Compounds and methods for treating fungal infections

Abstract

This article provides compositions for treating fungal infections and diseases, and methods of using them.

Description

Technical Field

[0001] This article provides compositions for treating fungal infections and diseases, and methods of using them. Prior Technology

[0002] Fungi infect humans and are a major cause of human health problems. They also infect plants and cause significant losses in agricultural productivity. This invention generally relates to the treatment and / or prevention of fungal infections and diseases. Summary of the Invention

[0003] In one embodiment, this document provides a pharmaceutical composition comprising: (i) a compound of formula (I): , Or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form intended for oral administration or delivery.

[0004] In another embodiment, a pharmaceutical composition is provided comprising: (i) fine particles of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or delivery or for inhalation delivery.

[0005] In some embodiments, the particles are micronized. In some embodiments, the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 10% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 20% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 30% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 40% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 50% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 60% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 70% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 80% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 90% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 95% of the particles have a particle size of about 1 µm to about 750 µm.

[0006] In some embodiments, the particles are nano-milled. In some embodiments, at least about 10% of the particles have a particle size of about 1 µm to about 750 nm. In some embodiments, at least about 20% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 30% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 40% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 50% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 60% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 70% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 80% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 90% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 95% of such particles have a particle size of about 1 nm to about 750 nm.

[0007] In some embodiments, the dosage form is a spontaneous microemulsion drug delivery system (SMEDDS). In some embodiments, the dosage form is a spontaneous emulsion drug delivery system (SEDDS). In some embodiments, the dosage form is a suspension or solution. In some embodiments, the dosage form is a nano suspension. In some embodiments, the dosage form is a solid dosage form. In some embodiments, the dosage form is a spray-dried dispersion. In some embodiments, the dosage form is a hot-melt granulated dosage form. In some embodiments, the dosage form is a hot-melt extrusion dosage form. In some embodiments, the dosage form is a microprecipitated bulk powder (MBP) dosage form. In some embodiments, the dosage form is a liquid. In some embodiments, the dosage form is a suspension, solution, syrup, or elixir. In some embodiments, the pharmaceutical composition is in a dosage form for oral administration or dosing.

[0008] In some embodiments, the dosage form is a tablet or a capsule. In some embodiments, the tablet or capsule has an enteric coating. In some embodiments, the dosage form is a tablet. In some embodiments, the tablet is an osmotically floatable tablet. In some embodiments, the capsule is a liquid-filled hard capsule. In some embodiments, the capsule is a soft gelatin capsule.

[0009] In some embodiments, the dosage form is a controlled-release dosage form. In some embodiments, the controlled-release dosage form is a delayed-release dosage form, an extended-release (ER) dosage form, or a targeted-release dosage form. In some embodiments, the ER dosage form is a sustained-release (SR) dosage form or a controlled-release (CR) dosage form. In some embodiments, the dosage form is an immediate-release dosage form.

[0010] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 600 mg of a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 150 mg, about 150 mg to about 250 mg, about 250 mg to about 350 mg, about 350 mg to about 450 mg, about 450 mg to about 550 mg, about 550 mg to about 650 mg, about 650 mg to about 750 mg, about 850 mg to about 950 mg, or about 950 mg to about 1050 mg of a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate.

[0011] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0012] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, in doses of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg or about 500 mg.

[0013] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, in doses of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg or about 500 mg.

[0014] In some embodiments, the at least one pharmaceutically acceptable excipient is a filler, disintegrant, binder, lubricant, or any combination thereof. In some embodiments, the at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, provitamin, magnesium stearate, colloidal silica, or any combination thereof.

[0015] In some embodiments, the pharmaceutical composition is stable for up to 36 months at a temperature of about 2°C to about 25°C. In some embodiments, the pharmaceutical composition is stable for a period of about 24 to about 36 months at a temperature of about 2°C to about 8°C. In some embodiments, the pharmaceutical composition is stable for up to 36 months at a temperature of about 2°C to about 25°C when stored in solid form. In some embodiments, the pharmaceutical composition is stable for a period of about 24 to about 36 months when stored in solid form at a temperature of about 2°C to about 8°C. In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg of a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate.

[0016] In one embodiment, this document provides a pharmaceutical composition comprising: (i) a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form intended for administration by injection or delivery.

[0017] In some embodiments, the pharmaceutical composition is in the form of a dosage form for intravenous (IV) injection or infusion, or for intramuscular, subcutaneous or intradermal injection.

[0018] In some embodiments, the pharmaceutical composition is in the form of an IV injection or infusion. In some embodiments, the dosage form is an IV dosage form. In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the dosage form comprises a co-solvent.

[0019] In some embodiments, the co-solvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cetyl alcohol, glycerol, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert-butanol, or any combination thereof. In some embodiments, the dosage form further comprises an oil. In some embodiments, the oil comprises sesame oil, soybean oil, vegetable oil, poppy seed oil, safflower oil, or a combination thereof.

[0020] In some embodiments, the dosage form further comprises a buffer solution. In some embodiments, the IV dosage form further comprises a buffer solution. In some embodiments, the buffer solution is a phosphate buffer. In some embodiments, the phosphate buffer solution is potassium phosphate. In some embodiments, the potassium phosphate is a monobasic or dibasic salt.

[0021] In some embodiments, the pharmaceutical composition has a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition has a pH of about 2.5 to about 5.0 or about 6.5 to about 10.5. In some embodiments, the pharmaceutical composition has a pH of about 2.5 to about 4.5 or about 7.0 to about 9.0.

[0022] In some embodiments, the pH of the pharmaceutical composition formulated for intravenous administration is adjusted with hydrochloric acid and / or sodium hydroxide.

[0023] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate of about 5 mg / mL to about 250 mg / mL. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate of about 10 mg / mL to about 50 mg / mL.

[0024] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate at a concentration of about 20 mg / mL to about 40 mg / mL. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate at a concentration of about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL.

[0025] In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for up to about 24 months. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C for a period of about 12 to about 24 months. In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0026] In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline, microcrystalline, amorphous, or lyophilized. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are amorphous. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are lyophilized.

[0027] In some embodiments, the pharmaceutical composition is substantially free of impurities. In some embodiments, the purity of the pharmaceutical composition is at least about 90%. In some embodiments, the purity of the pharmaceutical composition is at least about 95%. In some embodiments, the purity of the pharmaceutical composition is at least about 96%. In some embodiments, the purity of the pharmaceutical composition is at least about 97%. In some embodiments, the purity of the pharmaceutical composition is at least about 98%. In some embodiments, the purity of the pharmaceutical composition is at least about 99%. In some embodiments, the purity of the pharmaceutical composition is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100%. In some embodiments, the pharmaceutical composition contains at least 10% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition contains at least one impurity of less than about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w). In some embodiments, the pharmaceutical composition contains at least one impurity of less than about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w). In some embodiments, the pharmaceutical composition contains less than one impurity of about 0.9% (w / w), about 0.8% (w / w), about 0.7% (w / w), about 0.6% (w / w), about 0.5% (w / w), about 0.4% (w / w), about 0.3% (w / w), about 0.2% (w / w), or about 0.1% (w / w).

[0028] In some embodiments, the at least one impurity is a degradation product. In some embodiments, the at least one impurity is: Or any combination thereof.

[0029] In some embodiments, the at least one impurity is: .

[0030] In some embodiments, the pharmaceutical composition contains up to about 4.0% (w / w) of total impurities. In some embodiments, the pharmaceutical composition contains up to about 0.5% (w / w) of any individual impurity. In some embodiments, the pharmaceutical composition contains up to about 1.5% (w / w) of the following compounds: .

[0031] In another embodiment, a combined composition is provided comprising: (i) the compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one antifungal agent.

[0032] In some embodiments, the at least one antifungal agent is an azole, echinocandin, amphotericin B deoxycholate, amphotericin B cochleate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, ibrexafungerp, orotomide F901318, or a combination thereof. In some embodiments, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavuconazole, or miconazole. In some embodiments, the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin.

[0033] In one state sample, this document provides a combined composition comprising: (i) a compound of formula (I): or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; and (ii) Compounds of formula (II) , or its isotopic variants, tautomers, medically acceptable salts, solvates or hydrates.

[0034] In some embodiments, the combined composition further comprises at least one pharmaceutically acceptable excipient.

[0035] In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are all crystalline.

[0036] In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in a ratio of about 10:1. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in a ratio of about 9:1 to about 9.99:0.01. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in a ratio of about 9.5:0.5 to about 9.9:0.1. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in ratios of about 9:1, about 9.1:0.9, about 9.2:0.8, about 9.3:0.7, about 9.4:0.6, about 9.5:0.5, about 9.6:0.4, about 9.7:0.3, about 9.8:0.2 or about 9.9:0.1.

[0037] In one instance, this article provides a method for treating or preventing fungal infections or diseases, comprising administering to an individual in need a therapeutically effective amount of any of the pharmaceutical compositions or combined compositions described herein.

[0038] In some embodiments of the methods provided herein, the individual is administered about 10 mg to about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the individual is administered about 10 mg to about 2,400 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the individual is given about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, about 1,500 mg, about 1,800 mg, about 2,000 mg, about 2,100 mg, about 2,400 mg, about 2,500 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, or about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0039] In some embodiments of the methods provided herein, the individual is administered about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the individual is administered about 600 mg, about 700 mg, about 800 mg, about 900 mg, 1,000 mg, about 2,000 mg, or about 3,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0040] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual once, twice, three times, or four times daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual once daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual twice daily.

[0041] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual for a period of approximately 12 weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual for a period of at least one week. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual for a period of at least two weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual for a period of approximately two weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual for a period of one week, two weeks, six weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks.

[0042] In some embodiments of the methods provided herein, the individual is given about 10 mg to about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates. In some embodiments of the methods provided herein, the individual is given about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, or about 2,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0043] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual via IV infusion for a period of approximately 20 minutes, approximately 30 minutes, approximately 60 minutes, approximately 90 minutes, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, approximately 12 hours, approximately 18 hours, or approximately 24 hours.

[0044] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the individual via IV infusion over a period of up to about 3 hours.

[0045] In some embodiments of the methods provided herein, an initial dose is administered to the individual, followed by a maintenance dose. In some embodiments of the methods provided herein, the initial dose comprises about 1,000 mg to about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg to about 2,400 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the initial dose comprises about 1,000 mg to about 2,000 mg. In some embodiments of the methods provided herein, the initial dose is administered via IV infusion over a period of about 2 to 3 hours. In some embodiments of the methods provided herein, the initial dose is administered twice on the first day of treatment. In some embodiments of the methods provided herein, the second initial dose is administered about 9 hours after the first initial dose.

[0046] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the individual is administered the maintenance dose comprising about 800 mg or about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, administered orally.

[0047] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and is administered by intravenous infusion over a period of about 1 hour to about 3 hours.

[0048] In some embodiments of the methods provided herein, such as the methods of any one of Examples 157 to 164, approximately 600 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are administered by intravenous infusion over a period of approximately 3 hours.

[0049] In some embodiments of the methods provided herein, the maintenance dose is administered once daily.

[0050] In some embodiments of the methods provided herein, the maintenance dose is administered once daily, starting from the second day of treatment.

[0051] In some embodiments of the methods provided herein, about 600 mg or about 800 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are administered via IV infusion over a period of about 3 hours, starting on the second, third or fourth day of treatment.

[0052] In some embodiments of the methods provided herein, about 800 mg or about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are administered orally starting on the second, third or fourth day of treatment.

[0053] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 800 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the individual is administered about 600 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the individual is administered about 800 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, approximately 600 mg of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered via intravenous infusion over a period of approximately 1 hour to approximately 3 hours, and / or approximately 800 mg of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered orally. In some embodiments of the methods provided herein, the maintenance dose is administered once daily. In some embodiments of the methods provided herein, the maintenance dose is administered once daily starting from the second day of treatment. In some embodiments of the methods provided herein, approximately 600 mg of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered via intravenous infusion over a period of approximately 3 hours.

[0054] In some embodiments of the methods provided herein, approximately 600 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered via IV infusion over a period of approximately 3 hours, beginning on the second day of treatment.

[0055] In some embodiments of the methods provided herein, approximately 800 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered orally starting on the fourth day of treatment.

[0056] In some embodiments of the methods provided herein, the fungal infection is caused by an invasive fungus. In some embodiments of the methods provided herein, the method further comprises administering to the individual at least one antifungal agent in combination with a pharmaceutical composition comprising a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the at least one antifungal agent is an azole, echinocandin, deoxycholic acid amphotericin B, amphotericin B liposome, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, ibrene, oxytocin F901318, or a combination thereof. In some embodiments of the methods provided herein, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavuconazole, or miconazole. In some embodiments of the methods provided herein, the echinocandin is caspofungin, anidoxurine, micafungin, or rezafenamine, or a combination thereof.

[0057] In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and the antifungal agent are administered simultaneously, substantially simultaneously, or sequentially in any order. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and the antifungal agent are administered simultaneously or substantially simultaneously. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and the antifungal agent are administered sequentially. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, or a pharmaceutically acceptable salt thereof, is administered before the at least one antifungal agent. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or an isotopic variant thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof is administered after the at least one antifungal agent.

[0058] In some embodiments of the methods provided herein, the fungal infection or disease is caused by: *Aspergillus fumigatus*, *Blastomyces*, *Ajellomyces*, *Candida*, *Coccidioides*, *Cryptococcus*, *Histoplasma*, and *Rhizopus*. The fungal infection or disease is caused by fungi of the genera *Muco*, *Cunninghamell*, *Apophysomyces*, *Absidi*, *Saksenaea*, *Entomophthora*, *Conidiobolus*, *Basidiobolus*, *Sporothrix*, *Pneumocystis*, *Talaromyces*, *Asclepias*, *Fusarium*, *Scedosporium*, or fungi from the order *Mucorales*, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by fungi of the genera *Cryptococcus*, *Aspergillus*, *Candida*, *Fusarium*, *Scedosporium*, or fungi from the order *Mucorales*, or any combination thereof.In some embodiments of the methods provided herein, the fungal infection or disease is caused by: *Aspergillus fumigatus*, *Aspergillus flavus*, *Blastomyces dermatitidis*, *Ajellomyces dermatitidi*, *Candida albican*, *Candida glabrata*, *Candida rugosa*, *Candida auris*, *Coccidioides immitis*, *Coccidioides posadasii*, *Cryptococcus neoformans*, *Cryptococcus gattii*, *Histoplasma capsulatum*, *Rhizopus stolonifer*, *Rhizopus arrhizus*, and *Mucor*. *Indicus*, *Cunninghamella bertholletiae*, *Apophysomyces elegans*, *Absidia* species, *Pyrhodotorula* species, *Rhizomucor pusillus*, *Entomophyceae* species, *Otomycetes* species, *Frogdum* species, *Sporothrix schenckii*, *Pneumocystis jirovecii*, *Talaromyces marneffei*, *Asclepias albicans*, *Fusarium solani*, *Scedosporium apiospermum*, *Rhizomucor pusillus*, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by *Cryptococcus* or *Candida* fungi. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gutterusum, or Candida auris.

