Compounds and methods for treating fungal infections

Abstract

This provides a method for treating fungal infections. [Solution] For subjects with fungal infections, administer a therapeutically effective amount of compound 1: TIFF2026123115000011.tif50161 The present invention provides a method for treating fungal infections in a subject caused by Candida, Aspergillus, Skedosporium, Fusarium, Pesilomyces, Purpleocorium, or the like, comprising the step of administering a pharmaceutically acceptable salt, solvate, or hydrate thereof.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 040,450, filed June 17, 2020, which is incorporated herein by reference in its entirety.

[0002] Field of Invention Fungi infect humans and are a major cause of human health problems. This disclosure relates to general practices for the treatment of fungal infections in humans. [Background technology]

[0003] Fungi infect humans and are a major cause of human health problems. They also infect plants, causing enormous losses in agricultural productivity. [Overview of the project] [Problems that the invention aims to solve]

[0004] This disclosure generally relates to the treatment and / or prevention of fungal infections and diseases. [Means for solving the problem]

[0005] In one embodiment, a method for treating a fungal infection in a subject, comprising: a therapeutically effective amount of compound 1:

[0006] [ka] Methods comprising administering a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the subject is unsuitable for standard antifungal treatment, are described herein. In some embodiments, the unsuitability for standard antifungal treatment is due to impaired renal function. Standard treatments (amphotericin B and voriconazole) may cause nephrotoxicity.

[0007] In another embodiment, a method for treating a fungal infection in a subject is described herein, comprising the step of administering to the subject having the fungal infection a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein dose adjustment of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered to the subject is not required based on the subject's renal condition. In some embodiments, the fungal infection is an invasive fungal infection. In some embodiments, the fungal infection is candidiasis. In some embodiments, the fungal infection is aspergillosis.

[0008] In another embodiment, a method for treating a fungal infection in a subject is described herein, comprising the step of administering a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject having a fungal infection, wherein the subject has kidney disease. In some embodiments, kidney disease includes renal impairment. In some embodiments, a method for treating a fungal infection in a subject is described herein, comprising the step of administering a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject having a fungal infection, wherein the subject has renal impairment, and dose adjustment of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof is not required. In some embodiments, dose adjustment is not required for subjects with mild, moderate, or severe renal impairment. In some embodiments, a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a concentration of at least about 100 μg × hour / mL, at least about 150 μg × hour / mL, at least about 200 μg × hour / mL, or at least about 250 μg × hour / mL, where the area under the steady-state 24-hour concentration-time curve (AUC) of compound 1A in the subject. 0~24 ) provides.

[0009] [ka]

[0010] In some embodiments, the administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject comprises a treatment regimen comprising daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for at least 1 to 4 weeks. In some embodiments, the treatment regimen comprises administration of a loading dose, followed by a daily maintenance dose. In some embodiments, the loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprises at least about 2000 mg / day of compound 1. In some embodiments, the maintenance dose comprises at least about 600 mg / day, at least about 700 mg / day, at least about 800 mg / day, at least about 900 mg / day, or at least about 1000 mg / day of compound 1.

[0011] In one embodiment, a method for treating a fungal infection in a subject comprises the step of administering a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject having a fungal infection, wherein the fungal infection in the subject is caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., or Acremonium. spp.), Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scoplariopsis spp.), Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp.), Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or combinations thereof, and a therapeutically effective amount of compound 1 is used to determine the area under the steady-state 24-hour concentration-time curve (AUC) of compound 1A at a dose of at least approximately 150 μg × time / mL in the subject. 0~24 The present invention provides a treatment regimen comprising daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject that is unsuitable for standard antifungal treatment, for at least 1 to 4 weeks.

[0012] In another embodiment, a method for treating a fungal infection in a subject, comprising the step of administering to a subject having a fungal infection a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the fungal infection in the subject is caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., or Acremonium. spp.), Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scoplariopsis spp.), Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp.), Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or combinations thereof, and a therapeutically effective amount of compound 1 is administered, and the area under the steady-state 24-hour concentration-time curve (AUC) of compound 1A in the subject is at least approximately 100 μg × time / mL of compound 1. 0~24 The present invention provides a treatment regimen comprising daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject that is unsuitable for standard antifungal treatment, for at least 1 to 4 weeks.

[0013] In another embodiment, a method for treating a fungal infection in a subject comprising the step of administering a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject having a fungal infection, wherein the fungal infection in the subject is caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., or Acremonium. spp.), Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scoplariopsis spp.), Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp.) caused by Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp. or Emmonsia - like fungi, or combinations thereof, wherein the subject has an intolerance to standard - of - care antifungal therapy, and wherein administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to the subject comprises a treatment regimen that includes daily administration of compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least 1 - 4 weeks is described herein.

[0014] In some embodiments, the intolerance to standard - of - care antifungal therapy is due to reduced renal function.

[0015] In some embodiments, the intolerance to standard - of - care antifungal therapy is due to kidney disease in the subject.

[0016] [[ID=十二]]In some embodiments, the kidney disease is chronic kidney disease, metabolic syndrome, vesicoureteral reflux, tubulointerstitial fibrosis, IgA nephropathy, diabetic nephropathy, Alport syndrome, HIV - associated nephropathy, glomerulonephritis (GN), focal segmental glomerulosclerosis, membranous glomerulonephritis, mesangial capillary GN, interstitial fibrosis and tubular atrophy (IFTA), acute kidney injury (AKI), acute obstructive nephropathy, or drug - induced fibrosis.

[0017] [[ID=十六]]In some embodiments, the kidney disease is chronic kidney disease (CKD). In some embodiments, the chronic kidney disease (CKD) is stage 1 CKD, stage 2 CKD, stage 3 CKD, stage 4 CKD, or stage 5 CKD.

[0018] [[ID=二十]]In some embodiments, the subject has a high level of protein in their urine (proteinuria).

[0019] In some embodiments, a therapeutically effective amount of Compound 1 provides a steady-state 24-hour area under the concentration-time curve (AUC 0~24 ) of Compound 1A of at least 50 μg×hour / mL. In some embodiments, a therapeutically effective amount of Compound 1 provides a steady-state 24-hour area under the concentration-time curve (AUC 0~24 ) of Compound 1A of at least 100 μg×hour / mL. In some embodiments, a therapeutically effective amount of Compound 1 provides a steady-state 24-hour area under the concentration-time curve (AUC 0-24 ) of Compound 1A of at least 150 μg×hour / mL. In some embodiments, a therapeutically effective amount of Compound 1 provides a steady-state 24-hour area under the concentration-time curve (AUC 0-24 ) of Compound 1A of at least 200 μg×hour / mL.

[0020] In some embodiments, non-compliance with standard-of-care antifungal therapy includes azole antifungal agents, allylamine antifungal agents, echinocandin antifungal agents, or polyene antifungal agents.

[0021] In some embodiments, non-compliance with standard-of-care antifungal therapy includes amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isavuconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine or terbinafine, anidulafungin, caspofungin, micafungin, rezafungin, or a pharmaceutically acceptable salt of any of the foregoing antifungal agents.

[0022] In some embodiments, fungal infections are caused by Candida spp., Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., or Mucorales fungi, or combinations thereof.

[0023] In some embodiments, the subjects are in an immunodeficient state.

[0024] In some embodiments, the subjects are infected with HIV / AIDS or have cancer.

[0025] In some embodiments, the cancer is acute myeloid leukemia or acute lymphoblastic leukemia.

[0026] In some embodiments, the subject has neutropenia.

[0027] In some embodiments, the subject has lymphopenia.

[0028] In some embodiments, the subjects are currently receiving or have previously received cancer chemotherapy.

[0029] In some embodiments, the subjects are currently receiving or have previously received corticosteroid treatment.

[0030] In some embodiments, the subjects are currently receiving or have previously received TNF inhibitor treatment.

[0031] In some embodiments, the subject is an organ graft recipient.

[0032] In some embodiments, the subject is a hematopoietic stem cell graft recipient.

[0033] In some embodiments, the subject has graft-versus-host disease.

[0034] In some embodiments, the fungal infection is superficial, locally invasive, or disseminated through the subject.

[0035] In some embodiments, fungal infections include skin infections, lung infections, sinus infections, central nervous system infections, brain infections, eye infections, cardiac infections, kidney infections, gastrointestinal infections, stomach infections, pelvic infections, blood infections, or combinations thereof.

[0036] In some embodiments, fungal infections include fungal diseases or conditions that are candidiasis, aspergillosis, blastomycosis, coccidioidomycosis (valley fever), cryptococcosis, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), tinea, sporotrichumosis, talalomycosis, allergic bronchopulmonary aspergillosis, allergic sinusitis, azole-resistant A. fumigatus, aspergilloma, pulmonary aspergillosis, infiltrative aspergillosis, cutaneous aspergillosis, fusariosis, skedoporium, rhinocerebral mucormycosis, pulmonary mucormycosis, disseminated mucormycosis, pelvic mucormycosis, gastric mucormycosis, cutaneous mucormycosis, or combinations thereof.

[0037] In some embodiments, the treatment regimen comprises a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0038] In some embodiments, the treatment regimen includes a loading dose of approximately 2000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0039] In some embodiments, a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered to the subject by intravenous (IV) infusion.

[0040] In some embodiments, a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate comprises the administration of two doses of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to a subject by intravenous (IV) infusion.

[0041] In some embodiments, each loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered to the subject by intravenous (IV) infusion over a period of approximately 30 minutes to approximately 4 hours.

[0042] In some embodiments, each loading dose comprises approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0043] In some embodiments, the loading dose includes an intravenous (IV) infusion of approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to the subject, followed by a second intravenous (IV) infusion of approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to the subject, within approximately 24 hours of the first infusion.

[0044] In some embodiments, the maintenance dose is administered once daily, starting on the second day of treatment.

[0045] In some embodiments, the maintenance dose comprises a once-daily administration of approximately 600 mg to approximately 1500 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0046] In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes to approximately 4 hours, starting on the second, third, or fourth day of treatment.

[0047] In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate of compound 1, ranging from approximately 600 mg to approximately 1200 mg, is administered by IV infusion over a period of approximately 30 minutes to approximately 4 hours, starting on the second, third, or fourth day of treatment.

[0048] In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally to the subject, starting on the second, third, or fourth day of treatment.

[0049] In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate of compound 1, in an amount of approximately 800 mg to 1000 mg, is administered orally to the subject once daily, starting on the second, third, or fourth day of treatment.

[0050] In some embodiments, starting on the second, third, or fourth day of treatment: a) about 600 mg to about 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of about 30 minutes to about 3 hours; or b) about 700 mg to about 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally once daily.

[0051] In some embodiments, starting on the second day of treatment, approximately 600 mg to approximately 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours; starting on the fourth day of treatment: a) approximately 600 mg to approximately 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours; or b) approximately 700 mg to approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally once daily.

[0052] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with a further therapeutic agent.

[0053] In some embodiments, the treatment regimen includes daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for approximately 4 to 6 weeks.

[0054] In some embodiments, the treatment regimen includes daily administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate over a period of approximately 4 to 12 weeks.

[0055] In some embodiments, the treatment regimen comprises a loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a maintenance dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprises the administration of two doses of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject by intravenous (IV) infusion on day 1 of treatment, each dose comprising approximately 1000 mg of compound 1, or solvate, The regimen comprises a pharmaceutically acceptable salt, solvate, or hydrate thereof, followed by a maintenance dose of approximately 600 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered once daily by intravenous (IV) infusion for at least two days, followed by either approximately 600 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered once daily by intravenous (IV) infusion, or approximately 700 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered once daily orally.

[0056] In some embodiments, the treatment regimen includes administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for up to 14 days.

[0057] In some embodiments, the fungal infection in the subject is caused by Candida species (Candida spp.).

[0058] In some embodiments, the fungal infection in the subject is caused by Candida species (Candida spp.), and the treatment regimen includes administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for up to 14 days.

[0059] In some embodiments, the treatment regimen is to increase the subject's chances of survival, to reduce galactomannan levels in the subject, to reduce β-d-glucan levels in the subject, or a combination thereof.

