These surfactants may be present alone or as a mixture in various ratios in the formulation of the compound or derivative of the present invention.

[0205] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and plasticizers, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Microspheres formulated for oral administration can also be used. Such microspheres are well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0206] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0207] For administration by inhalation, the compounds for use according to the present invention can be conveniently delivered in the form of aerosol spray presentation from pressurized packs or nebulizers using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, for example, gelatin for use in inhalers or insufflators can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0208] Pulmonary delivery of the compounds of the invention (or derivatives thereof) is also contemplated herein. The compounds of the invention (or derivatives) are delivered to the lungs of a mammal upon inhalation and travel across the lung epithelial lining into the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprorelin acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-γ and tumor necrosis factor α), and U.S. Patent No. 5,284,656 to Platz et al. (granulocyte colony-stimulating factor). Methods and compositions for pulmonary delivery of drugs for systemic effect are described in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al.

[0209] A wide range of mechanical devices designed for pulmonary delivery of therapeutic products are contemplated for use in the practice of the present invention, including, but not limited to, nebulizers, metered dose inhalers, and dry powder inhalers, all of which are well known to those skilled in the art.

[0210] Some specific examples of commercially available devices suitable for practicing the present invention are the Ultravent nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Missouri; the Acorn II nebulizer manufactured by Marquest Medical Products, Inc., Englewood, Colorado; the Ventolin metered dose inhaler manufactured by Glaxo, Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler manufactured by Fison, Inc., Bedford, Massachusetts.

[0211] All such devices require the use of a formulation suitable for dispensing the compound (or derivative) of the present invention. Typically, each formulation is specific to the type of device used and may include the use of suitable propellant materials in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also contemplated is the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers. The chemically modified compounds of the present invention may also be prepared in different formulations depending on the type of chemical modification or the type of device used.

[0212] Formulations suitable for use in a nebulizer (either jet or ultrasonic) typically contain a compound (or derivative) of the invention dissolved in water at a concentration of about 0.1-25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for stabilization and regulation of the osmotic pressure of the compound of the invention). Nebulizer formulations may also include a surfactant to reduce or prevent surface-induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.

[0213] Formulations for use in metered dose inhalation devices generally comprise a fine powder containing the compound (or derivative) of the present invention suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material used for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soybean lecithin. Oleic acid may also be useful as a surfactant.

[0214] Formulations for dispensing from powder inhalation devices comprise a dry fine powder containing the compound (or derivative) of the invention and may also contain a bulking agent such as lactose, sorbitol, sucrose, or mannitol in an amount to facilitate dispersion of the powder from the device, for example 50-90% by weight of the formulation. The compound (or derivative) of the invention should advantageously be prepared in a particulate form having a mean particle size of less than 10 micrometers (μm), most preferably 0.5-5 μm, for most effective delivery to the deep lung.

[0215] Nasal delivery of the pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of the pharmaceutical composition of the present invention into the bloodstream immediately after administration of the therapeutic product to the nose, without the need for deposition of the product in the lungs. Formulations for nasal delivery include those using dextran or cyclodextran.

[0216] For nasal administration, a useful device is a small hard bottle with a metered dose sprayer attached.In one embodiment, a metered dose is delivered by drawing a solution of the pharmaceutical composition of the present invention into a chamber of a defined volume, which has an opening dimensioned to aerosolize the aerosol formulation by forming a spray when the liquid in the chamber is compressed.The chamber is compressed to administer the pharmaceutical composition of the present invention.In some embodiments, the chamber is a piston arrangement.Such devices are commercially available.

[0217] Alternatively, a plastic squeeze bottle is used with a hole or opening sized to aerosolize the aerosol formulation by forming a spray when squeezed. The opening is usually at the top of the bottle, and the top is generally tapered to partially fit into the nasal cavity to efficiently administer the aerosol formulation. Preferably, the nasal inhaler provides a metered amount of the aerosol formulation to administer a measured dose of the drug.

[0218] When it is desired to deliver the compound systemically, it can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion).The preparation for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives.The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents.

[0219] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or substances that increase the solubility of the compound, allowing the preparation of highly concentrated solutions.

[0220] Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0221] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0222] In addition to the above-mentioned formulations, the compound can also be formulated as a depot preparation.Such long-acting preparations can be formulated with suitable polymers or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).

[0223] The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0224] Suitable liquid or solid pharmaceutical formulations are, for example, aqueous or saline solutions for inhalation, microencapsulated, cochleated, coated on fine gold particles, encapsulated in liposomes, nebulized, aerosolized, pellets for skin implantation, or dried on a sharp object for scratching the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with sustained release of active compounds, in which excipients and additives and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweetening agents or solubilizers, are conventionally used as described above. Pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990), incorporated herein by reference.

[0225] The compounds of the present invention and optionally other therapeutic agents can be administered as such or in the form of pharmaceutically acceptable salts.When used in medicine, salts should be pharmaceutically acceptable, but pharmaceutically unacceptable salts can be conveniently used to prepare their pharmaceutically acceptable salts.Such salts include, but are not limited to, those 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 or alkaline earth salts, such as sodium, potassium or calcium salts of carboxylic acid group.

[0226] Suitable buffering agents 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); 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).

[0227] Pharmaceutical compositions of the present invention comprise an effective amount of a compound of the present invention, and optionally at least one additional therapeutic agent, in a pharma- ceutically acceptable carrier.

[0228] In particular, therapeutic agents, including but not limited to the compounds of the present invention, may be provided in particles. Particles, as used herein, refer to nanoparticles or microparticles (or possibly larger particles) that may consist entirely or partially of the compounds of the present invention or other therapeutic agents described herein. The particles may contain the therapeutic agent in a core surrounded by a coating, including but not limited to an enteric coating. The therapeutic agent may also be dispersed throughout the particle. The therapeutic agent may also be adsorbed onto the particle. The particles may have any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof. The particles may contain, in addition to the therapeutic agent, any of the materials routinely 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 that contain the compounds of the present invention in solution or in a semi-solid state. The particles may be virtually any shape.

[0229] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering therapeutic agents. Such polymers can be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include the bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acid, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, 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).

[0230] The therapeutic agent may be contained in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. It refers to immediate release formulations and non-immediate release formulations, including but not limited to sustained release and delayed release formulations. The term "sustained release" (also called "extended release") is used in its conventional sense to refer to a formulation that provides a gradual release of drug over an extended period of time, preferably, but not necessarily, resulting in a substantially constant blood concentration of drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of drug therefrom. "Delayed release" may or may not involve a gradual release of drug over an extended period of time, and therefore may or may not be a "sustained release".

[0231] The use of long-term sustained release implants may be particularly suitable for treating 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 well known to those skilled in the art and include some of the release systems described above.

[0232] Incorporation by Reference All U.S. patent application publications and U.S. patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0233] Other embodiments In the claims, articles such as "a," "an," and "the" can mean one or more, unless otherwise indicated or clear from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied if one or more, or all, of the group members are present in, used in, or otherwise relevant to a given product or process, unless otherwise indicated or clear from the context. The invention includes embodiments in which exactly one member of a group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all, of the group members are present in, used in, or otherwise relevant to a given product or process.

