Preparation of amphotericin B hybrid amide derivative in DSGPEG2K micelle

Abstract

Compositions comprising a lipid polymer excipient and an AmB or an AmB derivative are disclosed. The lipid polymer excipient can form micelles when formulated with AmB or an AmB derivative, and can solubilize and stabilize the drug. Also disclosed are methods of treating a fungal infection comprising administering to a subject in need thereof a therapeutically effective amount of the composition.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 355,345, filed on June 24, 2022. Technical Field

[0003] The present disclosure provides compositions of amphotericin B and its derivatives having improved solution stability and plasma compatibility, and methods of using such formulations. More particularly, the present disclosure relates to micellar formulations comprising amphotericin B or its derivatives and block copolymers that not only stabilize the active pharmaceutical ingredient, but also unexpectedly improve the potency of the compound and increase its half-life. Background Art

[0004] The morbidity and mortality of invasive fungal infections are significant and are mainly caused by fungal pathogens of two genera: Candida and Aspergillus. Candida species are the fourth most common pathogens isolated in all bloodstream infections. The treatment success rate of invasive candidiasis is limited (50-70%), and this is usually only in the healthiest patients. The attributable mortality rate of invasive candidiasis is quite large (20%-30%). The incidence of invasive aspergillosis caused by Aspergillus fumigatus has increased to three times in the past decade, and its mortality rate has risen by more than 300%. In addition, the current therapy of invasive aspergillosis has a low treatment success rate of 40-50%. Invasive aspergillosis is always the main killer of immunocompromised patients, and invasive mold infections (fusarium, scedosporosis and mucormycosis) have a higher mortality rate and no effective treatment options. Current guidelines recommend that the first-line treatment for invasive aspergillosis, as well as most other invasive mold infections, is the triazole antifungal agent voriconazole. However, pantriazole resistance in Aspergillus is as high as 30% in some locations and in certain high-risk patient groups. Recognizing this lack of effective treatment, the Infectious Diseases Society of America has highlighted Aspergillus fumigatus as one of only six pathogens that "urgently need substantial breakthroughs."

[0005] Amphotericin B (AmB) is a particularly promising starting point because the drug has highly potent and dose-dependent fungicidal activity against a broad range of fungal pathogens and has evaded resistance for more than half a century. AmB's fungicidal (rather than fungistatic) activity is critical in immunocompromised patients who lack a robust immune system to help clear infection. Broad antifungal activity is particularly important in critically ill patients when the identity of the pathogen is unknown and immediate empirical treatment is required. An international panel of experts recently suggested that new treatment approaches centered on AMB that do not have resistance issues are needed. The problem is that AmB is particularly toxic, which limits its use to low-dose regimens that often fail to eradicate the disease.

[0006] A new, paradigm-shifting mechanistic understanding of AMB that has evaded the field for half a century has been achieved. Previous studies reported that AmB binds to sterols, which is thought to primarily drive the formation of membrane permeabilization pores to kill fungi and human cells. After intensive synthesis-enabled atomistic interrogations and cutting-edge SSNMR experiments on this natural product over a decade, it was discovered that AmB kills fungi and human cells primarily by forming cell-killing extracellular sterol sponges. This large aggregate lands on the surface of the lipid bilayer and rapidly extracts membrane sterols, which leads to cell death. No membrane permeabilization is required. Based on this new mechanism and increasingly refined structural information, it is proposed that small molecule-based ligand-selective allosteric effects can enable selective binding of ergosterol relative to cholesterol. Guided by this model, a new derivative, C2'epiAmB, was found to eliminate cholesterol binding and thus eliminate mammalian toxicity.

[0007] However, a limitation of C2'epiAmB is the lack of efficacy against many clinically relevant yeasts and molds. Other AMB derivatives have poor plasma compatibility and solution stability. Therefore, there is still a need to develop AmB derivative formulations that retain potent, broad-spectrum and resistance-evading fungicidal activity, minimize dose-limiting toxicity, and improve the plasma compatibility and solution stability of these important compounds. Summary of the invention

[0008] In certain aspects, the present invention provides a composition comprising:

[0009] (i) a lipopolymer excipient having a structure of formula (X);

[0010]

[0011] wherein each occurrence of n is independently selected from 0-10; and

[0012] m is selected from 10-60; and

[0013] (ii) a compound selected from the group consisting of:

[0014]

[0015] A compound having the structure of formula (I):

[0016] and

[0017] A compound having the structure of formula (II):

[0018]

[0019] in:

[0020] R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; or

[0021] R 1 and R 2 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclyl;

[0022] R 3 Yes - NR 5 R 6 , substituted or unsubstituted amino, substituted or unsubstituted urea, substituted or unsubstituted carbamate or substituted or unsubstituted guanidino;

[0023] R 4 is hydrogen or substituted or unsubstituted C 1-6 alkyl;

[0024] R 5 and R 6 are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or

[0025] R 5 and R 6 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclyl; and

[0026] R f Selected from the group consisting of 2-en-1-yl, tert-butyl, benzyl and fluorenylmethyl.

[0027] In certain embodiments, the compound is:

[0028]

[0029] Also provided herein are methods of treating fungal infections comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention.

[0030] In another aspect, the present invention provides use of the composition of the present invention in the manufacture of a medicament for treating fungal infection.

[0031] The present invention also provides compositions for treating fungal infections. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The solution stability (in % loss) of AM-2-19 over time is shown. In IV compatible solvents, such as 5% dextrose in water ("D5W"), AM-2-19 is not stable even within hours.

[0033] Figure 2A Images of formulations of AM-2-19-OAc and DSG-PEG-2000 after plasma addition are shown to reveal plasma compatibility.

[0034] Figure 2B Images of AM-2-19-OAc formulations after plasma addition are shown to reveal plasma incompatibility.

[0035] Figure 3 Shown are the structures of AM-2-19-OAc and DSG-PEG-2000 ("DSGPEG2K"), including the micellar structure of the block copolymer.

[0036] Figure 4 Overlapping UV spectra of AM-2-19-OAc-DSG-PEG-2000 at 0 h, 3 h and 24 h are shown. After 24 h, >98% of the initial concentration remained.

[0037] Figure 5AOverlapping UV spectra of AM-2-19-OAc in D5W at 0 h, 3 h and 6 h are shown.

[0038] Figure 5B Overlapping UV spectra of AM-2-19-OAc-DSG-PEG-2000 in D5W at 0 h, 3 h and 6 h are shown.

[0039] Fig. 6A Shown is the UV spectrum of a 320 μM solution of AM-2-19-OAc in D5W.

[0040] Figure 6B Overlaid UV spectra of AM-2-19-OAc at different concentrations in D5W are shown.

[0041] Figure 6C Shown is the UV spectrum of a 320 μM solution of AM-2-19-OAc-DSG-PEG-2000 in D5W.

[0042] Fig.6D Shown are overlaid UV spectra of AM-2-19-OAc-DSG-PEG-2000 at different concentrations in D5W.

[0043] Figure 7 The deuterated D5W solutions of DSG-PEG-2000 and AM-2-19-OAc-DSG-PEG-2000 at various temperatures are shown. 1 H NMR spectrum; also shows the solution of AM-2-19-OAc in deuterated D5W at 25 °C 1 Part of the H NMR spectrum.

[0044] Figure 8 Contains a graph showing the plasma concentration of AM-2-19-OAc-DSG-PEG 2000 in mouse and rat plasma over time. As shown, the AM-2-19-OAc-DSG-PEG 2000 formulation exhibits an extended half-life in mice and rats relative to the half-life of AMM-2-19-OAc not in a micellar formulation.

[0045] Fig. 9 Contains a graph showing the concentration of AM-2-19-OAc-DSG-PEG 2000 formulations in various tissues over time.

[0046] Fig. 10A Overlapping UV spectra of 320 μM stock solutions of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 in D5W are shown.

[0047] Fig. 10BOverlapping UV spectra of diluted solutions of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 at 16 μM in RPMI 1640 are shown.

[0048] Fig. 10C Overlapping UV spectra of diluted RPMI 1640 solutions of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 at 4 μM are shown.

[0049] Fig. 10D Overlapping UV spectra of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 diluted in RPMI 1640 at 2 μM are shown.

[0050] Fig.11A Shown is the UV spectrum of AM-2-19-OAc solution in the absence of human plasma and human albumin.

[0051] Fig. 11B Shown are overlapping UV spectra of AM-2-19-OAc solutions in the presence of human plasma and human albumin, respectively.

[0052] Fig. 11C Shown is the UV spectrum of a solution of AM-2-19-OAc-DSG-PEG-2000 in the absence of human plasma and human albumin.

[0053] Fig.11D Shown are overlapping UV spectra of AM-2-19-OAc-DSG-PEG-2000 solutions in the presence of human plasma and human albumin, respectively.

[0054] Fig. 12A Shown are overlaid UV spectra of AM-2-19-OAc solutions titrated with albumin, each solution having a different molar ratio of AM-2-19-OAc to albumin.

[0055] Fig. 12B show Fig. 12A An enlarged portion of the overlapping UV spectra is shown in .

[0056] Fig. 12C Shown are overlaid UV spectra of AM-2-19-OAc-DSG-PEG-2000 solutions titrated with albumin, each solution having a different molar ratio of AM-2-19-OAc-DSG-PEG-2000 to albumin.

[0057] Fig.12D show Fig. 12C An enlarged portion of the overlapping UV spectra is shown in .

[0058] Fig.13Shown are the concentrations of various toxicity biomarkers in response to AM-2-19-OAc-DSG-PEG 2000 formulation (API-F100 (1:3)), various control formulations, and other antifungal compositions (eg, AmBisome-D5W).

[0059] Fig.14 Contains a graph demonstrating that AM-2-19-OAc-DSG-PEG 2000 retains the lack of in vitro toxicity observed for AM-2-19-OAc.

[0060] Fig.15 Shown is a series of histopathology graphs demonstrating that AM-2-19-OAc-DSG-PEG-2000 formulations do not cause renal damage in mice, rats, or dogs.

[0061] Fig.16 Shown are the concentrations of various toxicity biomarkers at several time points following a single dose of AM-2-19-OAc-DSG-PEG-2000.

[0062] Fig.17 Shown are the timeline, clinical pathology, and toxicokinetic analysis of renal toxicity resulting from a 2-week dosing regimen of AM-2-19-OAc-DSG-PEG-2000 in dogs on Dosing Regimen A (dosing every other day).

[0063] Fig.18 Shown are the timeline, clinical pathology, and toxicokinetic analysis of renal toxicity resulting from a 2-week dosing regimen of AM-2-19-OAc-DSG-PEG-2000 in dogs on Dosing Regimen B (dosing every four days).

[0064] Fig.19 Shown are the timeline, clinical pathology, and toxicokinetic analysis of renal toxicity resulting from a 2-week dosing regimen of AM-2-19-OAc-DSG-PEG-2000 in dogs on Dosing Regimen C (weekly dosing).

