Compounds and methods for treating fungal infections

Abstract

The present invention provides a composition for treating fungal infections and diseases and a method of using the same.

Description

Technology Field

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 725,971 filed on August 31, 2018, which is considered part of the disclosure of this application and is incorporated by reference into the disclosure of this application.

[0003] Technical field

[0004] The present invention relates to a compound and a method for treating fungal infections. Background Technology

[0005] Fungi infect humans and are a major cause of human health problems. They also infect plants and cause significant losses in agricultural productivity. This disclosure generally relates to the treatment and / or prevention of fungal infections and diseases.

[0006] Brief summary of the disclosure

[0007] In one aspect, the present invention is a pharmaceutical composition,

[0008] (i) a compound of the following formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and

[0009] (ii) at least one pharmaceutically acceptable excipient

[0010] The present invention provides a pharmaceutical composition comprising, wherein the pharmaceutical composition exists as an oral dosage or administration formulation:

[0011] .

[0012] In another aspect, the present invention, as a pharmaceutical composition,

[0013] (i) a compound of formula (I); or particulates of its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates or hydrates; and

[0014] (ii) at least one pharmaceutically acceptable excipient

[0015] The present invention provides a pharmaceutical composition comprising, wherein the pharmaceutical composition exists as an oral dosage or administration formulation or an inhalation delivery formulation.

[0016] 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.

[0017] In some embodiments, the particles are nano-ground. 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 the particles have a particle size of about 1 nm to about 750 nm.

[0018] In some embodiments, the formulation is a self-microemulsifying drug delivery system (SMEDDS). In some embodiments, the formulation is a self-emulsifying drug delivery system (SEDDS). In some embodiments, the formulation is a suspension or a liquid. In some embodiments, the formulation is a nanosuspension. In some embodiments, the formulation is a solid formulation. In some embodiments, the formulation is a spray-dried dispersion formulation. In some embodiments, the formulation is a hot melt granule formulation. In some embodiments, the formulation is a hot melt extrusion formulation. In some embodiments, the formulation is a microprecipitated bulk powder (MBP) formulation. In some embodiments, the formulation is a liquid formulation. In some embodiments, the formulation is a suspension, liquid, syrup, or elixir. In some embodiments, the pharmaceutical composition exists as a formulation for oral administration or treatment.

[0019] In some embodiments, the formulation is a tablet or a capsule. In some embodiments, the tablet or capsule has an enteric coating. In some embodiments, the formulation is a tablet. In some embodiments, the tablet is an osmotic suspension tablet. In some embodiments, the capsule is a liquid-filled hard capsule. In some embodiments, the capsule is a soft gelatin capsule.

[0020] In some embodiments, the formulation is a modified-release formulation. In some embodiments, the modified-release formulation is a delayed-release formulation, an extended-release (ER) formulation, or a targeted-release formulation. In some embodiments, the ER formulation is a sustained-release (SR) formulation or a controlled-release (CR) formulation. In some embodiments, the formulation is an immediate-release formulation.

[0021] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 1,000 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 600 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the compound of formula (I) or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates 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 1,050 mg.

[0022] 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 its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0023] 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, or about 500 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0024] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0025] In some embodiments, at least one pharmaceutically acceptable excipient is a filler, a disintegrant, a binder, a fluidizing agent, a lubricant, or any combination thereof. In some embodiments, at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate, colloidal silicon dioxide, or any combination thereof.

[0026] 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, when stored as a solid, the pharmaceutical composition is stable for up to 36 months at a temperature of about 2°C to about 25°C. In some embodiments, when stored as a solid, 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 comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0027] In one aspect, the present invention is a pharmaceutical composition,

[0028] (i) a compound of formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates or hydrates; and

[0029] (ii) at least one pharmaceutically acceptable excipient

[0030] The present invention provides a pharmaceutical composition comprising, wherein the pharmaceutical composition exists as a formulation for administration or administration by injection.

[0031] In some embodiments, the pharmaceutical composition is present as a formulation for intravenous (IV) injection or infusion, or for intramuscular, subcutaneous, or intradermal injection.

[0032] In some embodiments, the pharmaceutical composition exists as a formulation for IV injection or infusion. In some embodiments, the formulation is an IV formulation. In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the formulation includes a co-solvent.

[0033] In some embodiments, the cosolvent is PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremophor, glycerin, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert - It includes butanol, or any combination thereof. In some embodiments, the formulation further includes an oil. In some embodiments, the oil includes sesame oil, soybean oil, vegetable oil, poppy seed oil, safflower oil, or a combination thereof.

[0034] In some embodiments, the formulation further comprises a buffer. In some embodiments, the IV formulation further comprises a buffer. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the phosphate buffer is potassium phosphate. In some embodiments, the potassium phosphate is monobasic or dibasic.

[0035] 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.

[0036] In some embodiments, the pH of a pharmaceutical composition formulated for IV administration is adjusted with hydrochloric acid and / or sodium hydroxide.

[0037] In some embodiments, the pharmaceutical composition comprises about 5 mg / mL to about 250 mg / mL of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the pharmaceutical composition comprises about 10 mg / mL to about 50 mg / mL of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate.

[0038] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 40 mg / mL of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the pharmaceutical composition comprises about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0039] In some embodiments, the pharmaceutical composition is stable for up to about 24 months at a temperature of about -20°C to 8°C. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to about 24 months at a temperature of about -20°C. In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0040] In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is crystalline, microcrystalline, amorphous, or freeze-dried. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is crystalline. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is amorphous. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is freeze-dried.

[0041] In some embodiments, the pharmaceutical composition contains substantially no impurities. In some embodiments, the pharmaceutical composition is at least about 90% pure. In some embodiments, the pharmaceutical composition is at least about 95% pure. In some embodiments, the pharmaceutical composition is at least about 96% pure. In some embodiments, the pharmaceutical composition is at least about 97% pure. In some embodiments, the pharmaceutical composition is at least about 98% pure. In some embodiments, the pharmaceutical composition is at least about 99% pure. In some embodiments, 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% pure. In some embodiments, the pharmaceutical composition contains at least one impurity up to about 10% (w / w). In some embodiments, the pharmaceutical composition comprises at least one impurity of 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 less than about 1% (w / w). In some embodiments, the pharmaceutical composition comprises at least one impurity of about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or less than about 1% (w / w). In some embodiments, the pharmaceutical composition comprises at least 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 less than about 0.1% (w / w).

[0042] In some embodiments, at least one impurity is a degradant. In some embodiments, at least one impurity is

[0043] Or any combination of these.

[0044] In some embodiments, at least one impurity is am.

[0045] 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 impurities. In some embodiments, the pharmaceutical composition contains up to about 1.5% (w / w) of compounds

[0046] Includes

[0047] In another aspect, the present invention provides a combination composition comprising (i) a compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and (ii) at least one antifungal agent.

[0048] In some embodiments, at least one antifungal agent is an azole, an echinocandin, amphotericin B deoxycholate, amphotericin B cocliate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, ivlexafungup, orotomide F901318, or a combination thereof. In some embodiments, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavukonazole, or miconazole. In some embodiments, the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin.

[0049] In one aspect, the present invention is a combination composition,

[0050] (i) a compound of the following formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and

[0051] (ii) Compounds of the following formula (II), or isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates thereof

[0052] A combination composition comprising:

[0053]

[0054] .

[0055] In some embodiments, the combination composition further comprises at least one pharmaceutically acceptable excipient.

[0056] In some embodiments, the compound of formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates, and the compound of formula (II), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are both crystalline.

[0057] In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, are present in a ratio of about 10:1. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, 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 variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate 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 variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate are present in a ratio 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.

[0058] In one aspect, the present invention provides a method for treating or preventing a fungal infection or disease, comprising the step of administering a therapeutically effective amount of any of the pharmaceutical compositions or combination compositions described herein to a subject who requires treatment or prevention of a fungal infection or disease.

[0059] In some embodiments of the method provided herein, about 10 mg to about 8,000 mg of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, about 10 mg to about 2,400 mg of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, a compound of formula (I) of 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, or its Isotope dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to the subject.

[0060] In some embodiments of the method provided herein, 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 dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject. In some embodiments of the method provided herein, 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 dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject.

[0061] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject daily. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject once a day, twice a day, three times a day, or four times a day. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject once a day. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject twice a day.

[0062] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of up to about 12 weeks. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of at least 1 week. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of at least 2 weeks. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of up to about 2 weeks. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of 1 week, 2 weeks, 6 weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks.

[0063] In some embodiments of the method provided herein, about to about 10 mg to about 8,000 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject. In some embodiments of the method provided herein, 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 dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject.

[0064] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of about 20 minutes, about 30 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours.

[0065] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of up to about 3 hours.

[0066] In some embodiments of the method provided herein, a loading dose is administered to a subject, followed by a maintenance dose. In some embodiments of the method provided herein, the loading dose comprises about 1,000 mg to about 8,000 mg of the compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg to about 2,400 mg of the compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the loading dose comprises about 1,000 mg to about 2,000 mg. In some embodiments of the method provided herein, the loading dose is administered by IV infusion over a period of about 2 to about 3 hours. In some embodiments of the method provided herein, the loading dose is administered twice on the first day of treatment. In some embodiments of the method provided herein, a second loading dose is administered about 9 hours after the first loading dose.

[0067] In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the maintenance dose comprises about 800 mg or about 1,000 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and is administered to a subject. In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg or about 900 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and is administered orally.

[0068] In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and is administered by IV infusion over a period of about 1 hour to about 3 hours.

[0069] In any one of the embodiments of the method provided herein, embodiments 157-164, about 600 mg of a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered by IV infusion over a period of about 3 hours.

[0070] In some embodiments of the method provided herein, the maintenance dose is administered once daily.

[0071] In some embodiments of the method provided herein, the maintenance dose is administered once daily, starting on the second day of treatment.

[0072] In some embodiments of the method provided herein, about 600 mg or about 800 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates or hydrates, is administered by IV infusion over a period of about 3 hours, starting on the second, third, or fourth day of treatment.

[0073] In some embodiments of the method provided herein, about 800 mg or about 1,000 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates or hydrates, is administered orally starting on the second, third, or fourth day of treatment.

[0074] In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg or about 800 mg of the compound of formula (I), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the method provided herein, about 600 mg of the compound of formula (I), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, about 800 mg of the compound of formula (I), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, about 600 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of about 1 hour to about 3 hours and / or about 800 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered orally. In some embodiments of the method provided herein, the maintenance dose is administered once daily. In some embodiments of the method provided herein, the maintenance dose is administered once daily starting on the second day of treatment. In some embodiments of the method provided herein, about 600 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of about 3 hours.