[0059] In some embodiments of the methods provided herein, the fungal infection or disease is resistant to azoles and / or echinocandins.

[0060] In some embodiments of the methods provided herein, the individual is immunocompromised. In some embodiments of the methods provided herein, the individual is infected with HIV / AIDS or has cancer. In some embodiments of the methods provided herein, the individual has cancer. In some embodiments of the methods provided herein, the cancer is acute myeloid leukemia (AML). In some embodiments of the methods provided herein, the individual has neutropenia. In some embodiments of the methods provided herein, the individual is undergoing or has undergone cancer chemotherapy. In some embodiments of the methods provided herein, the individual is undergoing or has undergone corticosteroid therapy. In some embodiments of the methods provided herein, the individual is undergoing or has undergone TNF inhibitor therapy. In some embodiments of the methods provided herein, the individual is a transplant recipient. In some embodiments of the methods provided herein, the fungal infection or disease is in the individual's bloodstream. In some embodiments of the methods provided herein, the individual has a reduced fungal community count in the lungs after administration of the pharmaceutical composition.

[0061] In some embodiments of the methods provided herein, the plasma concentration versus time curve of the compound of formula (I) in the individual has a tmax of less than about 30 minutes to about 180 minutes. In some embodiments of the methods provided herein, the individual has a maximum plasma concentration (Cmax) of the compound of formula (I) of about 12,000 ng / mL to about 25,000 ng / mL. Incorporate by reference

[0062] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference. Simple Explanation of the Diagram

[0063] [picture] [1A] [To the image] [1B.] Administer 10 to 1000 mg via IV infusion to a healthy individual over 3 hours. [Compound] [1] After that, [Compound] [1A] Geometric mean plasma concentration - linear axis ( [picture] [1A]) and semi-logarithmic axis ( [picture] [1B]). [ ]

[0064] [picture] [2A] [To the image] [2B.] After an IV infusion of 1000 mg into a healthy individual over a period of 0.5 to 3 hours, [Compound] [1A] Geometric mean plasma concentration - linear axis ( [picture] [2A]) and semi-logarithmic axis ( [picture] [2B]). [ ]

[0065] [picture] [3A] [To the image] [3B.] 50, 150, 300, and 600 mg were administered intravenously to healthy individuals over a 3-hour period. [Compound] [1](qd×14 days) after, [Compound] [1A] Geometric mean plasma concentration - linear axis ( [picture] [3A]) and semi-logarithmic axis ( [picture] [3B]). [ ]

[0066] [picture] [4A] [To the image] [4B.] On day 1, administer 1000 mg of the starting regimen via IV infusion at 0 and 9 hours over a 2-hour period to healthy individuals. [Compound] [1] Following this, from day 2 to day 7, 600 mg was administered via intravenous infusion over 1 hour (qd×6 days). [Compound] [1A] Geometric mean plasma concentration - linear axis ( [picture] [4A]) and semi-logarithmic axis ( [picture] [4B]). [ ]

[0067] [picture] [5A] [To the image] [5B.] Following an IV infusion of 10 to 350 mg of compound 1 to healthy individuals over 3 hours and an IV infusion of 1000 mg over 0.5 to 3 hours, [Compound] [1] Geometric mean plasma concentration - linear axis ( [picture] [5A]) and semi-logarithmic axis ( [picture] [5B]). [ ]

[0068] [picture] [6A] [To the image] [6B.] 50, 150, 300, and 600 mg were administered intravenously to healthy individuals over a 3-hour period. [Compound] [1] After (QD×14 days), [Compound] [1] Geometric mean plasma concentration - linear axis ( [picture] [6A]) and semi-logarithmic axis ( [picture] [6B]). [ ]

[0069] [picture] [7A] [To the image] [7B.] On day 1, 1000 mg of the starting regimen was administered via IV infusion to healthy individuals at 0 and 9 hours over a 2-hour interval. [Compound] [1] Following this, from day 2 to day 7, 600 mg was administered via intravenous infusion over 1 hour (qd×6 days). [Compound] [1] Geometric mean plasma concentration - linear axis ( [picture] [7A]) and semi-logarithmic axis ( [picture] [7B]). [ ]

[0070] [picture] [8A] [To the image] [8B.] Under fasting conditions, 200 mg was administered intravenously to healthy individuals over a 3-hour period. [Compound] [1] and after oral administration of 100 to 500 mg, [Compound] [1A] Geometric mean plasma concentration - linear axis ( [picture] [8A]) and semi-logarithmic axis ( [picture] [8B]). [ ]

[0071] [picture] [9A] [To the image] [9B.] Under fasting and feeding conditions, 400 mg was administered orally to healthy individuals. [Compound] [1] After that, [Compound] [1A] Geometric mean plasma concentration - linear axis ( [picture] [9A]) and semi-logarithmic axis ( [picture] [9B]). [ ]

[0072] [picture] [10A] [To the image] [10B.] Under feeding conditions, oral administration of 500 and 1000 mg to healthy individuals... [Compound] [1] After (QD×14 days), [Compound] [1A] Geometric mean plasma concentration - linear axis ( [picture] [10A]) and semi-logarithmic axis ( [picture] [10B]). [ ]

[0073] [picture]

[11] . Solubility profile of 400 mg compound tablets. Implementation

[0074] [Cross-reference to related applications] [ ] This application claims the benefit of U.S. Provisional Application No. 62 / 725,971, filed on August 31, 2018, which is considered part of and incorporated herein by reference.

[0075] This article provides, for example, compositions for treating and / or preventing fungal infections or diseases. This article also provides, for example, methods for treating and / or preventing fungal infections or diseases. [I.] [definition]

[0076] The abbreviations used in this article have their common meanings in the fields of chemistry and biology. The chemical structures and formulas described in this article are constructed according to the standard rules of valence known in the field of chemistry.

[0077] As used in this article, a "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another.

[0078] Those skilled in the art will readily recognize that some of the compounds of this invention can exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this invention.

[0079] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of this invention, except for hydrogen substitution by deuterium or tritium or carbon substitution by 13C or 14C enrichment, are within the scope of this invention.

[0080] The compounds of this invention may also contain atomic isotopes in non-natural proportions at one or more of the atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variants of the compounds of this invention, whether or not radioactive, are covered within the scope of this invention.

[0081] The term "isotope variant" refers to a compound in which one or more of the atoms constituting the compound contain an isotope in a non-natural proportion. In some embodiments, the "isotopic variants" of the compound contain one or more isotopes in non-natural proportions, including (but not limited to) hydrogen (1H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In some embodiments, the "isotope variants" of the compounds are in a stable form, that is, non-radioactive. In some embodiments, the "isotope variant" of the compound contains one or more isotopes in non-natural proportions, including (but not limited to) hydrogen (¹H), deuterium (²H), carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In some embodiments, the "isotope variant" of the compound is in an unstable form, that is, radioactive.In some embodiments, the "isotopic variants" of the compound contain one or more isotopes in non-natural proportions, including (but not limited to) tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36Cl), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It should be understood that in the compounds provided herein, any hydrogen may be, for example, 2H, or any carbon may be, for example, 13C, or any nitrogen may be, for example, 15N, and any oxygen may be 18O, where it is feasible according to the judgment of one skilled in the art. In some embodiments, the "isotopic variant" of the compound contains a non-natural proportion of deuterium (D).

[0082] It should be noted that in this application, substitutes are written into a Markush group, for example, each containing more than one possible amino acid position. It is particularly anticipated that each member of the Markush group should be considered individually, thereby encompassing another embodiment, and that the Markush group is not read as a single unit.

[0083] As used herein, the term "a / an" means one or more (kinds). Additionally, as used herein, the phrase "substituted with one..." means that the specified group may be substituted with one or more of any or all named substituents. For example, in the case of a group such as an alkyl or heteroaryl group "substituted with an unsubstituted C1-C20 alkyl or an unsubstituted 2- to 20-membered heteroalkyl", the group may contain one or more unsubstituted C1- to C20 alkyls and / or one or more unsubstituted 2- to 20-membered heteroalkyls.

[0084] As used herein, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the individual being treated.

[0085] As used herein, the term "medically acceptable salt" includes both acid addition salts and base addition salts, that is, salts of active compounds prepared with a relatively non-toxic acid or base depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base in a solvent-free environment or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in a solvent-free environment or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphoric acid and their analogs, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, and their analogs. Also included are salts of amino acids such as arginine and its analogs, and salts of organic acids such as glucuronic acid or galacturonic acid and their analogs (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science).

[1977] (66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt, or that allow the compound to exist in zwitterionic form.

[0086] Therefore, the compounds of the present invention can exist in the form of salts of pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromates, phosphates, sulfates, methanesulfonates, nitrates, maleic acid salts, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts of amino acids such as glutamic acid and quaternary ammonium salts (e.g., iodomethane, iodoethane, and the like). These salts can be prepared by methods known to those skilled in the art.

[0087] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties, such as solubility in polar solvents. In some embodiments, the compounds of the present invention contain both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from various salt forms in certain physical properties, such as solubility in polar solvents, but unless specifically indicated, for the purposes of this invention, the salts disclosed herein are equivalent to the parent form of the compound.

[0088] In addition to salt forms, the present invention provides compounds in prodrug form. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. The prodrugs of the compounds described herein can be converted in vivo after administration. Furthermore, such prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods when contacted with suitable enzymes or chemical reagents.

[0089] Some of the compounds of this invention may exist in both unsolvated and solvated forms (including hydrated forms). Generally, the solvated form is equivalent to the unsolvated form and is covered within the scope of this invention. Some of the compounds of this invention may exist in various crystalline or amorphous forms. Generally, all physical forms are used equivalently for the purposes covered by this invention and are intended to be within the scope of this invention.

[0090] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the administration and absorption of compounds to an individual and can be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard saline solutions, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solutions), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments and the like. Such formulations may be sterilized and, as needed, mixed with adjuvants (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, and / or aromatic substances and the like) that will not harmfully react with the compounds of the present invention. Those skilled in this art will recognize that other pharmaceutical excipients are applicable to this invention.

[0091] The term "preparation" is intended to include the formulation of an active compound using an encapsulating material as a carrier to obtain a capsule, wherein the active component, with or without another carrier, is surrounded by the carrier and thus bound to it. Similarly, this includes flat capsules and lozenges. Lozenges, powders, capsules, pills, flat capsules, and lozenges are suitable for use in oral solid dosage forms.

[0092] The terms "disease" or "condition" refer to a state or health condition of a patient or individual that can be treated with the compounds or methods provided herein. A disease may be a fungal infection. In some other cases, "fungal infection or disease" may refer to a human fungal infection or disease, including cryptococcal, aspergillosis, or candidiasis.

[0093] As used herein, the terms "fungal infection" or "fungal disease" refer to a disease caused by pathogenic fungi. Fungal infections can be opportunistic or primary and can be caused by fungi that are yeasts and / or molds.

[0094] The term "treatment" refers to any successful outcome of treating or improving an injury, disease, lesion, or condition, including any objective or subjective parameters such as the reduction, relief, or elimination of symptoms, or making the injury, lesion, or condition more tolerable for the patient; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; or improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of physical examinations, neuropsychiatric examinations, and / or psychiatric assessments. The term "treatment" and its variant forms may include the prevention of an injury, lesion, condition, or disease. In some embodiments, treatment is prevention. In other embodiments, treatment does not include prevention.

[0095] The terms “treatment,” “parole,” or “improvement” are used interchangeably herein. As used herein (and as is well known in the art), these terms also broadly encompass any method of achieving a beneficial or desired outcome (including clinical outcomes) for an individual’s condition. Beneficial or desired clinical outcomes may include (but are not limited to) relief or improvement of one or more symptoms or conditions, reduction of the severity of the disease, stabilization of the disease state (i.e., no worsening), prevention of disease spread or transmission, delay or slowing of disease progression, improvement or parole of the disease condition, reduction of disease recurrence, and remission (whether local or systemic and whether detectable or undetectable). In other words, “treatment” as used herein includes any of the cure, improvement, or prevention of disease. Treatment may prevent the onset of disease; inhibit the spread of disease; relieve disease symptoms (e.g., itching, swelling, burning pain, cough, fever, chest pain, difficulty breathing); completely or partially eliminate the underlying cause of the disease; shorten the duration of the disease; or achieve a combination of these.

[0096] As used herein, "treatment" includes preventative treatment. Treatment methods include administering a therapeutically effective amount of the compound described herein to an individual. Administration may consist of a single administration or may include a series of administrations. The duration of treatment depends on various factors, such as the severity of the condition, the patient's age, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. Dosage changes can be achieved using standard diagnostic analyses known in this art, and such changes become readily apparent. In some cases, long-term administration may be required. For example, administering the composition to an individual in a dose and for a duration sufficient to treat the patient.

[0097] The term "prevention" refers to reducing the occurrence of disease symptoms in a patient. Prevention can be complete (without detectable symptoms) or partial, resulting in fewer observed symptoms than would be present without treatment. In some embodiments, prevention refers to slowing the progression of a disease, symptom, or condition or preventing its progression into a harmful or undesirable state.

[0098] "Patient" or "individual in need" means a living organism that suffers from or is susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammalian animals, including (but not limited to) fish and birds. In some embodiments, the patient is a human.