[0065] Fig. 20 Results of efficacy evaluations are shown, which show that AM-2-19-OAc-DSG-PEG-2000 exhibits lower minimum inhibitory concentrations (MICs) than the liposomal amphotericin B formulation AmBisome against a number of yeast and mold strains, including resistant and refractory Candida albicans (C. albicans) ATCC 90028.

[0066] Fig.21 Contains a series of graphs showing that AM-2-19-OAc-DSG-PEG-2000 reduces the fungal burden of many fungal pathogens in lung and kidney tissues compared to controls and AmBisome.

[0067] Fig. 22 Overlapping UV spectra of DSG-PEG-2000 micellar formulations containing several AmB derivatives at various time points, showing the stability of the formulations. DETAILED DESCRIPTION

[0068] The present invention is based on the discovery of micellar formulations of amphotericin B and its derivatives that provide improved solution stability and plasma concentrations of the antifungal payload. The present invention surprisingly found that such formulations unexpectedly increase the potency of amphotericin derivatives and also extend their half-life in vivo.

[0069] Amphotericin B (AmB) is a polyene macrolide with a mycosamine appendage. The complete compound has the following structure.

[0070]

[0071] Amphotericin B 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 infections such as systemic or deep tissue candidiasis, aspergillosis, cryptococcosis, blastomycosis, coccidioidomycosis, histoplasmosis, and mucormycosis. It is typically formulated for intravenous injection. Amphotericin B can be used, for example, as (Squibb), (Pfizer), (Enzon) and Because of its undesirable side effects, dosing is usually limited to a maximum of about 1.0 mg / kg / day, and the total cumulative dose in humans does not exceed about 3 g.

[0072] AmB kills fungi and human cells by forming a cell-killing extracellular sterol sponge. Anderson, TM et al., Nat Chem Biol 2014, 10 (5), 400-6. Such large aggregates fall on the surface of the lipid bilayer and rapidly extract membrane sterols, which leads to cell death. No membrane permeabilization is required. Based on this new mechanism, small molecule-based ligand-selective allosteric effects will enable selective binding of ergosterol relative to cholesterol and eliminate 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 discloses a K2'epiAmB sponge for binding of ergosterol and cholesterol to AmB. Ds, which provide quantitative and mechanistically based biophysical parameters to guide the rational optimization of the therapeutic index of this clinically important natural product.

[0073] Further derivatives of AmB have been identified and shown to have improved therapeutic indices compared to AmB. Such derivatives of AmB retain potent binding of ergosterol but exhibit no detectable cholesterol binding, and retain fungicidal efficacy against a number of yeasts and molds but exhibit no detectable mammalian toxicity. This demonstrates that differential binding of ergosterol relative to cholesterol is possible and provides non-toxic variants of AmB that retain desirable antifungal properties.

[0074] Although such AmB derivatives have the therapeutic potential to eradicate life-threatening invasive fungal infections with a significantly improved safety profile, these compounds also suffer from poor plasma compatibility and solution instability, which poses challenges to drug administration, especially intravenous administration.

[0075] Thus, the present invention is based in part on the discovery of novel formulations of AMB derivatives that (1) are effective against fungal pathogens, (2) minimize mammalian toxicity, (3) exhibit plasma compatibility, and (4) are stable in solution.

[0076] The compositions of the present invention can be used to inhibit the growth of fungi. In one embodiment, an effective amount of the composition of the present invention is contacted with a fungus, thereby inhibiting the growth of the fungus. In one embodiment, the composition of the present invention is added to or included in a tissue culture medium.

[0077] The compositions of the present invention can be used to treat a fungal infection in a subject. In one embodiment, a therapeutically effective amount of a composition of the present invention is administered to a subject in need thereof, thereby treating a fungal infection.

[0078] Yeast is a eukaryotic organism classified in the kingdom Fungi. Fungi include yeasts, molds and larger organisms, including mushrooms. Yeasts and molds have clinical relevance as infectious agents. Yeasts are generally described as budding forms of fungi. Of particular importance in connection with the present invention are yeast species that can cause infection in mammalian hosts. Such infections most often occur in immunocompromised hosts, including hosts with impaired infection barriers (e.g., burn victims) and hosts with compromised immune systems (e.g., hosts receiving chemotherapy or immunosuppressive therapy, and hosts infected with HIV). Pathogenic yeasts include, but are not limited to, various species of Candida and Cryptococcus. Of particular note among the pathogenic yeasts of the genus Candida are C. albicans, C. tropicalis, C. stellatoidea, C. glabrata, C. krusei, C. parapsilosis, C. guilliermondii, C. viswanathii and C. lusitaniae. The genus Cryptococcus specifically includes Cryptococcus neoformans. Yeasts can cause mucosal infections, such as oral, esophageal and vaginal infections in humans, as well as infections of the bones, blood, urogenital tract and central nervous system. This enumeration is exemplary and does not constitute a limitation in any way.

[0079] Many fungi (except yeast) can cause infection in mammalian hosts. Such infections most often occur in immunocompromised hosts, including hosts with impaired infection barriers (e.g., burn victims) and hosts with impaired immune systems (e.g., hosts receiving chemotherapy or immunosuppressive therapy, and hosts infected with HIV). Pathogenic fungi (except yeast) include but are not limited to species of Aspergillus, Rhizopus, Mucor, Histoplasma, Coccidioides, Blastomyces, Trichophyton, Microsporum and Epidermophyton. Of particular note among the above are Aspergillus fumigatus (A. fumigatus), Aspergillus flavus (A. flavus), Aspergillus niger (A. niger), H. capsulatum (H. capsulatum), C. immitis (C. immitis) and Bacillus dermatitidis (B. dermatitidis). Fungi can cause systemic and deep tissue infections in the lungs, bones, blood, urogenital tract and central nervous system (just to name a few). Some fungi are the cause of skin and nail infections.

[0080] Compositions of the present invention

[0081] In certain aspects, the present invention provides a composition comprising:

[0082] (i) a lipopolymer excipient having a structure of formula (X);

[0083]

[0084] wherein each occurrence of n is independently selected from 0-10; and

[0085] m is selected from 10-60; and

[0086] (ii) a compound selected from the group consisting of:

[0087] A compound having the structure of formula (I):

[0088] and a compound having the structure of formula (II):

[0089]

[0090] in:

[0091] R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; or

[0092] R 1 and R 2 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclyl;

[0093] R 3 Yes - NR 5 R 6 , substituted or unsubstituted amino, substituted or unsubstituted urea, substituted or unsubstituted carbamate or substituted or unsubstituted guanidino;

[0094] R 4 is hydrogen or substituted or unsubstituted C 1-6 alkyl;

[0095] R 5 and R 6 are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or

[0096] R 5 and R 6 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclyl; and

[0097] R f Selected from the group consisting of 2-en-1-yl, tert-butyl, benzyl and fluorenylmethyl.

[0098] In certain embodiments, the compound is AmB.

[0099] In certain embodiments, the compound is C2'epiAmB.

[0100] In certain embodiments, the compound is a compound having the structure of Formula (I).

[0101] In certain embodiments, the compound is a compound having the structure of Formula (II).

[0102] In certain embodiments, the compound is a compound having a structure of Formula (I) or Formula (II); and R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0103] In certain embodiments, the compound is a compound having a structure of Formula (I) or Formula (II); and R 1 and R 2 are independently hydrogen, unsubstituted C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino C 1-6 Alkyl, heterocyclic C 1-6 Alkyl, unsubstituted C 2-6 Alkynyl, unsubstituted C 3-10 Carbocyclic group, amino C 3-10carbocyclyl, unsubstituted 3- to 10-membered heterocyclyl, or hydroxy 3- to 10-membered heterocyclyl.

[0104] In certain embodiments, the compound is a compound having a structure of Formula (I) or Formula (II); and R 1 and R 2 At least one of the atoms is hydrogen.

[0105] In certain embodiments, the compound is a compound having a structure of Formula (I) or Formula (II); and R 1 and R 2 Not all hydrogen.

[0106] In certain embodiments, the compound is a compound having a structure of Formula (I) or Formula (II); and R 1 and R 2 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclic group.

[0107] In certain embodiments, the compound is a compound having a structure of Formula (I) or Formula (II);

[0108] R 3 Yes - NR 5 R 6 ;

[0109] R 5 and R 6 are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or

[0110] R 5 and R 6 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclyl; and

[0111] R f Selected from the group consisting of 2-en-1-yl, tert-butyl, benzyl and fluorenylmethyl.

[0112] In certain such embodiments, R 5 and R 6 are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0113] In further such embodiments, R 5 and R 6 are independently hydrogen or C(O)OR f , choose any one of R f is fluorenylmethyl. In certain such embodiments, R 5 and R 6 At least one of is hydrogen; preferably, R 5 and R 6 It's all hydrogen.

[0114] In certain embodiments, the compound is a compound having a structure of Formula (I) or Formula (II); and R 4 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 In certain such embodiments, R 4 is hydrogen, halogenated C 1-6 Alkyl or unsubstituted C 2-6 In certain preferred embodiments, R 4 It's hydrogen.

[0115] In certain embodiments, the compound is selected from the group consisting of:

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] Alternatively, the compound is selected from the group consisting of:

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] In a further embodiment, the compound is selected from the group consisting of:

[0154]

[0155]

[0156] For example, in some embodiments, the compound is:

[0157]

[0158] Alternatively, the compound may be:

[0159]

[0160] In certain embodiments, the compound is in the form of a pharmaceutically acceptable salt. For example, in certain preferred embodiments, the compound is:

[0161]

[0162] In other such embodiments, the compound is:

[0163]

[0164] These and other amphotericin B derivatives as well as synthetic routes and experimental procedures for preparing these compounds are disclosed in, for example, WO 2015 / 175875, WO 2021 / 026520 and WO 2022 / 035752, the disclosures of which are incorporated herein by reference.

[0165] In certain embodiments, each occurrence of n is independently selected from 1 to 9, from 2 to 8, from 3 to 7, or from 4 to 6. In certain preferred embodiments, each occurrence of n is 5.

[0166] In certain embodiments, m is selected from 20-60, selected from 30-50, or selected from 40-50. In certain preferred embodiments, m is 44.

[0167] In certain embodiments, the lipopolymer excipient forms micelles in aqueous solution.

[0168] In certain embodiments, the composition further comprises an agent for controlling plasma osmotic pressure.

[0169] In certain embodiments, the composition further comprises an agent for controlling pH.

[0170] In certain embodiments, the composition further comprises an agent for controlling oxidation.

[0171] In certain embodiments, the molar ratio of lipopolymer excipient to the compound is about 1:1 to about 10:1, about 1:1 to about 5:1, about 2:1 to about 4:1, or about 3:1.

[0172] In certain embodiments, the lipopolymer excipient is distearoyl-rac-glycerol-polyethylene glycol-2000 (referred to herein as DSG-PEG-2000). In other embodiments, the lipopolymer excipient is 1,2-dimyristoyl-rac-glyceryl-3-methoxypolyethylene glycol-2000 (or DMG-PEG-2000, or for a specific positional isomer, 1,2-DMG-PEG-2000). In certain embodiments, a mixture of two positional isomers of DMG-PEG-2000, 1,2-DMG-PEG-2000 and 1,3-DMG-PEG-2000.