[0060] In some embodiments, dose adjustment of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, administered to the subject is not required based on the subject's renal condition.

[0061] A product is provided which includes packaging material, a pharmaceutically acceptable salt, solvate, or hydrate of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate contained in the packaging material, and a label indicating that compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is used for treating fungal infections or for the prevention or alleviation of one or more symptoms of a fungal infection.

[0062] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description, so it should be understood that the detailed description and specific examples are given only as illustrations, while illustrating specific embodiments. [Modes for carrying out the invention]

[0063] For example, compositions for treating and / or preventing fungal infections or diseases are provided herein. Also, for example, methods for treating and / or preventing fungal infections or diseases are provided herein.

[0064] Many patients have limited or no antifungal treatment options due to reported / predicted resistance, contraindications, intolerance, or lack of clinical response to standard antifungal treatment (SOC). Under these circumstances, compound 1 (shown below) offers advantages over SOC antifungal treatment and therefore supports its preliminary investigation for the treatment of invasive fungal infections (IMI).

[0065] Compound 1, a prodrug rapidly converted in vivo by phosphatase to the microbiologically active partial compound 1A, is a broad-spectrum antifungal agent for the treatment of invasive fungal infections via both intravenous and oral administration. Compound 1 is a prodrug with an unstable phosphate moiety. The phosphate moiety improves the water solubility of the drug substance in a higher pH range, but also provides limited stability.

[0066] [ka]

[0067] Compound 1A inhibits the fungal glycosylphosphatidylinositol (GPI)-anchored wall transfer protein 1 (GWT1) enzyme, a highly conserved inositol acylase that catalyzes the initial steps in the GPI-anchored biosynthetic pathway. This inhibition has multifaceted effects on fungal cells, resulting from the inhibition of cell wall mannoprotein localization, including cell wall integrity, biofilm formation, germ tube formation, and fungal growth. Consistent with the potential for a significant target-based therapeutic window, Compound 1A does not inhibit the phosphatidylinositol glycan-anchored biosynthesis class W (PIGW) protein, the closest mammalian ortholog of the fungal GWT1 protein.

[0068] Compound 1A has demonstrated broad in vitro antifungal activity against Candida spp., Cryptococcus spp., Aspergillus spp., Scedosporium spp., Fusarium spp., and certain Mucorales fungi, including activity against azole-resistant and echinocandine-resistant strains. In 5-fluorouracil-suppressed mice carrying IMI (Aspergillus fumigatus, Scedosporium prolificans, and Fusarium solani), compound 1 or 1A demonstrated statistically significant improvements in survival rate and reduced lung fungal colony counts. In cyclophosphamide and cortisone acetate-suppressed mice carrying IMI (A. fumigatus, S. apiospermum, F. solani, and Rhizopus spp.), compound 1 demonstrated statistically significant improvements in survival rate and reduced fungal load.

[0069] Furthermore, compound 1A is effective against various Aspergillus species, Scedosporium species, Fusarium species, Paecilomyces species, Purpureocillium species, Dematiaceous species, Mucorales fungi, Magnusiomyces (Geotrichum) species, Trichosporon species, Malassezia species, Saprochaete species, Kodamaea species, and Rhodotorula species. It has demonstrated antifungal activity against a wide range of clinically isolated fungi of rare mold and yeast infections, including activity against Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi. These rare fungal and yeast species generally do not pose a threat to healthy subjects, but can cause invasive fungal infections in immunocompromised individuals.

[0070] In some embodiments, compound 1 or compound 1A is used in the treatment of various fungal infections caused by Candida, Cryptococcus, Blastomyces, Histoplasma, Coccidioides, or combinations thereof.

[0071] In some embodiments, compound 1 or compound 1A is used in the treatment of various fungal and rare fungal infections. In some embodiments, the fungi or rare fungi are caused by Aspergillus species, Mucorales fungi, Hyalohyphomycete fungi, Phaeohyphomycete fungi, or combinations thereof.

[0072] The Aspergillus spp. includes A. flavus, A. niger, A. fumigatus, and A. terreus.

[0073] The order Mucorals (fungi) includes species such as Rhizopus, Mucor, Lichtheimia, and Cunninghamella.

[0074] Hyalohyphomycete fungi include species such as Acremonium, Fusarium, Paecilomyces, Rasamsonia, Scedosporium, Schizophyllum, and Trichoderma.

[0075] Phaeohycete fungi include species such as Alternaria, Cladophialophora, Cladosporium, Exophiala, Fonsecaea, Lomentospora, Phialophora, and Scoplariopsis.

[0076] The species Scedosporium spp. includes S. apiospermum, S. boydii, and S. dehoogii.

[0077] The Fusarium spp. includes F. solani.

[0078] The Rhizopus species (Rhizopus spp.) includes Rhizopus oryzae.

[0079] In some embodiments, compound 1 or compound 1A includes Aspergillus spp., Scedosporium spp., Fusarium spp., and Paecilomyces species, including A. flavus, A. niger, A. fumigatus, A. terreus, S. apiospermum, S. boydii, S. dehoogii, F. solani, P. lilacinus, P. variotii, and Rhizopus oryzae. It is used in the treatment of infections caused by fungi of the order Mucorales, including spp., Purpureocillium species, Dematiaceous species, or combinations thereof.

[0080] In some embodiments, compound 1 or compound 1A includes species of Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., and Rhodotorula spp., including G. clavatum, T. asahii, T. mucoides, T. mycotoxinivorans, M. furfur, R. mucilaginosa, or S. cerevisiae. It is used in the treatment of various yeast and rare yeast infections, including those caused by Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., or Wickerhamomyces (Pichia) spp., or combinations thereof.

[0081] In some embodiments, compound 1 or compound 1A is used in the treatment of various further fungal infections, including dimorphic fungal infections caused by Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or combinations thereof, including T. marneffei.

[0082] Pharmacokinetic-pharmacodynamic (PK-PD) studies in immunosuppressed mice with infiltrative infections caused by A. fumigatus demonstrate that the ratio of area under the concentration-time curve (AUC) divided by the minimum effective concentration (MEC) is the driver of efficacy. The dose regimen used in this study provided compound 1 or its active metabolite (i.e., compound 1A) with a steady-state AUC ≥ 200 μg × time / mL, which is associated with efficacy (colony count and survival benefit) in immunosuppressed mice with infiltrative pulmonary aspergillosis (IPA). Furthermore, formal PK-PD studies demonstrated that this dose regimen has a favorable probability of achieving target (PTA) for the majority of isolates expected to be encountered in this study.

[0083] Phase 1 clinical studies of Compound 1 have investigated the safety, tolerability, and pharmacokinetics of single and multiple escalating doses administered intravenously (IV) and orally (PO). To date, a total of 197 healthy volunteers and 21 patients with acute myeloid leukemia (AML) have received Compound 1 across five Phase 1 studies. The durations of high-dose regimens in these studies were 7, 14, and 42 days (6 weeks).

[0084] Compound 1 may have potential benefits compared to current SOCs for the treatment of invasive infections caused by Candida spp., including candidiasis, and Aspergillus spp., or rare fungi. Furthermore, Compound 1 has a distinguished safety profile, is available as an IV and PO formulation, and may have a lower DDI than SOC treatments.

[0085] Patients with azole-resistant fungal infections, including azole-resistant Candida species (Candida spp.), A. fumigatus, and some rare fungi (e.g., Fusarium species, Scedosporium species, and species of Mucorales), typically receive IV treatment with polyenes. Polyenes have been associated with risks of nephrotoxicity, electrolyte imbalance, and infusion reactions, which can be limiting in patient treatment. Compound 1 has broad-spectrum antifungal activity with applicability to azole-resistant fungi and may be safer and easier to use compared to polyenes.

[0086] In some embodiments, compound 1 offers advantages over polyenes for the treatment of “breakthrough” infections in patients receiving prophylaxis with fungicidal triazoles. Compound 1 has the potential to provide antifungal coverage against Candida spp., A. fumigatus, and rare fungi without the potential for polyene-induced toxicity. Due to its broad tissue penetration, compound 1 may offer benefits for the treatment of patients with invasive fungal infections in the eyes and central nervous system.

[0087] In some embodiments, Compound 1 provides benefits to patients with invasive fungal infections who cannot be treated with antifungal azoles due to intolerance, toxicity, or clinically significant drug interactions. Compound 1 has the potential to provide a broad-spectrum antifungal applicability without the risk of hepatotoxicity or other azole-related toxicity and is expected to have a low likelihood of inducing clinically significant drug interactions.

[0088] Compound 1 possesses a novel mechanism of action with broad-spectrum activity against Candida spp. (yeast) and Aspergillus spp. (mold), including activity against polyene and azole-resistant strains of Aspergillus spp. Compound 1 has demonstrated efficacy in several animal models of IMI, including Aspergillus spp., Fusarium spp., Scedosporium spp., and Mucorales species. Compound 1 is available in both IV and PO formulations with broad tissue distribution, including the eye and central nervous system, and is safe and well-tolerated, with a favorable safety and drug-drug interaction (DDI) profile identified from SOC antifungal therapies. Compound 1 has the potential to be used as a first-line agent for the treatment of IMI through its unique mechanism of action. Therefore, Compound 1 has the potential to meet unmet needs in patients with limited or no antifungal treatment options due to reported / predicted resistance, contraindications, intolerance, or lack of clinical response to standard-of-care (SOC) antifungal treatments.

[0089] Nephrotoxicity is one of the more problematic adverse effects of antifungal therapy. Drug-induced kidney injury is one of the reasons for compound attenuation in drug development. This is a common adverse effect of amphotericin B, which is considered an “optimal” antifungal agent (Kuznar W., Baglin T. (2015). MD Conf. Express, 13(13), 12-13). Therefore, the nephrotoxic effects of existing antifungal agents, particularly amphotericin B, have been extensively studied using in vitro and in vivo models (van Etten et al., J Antimicrob Chemother., November 1993, 32(5):723-39).

[0090] Patients with significant renal impairment during amphotericin B treatment require continuous dialysis after discontinuation of the antifungal medication (Groll et al., Adv Pharmacol, 1998, 44:343-500). The risk of patients developing severe renal damage during amphotericin B treatment depends on the dose and duration of amphotericin B, the patient's underlying health and fluid status, previous or underlying kidney disease, and the use of other potentially nephrotoxic drugs (e.g., aminoglycoside antibiotics, radiographic dyes, cyclosporine, etc.).

[0091] In some cases, drug-induced kidney injury resulting from antifungal treatment, particularly among patients with invasive fungal infections, can lead to an increased risk of death and prolonged hospitalization.

[0092] In some embodiments, standard-of-care (SOC) antifungal therapy is contraindicated in patients with underlying conditions resulting in renal dysfunction, such as kidney disease and / or renal failure or impairment. Examples of such diseases and injuries include chronic kidney disease, metabolic syndromes, vesicoureteral reflux, tubulointerstitial fibrosis, IgA nephropathy, diabetes mellitus (including diabetic nephropathy), Alport syndrome, HIV-associated nephropathy, resulting glomerulonephritis (GN) (including, but not limited to, focal segmental glomerulosclerosis and membranous glomerulonephritis), mesangial capillary GN and resulting interstitial fibrosis and tubular atrophy (IFTA) (including, but not limited to, recovery after acute kidney injury (AKI), acute obstructive nephropathy, and drug-induced fibrosis), and resulting glomerulonephritis (GN) (including, but not limited to, focal segmental glomerulosclerosis and membranous glomerulonephritis).

[0093] Glomerulonephritis, an inflammation of the glomeruli, is a common cause of end-stage renal failure. Severe and widespread inflammation can damage the glomeruli and lead to kidney damage. Connective tissue growth factor (CTGF) is a member of the CCN matrix cell protein family, consisting of four domains, that modulates the signaling of other growth factors and promotes kidney damage.