[0099] The treatment mentioned herein also refers to the systemic delivery of the compounds disclosed herein to any type of plant, including trees, shrubs, flowering plants, foliage plants, houseplants, ground cover plants and grasses, as well as agronomic plants (including crops among agronomic plants).

[0100] As used herein, "hydrate" refers to a compound containing stoichiometric or nonstoichiometric amounts of water, and in some embodiments formed during a process of crystallization by water.

[0101] As used herein, the term "agronomic plant" refers to a plant in whole or in part that is being harvested or cultivated on a commercial scale or that serves as an important source of feed, food, fiber or other compounds.

[0102] "Effective amount" is the amount of a compound sufficient to achieve the stated purpose relative to the absence of the compound (e.g., to achieve the effect of administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce signal transduction pathways, or to reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to promote the treatment, prevention, or relief of one or more symptoms of a disease; this may also be called a "therapeutic effective amount." "Relief" of one or more symptoms (and its grammatical equivalent) means a reduction in the severity or frequency of the symptoms or the elimination of the symptoms. A "preventive effective amount" of a drug is the amount of drug that, when administered to an individual, will have the intended preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, lesion, or condition or its symptoms. Complete prevention may not occur with a single dose and may only occur after a series of doses. Therefore, a preventive effective amount can be administered in one or more doses. As used herein, "activity reduction amount" refers to the amount of antagonist required to reduce enzyme activity relative to the absence of an antagonist. Similarly, "functional disruption amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of an antagonist. The precise amount will depend on the therapeutic objective and can be determined by a person skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols. 1–3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins). Therapeuticly effective amounts can be determined by measuring relevant physiological effects and can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the individual's condition, or similar factors. For example, measuring the serum levels of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates (or, for example, their metabolites) at a specific time after administration can indicate whether a therapeutically effective dose has been administered.

[0103] For any compound described herein, the therapeutically effective amount can first be determined by cell culture analysis. The target concentration will be the concentration of the active compound that achieves the results described herein, as measured using methods described herein or known in this art.

[0104] As is well known in this technique, therapeutically effective doses for humans can also be determined from animal models. For example, human doses can be formulated to achieve concentrations found to be effective in animals. Human doses can be adjusted by monitoring compound potency and by adjusting the dose upwards or downwards as described above. Adjusting the dose to achieve maximum potency in humans using the methods described above and others is entirely within the capabilities of those generally skilled in this technique. Adjusting the dose to achieve the highest therapeutic window efficacy or toxicity in humans using the methods described above and others is entirely within the capabilities of those generally skilled in this technique.

[0105] As used herein, the term "therapeutic effective dose" refers to an amount of therapeutic agent sufficient to improve the condition as described above. For example, for a given parameter, the therapeutic effective dose will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy may also be expressed as an "increase or decrease" of "multiplying". For example, the therapeutic effective dose may have an effect that is at least 1.2 times, 1.5 times, 2 times, 5 times, or greater than the control.

[0106] Dosage may vary depending on the patient's needs and the compound used. In the context of this invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The dosage should also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the practitioner's skill. Generally, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved in a given situation. Dosage and intervals can be individually adjusted to provide an effective concentration of the compound for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0107] As used herein, the term "administration" means non-enteric or transenteric administration. Therefore, as used herein, "administration" refers to individual administration including (but not limited to) oral administration, administration in suppository form, local contact, intravenous, intraperitoneal, intramuscular, inhalation, nebulization, intralesional, intrathecal, intracranial, intranasal, subcutaneous administration, or implantation of a sustained-release device (e.g., a micro-osmotic pump). Administration is carried out via any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Non-enteric administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include (but are not limited to) the use of lipid formulations, intravenous infusion, percutaneous patches, ocular routes, and ear routes. "Co-administration" means administering the composition described herein simultaneously, before, or after the administration of one or more additional therapeutic agents (e.g., antifungal agents, antibacterial agents, antiviral agents, and / or chemotherapeutic agents). The compounds of this invention can be administered to a patient individually or co-administered. Co-administration is intended to include administering the compounds simultaneously, substantially simultaneously, or sequentially, individually or in combination (more than one compound or agent). Therefore, formulations can also be combined with other active substances as needed (e.g., to reduce metabolic degradation). The compositions of this invention can be delivered transdermally, via a local route, formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, coatings, powders, and aerosols. Oral formulations include tablets, pills, powders, sugar-coated pills, capsules, liquids, lozenges, capsules, gels, syrups, slurries, suspensions, etc., suitable for patient ingestion. Solid formulations include powders, tablets, pills, capsules, pouches, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present invention may further include components to provide sustained release and / or comfort. Such components include high molecular weight anionic mucosa-mimicking polymers, gelled polysaccharides, and finely powdered drug carrier matrices. These components are discussed in more detail in U.S. Patents 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be used for delivery in the form of slowly released microspheres in vivo.For example, the microspheres can be administered via intradermal injection as drug-containing microspheres that release slowly subcutaneously (see Rao, J. Biomater Sci. Polym. ed. 7:623-645, 1995); in the form of biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res. 12:857-863, 1995); or in the form of microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the present invention can be delivered by using liposomes fused to the cell membrane or by employing receptor ligands attached to the liposomes for endoplasmosis, which bind to cell surface membrane protein receptors to produce endoplasmosis. By using liposomes, especially when the liposomes carry receptor ligands specific to target cells on their surface or otherwise preferentially guide them to specific organs, we can focus on in vivo delivery of the compositions of the present invention to target cells. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989) The compositions of the present invention can also be delivered in nanoparticle form.

[0108] "Co-administration" means administering the composition described herein simultaneously, before, or after the administration of one or more additional therapeutic agents. The compounds of this invention may be administered to the patient individually or co-administered. Co-administration is intended to include compounds administered simultaneously or sequentially, individually or in combination (more than one compound). The compositions of this invention may be delivered transdermally, via a local route, or formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, coatings, powders, and aerosols.

[0109] For any compound described herein, the therapeutically effective amount can first be determined by cell culture analysis. The target concentration will be the concentration of the active compound that achieves the results described herein, as measured using methods described herein or known in this art.

[0110] As is well known in this technique, therapeutically effective doses for humans can also be determined from animal models. For example, human doses can be formulated to achieve concentrations found to be effective in animals. Human doses can be adjusted by monitoring compound potency and by adjusting the dose upwards or downwards as described above. Adjusting the dose to achieve maximum potency in humans based on the methods described above and other methods is entirely within the capabilities of someone generally skilled in this technique.

[0111] Dosage may vary depending on the patient's needs and the compound used. In the context of this invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The dosage should also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of the practitioner. Generally, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved under certain conditions.

[0112] Dosage and intervals can be individually adjusted to provide the appropriate level of compound administered for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0113] Using the teachings provided in this article, effective preventative or therapeutic treatment plans can be developed that do not cause significant toxicity and effectively treat the clinical symptoms presented by a specific patient. This planning should involve the careful selection of active compounds by considering factors such as compound potency, relative bioavailability, patient weight, presence and severity of adverse side effects, optimal administration mode, and the toxicity profile of the chosen agent.

[0114] The compounds described herein can be used in combination with other active agents known to be effective in treating infections (e.g., fungal infections).

[0115] In some embodiments, co-doping includes dosing a second active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week, or 1 month of dosing an active agent. Co-doping includes dosing the two active agents simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-doping may be achieved by co-formulation, i.e., preparing a single pharmaceutical composition comprising the two active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active agents and / or adjuvants may be combined or combined with each other. In some embodiments, the compounds described herein may be combined with treatments for infections (e.g., fungal infections, bacterial infections, viral infections, etc.).

[0116] The compounds described herein can be administered to treat fungal infections or diseases. In this regard, the compounds disclosed herein can be administered alone to treat such infections or diseases, or co-administered with another therapeutic agent to treat such infections or diseases.

[0117] The compounds disclosed in this article can be co-administered with antifungal agents such as polyenes, azoles, nucleoside analogs, echinocandins, and allylamine.

[0118] "Antifungal agent" is used in its general sense and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) that has antifungal properties or is capable of inhibiting the growth or proliferation of fungi. In some embodiments, an antifungal agent is a pharmaceutical agent identified herein as effective in methods of treating fungal infections or diseases. In some embodiments, an antifungal agent is a pharmaceutical agent approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of fungal infections or diseases.

[0119] As used herein, "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in this art, including, for example, the presence of an intact membrane, staining with a specific dye, the ability to produce offspring, or, in terms of gametes, the ability to produce offspring by combining with a second gamete. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include (but are not limited to) bacteria. Eukaryotic cells include (but are not limited to) yeast cells and cells derived from plants and animals, such as mammalian, insect (e.g., noctuid moth) and human cells. Cells may be applicable when they are naturally non-adhesive or have been treated to not adhere to a surface (e.g., by trypsin digestion).

[0120] "Control" or "controlled experiment" is used in its general sense and refers to an experiment in which the individuals or reagents are treated as in a parallel experiment, except that the procedures, reagents, or variables of the experiment are omitted. In some cases, controls are used as comparative standards for evaluating the effects of an experiment. In some embodiments, a control is a measurement of protein activity in the absence of compounds as described herein (including examples and instances).

[0121] The phrase "a quantity sufficient to achieve change" means a detectable difference between the levels of an indicator measured before (e.g., baseline) and after the administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., an individual's sense of health).

[0122] "Substantially pure" means that the components constitute more than about 75% of the total composition excluding excipients, and typically constitute more than about 85% of the total composition. More generally, "substantially pure" means that at least 90%, at least 95%, at least 96%, at least 97% or more of the total composition excluding excipients is the relevant component. In some cases, the relevant component will constitute more than about 90%, more than about 95%, or more than about 96% of the total composition excluding excipients (percentages by weight / weight). "Substantially pure" means that the composition contains less than, at most, or no more than about 25%, 15%, 10%, 5%, or 4% of known or unknown impurities. Impurities do not include excipients (e.g., binders, fillers, diluents, flow aids, lubricants, disintegrants, etc.). [I.] [Composition] [ ]

[0123] In one embodiment, this document provides a pharmaceutical composition comprising: (i) a compound of formula (I): , Or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; and (ii) at least one pharmaceutically acceptable excipient, At least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form intended for oral administration or delivery.

[0124] In another embodiment, a pharmaceutical composition is provided comprising: (i) fine particles of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or delivery or for inhalation delivery.

[0125] In some embodiments, the particles are micronized. In some embodiments, the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 10% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 20% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 30% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 40% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 50% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 60% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 70% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 80% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 90% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, at least about 95% of the particles have a particle size of about 1 µm to about 750 µm.

[0126] In some embodiments, the particles are nano-milled. In some embodiments, at least about 10% of the particles have a particle size of about 1 µm to about 750 nm. In some embodiments, at least about 20% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 30% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 40% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 50% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 60% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 70% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 80% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 90% of the particles have a particle size of about 1 nm to about 750 nm. In some embodiments, at least about 95% of such particles have a particle size of about 1 nm to about 750 nm.

[0127] In some embodiments, the dosage form is a spontaneous microemulsion drug delivery system (SMEDDS). In some embodiments, the dosage form is a spontaneous emulsion drug delivery system (SEDDS). In some embodiments, the dosage form is a suspension or solution. In some embodiments, the suspension is a colloidal suspension. In some embodiments, the dosage form is a nano-suspension. In some embodiments, the dosage form is a solid dosage form. In some embodiments, the dosage form is a spray-dried dispersion. In some embodiments, the dosage form is a hot-melt granulated dosage form. In some embodiments, the dosage form is a hot-melt extrusion dosage form. In some embodiments, the dosage form is a microprecipitated bulk powder (MBP) dosage form. In some embodiments, the dosage form is a liquid. In some embodiments, the dosage form is a suspension, solution, syrup, or elixir. In some embodiments, the pharmaceutical composition is in a dosage form for oral administration or dosing.

[0128] In some embodiments, the dosage form is a tablet or a capsule. In some embodiments, the tablet or capsule has an enteric coating. In some embodiments, the dosage form is a tablet. In some embodiments, the tablet is an osmotically floatable tablet. In some embodiments, the capsule is a liquid-filled hard capsule. In some embodiments, the capsule is a soft gelatin capsule.

[0129] In some embodiments, the dosage form is a controlled-release dosage form. In some embodiments, the controlled-release dosage form is a delayed-release dosage form, an extended-release (ER) dosage form, or a targeted-release dosage form. In some embodiments, the ER dosage form is a sustained-release (SR) dosage form or a controlled-release (CR) dosage form. In some embodiments, the dosage form is an immediate-release dosage form.

[0130] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 600 mg of a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 150 mg, about 150 mg to about 250 mg, about 250 mg to about 350 mg, about 350 mg to about 450 mg, about 450 mg to about 550 mg, about 550 mg to about 650 mg, about 650 mg to about 750 mg, about 850 mg to about 950 mg, or about 950 mg to about 1050 mg of a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate.

[0131] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0132] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, in doses of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg or about 500 mg.

[0133] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, in doses of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg or about 500 mg.

[0134] In some embodiments, the at least one pharmaceutically acceptable excipient is a filler, disintegrant, binder, lubricant, or any combination thereof. In some embodiments, the at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, provitamin, magnesium stearate, colloidal silica, or any combination thereof.

[0135] In some embodiments, the pharmaceutical composition is stable at a temperature of about 2°C to about 25°C for up to 36 months. In some embodiments, the pharmaceutical composition is stable at a temperature of about 2°C to about 8°C for a period of about 24 to about 36 months.

[0136] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg or about 400 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0137] In one embodiment, this document provides a pharmaceutical composition comprising: (i) a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for administration or delivery by intravenous (IV), intramuscular, subcutaneous or intradermal injection.

[0138] In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline, microcrystalline, amorphous, or lyophilized. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are amorphous. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are lyophilized.

[0139] In some embodiments, the dosage form is an IV dosage form. In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the dosage form comprises a co-solvent.

[0140] In some embodiments, the co-solvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cetyl alcohol polyoxyethylene ether, glycerol, benzyl alcohol, dimethyl acetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert-butanol, or any combination thereof. In some embodiments, the dosage form further comprises an oil. In some embodiments, the oil comprises sesame oil, soybean oil, vegetable oil, poppy seed oil, safflower oil, or a combination thereof.