[0173] In certain embodiments, the composition comprises, consists essentially of, or consists of:

[0174] (i) a lipopolymer excipient having a structure of formula (X);

[0175]

[0176] wherein n is 5; and

[0177] M is 44; and

[0178] (ii) a compound represented by the following formula:

[0179]

[0180] The molar ratio of the lipid polymer excipient to the compound is approximately 3:1.

[0181] In certain embodiments, the antifungal efficacy of the composition is greater than the antifungal efficacy of the compound alone.

[0182] In certain embodiments, the in vitro antifungal efficacy of the composition is greater than the in vitro antifungal efficacy of the compound alone.

[0183] In a further embodiment, the in vivo antifungal efficacy of the composition is greater than the in vivo antifungal efficacy of the compound alone.

[0184] In certain embodiments, the in vivo half-life of the composition is longer than the in vivo half-life of the compound alone.

[0185] In certain embodiments, the composition is a sustained release composition.

[0186] In certain embodiments, the composition is an intravenous dosage form.

[0187] In certain embodiments, the composition further comprises a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents or encapsulating materials that are 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 the active ingredient to facilitate administration. The components of the composition can also be mixed in a manner that does not exist that would substantially impair the desired drug efficacy.

[0188] The foregoing embodiments of the pharmaceutical compositions of the present invention are intended to be exemplary and not limiting.

[0189] Also provided is a method for preparing such a pharmaceutical composition, which comprises placing the compound of the present invention or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

[0190] Method of the present invention

[0191] The present invention provides a method of treating a fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of a composition of the present invention, thereby treating the fungal infection. In certain such embodiments, the composition is administered intravenously.

[0192] In certain embodiments, the subject is a mammal; or a primate, canine, feline, or bovine; or a human; or a human.

[0193] The present invention also provides the use of the composition of the present invention in the manufacture of a medicament for treating fungal infection. In certain such embodiments, the medicament is an intravenous dosage form.

[0194] The present invention also provides a composition for treating fungal infection.

[0195] In certain embodiments, administration of the composition delivers a dose of 0.01 mg to 10 mg of the compound (eg, AmB, C2'epiAmB, a compound of formula (I) or a compound of formula (II)).

[0196] In certain embodiments, for example, where the composition is a sustained release composition, administration of the composition delivers a daily dose of 0.01 mg to 10 mg of the compound.

[0197] In certain embodiments, for example, where the composition is a sustained release composition, the composition is administered once every six months, once every five months, once every four months, once every three months, once every two months, once a month, twice a month, once every two weeks, once a week, twice a week, or three times a week.

[0198] In certain embodiments, the composition is an intravenous dosage form.

[0199] The compositions of the invention can be used to inhibit the growth of fungi and yeasts, particularly fungi and yeasts of clinical significance including pathogens. The compositions of the invention can be used in methods of treating fungal and yeast infections, particularly including systemic fungal and yeast infections. The compositions of the invention can also be used in the manufacture of medicaments for treating fungal and yeast infections, particularly including systemic fungal and yeast infections. The invention further provides the use of the compositions of the invention for treating fungal and yeast infections, particularly including systemic fungal and yeast infections.

[0200] In certain embodiments, the composition is administered intravenously.

[0201] definition

[0202] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the periodic table of the elements on the inside cover of Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry as well as specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0203] The compounds described herein may contain one or more asymmetric centers and may therefore 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 may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers may 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).

[0204] The present invention additionally includes the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0205] When a range of values ​​is listed, it is intended to include each value and sub-range within that range. For example, "C 1-6 "Alkyl" is intended to cover 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.

[0206] The following terms are intended to have the meanings given below, and are helpful for understanding the specification and intended scope of the present invention. When describing the present invention (which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions), unless otherwise specified, the following terms (if present) have the following meanings. It should also be understood that, when described herein, any part defined below may be substituted by various substituents, and each definition is intended to include such substituted parts within its scope as described below. Unless otherwise specified, the term "substituted" is defined as described below. It should be further understood that, when used in this article, the terms "groups" and "radicals" can be considered to be interchangeable. The articles "a" and "an" can be used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. For example, "an analog" refers to an analog or more than one analog.

[0207] "Alkyl" refers to a straight chain or branched 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 1-8 In 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, the 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 (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 C 1-6Examples 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-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, alkyl groups are independently optionally substituted at each occurrence, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, alkyl groups are unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 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).

[0208] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent group, and it may be substituted or unsubstituted. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-), and the like.

[0209] "Alkenyl" refers to a straight or branched chain hydrocarbon radical 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). 2-20In certain embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the above-mentioned C 2-4 In some embodiments, alkenyl is an unsubstituted C 1-4- 1- 1, 1-6- 1- 1, 1-7- 1, 1-8- 1, 1-9- 1, 1-10- 1, 1-11- 1, 1-12- 1, 1-13- 1, 1-14- 1, 1-16- 1, 1-17- 1, 1-18- 1, 1-19- 1, 1-20- 1, 1-21- 1, 1-22- 1, 1-23- 1, 1-24- 1, 1-25- 1, 1-26- 1, 1-27- 1, 1-28- 1, 1-29- 2, 1-30- 2, 1-31- 2, 1-32- 2, 1-33- 2, 1-34- 2, 1-35- 2, 1-36- 2, 1-37- 2, 1-38- 2, 1-39- 2 2-10 In certain embodiments, alkenyl is a substituted C 2-10 Alkenyl.

[0210] "Alkenylene" refers to an alkenyl group in which two hydrogens are removed to provide a divalent group, and it may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted vinylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (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.

[0211] "Alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2-20 In some embodiments, an alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkynyl group has 2 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). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkenyl group include the above-mentioned C2-4 Alkynyl and pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, alkynyl is independently optionally substituted at each occurrence, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, alkynyl is unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0212] "Alkyne" refers to a straight chain alkynyl group in which two hydrogens are removed to provide a divalent group, and it may be substituted or unsubstituted. Exemplary divalent alkynyl groups include, but are not limited to, substituted or unsubstituted ethynyl, substituted or unsubstituted propynyl, and the like.

[0213] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl refers to a saturated group ("heteroalkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroalkyl”). 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 (“heteroalkyl”). 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 (“heteroalkyl”). 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroalkyl”). 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“heteroalkyl”). 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-2In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 alkyl"). 2-6 Unless otherwise specified, each instance of heteroalkyl is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, heteroalkyl is an unsubstituted heteroalkyl. 1-10 In certain embodiments, heteroalkyl is substituted heteroC 1-10 alkyl.

[0214] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkenyl refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 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 2-7 In 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 1 or 2 heteroatoms (“heteroC 2-4 In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 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 (an “unsubstituted heteroalkenyl group”) or substituted (a “substituted heteroalkenyl group”) with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC2-10 In certain embodiments, heteroalkenyl is a substituted heteroC 2-10 Alkenyl.

[0215] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more 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 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl"). 2-10 In 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 1 or 2 heteroatoms (“heteroC 2-4 In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 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 (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroalkynyl group. 2-10 In certain embodiments, heteroalkynyl is substituted heteroC 2-10 Alkynyl.

[0216] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" and "heteroalkynylene" refer to divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl, respectively. When a range or number of carbons is provided for a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" or "heteroalkynylene", it is understood that the range or number refers to the range or number of carbons in a straight carbon divalent chain. "Alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" and "heteroalkynylene" may be substituted or unsubstituted with one or more substituents as described herein.

[0217] "Aryl" refers to a group having 6-14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, The aryl group includes a group of coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenanthren, phenanthren, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. In particular, the aryl group includes phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, aryl is substituted C 6-14 Aryl.

[0218] In certain embodiments, aryl is selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, cyano, hydroxyl, C 1-8 The alkoxy and amino groups are substituted by one or more groups.

[0219] Representative examples of substituted aryl groups include the following:

[0220]

[0221] Where R 56 and R 57 One of them may be hydrogen, and R 56 and R 57 At least one of each independently selected from C 1-8 Alkyl, C 1-8 haloalkyl, 4- to 10-membered heterocyclic group, alkanoyl, C 1-8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 S02R 59 、COO alkyl、COO aryl、CONR 58 R 59 ,CONR 58 OR59 NR 58 R 59 、SO2NR 58 R 59 , S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from N, O or S. 60 and R 61 are independently hydrogen, C 1-8 Alkyl, C 1-4 Haloalkyl, C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10 Aryl, substituted C 6-10 aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0222] Other representative aryl groups having fused heterocyclic groups include the following:

[0223]

[0224] Wherein each W is selected from C(R 66 )2. NR 66 , O and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 are independently hydrogen, C 1-8 Alkyl, C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl.

[0225] "Fused aryl" refers to an aryl group having two of its ring carbons shared with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0226] "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.

[0227] "Heteroaryl" refers to a group of a 5 to 10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryls in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl).

[0228] In some embodiments, heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, heteroaryl is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise specified, heteroaryl is independently optionally substituted in each case, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, heteroaryl is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, heteroaryl is a substituted 5- to 14-membered heteroaryl.

[0229] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. 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, aza Azepinyl, oxa Oxepinyl and thio Thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0230] Representative examples of heteroaryl groups include the following:

[0231]

[0232] Wherein each Y is selected from carbonyl, N, NR 65 , O and S; and R 65 are independently hydrogen, C 1-8 Alkyl, C 3-10 Carbocyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl.

[0233] "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.

[0234] "Carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 In some embodiments, a 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 Carbocyclic 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 Carbocyclic groups include but are not limited to the above C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the above C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) etc. As shown in the foregoing examples, in certain embodiments, carbocyclyl is monocyclic ("monocyclic carbocyclyl") or contains fused, bridged or spirocyclic systems, such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such a case, the carbon number continues to represent the carbon number in the carbocyclic ring system. Unless otherwise specified, carbocyclyl is optionally substituted independently in each case, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, carbocyclyl is unsubstituted C 3-10 In certain embodiments, a carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0235] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-10 In some embodiments, a carbocyclyl group has 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, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 Carbocyclic group”) C 5-6 Examples of carbocyclic groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the carbocyclic group include the above-mentioned C 5-6 Carbocyclic groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the carbocyclic group include the above-mentioned C 3-6 carbocyclyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, a carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0236] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. A heterocyclyl may be a monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyls, wherein the point of attachment is on a carbocyclyl or heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryls or heteroaryls, wherein the point of attachment is on a heterocyclyl ring, and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Unless otherwise specified, heterocyclyl is optionally substituted independently in each case, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, heterocyclyl is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3- to 10-membered heterocyclyl.

[0237] In some embodiments, heterocyclyl is a 5 to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5 to 10-membered heterocyclyl”). In some embodiments, heterocyclyl is a 5 to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5 to 8-membered heterocyclyl”). In some embodiments, heterocyclyl is a 5 to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5 to 6-membered heterocyclyl”). In some embodiments, 5-6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5 to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0238] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0239] Specific examples of heterocyclic groups are shown in the following illustrative examples:

[0240]

[0241] Where each W is selected from CR 67 , C(R 67 )2. NR 67 , O and S; and each Y is selected from NR 67 , O and S; and R 67 are independently hydrogen, C 1-8 Alkyl, C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10The heterocyclic rings can be optionally substituted by one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amide), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, carbocyclic radical, halogen, hydroxyl, keto, nitro, sulfydryl,-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, lactams and urea derivatives.