[0234] Moreover, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, when the invention or aspects of the invention are referred to as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For the sake of brevity, these embodiments have not been specifically described herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended, allowing for the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the stated range in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0235] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any inconsistency between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such an embodiment may be excluded even if the exclusion is not expressly set forth herein, since it is believed to be known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0236] Those skilled in the art will be able to recognize or ascertain, without more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims. EXAMPLES

[0237] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0238] Example 1. Novel chemical designs with no mammalian toxicity The disclosed development of frontier synthesis methods allows for the efficient modification of novel AmB derivatives, and alternatively, AmB was found to kill fungal and human cells primarily by binding ergosterol and cholesterol, respectively (Figure 1A); channel formation is not required. All data are consistent with a "sterol sponge" model (Figure 1B), in which AmB self-assembles into large extramembrane aggregates that rapidly extract physiologically important sterols from fungal and human cells, thereby triggering cell death. Frontier SSNMR studies further revealed important insights into the structure of the AmB sponge-sterol complex. Anderson, TM et al., Nat Chem Biol 2014, 10 (5), 400-6.

[0239] This key discovery paved the way for the rational development of non-toxic AmB variants. To investigate its predicted role in sterol binding, the hydroxyl group at the C2' position of the mycosamine adduct was synthetically removed. The resulting derivative, C2'deOAmB (Figure 2A), was found to bind ergosterol but not cholesterol within the detection limits of isothermal titration calorimetry (ITC) (Figure 2C). Consistent with the sterol sponge model, this derivative retained good activity against yeast but, most importantly, was non-toxic to human erythrocytes and primary (hRECs) (Figure 2B).

[0240] 2-Deoxyglycosides are very challenging to synthesize, and their development has been hindered by the lack of scalable access to C2'deOAmB. However, these findings have led us to predictive models to guide the development of more synthetically accessible (or synthetically accessible) derivatives with similar selectivity profiles. Crich, D. et. al., The Journal of Organic Chemistry 2011, 76 (22), 9193-9209; Hou, D. et al., Carbohyd Res 2009, 344 (15), 1911-1940; Rodriguez, MA Et al., The Journal of Organic Chemistry 2005, 70 (25), 10297-10310; and Hou, D., et al., Organic Letters 2007, 9 (22), 4487-4490. Specifically, to rationalize the selective toxicity of C2'deOAmB to fungal cells versus human cells, a model was proposed in which the C2'-OH stabilizes a conformer of AmB that readily binds both ergosterol and cholesterol. The deletion of this hydroxyl group favors a shift to a different conformer or set of conformers that retains the ability to bind ergosterol but not the more sterically bulky cholesterol. Alternatively, this model suggests that the deletion of the C2'OH of AmB triggers a small-molecule-based allosteric effect that results in ligand-selective binding. Based on the high-resolution X-ray crystal structure of N-iodoacyl AmB (Figure 3A), there is a prominent water-bridging hydrogen bond between the hydroxyl groups of C2' and C13, which may help stabilize a specific conformation of the mycosamine adduct to the polyene macrolide core.This observation, combined with our previous findings that the mycosamine adduct is important for binding to both ergosterol and cholesterol, and the observation by SSNMR of direct intermolecular contacts between the AmB polyenes and the A / B rings of ergosterol, allowed us to propose specific structural models for both AmB-sterol complexes that are consistent with all our data (Figure 3B). Woerly, EM et al, Nat Chem 2014, 6 (6), 484-91; Anderson, TM et al., Nat Chem Biol 2014, 10 (5), 400-6.

[0241] Guided by this model, simple epimerization of the more synthetically accessible C2' hydroxyl group similarly eliminates the water-bridging C2'OH-C13OH interaction, causing a shift in the orientation of the mycosamine adduct similar to that predicted for C2'deOAmB. The resulting derivative, C2'epiAmB (Figure 2A), selectively binds ergosterol and exerts cytocidal effects on fungi but not human cells. Notably, C2'epiAmB differs from AmB only in stereochemistry at a single atom.

[0242] A practical 11-step synthesis of C2'epiAmB was developed using a frontier site-selective acylation methodology (Figure 4). Wilcock, BC et al., Nat Chem 2012, 4 (12), 996-1003; Uno, BE A synthesis enabled understanding of Amphotericin B leading to derivatives with improved therapeutic indices. University of Illinois at Urbana-Champaign, 2014. Next, sterol binding and cell killing activity were determined. As predicted, C2'epiAmB, like C2'deOAmB, was found by ITC to bind ergosterol but not (detectably) cholesterol, and most importantly, to kill fungi but not human cells (Figures 2A-2C).

[0243] These ITC studies did not yield sigmoidal isotherms and binding constants and other thermodynamic parameters could not be determined. However, an alternative method for the reproducible formation of homogeneous AmB and C2'epiAmB sterol sponge assemblies in vitro was developed. Using these preparations, the apparent K D A quantitative UV-Vis and principal component analysis (PCA) based assay was developed to determine s (Figures 5A-5D). Consistent with the small therapeutic index of this natural product, ergosterol (K D,erg = 120 nM) and cholesterol (K D,chol = 840 nM). Consistent with the in vitro evaluation of C2'epiAmB, strong binding of C2'epiAmB to ergosterol (K D,erg = 150 nM) was observed (Figure 5C), whereas little or no binding to cholesterol was observed (Figure 5D). The data show that for the latter interaction, DAlthough this did not allow for a confident assignment of K, it was estimated to be at least >2000 nM (this is the estimated K when fitting the data). D,chol Because C2'epiAmB does not exhibit mammalian toxicity, these mechanistically-based biophysical parameters can be used as benchmarks to prioritize new hybrid derivatives for further development.

[0244] Example 2. AmB derivatives with no observed animal toxicity We prepared >100 mg of C2'epiAmB, formulated it as the corresponding deoxycholate conjugate, and directly compared this derivative with AmB-deoxycholate to evaluate toxicity and efficacy in animal models. Intravenous (IV) administration of AmB-deoxycholate to mice was found to be lethal at 2-4 mg / kg (Figure 6, left). In contrast, IV injection of C2'epiAmB-deoxycholate did not result in mortality, even at 128 mg / kg (the highest dose tested). IV administration of AmB-deoxycholate to rats (2.5 mg / kg) caused significant increases in blood urea nitrogen (BUN), alanine transaminase / aspartate transaminase (ALT / AST), and mortality (Figure 6, right). Instead, when rats were treated with IV injections of C2'epiAmB at doses of 2, 10, and 17.5 mg / kg (the highest dose tested), no elevations in BUN or ALT / AST and no deaths were observed. max is the C of AmB at 1 mg / kg max was >16-fold higher than that

[0245] We directly compared the toxicity of C2'epiAmB against AmBisome®, a liposomal formulation of AmB that is widely used clinically because it is slightly less toxic than Fungizone® (AmB-deoxycholate) (Figure 7). Consistent with the precedent literature, we confirmed that AmBisome® exhibits significant toxicity in mice at 48 mg / kg, as judged by state-of-the-art renal genotoxicity biomarkers. Kondo, C. et al., J Toxicol Sci 2012, 37 (4), 723-37. Instead, when mice were injected with the same high dose (48 mg / kg) of C2'epiAmB-deoxycholate, we did not observe a significant increase in these same biomarkers. Thus, C2'epiAmB is significantly less toxic than AmBisome® in mice.