[0094] Metabolic syndromes are recognized as a cluster of abnormalities including diabetic features such as insulin resistance, as well as central or visceral obesity and hypertension. In almost all cases, glucose dysregulation leads to stimulation of cytokine release and upregulation of extracellular matrix deposition. Additional factors contributing to chronic kidney disease, diabetes, metabolic syndromes, and glomerulonephritis include hyperlipidemia, hypertension, and proteinuria, all of which lead to further damage to the kidneys and further stimulate extracellular matrix deposition. Therefore, regardless of the underlying cause, damage to the kidneys can lead to renal fibrosis and associated loss of renal function. (Schena, F. and Gesualdo, L., Pathogenic Mechanisms of Diabetic Nephropathy, J.Am.Soc.Nephrol., 16:S30~33(2005), Whaley-Connell, A. and Sower, JR, Chronic Kidney Disease and the Cardiometabolic Sundrome, J.Clin.Hypert., 8(8):546~48(2006)).

[0095] In some embodiments, treatment with compound 1 is not contraindicated in subjects with already impaired renal function. In some embodiments, treatment with compound 1 is not contraindicated in subjects with kidney disease. In some embodiments, kidney disease is chronic kidney disease (CKD). In some embodiments, kidney disease is Alport syndrome.

[0096] In some embodiments, treatment with compound 1 is not contraindicated in subjects with high levels of protein in their urine (proteinuria).

[0097] In some embodiments, the Specified Method describes a method for treating a fungal infection in a subject using compound 1, comprising administering compound 1, wherein the subject also has kidney disease, and the administration of compound 1 delays, slows, or prevents the progression of the kidney to end-stage renal disease (ESRD).

[0098] Chronic kidney disease (CKD) encompasses all five stages of kidney damage, from Stage 1 (very mild damage) to Stage 5 (complete kidney failure). The stages of kidney disease are based on how well the kidneys can filter and remove waste products and excess fluid from the blood. In the early stages of kidney disease, the kidneys can still filter and remove waste products from the blood. In later stages, the kidneys have to work harder than before to remove waste products and may eventually stop functioning completely.

[0099] The way doctors measure how well the kidneys filter waste products from the blood is by the estimated glomerular filtration rate, or eGFR. eGFR is a value based on a blood test for creatinine, a waste product in the blood.

[0100] The stage of kidney disease is based on eGFR values.

[0101] Stage 1 CKD: eGFR of 90 or higher. Stage 1 CKD refers to mild kidney damage with an eGFR of 90 or higher.

[0102] Stage 2 CKD: eGFR of 60-89. Stage 2 CKD refers to mild kidney damage with an eGFR of 60-89.

[0103] Stage 3 CKD: eGFR of 30-59. Stage 3 CKD refers to an eGFR of 30-59. An eGFR of 30-59 means that there is some degree of kidney damage and the kidneys are not functioning properly. Stage 3 is divided into two stages: Stage 3a refers to an eGFR of 45-59, and Stage 3b refers to an eGFR of 30-44. Many people with Stage 3 kidney disease have no symptoms.

[0104] Stage 4 CKD: eGFR of 15-29. Stage 4 CKD refers to an eGFR of 15-29. An eGFR of 15-30 indicates moderate to severe kidney damage, meaning the kidneys are not functioning properly. Stage 4 kidney disease is the final stage before kidney failure and should be taken very seriously.

[0105] Stage 5 CKD: eGFR less than 15. Stage 5 CKD means an eGFR of less than 15. An eGFR of less than 15 means that the kidneys are very close to or have completely failed. When the kidneys fail, waste products accumulate in the blood, which makes the person very pathological.

[0106] In some embodiments, the method is a method for treating fungal infections in subjects with renal impairment. In some embodiments, the treatment method includes a therapeutic regimen comprising administering compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to subjects with fungal infections. In some embodiments, dose adjustment of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, administered to the subject is not required based on the subject's renal condition. In some embodiments, the administered formulation does not contain cyclodextrin (i.e., does not contain one or more cyclodextrin excipients).

[0107] Fungal diseases In some embodiments, fungal diseases are selected from the group consisting of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (valley fever), cryptococcosis, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), tinea, sporotrichumosis, and talalomycosis.

[0108] In some embodiments, the fungal disease is aspergillosis. In some embodiments, aspergillosis is allergic bronchopulmonary aspergillosis (ABPA), allergic aspergillus sinusitis, chronic pulmonary aspergillosis, infiltrative aspergillosis, or cutaneous (skin) aspergillosis. In some embodiments, the subject has an aspergilloma.

[0109] In some embodiments, the fungal disease is blastomycosis.

[0110] In some embodiments, the fungal disease is candidiasis. In some embodiments, candidiasis is oropharyngeal candidiasis (thrush), vulvovaginal candidiasis (vaginal candidiasis), fungemia, or invasive candidiasis.

[0111] In some embodiments, the fungal disease is coccidioidomycosis (valley fever). In some embodiments, coccidioidomycosis is acute coccidioidomycosis (primary pulmonary coccidioidomycosis), chronic coccidioidomycosis, or disseminated coccidioidomycosis (including primary cutaneous coccidioidomycosis).

[0112] In some embodiments, the fungal disease is cryptococcosis. In some embodiments, cryptococcosis is wound or cutaneous cryptococcosis, pulmonary cryptococcosis, or cryptococcal meningitis. In some embodiments, the fungal disease is a fungal eye infection. In some embodiments, the fungal eye infection is a fungal keratitis, fungal exogenous endophthalmitis, or fungal endogenous endophthalmitis.

[0113] In some embodiments, the fungal disease is histoplasmosis. In some embodiments, histoplasmosis is acute histoplasmosis. In some embodiments, histoplasmosis is chronic histoplasmosis.

[0114] In some embodiments, the fungal disease is mucormycosis. In some embodiments, mucormycosis is rhinocephalic (sinus and brain) mucormycosis, pulmonary mucormycosis, gastrointestinal mucormycosis, cutaneous mucormycosis, or disseminated mucormycosis.

[0115] In some embodiments, the fungal disease is Pneumocystis pneumonia (PCP).

[0116] In some embodiments, the fungal disease is tinea. In some embodiments, tinea is tinea pedis, tinea cruris, tinea capitis, tinea folliculitis, tinea manuum, tinea onychomycosis, or tinea corporis. In some embodiments, tinea is caused by a species of fungus including Trichophyton, Microsporum, or Epidermophyton.

[0117] In some embodiments, the fungal disease is sporotrichumosis. In some embodiments, sporotrichumosis is cutaneous sporotrichumosis, pulmonary sporotrichumosis, or disseminated sporotrichumosis.

[0118] In some embodiments, the fungal disease is talalomycosis.

[0119] In some embodiments, fungal diseases or infections include Cryptococcus, Aspergillus, Candida, Coccidioides, Blastomyces, Ajellomyces, Histoplasma, Rhizopus, Apophysomyces, Absidia, Saksenaea, Rhizomucor pusillus, Entomophthora, Conidiobolus, Basidiobolus, Sporothrix, and Pneumocystis girobesii. Caused by fungi / species of *Talaromyces jirovecii*, *Talaromyces marneffei*, *Asclepias*, *Fusarium*, or *Scedosporium*. In some embodiments, fungal diseases include, but are not limited to, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Blastomyces dermatitidis, Ajellomyces dermatitidis, Candida albicans, Candida auris, Candida glabrata, Candida parapsilosis, Candida rugosa, and Candida tropicalis. Coccidioides imithis (tropicalis)immitis), Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusilus The fungal diseases are caused by fungal species including *Aspergillus pusillus*, *Entomophthora*, *Conidiobolus*, *Basidiobolus*, *Sporothrix schenckii*, *Pneumocystis jirovecii*, *Talaromyces marneffei*, *Asclepias albicans*, *Fusarium solani*, *Scedosporium apiospermum*, and *Rhizomucor pusillus*. In some embodiments, the fungal disease is caused by the fungal species *Aspergillus fumigatus*. In some embodiments, the fungal disease is caused by the fungal species Candida albicans. In some embodiments, the fungal disease is caused by the fungal species Fusarium solani. In some embodiments, the fungal disease is caused by the fungal species Mucor indicus.In some embodiments, the fungal disease is caused by the fungal species Scedosporium apiospermum. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus neoformans. In some embodiments, the fungal disease is caused by the fungal species Cryptococcus gattii. In some embodiments, the fungal disease is caused by the fungal species Candida auris.

[0120] In some embodiments, fungal diseases or infections are caused by Aspergillus fumigatus, Blastomyces, Ajellomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Rhizopus, Mucor, Cunninghamell, Apophysomyces, Absidi, Saksenaea, and E. It is caused by fungi from the orders Mucorales, including Entomophthora, Conidiobolus, Basidiobolus, Sporothrix, Pneumocystis, Talaromyces, Asclepias, Fusarium, Scedosporium, Fusar

[0121] In some embodiments, the fungal disease or infection is caused by fungi of the order Mucorales, including Cryptococcus, Aspergillus, Candida, Fusarium, Scedosporium, or any combination thereof. In some embodiments, fungal diseases or infections include Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Ajellomyces dermatitidi, Candida albican, Candida glabrata, Candida rugosa, Candida auris, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, and Cryptococcus gatiensis. gattii), Histoplasma capsulatum, Rhizopus stolonifer, Rhizopus arrhizus, Mucor indicus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia species, Saksenaea species, Rhizomucor pusillus, Entomophthora species, Conidiobolus species, Basidiobolus species, Sporothrix schenkyiIt is caused by *Pneumocystis jirovecii*, *Talaromyces marneffei*, *Asclepias albicans*, *Fusarium solani*, *Scedosporium apiospermum*, *Rhizomucor pusillus*, or any combination thereof.

[0122] In some embodiments, the compounds described herein are active against the fungal Gwt1 protein. This conserved enzyme catalyzes the post-translational modification of glycosylphosphatidylinositol (GPI), which anchors eukaryotic cell surface proteins to the cell membrane. In yeast, GPI mediates the cross-linking of cell wall mannoproteins to β-1,6-glucan. Inhibition of this enzyme in both Candida albicans and budding yeast (Saccharomyces cerevisiae) has been shown to result in inhibition of maturation and localization of GPI-anchored mannoproteins, thus demonstrating multifaceted effects including inhibition of fungal adhesion to the surface, inhibition of biofilm formation, inhibition of germinal tube formation, severe growth abnormalities, or lethality.

[0123] subject In some embodiments, the subjects are human. In some embodiments, the subjects are immunodeficient. In some embodiments, the subjects are receiving treatment with at least one immunosuppressant drug. In some embodiments, the immunosuppressant drug increases the risk of opportunistic infection in the subjects.

[0124] Immunosuppressants / drugs that can weaken the immune system include, but are not limited to, corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, everolimus, pomalidomide, omalizumab, azathioprine, lenamidomide, thalidomide, anti-TNF inhibitors, interleukin inhibitors, Janus kinase inhibitors, sphingosine-1-phosphate receptor (S1P) agonists, S1P antagonists, calcinurin inhibitors, mTOR inhibitors, nucleotide synthesis inhibitors, biologics, and monoclonal antibodies.

[0125] Corticosteroids include, but are not limited to, prednisone, budesonide, prednisolone, and methylprednisolone.

[0126] Janus kinase inhibitors include, but are not limited to, tofacitinib, baricitinib, filgotinib, and upadacitinib.

[0127] Sphingosine-1-phosphate receptor antagonists include, but are not limited to, FTY720.

[0128] S1P agonists include, but are not limited to, ozanimod and etrasimodo.

[0129] Calcinulin inhibitors include, but are not limited to, cyclosporine and tacrolimus.

[0130] mTOR inhibitors include, but are not limited to, sirolimus and everolimus.

[0131] Interleukin inhibitors include, but are not limited to, lilonacept, canakinumab, anakinra, reslizumab, brodalumab, ustekinumab, benralizumab, mepolizumab, tocilizumab, ixekizumab, dupilumab, secukinumab, tildrakizumab, guselkumab, sarilumab, basiliximab, risankizumab, siltuximab, dacrizumab, and dacrizumab.

[0132] Nucleotide synthesis inhibitors include, but are not limited to, azathioprine, leflunomide, and mycophenolate.

[0133] Biologics include, but are not limited to, TNF-alpha inhibitors, integrin inhibitors, and IL-12 / 23 inhibitors. Biologics include, but are not limited to, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, etrolizumab, and vedolizumab.