[0141] In some embodiments, the dosage form further comprises a buffer solution. In some embodiments, the IV dosage form further comprises a buffer solution. In some embodiments, the buffer solution is a phosphate buffer. In some embodiments, the phosphate buffer solution is potassium phosphate. In some embodiments, the potassium phosphate is a monobasic or dibasic salt.

[0142] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 2.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 2.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 2.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 2.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 6.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 5.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 5.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 4.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 4.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 3.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 2.5 to about 3.0.

[0143] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 3.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 3.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 3.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 3.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 6.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 5.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 5.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 4.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 4.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.0 to about 3.5.

[0144] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 3.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 3.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 3.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 3.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 6.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 3.5 to about 5.5. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 3.5 to about 5.0. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 3.5 to about 4.5. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 3.5 to about 4.0.

[0145] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 4.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 4.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 4.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 4.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 6.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.0 to about 5.5. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 4.0 to about 5.0. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 4.0 to about 4.5.

[0146] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 4.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 4.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 4.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 4.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 6.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 4.5 to about 5.5. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is about 4.5 to about 5.0.

[0147] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 5.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 5.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 5.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 5.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 6.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 5.0 to about 5.5.

[0148] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 5.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 5.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 5.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is type IV, and the pH is from about 5.5 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV, and the pH is from about 5.5 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV, and the pH is from about 5.5 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV, and the pH is from about 5.5 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV, and the pH is from about 5.5 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV, and the pH is from about 5.5 to about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV, and the pH is from about 5.5 to about 6.0.

[0149] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 6.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 6.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 6.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 6.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.0 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.0 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.0 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.0 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.0 to about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.0 to about 6.5.

[0150] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 6.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 6.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 6.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 6.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.5 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.5 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.5 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.5 to about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 6.5 to about 7.0.

[0151] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 7.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 7.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 7.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 7.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 7.0 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 7.0 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 7.0 to about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is an IV dosage form with a pH of about 7.0 to about 7.5.

[0152] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 7.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 7.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 7.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 7.5 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 7.5 to about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 7.5 to about 8.0.

[0153] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 8.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 8.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 8.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 8.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 8.0 to about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is from about 8.0 to about 8.5.

[0154] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 8.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 8.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 8.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 8.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, the dosage form is IV and the pH is about 8.5 to about 9.0.

[0155] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 9.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 9.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form is an IV dosage form, the pH is from about 9.0 to about 9.5.

[0156] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 9.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 9.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, wherein the dosage form is an IV dosage form, the pH is from about 9.5 to about 10.0.

[0157] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, the dosage form is an IV dosage form with a pH of about 10.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form.

[0158] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an IV (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions, the dosage form is an IV dosage form with a pH of about 10.5 to about 11.0.

[0159] In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 2.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 3.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 3.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 4.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 4.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 5.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 5.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.1. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.2. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.3. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.4. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.6. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.6. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.8. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 6.9. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.1. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.2. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.3. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.4. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.6. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.7. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.8. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 7.9.In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.1. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.2. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.3. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.4. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.6. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.7. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.8. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 8.9. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.1. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.2. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.3. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.4. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.6. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.9. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.8. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 9.9. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 10.0. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 10.1. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 10.2. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 10.3. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 10.4. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 10.5. In some embodiments of the pharmaceutical composition, the dosage form is type IV and the pH is about 10.6.In some embodiments of the pharmaceutical composition, the dosage form is type IV with a pH of about 10.7. In some embodiments of the pharmaceutical composition, the dosage form is type IV with a pH of about 10.8. In some embodiments of the pharmaceutical composition, the dosage form is type IV with a pH of about 10.9. In some embodiments of the pharmaceutical composition, the dosage form is type IV with a pH of about 11.0.

[0160] In some embodiments, the pharmaceutical composition formulated for intravenous administration has a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition formulated for intravenous administration has a pH of about 2.5 to about 5.0 or about 2.5 to about 5.0. In some embodiments, the pharmaceutical composition formulated for intravenous administration has a pH of about 2.5 to about 4.5 or about 7.0 to about 5.0. In some embodiments, the pH of the pharmaceutical composition formulated for intravenous administration is adjusted with hydrochloric acid and / or sodium hydroxide.

[0161] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate of about 5 mg / mL to about 250 mg / mL. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate of about 10 mg / mL to about 50 mg / mL.

[0162] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate at a concentration of about 20 mg / mL to about 40 mg / mL. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate at a concentration of about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL.

[0163] In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for up to about 24 months. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C for a period of about 12 to about 24 months. In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0164] In some embodiments, the pharmaceutical composition is stable for up to 24 months at a temperature of about -20°C to 8°C when stored in liquid form. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to 24 months at a temperature of about -20°C when stored in liquid form. In some embodiments, the pharmaceutical composition is stored in a pH-insensitive container. In some embodiments, the pH-insensitive container is made of glass or plastic. In some embodiments, the pharmaceutical composition is stable for up to 24 months at a temperature of about -20°C to 8°C when stored in liquid form in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to 24 months at a temperature of about -20°C when stored in liquid form in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable for up to 24 months at a temperature of about -20°C to 8°C when stored in liquid form having a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to 24 months at a temperature of about -20°C when stored in a liquid form having a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is stable for a period of about 24 months at a temperature of about -20°C to 8°C when stored in a pH-insensitive container in a liquid form having a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to 24 months at a temperature of about -20°C when stored in a pH-insensitive container in a liquid form having a pH of about 2.5 to about 11.0.

[0165] In some embodiments, when treating, preventing or improving one or more symptoms of the disease, condition or illness described herein, the appropriate dose concentration of the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug is generally in the range of about 1 to 8,000 mg, about 10 to about 2,000 mg, about 100 to about 800 mg, about 200 to about 600 mg, about 1,000 to about 2,000 mg or about 600 to about 800 mg, may be administered in a single or multiple doses. In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system, is administered in amounts of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 1 85, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600 1,700, 1,800, 1,900, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, or 8,000 mg. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, is administered in amounts of about 10 mg, about 2,000 mg, about 600 mg, or about 2,000 mg. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, is administered in amounts of about 600 mg. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 700 mg. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 800 mg. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 900 mg.In some embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 1,000 mg. In some embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 2,000 mg. In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in amounts of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, or 8,000 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered at an amount of about 10 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered at an amount of about 15 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered at an amount of about 20 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 25 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 30 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 35 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 40 mg / day.In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 45 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 50 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 100 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 150 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 200 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 300 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 400 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 500 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 600 mg / day. In some embodiments, the compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system is administered at an amount of about 700 mg / day. In some embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system, is administered at an amount of about 800 mg / day. In some embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system, is administered at an amount of about 900 mg / day. In some embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system, is administered at an amount of about 1,000 mg / day. In some embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug system, is administered at an amount of about 2,000 mg / day.

[0166] For oral administration, the pharmaceutical compositions provided herein may be formulated into solid dosage forms containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug. In one embodiment, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug, contains about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 600, about 700, about 800, about 900 and about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug, for symptomatic dosage adjustment in patients to be treated.

[0167] For oral administration, the pharmaceutical composition provided herein can be formulated into a solid dosage form containing approximately 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 19 A compound of formula (I) or its isotopic variants, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, in the amounts of 0, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1,000, 1,100, 1,200, 1,300, 1,400, or 1,500 mg. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a powder. In some embodiments, the solid dosage form is granules.

[0168] In some embodiments, the pharmaceutical compositions provided herein may be formulated into a solid dosage form containing about 50 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into a solid dosage form containing about 100 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into a solid dosage form containing about 150 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into a solid dosage form containing about 200 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into a solid dosage form containing about 250 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into a solid dosage form containing about 300 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into a solid dosage form containing about 400 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0169] For oral administration, the pharmaceutical compositions provided herein may be formulated into tablets containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug. In one embodiment, the tablets contain about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 600, about 700, about 800, about 900 and about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug, for symptomatic dosage adjustment in patients to be treated.

[0170] For oral administration, the pharmaceutical compositions provided herein can be formulated into tablets containing approximately 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, and 190 mg of glucose. Compounds of formula (I) or isotopic variants thereof, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs, in the amounts of 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1,000, 1,100, 1,200, 1,300, 1,400 or 1,500 mg.

[0171] In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablets containing about 50 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablets containing about 100 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablets containing about 150 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablets containing about 200 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablets containing about 250 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablets containing about 300 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablets containing about 400 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0172] For oral administration, the pharmaceutical compositions provided herein may be formulated as liquids (e.g., solutions, suspensions, or syrups) containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In one embodiment, the compound contains about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 600, about 700, about 800, about 900, and about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, for symptomatic dosage adjustment in patients to be treated.

[0173] For oral administration, the pharmaceutical compositions provided herein can be formulated into a liquid form (e.g., solution, suspension, or syrup) containing approximately 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 1 Compounds of formula (I) or isotopic variants thereof, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs, in the form of 85, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1,000, 1,100, 1,200, 1,300, 1,400 or 1,500 mg.

[0174] In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., solution, suspension, or syrup) containing about 50 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., solution, suspension, or syrup) containing about 100 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., solution, suspension, or syrup) containing about 150 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., solution, suspension, or syrup) containing about 200 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., solution, suspension, or syrup) containing about 250 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., solution, suspension, or syrup) containing about 300 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., solution, suspension or syrup) containing about 400 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug.

[0175] In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug. In one embodiment, the compound contains about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 600, about 700, about 800, about 900 and about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug, for symptomatic dosage adjustment in patients to be treated.

[0176] For oral administration, the pharmaceutical compositions provided herein can be formulated into liquid (e.g., IV) dosage forms containing approximately 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, and 185 mg / L. Compounds of formula (I) or isotopic variants thereof, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs, in the amounts of 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1,000, 1,100, 1,200, 1,300, 1,400 or 1,500 mg.

[0177] In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 50 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 100 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 150 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 200 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 250 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 300 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as a liquid (e.g., IV) dosage form containing about 400 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0178] The pharmaceutical composition can be administered 1 to 4 times daily, including once, twice, three times, and four times daily. In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for one day, followed by a 600 mg dose once daily for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for one day, followed by an 800 mg dose once daily for the duration of treatment.

[0179] In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to patients in need for one day, followed by a once-daily dose of 900 mg for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to patients in need for one day, followed by a once-daily dose of 1000 mg for the duration of treatment.

[0180] In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for two days, followed by a 600 mg dose once daily for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for two days, followed by an 800 mg dose once daily for the duration of treatment. In still other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for two days, followed by a 900 mg dose once daily for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate or prodrug, is administered twice daily to patients in need for two days, followed by a once daily dose of 1,000 mg for the duration of treatment.

[0181] In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for three days, followed by a 600 mg dose once daily for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for three days, followed by an 800 mg dose once daily for the duration of treatment. In still other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for three days, followed by a 900 mg dose once daily for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate or prodrug, is administered twice daily to patients in need for three days, followed by a once-daily administration of 1,000 mg for the duration of treatment.

[0182] In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for four days, followed by a 600 mg dose once daily for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for four days, followed by an 800 mg dose once daily for the duration of treatment. In still other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered twice daily to a patient in need for four days, followed by a 900 mg dose once daily for the duration of treatment. In other embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate or prodrug, is administered twice daily to patients in need for four days, followed by a once-daily administration of 1,000 mg for the duration of treatment.

[0183] In some embodiments, a single-use compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered daily to a patient in need at an amount of about 1,000 mg. In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a medically acceptable salt, solvate, hydrate, or prodrug, is administered daily to a patient in need at an amount of about 40 mg to about 145 mg, about 40 mg to about 1,000 mg, about 600 mg to about 1,000 mg, or about 600 mg to about 2,000 mg, until disease remission, recovery, or intolerable toxicity.

[0184] In another embodiment, a combined composition is provided comprising: (i) the compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one antifungal agent.

[0185] In some embodiments, the at least one antifungal agent is an azole, echinocandin, deoxycholic acid amphotericin B, amphotericin B liposome, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, ibrene, oxytocin F901318, or a combination thereof. In some embodiments, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isaconazole, or miconazole. In some embodiments, the echinocandin is caspofungin, anidoxuridine, micafungin, or rezafungin.

[0186] In one state sample, this document provides a combined composition comprising: (i) a compound of formula (I): , Or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; and (ii) Compounds of formula (II) , Or its isotopic variants, tautomers, medically acceptable salts, solvates or hydrates.

[0187] In some embodiments, the combined composition further comprises at least one pharmaceutically acceptable excipient.

[0188] In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are all crystalline.

[0189] In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in a ratio of about 10:1. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in a ratio of about 9:1 to about 9.99:0.01. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in a ratio of about 9.5:0.5 to about 9.9:0.1. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates and the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are present in ratios of about 9:1, about 9.1:0.9, about 9.2:0.8, about 9.3:0.7, about 9.4:0.6, about 9.5:0.5, about 9.6:0.4, about 9.7:0.3, about 9.8:0.2 or about 9.9:0.1.

[0190] In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is from about 100:0.01 to about 0.01:100. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 100:0.01. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 100:0.1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 100:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 100:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 80:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 70:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 60:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 50:1.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 40:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 30:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 9:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 8:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 7:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 6:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 5:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 4:1.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 3:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 2:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1.5:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:1.5. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:2. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:3. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:4. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:5.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:6. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:7. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:8. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:9. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:20. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:30. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:40. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:50.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:60. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:70. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:80. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:90. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:100. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.1:100. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates in the pharmaceutical composition is about 0.01:100.

[0191] In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is at least about 100:0.01, 100:0.1, 100:1, 90:1, 80:1, 70:1, 60:1, 50... :1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 0.1:100 or approximately 0.01:100. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is at most about 100:0.01, 100:0.1, 100:1, 90:1, 80:1, 70:1, 60:1, 50 :1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 0.1:100 or approximately 0.01:100.