[0242] 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 have been replaced by nitrogen, oxygen or sulfur heteroatoms. Hetero can be applied to any of the above hydrocarbon groups, such as alkyl groups (e.g., heteroalkyl groups) having 1 to 5, especially 1 to 3 heteroatoms, carbocyclic groups (e.g., heterocyclic groups), aryls (e.g., heteroaryls), cycloalkenyl groups (e.g., cycloheteroalkenyl groups), etc.

[0243] "Acyl" refers to the group -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. 20 is an acyl group that is not a hydrogen radical. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C 1-8 Alkyl, -C(O)-(CH2) t (C 6-10 Aryl), -C(O)-(CH2) t (5- to 10-membered heteroaryl), -C(O)-(CH2) t (C 3-10 carbocyclyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R is C substituted with halogen or hydroxy. 1-8 Alkyl; or C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl, each of which is replaced by an unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C 1-4 The substituted groups are haloalkoxy or hydroxy.

[0244] "Acylamino" refers to the group -NR 22 C(O)R 23 , where R 22 and R 23 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, or R 22 is an amino protecting group. Exemplary "acylamino" includes, but is not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. A specific exemplary "acylamino" is -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- to 10-membered heteroaryl), -NR 24 C(O)-(CH 2)t (C 3-10 carbocyclyl) and -NR 24 C(O)-(CH2) t (4- to 10-membered heterocyclic group), wherein t is an integer from 0 to 4, and each R 24 Independently represents H or C 1-8 In certain embodiments, R 25 is H, C substituted by halogen or hydroxyl 1-8 Alkyl; C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is replaced by an unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C 1-4 haloalkoxy or hydroxy; and R 26 is H, C substituted by halogen or hydroxyl 1-8 Alkyl; C 3-10 Carbocyclic group, 4-10 membered heterocyclic group, C 6-10aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is replaced by an unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C 1-4 haloalkoxy or hydroxy substituted; provided that R 25 and R 26 At least one of them is not H.

[0245] "Acyloxy" refers to the group -OC(O)R 27 , where R 27 R 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 C substituted by a halogen or hydroxyl group 1-8 Alkyl; C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl, each of which is replaced by an unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C 1-4 The substituted groups are haloalkoxy or hydroxy.

[0246] "Alkoxy" refers to the group -OR 29 , where R 29 is 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. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. More specific alkoxy groups have 1 to 4 carbon atoms.

[0247] In certain embodiments, R 29 is a compound selected from the group consisting of amino, substituted amino, C 6-10 Aryl, aryloxy, carboxyl, cyano, C 3-10One or more substituents, such as 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent, of the group consisting of carbocyclyl, 3- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary "substituted alkoxy" include, but are not limited to -O-(CH2) t (C 6-10 Aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C 3-10 carbocyclyl) and -O-(CH2) t (4- to 10-membered heterocyclyl), wherein t is an integer from 0 to 4, and any aryl, heteroaryl, carbocyclyl or heterocyclyl present may itself be replaced by an unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C 1-4 Specific exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0248] "Amino" refers to the group -NH2.

[0249] "Substituted amino" refers to a group of the formula -N(R 38 )2 amino group, wherein R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group or amino protecting group, wherein at least one R 38 In certain embodiments, each R 38 are independently selected from hydrogen, C 1-8 Alkyl, C 3-8 Alkenyl, C 3-8 Alkynyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group or C 3-10 Carbocyclic group; or C substituted by halogen or hydroxyl 1-8 Alkyl; C substituted by halogen or hydroxy 3-8 Alkenyl; C substituted by halogen or hydroxy 3-8 Alkynyl, or -(CH2) t (C 6-10Aryl), -(CH2) t (5- to 10-membered heteroaryl), -(CH2) t (C 3-10 carbocyclic) or -(CH2) t (4- to 10-membered heterocyclic group), wherein t is an integer between 0 and 8, each of which is replaced by an unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, or unsubstituted C 1-4 The R group is substituted with a haloalkoxy group or a hydroxy group; or two R groups are linked to form an alkylene group.

[0250] Exemplary "substituted amino" 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 heterocyclic group), wherein t is an integer from 0 to 4, such as 1 or 2, each R 39 Independently represents H or C 1-8 alkyl; and any alkyl present may itself be substituted by halogen, substituted or unsubstituted amino or hydroxy; and any aryl, heteroaryl, carbocyclyl or heterocyclyl present may itself be unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C 1-4 The term "substituted amino" refers to alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups as defined below. Substituted amino groups include monosubstituted amino and disubstituted amino groups.

[0251] "Azide" refers to the group -N3.

[0252] "Carbamoyl" or "amido" refers to the group -C(O)NH2.

[0253] "Substituted carbamoyl" or "substituted amido" refers to the group -C(O)N(R 62 )2, where each R 62 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group or amino protecting group, wherein at least one R 62 is not hydrogen. In certain embodiments, R 62 Selected from H, C 1-8 Alkyl, C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10 Aryl, aralkyl, 5- to 10-membered heteroaryl and heteroaralkyl; or C substituted by halogen or hydroxy 1-8 Alkyl; or C 3-10 Carbocyclic group, 4- to 10-membered heterocyclic group, C 6-10 aryl, aralkyl, 5- to 10-membered heteroaryl or heteroaralkyl, each of which is replaced by an unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C 1-4 haloalkoxy or hydroxy substituted; provided that at least one R 62 Not H.

[0254] Exemplary "substituted carbamoyl" 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- to 10-membered heteroaryl), -C(O)NR 64 -(CH2) t (C 3-10 carbocyclyl) and -C(O)NR 64 -(CH2) t (4- to 10-membered heterocyclic group), wherein t is an integer from 0 to 4, each R 64 Independently represents H or C 1-8 alkyl, and any aryl, heteroaryl, carbocyclyl or heterocyclyl groups present may themselves be replaced by unsubstituted C 1-4 Alkyl, halogen, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl or unsubstituted C1-4 The substituted groups are haloalkoxy or hydroxy.

[0255] "Carboxy" refers to the group -C(O)OH.

[0256] "Cyano" refers to the radical -CN.

[0257] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, the halo group is fluorine or chlorine.

[0258] "Hydroxy" refers to the radical -OH.

[0259] "Nitro" refers to the radical -NO2.

[0260] "Carbocyclylalkyl" refers to an alkyl group 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.

[0261] "Heterocyclylalkyl" refers to an alkyl group 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.

[0262] "Cycloalkenyl" refers to a substituted or unsubstituted carbocyclic group having 3 to 10 carbon atoms and having a single cyclic ring or multiple fused rings (including fused and bridged ring systems) and having at least one, particularly 1 to 2, sites of olefinic unsaturation. Such cycloalkenyl groups include, for example, monocyclic structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[0263] "Fused cycloalkenyl" refers to a cycloalkenyl group having two of its ring carbon atoms shared with a second aliphatic or aromatic ring and wherein the olefinic unsaturation is positioned to render the cycloalkenyl ring aromatic.

[0264] "Ethylene" means a substituted or unsubstituted -(CC)-.

[0265] "Vinyl" means a substituted or unsubstituted -(C=C)- group.

[0266] "Ethynyl" refers to -(C≡C)-.

[0267] "Nitrogen-containing heterocyclic group" refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines, such as N-methylpiperazine. Specific examples include azetidine, piperidone and piperazinone.

[0268] "Thioketo" refers to the group =S.

[0269] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted (e.g., "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). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, such as a substituent that, upon substitution, results in a stable compound, such as a compound that does not spontaneously undergo transformation (e.g., 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 substituent at each position is the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds (any substituents described herein that result in the formation of stable compounds). For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatoms and result in the formation of a stable moiety.

[0270] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )-TXk、-N(OR cc )R bb , -SH, -SR aa 、-SSR CC 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc 2. -CO2R aa 、-OC(=O)R aa 、-OCO2Raa 、-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(Rbb )2、-OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2.-NR bb P(=O)(OR cc )2.-NR bb P(=O)(NR bb )2. -P(R CC )2. -P(R CC )3.-OP(R cc )2.-OP(R cc )3. -B(R aa )2、-B(OR cc )2. -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0271] or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)0R aa , =NNR bb S(=O)2R aa , =NR bb or = NOR CC Replacement;

[0272] R aa In each case, independently selected from C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd group substitution;

[0273] R bb is independently selected at each occurrence from hydrogen, -OH, -OR aa 、-N(R CC )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R CC 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa ,-P(=O)(R aa )2、-P(=O)2N(R cc )2, -P(=O)(NR cc 2. C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R bb The groups are connected to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0274] R cc is independently selected at each occurrence from hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R ccThe groups are connected to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0275] R dd is independently selected at each occurrence from 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 S02R ee 、-SO2N(R ff 2. -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee)3.-OSi(R ee )3. -C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2.-OP(=O)(R ee )2.-OP(=O)(OR ee 2. C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may be linked to form =O or =S;

[0276] R ee In each case, independently selected from C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R gg Group substitution;

[0277] R ff is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff The groups are connected to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution; and

[0278] R ggis independently at each occurrence halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 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(=0)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)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 Carbocyclic group, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - It is a counter ion.

[0279] "Counter ions" or "anionic counter ions" are negatively charged groups that associate with cationic quaternary amino groups to maintain electronic neutrality. Exemplary counter ions include halides (e.g., F - , Cl - Br - ,I - )、NO3 - 、ClO4 - OH - 、H2PO4 - 、HSO4 - 、SO4 2-Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0280] The nitrogen atoms may be substituted or unsubstituted, as 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 Carbocyclic group, 3- to 14-membered heterocyclic group, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R attached to a nitrogen atom cc The groups are connected to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc and R ddAs defined above.

[0281] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims.It is not intended that the present invention be limited in any manner by the foregoing list of exemplary substituents.

[0282] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or equivalent in countries outside the United States or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0283] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has 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, which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- or (2) when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochlorides, hydrobromides, tartrates, methanesulfonates, acetates, maleates, oxalates, etc.

[0284] "Pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge et al., J. Pharm. Sci. 66 (1): 1-79 (January 1977).

[0285] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0286] "Pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to produce the parent molecule of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR and -CH2OR groups, wherein R at each occurrence is independently selected from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxyl or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl.