[0134] Monoclonal antibodies include, but are not limited to, basiliximab, dacritumab, alemtuzumab, rituximab, and belatacept.

[0135] In some embodiments, the human subject is under 1 year of age. In some embodiments, the human subject is an infant under 1 month of age. In some embodiments, the human subject is over 70 years of age. In some embodiments, the subject is infected with HIV / AIDS. In some embodiments, the subject is currently receiving or has received cancer chemotherapy. In some embodiments, the subject is currently receiving or has received corticosteroid treatment. In some embodiments, the subject is currently receiving or has received TNF inhibitor treatment. In some embodiments, the subject is a graft recipient. In some embodiments, the subject is a recipient of a hematopoietic stem cell graft, bone marrow graft, lung graft, liver graft, heart graft, kidney graft, pancreas graft, or a combination thereof. In some embodiments, the subject is a recipient of a hematopoietic stem cell graft. In some embodiments, the subject is a recipient of a bone marrow graft. In some embodiments, the subject is a recipient of a lung graft. In some embodiments, the subject is a recipient of a liver graft. In some embodiments, the subject is a recipient of a heart graft. In some embodiments, the subject is a recipient of a kidney graft. In some embodiments, the subject is a recipient of a pancreatic graft.

[0136] In a certain world Unless otherwise noted, the following terms used in this application have the definitions given below. The use of the term "including" and other forms, such as "include," "includes," and "included," is not limiting. Section headings used herein are for systematization purposes only and should not be construed as limiting the subject matter described herein.

[0137] The term "acceptable," as used herein with respect to a formulation, composition, or component, means that it does not have any lasting adverse effects on the overall health of the subject being treated.

[0138] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the mammal to which it is administered and does not substantially neutralize the biological activity and properties of the compound. (Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SMBerge, LDBighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and C.G. Wermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.) In some embodiments, pharmaceutically acceptable salts are typically more soluble than nonionic species, more rapidly soluble in gastric and intestinal fluids, and therefore useful in solid dosage forms. Furthermore, since their solubility is often a function of pH, selective dissolution in any part of the digestive tract is possible, and this ability is, in some cases, manipulated as a form of delayed and sustained release behavior. Also, since salt-forming molecules are, in some cases, in equilibrium with a neutral form, their passage across biological membranes is, in some cases, regulated.

[0139] In some embodiments, pharmaceutically acceptable salts are generally prepared by reacting a free base with a suitable organic or inorganic acid, or by reacting an acid with a suitable organic or inorganic base. This term may be used in reference to any compound of the present invention. Representative salts include: acetates, benzenesulfons, benzoates, bicarbonates, bisulfates, hydrogen tartrates, borates, bromides, calcium edetate, cansylates, carbonates, chlorides, clavulanic acid, citrates, dihydrochlorides, edetates, edisylates, estolates, esylates, fumarates, gluceptates, glucons, glutamates, glycolylarsanilates, hexylresorcinates, hydrabamines, hydrobroms, hydrochlorides, hydroxynaphthoates, iodides, Isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, basic acetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, trimethylammonium, and valerate. In some embodiments, when acidic substituents, such as -CO2H, are present, ammonium, morpholinium, sodium, potassium, barium, or calcium salts are formed. In some embodiments, when a basic group, such as an amino acid, or a basic heteroaryl ring, such as pyridyl, is present, an acid addition salt is formed, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate, etc.Further pharmaceutically acceptable salt forms of therapeutic agents are listed in Berge et al., Journal of Pharmaceutical Sciences, Vol. 66(1), pp. 1-19 (1977).

[0140] As used herein, the term “modulate” means to interact with a target, either directly or indirectly, to alter its activity, including, but not limited to, enhancing, inhibiting, limiting, or prolonging its activity.

[0141] The terms “administer,” “administering,” and “dosage,” as used herein, refer, in some cases, to a method that enables the delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral, intraduodenal, and parenteral routes (including intravenous, intraperitoneal, intravascular, or infusion). Those skilled in the art will be familiar with the administration techniques that may be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. In some embodiments, the compounds and compositions described herein are administered intravenously. In some embodiments, the compounds and compositions described herein are administered by intravenous infusion.

[0142] When used herein, terms such as "co-administration" encompass the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0143] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of an administered drug or compound that reduces, to some extent, one or more symptoms of the disease or condition being treated. Results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired modification of the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein required to provide a clinically significant reduction in disease symptoms. An appropriate “effective” dose in any individual case may be determined using techniques such as dose-escalation studies.

[0144] The terms “enhance” or “enhancing,” as used herein, mean increasing or prolonging a desired effect, either in terms of potency or duration. Therefore, in relation to enhancing the effect of a therapeutic agent, “enhance” refers to the ability to increase or prolong the effect of one therapeutic agent on a given system, either in terms of potency or duration. “Enhancing effective dose,” as used herein, refers to an appropriate amount for enhancing the effect of another therapeutic agent on a desired system.

[0145] As used herein, the terms “fungal infection” or “fungal disease” refer to a disease caused by pathogenic fungi. A fungal infection may be opportunistic or primary, and may be caused by fungi, which are yeasts and / or molds.

[0146] As used herein, the term “pharmaceutical combination” means a product resulting from a mixture or combination of more than one active ingredient, and includes both fixed and unfixed combinations of active ingredients. The term “fixed combination” means that the active ingredient, e.g., a compound described herein or its pharmaceutically acceptable salt, solvate, or hydrate, and the co-agent are administered together to the patient simultaneously in the form of a single entity or dosage. The term “unfixed combination” means that the active ingredient, e.g., a compound described herein or its pharmaceutically acceptable salt, solvate, or hydrate, and the co-agent are administered to the patient as separate entities simultaneously, concurrently, or sequentially, without any specific intervening time constraints, where such administration provides effective levels of two compounds in the patient’s body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0147] The terms "kit" and "manufactured product" are used as synonyms.

[0148] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other apes and monkey species. In one aspect, a mammal is a human.

[0149] The terms “treat,” “treating,” or “treatment,” as used herein, include, either preventively or / or therapeutically, alleviating, suppressing or improving at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, for example, stopping the onset of a disease or condition, reducing a disease or condition, causing regression of a disease or condition, reducing a condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0150] As used herein, the term "approximately" means within ±10% of the value.

[0151] How to use In one embodiment, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is used in the preparation of a pharmaceutical for the treatment of a disease or condition caused by a fungal infection in a mammal. A method for treating any of the diseases or conditions described herein in a mammal requiring such treatment involves administering to the mammal a pharmaceutical composition containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an active metabolite of compound 1 (i.e., compound 1A).

[0152] In certain embodiments, compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic applications, these compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially cessate at least one of the symptoms of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight and response to the drug, and the judgment of the attending physician. The therapeutically effective dose may be determined by methods including, but not limited to, dose escalation and / or dose-range exploration clinical trials.

[0153] In prophylactic use, a composition containing compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a patient who is susceptible to a particular disease or condition, or otherwise at risk of a particular disease or condition. Such an amount is defined as a “prophylactic effective dose or dosage.” In this use, the exact amount also depends on the patient’s health, weight, etc. When used in a patient, the effective dose for this use depends on the underlying risk of developing a fungal infection, previous treatments, the patient’s health and response to the drug, and the judgment of the attending physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a mammal that has previously experienced or is currently in remission of at least one symptom of the disease being treated, in order to prevent the recurrence of symptoms of the disease or condition.

[0154] In certain embodiments where the patient's condition does not improve, at the discretion of the physician, administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may be administered chronically, i.e., over an extended period including throughout the patient's lifetime, to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

[0155] Once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in specific embodiments, the dosage, frequency, or both of the medication are reduced as a function of the symptoms to a level at which the improved disease or condition is maintained. However, in certain embodiments, the patient requests long-term intermittent treatment based on any recurrence of symptoms.

[0156] In one embodiment, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered daily to a person requiring treatment with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered once daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice daily.

[0157] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice daily, for example, in the morning and evening.

[0158] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least ten weeks, at least eleven weeks, at least twelve weeks, at least one month, at least two months, at least three months, at least four months, or longer.

[0159] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered to humans in a continuous dosing schedule. In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered to humans in a continuous daily dosing schedule.

[0160] The term “continuous dosing schedule” refers to the administration of a specific therapeutic agent at regular intervals. In some embodiments, a continuous dosing schedule refers to the administration of a specific therapeutic agent at regular intervals without any rest periods for that particular therapeutic agent. In some other embodiments, a continuous dosing schedule refers to the administration of a specific therapeutic agent in cycles. In some other embodiments, a continuous dosing schedule refers to the administration of a specific therapeutic agent in cycles of drug administration followed by rest periods for that particular therapeutic agent (e.g., wash-out periods, or other such periods during which the drug is not administered). For example, in some embodiments, the therapeutic agent is administered once a day, twice a day, daily for one week followed by one week without administration of the therapeutic agent, daily for two weeks followed by one or two weeks without administration of the therapeutic agent, daily for three weeks followed by one, two, or three weeks without administration of the therapeutic agent, daily for four weeks followed by one, two, three, or four weeks without administration of the therapeutic agent, weekly administration of the therapeutic agent followed by one week without administration of the therapeutic agent, or biweekly administration of the therapeutic agent followed by two weeks without administration of the therapeutic agent. In some embodiments, daily administration is once a day. In some embodiments, daily administration is twice a day.

[0161] The term "sequential daily medication schedule" refers to the administration of a specific therapeutic agent at approximately the same time each day. In some embodiments, the daily dose is once a day. In some embodiments, the daily dose is twice a day. In some embodiments, the daily dose is three times a day. In some embodiments, the daily dose is more than three times a day.

[0162] In some embodiments, an amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered once daily. In some other embodiments, an amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered twice daily.

[0163] In certain embodiments where no improvement in the condition of a disease or condition in a human is observed, the daily dosage of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is increased. In some embodiments, a once-daily dosing schedule is changed to a twice-daily dosing schedule. In some embodiments, the frequency of administration is increased to provide a maintained or more consistent exposure to Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the frequency of administration is increased to provide a maintained or more consistent exposure to Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an active metabolite of Compound 1 (i.e., Compound 1A), for example a higher AUC level. In some embodiments, the frequency of administration is increased to provide a maintained or more consistent exposure to Compound 1A. In some embodiments, the frequency of administration is increased to provide a more consistent baseline of repeated high C max levels and a maintained or more consistent exposure to Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or an active metabolite of Compound 1 (i.e., Compound 1A), for example a higher AUC level. In some embodiments, the frequency of administration is increased to provide a maintained or more consistent exposure to Compound 1A. In some embodiments, the frequency of administration is increased to provide a more consistent baseline of repeated high C max levels and a maintained or more consistent exposure to Compound 1A, for example a higher AUC level.

[0164] Further embodiments include a single administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, including embodiments where Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered (i) once daily; or (ii) multiple times over the course of a day.

[0165] Any of the embodiments described above includes further embodiments comprising multiple administrations of an effective amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, including: (i) compound 1 is administered continuously or intermittently, as in the case of a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) compound 1 is administered to a mammal every 8 hours; (iv) compound 1 is administered to a mammal every 12 hours; and (v) compound 1 is administered to a mammal every 24 hours. In further or alternative embodiments, the method includes a drug-free period during which the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug-free period, administration of the compound is resumed. In one embodiment, the length of the drug-free period varies from 2 days to 1 year.

[0166] Generally, appropriate doses of compound 1 or its pharmaceutically acceptable salts, solvates, or hydrates for administration to humans are in the range of approximately 500 mg / day to approximately 2000 mg / day; approximately 600 mg / day to approximately 2000 mg / day; approximately 800 mg / day to approximately 2000 mg / day; or approximately 1000 mg / day to approximately 2000 mg / day.

[0167] In some embodiments, administration of an effective amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate comprises a treatment regimen including an administration of a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate, followed by a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered in a different manner than the maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered in the same manner as the maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0168] In some embodiments, the loading dose is administered as a solution by intravenous (IV) infusion.

[0169] In some embodiments, the maintenance dose is administered orally in the form of a solid medication. In some embodiments, the solid medication is a tablet. In some embodiments, the maintenance dose is administered as a solution by intravenous (IV) infusion.