[0075] In some embodiments of the method provided herein, about 600 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered by IV infusion over a period of about 3 hours, starting on the second day of treatment.

[0076] In some embodiments of the method provided herein, about 800 mg of a compound of formula (I), or its isotopic isoforms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates is administered orally starting on the fourth day of treatment.

[0077] In some embodiments of the method provided herein, the fungal infection is caused by an invasive fungus. In some embodiments of the method provided herein, the method further comprises the step of administering to a subject at least one antifungal agent in combination with a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the method provided herein, at least one antifungal agent is an azole, an echinocandin, amphotericin B deoxycholate, amphotericin B cocliate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, Ibrexafungup, orotomide F901318, or a combination thereof. In some embodiments of the method provided herein, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavuconazole, or miconazole. In some embodiments of the method provided herein, the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin, or a combination thereof.

[0078] In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; and an antifungal agent are administered simultaneously, nearly simultaneously, or sequentially in any order. In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; and an antifungal agent are administered simultaneously or nearly simultaneously. In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; and an antifungal agent are administered sequentially. In some embodiments of the method provided herein, a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; A pharmaceutical composition comprising, or a pharmaceutically acceptable salt thereof, is administered prior to at least one antifungal agent. In some embodiments of the method provided herein, a compound of formula (I), or its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate; or a pharmaceutical composition comprising its pharmaceutically acceptable salt is administered after at least one antifungal agent.

[0079] In some embodiments of the method provided herein, the fungal infection or disease is Aspergillus fumigatus ( Aspergillus fumigatus ), Blastomyces( Blastomyces ), Azelomyces( Ajellomyces ), Candida( Candida ), Coccidioides( Coccidioides ), Cryptococcus( Cryptococcus ), histoplasma( Histoplasma ), Rhizopus( Rhizopus ), Mukor( Mucor ), Kuninghamela( Cunninghamella ), Apophysomyces( Apophysomyces), Absidia( Absidia ), Saxenaea( Saksenaea ), Entomoptora( Entomophthora ), Conidiobolus( Conidiobolus ), Basidiobolus( Basidiobolus ), Sporotrix( Sporothrix ), Pneumocystis( Pneumocystis ), Thalaromyces( Talaromyces ), Asclepias( Asclepias ), Fusarium( Fusarium ), Sedosporium( Scedosporium ) Fungi or mucorales( Mucorales It is caused by fungi from the order ) or any combination thereof. In some embodiments of the method provided herein, the fungal infection or disease is caused by fungi from the order Cryptococcus, Aspergillus, Candida, Fusarium, Sedosporium, or Mucoraleles, or any combination thereof. In some embodiments of the method provided herein, the fungal infection or disease is caused by Aspergillus fumigatus (Aspergillus fumigatus) , Aspergillus flavus ( Aspergillus flavus ), Blastomyces dermatidis( Blastomyces dermatitidis ), Azelomyces dermatitidis( Ajellomyces dermatitidis ), Candida albicans( Candida albicans ), Candida glabrata( Candida glabrata ), Candida lugosa( Candida rugosa ), Candida auris( Candida auris ), Coccidioides imitis( Coccidioides immitis ), Coccidioides posadasii( Coccidioides posadasii ), Cryptococcus neoformans( Cryptococcus neoformans ), Cryptococcus gatii( Cryptococcus gattii ), Histoplasma capsulatum( Histoplasma capsulatum ), Rhizopus stolonifer ( Rhizopus stolonifer ), Rhizopus arijus( Rhizopus arrhizus ), Mucor Indicus( Mucor indicus ), Kuninghamela Bertoletiae( Cunninghamella bertholletiae ), Apophysomyces elegans( Apophysomyces elegans ), Absidia species (Absidia species) , Saxenaea species(Saksenaea species) , Rhizomucor fusillus ( Rhizomucor pusillus ), Entomoptora species (Entomophthora species) , conidiobolus Species (Conidiobolus species) , Basidiobulus species (Basidiobolus species) , Sporotrix Shenkiyi( Sporothrix schenckii ), Pneumocystis jirobesii ( Pneumocystis jirovecii ), Thalaromyces marnepei( Talaromyces marneffei ), Asclepias Albicans( Asclepias albicans ), Fusarium solani( Fusarium solani ), Sedosporium apiospermum ( Scedosporium apiospermum ), Rhizomucor fusillus (Rhizomucor pusillus) , or is caused by any combination thereof. In some embodiments of the method provided herein, the fungal infection or disease is caused by Cryptococcus fungi or Candida fungi. In some embodiments of the method provided herein, the fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gatii, or Candida auris.

[0080] In some embodiments of the method provided herein, the fungal infection or disease has azole resistance and / or echinocandin resistance.

[0081] In some embodiments of the method provided herein, the subject is immunocompromised. In some embodiments of the method provided herein, the subject is infected with HIV / AIDS or has cancer. In some embodiments of the method provided herein, the subject has cancer. In some embodiments of the method provided herein, the cancer is acute myeloid leukemia (AML). In some embodiments of the method provided herein, the subject has neutropenia. In some embodiments of the method provided herein, the subject is receiving or has received cancer chemotherapy. In some embodiments of the method provided herein, the subject is receiving or has received corticosteroid treatment. In some embodiments of the method provided herein, the subject is receiving or has received TNF inhibitor treatment. In some embodiments of the method provided herein, the subject is a transplant recipient. In some embodiments of the method provided herein, a fungal infection or disease is present in the subject's bloodstream. In some embodiments of the method provided herein, the subject has a reduced fungal colony count in the lungs after administration of the pharmaceutical composition.

[0082] In some embodiments of the method provided herein, the plasma concentration versus time curve of the compound of formula (I) in a subject is t less than about 30 minutes to about 180 minutes max ... has. In some embodiments of the method provided herein, the subject has a maximum plasma concentration (C) of a compound of formula (I) of about 12,000 ng / mL to about 25,000 ng / mL. max has ).

[0083] Incorporation by reference

[0084] All published documents, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual published document, patent, or patent application were specified to be included by reference specifically and individually. Brief explanation of the drawing

[0085] Figures 1a - 1b . Healthy subjects were given 10 to 1,000 mg over 3 hours Compound 1 After IV infusion Compound 1A Geometric mean plasma concentration—linear (Fig. 1a) and semi-logarithmic (Fig. 1b) axes. Figures 2a - 2b . After IV infusion of 1,000 mg over 0.5 to 3 hours to healthy subjects Compound 1A The geometric mean plasma concentration of ― linear( Figure 2a ) and half-log( Figure 2b ) axis. Figures 3a - 3b . Healthy subjects were administered 50, 150, 300, and 600 mg over 3 hours at qd x 14 days Compound 1 After IV infusion Compound 1A The geometric mean plasma concentration of ― linear( Figure 3a ) and half-log( Figure 3b ) axis. Figures 4a - 4b . Healthy subjects were given 1,000 mg over 2 hours from 0 to 9 hours on Day 1 Compound 1 After IV infusion as a loading regimen, followed by IV infusion of 600 mg over 1 hour at qd x 6 days on days 2 to 7, Compound 1A The geometric mean plasma concentration of ― linear( Figure 4a ) and half-log( Fig. 4b ) axis. Figs. 5a-5b . 10 to 350 mg to healthy subjects over 3 hours Compound 1 and after IV infusion of 1,000 mg over 0.5 to 3 hours Compound 1 Geometric mean plasma concentration of mean plasma concentration ― linear( Fig. 5a ) and half-log( Fig. 5b ) axis. Figs. 6a-6b . Healthy subjects were administered 50, 150, 300, and 600 mg over 3 hours at QD x 14 days Compound 1 After IV infusion Compound 1 The geometric mean plasma concentration of ― linear( Fig. 6a ) and half-log( Fig. 6b ) axis. Figs. 7a-7b . Healthy subjects were given 1,000 mg over 2 hours from 0 to 9 hours on Day 1 Compound 1 After IV infusion as a loading regimen, followed by IV infusion of 600 mg over 1 hour at qd x 6 days on days 2 to 7, Compound 1 The geometric mean plasma concentration of ― linear( Fig. 7a ) and half-log( Fig. 7b ) axis. Figures 8a-8b 200 mg administered to healthy subjects over 3 hours under fasting conditions Compound 1 After intravenous infusion and oral administration of 100 to 500 mg Compound 1A The geometric mean plasma concentration of ― linear( Fig. 8a ) and half-log( Fig. 8 b) Axis. Figs. 9a-9b 400 mg to healthy subjects under fasting and intake conditions Compound 1 After oral administration of Compound 1A The geometric mean plasma concentration of ― linear( Fig. 9a ) and half-log( Fig. 9b ) axis. Figs. 10a-10b . Under intake conditions, healthy subjects were given 500 and 1,000 mg at QD x 14 days. Compound 1 After oral administration of Compound 1A The geometric mean plasma concentration of ― linear( Fig. 10a ) and half-log( Fig. 10b ) axis. Fig. 11 . Solubility profile for 400 mg Compound 1 Tablet. Specific details for implementing the invention

[0086] Detailed description of the present disclosure

[0087] The present invention provides, for example, a composition for treating and / or preventing a fungal infection or disease. The present invention also provides, for example, a method for treating and / or preventing a fungal infection or disease.

[0088] I. Definition

[0089] The abbreviations used herein have their ordinary meanings within the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0090] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomer form to another isomer form.

[0091] It will be obvious to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms, and that all such tautomeric compounds are included within the scope of the present invention.

[0092] Unless otherwise noted, the structures shown herein are to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, substitution of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having this structure, except for the substitution of carbon by C-enriched carbon, are included within the scope of the present invention.

[0093] The compound of the present invention may also contain atomic isotopes in non-natural proportions from one or more atoms among the atoms constituting the compound. For example, the compound may contain radioactive isotopes, such as, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It may be radiolabeled as C). Regardless of whether or not it is radioactive, all isotopic variants of the compound of the present invention are included within the scope of the present invention.