[0192] In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is from about 10:0.1 to about 0.1:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.2. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.3. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.4. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.5. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.6. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.7. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.8.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:0.9. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 10:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 9:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 8:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 7:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 6:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 5:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 4:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 3:1.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 2:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1.5:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:1.5. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:2. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:2. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:3. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:4. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:5.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:6. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:7. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:8. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:9. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.9:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.8:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.7:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.6:10.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.5:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.4:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.3:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.2:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.1:10. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 0.01:10.

[0193] In some embodiments, the ratio of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates to the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates in the pharmaceutical composition is at least about 10:0.1, 10:0.2, 10:0.3, 10:0.4, 10:0.5, 10:0.6, 10:0.7, 10:0.8, 10:0. 9, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 0.9:10, 0.8:10, 0.8:10, 0.7:10, 0.6:10, 0.5:10, 0.4:10, 0.3:10, 0.2:10 or approximately 0.1:10. In some embodiments, the ratio of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates to the compound of formula (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates in the pharmaceutical composition is at most about 10:0.1, 10:0.2, 10:0.3, 10:0.4, 10:0.5, 10:0.6, 10:0.7, 10:0.8, 10:0. 9, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 0.9:10, 0.8:10, 0.8:10, 0.7:10, 0.6:10, 0.5:10, 0.4:10, 0.3:10, 0.2:10 or approximately 0.1:10.

[0194] In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 5:1 to about 1:5. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 5:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 4:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 3:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 2:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1.5:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:1. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:1.5. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:2.In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:3. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:4. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is about 1:5.

[0195] In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is at least about 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, or about 1:5. In some embodiments, the ratio of compound (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates to compound (II) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical composition is at most about 5:1, 4:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, or about 1:5.

[0196] In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are substantially pure. In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are substantially free of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 10.0% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 9.0% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 8.0% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 7.0% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 6.0% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 5.0% impurity. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 4.0% (w / w) impurity. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 3.9% (w / w) impurity. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 3.8% (w / w) impurity. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 3.7% (w / w) impurity. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 3.6% (w / w) impurity. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 3.5% (w / w) impurity. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 3.4% (w / w) impurity. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 3.3% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 3.2% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 3.1% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 3.0% (w / w) of impurities.In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.9% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.8% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.7% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.6% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.5% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.4% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.3% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 2.2% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 2.1% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 2.0% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 1.9% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 1.8% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 1.7% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 1.6% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 1.5% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as less than about 1.4% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 1.3% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 1.2% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 1.1% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 1.0% (w / w) of impurities.In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.9% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.8% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.7% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.6% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.5% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.4% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.3% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as less than about 0.2% (w / w) of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as impurities present in a content of less than about 0.1%. In some embodiments of the pharmaceutical compositions disclosed herein, "substantially free of impurities" is defined as impurities present in a content of less than about 0.05% (w / w).

[0197] In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are substantially free of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 10.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 9.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 8.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 7.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 6.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 5.0%. In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as impurities at a content of up to about 4.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as impurities at a content of up to about 3.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as impurities at a content of up to about 3.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as impurities at a content of up to about 3.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as impurities at a content of up to about 3.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as impurities at a content of up to about 3.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as impurities at a content of up to about 3.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the composition is substantially free of impurities defined as impurities at a content of up to about 3.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the composition is substantially free of impurities defined as impurities at a content of up to about 3.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the composition is substantially free of impurities defined as impurities at a content of up to about 3.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the composition is substantially free of impurities defined as impurities at a content of up to about 3.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the composition is substantially free of impurities defined as impurities at a content of up to about 2.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the composition is substantially free of impurities defined as impurities at a content of up to about 2.8% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, there is essentially no impurity defined as an impurity content of up to about 2.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, there is essentially no impurity defined as an impurity content of up to about 2.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, there is essentially no impurity defined as an impurity content of up to about 2.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, there is essentially no impurity defined as an impurity content of up to about 2.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, there is essentially no impurity defined as an impurity content of up to about 2.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, there is essentially no impurity defined as an impurity content of up to about 2.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, there is essentially no impurity defined as an impurity content of up to about 2.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of up to about 2.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of up to about 1.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of up to about 1.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of up to about 1.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of up to about 1.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of up to about 1.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of up to about 1.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as an impurity content of at most about 1.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as an impurity content of at most about 1.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as an impurity content of at most about 1.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as an impurity content of at most about 1.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as an impurity content of at most about 0.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, the presence of essentially no impurities is defined as an impurity content of at most about 0.8% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as impurities at a content of at most about 0.05% (w / w). .

[0198] In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 90%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 91%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 92%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 93%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 94%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 95%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 96%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 97%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 98%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is at least about 99%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical compositions is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100%.

[0199] In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 90%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 91%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 92%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 93%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 94%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 95%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 96%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 97%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 98%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical composition is up to about 99%. In some embodiments of the pharmaceutical compositions disclosed herein, the purity of the pharmaceutical compositions is up to about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100%.

[0200] In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates contains less than about 10% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 9% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 8% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 7% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 6% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 5% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 4% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 3% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 2% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 1% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.9% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.8% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.7% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.6% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.5% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.4% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.3% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 0.2% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain less than about 0.1% of at least one impurity.

[0201] In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 10% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 9% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 8% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 7% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 6% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 5% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 4% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 3% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 2% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least 1% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.9%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.8%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.7%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.6%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.5%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.4%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.3%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.2%. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.1%.

[0202] In some embodiments, the pharmaceutical composition is substantially free of impurities. In some embodiments, the purity of the pharmaceutical composition is at least about 90%. In some embodiments, the purity of the pharmaceutical composition is at least about 95%. In some embodiments, the purity of the pharmaceutical composition is at least about 96%. In some embodiments, the purity of the pharmaceutical composition is at least about 97%. In some embodiments, the purity of the pharmaceutical composition is at least about 98%. In some embodiments, the purity of the pharmaceutical composition is at least about 99%. In some embodiments, the purity of the pharmaceutical composition is at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 100%. In some embodiments, the pharmaceutical composition contains at least 10% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition contains at least one impurity of less than about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w). In some embodiments, the pharmaceutical composition contains at least one impurity of less than about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w). In some embodiments, the pharmaceutical composition contains less than one impurity of about 0.9% (w / w), about 0.8% (w / w), about 0.7% (w / w), about 0.6% (w / w), about 0.5% (w / w), about 0.4% (w / w), about 0.3% (w / w), about 0.2% (w / w), or about 0.1% (w / w).

[0203] In some embodiments, the at least one impurity is a degradation product. In some embodiments, the at least one impurity is: Or any combination thereof.

[0204] In some embodiments, the at least one impurity is: .

[0205] In some embodiments, the pharmaceutical composition contains up to about 4.0% (w / w) of total impurities. In some embodiments, the pharmaceutical composition contains up to about 0.5% (w / w) of any individual impurity. In some embodiments, the pharmaceutical composition contains up to about 1.5% (w / w) of the following compounds: .

[0206] In some embodiments, the impurities in the pharmaceutical compositions disclosed herein are: Compound 1A.

[0207] The compound of formula (I) of the present invention, or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates thereof, may be in a compositional form suitable for administration to an individual. Generally, such compositions are “medical compositions” comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are present in therapeutically acceptable amounts. This pharmaceutical composition may be used in the methods of the present invention; thus, for example, the pharmaceutical composition may be administered to an individual ex vivo or in vivo to practice the treatment and preventative methods and uses described herein.

[0208] The pharmaceutical compositions of the present invention can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein.

[0209] Pharmaceutical compositions containing a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates may be in forms suitable for oral use, such as tablets, capsules, sugar-coated tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in this art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents such as sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable formulation. Tablets, capsules, and the like contain a mixture of the active ingredient and a non-toxic, pharmaceutically acceptable excipient suitable for their manufacture. These excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.

[0210] Suitable for oral administration of tablets, capsules, and the like, may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated using techniques known in this art to form osmotic therapeutic tablets for controlled release. Additional pharmaceutical agents include biodegradable or biocompatible particles or polymers such as polyesters, polyamines, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolic acid copolymers, polylactic acid / glycolic acid copolymers, or ethylene-vinyl acetate copolymers to control the delivery of the administered composition. For example, oral medications can be retained in microcapsules prepared by coagulation techniques or interfacial polymerization by using hydroxymethyl cellulose or gelatin microcapsules or poly(methyl methacrylate) microcapsules, or in colloidal drug delivery systems. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid-based systems including oil-in-water emulsions, microcells, mixed microcells, and liposomes. The methods for preparing the formulations mentioned above will be readily apparent to those skilled in the art.

[0211] Formulations intended for oral use may also be presented in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose; or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin, or olive oil.

[0212] Aqueous suspensions contain a mixture of active substances and excipients suitable for their manufacture. Such excipients can be suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecanethoxylated cetyl alcohol), or condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and esters derived from fatty acids and hexitol anhydrides (e.g., polyvinyl sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0213] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavorings may be added to provide a palatable oral formulation.

[0214] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide mixtures of active ingredients and dispersants or wetting agents, and, where appropriate, one or more suspending agents and / or preservatives. Examples of suitable dispersants or wetting agents and suspending agents are shown herein.

[0215] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or flower oil; or a mineral oil, such as liquid paraffin; or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or gum tragali; naturally occurring phospholipids, such as soybean lecithin, and esters or metaesters derived from fatty acids; hexitan anhydrides, such as sorbitan monooleate; and condensation products of metaesters and ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0216] The pharmaceutical composition typically comprises a therapeutically effective amount of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and one or more pharmaceutically and physiologically acceptable formulations. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include (but are not limited to) antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethylparaben, or n-propylparaben), emulsifiers, suspending agents, dispersants, solvents, fillers, build-up agents, detergents, buffers, mediators, diluents, and / or adjuvants. For example, a suitable mediator may be a physiological saline solution or a citrate-buffered saline solution, which may be supplemented with other materials commonly found in pharmaceutical compositions used for non-enteral administration. Neutral-buffered saline or saline mixed with serum albumin are other exemplary mediators. Those skilled in this art will readily identify the various buffer solutions that can be used in the pharmaceutical compositions and dosage forms covered herein. Typical buffer solutions include (but are not limited to) pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, buffer components may be water-soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts (e.g., potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.). Acceptable buffer solutions include, for example, Tris buffer; N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-(N-morpholino))ethanesulfonic acid (MES); sodium 2-(N-(N-morpholino))ethanesulfonate (MES); 3-(N-(N-morpholino))propanesulfonic acid (MOPS); and N-[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS), potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0217] After a pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in ready-to-use form, lyophilized form requiring reconstitution before use, liquid form requiring dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, for example, EpiPen®)), while a multi-use container (e.g., a multi-use vial) is provided in other embodiments.

[0218] The formulation may also include a carrier to prevent the composition from rapid degradation or excretion from the body, such as controlled-release formulations, including liposomes, hydrogels, prodrugs, and microencapsulation delivery systems. For example, time-delayed materials may be used, such as glyceryl monostearate alone or glyceryl stearate alone or combinations thereof with waxes. Any drug delivery device may be used to deliver the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates; including implants (e.g., implantable pumps) and catheter systems, slow-infusion pumps and devices, all of which are well known to those skilled in the art.

[0219] Subcutaneous or intramuscular administration of reservoir-type injections can also be used to release the compounds disclosed herein (e.g., compounds of formula (I) or their isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates) over a defined time period. Reservoir-type injections are typically solid- or oil-based and generally contain at least one of the formulation components described herein. Those skilled in the art are familiar with the possible formulations and uses of reservoir-type injections.

[0220] Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned herein, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in nontoxic, non-enteric acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media include water, Ringer's solution, isotonic sodium chloride solution, Cremophor® EL (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile nonvolatile oils are conventionally used as solvents or suspension media; for this purpose, any mild nonvolatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid may be used in the preparation of injectable formulations. Prolonged absorption of certain injectable formulations can be achieved by using agents that delay absorption (such as aluminum monostearate or gelatin).

[0221] This invention covers the administration of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the form of a suppository for rectal administration. The suppository can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include (but are not limited to) cocoa butter and polyethylene glycol.

[0222] Compounds of formula (I) or their isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates may be in any other form currently known or to be developed in the future suitable for pharmaceutical compositions (e.g., sprays for nasal or inhalation purposes). [II.] [How to use] [ ]

[0223] In one instance, this document provides a method for treating and / or preventing fungal infections or diseases, comprising administering to an individual in need a therapeutically effective amount of any of the pharmaceutical compositions or combined compositions described herein.

[0224] In one embodiment, this article provides a method for treating and / or preventing fungal infections or diseases, comprising administering to an individual in need a therapeutically effective amount of a pharmaceutical composition comprising: (i) a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, the pharmaceutical composition being in a dosage form for oral administration or administration.

[0225] In another embodiment, this document provides a method for treating and / or preventing fungal infections or diseases, comprising administering to an individual in need a therapeutically effective amount of a pharmaceutical composition comprising: (i) fine particles of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or administration or for inhalation delivery.

[0226] In some embodiments of the methods provided herein, the dosage form is a spontaneous microemulsion drug delivery system (SMEDDS). In some embodiments of the methods provided herein, the dosage form is a spontaneous emulsion drug delivery system (SEDDS). In some embodiments of the methods provided herein, the dosage form is a suspension or solution. In some embodiments of the methods provided herein, the dosage form is a nano-suspension. In some embodiments of the methods provided herein, the dosage form is a solid dosage form. In some embodiments of the methods provided herein, the dosage form is a spray-dried dispersion. In some embodiments of the methods provided herein, the dosage form is a hot-melt granulated dosage form. In some embodiments of the methods provided herein, the dosage form is a hot-melt extrusion dosage form. In some embodiments of the methods provided herein, the dosage form is a microprecipitated bulk powder (MBP) dosage form. In some embodiments of the methods provided herein, the dosage form is a liquid. In some embodiments of the methods provided herein, the dosage form is a suspension, solution, syrup, or elixir. In some embodiments of the methods provided herein, the pharmaceutical composition is in a dosage form intended for oral administration or delivery.