[0287] "Prodrug" refers to a compound having a cleavable group and becoming a compound of the present invention having pharmaceutical activity in vivo by solvolysis or under physiological conditions, including derivatives of the compound of the present invention. Such examples include, but are not limited to, choline ester derivatives, N-alkyl morpholine esters, etc. Other derivatives of the compound of the present invention are active in its acid and acid derivative forms, but generally provide solubility, tissue compatibility or delayed release advantages in mammalian organisms in acid-sensitive forms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives known to those skilled in the art, such as esters prepared by the reaction of parent acid with suitable alcohols, or amides prepared by the reaction of parent acid compounds with substituted or unsubstituted amines, or anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from the acidic groups of the side joints on the compound of the present invention are specific prodrugs. In some cases, it is desirable to prepare a double ester type prodrug, such as an (acyloxy)alkyl ester or a (alkoxycarbonyl)oxy)alkyl ester. 2-8 Alkenyl, C 2-8 Alkynyl, aryl, C 7-12 Substituted aryl and C 7-12 Aryl alkyl esters.

[0288] "Solvate" refers to a form of a compound that is combined with a solvent or water, usually by a solvolysis reaction (also referred to as a "hydrate"). This physical combination includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, etc. The compounds of the present invention can be prepared, for example, in a crystalline form, and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate can be separated, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solution phase and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0289] As used herein, "subject" refers to a living mammal. In various embodiments, the subject is a non-human mammal, including but not limited to mice, rats, hamsters, guinea pigs, rabbits, sheep, goats, cats, dogs, pigs, horses, cattle, or non-human primates. In one embodiment, the subject is a human.

[0290] As used herein, a "subject with a fungal infection" refers to a subject that exhibits at least one objective manifestation of a fungal infection. In one embodiment, a subject with a fungal infection is a subject that has been diagnosed as having a fungal infection and is in need of treatment. Methods for diagnosing fungal infections are well known and need not be described in detail here.

[0291] As used herein, "a subject having a yeast infection" refers to a subject that exhibits at least one objective manifestation of a yeast infection. In one embodiment, a subject having a yeast infection is a subject that has been diagnosed as having a yeast infection and is in need of treatment for the infection. Methods of diagnosing yeast infections are well known and need not be described in detail herein.

[0292] As used herein, the phrase "effective amount" refers to any amount sufficient to achieve a desired biological effect.

[0293] As used herein, the phrase "therapeutically effective amount" refers to an amount sufficient to achieve the desired therapeutic effect, such as treating a fungal or yeast infection.

[0294] For any compound described herein, a therapeutically effective amount can generally be initially determined from in vitro studies, animal models, or both. In vitro methods are well known and may include determining the minimum inhibitory concentration (MIC), the minimum fungicidal concentration (MFC), the concentration at which growth is inhibited by 50% (IC 50 ), the concentration at which growth is inhibited by 90% (IC 90 ) and the like. The therapeutically effective amount can also be determined by human data of compounds of the present invention and compounds known to exhibit similar pharmacological activity, such as other related active agents (e.g., AmB), which have been tested in humans. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and efficacy of the administered compound. It is entirely within the capabilities of ordinary technicians to adjust the dose to achieve maximum efficacy based on the methods described herein and other methods known in the art.

[0295] For any compound described herein, the therapeutically effective amount for human subjects can be initially determined by in vitro studies, animal models, or in vitro studies and animal models. The therapeutically effective amount for human subjects can also be determined by the compounds of the present invention tested in humans and known compounds that show similar pharmacological activity, such as human data of other related activators (e.g., AmB). Parenteral administration may require higher dosages. The applied dosage can be adjusted based on the relative bioavailability and effectiveness of the compound administered. It is completely within the capabilities of ordinary technicians to adjust the dosage based on the above methods and other methods known in the art to achieve maximum effectiveness.

[0296] As used herein, "inhibit" or "inhibiting" refers to a reduction in an objectively measurable amount or degree compared to a control. In one embodiment, inhibition refers to a reduction in at least a statistically significant amount compared to a control. In one embodiment, inhibition refers to a reduction of at least 5% compared to a control. In various independent embodiments, inhibition refers to a reduction of at least 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, or 95% compared to a control.

[0297] In one embodiment, "treating" or "treatment" or "therapeutic treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent, or severity of at least one clinical symptom thereof). In another embodiment, "treating" refers to improving at least one physical parameter, which may be imperceptible to the subject. In yet another embodiment, "treating" refers to regulating the disease or disorder physically (e.g., stabilization of perceptible symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" involves slowing the progression of a disease. For example, in one embodiment, the term "treating" refers to performing an intervention to result in (a) inhibiting a fungal infection, e.g., slowing or arresting its development; or (b) alleviating or ameliorating a fungal infection, e.g., causing regression of a fungal infection.

[0298] "Preventing" or "prevention" or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., preventing the development of at least one clinical symptom of a disease prior to the onset of the disease in a subject not yet exposed to the disease-causing agent or susceptible to the disease).

[0299] It is also to be 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."

[0300] Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, and are designated as right- or left-handed (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".

[0301] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and differ in the displacement of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium by the movement of their electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert by treatment with an acid or base. Another example of tautomerism is the acid- and nitro- forms of phenylnitromethane, which are also formed by treatment with an acid or base. Tautomeric forms may be relevant to obtaining the best chemical reactivity and biological activity for the compounds of interest.

[0302] As used herein, a pure enantiomer compound is substantially free of the other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and is therefore an enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight, or greater than 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0303] As used herein and unless otherwise indicated, the term "enantiomerically pure R-compound" refers to at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, at least about 99% by weight of the R-compound and at most about 1% by weight of the S-compound, or at least about 99.9% by weight of the R-compound and at most about 0.1% by weight of the S-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0304] As used herein and unless otherwise indicated, the term "enantiomerically pure S-compound" or "S-compound" refers to at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, at least about 99% by weight of the S-compound and up to about 1% by weight of the R-compound, or at least about 99.9% by weight of the S-compound and up to about 0.1% by weight of the R-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0305] In the compositions provided herein, the enantiomerically pure compound or its pharmaceutically 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% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may, for example, comprise at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound by the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may, for example, comprise at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound by the total weight of the compound. In certain embodiments, the active ingredient may be formulated with almost no excipient or carrier.

[0306] The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0307] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and racemic or other mixtures thereof.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0308] The phrases "conjoint administration" and "administered conjointly" refer to any form of administration of two or more different therapeutic compounds so that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are effective in the patient's body at the same time, which may include a synergistic effect of the two compounds). For example, different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or in separate formulations. In certain embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or a week of each other. Therefore, individuals receiving such treatment can benefit from the combined effects of different therapeutic compounds.

[0309] As used herein, "fungal infection" refers to a subject being infected with a fungus as defined herein. In one embodiment, the term "fungal infection" includes a yeast infection. As used herein, "yeast infection" refers to a subject being infected with a yeast as defined herein.

[0310] As used herein, "active ingredient," "therapeutically active ingredient," "active agent," "drug," or "drug substance" refers to the active component of a drug, also known as an active pharmaceutical ingredient (API).

[0311] As used herein, "drug loading" refers to the percentage of active ingredient in the total mass of the formulation on a mass basis.

[0312] The term "about" refers to variations in values ​​typically encountered by those skilled in the art of inhalable formulations, including variations of plus or minus 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the values ​​recited herein.

[0313] Throughout the specification and the claims that follow, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to mean the inclusion of a specified integer or step, or group of integers or steps, but not the exclusion of any other integer or step, or group of integers or steps.

[0314] Unless otherwise stated or clear from the context, numerical ranges include the endpoints and any values ​​therebetween.

[0315] Packaging of pharmaceutical products

[0316] In a further aspect, provided herein is a packaged pharmaceutical product comprising a composition of the present invention.

[0317] In certain embodiments, the composition is a sustained release composition.

[0318] In certain embodiments, the composition is an intravenous dosage form.

[0319] As mentioned above, "effective amount" refers to any amount sufficient to achieve the desired biological effect. In combination with the teachings provided herein, by selecting among various active compounds and weighing factors such as efficacy, relative bioavailability, patient weight, severity of adverse side effects and preferred modes of administration, an effective preventive or therapeutic treatment regimen can be planned that does not cause substantial undesirable toxicity and still effectively treats a particular subject. The effective amount for any particular application can vary according to factors such as the disease or condition being treated, the specific compound of the present invention being administered, the size of the subject, or the severity of the disease or condition. Those of ordinary skill in the art can empirically determine the effective amount of a specific compound of the present invention and / or other therapeutic agents without excessive experimentation. It is generally preferred to use the maximum dose, i.e., the highest safe dose according to some medical judgment. Multiple doses per day can be considered to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the peak or sustained plasma levels of the patient's drug. "Dose" and "dosage" are used interchangeably herein.

[0320] In some embodiments, the intravenous administration of the compound of the present invention may generally be 0.1 mg / kg / day to 20 mg / kg / day. Therefore, intravenous administration may be similar to or advantageously may exceed the maximum tolerated dose of AmB. Intravenous administration may also be similar to or advantageously may exceed the maximum tolerated daily dose of AmB. Intravenous administration may also be similar to or advantageously may exceed the maximum tolerated cumulative dose of AmB.

[0321] Intravenous administration may also be similar to or advantageously may exceed the maximum recommended dose of AmB. Intravenous administration may also be similar to or advantageously may exceed the maximum recommended daily dose of AmB. Intravenous administration may also be similar to or advantageously may exceed the maximum recommended cumulative dose of AmB.

[0322] For any compound described herein, the therapeutically effective amount can be initially determined by an animal model. The therapeutically effective dose can also be determined by human data of compounds of the present invention and known compounds that exhibit similar pharmacological activity, such as other related active agents, that have been tested in humans. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and efficacy of the administered compound. It is entirely within the capabilities of ordinary technicians to adjust the dose based on the above methods and other methods known in the art to achieve maximum efficacy.

[0323] The formulations of the present invention are administered in pharmaceutically acceptable solutions, which may generally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0324] Amphotericin B is commercially available in a variety of formulations, including deoxycholate-based (sometimes referred to as desoxycholate-based) formulations and lipid-based (including liposomes) formulations.

[0325] For intravenous administration, the active pharmaceutical ingredient can be stabilized in micelles. In certain embodiments, the micelles are formed by block copolymers. In further embodiments, the micelles are formed by multiple components (e.g., block copolymers and deoxycholate compounds) and can therefore be referred to as "mixed micelles."

[0326] When it is desired to deliver them systemically, the compound can be formulated to be administered parenterally by injection, for example by bolus injection or continuous infusion. Injection preparations can be presented in unit dosage form, for example in ampoules or multidose containers to which a preservative is added. Alternatively, injection preparations can be formulated to be sustained or slow release. The composition can be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain preparatons, such as suspending agents, stabilizers and / or dispersants. Stabilizers include, for example, compounds capable of forming micelles.

[0327] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In addition, the suspension of the active compound can be prepared as a suitable oily injection suspension. 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 can contain substances that improve the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also contain a suitable stabilizer or improve the solubility of the compound to allow the preparation of a highly concentrated solution or improve the half-life of the compound in solution.

[0328] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0329] In addition to the above formulations, the compound can also be formulated as a storage preparation (depot preparation). Such long-acting preparations can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0330] The pharmaceutical composition may also comprise a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycol.