[0094] The term "isotope variant" refers to a compound containing isotopes in non-natural proportions in one or more atoms among the atoms constituting the compound. In some embodiments, the "isotope variant" of the compound is hydrogen (1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), Nitrogen-14( 14 N), Nitrogen-15( 15 N), Oxygen-14( 14 O), Oxygen-15( 15 O), Oxygen-16 ( 16 O), Oxygen-17( 17 O), Oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18 ( 18 F), Phosphorus-31( 31 P), Phosphorus-32( 32 P), Phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131 ( 131 It contains one or more isotopes in non-natural proportions, including but not limited to I). In some embodiments, the "isotopic variant" of the compound is a stable form, i.e., non-radioactive. In some embodiments, the "isotopic variant" of the compound is hydrogen ( 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13(13 C), nitrogen-14( 14 N), Nitrogen-15( 15 N), oxygen-16( 16 O), Oxygen-17( 17 O), Oxygen-18( 18 O), Fluorine-17( 17 F), Phosphorus-31( 31 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), and iodine-127( 127 It contains one or more isotopes in non-natural proportions, including but not limited to I). In some embodiments, the "isotopic variant" of the compound is an unstable form, i.e., radioactive. In some embodiments, the "isotopic variant" of the compound is tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), Oxygen-14( 14 O), Oxygen-15( 15 O), Fluorine-18( 18 F), Phosphorus-32( 32 P), Phosphorus-33( 33 P), Sulfur-35( 35 S), Chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), and iodine-131 ( 131 It contains one or more isotopes in non-natural proportions, including but not limited to I). In compounds such as those provided herein, for example, if feasible in the judgment of a person skilled in the art, any hydrogen 2 It can be H, or, for example, any carbon13 It could be C, or, for example, any nitrogen 15 N can be, for example, any oxygen 18 You will understand that it can be O. In some embodiments, the "isotopic variant" of the compound contains deuterium (D) in a non-natural proportion.

[0095] It should be recognized that throughout this application, alternatives are composed of Markush groups, for example, each amino acid position containing more than one possible amino acid. Specifically, each member of a Markush group is considered to constitute another embodiment by being regarded separately, and the Markush group should not be interpreted as a single unit.

[0096] As used herein, the term "one" (“a” or “an”) means one or more. Additionally, as used herein, the phrase “substituted with” means that a specified group may be substituted with one or more of any or all listed substituents. For example, a group such as an alkyl or heteroaryl group may be substituted with an “unsubstituted C1-C 20 In the case where "substituted with an alkyl, or an unsubstituted 2 to 20-membered heteroalkyl," the group comprises one or more unsubstituted C1-C 20 It may contain an alkyl group and / or one or more unsubstituted binary to 20-membered heteroalkyl groups.

[0097] As used herein, the term "acceptable" in relation to a formulation, composition, or component means that it does not cause a sustained adverse effect on the general health of the subject being treated.

[0098] As used herein, the term “pharmaceuticalally acceptable salt” includes both acid and base addition salts comprising a salt of an active compound prepared by using a relatively non-toxic acid or base according to a specific substituent found on the compound described herein. When the compound of the present invention contains a relatively acidic functional group, a base addition salt may be obtained by contacting a neutral form of such compound with a sufficient amount of a pure desired base or a desired base in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt may be obtained by contacting a neutral form of such compound with a sufficient amount of a pure desired acid or a desired acid in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, souveric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc., as well as salts derived from inorganic acids such as hydrochloric acid, hydrobromide, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphate, dihydrophosphate, sulfuric acid, monohydrosulfuric acid, hydroiodide, or phosphite. Salts of amino acids such as arginates, etc., and salts of organic acids such as glucuronic acid or galacturonic acid are also included (e.g., literature [Berge et al. , "Pharmaceutical Salts," Journal of Pharmaceutical Science , 1977 , 66 [See , 1-19]). Some specific compounds of the present invention contain both basic and acidic functional groups so that the compound can be converted into a base or acid addition salt, or exist as an amphoteric ion.

[0099] Accordingly, the compounds of the present invention may exist as salts, for example, salts formed by using pharmaceutically acceptable acids. The present invention comprises such salts. Non-limiting examples of said salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzosates, and salts formed by using amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts may be prepared by methods known to those skilled in the art.

[0100] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in some physical properties, such as solubility in polar solvents. In some embodiments, the compound of the present invention contains both basic and acidic functional groups that allow the compound to be converted into a base or acid addition salt. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. Although the parent form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, unless otherwise specified, the salt disclosed herein is equivalent to the parent form of the compound for the purposes of the present invention.

[0101] In addition to the salt form, the present invention provides a compound existing in the form of a prodrug. The prodrug of the compound described herein is a compound that is readily chemically altered under physiological conditions to provide the compound of the present invention. The prodrug of the compound described herein can be converted in vivo after administration. Additionally, the prodrug can be converted into the compound of the present invention by chemical or biochemical methods in an in vivo environment, for example, upon contact with a suitable enzyme or chemical reagent.

[0102] Certain compounds of the present invention may exist in solvated forms, including hydrated forms, as well as in nonsolved forms. Generally, the solvated form is equivalent to the nonsolved form and is included within the scope of the present invention. Certain compounds of the present invention may exist in a number of crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses anticipated by the present invention and are within the scope of the present invention.

[0103] “Pharmaceuticalally acceptable excipients” and “pharmaceutically acceptable carriers” refer to substances that may be included in the composition of the present invention, which aid in the administration of the compound to a subject and absorption by the subject, without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, ordinary physiological saline, Ringer’s solution with added lactic acid, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer’s solution), alcohols, oils, gelatin, carbohydrates, e.g., lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. These formulations may be sterilized and, if desired, may be mixed with adjuvants that do not react adversely with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, coloring agents and / or flavoring substances. Those skilled in the art will recognize that other pharmaceutical excipients may be useful for the present invention.

[0104] The term “formulation” is intended to include the formulation of an active compound using an encapsulating material as a carrier, providing a capsule formulation in which the active ingredient is associated with a carrier by being surrounded by a carrier with or without another carrier. Similarly, caseases and lozenges are included. Tablets, powders, capsules, pills, caseases, and lozenges may be used as solid formulations suitable for oral administration.

[0105] The terms “disease” or “condition” refer to the state or health condition of a patient or subject that can be treated by the compounds or methods provided herein. A disease may be a fungal infection. In some additional cases, “fungal infection or disease” refers to a human fungal infection or disease, including Cryptococcus, Aspergillus, or Candida disease or infection.

[0106] As used herein, the terms "fungal infection" or "fungal disease" refer to a disease caused by pathogenic fungi. Fungal infections may be opportunistic or primary infections and may be caused by fungi, such as yeasts and / or molds.

[0107] As used herein, the terms “treating” or “treatment” refer to any indicators indicating the success of therapy or improvement of impairment, disease, condition, or condition, including any objective or subjective parameters such as alleviation; relief; reduction of symptoms or making the patient more tolerance to impairment, condition, or condition; slowing the rate of regression or decline; making the end point of regression 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 a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term “treating” and its verb conjugations may include the prevention of impairment, condition, condition, or disease. In some embodiments, treatment is prevention. In other embodiments, treatment does not include prevention.

[0108] The terms “treating,” “treatment,” “relieving,” or “improving” are used interchangeably herein. These terms, as used herein (and as widely understood in the art), broadly include any approach to obtain a favorable or desired outcome of a subject’s condition, including clinical outcomes. A favorable or desired clinical outcome includes, but is not limited to, the alleviation or improvement of one or more symptoms or conditions; a reduction in the severity of the disease; the stabilization of the condition of the disease (i.e., not worsening); prevention of the spread or transmission of the disease; delay or slowing of the progression of the disease; improvement or alleviation of the condition of the disease; a reduction in the recurrence of the disease; and such remission, whether partial or total, and detectable or undetectable. In other words, as used herein, “treatment” includes any cure, improvement, or prevention of the disease. Treatment may prevent the occurrence of the disease; may suppress the spread of the disease; It can alleviate the symptoms of the disease (e.g., itching, swelling, burning, cough, fever, chest pain, shortness of breath); eliminate the underlying cause of the disease wholly or partially; shorten the duration of the disease; or produce a combination of these effects.

[0109] As used herein, "treating" and "treatment" include prophylactic treatment. A treatment method comprises the step of administering a therapeutically effective amount of the compound described herein to a subject. The administration step may consist of a single dose or may include a series of doses. The duration of treatment is determined by various factors such as the severity of the disease, the age of the patient, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. It will also be recognized that the effective dose of the agent used for treatment or prevention may be increased or decreased over the course of a specific treatment or prophylactic regimen. Changes in dosage may be caused and identified by standard diagnostic methods known in the art. In some cases, long-term administration may be required. For example, the composition is administered to a subject for a sufficient duration in an amount sufficient to treat the patient.

[0110] The terms "prevent," "preventing," and "prevention" refer to a reduction in the occurrence of disease symptoms in a patient. Preventing or prevention may be complete (no detectable symptoms) or partial so that fewer symptoms are observed than would likely occur in the absence of treatment. In some embodiments, prevention refers to slowing the progression of a disease, disorder, or condition, or preventing them from progressing to a harmful or other unwanted state.

[0111] “Patient” or “subject in need” refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of the pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, horses, rats, mice, dogs, cats, monkeys, goats, sheep, cows, deer, and other non-mammalians including fish and birds, but not limited thereto. In some embodiments, the patient is a human.

[0112] As referred to herein, treatment also refers to the systemic delivery of the compounds disclosed herein to any type of plant, including trees, shrubs, flowering plants, foliage plants, indoor plants, ground cover plants and grasses, and agricultural plants (including crops of agricultural plants).

[0113] As used herein, "hydrate" is a compound containing stoichiometric or non-stoichiometric amounts of water and, in some embodiments, formed during a crystallization process using water.

[0114] As used herein, the term “agricultural plant” refers to a plant in which part or all is harvested or cultivated on a commercial scale, or a plant that has been harvested or cultivated, or a plant used as a significant source of fodder, food, fiber, or other compounds.

[0115] "Effective dose" is an amount sufficient to achieve the stated purpose compared to the absence of the compound (e.g., to achieve the effect desired by administration, to treat a disease, to reduce or increase enzyme activity, to reduce signaling pathways, or to reduce one or more symptoms of a disease or disorder). An example of an "effective dose" is an amount sufficient to contribute to the treatment, prevention, or reduction of symptoms or signs of a disease, which may also be referred to as a "therapeutic effective dose." "Reduction" of symptoms or signs (and grammatically equivalent phrases thereof) means a reduction in the severity or frequency of the symptom(s), or the elimination of the symptom(s). The "preventive effective dose" of a drug is an amount of drug capable of exerting the intended preventive effect when administered to a subject, e.g., prevention or delay of the onset (or recurrence) of injury, disease, condition, or state, or a reduction in the likelihood of the onset (or recurrence) of injury, disease, condition, or symptoms thereof. Complete prophylactic effect does not necessarily occur with a single dose administration, but may occur only after a series of dose administrations. Therefore, an effective prophylactic dose may be administered in one or more doses. As used herein, "reduction in activity" refers to the amount of antagonist required to reduce the activity of the enzyme compared to the absence of the antagonist. As used herein, "disruption in function" refers to the amount of antagonist required to disrupt the function of the enzyme or protein compared to the absence of the antagonist. The precise amount will depend on the purpose of treatment and can be determined by a person skilled in the art by using known techniques (e.g., the literature [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[See , 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins]). The therapeutically effective dose can be determined by measuring relevant physiological effects and can be adjusted in relation to medication regimens and diagnostic analysis of the subject's condition. For example, measurement of serum levels of the compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates (or, e.g., its metabolites) at a specific time after administration may indicate whether a therapeutically effective dose has been administered.