[0170] In some embodiments, the loading dose comprises approximately 1500 mg to approximately 2500 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the loading dose comprises approximately 2000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate comprises the administration of two doses of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to the subject by intravenous (IV) infusion. In some embodiments, each loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered to the subject by intravenous (IV) infusion over a period of approximately 30 minutes to approximately 3 hours. In some embodiments, each loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered to the subject by intravenous (IV) infusion over a period of approximately 30 minutes, approximately 45 minutes, approximately 1 hour, approximately 1.5 hours, approximately 2 hours, approximately 2.5 hours, approximately 3 hours, or longer than 3 hours. In some embodiments, each of the two loading doses comprises approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0171] In some embodiments, the loading dose includes the administration of approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to a subject by intravenous (IV) infusion, and a second administration of approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to a subject by intravenous (IV) infusion within approximately 24 hours of the first infusion. In some embodiments, the second loading dose is administered within approximately 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours of the first loading dose.

[0172] In some embodiments, the maintenance dose is initiated on the second day of treatment. In some embodiments, the maintenance dose is initiated on the second day of treatment and administered once daily.

[0173] In some embodiments, each maintenance dose comprises a once-daily dose of approximately 1000 mg to approximately 2000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises a once-daily dose of approximately 600 mg to approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises a once-daily dose of approximately 600 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises a once-daily dose of approximately 650 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises a once-daily dose of approximately 700 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises a once-daily dose of approximately 750 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises approximately 800 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate once daily. In some embodiments, each maintenance dose comprises approximately 850 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate once daily. In some embodiments, each maintenance dose comprises approximately 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate once daily. In some embodiments, each maintenance dose comprises approximately 950 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate once daily. In some embodiments, each maintenance dose comprises approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate once daily. In some embodiments, each maintenance dose comprises approximately 1050 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate once daily. In some embodiments, each maintenance dose comprises a once-daily administration of approximately 1100 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises a once-daily administration of approximately 1150 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.In some embodiments, each maintenance dose comprises a once-daily administration of approximately 1200 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, each maintenance dose comprises a once-daily administration of more than approximately 1200 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0174] In some embodiments, each maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours, starting on the second, third, or fourth day of treatment. In some embodiments, each maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes, approximately 45 minutes, approximately 1 hour, approximately 1.5 hours, approximately 2 hours, approximately 2.5 hours, approximately 3 hours, or longer than 3 hours, starting on the second, third, or fourth day of treatment.

[0175] In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate of compound 1 in an amount of approximately 600 mg to approximately 1500 mg is administered by IV infusion over a period of approximately 30 minutes to approximately 5 hours, starting on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate of compound 1 in an amount of approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, or approximately 1200 mg is administered by IV infusion over a period of approximately 30 minutes to approximately 5 hours, starting on the second, third, or fourth day of treatment.

[0176] In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate of compound 1 in an amount of approximately 600 mg to approximately 900 mg is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours, starting on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate of compound 1 in an amount of approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, or approximately 900 mg is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours, starting on the second, third, or fourth day of treatment.

[0177] In some embodiments, each maintenance dose comprises a once-daily administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate in an amount greater than approximately 900 mg. In some embodiments, each maintenance dose comprises a once-daily administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate in an amount of approximately 900 mg to approximately 2000 mg. In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate in an amount of approximately 900 mg to approximately 2000 mg is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours, starting on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate in an amount of approximately 900 mg to approximately 2000 mg is administered by IV infusion over a period of longer than 3 hours, starting on the second, third, or fourth day of treatment.

[0178] In some embodiments, a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally to the subject, starting on the second, third, or fourth day of treatment.

[0179] In some embodiments, a maintenance dose of approximately 800 mg to approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally to the subject once daily, starting on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of approximately 800 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally to the subject once daily, starting on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of approximately 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally to the subject once daily, starting on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally to the subject once daily, starting on the second, third, or fourth day of treatment.

[0180] In some embodiments, starting on the second, third, or fourth day of treatment: a) about 600 mg to about 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of about 30 minutes to about 3 hours; or b) about 800 mg to about 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally once daily.

[0181] In some embodiments, starting on the second day of treatment, approximately 600 mg to approximately 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours; starting on the fourth day of treatment: a) approximately 600 mg to approximately 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes to approximately 3 hours; or b) approximately 800 mg to approximately 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally once daily.

[0182] In some embodiments, the daily dose or amount of the active ingredient in the drug formulation is lower or higher than the ranges shown herein, based on several variables relating to the individual treatment regimen. In various embodiments, the daily and unit doses are modified depending on several variables, including but not limited to the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, human characteristics (e.g., body weight), and specific further therapeutic agents to be administered (if applicable), and practitioner's judgment.

[0183] The toxicity and therapeutic efficacy of such treatment regimens are determined by the LD (Low Life Quantity). 50 and ED 50 The determination includes, but is not limited to, the standard pharmaceutical procedures in cell cultures or experimental animals. The dose-to-toxicity ratio is the therapeutic index, which is the LD50. 50 and ED 50 It is expressed as a ratio between [a certain value] and [another value]. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of compound 1 is defined as an ED with minimal toxicity. 50 It falls within a range of circulating concentrations, including [specific values]. In certain embodiments, the daily dosage range and / or unit dose varies within this range, depending on the form of medication used and the route of administration utilized.

[0184] In some embodiments, a method for treating fungal infections in mammals using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof results in improvement of clinical symptoms attributable to the infection, improvement in radiological abnormalities, and resolution of fungemia, if present. In some embodiments, clinical symptoms attributable to the infection include, for example, the appearance of the skin, head, eyes, ears, nose, throat, neck, torso or lymph nodes, or the whole body, including the appearance of the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, psychological, lymphoid / hematological, and endocrine / metabolic systems of the mammal.

[0185] In some embodiments, improvement in one or more outcome measures is greater than at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 95%, or approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 95%. In some embodiments, administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to mammals having a fungal or mold infection results in an improvement of one or more outcome measures, at least 0.5 times, 1 time, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, or greater than 10 times, or about 0.5 times, 1 time, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, or greater than 10 times. The improvement is compared to a control in some embodiments. In some embodiments, the control is an individual that does not receive compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the control is an individual that does not receive a full dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the control is a baseline of the individual before receiving compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0186] In some embodiments, a method for treating fungal or mold infections in a subject using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate results in improvement on one or more outcome measures. In some embodiments, the baseline assessment is typically determined before administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. Improvement on outcome measures is assessed using repeated assessments performed during treatment with compound 1, as well as comparisons to the baseline assessment and / or any prior assessment(s).

[0187] Evaluating patients for fungal infections and assessing the effectiveness of treatment with compound 1 or its pharmaceutically acceptable salts, solvates, or hydrates includes diagnostic tests of multiple modalities, including: radiological evaluation including CT scans of the chest, sinuses, and abdomen; fungal cultures and microscopy of respiratory specimens; fungal antigen tests of blood, serum, or bronchoalveolar fluid; pathogenicity DNA tests of blood, serum, or bronchoalveolar fluid; lung biopsy (open, percutaneous, or transbronchial); aspergillosis urine test; and other molecular tests of respiratory specimens.

[0188] In some embodiments, a method for treating fungal infections in mammals using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof produces an improvement measured by radiological evaluation, such as computed tomography (CT) scans. In some embodiments, imaging methods for detecting inflammation, such as positron emission tomography or indium-labeled leukocyte scintigraphy, are used. In some embodiments, radiological evaluation is used to determine whether a fungal infection is present.

[0189] In some embodiments, radiological evaluation is used to determine the size or extent of the infection. In some embodiments, CT scans are performed every 7 or 14 days while the mammal is being treated with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the total infection load is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% after the treatment regimen with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0190] In some embodiments, a method for treating fungal infections in mammals using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate produces an improvement, as measured by fungal cultures of body fluids, e.g., bronchoalveolar fluid, sputum, bronchial brush, or sinus aspirate. In some embodiments, the fungal load determined in fungal cultures decreases by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% after a treatment regimen with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0191] In some embodiments, a method for treating fungal infections in mammals using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof yields an improvement as measured by appropriate pathogen DNA testing. In some embodiments, pathogen DNA levels are measured in mammalian blood samples. In some embodiments, pathogen DNA levels are measured in mammalian serum samples. In some embodiments, pathogen DNA levels are measured in mammalian bronchoalveolar lavage fluid samples. In some embodiments, pathogen DNA levels are determined using known pathogen DNA detection assays. In some embodiments, pathogen DNA levels are determined using next-generation sequencing and / or polymerase chain reaction (PCR) analysis. In some embodiments, pathogen DNA levels are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% after treatment regimens with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0192] In some embodiments, a method for treating a fungal infection in a subject using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof results in histological improvement in a biopsy tissue sample taken from a subject having a fungal or mold infection. In some embodiments, the biopsy tissue is lung tissue.

[0193] In some embodiments, a method for treating fungal infections in mammals using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof increases the overall survival rate of subjects by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%. In some embodiments, overall survival is measured after 42 days. In some embodiments, overall survival is measured after 84 days.

[0194] In some embodiments, a method for treating fungal infections in mammals using compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof reduces the all-cause mortality rate of the subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%. In some embodiments, the all-cause mortality rate is measured after 42 days. In some embodiments, the all-cause mortality rate is measured after 84 days.

[0195] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert components that facilitate the processing of the active compound into a pharmaceutically used formulation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

[0196] In some embodiments, the compounds described herein are administered in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. Administration of the compounds and compositions described herein is carried out by any method that enables delivery of the compound to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric, or duodenal feeding tubes) or parenteral routes (injection or infusion), although most suitable routes depend, in some cases, for example, on the recipient's condition and disease.

[0197] In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is included in the pharmaceutical composition. As used herein, the term “pharmaceutical composition” means a liquid or solid composition containing a pharmaceutically active ingredient (e.g., compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof) and at least a carrier, wherein, in general, none of the ingredients are biologically undesirable in the administered amount.

[0198] A pharmaceutical composition incorporating compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof may take any pharmaceutically acceptable physical form. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for oral administration. In one embodiment of such a pharmaceutical composition, a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is incorporated.

[0199] In some embodiments, conventional inert ingredients and forms for formulating pharmaceutical compositions are used. In some embodiments, known methods for formulating pharmaceutical compositions are followed. All common types of compositions are considered, including but not limited to tablets, capsules, and solutions. However, the amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is best defined as an effective amount, i.e., the amount of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof that provides a desired dose to an object requiring such treatment.

[0200] In some cases, capsules are prepared by mixing compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate with a suitable diluent and filling the capsule with an appropriate amount of the mixture. Common diluents include inert powdered substances, such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars, such as fructose, mannitol, and sucrose, grain flour, and similar edible powders.

[0201] In some cases, tablets are prepared by direct compression, wet granulation, or dry granulation. These formulations typically incorporate diluents, binders, lubricants, and disintegrants, as well as compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugars. Powdered cellulose derivatives are also useful. Typical tablet binders include, for example, starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic rubbers, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone, are also readily available. In some cases, polyethylene glycol, ethylcellulose, and waxes function as binders.

[0202] In some cases, lubricants in tablet formulations help prevent the tablets and dies from sticking to the die-cutting machine. In some cases, the lubricant is selected from solids such as talc, magnesium stearate and calcium stearate, stearic acid, and hydrogenated vegetable oil.

[0203] Tablet disintegrants are substances that swell when wet, causing tablets to disintegrate and release compounds. These include starch, clay, cellulose, algin, and rubber. More specifically, tablet disintegrants include corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, and sodium lauryl sulfate.

[0204] Enteric-coated formulations are often used to protect active ingredients from the highly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a polymer film that is insoluble in acidic environments and soluble in alkaline environments. Exemplary films include cellulose phthalate acetate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose succinate acetate.

[0205] Tablets are often coated with sugars as flavorings and sealants. Tablets may also be coated to provide a desired color.

[0206] In some embodiments, pharmaceutical compositions for use in any of the methods provided herein are described in the examples.