[0331] Suitable liquid or solid pharmaceutical preparation forms are aqueous or saline solutions for inhalation, microencapsulation, encochleated, coated on microscopic gold particles, contained in liposomes, atomized, aerosol, pellets for implantation in the skin, or dried on sharp objects to scratch into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with extended release of active compounds, in which excipients and additives and / or adjuvants are routinely used as described above in their preparation, such as disintegrants, adhesives, coatings, swelling agents, lubricants, flavorings, sweeteners or solubilizers. The pharmaceutical composition is suitable for use in various drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249: 1527-33 (1990), which is incorporated herein by reference.

[0332] The compounds of the present invention and optionally other therapeutic agents can be administered in themselves (pure) or in the form of pharmaceutically acceptable salts. When used in medicine, salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can be conveniently used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared by 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. In addition, such salts can be prepared as alkali metal or alkaline earth metal salts, such as sodium salts, potassium salts or calcium salts of carboxylic acid groups.

[0333] Suitable buffers include: acetic acid and salts (1-2% w / v); citric acid and salts (1-3% w / v); boric acid and salts (0.5-2.5% w / v); and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[0334] The pharmaceutical compositions of the present invention contain an effective amount of a compound of the present invention and optionally at least one additional therapeutic agent in a pharmaceutically acceptable carrier.

[0335] The therapeutic agent (specifically including but not limited to the compounds of the present invention) can be provided in the form of particles. As used herein, particles refer to nanoparticles or microparticles (or larger particles in some cases), which can be composed of compounds of the present invention or other therapeutic agents as described herein in whole or in part. The particles can contain therapeutic agents in a core surrounded by a coating (including but not limited to an enteric coating). The therapeutic agent can also be dispersed throughout the particles. The therapeutic agent can also be adsorbed into the particles. The particles can have any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic agent, the particles can also include any material conventionally used in the field of pharmacy and medicine, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof. The particles can be microcapsules containing the compounds of the present invention in solution or in a semi-solid state. The particles can have almost any shape.

[0336] Non-biodegradable and biodegradable polymeric materials can all be used to manufacture particles for delivering therapeutic agents.Such polymers can be natural or synthetic polymers.Select polymers based on the duration of expected release.Particularly interesting bioadhesive polymers are included in the bioerodible hydrogels described in the people such as Sawhney HS (1993) Macromolecules 26:581-7, and its teaching is incorporated into this paper.These include polyhyaluronic acid, casein, gelatin, gelatin protein (glutin), polyanhydride, 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).

[0337] Therapeutic agents, such as compounds described herein, can be provided in micellar formulations. Micellar formulations can be prepared using standard techniques whereby the polymer component (e.g., lipopolymer excipient) and the active pharmaceutical ingredient are thoroughly mixed or blended. Mechanical mixing procedures can be used to achieve full blending of the ingredients of the composition.

[0338] The injection device, such as a syringe, can be prepared by using any technique to contain the micellar formulation, thereby placing the composition in the injection device so that the composition can be injected through the device. For example, the composition of the present invention can be placed in the barrel of a syringe by mechanical means or extrusion.

[0339] The compositions of the present invention can be stored for a considerable period of time. In certain embodiments, the compositions can be stored at room temperature or at a temperature below room temperature.

[0340] The composition of the present invention can be placed in a sterile container for subsequent drug formulation. Such a container can be a sealed vial, which preferably contains enough space for the subsequent addition of a physiologically acceptable aqueous carrier. Therefore, the composition of the present invention can be used to produce drug-containing micelles in the above-mentioned container after the introduction of an aqueous carrier. The dissolution of the composition in the carrier and the subsequent formation of drug-containing micelles can be accelerated over time by stirring (e.g., shaking) or without stirring.

[0341] The method of administering the composition according to the present invention can be carried out according to methods known in the art. The method for injecting such a composition or solution at a selected site in the patient's body can be selected and performed by a medical professional.

[0342] In certain embodiments, the lipid polymer excipient in the composition of the present invention is a biocompatible micelle-forming polymer. Exemplary biocompatible micelle-forming polymers include polymers known in the art, such as those described in WO 01 / 87345. In certain embodiments, one or more micelle-forming polymers in the composition of the present invention are diblock copolymers suitable for forming micelles as taught in the art or as specifically described herein.

[0343] The hydrophobic portion of such a diblock copolymer may comprise one or more hydrophobic polymers, such as polyesters, polyanhydrides, polyglycolic acid, polybutyrolactone, polyhydroxybutyrate, polylactic acid, and polycaprolactone. The hydrophobic portion of the copolymer may comprise one or more different random or block oriented hydrophobic polymers. In certain embodiments, the hydrophobic portion of the copolymer has a molecular weight of about 200 to about 5000.

[0344] The hydrophilic portion of the micelle-forming copolymer useful in the present invention has a molecular weight of from about 750 to about 8000. In some embodiments, the molecular weight is in the range of about 1000 or 2000-3000 or 5000. In some embodiments, the hydrophilic portion of the micelle-forming copolymer is polyethylene glycol.

[0345] The weight ratio of the hydrophobic and hydrophilic components of the micelle-forming polymers used in the present invention can be adjusted to provide the desired chemistry, manufacturing and control. For injection, it is preferred that the amount of the lipopolymer excipient is such that the resulting mixture or matrix is ​​injectable (as defined herein). The amount of active pharmaceutical ingredient included in the composition is such that the desired amount of drug-loaded micelles is provided, preferably not exceeding an amount that can be fully distributed within the micelle-forming composition.

[0346] In certain embodiments, the drug-loaded micelles in the compositions of the present invention are freeze-dried after preparation and stored in a dry state. The dried micelles can be reconstituted in a pharmaceutically acceptable carrier, such as sterile saline or sterile dextrose solution, e.g., 5% dextrose, and after thorough hydration, they can be filter-sterilized (optionally through a 0.22 μm filter) before administration.

[0347] The therapeutic agent can be included in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the mode and curve of drug release from the formulation are controlled. This refers to immediate release formulations as well as non-immediate release formulations, which include but are not limited to sustained release formulations and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a drug formulation that provides a gradual release of the drug over an extended period of time, and preferably but not necessarily results in a blood drug concentration that is substantially constant 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 the administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not involve gradually releasing the drug over an extended period of time, and therefore may or may not be "sustained release".

[0348] The use of long-term sustained release implants may be particularly useful for treating chronic conditions. As used herein, "long-term" release means that the implant is constructed and arranged to deliver therapeutic levels of active ingredients for at least 7 days, preferably 30-60 days. Long-term sustained release implants are well known to those of ordinary skill in the art, and include some of the above-mentioned release systems.

[0349] Example

[0350] Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herein for purposes of illustration only and are not intended to limit the present invention.

[0351] Amphotericin B derivatives used in the compositions of the present invention, as well as synthetic routes and experimental procedures for making these compounds, are disclosed in, for example, WO 2015 / 175875, WO 2021 / 026520, and WO 2022 / 035752, the disclosures of which are incorporated herein by reference.

[0352] Example 1: Stability and plasma compatibility of AM-2-19

[0353]

[0354] AM-2-19 (and its acetate AM-2-19-OAc) is a potent antifungal compound that exhibits superior potency against many fungal pathogens compared to AmB and other AmB derivatives, exhibits a long half-life, and reduces nephrotoxicity. However, AM-2-19 has poor plasma compatibility and solution stability over time.

[0355] The in vitro plasma compatibility of AM-2-19 in human plasma is shown below:

[0356]

[0357] like Figure 1 As shown in , AM-2-19 lacks solution stability in IV compatible solvents, such as 5% dextrose / water (D5W).

[0358] The following experiments were performed to improve the plasma compatibility and solution stability of this promising antifungal compound.

[0359] Example 2: Stability and plasma compatibility of micellar formulations

[0360] Several micellar formulations of AM-2-19OAc were prepared and tested according to the following protocol:

[0361] Mix 0.5 mL of the formulation solution (2.5 mg / mL) into 0.5 mL of plasma (ITR regimen)

[0362] Visually inspect the solution

[0363] Spin it at 1600g and check for pelleting

[0364] Spin it at 5000g and check for pelleting

[0365] Spin it at 20,000 g and check for pelleting

[0366] Negative control: AM-2-19-OAc in D5W, saline and water

[0367] Positive controls: D5W, saline, and water only

[0368] Plasma incompatibility is manifested as a turbid mixture after mixing the micellar formulation with plasma. In addition, the presence of a pellet after centrifugation of the plasma-micelle formulation mixture indicates plasma incompatibility.

[0369] The result is shown below.

[0370] Micellar formulation of AM-2-19-Oac

[0371]

[0372] Control preparation

[0373]

[0374] Formulations of AM-2-19-OAc and DSG-PEG-2000 showed plasma compatibility in D5W, saline, and water, whereas none of the AM-2-19-OAc formulations alone showed plasma compatibility.

[0375] The images of AM-2-19-OAc and DSG-PEG-2000 formulations (i.e., Experiments 2, 3, and 4) after plasma addition are shown in Figure 2A , while the images of negative control preparations (i.e., Experiments 23, 24, and 25) after plasma addition were shown in Figure 2B middle.

[0376] Example 3: Formulation of AM-2-19-FB (free base) in 30 mM acetate / D5W pH 5, DSG-PEG2000

[0377] As shown in Example 1, the concentration of AM-2-19-OAc in D5W solution changes over time. In addition, the solution of AM-2-19-OAc in D5W is incompatible with plasma, which prevents the intravenous formulation of this compound.

[0378] The inventors hypothesize that the concentration changes may be caused by aggregation and / or adsorption on glass. Similarly, aggregation promoted by pH and the amphiphilic nature of the compound may lead to plasma incompatibility.

[0379] The present inventors have surprisingly discovered that micellar stabilization of amphotericin derivatives, as described in detail below, not only significantly improves stability and plasma compatibility, but also leads to surprising improvements in potency and half-life.

[0380] Note: The molar ratio of AM-2-19-FB:DSG-PEG2000 is fixed at 1:3

[0381] Step 1. Placebo preparation (30 mM acetate / D5W, pH 5, DSG-PEG 2000)

[0382] Prepare 30 mM acetate / D5W using glacial acetic acid in a beaker

[0383] Adjust pH with 10N NaOH

[0384] Transfer to a volumetric flask and use D5W QS

[0385] Recheck pH (usually no change)

[0386] Bubble nitrogen through the solution for 5-15 minutes (depending on the volume prepared)

[0387] Weigh DSG-PEG2000 into the vial

[0388] Weigh the required amount of 30 mM acetate / D5W pH 5 into the vial containing DSG-PEG2000

[0389] Ultrasonic treatment for 5 minutes

[0390] Add a stir bar and stir until completely dissolved.

[0391] Step 2. Preparation of AM-2-19-FB

[0392] Weigh AM-2-19-FB into the vial

[0393] Weigh the required amount of placebo formulation prepared in step 1 and add to the vial

[0394] Vortex for 10 seconds

[0395] Add a stir bar and heat at 50°C for 30 minutes with rapid stirring

[0396] Cool on ice to room temperature

[0397] · Filtered through a 0.22μm PVDF syringe filter

[0398] Lower concentrations of AM-2-19-FB can be prepared by serial dilution of the above formulation using D5W as the diluent.