[0116] For any of the compounds described herein, the therapeutically effective dose may first be measured by a cell culture assay. The target concentration will be the concentration of the active compound(s) that can achieve the method described herein when measured using the method described herein or a method known in the art.

[0117] As is widely known in the art, the therapeutically effective dose to be used in humans may be determined from animal models. For example, the dose for humans may be formulated to achieve a concentration found to be effective in animals. The dosage in humans may be adjusted by monitoring the effect of the compound and by upgrading or downgrading the dosage, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the methods described above and other methods is within the capability of a person skilled in the art. Adjusting the dosage to achieve maximum therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is within the capability of a person skilled in the art.

[0118] As used herein, the term "therapeutic effective dose" refers to an amount of therapeutic agent sufficient to improve the disorder as described above. For example, the therapeutic effective dose for a given parameter 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 a "fold" increase or decrease. For example, the therapeutic effective dose may have an effect of at least 12 times, 15 times, 2 times, or 5 times or more compared to the control group.

[0119] The dosage may vary depending on the patient's requirements and the compound used. In relation to the present invention, the dosage administered to the patient must be sufficient to produce a beneficial therapeutic response over time. The size of the dosage will be determined by the presence, nature, and severity of any adverse side effects. Determining the appropriate dosage for a specific situation is within the skill of the practitioner. Generally, treatment is initiated with a small dose lower than the optimal dose of the compound. Subsequently, the dosage is increased in small increments until optimal effect is achieved under the given circumstances. The dosage and intervals may be individually adjusted to provide the compound at a level effective for the specific clinical indication being treated. This will provide a therapeutic regimen suitable for the severity of the individual's disease state.

[0120] As used herein, the term “administering” means parenteral or enteral administration. Accordingly, as used herein, “administering” means administration to a subject as oral administration, suppositories, local contact, intravenous, intraperitoneal, intramuscular, inhalation, spray, intralesional, intradural, intracranial, intranasal, or subcutaneous administration, or implantation of a sustained-release device, e.g., a mini osmotic pump. Administration is administration by any route including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery methods include, but are not limited to, the use of liposomal preparations, intravenous infusion, transdermal patches, etc. "Co-administration" means administering the compositions described herein simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., antifungal agents, antibacterial agents, antiviral agents, and / or chemotherapy agents). The compounds of the present invention may be administered to a patient alone or co-administered. Co-administration means administering the compounds individually or in combination (more than one compound or agent) simultaneously or sequentially. Accordingly, the formulations may be combined with other active substances when desired (e.g., to reduce metabolic degradation). The compositions of the present invention may be formulated as applicator sticks, liquids, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols, and may be delivered transdermally by a local route. Oral formulations include tablets, pills, powders, coated tablets, capsules, liquid formulations, lozenges, case preparations, gels, syrups, slurries, suspensions, etc., suitable for intake by patients. Solid form formulations include powders, tablets, pills, capsules, case preparations, suppositories, and dispersible granules. Liquid form formulations include liquids, suspensions, and emulsions, for example, water or water / propylene glycol liquids.The compositions of the present invention may further comprise components to provide sustained release and / or convenience. Such components include high molecular weight, anionic mucomimetic polymers, gelled polysaccharides, and finely divided drug carrier substrates. These components are discussed in more detail in U.S. Patents No. 4,911,920; No. 5,403,841; No. 5,212,162; and No. 4,861,760. The full contents of such patents are incorporated herein by reference for all purposes. The compositions of the present invention may also be delivered as microspheres for sustained release within the body. For example, microspheres may be administered via intradermal injection of drug-containing microspheres for sustained subcutaneous release (see reference [Rao,. J. Biomater Sci. Polym. Ed [See . 7:623-645, 1995]); or can be administered as a biodegradable and injectable gel formulation (e.g., literature [Gao Pharm. Res [See . 12:857-863, 1995]); or it may be administered as microspheres for oral administration (e.g., the literature [Eyles, J. Pharm. Pharmacol. (See [49:669-674, 1997]). In another embodiment, formulations of the compositions of the present invention may be delivered by the use of liposomes that fuse with a cell membrane, or by the use of liposomes that are endocytosed, that is, by using receptor ligands attached to the liposomes that bind to surface membrane protein receptors of the cell causing endocytosation. In particular, if the liposome surface has receptor ligands specific to target cells or otherwise preferentially orients toward a specific organ, the use of liposomes may focus on delivering the compositions of the present invention into specific cells in vivo (e.g., [Al-Muhammed, J. Microencapsul. 13:293-306, 1996]; [Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995]; [Ostro, Am. J. Hosp. Pharm.[See 46:1576-1587, 1989]). The composition of the present invention may also be delivered as nanoparticles.

[0121] "Co-administration" means administering the compositions described herein simultaneously with, immediately before, or immediately after the administration of one or more additional therapies. The compounds of the present invention may be administered to a patient alone or co-administered. Co-administration means administering the compounds individually or in combination (more than one compound or agent) simultaneously or sequentially. The compositions of the present invention may be formulated as applicator sticks, liquids, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols, and may be delivered transdermally by a local route.

[0122] For any of the compounds described herein, the therapeutically effective dose may first be measured by a cell culture assay. The target concentration will be the concentration of the active compound(s) that can achieve the method described herein when measured using the method described herein or a method known in the art.

[0123] As is widely known in the art, the therapeutically effective dose to be used in humans may be determined from animal models. For example, the dose for humans may be formulated to achieve a concentration found to be effective in animals. The dosage in humans may be adjusted by monitoring the effect of the compound and adjusting the dosage up or down, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the methods described above and other methods is within the capability of a person skilled in the art.

[0124] The dosage may vary depending on the patient's requirements and the compound used. In connection with the present invention, the dosage administered to the patient must be sufficient to produce a beneficial therapeutic response over time. The size of the dosage will be determined by the presence, nature, and severity of any adverse effects. Determining the appropriate dosage for a specific situation is within the skill of the practitioner. Generally, treatment is initiated with a small dosage that is less than the optimal dose of the compound. Subsequently, the dosage is increased in small increments until the optimal effect is reached under the given circumstances.

[0125] The dosage and interval can be individually adjusted to provide compounds administered at levels effective for the specific clinical indication being treated. This will provide a therapeutic regimen suitable for the severity of the individual's disease state.

[0126] By utilizing the teachings provided herein, effective prophylactic or therapeutic regimens can be planned that are effective in treating clinical symptoms in specific patients without substantially causing toxicity. Such plans should include the careful selection of an active compound by considering factors such as, for example, compound efficacy, relative bioavailability, patient body weight, the presence and severity of adverse effects, the preferred mode of administration, and the toxicity profile of the selected agent.

[0127] The compounds described herein may be used in combination with other active agents known to be useful for treating infections (e.g., fungal infections).

[0128] In some embodiments, co-administration includes administering one activator within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week, or 1 month of the second activator. Co-administration includes administering two activators simultaneously, nearly simultaneously (e.g., within approximately 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration may be achieved by co-formulation, that is, by preparing a single pharmaceutical composition containing both activators. In other embodiments, the activators may be formulated separately. In yet another embodiment, the activators and / or adjuvants may be linked or conjugated to each other. In some embodiments, the compounds described herein may be combined for the treatment of infections (e.g., fungal infections, bacterial infections, viral infections).

[0129] The compounds described herein may be administered to treat fungal infections or diseases. In this regard, the compounds disclosed herein may be administered alone to treat said infections or diseases, or may be co-administered with another therapeutic agent to treat said infections or diseases.

[0130] The compounds disclosed herein may be co-administered with antifungal agents, such as polyenes, azoles, nucleoside analogs, echinocandins, and allylamines.

[0131] The term “antifungal agent” is used in its general and ordinary sense and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modifier) ​​having antifungal properties or ability to inhibit the growth or proliferation of fungi. In some embodiments, an antifungal agent is an agent identified herein as having utility in a method of treating a fungal infection or disease. In some embodiments, an antifungal agent is an agent approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of a fungal infection or disease. Examples of antifungal agents include, but are not limited to,

[0132] As used herein, “cell” refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells may be identified by methods widely known in the art, including, for example, the presence of an intact membrane, staining by a specific dye, the ability to produce offspring, or, if germ cells, the ability to produce viable offspring in combination with a second germ cell. 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, for example, mammals, insects (e.g., spodoptera), and human cells. Cells may be useful when they are naturally non-adherent or, for example, when treated so as not to adhere to a surface by trypsin treatment.

[0133] "Control group" or "control group experiment" is used in its general and ordinary sense and refers to an experiment in which the subject or reagent of the experiment is treated as in a similar experiment conducted concurrently, except that the method, reagent, or variable of this experiment is omitted. In some cases, the control group is used as a standard of comparison to evaluate the experimental effect. In some embodiments, the control group is a measurement of protein activity in the absence of the compound described herein (including the embodiments and examples).

[0134] The phrase "in an amount sufficient to cause a change" implies the existence of a detectable difference between the level of an indicator measured before (e.g., baseline level) and after the administration of a specific therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., subject's euphoria).

[0135] "Substantially pure" means that the component constitutes more than about 75% of the total content of the composition excluding excipients, and typically more than about 85% of the total content. More typically, "substantially pure" means that the component of interest constitutes at least 90%, at least 95%, at least 96%, or at least 97% of the total composition excluding excipients. In some cases, the component of interest constitutes more than about 90%, more than about 95%, or more than about 96% of the composition excluding excipients (on a weight / weight (%) basis). "Substantially pure" means that the composition contains known or unknown impurities in an amount of less than about 25%, 15%, 10%, 5%, or 4%, up to that amount, or less than or equal to that amount. The impurities do not include excipients (e.g., binders, fillers, diluents, fluidizers, lubricants, disintegrants, etc.).