[0246] In all cases, C2'epiAmB is non-toxic to human erythrocytes, primary hRECs, mice, and rats up to the highest doses tested. These results are consistent with the finding that C2'epiAmB does not bind cholesterol within the detection limits of all experiments.

[0247] Example 3. Partially retained in vitro antifungal activity The in vitro antifungal activity of C2'epiAmB was compared with that of AmB against an extensive series of Candida and Aspergillus clinical isolates (Figure 8A) at Evotec (Oxfordshire, UK). C2'epiAmB showed good activity against many Candida strains and some Aspergillus strains. However, there were several strains of A. fumigatus (AF293, A1163, and ATC204305) in which C2'epiAmB was 4-fold less potent than AmB, and in one strain (AF91) C2'epiAmB was >32-fold less potent. We also sent C2'epiAmB to the US national Fungus Testing Laboratory at the University of Texas at San Antonio for antifungal testing against an expanded panel of 40 particularly challenging clinical isolates of Aspergillus, including azole-resistant A. fumigatus, A. flavus, and A. terreus (Figure 8B). C2'epiAmB was found to be 2- to 16-fold less potent than AmB (5.6-fold less potent on average across all 40 strains). Recently, Steinbach and Burke directly compared the activity of AmB, AmBisome®, Caspofungin, Voriconazole, and C2'epiAmB against an even broader panel of clinically relevant invasive filamentous fungi (Figure 8C). These studies again demonstrated superior antifungal efficacy of C2'epiAmB against many strains, including a pan-azole resistant strain (F14196), but also demonstrated significant opportunities to improve activity against Aspergillus spp.

[0248] Example 4. Main mechanism of in vitro antifungal activity To provide strong evidence for a sterol sponge mechanism, it was previously demonstrated that precomplexing the AmB sterol sponge with ergosterol, thereby blocking its ability to extract ergosterol from yeast cells, reduced the antifungal activity of AmB. Anderson, TM et al., Nat Chem Biol 2014, 10 (5), 400-6. Follow-up studies conducted in collaboration with Susan Lindquist at MIT showed that this mechanism also essentially circumvents clinical resistance, as mutating the ergosterol target causes loss of virulence. Davis, SA, et al., Nat Chem Biol 2015, 11 (7), 481-7. To test whether C2'epiAmB kills cells primarily via the same sterol sponge mechanism, we similarly precomplexed the C2'epiAmB sponge with ergosterol (Figure 9). The same reduction in potency was observed for AmB and C2'epiAmB when ergosterol was precomplexed. Thus, C2'epiAmB similarly kills yeast primarily through sterol binding, and thus the novel compounds covered in this application are expected to have a similar barrier to fungal resistance as has been observed with AmB over the past 50 years.

[0249] Example 5. Non-toxic dose-dependent efficacy in murine invasive candidiasis Finally, we tested the dose-dependent efficacy of the C2'epiAmB-deoxycholate complex in a mouse model of invasive candidiasis (Figure 10). Neutropenic ICR / Swiss mice were injected with a lethal inoculum of C.albicans via the lateral tail vein and then treated with a single IP injection of AmB-deoxycholate (1 or 4 mg / kg) or C2'epiAmB-deoxycholate (1, 4, 8, or 16 mg / kg). Previous studies from the Andes laboratory show a dose-dependent efficacy of AmB-deoxycholate. Andes, D. et al., Antimicrobial agents and chemotherapy 2001, 45 (3), 922-6. In fact, the PD parameter that best correlates with the outcome is the Cmax- / MIC. The same was subsequently observed in a pulmonary model of invasive aspergillosis. Wiederhold, NP et al., Antimicrobial agents and chemotherapy 2006, 50 (2), 469-73. As shown in Figure 10, C2'epiAmB also demonstrated dose-dependent efficacy, with a significant reduction in fungal burden at a dose of 16 mg / kg.

[0250] These results indicate that C2'epiAmB is a unique antifungal agent that is the first amphotericin derivative to have potent antifungal activity against several Candida and Aspergillus strains and no detectable mammalian toxicity. However, C2'epiAmB has some important limitations with respect to efficacy and pathogen spectrum. Therefore, the next plan is to develop a novel series of "hybrid" derivatives designed to improve the antifungal efficacy and pathogen spectrum of C2'epiAmB while maintaining its lack of toxicity.

[0251] Part I. C16 Amide AmB Example 6. General synthesis procedure and HPLC method for C16 amide AmB General synthesis procedure: [ka]

[0252] Freshly distilled Et3N was added dropwise to a solution of amphotericin B (10 mg; 0.01 mmol) and amine (3 eq.) in DMF (500 μL) until pH=9 was reached (by pH paper). The reaction mixture was stirred at room temperature for 15 min. Solid PyBOP (1.5 eq.; 8.4 mg) was added under nitrogen atmosphere and the sealed vial was stirred at room temperature (RT) overnight. The progress of the reaction was monitored by analytical HPLC traces.

[0253] Upon completion, the product was precipitated and washed with anhydrous diethyl ether (10 mL). The suspension was centrifuged at 3000 g for 5 min. The solvent was decanted and the pellet was dissolved in DMSO and filtered through a 0.2 micron syringe filter for purification on a C18 preparative HPLC system. The pure product was dried in a lyophilizer as a yellowish powder and stored at -80°C under nitrogen atmosphere.

[0254] HPLC method: TIFF0007636004000051.tif73169

[0255] TIFF0007636004000052.tif79169

[0256] Example 7. Characterization Data for Exemplary C16 Amide AmB Derivatives [ka] NMR: 1HNMR(500MHz, PyrMeOD) δ 6.55 (m, 2H), 6.42 (m, 1H), 6.30 (m, 7H), 6.20 (m, 3H), 5.56 (m, 1H), 5.42 - 5.37 (m, 1H), 4.88 - 4.81 (m, 1H), 4.72 (s, 1H), 4.70 - 4.63 (m, 2H), 4.56 (s, 1H), 4.41 - 4.33 (m, 1H), 4.18 (d, J = 3.0 Hz, 1H), 3.87 (s, 1H), 3.78 (d, J = 11.0 Hz, 1H), 3.49 - 3.42 (m, 1H), 3.25 (d, J = 9.5 Hz, 1H), 3.20 (m, 1H), 2.87 (m, 1H), 2.47 (d, J = 6.5 Hz, 1H), 2.42 - 2.27 (m, 4H), 2.26 - 2.19 (m, 1H), 2.11 - 2.03 (m, 1H), 2.02 (s, 1H), 1.95 - 1.86 (m, 2H), 1.84 - 1.66 (m, 4H), 1.63 - 1.46 (m, 6H), 1.46 - 1.40 (m, 2H), 1.36 (d, J = 6.0 Hz, 3H), 1.26 (d, J = 6.5 Hz, 3H), 1.25 - 1.16 (m, 4H), 1.14 (d, J = 6.5 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H), 0.76 (t, J = 7.0 Hz, 3H). LCMS: [M + H] + Calculated for C 52 H 84 N2O 16 , 992.5821, found 993.5899.

[0257]

Chem.

[0258]

Chem.

[0259]

Chem.

[0260]

Chem.

[0261]

Chem.