[0227] In some embodiments of the methods described herein, the dosage form is a tablet or capsule. In some embodiments of the methods described herein, the tablet or capsule has an enteric coating. In some embodiments of the methods described herein, the dosage form is a tablet. In some embodiments of the methods described herein, the tablet is an osmotic flotation tablet. In some embodiments of the methods described herein, the capsule is a liquid-filled hard capsule. In some embodiments of the methods described herein, the capsule is a soft gelatin capsule.

[0228] In some embodiments of the methods described herein, the dosage form is a controlled-release dosage form. In some embodiments of the methods described herein, the controlled-release dosage form is a delayed-release dosage form, an extended-release (ER) dosage form, or a targeted-release dosage form. In some embodiments of the methods described herein, the ER dosage form is a sustained-release (SR) dosage form or a controlled-release (CR) dosage form. In some embodiments of the methods described herein, the dosage form is an immediate-release dosage form.

[0229] In one embodiment, this document provides a method for treating and / or preventing fungal infections or diseases, comprising administering to an individual in need a therapeutically effective amount of a pharmaceutical composition comprising: (i) a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for administration or delivery by intravenous (IV), intramuscular, subcutaneous, or intradermal injection. In some embodiments of the method described herein, the dosage form is an IV dosage form.

[0230] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual via IV infusion over a period of approximately 20 minutes, approximately 30 minutes, approximately 60 minutes, approximately 90 minutes, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, approximately 12 hours, approximately 18 hours, or approximately 24 hours.

[0231] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual via intravenous infusion over a period of up to about 1 hour. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual via intravenous infusion over a period of up to about 2 hours. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual via intravenous infusion over a period of up to about 3 hours.

[0232] In another embodiment, a method for treating a fungal infection or disease is provided, comprising administering to an individual in need a therapeutically effective amount of a combined composition comprising: (i) a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one antifungal agent.

[0233] In one embodiment, this article provides a method for treating and / or preventing fungal infections or diseases, comprising administering to an individual in need a therapeutically effective amount of a combined composition comprising: (i) a compound of formula (I): , Or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; and (ii) Compounds of formula (II): , Or its isotopic variants, tautomers, medically acceptable salts, solvates or hydrates.

[0234] In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline, microcrystalline, amorphous, or lyophilized. In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline. In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are amorphous. In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are lyophilized.

[0235] In some embodiments of the methods provided herein, an individual is administered about 10 mg to about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, an individual is administered about 10 mg to about 2,400 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, an individual is given about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, about 1,500 mg, about 1,800 mg, about 2,000 mg, about 2,100 mg, about 2,400 mg, about 2,500 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, or about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0236] In some embodiments of the methods provided herein, an individual is administered about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, or about 900 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, an individual is administered about 600 mg, about 700 mg, about 800 mg, about 900 mg, 1,000 mg, about 2,000 mg, or about 3,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0237] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual once, twice, three times, or four times daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual once daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual twice daily.

[0238] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual for a period of approximately 12 weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual for a period of at least one week. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual for a period of at least two weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual for a period of approximately two weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual for a period of one week, two weeks, six weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks.

[0239] In some embodiments of the methods provided herein, an individual is administered about 10 mg to about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, an individual is administered about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, or about 2,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0240] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual via IV infusion over a period of approximately 20 minutes, approximately 30 minutes, approximately 60 minutes, approximately 90 minutes, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, approximately 12 hours, approximately 18 hours, or approximately 24 hours.

[0241] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to an individual via IV infusion over a period of up to about 3 hours.

[0242] In some embodiments of the methods provided herein, an initial dose is administered to an individual, followed by a maintenance dose. In some embodiments of the methods provided herein, the initial dose comprises about 1,000 mg to about 8,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg to about 2,400 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the initial dose comprises about 1,000 mg to about 2,000 mg. In some embodiments of the methods provided herein, the initial dose is administered via IV infusion over a period of about 2 to 3 hours. In some embodiments of the methods provided herein, the initial dose is administered twice on the first day of treatment. In some embodiments of the methods provided herein, the second initial dose is administered about 9 hours after the first initial dose.

[0243] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, an individual is administered the maintenance dose comprising about 800 mg or about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, administered orally.

[0244] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and is administered by intravenous infusion over a period of about 1 hour to about 3 hours.

[0245] In some embodiments of the methods provided herein, such as the methods of any one of Examples 157 to 164, approximately 600 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are administered by intravenous infusion over a period of approximately 3 hours.

[0246] In some embodiments of the methods provided herein, the maintenance dose is administered once daily.

[0247] In some embodiments of the methods provided herein, the maintenance dose is administered once daily, starting from the second day of treatment.

[0248] In some embodiments of the methods provided herein, about 600 mg or about 800 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are administered via IV infusion over a period of about 3 hours, starting on the second, third or fourth day of treatment.

[0249] In some embodiments of the methods provided herein, about 800 mg or about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are administered orally starting on the second, third or fourth day of treatment.

[0250] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 800 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, an individual is administered about 600 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, an individual is administered about 800 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, approximately 600 mg of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered via intravenous infusion over a period of approximately 1 hour to approximately 3 hours, and / or approximately 800 mg of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered orally. In some embodiments of the methods provided herein, the maintenance dose is administered once daily. In some embodiments of the methods provided herein, the maintenance dose is administered once daily, starting from the second day of treatment. In some embodiments of the methods provided herein, approximately 600 mg of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered via intravenous infusion over a period of approximately 3 hours.

[0251] In some embodiments of the methods provided herein, approximately 600 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered via IV infusion over a period of approximately 3 hours, beginning on the second day of treatment.

[0252] In some embodiments of the methods provided herein, approximately 800 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered orally starting on the fourth day of treatment.

[0253] In some embodiments of the methods provided herein, the fungal infection is caused by an invasive fungus. In some embodiments of the methods provided herein, the method further comprises administering to an individual a combination of at least one antifungal agent and a pharmaceutical composition comprising a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the at least one antifungal agent is an azole, echinocandin, deoxycholic acid amphotericin B, amphotericin B liposome, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, ibrene, oxytocin F901318, or a combination thereof. In some embodiments of the methods provided herein, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isaconazole, or miconazole. In some embodiments of the methods provided herein, the echinocandin is caspofungin, anidoxurine, micafungin, or rezafungin, or a combination thereof.

[0254] In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and the antifungal agent are administered simultaneously, substantially simultaneously, or sequentially in any order. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and the antifungal agent are administered simultaneously or substantially simultaneously. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and the antifungal agent are administered sequentially. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, or a pharmaceutically acceptable salt thereof, is administered before at least one antifungal agent. In some embodiments of the methods provided herein, a pharmaceutical composition comprising a compound of formula (I) or an isotopic variant thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof is administered after at least one antifungal agent.

[0255] In some embodiments of the methods provided herein, the fungal infection or disease is caused by: *Aspergillus fumigatus*, *Blastomyces*, *Ajronium*, *Candida*, *Cryptococcus*, *Histoplasma*, *Rhizopus*, *Hymenopterus*, *Squama*, *Absidius*, *Phyllostachys*, *Entomophytes*, *Otophytes*, *Sporothrix*, *Pneumocystis*, *Basilella*, *Fusarium*, *Cetiophyton*, or fungi from the Mucorales order, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by: *Cryptococcus*, *Aspergillus*, *Candida*, *Fusarium*, *Cetiophyton*, or fungi from the Mucorales order, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by: *Aspergillus fumigatus*, *Aspergillus flavus*, *Blastomyces dermatitidis*, *Ajorhizium dermatitidis*, *Candida albicans*, *Candida glabrata*, *Candida auris*, *Cochloa crus-galli*, *C. posadae*, *Cryptococcus neoformans*, *Cryptococcus gattii*, *Histoplasma capsulatum*, *Rhizopus spp.*, *Rhizopus cryptana*, *Mucor*, *Scutellaria baicalensis*, *Squama* species, *Pneumocystis carinii*, *Basilella marneffei*, *Leymus chinensis*, *Fusarium solani*, *Sedum acutum*, *Scutellaria baicalensis*, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by *Cryptococcus* or *Candida* fungi. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gutterusum, or Candida auris.

[0256] In some embodiments of the methods provided herein, the fungal infection or disease is resistant to azoles and / or echinocandins.

[0257] In some embodiments of the methods provided herein, the individual is immunocompromised. In some embodiments of the methods provided herein, the individual is infected with HIV / AIDS or has cancer. In some embodiments of the methods provided herein, the individual has cancer. In some embodiments of the methods provided herein, the cancer is acute myeloid leukemia (AML). In some embodiments of the methods provided herein, the individual has neutropenia. In some embodiments of the methods provided herein, the individual is undergoing or has undergone cancer chemotherapy. In some embodiments of the methods provided herein, the individual is undergoing or has undergone corticosteroid therapy. In some embodiments of the methods provided herein, the individual is undergoing or has undergone TNF inhibitor therapy. In some embodiments of the methods provided herein, the individual is a transplant recipient. In some embodiments of the methods described herein, a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to the individual in combination with posaconazole.

[0258] In some embodiments of the methods described herein, an individual is administered a compound of formula (I) or an isotopic variant, tautomer, medically acceptable salt, solvate, or hydrate thereof to prevent fungal infection or disease. In some embodiments of the methods described herein, an individual is administered a compound of formula (I) or an isotopic variant, tautomer, medically acceptable salt, solvate, or hydrate thereof to treat an existing fungal infection or disease.

[0259] In some embodiments of the methods provided herein, the fungal infection or disease is in the bloodstream of the individual. In some embodiments of the methods provided herein, the individual has a reduced fungal community count in the lungs after administration of the pharmaceutical composition. In some embodiments of the methods provided herein, the plasma concentration-time curve of the compound of formula (I) in the individual has a tmax of less than about 30 minutes to about 180 minutes. In some embodiments of the methods provided herein, the individual has a maximum plasma concentration (Cmax) of the compound of formula (I) of about 12,000 ng / mL to about 25,000 ng / mL. [Administration]

[0260] In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the pharmaceutical compositions described herein are provided at the maximum tolerated dose (MTD) of the compound of formula (I). In other embodiments, the amount of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates administered to the pharmaceutical composition is from about 10% to about 90% of the maximum tolerated dose (MTD), from about 25% to about 75% of the MTD, or from about 50% of the MTD. In some other embodiments, the amount of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates added to the pharmaceutical composition is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or higher, or any range thereof, of the MTD of the compound of formula (I).

[0261] In some embodiments, when treating, preventing, or improving one or more symptoms of the condition, disease, or illness described herein (e.g., fungal infection or disease), the appropriate dose concentration of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is generally in the range of about 1 to 8,000 mg, about 10 to 8,000 mg, about 10 to 2,000 mg, about 1 to about 1,000 mg, about 25 to about 1,000 mg, about 25 to about 800 mg, about 25 to about 600 mg, about 50 to about 600 mg, about 50 to about 300 mg, about 50 to about 150 mg, about 150 to about 250 mg, about 250 mg to about 350 mg, about 350 to about 450 mg, about 450 to about 550 mg, about 550 to about 650 mg, about 650 to about 750 mg, about 750 to about 850 mg. Within the mg range, it can be administered in single or multiple doses. In some embodiments, the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered in the following amounts: about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 115 mg, about 105 mg, about 105 mg, about 110 mg, about 115 mg, about 115 mg, about 100 mg, about 105 mg, about 110 mg, about 115 ... mg, approximately 120, approximately 125, approximately 130, approximately 135, approximately 140, approximately 145, approximately 150, approximately 155, approximately 160, approximately 165, approximately 170, approximately 175, approximately 180, approximately 185, approximately 190, approximately 195, approximately 200, approximately 205, approximately 210, approximately 215, approximately 220, approximately 225, approximately 230, approximately 240, approximately 250, approximately 260, approximately 270, approximately 275, approximately 280, approximately 290, approximately 300, approximately 310, approximately 320, approximately 330, approximately 340, approximately 350, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg,410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg mg, about 1,000, about 1,100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, about 2,000, about 2,100, about 2,200, about 2,300, about 2,400, about 2,500, about 2,600, about 2,700, about 2,800, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000 mg, or any range thereof.

[0262] In some embodiments, a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to an individual in the following amounts: about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg. mg, approximately 120, approximately 125, approximately 130, approximately 135, approximately 140, approximately 145, approximately 150, approximately 155, approximately 160, approximately 165, approximately 170, approximately 175, approximately 180, approximately 185, approximately 190, approximately 195, approximately 200, approximately 205, approximately 210, approximately 215, approximately 220, approximately 225, approximately 230, approximately 240, approximately 250, approximately 260, approximately 270, approximately 275, approximately 280, approximately 290, approximately 300, approximately 310, approximately 320, approximately 330, approximately 340, approximately 350, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, approximately 1,000, approximately 1,100, approximately 1,200, approximately 1,300, approximately 1,400, approximately 1,500, approximately 1,600, approximately 1,700, approximately 1,800, approximately 1,900, approximately 2,000, approximately 2,100, approximately 2,200, approximately 2,300, approximately 2,400, approximately 2,500, approximately 2,600, approximately 2,700, approximately 2,800, approximately 3,000, approximately 4,000, approximately 5,000, approximately 6,000, approximately 7,000, approximately 8,000 mg.

[0263] In some embodiments, a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered in amounts of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, or about 115 mg per day. mg, approximately 120, approximately 125, approximately 130, approximately 135, approximately 140, approximately 145, approximately 150, approximately 155, approximately 160, approximately 165, approximately 170, approximately 175, approximately 180, approximately 185, approximately 190, approximately 195, approximately 200, approximately 205, approximately 210, approximately 215, approximately 220, approximately 225, approximately 230, approximately 240, approximately 250, approximately 260, approximately 270, approximately 275, approximately 280, approximately 290, approximately 300, approximately 310, approximately 320, approximately 330, approximately 340, approximately 350, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, approximately 1,000, approximately 1,100, approximately 1,200, approximately 1,300, approximately 1,400, approximately 1,500, approximately 1,600, approximately 1,700, approximately 1,800, approximately 1,900, approximately 2,000, approximately 2,100, approximately 2,200, approximately 2,300, approximately 2,400, approximately 2,500, approximately 2,600, approximately 2,700, approximately 2,800, approximately 3,000, approximately 4,000, approximately 5,000, approximately 6,000, approximately 7,000, approximately 8,000 mg.