[0207] Combination treatment In certain cases, it is appropriate to administer compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate in combination with one or more other therapeutic agents.

[0208] In one embodiment, the therapeutic efficacy of compound 1 or a pharmaceutically acceptable salt is enhanced by the administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate together with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0209] In one specific embodiment, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is co-administered with a second therapeutic agent, and compound 1 or a pharmaceutically acceptable salt and the second therapeutic agent modulate different aspects of the disease or condition being treated, thereby providing a greater overall benefit than the administration of either therapeutic agent alone.

[0210] In either case, regardless of the disease or condition being treated, the overall benefit experienced by the patient is simply the sum of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0211] In certain embodiments, when compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered in combination with one or more further agents, such as further therapeutically effective drugs, adjuvants, etc., different therapeutically effective doses of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate are utilized when formulating pharmaceutical compositions and / or in treatment regimens. The therapeutically effective doses of the drug and other agents for use in combination treatment regimens may be determined by means similar to those described herein for the active substance itself. Furthermore, the preventive / treatment methods described herein include the use of metronomic dosing, i.e., providing lower doses at higher frequencies to minimize toxic side effects. In some embodiments, the combination treatment regimen includes a treatment regimen in which the administration of compound 1 or a pharmaceutically acceptable salt or solvate is initiated before, during, or after treatment with a second agent described herein and continues until any point during treatment with the second agent or after the conclusion of treatment with the second agent. A combination treatment regimen also includes treatments in which compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate used in the combination, and a second agent, are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatments may further include cyclical treatments initiated and stopped at various points in time to aid in the clinical management of the patient.

[0212] It is understood that drug regimens for treating, preventing, or alleviating the one or more conditions to be alleviated will be modified according to various factors (e.g., the disease or condition the subject is suffering from; the subject's age, weight, sex, diet, and medical condition). Therefore, in some cases the drug regimen actually used will vary, and in some embodiments it will deviate from the drug regimens shown herein.

[0213] For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the specific drug used, the disease or condition being treated, and so on. In further embodiments, when co-administered with one or more other therapeutic agents, compound 1 or a pharmaceutically acceptable salt or solvate thereof may be administered either simultaneously with or sequentially with the one or more other therapeutic agents.

[0214] In combination therapy, multiple therapeutic agents (one of which is compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate) are administered in any order, or even simultaneously. When administered simultaneously, the multiple therapeutic agents are provided, as just one example, in a single unified form or in multiple forms (e.g., as a single pill or as two separate pills; or as a single IV infusion solution or as two separate IV infusion solutions).

[0215] Compound 1 or its pharmaceutically acceptable salts, solvates, or hydrates, as well as combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing Compound 1 or its pharmaceutically acceptable salts, solvates, or hydrates varies. Therefore, in one embodiment, Compound 1 or its pharmaceutically acceptable salts, solvates, or hydrates are used as prophylactic agents, administered sequentially to subjects prone to developing a condition or disease to prevent its onset. In another embodiment, Compound 1 or its pharmaceutically acceptable salts, solvates, or hydrates are administered to subjects during the onset of symptoms or as soon as possible after the onset of symptoms. In a specific embodiment, Compound 1 or its pharmaceutically acceptable salts or solvates are administered as soon as feasible after the onset of a disease or condition is detected or suspected, for a duration necessary for treating the disease. In some embodiments, the duration required for treatment varies, and the duration of treatment is adjusted to suit the specific requirements of each subject. For example, in a specific embodiment, compound 1 or a pharmaceutically acceptable salt or solvate thereof, or a formulation containing compound 1 or a pharmaceutically acceptable salt or solvate thereof, is administered over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, or longer than 12 weeks.

[0216] Exemplary drugs for use in combination therapy In some embodiments, compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with one or more further treatments used to treat fungal and / or mold infections in mammals.

[0217] In certain embodiments, at least one further treatment is administered at the same time as compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In certain embodiments, at least one further treatment is administered at a lower frequency than compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In certain embodiments, at least one further treatment is administered at a higher frequency than compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In certain embodiments, at least one further treatment is administered before the administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate. In certain embodiments, at least one further treatment is administered after the administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

[0218] In some embodiments, at least one further treatment is an antifungal agent. In some embodiments, the second therapeutic agent is an antifungal agent selected from the group consisting of polyene antifungal agents, azole antifungal agents, allylamine antifungal agents, and echinocandin antifungal agents.

[0219] In some embodiments, the polyene antifungal agent is amphotericin B, candicidine, philipin, hamycin, natamycin, nystatin, or rimocidine.

[0220] In some embodiments, the azole antifungal agent is imidazole, triazole, or thiazole. In some embodiments, the imidazole is bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, ketoconazole, luliconazole, miconazole, omoconazole, oxyconazole, certaconazole, sulconazole, or thioconazole. In some embodiments, the triazole is albaconazole, efinaconazole, epoxyconazole, fluconazole, isabconazole, itraconazole, posaconazole, propiconazole, ravconazole, terconazole, or voriconazole. In some embodiments, the thiazole is abafungin.

[0221] In some embodiments, the allylamine antifungal agent is amorolfine, butenafine, naphthifine, or terbinafine.

[0222] In some embodiments, echinocandin antifungal agents are selected from the group consisting of anidurafungin, caspofungin, micafungin, and rezafungin.

[0223] Adjunctive treatment In addition to antifungal treatment, optimal management of patients with fungal infections includes surgical reduction of infected tissue and removal of intravenous catheters in incidental patients with confirmed catheter-related fungal infections. In some embodiments, treatment with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate includes G-CSF or GM-CSF, G-CSF-stimulated granulocyte infusion. In some embodiments, treatment with compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate includes gamma interferon.

[0224] Kits and manufactured products This specification describes a kit for treating a fungal infection in a subject, comprising administering compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the subject.

[0225] Kits and products for use in the therapeutic applications described herein are also described herein. In some embodiments, such kits include a compartmentalized carrier, package, or container for receiving one or more containers, e.g., vials, tubes, etc., each of which includes one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In some embodiments, the containers are formed from various materials, e.g., glass or plastic.

[0226] The products provided herein include packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any other packaging materials appropriate to the selected formulation and the intended mode of administration and treatment. The abundant formulations of the compounds and compositions provided herein are intended as well as various treatment regimens that benefit from the administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0227] The container(s) may have a sterile access port (for example, the container may be an intravenous solution bag or vial with a stopper that can be pierced by a subcutaneous needle). Such a kit may contain the compound, along with an identifying description or label or instructions for its use in the method described herein.

[0228] The kit typically includes one or more further containers, each containing one or more of various materials (e.g., reagents in optionally concentrated forms, and / or devices) that are desirable from a commercial and user standpoint for the use of the compounds described herein. Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; labels for carriers, packages, containers, vials, and / or tubes listing the contents; and / or instructions for use, accompanying documentation including instructions for use. A set of instructions is also typically included.

[0229] In some embodiments, the label is on or associated with the container. The label is on the container if, in some cases, the letters, numbers, or other characters constituting the label are affixed to the container itself, molded into the container itself, or etched into the container itself; the label is associated with the container if, in some cases, the label is present within the receptacle or carrier holding the container, for example, as an accompanying document. The label is used in some cases to indicate that the contents are to be used for a specific therapeutic application. The label is used in some cases to indicate, for example, instructions for the use of the contents in the methods described herein.

[0230] In certain embodiments, a pharmaceutical composition containing compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is, in some cases, contained in a pack or dispenser device containing one or more unit dosage forms. The pack, in some cases, contains, for example, metal or plastic foil, such as a blister pack. The pack or dispenser device is, in some cases, accompanied by instructions for administration. The pack or dispenser is also, in some cases, accompanied by a container-related notice in the form prescribed by the administrative agency that regulates the manufacture, use, or sale of the drug, which reflects the agency's approval of the drug in a form for human or veterinary administration. Such notice is, in some cases, a labeling or approved product documentation approved by the U.S. Food and Drug Administration with respect to the prescription drug. Compositions containing the compounds provided herein, formulated in a suitable pharmaceutical carrier, are also, in some cases, prepared, placed in a suitable container, and labeled for treatment of the indicated conditions. [Examples]

[0231] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0232] (Example 1) compound 1 injection Compound 1 injection is prepared as a sterile solution that is further diluted in 0.9% sodium chloride injection before administration. Compound 1 injection is a solution formulated at a concentration of 20 mg / mL. This formulation consists of Compound 1 drug substance, sodium chloride, potassium phosphate (dibasic and monobasic), hydrochloric acid, sodium hydroxide, and water for injection (WFI).

[0233] Fill a 50 mL sterile glass vial with 35 mL of Compound 1 injection to obtain 700 mg / vial. Further dilute Compound 1 injection and administer as an IV infusion as specified in the clinical protocol. While preparing the mixed solution containing Compound 1, filter Compound 1 injection through a 0.2 μm filter before injection to remove all intrinsic particles.

[0234] Table 1 lists the composition of Compound 1 injection at 20 mg / mL for a volume of 35 mL in a 50 mL vial.

[0235] [Table 1]

[0236] To prepare Compound 1 injection: 1. Add sodium chloride and potassium phosphate (monobasic and dibasic) to a container containing water for injection; 2. Adjust the pH to 8.0 using 1M hydrochloric acid solution and / or 1M sodium hydroxide solution; 3. Slowly add Compound 1 drug substance to the solution and stir / mix at 15°C to 30°C; 4. Dissolve by adjusting the pH to 8.0 using hydrochloric acid solution and / or sodium hydroxide solution; 5. QS with water for injection and continue stirring at 15°C to 30°C; 6. Aseptically filter through a 2 × 0.2 μm membrane filter into a sterile 50 mL vial containing a volume of 35 mL sealed with a chlorobutyl stopper (Note: At the completion of each prepared batch, test the integrity of the filter using a bubble point test and report the results in the batch record); and 7. Inspect the vial before packaging and labeling.

[0237] (Example 2) Compound 1 tablet Compound 1 tablets are formulated into coated white tablets at strengths of 100 mg and 200 mg. Tables 2 and 3 list the contents of Compound 1 tablets at strengths of 100 mg and 200 mg, respectively.

[0238] [Table 2]

[0239] [Table 3]

[0240] (Example 3) An open-label study evaluating the efficacy and safety of compound 1 in non-neutropenic patients with candidiasis, with or without invasive candidiasis, including patients suspected of resistance to standard antifungal treatment. The need for improved treatment of IFD remains high, particularly given the increasing number of immunocompromised patients, such as hematopoietic stem cell and solid organ transplant recipients, who are at particularly high risk of developing these infections and whose treatment can be complex. While Candida and Aspergillus species are recognized as the two main causes of fungal diseases in these patients, other emerging fungi, such as non-C. albicans (e.g., C. glabrata and C. auris), Fusarium species, Scedosporium species, and fungi of the Mucorales order, contribute to the need to find novel and better strategies for managing these infections. Existing antifungal agents can be difficult to use, are often poorly tolerated, or become increasingly ineffective due to the emergence of drug-resistant fungal strains.

[0241] A 1000 mg IV dose of compound 1 at a BID concentration is administered on day 1, followed by a 600 mg IV dose of QD on days 2 and 3, and then a 600 mg IV dose or a 700 mg PO dose throughout the entire study drug treatment period. This treatment may offer advantages over standard treatment (SOC) for certain resistant fungal diseases where SOC treatment may not be effective or may have limited effectiveness.

[0242] primary purpose The primary objective of this study is to evaluate the efficacy and safety of compound 1 for treating adult non-neutropenic patients aged 18–80 years (inclusive) with candidiasis, including patients suspected or confirmed to be resistant to SOC antifungal treatment.

[0243] Secondary purpose A secondary objective of this study is, • Evaluate the time to the first negative blood culture. • Evaluate the percentage of patients with mycological outcomes at the end of research drug treatment (EOST), the end of antifungal treatment (EOT), and 2 and 4 weeks after EOT. • Evaluate the percentage of patients who have a successful treatment at EOT and 2 and 4 weeks after EOT. • Evaluate overall survival on day 30 of the study. • Evaluate safety parameters, including the number of patients with TEAEs. • Evaluate the PK parameter of compound 1. That is the case.