[0262]

change

[0263]

change

[0264]

change

[0265]

change

[0266]

change

[0267] NMR: 1HNMR(500MHz,1:1ピリジンd-5:メタノールd-4)δ6.54(ddd,J=21.8,14.8,10.9Hz,2H),6.42(dd,J=14. 0,11.1Hz,1H),6.36-6.25(m,7H),6.25-6.13(m,3H),5.59-5.52(m,1H),5.4 2-5.36(m,1H),4.86-4.79(m,2H),4.65-4.51(m,3H),4.39-4.32(m,2H),3.9 6(dt,J=13.8,6.7Hz,1H),3.86(t,J=9.7Hz,1H),3.81-3.75(m,2H),3.61(t, J=9.5Hz,1H),3.53-3.46(m,3H),3.27-3.23(m,1H),2.47(td,J=9.7,6.2Hz, 1H),2.43-2.35(m,2H),2.31-2.18(m,3H),2.08-1.99(m,1H),1.94-1.85(m, 2H),1.79-1.67(m,4H),1.60-1.49(m,3H),1.45-1.38(m,2H),1.34(d,J=6.2 Hz,3H),1.26(d,J=6.5Hz,3H),1.15(d,J=6.3Hz,3H),1.07(d,J=7.1Hz,2H). LCMS: [M+H] + Calculate C 49 H 79 N3O 18 S, 1029.5079, 1030.6719.

[0268]

change

change

[0269]

change

[0270]

change

[0271]

change

change

[0272] Example 8. C16 amide AmB (AmBHEA) shows efficacy equivalent to AmB

Chemical Structure

Table 1

[0273] Killing kinetics of C16 amide AmB (AmBHEA; compound AA) compared to AmB or DMSO (Figure 11).

[0274] Colonies of C. albicans SN250 from the SDA plate were suspended in RPMI medium and seeded at a density of 10 5 CFU / ml. An aliquot of 990 μL of the diluted cell suspension was added to a sterile 1.7 mL Eppendorf tube, followed by 10 μL of a 400 μM solution of compound (in DMSO). The concentration of DMSO in each Eppendorf tube was 1%, and a control sample was also run to check viability using only 1% DMSO. At predetermined time points (0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 24 hours), a 10 μL sample was removed from each tube and serially diluted 10-fold in RPMI, and a 10 μL aliquot was plated on SDA plates for colony count determination. If colony counts were expected to be less than 1,000 CFU / mL, a 50 μL aliquot was taken directly from the test solution and plated undiluted on SDA plates. Plates were incubated at 37°C (C. albicans) for 24 hours before testing. All experiments were performed in duplicate.

[0275] Example 9. Additional Compounds Similar to AmBHEA (Compound AA) [Table 2-1] [Table 2-2] [Table 2-3]

[0276] Example 10. Antifungal efficacy of AmBHEA analogs [Table 3]

[0277] [Table 4]

[0278] Example 11. Plasma stability [Table 5]

[0279] Example 12. In vitro metabolism [Table 6]

[0280] Example 13. Additional C16 amide AmB variants synthesized [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12]

[0281] Example 14. Structure-activity relationships Structure-activity relationships - aliphatic rings [ka] [Table 8]

[0282] Structure-activity relationships - aliphatic acyclic chains [ka] [Table 9]

[0283] The effects of aliphatic rings and aliphatic acyclic chains are summarized in FIG.

[0284] Structure-activity relationships – effect of polar functional groups [ka]

[0285] The effect of various polar functional groups is summarized in FIG.

[0286] Part II. C16 amide C2'epiAmB derivatives Example 15. General synthesis procedure and HPLC method for C16 amide of C2'epiAmB Synthesis procedure [ka]

[0287] Freshly distilled Et3N was added dropwise to a solution of C2'-epi-amphotericin B (10 mg; 0.01 mmol) and amine (3 eq.) in DMF (500 μL) until pH=9 was reached (by pH paper). The reaction mixture was stirred at room temperature for 15 min. Solid PyBOP (1.5 eq.; 8.4 mg) was added under nitrogen atmosphere and the sealed vial was stirred at room temperature (RT) overnight. The progress of the reaction was monitored by analytical HPLC traces.

[0288] Upon completion, the product was precipitated and washed with anhydrous diethyl ether (10 mL). The suspension was centrifuged at 3000 g for 5 min. The solvent was decanted and the pellet was dissolved in DMSO and filtered through a 0.2 micron syringe filter for purification on a C18 preparative HPLC system. The pure product was dried in a lyophilizer as a yellowish powder and stored at -80°C under nitrogen atmosphere.

[0289] HPLC method: TIFF0007636004000097.tif72170

[0290] TIFF0007636004000098.tif79169

[0291] Example 16. Synthesis of representative C16 amide C2'epiAmB derivatives Synthesis of C2'epiAmB methylamide (C2'epiAmBMA) [ka]

[0292] A 7 mL reaction vial was charged with C2'epiAmB (5 mg, 1 equiv.) and Fmoc-succinimide (3 mg, 1.5 equiv.), which was dissolved in a 2:1 mixture of DMF:MeOH (150 μL) at room temperature. Pyridine (3 μL, 6 equiv.) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was then poured into diethyl ether (5 mL) and a yellow solid was collected as a pellet by centrifugation. The solid was dried under a stream of N2 for 2 min and used in the next step without purification.

[0293] To a stirred solution of Fmoc-epiAmB(A) in DMF (250 μL) in a 7 mL oven-dried clean vial, PyBOP (9 mg; 1 eq.) and DIPEA (1.25 μL; 2 eq.) were added at 23° C. and stirred for 5 min. Then, a solution of MeNH2 in THF (3.5 μL; 1 (M) in THF; 1.5 eq.) was added and the mixture was stirred for 2 h. The progress of the reaction was monitored by HPLC.

[0294] Once the substrate was completely consumed (2 h), piperidine (5 μL; 2 equiv.) was added to the reaction and stirred for an additional hour. Completion of the reaction was monitored by HPLC. The mixture was poured into 5 mL of diethyl ether and the resulting yellow solid was collected as a pellet by centrifugation (5 min; 3000 g). The solid was resuspended in DMSO and purified by single preparative HPLC (C18, 5 μm, 50 × 250 mm, 75 mL / min, 95:5 to 5:95 15 mM NHOAc (aq):MeCN, 22 min). After HPLC, the solvent was removed under reduced pressure and the compound was redissolved in DMSO and lyophilized to give a pale yellow solid. The compound was stored at -80 °C in an airtight vial. Overall yield = 35%; mass: observed [M+H + ]=937.5249; Calculated value [M+H + ]=937.5268; measured value [M+Na + ]=959.5065; Calculated value [M+Na + ]=950.5087.

[0295] Synthesis of C2'epiAmB aminoethyl amide (C2'epiAmBAEA) [ka]

[0296] A 7 mL reaction vial was charged with C2'epiAmB (5 mg, 1 equiv.) and Fmoc-succinimide (3 mg, 1.5 equiv.), which was dissolved in a 2:1 mixture of DMF:MeOH (150 μL) at room temperature. Pyridine (3 μL, 6 equiv.) was then added and the reaction was stirred at room temperature overnight. The reaction mixture was then poured into diethyl ether (5 mL) and the yellow solid was collected as a pellet by centrifugation. The solid was dried under a stream of N2 for 2 min and used in the next step without purification.