[0136] I. Composition

[0137] In one aspect, the present invention is a pharmaceutical composition,

[0138] (i) a compound of the following formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and

[0139] (ii) at least one pharmaceutically acceptable excipient

[0140] The present invention provides a pharmaceutical composition comprising, wherein the pharmaceutical composition exists as an oral dosage or administration formulation:

[0141] .

[0142] In another aspect, the present invention, as a pharmaceutical composition,

[0143] (i) a compound of formula (I); or particulates of its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates or hydrates; and

[0144] (ii) at least one pharmaceutically acceptable excipient

[0145] The present invention provides a pharmaceutical composition comprising, wherein the pharmaceutical composition exists as an oral dosage or administration formulation or an inhalation delivery formulation.

[0146] 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, about 10% of the particles have a particle size of about 1 µm to about 750 µm. In some embodiments, 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.

[0147] In some embodiments, the particles are nano-ground. 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 the particles have a particle size of about 1 nm to about 750 nm.

[0148] In some embodiments, the formulation is a self-microemulsifying drug delivery system (SMEDDS). In some embodiments, the formulation is a self-emulsifying drug delivery system (SEDDS). In some embodiments, the formulation is a suspension or a liquid. In some embodiments, the suspension is a colloidal suspension. In some embodiments, the formulation is a nanosuspension. In some embodiments, the formulation is a solid formulation. In some embodiments, the formulation is a spray-dried dispersion formulation. In some embodiments, the formulation is a hot melt granule formulation. In some embodiments, the formulation is a hot melt extrusion formulation. In some embodiments, the formulation is a microprecipitated bulk powder (MBP) formulation. In some embodiments, the formulation is a liquid formulation. In some embodiments, the formulation is a suspension, liquid, syrup, or elixir. In some embodiments, the pharmaceutical composition exists as a formulation for oral administration or treatment.

[0149] In some embodiments, the formulation is a tablet or a capsule. In some embodiments, the tablet or capsule has an enteric coating. In some embodiments, the formulation is a tablet. In some embodiments, the tablet is an osmotic suspension tablet. In some embodiments, the capsule is a liquid-filled hard capsule. In some embodiments, the capsule is a soft gelatin capsule.

[0150] In some embodiments, the formulation is a modified-release formulation. In some embodiments, the modified-release formulation is a delayed-release formulation, an extended-release (ER) formulation, or a targeted-release formulation. In some embodiments, the ER formulation is a sustained-release (SR) formulation or a controlled-release (CR) formulation. In some embodiments, the formulation is an immediate-release formulation.

[0151] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 1,000 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 600 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the compound of formula (I) or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates 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.

[0152] 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 its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0153] 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, or about 500 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0154] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0155] In some embodiments, at least one pharmaceutically acceptable excipient is a filler, a disintegrant, a binder, a fluidizing agent, a lubricant, or any combination thereof. In some embodiments, at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate, colloidal silicon dioxide, or any combination thereof.

[0156] 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.

[0157] 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 its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0158] In one aspect, the present invention is a pharmaceutical composition,

[0159] (i) a compound of formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates or hydrates; and

[0160] (ii) at least one pharmaceutically acceptable excipient

[0161] The present invention provides a pharmaceutical composition comprising, wherein the pharmaceutical composition exists as a formulation for administration or administration by intravenous (IV), intramuscular, subcutaneous, or intradermal injection.

[0162] In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is crystalline, microcrystalline, amorphous, or freeze-dried. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is crystalline. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is amorphous. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is freeze-dried.

[0163] In some embodiments, the formulation is an IV formulation. In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the formulation includes a co-solvent.

[0164] In some embodiments, the cosolvent is PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremophor, glycerin, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert- It includes butanol, or any combination thereof. In some embodiments, the formulation further includes an oil. In some embodiments, the oil includes sesame oil, soybean oil, vegetable oil, poppy seed oil, safflower oil, or a combination thereof.

[0165] In some embodiments, the formulation further comprises a buffer. In some embodiments, the IV formulation further comprises a buffer. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the phosphate buffer is potassium phosphate. In some embodiments, the potassium phosphate is monobasic or dibasic.

[0166] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 6.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 5.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 5.0. In some embodiments of the pharmaceutical composition, the formulation is I.V. It is a formulation, and the pH is about 2.5 to about 4.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 4.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 3.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 2.5 to about 3.0.

[0167] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 6.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 5.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 5.0. In some embodiments of the pharmaceutical composition, the formulation is I.V. It is a formulation, and the pH is about 3.0 to about 4.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 4.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.0 to about 3.5.

[0168] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 6.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 5.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 5.0. In some embodiments of the pharmaceutical composition, the formulation is I.V. is a formulation, and the pH is about 3.5 to about 4.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 3.5 to about 4.0.

[0169] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 6.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 5.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.0 to about 5.0. In some embodiments of the pharmaceutical composition, the formulation is I.V. It is a formulation, and the pH is about 4.0 to about 4.5.

[0170] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 6.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 5.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 4.5 to about 5.0.

[0171] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 6.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.0 to about 5.5.

[0172] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 5.5 to about 6.0.

[0173] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.0 to about 6.5.

[0174] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 6.5 to about 7.0.

[0175] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.0 to about 7.5.

[0176] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.5 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.5 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.5 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.5 to about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.5 to about 8.0.

[0177] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.0 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.0 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.0 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.0 to about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.0 to about 8.5.

[0178] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.5 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.5 to about 9.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 8.5 to about 9.0.

[0179] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.0 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.0 to about 10.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.0 to about 9.5.

[0180] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.5 to about 10.0.

[0181] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 10.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation.

[0182] In some embodiments of the pharmaceutical composition disclosed herein, the formulation is an IV (i.e., infusion) formulation. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 10.5 to about 11.0.

[0183] In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 2.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 3.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 3.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 4.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 4.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 5.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 5.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.1. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.2. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.3. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.4. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.6. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.6. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.8. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 6.9. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.1. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.2. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 7.3.In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.4. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.6. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.7. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.8. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 7.9. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.1. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.2. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.3. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.4. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.6. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.7. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.8. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 8.9. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.1. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.2. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.3. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation, and the pH is about 9.4.In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.6. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.9. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.8. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 9.9. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.0. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.1. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.2. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.3. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.4. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.5. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.6. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.7. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.8. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 10.9. In some embodiments of the pharmaceutical composition, the formulation is an IV formulation and the pH is about 11.0.

[0184] In some embodiments, the pharmaceutical composition is for intravenous administration and is formulated to have a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is for intravenous administration and is formulated to have a pH of about 2.5 to about 5.0 or about 2.5 to about 5.0. In some embodiments, the pharmaceutical composition is for intravenous administration and is formulated to have 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.

[0185] In some embodiments, the pharmaceutical composition comprises about 5 mg / mL to about 250 mg / mL of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the pharmaceutical composition comprises about 10 mg / mL to about 50 mg / mL of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate.

[0186] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 40 mg / mL of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the pharmaceutical composition comprises about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0187] In some embodiments, the pharmaceutical composition is stable for up to about 24 months at a temperature of about -20°C to 8°C. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to about 24 months at a temperature of about -20°C. In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0188] In some embodiments, the pharmaceutical composition is stable for up to about 24 months at a temperature of about -20°C to 8°C when stored as a liquid formulation. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to about 24 months at a temperature of about -20°C when stored as a liquid formulation. 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 about 24 months at a temperature of about -20°C to 8°C when stored as a liquid formulation in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to about 24 months at a temperature of about -20°C when stored as a liquid formulation in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable for up to about 24 months at a temperature of about -20°C to 8°C when stored as a liquid formulation with 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 about 24 months at a temperature of about -20°C when stored as a liquid formulation with a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is stable for up to about 24 months at a temperature of about -20°C to 8°C when stored as a liquid formulation with a pH of about 2.5 to about 11.0 in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable for a period of about 12 to about 24 months at a temperature of about -20°C when stored as a liquid formulation with a pH of about 2.5 to about 11.0 in a pH-insensitive container.

[0189] In certain embodiments, for the treatment, prevention, or improvement of one or more symptoms of the disorder, disease, or condition described herein, appropriate dosage levels of the compound of formula (I), or its isotope variant; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug are 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, which may be administered as a single or multiple dose. In certain embodiments, the compound of formula (I), or its isotope variant; Or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs are 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, It is administered in amounts of 6,000, 6,500, 7,000, 7,500, or 8,000 mg.In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 10 mg, about 2,000 mg, about 600 mg, or about 2,000 mg. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 600 mg. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 700 mg. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 800 mg. In certain embodiments, the compound of formula (I), or its isotope variant; Or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 900 mg. In certain embodiments, a compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 1,000 mg. In certain embodiments, a compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 2,000 mg.In certain embodiments, a compound of formula (I), or its isotope variant; Or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs are 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, It is administered in amounts of 6,000, 6,500, 7,000, 7,500, or 8,000 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 10 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 15 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 20 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 25 mg / day.In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 30 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 35 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 40 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 45 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; Or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 50 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 100 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 150 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 200 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 300 mg / day. In certain embodiments, a compound of formula (I), or its isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 400 mg / day.In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 500 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 600 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 700 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 800 mg / day. In certain embodiments, the compound of formula (I), or its isotope variant; Or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 900 mg / day. In certain embodiments, a compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 1,000 mg / day. In certain embodiments, a compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered in an amount of about 2,000 mg / day.

[0190] For oral administration, the pharmaceutical composition provided herein comprises, for symptomatic adjustment of the dosage to the patient to be treated, 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 isotope variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, in one embodiment, 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 isotope variant thereof; Alternatively, it may be formulated into a solid formulation containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0191] In the case of oral administration, the pharmaceutical composition provided herein is 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, It may be formulated into a solid formulation containing 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 of a compound of formula (I) or its isotope variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the solid formulation is a tablet. In some embodiments, the solid formulation is a capsule. In some embodiments, the solid formulation is a powder. In some embodiments, the solid formulation is a granule.