[0399] Example of 2 mg / mL AM-2-19-FB formulation (typical stock solution concentration)

[0400]

[0401]

[0402] Note: The solubility of AM-2-19-FB in D5W / DSG-PEG2000 (1:3 molar ratio) without acetate buffer is approximately 0.1 mg / mL. The solubility of the free base in the presence of acetate buffer is >8 mg / mL.

[0403] Example 4: Preparation of AM-2-19-OAc Dosing Solution

[0404] The dosing solution was prepared using a micellar solution vehicle containing distearoyl-rac-glycerol PEG 2000 (DSG-PEG 2000) in 5% dextrose / water (D5W). DSG-PEG 2000 is a pegylated lipopolymer excipient that forms mixed micelles when formulated with AM-2-19 and serves to solubilize and stabilize the drug.

[0405] Assumptions:

[0406] Dose levels: 0.3, 1.0, 3.0 and 7.0 mg / kg

[0407] Dog weight - 10kg

[0408] Dose volume - 1 mL / kg (IV bolus)

[0409] Concentration - 0.3, 1.0, 3.0 and 7.0 mg / mL AM-2-19 free base

[0410] Bolus Infusion - 10 mL per animal

[0411] This study requires sterile filtration

[0412] drug:

[0413] AM-2-19 acetate (molecular weight: 1057.24 g / mol). Note that the molecular weight of AM-2-19 free base is 997.19 g / mol.

[0414] Purity and correction factor for AM-2-19 acetate are provided with a Certificate of Analysis.

[0415] Vehicle components:

[0416] Dextrose 5% (D5W) USP should be purchased from a commercial source. This is also known as D-glucose 5% (w / w)

[0417] Distearoyl-rac-glycerol PEG 2000 (DSG-PEG 2000) (molecular weight 2621.4 g / mol).

[0418] Note that over the range of DSG-PEG 2000 concentrations used in this study, the average density of the vehicle was 1.026 g / ml.

[0419] Dosage Formulation Preparation

[0420] Refer to the table below for the amounts of drug (AM-2-19 free base) and DSG-PEG 2000 used to prepare vehicle and dosing solutions. Note that the drug is provided as an acetate salt, so the amount of acetate to be weighed out must be calculated using the correction factor provided on CoA. A program was written to prepare a stock solution of the highest drug concentration, which was then sterile filtered. Lower dosing concentration solutions were prepared by dilution of the high concentration solution (in D5W / glucose 5% (w / w)).

[0421] If necessary, the vehicle solution (DSG-PEG 2000 in D5W) can be prepared in advance, 0.22 um filtered, and stored in a refrigerator (2-8°C) between uses. The vehicle solution is stable for 7 days.

[0422] The dosing solution must be prepared fresh on each day of dosing. The stability of the dosing solution is such that it should be prepared and administered within 6 hours.

[0423] Below are instructions for preparing a 100.0 mL vehicle formulation. The volume can be scaled up to 750 mL (the limit of our experience) as needed:

[0424] 4A. Vehicle preparation (100 mL of 55.20 mg / mL DSG-PEG2000)

[0425] a. Accurately pipette (or weigh) 100.0 mL of D5W into an appropriate glass container

[0426] b. Insert the stirring rod into the container and begin stirring the D5W.

[0427] c. Accurately weigh 5.52 g of DSG-PEG 2000 and transfer to D5W. It may help to add the DSG-PEG 2000 in portions to prevent agglomeration / caking.

[0428] d. Sonicate at room temperature for 5 minutes to promote the dissolution of DSG-PEG 2000.

[0429] e. Stir the solution on a stirring plate at room temperature for at least 15 minutes to ensure complete dissolution of DSG-PEG 2000.

[0430] f. If necessary, sonicate the vehicle for an additional 5 minutes, then stir for 15 minutes or longer until DSG-PEG2000 is completely dissolved. The micellar solution formed should be clear.

[0431] g. Measure and record the final pH.

[0432] h. If the prepared DSG-PEG 2000 solution is used within one day, skip steps i. and j.

[0433] i. Filter the DSG-PEG 2000 solution through a 0.22 um filter. If desired, a larger Millex GV filter (e.g., 33 mm) can be used than the same Durapore PVDF membrane specified above.

[0434] j. When prepared in this manner, the vehicle solution can be prepared in advance and stored in a refrigerator (2-8°C) for 7 days.

[0435] 4B. Preparation of dosing solution

[0436] Dose formulations were prepared fresh on the day of dosing. First, a stock solution of the highest drug concentration to be dosed (7.0 mg / mL) was prepared and sterile filtered. Lower concentration dosing solutions were subsequently prepared by dilution using D5W as a diluent. Test item dose formulations were prepared under a laminar flow hood using clean techniques. These formulations are light sensitive. Therefore, all containers were protected from light during preparation.

[0437] Stock solution preparation (60.0 mL of 7.0 mg / mL dosing solution)

[0438] k. Accurately weigh 420.0 mg of the test item (AM-2-19) into a suitable glass container (Note: Use the correction factor provided on the COA to calculate the amount of AM-2-19 acetate to weigh). AM-2-19 acetate is fluffy and may require static charge reduction.

[0439] 1. Accurately add 60.0 mL of vehicle solution (at room temperature) to dissolve the drug.

[0440] m. Place container in water bath on heated stir plate, cover container and keep covered to minimize evaporation and begin stirring.

[0441] n. Heat the water until it reaches a temperature of 50 ± 2°C while constantly monitoring the temperature by placing a thermometer in the water bath.

[0442] o. Once the water bath reaches a temperature of 50 ± 2°C, continue stirring the formulation for an additional 30 minutes. Monitor the temperature and, if necessary, use ice or cold water to maintain the water bath temperature at 50 ± 2°C.

[0443] p. Remove the flask containing the dosage formulation from the water bath and allow the solution to cool to room temperature by placing the container in an ice bath or by placing it in a fume hood while swirling the flask occasionally.

[0444] q. After equilibrating it to room temperature (15 to 30°C), filter the dose formulation solution using a 0.22um PVDF syringe filter (33mm membrane size) and discard the first 2mL. Lower solution concentrations do not require filtration and should be prepared under a laminar flow hood using clean techniques.

[0445] The recommended dilutions for preparing 35.0 mL of a lower concentration dosing solution are shown in the table below. For example, to prepare a 3.0 mg / mL dosing solution, dilute the 7.0 mg / mL stock solution prepared in steps 2.a-2.g above 1:2.33 with D5W (15.0 mL of stock solution + 20.0 mL of D5W).

[0446]

[0447]

[0448] The time that elapses between preparation of the dosing solution and administration should be less than 6 hours.

[0449] Example 5: Characterization of AM-2-19-OAc-DSG-PEG-2000 Formulation

[0450] The structures of AM-2-19-OAc and DSG-PEG-2000 are shown in Figure 3 middle.

[0451] The micelle size was characterized by dynamic light scattering (DLS), as shown below, which demonstrates the stability of the micelles over time.

[0452] DLS(0h;d nm)* DLS (3h; d nm)* 6.48(100％) 7.54(100％)

[0453] *Based on volume distribution

[0454] like Figure 4 As shown in , the UV spectra did not change significantly over time, indicating the stability of the DSG-PEG2000 micellar formulation of AM-2-19-OAc. In fact, after 24 hours, >98% of the initial concentration was retained.

[0455] Example 6: Aqueous solution stability of AM-2-19-OAc compared to AM-2-19-OAc-DSG-PEG-2000

[0456] The aqueous stability of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 stock solutions in D5W was evaluated at 2.5 mg / mL. AM-2-19-OAc-DSG-PEG-2000 stock solution was prepared by adding AM-2-19-OAc to a solution of DSG-PEG 2000 in D5W to prepare a 1:3 (drug: excipient) composition, which was then stirred at 50°C for 30 minutes to form a micellar formulation.

[0457] To measure the solution stability of each solution, aliquots were carefully collected from the top of each stock solution at predetermined time points and diluted 500-fold with methanol for UV measurement. In the AM-2-19-OAc stock solution, >10% concentration loss was recorded over 6 hours ( Figure 5A In contrast, the AM-2-19-OAc-DSG-PEG-2000 stock solution remained stable and no significant loss in concentration was observed after 6 h at room temperature ( Figure 5B ).

[0458] Example 7: Solution Behavior of AM-2-19-OAc-DSG-PEG-2000

[0459] The solution behavior of AM-2-19-OAc-DSG-PEG-2000 was evaluated using UV-Vis and NMR techniques. The UV spectrum of AM-2-19-OAc solution was found to be concentration-dependent, where the monomer-like UV at lower concentrations transformed into an aggregate-like spectrum at higher concentrations, with an absorption peak at 410 nm ( Fig. 6A In AM-2-19-OAc-DSG-PEG-2000, no such concentration-dependent UV changes were observed, and a sharp absorption peak appeared at 415 nm, which was presumably derived from the drug encapsulated in the micelles ( Figure 6C &6D).

[0460] To further understand the encapsulation phenomenon, solutions of AM-2-19-OAc, AM-2-19-OAc-DSG-PEG-2000, and DSG-PEG-2000 were prepared in deuterated D5W and subjected to 4% CO 2 at variable temperatures. 1 H-NMR detection. In the DSG-PEG-2000 control, no characteristic peaks were observed until 35°C. However, at ~40°C, a clear peak appeared, which may be attributed to the micelle phase transition ( Figure 7). See Otten, D. et al., Biophysical Journal, 1995, 68(2), 584-597. When the same experiment was performed with AM-2-19-OAc-DSG-PEG-2000, no characteristic AM-2-19 peak was observed between 25-36°C ( Figure 7 However, at ∼40 °C (which corresponds to the micellar phase transition), the polyene signal of AM-2-19 begins to appear, consistent with the faster relaxation of the encapsulated drug molecules during the phase transition of DSG-PEG-2000 ( Figure 7 In the absence of DSG-PEG 2000 micelles, the polyene signal of AM-2-19 can be seen at 25 °C ( Figure 7 ). These results indicate that most of the drug molecules were encapsulated in AM-2-19-OAc-DSG-PEG-2000.

[0461] Example 8: Spectral antifungal activity of AM-2-19-OAc-DSG-PEG-2000 formulation

[0462] AM-2-19-OAc-DSG-PEG-2000 formulations were tested against various fungal strains and compared with AmB, AM-2-19-OAc (in vehicle) and DSG-PEG-2000 micelles (without API). The results are given in the table below:

[0463]

[0464]

[0465] Surprisingly, DSG-PEG-2000 enhanced the in vitro potency of AM-2-19-OAc.

[0466] Additionally, DSG-PEG-2000 increased the in vivo half-life of AM-2-19-OAc compared to the half-life of AM-2-19-OAc not in a micellar formulation (see Figure 8 ).

[0467] Micellar formulations also provide favorable tissue distribution data in mice (see Fig. 9 ).