[0297] To a stirred solution of Fmoc-epiAmB in DMF (250 μL) in a 7 mL oven-dried clean vial, PyBOP (2.25 mg; 1 eq.) and DIPEA (1.25 μL; 2 eq.) were added at 23° C. and stirred for 5 min. Solid Fmoc-ethylamine, HCl salt (2.5 mg; 1.5 eq.) was added sequentially and the mixture was stirred for 2 h. The progress of the reaction was monitored by HPLC.

[0298] Once the substrate was completely consumed (2 h), piperidine (5 μL; 2 equiv.) was added to the reaction and stirred for an additional 1 h. Completion of the reaction was monitored by HPLC. The mixture was poured into 5 mL of diethyl ether and the resulting yellow solid was collected as a pellet by centrifugation (5 min; 3000 g). The solid was resuspended in DMSO and purified by single preparative HPLC (C18, 5 μm, 50 × 250 mm, 75 mL / min, 95:5 to 5:95 15 mM NHOAC (aq):MeCN, 22 min). After HPLC, the solvent was removed under reduced pressure and the compound was redissolved in DMSO and lyophilized to give a pale yellow solid. The compound was stored at -80 °C in an airtight vial. Overall yield = 29%; mass: observed [M+Na + ]=988.53; Calculated value [M+Na + ]=988.5353.

[0299] Example 17. Synthesized exemplary C16 amide C2'epiAmB [Table 10-1] [Table 10-2] [Table 10-3]

[0300] Example 18. C16 amide C2'epiAmB derivatives show strong inhibition against Aspergillus fumigatus (A. fumigatus) [Table 11]

[0301] [Table 11A]

[0302] Example 19. Additional C16 amides of C2'epiAmB synthesized and their mean minimum inhibitory concentrations (MICs) [Table 12-1] [Table 12-2]

[0303] [Table 13]

[0304] [Table 13A]

[0305] [Table 13B]

[0306] Example 20. Mouse studies of AmB, C2'epiAmB, and C2'epiAmB-L-His in AmBisome®-like formulations Procedure: Experiments were performed with AmB, C2'epiAmB, and C2'epiAmB-L-His in an AmBisome-like formulation. All compounds were dissolved in D5W (5% dextrose in water) for intravenous (IV) injection. Male CD-1 mice (3 per group; 30 g body weight each) were injected with drugs / compounds and monitored for 24 hours for death or signs of distress. After 24 hours, mice were sacrificed and kidneys were harvested, homogenized, and analyzed for biomarkers of renal injury by RTPCR.

[0307] The results are summarized in FIG.

[0308] Example 21. In vitro stability study of Compound BA Liver microsomes: Working compound solution: 10 μM in 50 mM potassium phosphate buffer containing 9% MeOH and 1% DMSO Microsome solution: working concentration 0.625mg / ml Stop solution: cold ACN (4° C.) containing 200 ng / ml tolbutamide and 200 ng / ml labetalol.

[0309] Procedure: To the well plates (T5, T10, T20, T30, T60, NCF60 (60 without cofactors)), 10 μL of compound / control working solution was added (except T0 and matrix blank), followed by microsome solution (80 μL) and the mixture was incubated at 37 °C for about 10 min. A solution of potassium phosphate (10 μl of 50 mM) was added to the NCF60 wells, incubated at 37 °C and time counting was started. After pre-heating, 10 μl of NADPH regenerating solution was added to each plate to start the reaction. The reaction is terminated with 300 μL / well of stop solution at different time points. The sampling plate was shaken for 10 min and centrifuged at 4000 rpm for 20 min. The supernatant was diluted in half with ultrapure water and analyzed using LCMS.

[0310] Plasma stability: Procedure: To perform the experiments, a 25 μM working solution of the compound for TA analysis and a 50 μM working solution for PC analysis were prepared (2.5% DMSO, 20% MeOH, water). Prior to the experiment, the plasma was warmed to 37°C and centrifuged at 4000 rpm for 5 min. The pH of the samples was adjusted to 7.4 ± 0.1. 96 μL / well of blank plasma from each species was transferred and pre-incubated for 5 min. Each time point was monitored in triplicate (0, 10, 30, 60 and 120 min). A 4 μL / well aliquot of the working solution was mixed with blank plasma and incubated at 37°C. At each time point, the samples were quenched with ACN stop solution containing 200 ng / ml tolbutamide and 200 ng / ml labetalol in a 1:3 ratio, mixed well on a shaker for 10 min, then centrifuged at 4000 rpm for 15 min. A 100 μl aliquot of the supernatant was mixed with 100 μL of ultrapure water and subjected to LC-MS / MS analysis.

[0311] CYP Inhibitors: Working solutions of test compounds and standard inhibitors were prepared in DMSO (100x final concentration). 20 μl of substrate solution (5 in 1 cocktail) was added to the wells, followed by 2 μl of test compound solution. 158 μl of human liver microsomes (HLM) was added to all wells of the incubated plate and warmed to 37° C. for 10 minutes. 20 μl of NADPH cofactor solution was then added to all wells of the incubated plate and incubated at 37° C. for 10 minutes. At that point, the reaction was quenched by adding 400 μL of cold stop solution. Samples were centrifuged at 4000 rpm for 20 minutes to precipitate proteins. 100 μl of the supernatant was diluted with 100 μl of ultrapure water and analyzed using LCMS.

[0312] [Table 14]

[0313] [Table 15]

[0314] [Table 16]

[0315] [Table 17]

[0316] Example 22. Compound BA is well tolerated in mice Procedure: Experiments were performed with commercially available Fungizone and AmBisome. Compound BA was used directly after purification without any special treatment. All compounds were dissolved in D5W (5% dextrose in water) for IV injection. Female CD-1 mice (3 per group; each weighing 30 g) were injected with drugs / compounds and monitored for 24 hours for death or signs of distress. After 24 hours, mice were sacrificed and kidneys were harvested, homogenized, and analyzed for biomarkers of kidney injury by RTPCR.

[0317] [Table 18]

[0318] Biomarkers of kidney injury were analyzed and summarized in FIG.

[0319] Example 23. Compound BA is highly effective in a mouse model of invasive candidiasis, but is less potent than Ambisome® Procedure: Experiments were performed using commercially available Ambisome, C2'epiAmB-deoxycholate (1:2), and BA. Female CD-1 mice (n=3 or 4 / group) were infected with C. albicans SN250 by IV injection. Two hours after inoculation, mice were treated with compounds and monitored. Twenty-four hours after treatment, mice were sacrificed and kidneys were harvested and homogenized. Serum was plated to enumerate C. albicans (CFU / mL) in kidney homogenates (detection limit ~10 2 ).

[0320] The results of the mouse study are summarized in FIG.

[0321] Example 24. In vitro and in vivo safety of compound BA UV-Vis binding assay (Figure 21A): The protocol for sterol binding assay (UV-Vis) was developed in our laboratory. Compounds were dissolved in DMSO at a final concentration of 1 mM. Sterols were first dissolved in CHCl3 (>200 mM) and then diluted to a concentration of 1 mM with DMSO. To synthesize the complexes, 1 μl of compound solution was placed in a clean Eppendorf tube (2 ml) to which the sterol solution (volume depends on stoichiometry) was added and the volume was made up to 20 μl with DMSO. 0.98 ml of PBS buffer was added to the Eppendorf tube and mixed properly. The absorbance of the solution was measured after 30 min of incubation.