[0192] In some embodiments, the pharmaceutical composition provided herein may be formulated into a solid formulation containing about 50 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a solid formulation containing about 100 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a solid formulation containing about 150 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a solid formulation containing about 200 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a solid formulation containing about 250 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a solid formulation containing about 300 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a solid formulation containing about 400 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0193] For oral administration, the pharmaceutical composition provided herein comprises, for symptomatic adjustment of the dosage to the patient to be treated, 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 isotope variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, in one embodiment, 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 isotope variant thereof; Alternatively, it may be formulated in the form of tablets containing pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[0194] For oral administration, the pharmaceutical composition provided herein comprises 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, or 1,500 mg of a compound of formula (I) or its isotope variants; or may be formulated in the form of tablets containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0195] In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 50 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 100 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 150 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 200 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 250 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 300 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 400 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0196] For oral administration, the pharmaceutical composition provided herein comprises, for symptomatic adjustment of the dosage to the patient to be treated, 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 isotope variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, in one embodiment, 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 isotope variant thereof; Alternatively, it may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0197] In the case of oral administration, the pharmaceutical composition provided herein is 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, or 1,500 mg of a compound of formula (I) or its isotope variants; or may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0198] In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing about 50 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing about 100 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing about 150 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing about 200 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing about 250 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing about 300 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a liquid preparation (e.g., liquid, suspension, or syrup) containing about 400 mg of a compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0199] In some embodiments, the pharmaceutical composition provided herein comprises, for symptomatic adjustment of the dosage to a patient to be treated, 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 isotope variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug, in one embodiment, 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 isotope variant thereof; Alternatively, it may be formulated into a liquid formulation (e.g., IV) containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0200] In the case of oral administration, the pharmaceutical composition provided herein is 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, or 1,500 mg of a compound of formula (I) or its isotope variants; or may be formulated into a liquid formulation (e.g., IV) containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0201] In some embodiments, the pharmaceutical composition provided herein may be formulated into a liquid formulation (e.g., IV) containing about 50 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a liquid formulation (e.g., IV) containing about 100 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a liquid formulation (e.g., IV) containing about 150 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into about 200 mg of the compound of formula (I) or its isotope variant; Alternatively, it may be formulated into a liquid formulation (e.g., IV) containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a liquid formulation (e.g., IV) containing about 250 mg of the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a liquid formulation (e.g., IV) containing about 300 mg of the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated into a liquid formulation (e.g., IV) containing about 400 mg of the compound of formula (I), or its isotope variant; Alternatively, it may be formulated into a liquid formulation (e.g., IV) containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0202] The pharmaceutical composition may be administered in a regimen of 1 to 4 doses per day, including once, twice, three, and four times per day. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice per day for one day, followed by an amount of 600 mg once daily for the duration of treatment. In other embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice per day for one day, followed by an amount of 800 mg once daily for the duration of treatment.

[0203] In another embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for one day, followed by an amount of 900 mg once daily for the duration of treatment. In another embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for one day, followed by an amount of 1,000 mg once daily for the duration of treatment.

[0204] In a specific embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 2 days, followed by an amount of 600 mg once daily during the duration of treatment. In another embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 2 days, followed by an amount of 800 mg once daily during the duration of treatment. In another embodiment, the compound of formula (I), or its isotope variant; Or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 2 days, followed by an amount of 900 mg once daily during the duration of treatment. In another embodiment, a compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 2 days, followed by an amount of 1,000 mg once daily during the duration of treatment.

[0205] In a specific embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 3 days, followed by an amount of 600 mg once daily during the duration of treatment. In another embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 3 days, followed by an amount of 800 mg once daily during the duration of treatment. In another embodiment, the compound of formula (I), or its isotope variant; Or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 3 days, followed by an amount of 900 mg once daily during the duration of treatment. In another embodiment, a compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 3 days, followed by an amount of 1,000 mg once daily during the duration of treatment.

[0206] In a specific embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 4 days, followed by an amount of 600 mg once daily during the duration of treatment. In another embodiment, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 4 days, followed by an amount of 800 mg once daily during the duration of treatment. In another embodiment, the compound of formula (I), or its isotope variant; Or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 4 days, followed by an amount of 900 mg once daily during the duration of treatment. In another embodiment, a compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered to a patient requiring it in an amount of about 1,000 mg twice daily for 4 days, followed by an amount of 1,000 mg once daily during the duration of treatment.

[0207] In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered once daily in an amount of about 1,000 mg to a patient requiring it. In certain embodiments, the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug is administered daily to a patient requiring it in 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 intolerance toxicity is achieved.

[0208] In another aspect, the present invention is a combination composition,

[0209] (i) a compound of formula (I); or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates or hydrates; and

[0210] (ii) at least one antifungal agent

[0211] A combination composition comprising

[0212] In some embodiments, at least one antifungal agent is an azole, an echinocandin, amphotericin B deoxycholate, amphotericin B cocliate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, ivlexafungup, orotomide F901318, or a combination thereof. In some embodiments, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavukonazole, or miconazole. In some embodiments, the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin.

[0213] In one aspect, the present invention is a combination composition,

[0214] (i) a compound of the following formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and

[0215] (ii) Compounds of the following formula (II), or isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates thereof

[0216] A combination composition comprising:

[0217]

[0218] .

[0219] In some embodiments, the combination composition further comprises at least one pharmaceutically acceptable excipient.

[0220] In some embodiments, the compound of formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates and the compound of formula (II), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are both crystalline.

[0221] In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, are present in a ratio of about 10:1. In some embodiments, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, 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 variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate 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 variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate are present in a ratio 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.

[0222] In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 100:0.01 to about 0.01:100. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 100:0.01. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 100:0.1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 100:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I), or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 100:1.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 80:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 70:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 60:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 50:1. In certain embodiments, the ratio of the compound of formula (II) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 40:1.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 30:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 9:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 8:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 7:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 6:1.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 5:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 4:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 3:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 2:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1.5:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:1.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:1.5. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:2. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:3. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:4. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:5. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:6.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:7. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:8. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:9. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:20. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:30.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:40. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:50. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:60. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:70. In certain embodiments, the ratio of the compound of formula (II) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:80.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:90. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:100. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.1:100. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.01:100.

[0223] In certain embodiments, the ratio of the compound of Formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, to the ratio of the compound of Formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof 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, 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 about 0.01:100. In certain embodiments, the ratio of the compound of Formula (II), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates thereof, to the compound of Formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates thereof 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, 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 about 0.01:100.

[0224] In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.1 to about 0.1:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.2. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.3. In certain embodiments, the ratio of the compound of formula (II) or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I) or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.4.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.5. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.6. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.7. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.8. In certain embodiments, the ratio of the compound of formula (II), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:0.9.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 10:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 9:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 8:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 7:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 6:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 5:1.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 4:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 3:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 2:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1.5:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:1.5.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:2. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:2. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:3. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:4. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:5. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:6.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:7. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:8. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:9. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.9:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.The ratio is 8:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.7:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.6:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.5:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.4:10. In certain embodiments, the ratio of the compound of formula (II) or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I) or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.3:10.In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.2:10. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.1:10. In certain embodiments, the ratio of the compound of formula (II) or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I) or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 0.01:10.

[0225] In certain embodiments, the ratio of the compound of Formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, to the ratio of the compound of Formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof 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 about 0.1:10. In certain embodiments, the ratio of the compound of Formula (II), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, to the compound of Formula (I), or its isotopic isomorphs, 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 about 0.1:10.

[0226] In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 5:1 to about 1:5. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 5:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 4:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 3:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 2:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1.The ratio is 5:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:1. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:1.5. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:2. In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:3. In certain embodiments, the ratio of the compound of formula (II) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:4.In certain embodiments, the ratio of the compound of formula (II) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I) or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate in the pharmaceutical composition is about 1:5.

[0227] In certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate 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 certain embodiments, the ratio of the compound of formula (II), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate to the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate 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.

[0228] In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, is substantially pure. In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, is substantially free of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means that the impurity content is less than about 10.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means that the impurity content is less than about 9.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means that the impurity content is less than about 8.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 7.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 6.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 5.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 4.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is about 3.It means less than 8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 3.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is about 2.It means less than 7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 2.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is about 1.It means less than 6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 1.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is about 0.It means less than 5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means that the impurity content is less than about 0.05% (w / w).

[0229] In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, is substantially free of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means at most about 10.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means at most about 9.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means at most about 8.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means at most about 7.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means at most about 6.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, being substantially free of impurities means at most about 5.0%. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 4.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.6% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 3.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.It means 3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 2.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.1% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 1.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.1%. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities means up to about 0.05% (w / w).

[0230] In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 90% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 91% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 92% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 93% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 94% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 95% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 96% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 97% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 98% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is at least about 99% pure. In some embodiments of the pharmaceutical composition disclosed herein, 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% pure.

[0231] In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 90% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 91% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 92% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 93% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 94% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 95% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 96% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 97% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 98% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is up to about 99% pure. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition 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% pure.

[0232] In some embodiments of the pharmaceutical composition disclosed herein, the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate comprises at least one impurity of less than about 10%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 9%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 8%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 7%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 6%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 5%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 4%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 3%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 2%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 1%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.9%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.8%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.7%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.6%.In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.5%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.4%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.3%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.2%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of less than about 0.1%.

[0233] In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 10%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 9%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 8%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 7%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 6%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 5%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 4%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 3%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 2%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 1%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 0.9%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 0.8%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 0.7%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 0.6%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises at least one impurity of up to about 0.5%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition comprises up to about 0.It contains at least one impurity of 4%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.3%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.2%. In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition contains at least one impurity of up to about 0.1%.

[0234] In some embodiments, the pharmaceutical composition contains substantially no impurities. In some embodiments, the pharmaceutical composition is at least about 90% pure. In some embodiments, the pharmaceutical composition is at least about 95% pure. In some embodiments, the pharmaceutical composition is at least about 96% pure. In some embodiments, the pharmaceutical composition is at least about 97% pure. In some embodiments, the pharmaceutical composition is at least about 98% pure. In some embodiments, the pharmaceutical composition is at least about 99% pure. In some embodiments, 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% pure. In some embodiments, the pharmaceutical composition contains at least one impurity up to about 10% (w / w). In some embodiments, the pharmaceutical composition comprises at least one impurity of 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 less than about 1% (w / w). In some embodiments, the pharmaceutical composition comprises at least one impurity of about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or less than about 1% (w / w). In some embodiments, the pharmaceutical composition comprises at least 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 less than about 0.1% (w / w).

[0235] In some embodiments, at least one impurity is a decomposition product. In some embodiments, at least one impurity is

[0236] , or any combination thereof.

[0237] In some embodiments, at least one impurity is am.

[0238] 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 impurities. In some embodiments, the pharmaceutical composition contains up to about 1.5% (w / w) of the following compounds:

[0239] .

[0240] In some embodiments, impurities in the pharmaceutical compositions disclosed herein are am.