[0468] Example 9: AM-2-19-OAc-DSG-PEG-2000 retains characteristic UV spectrum in RPMI

[0469] To probe the structure of AM-2-19-OAc-DSG-PEG-2000 under biologically relevant conditions, 320 μM stock solutions of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 were diluted with RPMI 1640 (pH = 7) to simulate in vitro antifungal efficacy evaluation conditions. The characteristic 415 nm UV peak of micellar AM-2-19-OAc-DSG-PEG-2000 was retained at concentrations ≥ 2 μM, while the characteristic AM-2-19-OAc 410 nm UV peak was not observed in the diluted samples ( Figures 10A-10D The retention of the micellar structure at these concentrations is consistent with the improved MICs of AM-2-19-OAc-DSG-PEG-2000 compared to AM-2-19-OAc against the fungal isolates.

[0470] Example 10: Binding of AM-2-19 in AM-2-19-OAc-DSG-PEG-2000 to plasma proteins

[0471] The effects of plasma dilution and albumin titration on AM-2-19-OAc-DSG-PEG-2000 were investigated, which simulates the fate of the drug molecule after IV administration or infusion. The UV spectra of the stock solutions of AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 include their respective characteristic peaks at 410 nm and 415 nm ( Fig.11A &11B). However, after dilution with plasma, the UV spectra of both AM-2-19-OAc and AM-2-19-OAc-DSG-PEG-2000 solutions provided a characteristic peak at 418 nm, indicating that AM-2-19 binds to plasma proteins ( Fig. 11C &11D).

[0472] Similar peaks were observed when human serum albumin was used to titrate these two solutions ( Fig. 11C &11D). See Xie, M et al., Biochim Biophys Acta. 2006, 1760(8), 1184-91.

[0473] The two solutions were titrated with albumin and the UV spectra of the resulting solutions were measured at various ratios of AM-2-19 to albumin ( Figures 12A-12D ). The shift of the UV spectrum of each solution begins to appear at a 1:0.8 ratio. For the titration of AM-2-19-OAc, a broad transition from 410 nm to 418 nm peak was recorded at a 1:1 ratio ( Fig. 12A & 12B), while AM-2-19-OAc-DSG-PEG-2000 produced a sharp red shift from 415 nm to 418 nm at a 1:1 ratio ( Fig. 12C&12D), indicating that AM-2-19-OAc-DSG-PEG-2000 efficiently transferred AM-2-19 to albumin.

[0474] These data suggest that AM-2-19-OAc-DSG-PEG-2000 provides improved aqueous stability and plasma compatibility and retains the micellar structure at biologically relevant concentrations without interfering with binding to plasma proteins.

[0475] Example 11: Analysis of toxicity biomarkers

[0476] A panel of AM-2-19-OAc formulations, other AmB formulations, and a control formulation were evaluated for toxicity.

[0477] like Fig.13 As shown in Figure 3, AM-2-19-OAc-DSG-PEG-2000 did not increase common toxicity biomarkers.

[0478] Fig.14 This indicates that AM-2-19-OAc-DSG-PEG-2000 retains a loss of toxicity in vitro.

[0479] Fig.15 Shown is a series of histopathology graphs demonstrating that AM-2-19-OAc-DSG-PEG-2000 formulations do not cause renal damage in mice, rats, or dogs.

[0480] Example 12: Toxicokinetics

[0481] The toxicokinetics and tolerability of a single dose of AM-2-19-OAc-DSG-PEG-2000 was studied in rats. The following table summarizes the experimental setup.

[0482]

[0483] Toxicity biomarkers are shown in Fig.16 middle.

[0484] AM-2-19-OAc-DSG-PEG-2000 was also evaluated in dogs over a two-week period and at several dosing schedules. All dogs survived at all doses in the dosing schedules, with no clinical observations or signs of distress in any dog. There was also no change in food intake in any dog.

[0485] Results for regimen A (dosing every other day) are shown in Fig.17 middle.

[0486] Results for regimen B (dosing every four days) are shown in Fig.18 middle.

[0487] The results of regimen C (weekly dosing) are shown in Fig.19 middle.

[0488] Example 13: Efficacy of Micellar Formulations

[0489] AM-2-19-OAc-DSG-PEG-2000 is a highly potent antifungal agent against a range of fungal infections, including resistant and refractory strains and other difficult-to-treat fungi such as Aspergillus terreus. Fig. 20 As shown in , AM-2-19-OAc-DSG-PEG-2000 exhibits a lower minimum inhibitory concentration (MIC) against many strains of yeast and mold (including resistant and refractory Candida albicans ATCC 90028) than the liposomal formulation of amphotericin B, Ambisome. Fig.21 As shown in , AM-2-19-OAc-DSG-PEG-2000 significantly reduced fungal burden in kidney and lung tissues compared to controls and AmBisome in various fungal strains. Fig.21 In the graph, "Pre" represents the fungal load at t (time) = 0.

[0490] Example 14: Application of the Micellar Formulation Platform to Additional AmB Derivatives

[0491] The surprising benefits of DSG-PEG 2000 micellar formulations are not limited to AM-2-19-OAc. Other derivatives of amphotericin B were formulated with DSG-PEG 2000, including AmB amide and C2'epi amide, having the structures shown below.

[0492]

[0493]

[0494] For the compounds to be studied, 2 mg of the compound was weighed into a clean 7 mL glass vial. Then, 3 equivalents of DSG-PEG 2000 (DP2K) were weighed into a separate 7 mL glass vial.

[0495] 1 mL of D5W was added to the second vial and sonicated for 15 minutes to prepare a clear solution of DP2K and, for C2'epic compound, filtered through a 0.22 μm syringe filter. The solution in the first vial containing the compound (as acetate) was transferred to the DP2K solution and stirred at 50°C for 30 minutes to make a clear yellow solution. The solution was then cooled to room temperature.

[0496] like Fig. 22As shown in the table below, the DSG-PEG 2000 micelle formulation also significantly improved the solution stability of AM-290-2, AM-243-2, C2'epiMA, and C2'epiC5. Fig. 22 UV spectra of samples with a target concentration of 2 mg / mL are shown. Samples at different time points were prepared by diluting 10 μl aliquots with 990 μl MeOH (100-fold dilution). As shown, the UV spectra did not change significantly over time, indicating the stability of the DSG-PEG 2000 micellar formulation of the AmB derivative.

[0497] Table: Concentration of AmB derivatives over time in DSG-PEG 2000 micellar formulation and in D5W vehicle

[0498]

[0499]

[0500] Incorporated by reference

[0501] All patents and published patent applications mentioned in the above specification are incorporated herein by reference in their entirety.

[0502] Equivalent

[0503] The present invention has been fully described in considerable detail by way of illustration and example for ease of understanding, but it will be apparent to one of ordinary skill in the art that the present invention may be practiced by modifying or changing the present invention within a broad and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any specific embodiment thereof, and such modifications or changes are intended to be included within the scope of the appended claims.

Claims

1. A composition comprising: (i) a lipopolymer excipient having a structure of formula (X); wherein each occurrence of n is independently selected from 0-10; and m is selected from 10-60; and (ii) a compound selected from the group consisting of: A compound having the structure of formula (I): and a compound having the structure of formula (II): in: R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; or R 1 and R 2 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclyl; R 3 Yes - NR 5 R 6 , substituted or unsubstituted amino, substituted or unsubstituted urea, substituted or unsubstituted carbamate or substituted or unsubstituted guanidino; R 4 is hydrogen or substituted or unsubstituted C 1-6 alkyl; R 5 and R 6 are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; or R 5 and R 6 Together with the nitrogen to which they are attached, they form a substituted or unsubstituted 3- to 10-membered heterocyclyl; and R f Selected from the group consisting of 2-en-1-yl, tert-butyl, benzyl and fluorenylmethyl.

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

3. The composition of claim 1, wherein the compound is C2'epiAmB.

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

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

6. The composition according to claim 1, wherein the compound is a compound having a structure of formula (I) or formula (II); and R 1 and R 2 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

7. The composition according to claim 1 or 6, wherein the compound is a compound having a structure of formula (I) or formula (II); and R 1 and R 2 are independently hydrogen, unsubstituted C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, alkoxy C 1-6 Alkyl, halogenated C 1-6 Alkyl, amino C 1-6 Alkyl, heterocyclic C 1-6 Alkyl, unsubstituted C 2-6 Alkynyl, unsubstituted C 3-10 Carbocyclic group, amino C 3-10 carbocyclyl, unsubstituted 3- to 10-membered heterocyclyl, or hydroxy 3- to 10-membered heterocyclyl.

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

9. The composition according to any one of claims 1 and 6-8, wherein the compound is a compound having a structure of formula (I) or formula (II); and R 1 and R 2 Not all hydrogen.

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

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

12. The composition according to claim 11, wherein R 5 and R 6 are independently hydrogen, C(O)OR f , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-10 carbocyclic group, substituted or unsubstituted 3- to 10-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl.

13. The compound according to claim 12, wherein R 5 and R 6 are independently hydrogen or C(O)OR f , choose any one of R f It is fluorenylmethyl.

14. The composition according to claim 11, wherein R 5 and R 6 At least one of the atoms is hydrogen.

15. The composition according to claim 11, wherein R 5 and R 6 It's all hydrogen.

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

17. The composition according to claim 16, wherein R 4 is hydrogen, halogenated C 1-6 Alkyl or unsubstituted C 2-6 Alkenyl.

18. The composition according to claim 17, wherein R 4 It's hydrogen.

19. The composition of claim 1, wherein the compound is selected from the group consisting of:

20. The composition of claim 1, wherein the compound is selected from the group consisting of:

21. The composition of claim 1, wherein the compound is selected from the group consisting of:

22. The composition of claim 21, wherein the compound is:

23. The composition of claim 21, wherein the compound is:

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

25. The composition of claim 1, wherein the compound is:

26. The composition of claim 1, wherein the compound is:

27. The composition of any one of claims 1-26, wherein each occurrence of n is independently selected from 1-9.

28. The composition of any one of claims 1-26, wherein each occurrence of n is independently selected from 2-8.

29. The composition of any one of claims 1-26, wherein each occurrence of n is independently selected from 3-7.

30. The composition of any one of claims 1-26, wherein each occurrence of n is independently selected from 4-6.

31. The composition of any one of claims 1-26, wherein each occurrence of n is 5.

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

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

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

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

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

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

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

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

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

1.

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

1.

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

1.

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

1.

44. The composition of claim 1 comprising, consisting essentially of, or consisting of: (i) a lipopolymer excipient having a structure of formula (X); wherein n is 5; and M is 44; and (ii) a compound represented by the following formula: The molar ratio of the lipid polymer excipient to the compound is about 3:

1.

45. The composition of any one of claims 1-44, wherein the antifungal efficacy of the composition is greater than the antifungal efficacy of the compound alone.

46. ​​The composition of claim 45, wherein the in vitro antifungal efficacy of the composition is greater than the in vitro antifungal efficacy of the compound alone.

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

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

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

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

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

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

53. The method of claim 51 or 52, wherein the subject is a mammal; or a primate, canine, feline, or bovine; or a human; or a human.

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

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

56. A composition according to any one of claims 1 to 50 for use in treating a fungal infection.

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