[0322] MHC (FIG. 21B): The protocol for the hemolysis assay was adapted from Paquet and coworkers (Chem. Eur. J. 2008, 14, 2465-2481). Human whole blood (sodium heparin) was purchased from Bioreclamation LLC (Westbury, NY), stored at 4°C, and used within 2 days of receipt. To a 2.0 mL Eppendorf tube, 1 mL of human whole blood was added and centrifuged at 10,000 g for 2 min. The supernatant was removed and the red blood cell pellet was washed with 1 mL of sterile saline and centrifuged at 10,000 g for 2 min. The saline wash was repeated a total of three times. The red blood cell pellet was suspended in 1 mL of RBC buffer (10 mM NaH2PO4, 150 mM NaCl, 1 mM MgCl2, pH 7.4) to form the red blood cell stock suspension.

[0323] Compounds were prepared as stock solutions of >15 mM in DMSO and serially diluted in DMSO to the following concentrations: 7689, 5126, 2563, 2050, 1538, 1025, 769, 513, 384, 256, 205, 154, 103, 77, 51, 26 μM. To 0.2 mL PCR tubes, 24 μL of RBC buffer and 1 μL of compound stock solution were added, giving final concentrations of 500, 300, 200, 100, 80, 60, 40, 30, 20, 15, 10, 8, 6, 4, 3, 2, 1 μM. Positive and negative controls were prepared by adding 1 μL of DMSO and MilliQ water or RBC buffer, respectively, to 0.2 mL PCR tubes. To each PCR tube, 0.63 μL of red blood cell stock suspension was added and mixed by inversion. Samples were incubated at 37°C for 2 hours. Samples were mixed by inversion and centrifuged at 10,000g for 2 minutes. 15 μL of supernatant from each sample was added to a 384-well plate. Absorbance was read at 540 nm using a Biotek H1 Synergy Hybrid Reader (Wanooski, VT). Experiments were performed in triplicate and reported MHCs represent the average of three experiments.

[0324] In vivo toxicity (Figure 21C and Figure 21D): Experiments were performed with commercially available Fungizone and AmBisome. Compound BA was used directly after purification without any special treatment. All compounds were dissolved in D5W (5% dextrose in water) for IV injection. Female CD-1 mice (3 per group; each weighing 30 g) were injected with drugs / compounds and monitored for 24 hours for death or signs of distress. After 24 hours, mice were sacrificed and kidneys were harvested, homogenized, and analyzed for biomarkers of kidney injury by RTPCR.

[0325] Example 25. In vivo mouse pharmacokinetics experiment using compound BA Experiments were performed with compounds (>91%) synthesized in the laboratory and purified by preparative HPLC. All compounds were dissolved in D5W (5% dextrose in water) for IV injection. Female CD-1 mice (3 per group; weighing approximately 30 g each) were injected with the compounds (according to the planned dosage), blood samples were taken at different time points, and compound content was analyzed using the following procedure.

[0326] Equipment: Triple Quad 6500+ Matrix: Male CD-1 mouse plasma (EDTA-K2) Sample: Compound BA Internal standards: 100 ng / mL labetalol and 100 ng / mL tolbutamide in ACN MS Conditions ESI: Positive SRM detection Compound BA:[M+H]+ m / z 949.8>732.6 Labelator (IS): [M+H]+ m / z 329.2>162.1.

[0327] UPLC conditions Mobile phase A: 0.1% FA in water Mobile phase B: 0.1% FA in ACN Time (min) Mobile phase B (%) 1.10 98 1.50 98 1.51 15 2.10 Stop Column: Waters ACQUITY UPLC HSS T3 1.8μm 2.1×50mm Flow rate: 0.6000mL / min Retention time: Labelator (IS): 0.998 min.

[0328] Sample preparation: An aliquot of 24 μL of sample was protein precipitated with 120 μL of IS solution (100 ng / mL labetalol and 100 ng / mL tolbutamide in ACN), the mixture was vortexed well and centrifuged at 3900 rpm for 10 min at 4°C. An aliquot of 90 μL of supernatant was transferred to a sample plate and mixed with 60 μL of water, then the plate was shaken at 800 rpm for 10 min. 15.0 μL of supernatant was injected for LC-MS / MS analysis.

[0329] Calibration curve: 1.00-3000 ng / mL for compound BA in female CD-1 mouse plasma (EDTA-K2).

[0330] The results of this experiment are shown in FIG.

[0331] Example 26. Solubility of the disclosed compounds Test Article 1: Synthesized in the laboratory (>95% purity) D5W: Braun USA (product number: L5101) Equipment Details: Sonicator: Branson Ultrasonics 2800; Vortex-Genie 2 Lab Mixer UV-Vis:Thermo Fisher Nanodrop oneC.

[0332] Steps: * Place 6 mg of sample (measured by UV-Vis) into a clean, oven-dried 7 mL vial Add 1.65 mL of sterile D5W (at room temperature) Vortex for 2 minutes Water bath sonication: 2 min x 2 Repeat steps 3 and 4 until the solution is clear. Transfer to a 2 mL Eppendorf tube and centrifuge (3000 g x 2 min) to ensure that the compound is completely dissolved and no insoluble parts remain (optional step) Measure concentration by UV (absorbance at 406 nm) (optional step) * Amounts are based on solutions prepared for in vivo toxicity studies at a dose of 50 mg / kg.

[0333] [Table 19]

[0334] Example 27. Summary Data for Compounds BA and BM Compared to AmB TIFF0007636004000117.tif205159References