[0241] The compound of Formula (I) of the present disclosure, or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, may be in the form of a composition suitable for administration to a subject. Generally, said composition is a “pharmaceutical composition” comprising the compound of Formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients. In certain embodiments, the compound of Formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, is present in therapeutically acceptable amounts. The pharmaceutical composition may be used in the methods of the present invention; thus, for example, the pharmaceutical composition may be administered to a subject in vitro or in vivo to carry out the therapeutic and prophylactic methods and uses disclosed herein.

[0242] The pharmaceutical composition of the present invention may be formulated to be compatible with an intended method or route of administration; exemplary routes of administration are described herein.

[0243] A pharmaceutical composition containing a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates may be in a form suitable for oral administration, e.g., tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, liquids, micro beads, or elixirs. A pharmaceutical composition intended for oral administration may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and said composition may contain one or more agents, e.g., sweeteners, flavorings, colorings, and preservatives, to provide a pharmaceutically excellent and palatable formulation. Tablets, capsules, etc. may contain the active ingredient by mixing with non-toxic, pharmaceutically acceptable excipients suitable for the preparation of tablets and capsules. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulizing agents and disintegrants, such as corn starch, or alginic acid; binders, such as starch, gelatin, or acacia; and lubricants, such as magnesium stearate, stearic acid, or talc.

[0244] Tablets, capsules, etc. suitable for oral administration may not be coated, or may be coated using known methods to delay disintegration in the gastrointestinal tract and sustain action. For example, time-delaying agents, such as glyceryl monostearate or glyceryl distearate, may be used. These may also be coated by techniques known in the art to form controlled-release osmotic therapeutic tablets. Additional agents include biodegradable or biocompatible particles or polymeric materials to control the delivery of the administered composition, such as polyesters, polyamine acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acids, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfates, or lactide / glycolide copolymers, polylactide / glycolide copolymers, or ethylene vinyl acetate copolymers. For example, oral agents may be captured in microcapsules prepared by interfacial polymerization, or by coacervation technology using hydroxymethylcellulose or gelatin-microcapsules or poly(methyl methacrolate), or in colloidal drug delivery systems. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the aforementioned formulations will be obvious to those skilled in the art.

[0245] Oral formulations may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, e.g., peanut oil, liquid paraffin, or olive oil.

[0246] An aqueous suspension contains an active substance mixed with an excipient suitable for its manufacture. The excipient is a suspending agent, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth gum, and acacia gum; A dispersant or wetting agent may be, for example, a naturally occurring phosphatid (e.g., lecithin), or a condensation product of an alkylene oxide and a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol anhydride (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives.

[0247] Oily suspensions can be formulated by suspending an active ingredient in vegetable oils, e.g., peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils, e.g., liquid paraffin. Oily suspensions may contain thickeners, e.g., beeswax, hard paraffin, or cetyl alcohol. Sweeteners, e.g., those described above, and flavoring agents may be added to provide a palatable oral formulation.

[0248] Dispersible powders and granules suitable for the preparation of aqueous suspensions by water addition provide an active ingredient by mixing with a dispersing agent or a wetting agent, and optionally one or more suspending agents and / or preservatives. Suitable dispersing agents or wetting agents and suspending agents are exemplified herein.

[0249] The pharmaceutical composition of the present invention may also exist in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, e.g., olive oil or peanut oil, or a mineral oil, e.g., liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, e.g., acacia gum or tragacanth gum; naturally occurring phosphatides, e.g., esters or partial esters derived from soybeans, lecithin, and fatty acids; hexitol anhydrides, e.g., sorbitol monooleate; and condensation products of partial esters and ethylene oxide, e.g., polyoxyethylene sorbitol monooleate.

[0250] The pharmaceutical composition typically comprises a therapeutically effective amount of a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates; and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable 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, methyl paraben, ethyl or n-propyl, p-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, bulking agents, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be physiological saline or citrate-buffered saline, possibly supplemented with other substances common to the pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin is an additional exemplary vehicle. Those skilled in the art will readily recognize the various buffers that may be used in the pharmaceutical compositions and formulations considered herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer component may be a water-soluble substance, e.g., phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof (e.g., potassium phosphate monobasic, potassium phosphate dibasic, etc.). Acceptable buffers include, for example, Tris buffer; N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-morpholino)ethanesulfonic acid (MES); Sodium 2-(N-morpholino)ethanesulfonate salt (MES); 3-(N-morpholino)propanesulfonic acid (MOPS); and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS), potassium phosphate monobasic, and potassium phosphate dibasic.

[0251] After the pharmaceutical composition is formulated, it may be stored in sterile vials as a liquid, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. The formulation may be stored in a form ready for immediate use, a lyophilized form that must be reconstituted before use, a liquid form that must be diluted 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 auto-injector (e.g., similar to EpiPen®), whereas in other embodiments, a multi-use container (e.g., a multi-use vial) is provided.

[0252] The formulation may also include a carrier to protect the composition from rapid degradation or removal from the body, such as in controlled-release formulations including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time-delaying agent, such as glyceryl monostearate or glyceryl stearate, may be used alone or in combination with wax. Any drug delivery device may be used to deliver the compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, including implants (e.g., implantable pumps) and catheter systems, low-speed injection pumps and devices (all of which are widely known to those skilled in the art).

[0253] Depot injections, generally administered subcutaneously or intramuscularly, may also be used to release the compounds disclosed herein (e.g., compounds of formula (I), or their isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates) over a defined period. Depot injections are generally solid or oil-based and generally contain at least one of the formulation components described herein. Those skilled in the art are well aware of the possible formulations and uses of depot injections.

[0254] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. The suspension may be formulated according to the art using suitable dispersants or wetting agents and suspending agents mentioned herein. The sterile injectable formulation may also be a sterile injectable liquid or suspension in a non-toxic, orally acceptable diluent or solvent, e.g., a liquid in 1,3-butanediol. Acceptable diluents, solvents that may be used, and dispersion media include water, Ringer's solution, isotonic sodium chloride solution, and Cremophor. ® It comprises EL (BASF, Parsippany, NJ, USA) or phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile fixatives are typically used as a solvent or suspension medium; for this purpose, any non-irritating fixative, including synthetic mono or diglycerides, may be used. Additionally, fatty acids, e.g., oleic acid, may be used in the preparation of the injectable solution. Long-term absorption of a specific injectable formulation may be achieved by including an absorption-delaying agent (e.g., aluminum monostearate or gelatin).

[0255] The present invention is considered to be administered a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates in the form of suppositories for rectal administration. The suppositories may be prepared by mixing the drug with a suitable non-irritating pharmaceutical excipient, which is solid at normal temperatures but liquid at rectal temperatures, thereby melting at the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0256] The compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates may exist in any other suitable pharmaceutical composition form (e.g., nasal or inhalation sprays) that is currently known or will be developed in the future.

[0257] II. How to Use

[0258] In one aspect, the present invention provides a method for treating and / or preventing a fungal infection or disease, comprising the step of administering a therapeutically effective amount of any of the pharmaceutical compositions or combination compositions described herein to a subject who requires treatment and / or prevention of a fungal infection or disease.

[0259] In one aspect, the present invention provides a method for treating and / or preventing a fungal infection or disease, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition to a subject requiring treatment and / or prevention of a fungal infection or disease, the pharmaceutical composition comprising: (i) a compound of formula (I), or its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition exists as an oral medication or a dosage form for administration.

[0260] In another aspect, the present invention provides a method for treating and / or preventing a fungal infection or disease, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition to a subject requiring treatment and / or prevention of a fungal infection or disease, the pharmaceutical composition comprising: (i) a particulate of a compound of formula (I), or its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is present as an oral or inhalation delivery formulation.

[0261] In some embodiments of the method provided herein, the formulation is a self-microemulsifying drug delivery system (SMEDDS). In some embodiments of the method provided herein, the formulation is a self-emulsifying drug delivery system (SEDDS). In some embodiments of the method provided herein, the formulation is a suspension or a liquid. In some embodiments of the method provided herein, the formulation is a nanosuspension. In some embodiments of the method provided herein, the formulation is a solid formulation. In some embodiments of the method provided herein, the formulation is a spray-dried dispersion formulation. In some embodiments of the method provided herein, the formulation is a hot melt granule formulation. In some embodiments of the method provided herein, the formulation is a hot melt extrusion formulation. In some embodiments of the method provided herein, the formulation is a microprecipitated bulk powder (MBP) formulation. In some embodiments of the method provided herein, the formulation is a liquid formulation. In some embodiments of the method provided herein, the formulation is a suspension, a liquid, a syrup, or an elixir. In some embodiments of the method provided herein, the pharmaceutical composition exists as a formulation for oral administration or treatment.

[0262] In some embodiments of the method described herein, the formulation is a tablet or a capsule. In some embodiments of the method described herein, the tablet or capsule has an enteric coating. In some embodiments of the method described herein, the formulation is a tablet. In some embodiments of the method described herein, the tablet is an osmotic suspension tablet. In some embodiments of the method described herein, the capsule is a liquid-filled hard capsule. In some embodiments of the method described herein, the capsule is a soft gelatin capsule.

[0263] In some embodiments of the method described herein, the formulation is a modified-release formulation. In some embodiments of the method described herein, the modified-release formulation is a delayed-release formulation, an extended-release (ER) formulation, or a targeted-release formulation. In some embodiments of the method described herein, the ER formulation is a sustained-release (SR) formulation or a controlled-release (CR) formulation. In some embodiments of the method described herein, the formulation is an immediate-release formulation.

[0264] In one aspect, the present invention provides a method for treating and / or preventing a fungal infection or disease, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition to a subject requiring treatment and / or prevention of a fungal infection or disease, the pharmaceutical composition comprising: (i) a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is present in a formulation for administration or administration by intravenous (IV), intramuscular, subcutaneous, or intradermal injection. In some embodiments of the method described herein, the formulation is an IV formulation.

[0265] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of about 20 minutes, about 30 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours.

[0266] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of up to about 1 hour. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of up to about 2 hours. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of up to about 3 hours.

[0267] In another aspect, the present invention provides a method for treating a fungal infection or disease, comprising the step of administering to a subject requiring treatment for a fungal infection or disease a therapeutically effective amount of (i) a compound of formula (I), or its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate; and (ii) a combination composition comprising at least one antifungal agent.

[0268] In one aspect, the present invention provides a method for treating and / or preventing fungal infections or diseases, wherein a therapeutically effective amount is administered to a subject requiring treatment and / or prevention of a fungal infection or disease.

[0269] (i) a compound of the following formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and

[0270] (ii) Compounds of the following formula (II), or isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates thereof

[0271] A method is provided comprising the step of administering a combination composition including:

[0272]

[0273] .