[0264] For oral administration, the pharmaceutical compositions provided herein may be formulated into tablets or capsules containing about 1 to 2,000 mg, about 10 to 2,000 mg, about 1 to about 1,000 mg, about 25 to about 1,000 mg, about 25 to about 800 mg, about 25 to about 600 mg, about 50 to about 600 mg, about 50 to about 300 mg, about 50 to about 150 mg, about 150 to about 250 mg, about 250 mg to about 350 mg, about 350 to about 450 mg, about 450 to about 550 mg, about 550 to about 650 mg, about 650 to about 750 mg, or about 750 to about 850 mg.In one embodiment, the content is 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg. mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg Compounds of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates of the following amounts: approximately 690 mg, approximately 700 mg, 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, approximately 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, approximately 1,000 or approximately 2,000 mg, for symptomatic dose adjustment in patients to be treated. ;

[0265] In some embodiments, the pharmaceutical compositions provided herein may be formulated as tablets or capsules containing about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0266] In some embodiments, the pharmaceutical compositions provided herein may be formulated for oral administration and contain about 200 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for oral administration and contain about 300 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for oral administration and contain about 400 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for oral administration and contain about 500 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0267] In some embodiments, the pharmaceutical compositions provided herein may be formulated as tablets containing about 200 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as tablets containing about 300 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as tablets containing about 400 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated as tablets containing about 500 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0268] The pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion and contain about 1 to 2,000 mg, about 10 to 2,000 mg, about 1 to about 1,000 mg, about 25 to about 1,000 mg, about 25 to about 800 mg, about 25 to about 600 mg, about 50 to about 600 mg, about 50 to about 300 mg, about 50 to about 150 mg, about 150 to about 250 mg, about 250 mg to about 350 mg, about 350 to about 450 mg, about 450 to about 550 mg, about 550 to about 650 mg, about 650 to about 750 mg, about 750 to about 850 mg, about 850 to about 950 mg, and about 950 to about 1050 mg;In one embodiment, the content is 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg. mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg Compounds of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates of the following amounts: approximately 690 mg, approximately 700 mg, 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, approximately 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, approximately 1,000 or approximately 2,000 mg, for symptomatic dosage adjustment in patients to be treated. ;

[0269] In some embodiments, the pharmaceutical compositions provided herein may be formulated for administration by intravenous injection or infusion and contain about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 950 mg, or about 1,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0270] In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 200 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 300 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 400 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 500 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 600 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 700 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 800 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for intravenous injection or infusion and contain about 900 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical compositions provided herein may be formulated for administration by intravenous injection or infusion and contain about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug.

[0271] In some embodiments, the pharmaceutical compositions provided herein may be formulated as an injection or IV infusion containing about 5 mg / mL to about 250 mg / mL, about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 40 mg / mL, or about 10 mg / mL to about 30 mg / mL; in one embodiment, containing 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, or about 10 mg / mL. A compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates thereof, at concentrations of approximately 1 mg / mL, approximately 95 mg / mL, approximately 100 mg / mL, approximately 105 mg / mL, approximately 110 mg / mL, approximately 115 mg / mL, approximately 120 mg / mL, approximately 125 mg / mL, approximately 130 mg / mL, approximately 135 mg / mL, approximately 140 mg / mL, approximately 145 mg / mL, approximately 150 mg / mL, approximately 155 mg / mL, approximately 160 mg / mL, approximately 170 mg / mL, approximately 180 mg / mL, approximately 190 mg / mL, approximately 200 mg / mL, approximately 210 mg / mL, approximately 220 mg / mL, approximately 230 mg / mL, approximately 240 mg / mL, approximately 250 mg / mL.

[0272] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate at a concentration of about 20 mg / mL to about 40 mg / mL. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or an isotopic variant thereof, tautomer, pharmaceutically acceptable salt, solvate, or hydrate at a concentration of about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL.

[0273] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. The daily dose described herein may be administered in sub-dose form once daily or multiple times daily, twice daily, three times daily, four times daily, etc., wherein the number of sub-dose is equal to the daily dose. The pharmaceutical composition may be administered 1 to 4 times daily, including once, twice, three times, and four times daily. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the pharmaceutical composition is administered three times daily. In some embodiments, the pharmaceutical composition is administered four or more times daily. In some embodiments, an initial dose of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is administered, followed by a maintenance dose.

[0274] In some embodiments, the pharmaceutical composition provided herein is administered in tablet form. In some embodiments, the pharmaceutical composition provided herein is administered in capsule form. In some embodiments, the pharmaceutical composition provided herein is administered in injection form. In some embodiments, the pharmaceutical composition provided herein is administered in IV injection or infusion form.

[0275] In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately 10 minutes. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately 15 minutes. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately 20 minutes. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately 30 minutes. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately 45 minutes. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately one hour. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately 90 minutes. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately two hours. In some embodiments, the pharmaceutical composition provided herein is administered via IV infusion over a period of approximately three hours. In some embodiments, the pharmaceutical compositions provided herein are administered via intravenous infusion over a period of up to about three hours. In some embodiments, the pharmaceutical compositions provided herein are administered via intravenous infusion over a period of at least three hours. In some embodiments, the pharmaceutical compositions provided herein are administered via intravenous infusion over a period of at least 30 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered via intravenous infusion over a period of at least two hours. In some embodiments, the pharmaceutical compositions provided herein are administered via intravenous infusion over a period of up to two hours.

[0276] In some embodiments, the pharmaceutical composition provided herein is administered as an IV infusion over a period of up to 30 minutes.

[0277] In some embodiments, an initial dose of the pharmaceutical composition provided herein is administered, followed by a maintenance dose. In some embodiments, both the initial and maintenance doses are administered via intravenous infusion. In some embodiments, both the initial and maintenance doses are administered orally (PO). In some embodiments, the initial dose is administered via intravenous infusion, and the maintenance dose is administered orally (PO). In some embodiments, an initial dose comprising about 2,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered via intravenous infusion. In some embodiments, an initial dose comprising about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered twice daily (BID) via intravenous infusion. In some embodiments, an initial dose comprising about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered via intravenous infusion BID on the first day of treatment. In some embodiments, the initial dose comprising about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, medically acceptable salts, solvates, or hydrates is administered via intravenous BID only on the first day of treatment. In some embodiments, the initial dose comprising about 1,000 mg of a compound of formula (I) or its isotopic variants, tautomers, medically acceptable salts, solvates, or hydrates is administered via 2-hour or 3-hour BID IV infusion. In some embodiments, the maintenance dose comprising about 600 mg of a compound of formula (I) or its isotopic variants, tautomers, medically acceptable salts, solvates, or hydrates is administered via intravenous QD. In some embodiments, the maintenance dose comprising about 600 mg of a compound of formula (I) or its isotopic variants, tautomers, medically acceptable salts, solvates, or hydrates is administered via intravenous QD starting from the second day of treatment. In some embodiments, a maintenance dose comprising about 600 mg of the pharmaceutical composition provided herein is administered via a 1-hour or 2-hour IV infusion QD. In some embodiments, a maintenance dose comprising about 800 mg of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered via a PO QD. In some embodiments, a 1,000 mg IV infusion of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered via a BID (initial dose), followed by a 600 mg IV infusion QD (maintenance dose).In some embodiments, a 1,000 mg BID IV infusion of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered over 2 or 3 hours (starting dose), followed by a 600 mg IV QD infusion over 1, 2, or 3 hours (maintenance dose). In some embodiments, a 1,000 mg BID IV infusion of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered over 3 hours (starting dose), followed by a 600 mg IV QD infusion over 3 hours (maintenance dose). In some embodiments, a 1,000 mg BID IV infusion of a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered over 3 hours (starting dose), followed by an 800 mg PO QD (maintenance dose). In some embodiments, a starting dose of 1,000 mg BID IV is administered via 2-hour or 3-hour IV infusion, wherein a second dose is administered approximately 9 to approximately 12 hours after the first dose.

[0278] In some embodiments, the pharmaceutical composition provided herein is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days.

[0279] In some embodiments, the pharmaceutical composition provided herein is administered daily, every other day, every other day three times a week, every two weeks, every three weeks, every four weeks, every five weeks, every three days, every four days, every five days, every six days, weekly, every two weeks, three times a week, four times a week, five times a week, six times a week, once a month, twice a month, three times a month, once every two months, once every three months, once every four months, once every five months, or once every six months.

[0280] In some cases, methods for administering multiple compounds (e.g., compounds of formula (I) or isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and antifungal agents) involve administering the compounds at intervals of 48 hours or less. In some embodiments, administration occurs within 24 hours, 16 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 15 minutes, or 10 minutes. In some cases, these compounds are administered simultaneously. An example of simultaneous administration is the injection of a compound immediately before, after, or during the oral administration of a second compound, with "immediately" referring to a time of less than about 5 minutes.

[0281] In some embodiments of the pharmaceutical compositions described herein, a second dose is administered approximately 10 minutes after the first dose, approximately 15 minutes after the first dose, approximately 20 minutes after the first dose, approximately 30 minutes after the first dose, approximately 40 minutes after the first dose, approximately 45 minutes after the first dose, approximately 1 hour after the first dose, approximately 2 hours after the first dose, approximately 3 hours after the first dose, approximately 4 hours after the first dose, approximately 5 hours after the first dose, approximately 6 hours after the first dose, approximately 7 hours after the first dose, approximately 8 hours after the first dose, and approximately 9 hours after the first dose. The second dose may be administered approximately 10 hours after the first dose, approximately 11 hours after the first dose, approximately 12 hours after the first dose, approximately 13 hours after the first dose, approximately 14 hours after the first dose, approximately 15 hours after the first dose, approximately 16 hours after the first dose, approximately 17 hours after the first dose, approximately 18 hours after the first dose, approximately 19 hours after the first dose, approximately 20 hours after the first dose, approximately 21 hours after the first dose, approximately 22 hours after the first dose, approximately 23 hours after the first dose, or approximately 24 hours after the first dose. In some embodiments of the pharmaceutical compositions described herein, a second dose is administered approximately 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 22 hours, or 48 hours after the completion of administration of the first dose via IV infusion.In some embodiments of the pharmaceutical composition, a second dose is administered approximately 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 22 hours, or 48 hours after the initiation of the first dose via intravenous infusion.

[0282] In some embodiments, the pharmaceutical composition described herein is administered in combination with an antifungal agent. In some embodiments, the pharmaceutical composition described herein is administered before antifungal treatment. In some embodiments, the pharmaceutical composition described herein is administered after antifungal treatment. In some embodiments, the pharmaceutical composition described herein and the antifungal agent are administered simultaneously. In some embodiments, both the pharmaceutical composition described herein and the antifungal agent are administered via intravenous infusion. In some embodiments, both the pharmaceutical composition described herein and the antifungal agent are administered orally. In some embodiments, the pharmaceutical composition described herein is administered orally and the antifungal agent is administered via intravenous infusion. In some embodiments, the pharmaceutical composition described herein is administered via intravenous infusion and the antifungal agent is administered orally. In some embodiments, both the pharmaceutical composition described herein and the antifungal agent are administered orally. In some embodiments, both the pharmaceutical composition described herein and the antifungal agent are administered via intravenous infusion.

[0283] In some embodiments, the pharmaceutical formulations provided herein are formulated to achieve a maximum plasma concentration (Cmax) of about 12,000 ng / mL to about 25,000 ng / mL (i.e., about 12 µg / mL to about 25 µg / mL) after the shortest possible time following administration. In some embodiments, the pharmaceutical formulations provided herein are formulated to achieve the following Cmax after the shortest possible time following administration: about 12 µg / mL to about 13 µg / mL, 12 µg / mL to about 14 µg / mL, 12 µg / mL to about 15 µg / mL, 12 µg / mL to about 16 µg / mL, 12 µg / mL to about 17 µg / mL, 12 µg / mL to about 18 µg / mL, 12 µg / mL to about 19 µg / mL, 12 µg / mL to about 20 µg / mL, 12 µg / mL to about 21 µg / mL, 12 µg / mL to about 22 µg / mL, 12 µg / mL to about 23 µg / mL, 12 µg / mL to about 24 µg / mL, 13 µg / mL to about 14 µg / mL, 13 µg / mL to about 15 µg / mL, 13 µg / mL to about 16 ...4 µg / mL, 13 µg / mL to about 15 µg / mL, 13 µg / mL to about 16 µg / mL, 13 µg / mL µg / mL to about 17 µg / mL, 13 µg / mL to about 18 µg / mL, 13 µg / mL to about 19 µg / mL, 13 µg / mL to about 20 µg / mL, 13 µg / mL to about 21 µg / mL, 13 µg / mL to about 22 µg / mL, 13 µg / mL to about 23 µg / mL, 13 µg / mL to about 24 µg / mL, 13 µg / mL to about 25 µg / mL, 14 µg / mL to about 15 µg / mL, 14 µg / mL to about 16 µg / mL, 14 µg / mL to about 17 µg / mL, 14 µg / mL to about 18 µg / mL, 14 µg / mL to about 19 µg / mL, 14 µg / mL to about 20 µg / mL, 14 µg / mL to about 21 µg / mL, 14 µg / mL to about 22 µg / mL, 14 µg / mL to about 23 µg / mL µg / mL, 14 µg / mL to about 24 µg / mL, 14 µg / mL to about 25 µg / mL, 15 µg / mL to about 16 µg / mL, 15 µg / mL to about 17 µg / mL, 15 µg / mL to about 18 µg / mL, 15 µg / mL to about 19 µg / mL, 15 µg / mL to about 20 µg / mL, 15 µg / mL to about 21 µg / mL, 15 µg / mL to about 22 µg / mL, 15 µg / mL to about 23 µg / mL, 15 µg / mL to about 24 µg / mL, 15 µg / mL to about 25 µg / mLµg / mL, 16 µg / mL to about 17 µg / mL, 16 µg / mL to about 18 µg / mL, 16 µg / mL to about 19 µg / mL, 16 µg / mL to about 20 µg / mL, 16 µg / mL to about 21 µg / mL, 16 µg / mL to about 22 µg / mL, 16 µg / mL to about 23 µg / mL, 16 µg / mL to about 24 µg / mL, 16 µg / mL to about 25 µg / mL, 18 µg / mL to about 19 µg / mL, 18 µg / mL to about 20 µg / mL, 18 µg / mL to about 21 µg / mL, 18 µg / mL to about 22 µg / mL, 18 µg / mL to about 23 µg / mL, 18 µg / mL to about 24 µg / mL, 18 µg / mL to about 25 µg / mL, 19 µg / mL to about 20 µg / mL, 19 µg / mL to about 21 µg / mL, 19 µg / mL to about 22 µg / mL, 19 µg / mL to about 23 µg / mL, 19 µg / mL to about 24 µg / mL, 19 µg / mL to about 25 µg / mL, 20 µg / mL to about 21 µg / mL, 20 µg / mL to about 22 µg / mL, 20 µg / mL to about 23 µg / mL, 20 µg / mL to about 24 µg / mL, 20 µg / mL to about 25 µg / mL, 21 µg / mL to about 22 µg / mL, 21 µg / mL to about 23 µg / mL, 21 µg / mL to about 24 µg / mL, 21 µg / mL to about 25 µg / mL, 22 µg / mL to about 23 µg / mL, 22 µg / mL to about 24 µg / mL, 22 µg / mL to about 25 µg / mL, 23 µg / mL to about 24 µg / mL µg / mL, 23 µg / mL to about 25 µg / mL, or 24 µg / mL to about 25 µg / mL.