[0335] 1. Eggimann, P.; Garbino, J.; Pittet, D., Management of Candida species infections in critically ill patients. The Lancet. Infectious diseases 2003, 3 (12), 772-85. 2. Pfaller, MA; Diekema, DJ; Colombo, AL; Kibbler, C.; Ng, KP; Gibbs, DL; Newell, VA, Candida rugosa, an emerging fungal pathogen with resistance to azoles: Geographic and temporal trends from the ARTEMIS DISK antifungal surveillance program. J Clin Microbiol 2006, 44 (10), 3578-3582. 3. Martin, CA, Invasive Fungal Infections in the Critically Ill Patient. Journal of Pharmacy Practice 2005, 18 (1), 9-17. 4. Howard, S. J.; Webster, I.; Moore, C. B.; Gardiner, R. E.; Park, S.; Perlin, D. S.; Denning, D. W., Multi-azole resistance in Aspergillus fumigatus. Int J Antimicrob Ag 2006, 28 (5), 450-453. 5. Hakki, M.; Staab, J. F.; Marr, M. A., Emergence of a Candida krusei isolate with reduced susceptibility to caspofungin during therapy. Antimicrobial agents and chemotherapy 2006, 50 (7), 2522-2524. 6. Cannon, R. D.; Lamping, E.; Holmes, A. R.; Niimi, K.; Tanabe, K.; Niimi, M.; Monk, B. C., Candida albicans drug resistance - another way to cope with stress. Microbiol-Sgm 2007, 153, 3211-3217. 7. Barker, K.; Rogers, P., Recent insights into the mechanisms of antifungal resistance. Current Infectious Disease Reports 2006, 8 (6), 449-456. 8. Agarwal, R.; Singh, N., Amphotericin B is still the drug of choice for invasive aspergillosis. Am J Resp Crit Care 2006, 174 (1), 102-102. 9. May, R. C.; Stone, N. R. H.; Wiesner, D. L.; Bicanic, T.; Nielsen, K., Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Micro 2016, 14 (2), 106-117. 10. Chen, S. C.; Meyer, W.; Sorrell, T. C., Cryptococcus gattii infections. Clinical microbiology reviews 2014, 27 (4), 980-1024. 11. Morens, D. M.; Fauci, A. S., Emerging Infectious Diseases: Threats to Human Health and Global Stability. PLOS Pathogens 2013, 9 (7), e1003467. 12. Andes, D.; Stamsted, T.; Conklin, R., Pharmacodynamics of amphotericin B in a neutropenicmouse disseminated-candidiasis model. Antimicrobial agents and chemotherapy 2001, 45 (3), 922-6. 13. Edmond, M. B.; Wallace, S. E.; McClish, D. K.; Pfaller, M. A.; Jones, R. N.; Wenzel, R. P., Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 1999, 29 (2), 239-44. 14. Marr, K. A.; Carter, R. A.; Crippa, F.; Wald, A.; Corey, L., Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2002, 34 (7), 909-17. 15. Jolliffe, I. T., Principal Component Analysis and Factor Analysis. In Principal component analysis, Springer: 1986; pp 115-128. 16. Smith, P. B.; Alexander, B. D.; Perfect, J. R.; Johnson, M. D. In Mortality rates in candidemia over the last decade, 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, American Society of Microbiology: San Francisco, 2009; p Abstract M1009. 17. McNeil, M. M.; Nash, S. L.; Hajjeh, R. A.; Phelan, M. A.; Conn, L. A.; Plikaytis, B. D.; Warnock, D. W., Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2001, 33 (5), 641-7. 18. Herbrecht, R.; Denning, D. W.; Patterson, T. F.; Bennett, J. E.; Greene, R. E.; Oestmann, J. W.; Kern, W. V.; Marr, K. A.; Ribaud, P.; Lortholary, O.; Sylvester, R.; Rubin, R. H.; Wingard, J. R.; Stark, P.; Durand, C.; Caillot, D.; Thiel, E.; Chandrasekar, P. H.; Hodges, M. R.; Schlamm, H. T.; Troke, P. F.; de Pauw, B., Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. The New England journal of medicine 2002, 347 (6), 408-15. 19. Maertens, J.; Raad, I.; Petrikkos, G.; Boogaerts, M.; Selleslag, D.; Petersen, F. B.; Sable, C. A.; Kartsonis, N. A.; Ngai, A.; Taylor, A.; Patterson, T. F.; Denning, D. W.; Walsh, T. J., Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2004, 39 (11), 1563-71. 20. Kontoyiannis, D. P.; Marr, K. A.; Park, B. J.; Alexander, B. D.; Anaissie, E. J.; Walsh, T. J.; Ito, J.; Andes, D. R.; Baddley, J. W.; Brown, J. M.; Brumble, L. M.; Freifeld, A. G.; Hadley, S.; Herwaldt, L. A.; Kauffman, C. A.; Knapp, K.; Lyon, G. M.; Morrison, V. A.; Papanicolaou, G.; Patterson, T. F.; Perl, T. M.; Schuster, M. G.; Walker, R.; Wannemuehler, K. A.; Wingard, J. R.; Chiller, T. M.; Pappas, P. G., Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2010, 50 (8), 1091-100. 21. Neofytos, D.; Horn, D.; Anaissie, E.; Steinbach, W.; Olyaei, A.; Fishman, J.; Pfaller, M.; Chang, C.; Webster, K.; Marr, K., Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2009, 48 (3), 265-73. 22. Pagano, L.; Caira, M.; Candoni, A.; Offidani, M.; Fianchi, L.; Martino, B.; Pastore, D.; Picardi, M.; Bonini, A.; Chierichini, A.; Fanci, R.; Caramatti, C.; Invernizzi, R.; Mattei, D.; Mitra, M. E.; Melillo, L.; Aversa, F.; Van Lint, M. T.; Falcucci, P.; Valentini, C. G.; Girmenia, C.; Nosari, A., The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006, 91 (8), 1068-75. 23. Pappas, P. G.; Alexander, B. D.; Andes, D. R.; Hadley, S.; Kauffman, C. A.; Freifeld, A.; Anaissie, E. J.; Brumble, L. M.; Herwaldt, L.; Ito, J.; Kontoyiannis, D. P.; Lyon, G. M.; Marr, K. A.; Morrison, V. A.; Park, B. J.; Patterson, T. F.; Perl, T. M.; Oster, R. A.; Schuster, M. G.; Walker, R.; Walsh, T. J.; Wannemuehler, K. A.; Chiller, T. M., Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2010, 50 (8), 1101-11. 24. Patterson, T. F.; Thompson, G. R., 3rd; Denning, D. W.; Fishman, J. A.; Hadley, S.; Herbrecht, R.; Kontoyiannis, D. P.; Marr, K. A.; Morrison, V. A.; Nguyen, M. H.; Segal, B. H.; Steinbach, W. J.; Stevens, D. A.; Walsh, T. J.; Wingard, J. R.; Young, J. A.; Bennett, J. E., PracticeGuidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2016, 63 (4), e1-e60. 25. Tortorano, AM; Richardson, M.; Roilides, E.; van Diepeningen, A.; Caira, M.; Munoz, P.; Johnson, E.; Meletiadis, J.; Pana, ZD; Lackner, M.; Verweij, P.; Freiberger, T.; Cornely, OA; Arikan-Akdagli, S.; Dannaoui, E.; Groll, AH; Lagrou, K.; Chakrabarti, A.; Lanternier, F.; Pagano, L.; Skiada, A.; Akova, M.; Arendrup, MC; Boekhout, T.; Chowdhary, A.; Cuenca-Estrella, M.; Guinea, J.; Guarro, J.; de Hoog, S.; Hope, W.; Kathuria, S.; Lortholary, O.; Meis, JF; Ullmann, AJ; Petrikkos, G.; Lass-Florl, C., ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2014, 20 Suppl 3, 27-46. 26. Fuhren, J.; Voskuil, WS; Boel, CH; Haas, P.J.; Hagen, F.; Meis, JF; Kusters, JG, High prevalence of azole resistance in Aspergillus fumigatus isolates from high-risk patients. The Journal of antimicrobial chemotherapy 2015, 70 (10), 2894-8. 27. Talbot, G. H.; Bradley, J.; Edwards, J. E., Jr.; Gilbert, D.; Scheld, M.; Bartlett, J. G., Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2006, 42 (5), 657-68. 28. Wiederhold, N. P.; Tam, V. H.; Chi, J.; Prince, R. A.; Kontoyiannis, D. P.; Lewis, R. E., Pharmacodynamic activity of amphotericin B deoxycholate is associated with peak plasma concentrations in a neutropenic murine model of invasive pulmonary aspergillosis. Antimicrobial agents and chemotherapy 2006, 50 (2), 469-73. 29. Anderson, TM; Clay , MC ; Cioffi , AG ; Diaz, KA; Hisao, GS; Tuttle , MD ; Nieuwkoop , AJ ; Commellas, G.; Maryum, N.; Wang, S.; One, BE; Wildeman, THE; Gonen, T.; Rienstra , CM ; Burke, MD, Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 2014, 10(5), 400–6. 30. Verweij, PE; Ananda-Rajah, M.; Andes, D.; Arendrup , MC ; Bruggemann, RJ; Chowdhary , A. ; Cornely , OA ; Denning , DW ; Groll , AH ; Izumikawa , K. ; Kullberg , BJ ; Lagrou, K.; Maertens , J. ; Meis , JF ; Newton, P.; Page, I.; Seyedmousavi, S.; Sheppard, DC; Viscoli , C. ; Warris, A.; Donnelly, JP, International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 2015, 21-22, 30-40. 31. Taubes, G., The bacteria fight back. Science 2008, 321 (5887), 356-361. 32. Monk, B. C.; Goffeau, A., Outwitting multidrug resistance to antifungals. Science 2008, 321 (5887), 367-369. 33. Walsh, T. J.; Anaissie, E. J.; Denning, D. W.; Herbrecht, R.; Kontoyiannis, D. P.; Marr, K. A.; Morrison, V. A.; Segal, B. H.; Steinbach, W. J.; Stevens, D. A.; van Burik, J. A.; Wingard, J. R.; Patterson, T. F., Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2008, 46 (3), 327-60. 34. Pappas, P. G.; Kauffman, C. A.; Andes, D.; Benjamin, D. K., Jr.; Calandra, T. F.; Edwards, J. E., Jr.; Filler, S. G.; Fisher, J. F.; Kullberg, B. J.; Ostrosky-Zeichner, L.; Reboli, A. C.; Rex, J. H.; Walsh, T. J.; Sobel, J. D., Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2009, 48 (5), 503-35. 35. Pappas, P. G.; Kauffman, C. A.; Andes, D. R.; Clancy, C. J.; Marr, K. A.; Ostrosky-Zeichner, L.; Reboli, A. C.; Schuster, M. G.; Vazquez, J. A.; Walsh, T. J.; Zaoutis, T. E.; Sobel, J. D., Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2016, 62 (4), e1-50. 36. Andes, D. R.; Safdar, N.; Baddley, J. W.; Alexander, B.; Brumble, L.; Freifeld, A.; Hadley, S.; Herwaldt, L.; Kauffman, C.; Lyon, G. M.; Morrison, V.; Patterson, T.; Perl, T.; Walker, R.; Hess, T.; Chiller, T.; Pappas, P. G., The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated InfectionSurveillance Network (TRANSNET). Transplant infectious disease: an official journal of the Transplantation Society 2016, 18 (6), 921-931. 37. Davis, S. A.; Vincent, B. M.; Endo, M. M.; Whitesell, L.; Marchillo, K.; Andes, D. R.; Lindquist, S.; Burke, M. D., Nontoxic antimicrobials that evade drug resistance. Nat Chem Biol 2015, 11 (7), 481-7. 38. Gray, K. C.; Palacios, D. S.; Dailey, I.; Endo, M. M.; Uno, B. E.; Wilcock, B. C.; Burke, M. D., Amphotericin primarily kills yeast by simply binding ergosterol. Proc Natl Acad Sci U S A 2012, 109 (7), 2234-9. 39. Wilcock, B. C.; Endo, M. M.; Uno, B. E.; Burke, M. D., C2'-OH of amphotericin B plays an important role in binding the primary sterol of human cells but not yeast cells. J Am Chem Soc 2013, 135 (23), 8488-91.