[0244] Summary of the research design This is a multicenter, open-label, non-comparative, single-arm study to evaluate the efficacy and safety of compound 1 for the first-line treatment of candidiasis, including suspected or confirmed antifungal-resistant candidiasis, in non-neutropenic patients aged 18–80 years (inclusive). Enrollment requires only suspected antifungal-resistant candidiasis; subsequent recorded resistance is not required. The study drug treatment period will be up to 14 days (including the loading dose [Study Day 1]). After completion of 14 days of study drug therapy, fluconazole (unless susceptibility results justify alternative antifungal treatment) may be initiated for up to an additional 7 days if further antifungal treatment is indicated to complete the treatment of candidiasis according to standard practice guidelines. There will be a 4-week (+4 day) follow-up period after end-of-treatment (EOT). The total duration of participation in the study will be approximately 7.5 weeks (including the screening period [≤96 hours prior to baseline]).

[0245] Patients in whom yeast has been identified in blood cultures or who have a positive rapid diagnostic test are eligible to consent and be screened for the study. To be considered for enrollment in the study, patients must have at least one positive blood test for Candida spp. (or yeast suspected to be Candida) in the diagnosis of candidiasis. Patients with positive blood cultures showing yeast suspected to be Candida must have the identification of Candida spp. from the positive blood culture confirmed before administration. Screening and baseline procedures and initiation of the study drug Compound 1 will begin within 96 hours of collection of the SOC blood sample for Candida spp. positive culture or rapid diagnostic test. Patients with prior systemic antifungal treatment at an approved dose equivalent to 2 days (>48 hours) to treat a current onset of candidiasis will be excluded within 96 hours prior to the first dose. However, patients with a Candida infection who have been proven resistant to a specific antifungal agent administered may have received a dose equivalent to ≤5 days (≤120 hours) of that previous treatment (results of a susceptibility test are required before registration).

[0246] Patients with prior systemic antifungal treatment at an approved dose equivalent to >2 days (>48 hours) to treat a current onset of candidiasis within 96 hours prior to the first dose should be excluded. However, patients with a Candida infection that has been proven resistant to the specific antifungal agent administered may have received that prior treatment at an equivalent dose of ≤5 days (≤120 hours) (results of susceptibility testing are required before enrollment).

[0247] On day 1 of the study (or within the first 24 hours if initiated in the evening), a loading dose of 1000 mg of compound 1 is administered intravenously (BID) over 3 hours. On days 2 and 3 of the study, a maintenance dose of 600 mg of compound 1 is administered intravenously (QD) over 3 hours. On day 4 and thereafter, the maintenance dose of compound 1 is administered either as 600 mg of compound 1 intravenously (QD) over 3 hours, or as 700 mg of compound 1 (PO) (QD). Patients who have completed at least 3 days of intravenous compound 1, are clinically stable as determined by the investigator, are able to swallow tablets, and have no further growth of infectious organisms 48 hours after the most recent blood culture may be switched from intravenous to PO administration on day 4 and thereafter. The study drug is administered for a maximum of 14 days. Patients requiring longer-term antifungal treatment, at the investigator's discretion, should be switched to fluconazole (unless susceptibility results justify alternative antifungal therapy) in accordance with the IDSA clinical practice guidelines for the management of candidiasis. Candida spp. bloodstream infections should be monitored by daily blood cultures during the study drug treatment until two consecutive blood cultures are negative, as well as at EOST, EOT, 2 and 4 weeks after EOT, or at early termination. Concurrently collected blood samples should be taken for Candida testing by T2 magnetic resonance (T2MR) assay at baseline, during the study drug treatment, and at EOST or early termination. Other culture, histopathology, and imaging tests should be performed as clinically directed to assess the site and extent of candidiasis infections at other sites, and the results should be recorded in the electronic case record (eCRF). Management of intravascular catheters, intravascular devices, and all drains, if applicable, including all relevant microbiological results, should be recorded. Patients will be monitored for safety throughout the entire duration of the study.

[0248] Plasma samples for PK (compound 1 [prodrug] and compound 1A [active portion]) are collected at baseline (pre-dose), twice weekly during study drug treatment, at EOST, EOT, two weeks after EOT, or at early termination. Serum samples for (1,3)-β-D-glucan levels are collected at baseline (pre-dose) and at EOST, or at early termination (if applicable).

[0249] Treatment outcomes will be evaluated at EOST, EOT, and 2 and 4 weeks after EOT, or at early termination. Study termination will occur after the last visit of the last patient in the study.

[0250] Indications: Treatment of non-neutropenic patients with candidiasis, including patients suspected or confirmed to have antifungal-resistant candidiasis.

[0251] Group: This study will enroll male and female patients aged 18–80 years (inclusive) who have been newly diagnosed with candidiasis (positive blood test for Candida spp.).

[0252] Test eligibility criteria: To be eligible to participate in the study, patients must meet all of the following criteria: 1. Male or female, 18-80 years old (inclusive) 2. A new diagnostic method for candidiasis based on blood samples collected within 96 hours of medication administration, using the following: a. Positive blood cultures for Candida spp., including Candida spp. suspected (in the opinion of the investigator) or documented resistance to at least one SOC systemic antifungal agent, or b. Positive results from a rapid diagnostic blood test approved by the sponsor of Candida spp. infection (a rapid diagnostic test may be used to initiate eligibility assessment, but a confirmatory blood culture is required before administration of compound 1). 3. Existing intravascular catheters can be removed and replaced (if necessary).

[0253] Medication guidelines In order for a patient to begin medication, they must meet the following criteria: 1. Confirmed diagnosis of candidiasis 2. Prior systemic antifungal treatment at an approved dose equivalent to ≤2 days (≤48 hours) to treat a current onset of candidiasis, or prior treatment for candidiasis caused by a Candida species (Candida spp.) with recorded resistance to a previously administered specific antifungal agent, at a dose equivalent to ≤5 days (≤120 hours).

[0254] Treatment group All patients will receive a loading dose of 1000 mg of compound 1 via BID, followed by a maintenance dose of 600 mg of compound 1 via QD on days 2 and 3 of the study. From day 4 onward, the maintenance dose of compound 1 will be 600 mg of compound 1 administered intravenously over 3 hours as a QD, or 700 mg may be switched to a QD via PO when / if the criteria for PO dosing are met.

[0255] dose In the PK-PD study, immunodeficient mice were infected with one of three Candida species (C. albicans, C. glabrata, or C. auris), and compound 1 was administered to the animal groups in different dose divisions. The AUC / MIC ratio was determined to be the PK-PD variable that best correlated with antifungal efficacy, assessed by fungal load (colony-forming units [CFU]) in the kidneys. Probability to reach target (PTA) was calculated separately for each Candida species tested. In the PTA calculation, the drug AUC level without compound 1A at the resting endpoint was used to determine the MIC (MIC) required to inhibit 90% of the growth of each Candida species tested. 90The value obtained by dividing by ) was used. AUC levels were estimated from population PK models, primarily derived from Phase 1 PK data. The quiescent endpoint was defined as the amount of Candida spp. in CFU immediately prior to compound 1 administration, compared to CFU at the evaluation endpoint (i.e., 24 hours for C. albicans, and 96 hours for C. glabrata and C. auris). MIC data for the Candida strains tested were obtained from recent surveillance data. Using the AUC at the quiescent endpoint, along with MIC90 from surveillance data and predicted exposure at the dose regimen used in this study, the PTA for the three Candida spp. tested was shown to be approximately 100%. Furthermore, increased variability of PK parameters and higher Candida spp. MIC 90 A sensitivity analysis was conducted to evaluate PTA under various scenarios, including those involving specific values. In both scenarios, PTA remained >90%.

[0256] In two Phase 1 studies in healthy volunteers, IV and PO formulations of compound 1 were safe and well-tolerated. The majority of TEAEs were mild, transient, and resolved without intervention. No DLTs were observed. Specifically, in the FIH Phase 1 clinical study, a 1000 mg IV, 2-hour infusion, BID loading dose of compound 1 on day 1, followed by a 600 mg IV, 1-hour infusion, QD maintenance dose of compound 1 on days 2 through 7, was safe and well-tolerated. This IV dose regimen is identical to the IV dose regimen used in this study. In the second Phase 1 clinical study, a 1000 mg dose of compound 1 administered on days 1 through 14 with PO and QD was safe and well-tolerated. This PO dose regimen is higher than the 700 mg PO dose used in this study.

[0257] schedule To ensure the safety and tolerance of compound 1 administration over 14 days, this study will use the compound 1 dose and infusion duration already studied in Phase 1 for a 14-day treatment including IV and PO investigational drug treatment. Patient safety and tolerance for the study will be optimized with a 1000 mg IV, BID loading dose in a 3-hour infusion, followed by a 600 mg IV, QD in a 3-hour infusion. On day 4 of the study, subject to the condition that the patient meets the criteria defined in the protocol for PO switching, a switch to a 700 mg QD of compound 1 PO dose will occur, and the combined IV and PO compound 1 treatment will not exceed 14 days.

[0258] Randomization and blinding This is an open-label, non-randomized study.

[0259] Drug supply Compound 1 injection is formulated and packaged at a concentration of 20 mg / mL. The formulation consists of the active pharmaceutical ingredient of Compound 1, sodium chloride, potassium phosphate (dibasic and monobasic), hydrochloric acid, sodium hydroxide, and sterile water for injection. Fill a 50 mL sterile vial with 35 mL of Compound 1 injection. Reconstitute the Compound 1 injection and administer as an IV infusion. Preparation and dilution instructions are provided in the pharmacy manual.

[0260] Compound 1 is formulated as white coated tablets of 100 mg and 200 mg strength. The formulation consists of the active pharmaceutical ingredient of Compound 1, microcrystalline cellulose, anhydrous dibasic calcium phosphate, colloidal silicon dioxide, pregelatinized starch, povidone, talc, and magnesium.

[0261] Administration of research drugs On day 1 of the study (or within the first 24 hours if started in the evening), a loading dose of 1000 mg of Compound 1 is administered intravenously (BID) over 3 hours. On days 2 and 3 of the study, a maintenance dose of 600 mg of Compound 1 is administered intravenously (QD) over 3 hours. On day 4 and thereafter, the maintenance dose of Compound 1 is administered either as 600 mg of Compound 1 intravenously (QD) over 3 hours, or as 700 mg of Compound 1 (PO) (QD). Patients who have completed at least 3 days of intravenous Compound 1, are clinically stable as determined by the investigator, are able to swallow tablets, and have no further growth of infectious organisms 48 hours after the most recent blood culture may be switched from intravenous to PO administration on day 4 and thereafter. The study drug will be administered for a maximum of 14 days (including the loading dose [day 1 of the study]). Tablets should be administered whole, at the same time each day, by mouth with water, within 30 minutes of being removed from the refrigerator. Do not split or crush tablets. If antifungal treatment is prescribed for longer than 14 days, fluconazole may be initiated for an additional 7 days at the investigator's discretion (unless susceptibility results justify alternative antifungal treatment) in accordance with the IDSA clinical practice guidelines for the treatment of candidiasis.

[0262] End of antifungal treatment (EOT): Following the completion of 14 days of study-based drug therapy, if further antifungal treatment is indicated to complete the management of candidiasis according to standard practice guidelines, fluconazole (unless susceptibility results justify alternative antifungal treatment) may be initiated for up to an additional 7 days. Where applicable, the Endotherapy Team (EOT) will also evaluate the effectiveness of this antifungal treatment at the end of the treatment. Success of the treatment is defined as meeting all of the following criteria: • Two consecutive blood cultures are negative for Candida species (Candida spp.). • Living in EOT • No additional systemic antifungal treatments (other than step-down treatments permitted in the protocol [e.g., fluconazole]) have been administered by the end of treatment (EOT). A treatment failure is defined as any instance where the criteria for treatment success are not met.

[0263] Mycological results: Eradication is defined as negative blood cultures for Candida spp. in the absence of additional antifungal treatment (other than the protocol - permitted step - down treatment, e.g., fluconazole) until EOT.