[0284] In some embodiments, the pharmaceutical preparations provided herein are prepared to achieve the following Cmax after the shortest time period following administration: approximately 1 µg / mL, approximately 2 µg / mL, approximately 3 µg / mL, approximately 4 µg / mL, approximately 5 µg / mL, approximately 6 µg / mL, approximately 7 µg / mL, approximately 8 µg / mL, approximately 9 µg / mL, approximately 10 µg / mL, approximately 11 µg / mL, approximately 12 µg / mL, approximately 13 µg / mL, approximately 14 µg / mL, approximately 15 µg / mL, approximately 16 µg / mL, approximately 17 µg / mL, approximately 18 µg / mL, approximately 19 µg / mL, approximately 20 µg / mL, approximately 21 µg / mL, approximately 22 µg / mL, approximately 23 µg / mL, approximately 24 µg / mL, approximately 25 µg / mL, approximately 26 µg / mL, approximately 27 µg / mL, approximately 28 µg / mL, approximately 29 ... µg / mL or approximately 30 µg / mL.

[0285] In some embodiments, the pharmaceutical spray formulation is formulated to achieve the following Cmax after the shortest possible time following administration: at least about 10 µg / mL, about 11 µg / mL, about 12 µg / mL, about 13 µg / mL, about 14 µg / mL, about 15 µg / mL, about 16 µg / mL, about 17 µg / mL, about 18 µg / mL, about 19 µg / mL, about 20 µg / mL, about 21 µg / mL, about 22 µg / mL, about 23 µg / mL, about 24 µg / mL, or about 25 µg / mL. [Fungal Diseases]

[0286] 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, sporotrichosis, and talaromycosis.

[0287] In some embodiments, the fungal disease is aspergillosis. In some embodiments, aspergillosis is allergic bronchopulmonary aspergillosis (ABPA), allergic aspergillus sinusitis, chronic pulmonary aspergillosis, invasive aspergillosis, or cutaneous / skin aspergillosis. In some embodiments, the individual has aspergilloma.

[0288] In some embodiments, the fungal disease is blastomycosis. In some embodiments, the fungal disease is candidiasis. In some embodiments, candidiasis is oropharyngeal candidiasis (thrush), vulvovaginal candidiasis (vaginal candidiasis), fungemia, or invasive candidiasis. 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. In some embodiments, the fungal disease is cryptococcosis. In some embodiments, cryptococcosis is traumatic or cutaneous cryptococcosis, pulmonary cryptococcosis, or cryptococcal meningitis. In some embodiments, the fungal disease is an ocular fungal infection. In some embodiments, an ocular fungal infection is fungal keratitis, fungal extrinsic endophthalmitis, or fungal endogenous endophthalmitis. In some embodiments, the fungal disease is histoplasmosis. In some embodiments, histoplasmosis is acute histoplasmosis. In some embodiments, histoplasmosis is chronic histoplasmosis. In some embodiments, the fungal disease is leukomycosis. In some embodiments, leukomycosis is nasocerebral (sinus and brain) leukomycosis, pulmonary (lung) leukomycosis, gastrointestinal leukomycosis, cutaneous leukomycosis, or disseminated leukomycosis. In some embodiments, the fungal disease is Pneumocystis pneumonia (PCP). In some embodiments, the fungal disease is tinea. In some embodiments, tinea is tinea pedis, tinea cruris, tinea capitis, tinea barbae, tinea manuum, onychomycosis, or tinea corporis. In some embodiments, tinea is caused by a fungus including Trichophyton, Microsporum, or Epidermophyton. In some embodiments, the fungal disease is sporotrichosis. In some embodiments, sporotrichosis is dermatosporotrichosis, pulmonary (lung) sporotrichosis, or disseminated sporotrichosis. In some embodiments, the fungal disease is basidiomycosis.

[0289] In some embodiments, fungal diseases or infections are caused by the following fungi / species: Cryptococcus, Aspergillus, Candida, Coccus, Blastomyces, Ajronia, Histoplasma, Rhizopus, Lepidodendron, Pyroderma, Hypnotus, Microrhizopus, Entomophthora, Ototrichum, Frogdum, Sporothrix, Pneumocystis, Basilaria, Fusarium, and Cetacea. In some embodiments, the fungal disease is caused by a fungal species, including (but not limited to): *Aspergillus fumigatus*, *Aspergillus flavonoids*, *Aspergillus niger*, *Aspergillus terrestris*, *Blastomyces dermatitidis*, *Ajorhizium dermatitidis*, *Candida albicans*, *Candida auris*, *Candida glabrata*, *Candida parapsilosis*, *Candida tropaeolum*, *Candida tropicalis*, *C. coccidioidomycetes*, *C. posadae*, *C. neonicotinoids*, *C. gutterwes*, *Histoplasma capsulatum*, *Rhizopus stolonifer*, *Rhizopus cryptorchidica*, *Mucor*, *Salmonella gravidarum*, *Squama* species, *Pneumocystis carinii*, *Basilella marneffei*, *Leymus chinensis*, *Fusarium solani*, *Salmonella tricuspidata*, *Rhizopus microphylla*, or any combination thereof. 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 solanum*. In some embodiments, the fungal disease is caused by the fungal species *Mucor* indicum. In some embodiments, the fungal disease is caused by the fungal species *Cetosporium auriculatum*. 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 grate*. In some embodiments, the fungal disease is caused by the fungal species *Candida auris*.

[0290] In some embodiments, fungal diseases or infections are caused by fungi such as *Aspergillus fumigatus*, *Blastomyces*, *Ajronia*, *Candida*, *Cryptococcus*, *Histoplasma*, *Rhizopus*, *Hymenopterus*, *Squama*, *Pterygotylea*, *Pyrotypha*, *Phyllostachys ... or fungi from the order Mucorales, or any combination thereof.

[0291] In some embodiments, fungal diseases or infections are caused by fungi of the genera Cryptococcus, Aspergillus, Candida, Fusarium, Cetirizium, or Mucorales, or any combination thereof. In some embodiments, fungal diseases or infections are caused by: *Aspergillus fumigatus*, *Aspergillus ...

Claims

1. Use of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof for the preparation of a pharmaceutical composition for the treatment or prevention of fungal infections or diseases in a human individual, wherein the pharmaceutical composition comprises: (i) a therapeutically effective amount of the compound of formula (I); and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or oral delivery, or wherein the pharmaceutical composition is in a dosage form for injection or delivery; wherein the pharmaceutical composition is administered to the individual according to a treatment regimen comprising a loading dose and a maintenance dose; the loading dose is administered to the individual prior to the maintenance dose; the loading dose comprises 2,000 mg of the compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, and is administered to the individual via intravenous (IV) infusion; the maintenance dose comprises 600 mg to 1,000 mg of the compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, and is administered to the individual via intravenous (IV) infusion; the maintenance dose comprises 600 mg to 1,000 mg of the compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. mg of the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates; the maintenance dose is administered to the individual once daily starting from the second day of treatment; and the fungal infection is caused by an invasive fungus.

2. As claimed in claim 1, wherein the pharmaceutical composition is administered to the individual for a period of up to 12 weeks and for a period of at least one week.

3. As claimed in claim 1, wherein the pharmaceutical composition is administered to the individual for a period of 6 weeks.

4. As claimed in claim 1, wherein the initial dose comprises 2,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, and is administered to the individual via intravenous (IV) infusion.

5. As requested in item 1, wherein the initial dose is administered to the individual twice on the first day of treatment.

6. As claimed in claim 1, wherein the maintenance dose comprises 1,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, and is administered to the individual twice daily via intravenous (IV) infusion.

7. As requested in item 1, wherein the initial dose is administered to the individual via intravenous (IV) infusion over 2 to 3 hours.

8. As claimed in claim 1, wherein the maintenance dose comprises 600 mg, 700 mg, 800 mg, 900 mg or 1,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

9. As claimed in claim 1, wherein the maintenance dose comprises 800 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, and is administered orally to the individual once daily.

10. As claimed in claim 1, wherein the maintenance dose comprises 600 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, and is administered to the individual once daily via intravenous (IV) infusion.

11. As requested in claim 1, wherein the maintenance dose is administered to the individual once daily, starting from the second day of treatment.

12. As claimed in claim 1, wherein the initial dose is administered to the individual twice on the first day of treatment; wherein the initial dose comprising 1,000 mg of the compound of formula (I) or its isotopic variants, tautomers, medically acceptable salts, solvates or hydrates is administered to the individual twice daily via intravenous (IV) infusion on the first day of treatment; wherein the maintenance dose is administered to the individual once daily starting from the second day of treatment; wherein the maintenance dose comprises 800 mg of the compound of formula (I) or its isotopic variants, tautomers, medically acceptable salts, solvates or hydrates, and is administered orally to the individual once daily; or wherein the maintenance dose comprises 600 mg of the compound of formula (I) or its isotopic variants, tautomers, medically acceptable salts, solvates or hydrates, and is administered to the individual once daily via intravenous (IV) infusion.

13. As claimed in claim 1, wherein the treatment regimen further comprises administering to the individual a combination of at least one antifungal agent and the pharmaceutical composition comprising a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, and wherein the at least one antifungal agent is an azole, echinocandin, amphotericin B deoxycholate, amphotericin B cochleate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, ibrexafungerp, orotomide F901318 or a combination thereof.

14. For the purposes of claim 1, wherein the fungal infection is caused by: *Aspergillus fumigatus*, *Blastomyces*, *Ajellomyces*, *Candida*, *Coccidioides*, *Cryptococcus*, *Histoplasma*, *Rhizopus* Muco), Cunninghamell, Apophysomyces, Absidi, Saksenaea, Entomophthora, Conidiobolus, Basidiobolus, Sporothrix, Pneumocystis, Talaromyces, Asclepias, Fusarium, Scedosporium fungus, or fungi from the Mucorales order, or any combination thereof.

15. As claimed in claim 1, wherein the fungal infection or disease is caused by: Cryptococcus, Aspergillus, Candida, Fusarium, Scedosporium fungus, or fungi from the Mucorales order, or any combination thereof.

16. For the purposes of claim 1, wherein the fungal infection or disease is caused by: *Aspergillus fumigatus*, *Aspergillus flavus*, *Blastomyces dermatitidis*, *Ajellomyces dermatitidi*, *Candida albican*, *Candida glabrata*, *Candida rugosa*, *Candida auris*, *Coccidioides immitis*, *Coccidioides posadasii*, *Cryptococcus neoformans*, *Cryptococcus gattii*, *Histoplasma capsulatum*, *Rhizopus stolonifer*, *Rhizopus arrhizus*, *Mucor*. *Indicus*, *Cunninghamella bertholletiae*, *Apophysomyces elegans*, *Absidia* species, *Pyrtomyces* species, *Rhizomucor pusillus*, *Entomophycetes* species, *Otophycetes* species, *Frogdactycetes* species, *Sporothrix schenckii*, *Pneumocystis jirovecii*, *Talaromyces marneffei*, *Asclepias albicans*, *Fusarium solani*, *Scedosporium apiospermum*, *Rhizomucor pusillus*, or any combination thereof.

17. As requested in claim 1, wherein the fungal infection or disease is caused by a fungus of the genus Cryptococcus or Candida.

18. As claimed in claim 1, wherein the fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gattii, or Candida auris.

19. As requested in claim 1, wherein the fungal infection or disease is caused by a fungus of the genus Candida.

20. As requested in claim 1, wherein the fungal infection or disease is caused by Candida auris.

21. As requested in claim 1, wherein the fungal infection or disease is caused by a fungus of the genus Aspergillus.

22. As requested in claim 1, wherein the fungal infection or disease is resistant to azoles and / or echinocandin.

23. For the purposes of claim 1, wherein the individual is an immunocompromised person; or wherein the individual is infected with HIV / AIDS or has cancer; or wherein the individual has cancer; or wherein the cancer is acute myeloid leukemia (AML); or wherein the individual has neutropenia; or wherein the individual is undergoing or has undergone cancer chemotherapy; or wherein the individual is undergoing or has undergone corticosteroid therapy; or wherein the individual is undergoing or has undergone TNF inhibitor therapy; or wherein the individual is a transplant recipient.

24. As requested in claim 1, wherein the fungal infection or disease is in the bloodstream of the individual.

25. As claimed in claim 1, wherein after administration of the pharmaceutical composition, the individual has a reduced number of fungal colonies in the lungs.

26. As requested in claim 1, wherein the plasma concentration-time curve of the compound of formula (I) in the individual has a tmax of less than 30 minutes to 180 minutes.

27. As claimed in claim 1, wherein the individual has a maximum plasma concentration (Cmax) of the compound of formula (I) of 12,000 ng / mL to 25,000 ng / mL.

28. As claimed in claim 1, wherein the compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates are compounds of formula (I) or their solvates or hydrates.

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