Claims

1. A compound of formula (I), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [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 Carbocyclyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C ５－１０ aryl, substituted or unsubstituted 5-10 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 -NR5R6; 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; R f is selected from the group consisting of 2-alkene-1-yl, tert-butyl, benzyl, and fluorenylmethyl; 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 ４ is hydrogen or substituted or unsubstituted C １－６ is alkyl.

2. 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 The compound of claim 1 which is aryl, or a substituted or unsubstituted 5-10 membered heteroaryl.

3. R １ and R ２ are independently hydrogen, unsubstituted C １－６ Alkyl, alkoxy C １－６ Alkyl, haloC 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 The compound of claim 2 which is a carbocyclyl, an unsubstituted 3- to 10-membered heterocyclyl, or a hydroxyl 3- to 10-membered heterocyclyl.

4. R １ and R ２ at least one of R １ and R ２ The compound according to any one of claims 1 to 3, wherein both are not hydrogen.

5. R １ and R ２ The compound of claim 1, wherein, together with the nitrogen to which they are attached, form a substituted or unsubstituted 3- to 10-membered heterocyclyl.

6. R １ and R ２ The compound of claim 5, wherein, together with the nitrogen to which they are attached, form an unsubstituted 3- to 10-membered heterocyclyl, amino 3- to 10-membered heterocyclyl, hydroxyl 3- to 10-membered heterocyclyl, or heterocyclyl 3- to 10-membered heterocyclyl.

7. 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 The compound of claim 1 which is aryl, or a substituted or unsubstituted 5-10 membered heteroaryl.

8. R ５ is hydrogen and R 6 is C(O)OR ｆ 8. The compound of claim 7, wherein

9. R ｆ The compound of claim 8, wherein is fluorenylmethyl.

10. R ５ and R ６ 8. The compound of claim 7, wherein at least one of is hydrogen.

11. R ５ and R ６ and R are both hydrogen.

12. R ４ is hydrogen or haloC １－６ The compound according to any one of claims 1 to 11, which is alkyl.

13. R ４ The compound of claim 12 , wherein is hydrogen.

14. A compound selected from the group consisting of: 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】

15. A compound selected from the group consisting of: 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 【Chemistry 3-4】 【Chemistry 3-5】 【Chemistry 3-6】 【Chemistry 3-7】 【Chemistry 3-8】 【Chemistry 3-9】 【Chemistry 3-10】 【Chemistry 3-11】 【Chemistry 3-12】 【Chemistry 3-13】 【Chemistry 3-14】 【Chemistry 3-15】 【Chemistry 3-16】 【Chemistry 3-17】 【Chemistry 3-18】 【Chemistry 3-19】 【Chemistry 3-20】 【Chemistry 3-21】 【Chemistry 3-22】 【Chemistry 3-23】 【Chemistry 3-24】 【Chemistry 3-25】 【Chemistry 3-26】 【Chemistry 3-27】 【Chemistry 3-28】 【Chemistry 3-29】 【Chemistry 3-30】 【Chemistry 3-31】

16. 【Chemical 4】 or a pharma- ceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharma- ceutically acceptable carrier.

18. 18. The pharmaceutical composition of claim 17 in an intravenous or oral dosage form.

19. A composition for treating a fungal infection comprising a compound according to any one of claims 1 to 16.

20. 20. The composition of claim 19, which is administered intravenously or orally.

21. A method for preparing the C16 amide of C2'-epi-amphotericin B according to the transformations shown in Scheme 1: 【Chemistry 5】 [In the scheme, 1 is, 【Chemistry 6】 represents The base is a tertiary amine; The peptide coupling reagent is a peptide coupling reagent used in solid phase peptide synthesis; R is H or an amine protecting group; 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, substituted or unsubstituted 5-10 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.

22. 22. The method of claim 21, wherein R is H; or R is a carbamate protecting group selected from the group consisting of Fmoc, t-Boc, alloc, and Cbz.

23. 23. The method of claim 21 or 22, wherein the base is a trialkylamine.

24. The base is Et ３ The method of claim 23, wherein N is N.

25. The method of any one of claims 21 to 24, wherein the peptide coupling reagent is PyBOP, BOP, HATU, HBTU, DPBT, DCC, or EDCI.

Images