[0264] During follow - up (2 and 4 weeks after the end of antifungal treatment): Relapse (mycological) is defined as a mycologically confirmed infection based on blood cultures using the same baseline Candida spp. during the 4 - week period after EOT. Relapse (DRC assessment) is defined as a diagnostic parameter indicating the reappearance of Candida in blood cultures during the follow - up period, or the recurrence or delayed dissemination of Candida infection.

[0265] Results A total of 21 patients were registered in the study, and 20 were included in the mITT. The median duration of compound 1 treatment was 11 days (range 5 - 14). All patients received IV compound 1, and 48% (10 / 21) received PO compound 1. The success rate evaluated by DRC at EOST was 80% (16 / 20). Survival at day 3 was 85% (17 / 20), and death was not related to compound 1. Compound 1 was well - tolerated, with no treatment - related serious adverse events or interruptions. Compound 1 had potent in vitro activity against all Candida spp. from this study, including isolates resistant to other antifungal agents.

[0266] Results in patients with renal insufficiency: subgroup analysis Approximately 66% (14 / 21) of the subjects had some degree of renal insufficiency: 7 had mild renal insufficiency (GFR: 60 - 89), 5 had moderate renal insufficiency (GFR: 30 - 59), and 2 had severe renal insufficiency (GFR: 15 - 29). Most (12 / 14) completed the study treatment. The success rate of treatment with EOST in patients with renal insufficiency was 86% (12 / 14). None had deterioration of renal function with EOST. Four patients had deterioration of renal function during the follow-up period. Renal dysfunction did not increase FMGX exposure. There were no treatment-related adverse events.

[0267] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be within the spirit and scope of this application and within the scope of the appended claims.

Claims

1. A method for treating fungal infections in a subject, comprising: administering a therapeutically effective amount of compound 1 to a subject with a fungal infection. 【Chemistry 1】 The procedure includes administering a pharmaceutically acceptable salt, solvate, or hydrate thereof, The fungal infections in the subjects include Candida sp., Aspergillus sp., Scedosporium sp., Fusarium sp., Paecilomyces sp., Purpureocillium sp., Dematiaceous sp., Rhizopus, Mucor sp., Lichtheimia sp., and Cunninghamella. ), Acremonium spp., Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsequea spp., Lomentospora ), Phialophora spp., Scopulariopsis spp., Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma Sporobolomyces spp., Exophiala spp., Lacazia spp., EmmonsiaCaused by fungi such as Wickerhamomyces (Pichia) sp., Emergomyces sp., Talaromyces sp., or Emmonsia-like fungi, or combinations thereof. A therapeutically effective amount of compound 1 is compound 1A at a concentration of at least approximately 100 μg × time / mL: 【Chemistry 2】 The area under the steady-state 24-hour concentration-time curve (AUC) in the subject. ０～２４ ) provides, The subject is unsuitable for standard antifungal treatment, A method comprising a therapeutic regimen in which compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to a subject for at least 1 to 4 weeks, comprising daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. The method according to claim 1, wherein the inability to respond to standard antifungal treatment is due to impaired renal function.

3. The method according to claim 1 or 2, wherein the inability to respond to standard antifungal treatment is due to kidney disease in the subject.

4. The method according to claim 3, wherein the kidney disease is chronic kidney disease, metabolic syndrome, vesicoureteral reflux, tubulointerstitial fibrosis, IgA nephropathy, diabetic nephropathy, Alport syndrome, HIV-associated nephropathy, glomerulonephritis (GN), focal segmental glomerulosclerosis, membranous glomerulonephritis, mesangial capillary GN, interstitial fibrosis and tubular atrophy (IFTA), acute kidney injury (AKI), acute obstructive nephropathy, or drug-induced fibrosis.

5. The method according to claim 3, wherein the kidney disease is chronic kidney disease (CKD).

6. The method according to claim 5, wherein the chronic kidney disease (CKD) is stage 1 CKD, stage 2 CKD, stage 3 CKD, stage 4 CKD, or stage 5 CKD.

7. The method according to claim 2, wherein the subject has a high level of protein in its urine (proteinuria).

8. The therapeutically effective amount of compound 1 is at least 150 μg × time / mL of compound 1A, and the area under the steady-state 24-hour concentration-time curve (AUC) ０～２４ The method according to any one of claims 1 to 7, which provides ).

9. The method according to any one of claims 1 to 8, wherein the non-suitability for standard antifungal treatment includes an azole antifungal agent, an allylamine antifungal agent, an echinocandin antifungal agent, or a polyene antifungal agent.

10. Incompatibility with standard antifungal treatments includes amphotericin B, candicidine, philipinazole, hamycin, natamycin, nystatin, rimocidine, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isabconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, thioconazole, albaconazole, efinaconazole, and epoxin. The method according to any one of claims 1 to 8, comprising siconazole, fluconazole, isabconazole, itraconazole, posaconazole, propiconazole, ravconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine, or terbinafine, anidurafungin, caspofungin, micafungin, rezafungin, or a pharmaceutically acceptable salt of any of the aforementioned antifungal agents.

11. The method according to any one of claims 1 to 10, wherein the fungal infection is caused by a fungus of the order Mucorales, or a combination thereof, such as Candida sp., Aspergillus sp., Skedosporium sp., Fusarium sp., Paecilomyces sp., Purpureocillium sp., Dematiaceous sp., or a fungus of the order Mucorales.

12. The method according to any one of claims 1 to 11, wherein the subject is in an immune-deficient state.

13. The method according to any one of claims 1 to 12, wherein the subject is infected with HIV / AIDS or has cancer.

14. The method according to claim 13, wherein the cancer is acute myeloid leukemia or acute lymphoblastic leukemia.

15. The method according to any one of claims 1 to 14, wherein the subject has neutropenia.

16. The method according to any one of claims 1 to 15, wherein the subject has lymphopenia.

17. The method according to any one of claims 1 to 16, wherein the subject is a person who is currently receiving or has received cancer chemotherapy.

18. The method according to any one of claims 1 to 17, wherein the subject is a person who is receiving or has received corticosteroid treatment.

19. The method according to any one of claims 1 to 18, wherein the subject is a person who is receiving or has received TNF inhibitor treatment.

20. The method according to any one of claims 1 to 19, wherein the subject is an organ transplant recipient.

21. The method according to any one of claims 1 to 16, wherein the subject is a hematopoietic stem cell transplant recipient.

22. The method according to any one of claims 1 to 16, wherein the subject has graft-versus-host disease.

23. The method according to any one of claims 1 to 22, wherein the fungal infection is superficial, locally invasive, or disseminated throughout the subject.

24. The method according to any one of claims 1 to 23, wherein the fungal infection is a skin infection, a lung infection, a sinus infection, a central nervous system infection, a brain infection, an eye infection, a heart infection, a kidney infection, a gastrointestinal infection, a stomach infection, a pelvic infection, a blood infection, or a combination thereof.

25. The method according to any one of claims 1 to 24, wherein the fungal infection is a fungal disease or condition in which candidiasis, aspergillosis, blastomycosis, coccidioidomycosis (valley fever), cryptococcosis, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), tinea, sporotrichumosis, talalomycosis, allergic bronchopulmonary aspergillosis, allergic sinusitis, azole-resistant A. fumigatus, aspergilloma, pulmonary aspergillosis, infiltrative aspergillosis, cutaneous aspergillosis, fusariosis, skedoporium, rhinocerebral mucormycosis, pulmonary mucormycosis, disseminated mucormycosis, pelvic mucormycosis, gastric mucormycosis, cutaneous mucormycosis, or a combination thereof.

26. The method according to any one of claims 1 to 25, wherein the treatment regimen comprises a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

27. The method according to claim 26, wherein the treatment regimen comprises approximately 2000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate, which is a loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate.

28. The method according to claim 26 or claim 27, wherein a loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to a subject by intravenous (IV) infusion.

29. The method according to claim 26 or claim 27, wherein a loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprises the administration of two doses of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject by intravenous (IV) infusion.

30. The method according to claim 26 or claim 27, wherein each loading dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject by intravenous (IV) infusion over a period of about 30 minutes to about 4 hours.

31. The method according to claim 26 or claim 27, wherein each dose of the loading dose comprises about 1,000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

32. The method according to claim 26 or claim 27, wherein the loading dose comprises administering approximately 1,000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to the subject by intravenous (IV) infusion, and a second administration of approximately 1,000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate to the subject by intravenous (IV) infusion within approximately 24 hours of the first infusion.

33. The method according to any one of claims 26 to 32, wherein the maintenance dose is administered once daily, starting on the second day of treatment.

34. The method according to claim 33, wherein the maintenance dose comprises a once-daily administration of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate in an amount of about 600 mg to about 1500 mg.

35. The method according to any one of claims 26 to 34, wherein the maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by IV infusion for a period of about 30 minutes to about 4 hours, starting on the second, third, or fourth day of treatment.

36. The method according to any one of claims 26 to 35, wherein the maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate in an amount of approximately 600 mg to approximately 1200 mg is administered by IV infusion over a period of approximately 30 minutes to approximately 4 hours, starting on the second, third, or fourth day of treatment.

37. The method according to any one of claims 26 to 34, wherein the maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally to the subject, starting on the second, third, or fourth day of treatment.

38. The method according to any one of claims 26 to 34, wherein a maintenance dose of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof in an amount of approximately 800 mg to approximately 1000 mg is administered orally to the subject once daily, starting on the second, third, or fourth day of treatment.

39. Start on the second, third, or fourth day of treatment: a) Approximately 600 mg to 900 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of approximately 30 minutes to 3 hours; or b) Approximately 700 mg to 1000 mg of compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate is administered orally once daily. The method according to any one of claims 26 to 34.

40. Starting on the second day of treatment, administer approximately 600 mg to 900 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, by intravenous infusion over a period of approximately 30 minutes to 3 hours. Start on the fourth day of treatment: a) Administer approximately 600 mg to approximately 900 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, by intravenous injection over a period of approximately 30 minutes to approximately 3 hours, or b) Administer approximately 700 mg to 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, once daily. The method according to any one of claims 26 to 34.

41. The method according to any one of claims 1 to 40, wherein the compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with a further therapeutic agent.

42. The method according to any one of claims 1 to 41, wherein the treatment regimen comprises daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for a period of approximately 4 to 6 weeks.

43. The method according to any one of claims 1 to 42, wherein the treatment regimen comprises daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for a period of approximately 4 to 12 weeks.

44. The treatment regimen comprises compound 1 as a loading dose, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and compound 1 as a maintenance dose, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The loading dose of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprises two doses of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered intravenously (IV) to the subject on day 1 of treatment, with each dose containing approximately 1000 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Subsequently, the maintenance dose is administered once daily by intravenous (IV) infusion of approximately 600 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for at least two days, followed by... Approximately 600 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, administered once daily by intravenous (IV) infusion, or Approximately 700 mg of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, administered orally once daily. including, The method according to any one of claims 1 to 25.

45. The method according to claim 44, wherein the treatment regimen comprises administering compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for up to 14 days.

46. The method according to any one of claims 1 to 45, wherein the fungal infection in the subject is caused by a Candida species (Candida spp.).

47. The method according to any one of claims 1 to 46, wherein the treatment regimen is to increase the chances of survival of the subject, to decrease galactomannan levels in the subject, to decrease β-d-glucan levels in the subject, or a combination thereof.

48. The method according to any one of claims 1 to 47, wherein dose adjustment of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof administered to the subject is not required based on the subject's renal condition.

49. A method for treating fungal infections in a subject, comprising: administering a therapeutically effective amount of compound 1 to a subject with a fungal infection. 【Transformation 3】 The procedure includes administering a pharmaceutically acceptable salt, solvate, or hydrate thereof, The therapeutically effective amount of compound 1, at least about 100 μg × time / mL of compound 1A, is the area under the steady-state 24-hour concentration-time curve (AUC) in the subject. ０～２４ ) provided by: 【Chemistry 4】 The administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to the subject comprises a treatment regimen including daily administration of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for at least 1 to 4 weeks. A method in which dose adjustment of compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, administered to the subject is not required based on the subject's renal condition.

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