[0274] In some embodiments of the method described herein, the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is crystalline, microcrystalline, amorphous, or freeze-dried. In some embodiments of the method described herein, the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is crystalline. In some embodiments of the method described herein, the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is amorphous. In some embodiments of the method described herein, the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is freeze-dried.

[0275] In some embodiments of the method provided herein, about 10 mg to about 8,000 mg of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, about 10 mg to about 2,400 mg of the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, a compound of formula (I) of 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, or its Isotope dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to the subject.

[0276] In some embodiments of the method provided herein, 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 dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject. In some embodiments of the method provided herein, 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 dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject.

[0277] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject daily. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject once a day, twice a day, three times a day, or four times a day. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject once a day. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject twice a day.

[0278] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of up to about 12 weeks. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of at least 1 week. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of at least 2 weeks. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of up to about 2 weeks. In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject for a period of 1 week, 2 weeks, 6 weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks.

[0279] In some embodiments of the method provided herein, about 10 mg to about 8,000 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered to a subject. In some embodiments of the method provided herein, 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 dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject.

[0280] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of about 20 minutes, about 30 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours.

[0281] In some embodiments of the method provided herein, the pharmaceutical composition is administered to a subject by IV infusion over a period of up to about 3 hours.

[0282] In some embodiments of the method provided herein, a loading dose is administered to a subject, followed by the administration of a maintenance dose. In some embodiments of the method provided herein, the loading dose comprises about 1,000 mg to about 8,000 mg of the compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg to about 2,400 mg of the compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the loading dose comprises about 1,000 mg to about 2,000 mg. In some embodiments of the method provided herein, the loading dose is administered by IV infusion over a period of about 2 to about 3 hours. In some embodiments of the method provided herein, the loading dose is administered twice on the first day of treatment. In some embodiments of the method provided herein, a second loading dose is administered about 9 hours after the first loading dose.

[0283] In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the maintenance dose comprises about 800 mg or about 1,000 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, which are administered to a subject. In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg or about 900 mg of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and is administered orally.

[0284] In some embodiments of the method provided herein, a maintenance dose of about 600 mg or about 900 mg of a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered by IV infusion over a period of about 1 hour to about 3 hours.

[0285] In some embodiments of the method provided herein, any one of embodiments 157-164, wherein about 600 mg of a compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates is administered by IV infusion over a period of about 3 hours.

[0286] In some embodiments of the method provided herein, the maintenance dose is administered once daily.

[0287] In some embodiments of the method provided herein, the maintenance dose is administered once daily, starting on the second day of treatment.

[0288] In some embodiments of the method provided herein, about 600 mg or about 800 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates or hydrates, is administered by IV infusion over a period of about 3 hours, starting on the second, third, or fourth day of treatment.

[0289] In some embodiments of the method provided herein, about 800 mg or about 1,000 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates or hydrates, is administered orally starting on the second, third, or fourth day of treatment.

[0290] In some embodiments of the method provided herein, the maintenance dose comprises about 600 mg or about 800 mg of the compound of formula (I), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the method provided herein, about 600 mg of the compound of formula (I), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, about 800 mg of the compound of formula (I), or its isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. In some embodiments of the method provided herein, about 600 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of about 1 hour to about 3 hours and / or about 800 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered orally. In some embodiments of the method provided herein, the maintenance dose is administered once daily. In some embodiments of the method provided herein, the maintenance dose is administered once daily starting on the second day of treatment. In some embodiments of the method provided herein, about 600 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of about 3 hours.

[0291] In some embodiments of the method provided herein, about 600 mg of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered by IV infusion over a period of about 3 hours, starting on the second day of treatment.

[0292] In some embodiments of the method provided herein, about 800 mg of a compound of formula (I), or its isotopic isoforms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates is administered orally starting on the fourth day of treatment.

[0293] In some embodiments of the method provided herein, the fungal infection is caused by an invasive fungus. In some embodiments of the method provided herein, the method further comprises the step of administering to a subject at least one antifungal agent in combination with a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the method provided herein, at least one antifungal agent is an azole, an echinocandin, amphotericin B deoxycholate, amphotericin B cocliate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, Ibrexafungup, orotomide F901318, or a combination thereof. In some embodiments of the method provided herein, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavuconazole, or miconazole. In some embodiments of the method provided herein, the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin, or a combination thereof.

[0294] In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; and an antifungal agent are administered simultaneously, nearly simultaneously, or sequentially in any order. In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; and an antifungal agent are administered simultaneously or nearly simultaneously. In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; and an antifungal agent are administered sequentially. In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate; and an antifungal agent is administered prior to at least one antifungal agent. In some embodiments of the method provided herein, a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate; or its pharmaceutically acceptable salt is administered after at least one antifungal agent.

[0295] In some embodiments of the method provided herein, the fungal infection or disease is caused by Aspergillus fumigatus, Blastomyces, Azelomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Rhizopus, Mucor, Cunninghamela, Apophysomyces, Absidia, Saxenaea, Entomoptora, Conidiobolus, Basidiobolus, Sporotrix, Pneumocystis, Thalaromyces, Asclepias, Fusarium, Sedosporium fungi, or fungi from the Mucorales order, or any combination thereof. In some embodiments of the method provided herein, the fungal infection or disease is caused by Cryptococcus, Aspergillus, Candida, Fusarium, Sedosporium fungi, or fungi from the Mucorales order, or any combination thereof. In some embodiments of the method provided herein, the fungal infection or disease is Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatidis, Azelomyces dermatitidis, Candida albicans, Candida glabrata, Candida rugosa, Candida auris, Coccidioides imitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gatiii, Histoplasma capsulatum, Rhizopus stolonifera, Rhizopus arijus, Mycordicus, Cunninghamela bertoletiae, Apophaesomyces elegans, Absidia species, Saxenaea species, Rhizomucor fusillus, Entomoptora species, Conidiobolus species, Basidiobolus species, Sporotrix schönkiii, Pneumocystis It is caused by *Girobesi*, *Thalaromyces marnephei*, *Asclepias albicans*, *Fusarium solani*, *Sedosporium apiospermum*, *Rhyzomucor fusillus*, or any combination thereof. In some embodiments of the method provided herein, the fungal infection or disease is caused by Cryptococcus fungi or Candida fungi. In some embodiments of the method provided herein, the fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gatii, or Candida auris.

[0296] In some embodiments of the method provided herein, the fungal infection or disease has azole resistance and / or echinocandin resistance.

[0297] In some embodiments of the method provided herein, the subject is immunocompromised. In some embodiments of the method provided herein, the subject is infected with HIV / AIDS or has cancer. In some embodiments of the method provided herein, the subject has cancer. In some embodiments of the method provided herein, the cancer is acute myeloid leukemia (AML). In some embodiments of the method provided herein, the subject has neutropenia. In some embodiments of the method provided herein, the subject is receiving or has received cancer chemotherapy. In some embodiments of the method provided herein, the subject is receiving or has received corticosteroid treatment. In some embodiments of the method provided herein, the subject is receiving or has received TNF inhibitor treatment. In some embodiments of the method provided herein, the subject is a transplant recipient. In some embodiments of the method described herein, the compound of formula (I), or its isotopic isomorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to the subject in combination with posaconazole.

[0298] In some embodiments of the method described herein, a compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject for the prevention of a fungal infection or disease. In some embodiments of the method described herein, a compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject for the treatment of an existing fungal infection or disease.

[0299] In some embodiments of the method provided herein, a fungal infection or disease is present in the bloodstream of the subject. In some embodiments of the method provided herein, the subject has a reduced fungal colony count in the lungs after administration of the pharmaceutical composition. In some embodiments of the method provided herein, the plasma concentration versus time curve of the compound of formula (I) in the subject is less than t, from about 30 minutes to about 180 minutes. max ... has. In some embodiments of the method provided herein, the subject has a maximum plasma concentration (C) of a compound of formula (I) of about 12,000 ng / mL to about 25,000 ng / mL. max has ).

[0300] dosage

[0301] In some embodiments, the compound of formula (I) described herein, or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and pharmaceutical compositions are provided at the maximum tolerated dose (MTD) for the compound of formula (I). In other embodiments, the dosage of the compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and pharmaceutical compositions is about 10% to about 90% of the maximum tolerated dose (MTD), about 25% to about 75% of the MTD, or about 50% of the MTD. In some other embodiments, the dosage of the compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates of 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 more of the MTD for the compound of formula (I), or any range derivable from these values.

[0302] In certain embodiments, for the treatment, prevention, or improvement of one or more symptoms of the disorder, disease, or disorder (e.g., fungal infection or disease) described herein, appropriate dosage levels of the compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates are 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 to about 350 mg, about 350 to about 450 mg, about The range is 450 to about 550 mg, about 550 to about 650 mg, about 650 to about 750 mg, and about 750 to about 850 mg, and can be administered as a single or multiple dose. In certain embodiments, the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates or hydrates, is 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 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, approximately 165 mg, approximately 170 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, approximately 200 mg, approximately 205 mg, approximately 210 mg, approximately 215 mg,Approx. 220 mg, Approx. 225 mg, Approx. 230 mg, Approx. 240 mg, Approx. 250 mg, Approx. 260 mg, Approx. 270 mg, Approx. 275 mg, Approx. 280 mg, Approx. 290 mg, Approx. 300 mg, Approx. 310 mg, Approx. 320 mg, Approx. 330 mg, Approx. 340 mg, Approx. 350 mg, Approx. 360 mg, Approx. 370 mg, Approx. 380 mg, Approx. 390 mg, Approx. 400 mg, 410 mg, Approx. 420 mg, Approx. 430 mg, Approx. 440 mg, Approx. 450 mg, Approx. 460 mg, Approx. 470 mg, Approx. 480 mg, Approx. 490 mg, Approx. 500 mg, Approx. 510 mg, Approx. 520 mg, Approx. 530 mg, Approx. 540 mg, Approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 580 mg, approx. 590 mg, approx. 600 mg, approx. 610 mg, approx. 620 mg, approx. 630 mg, approx. 640 mg, approx. 650 mg, approx. 660 mg, approx. 670 mg, approx. 680 mg, approx. 690 mg, approx. 700 mg, 710 mg, approx. 720 mg, approx. 730 mg, approx. 740 mg, approx. 750 mg, approx. 760 mg, approx. 770 mg, approx. 780 mg, approx. 790 mg, approx. 800 mg, approx. 810 mg, approx. 820 mg, approx. 830 mg, approx. 840 mg, approx. 850 mg, approx. 860 mg, approx. 870 mg, approx. 880 mg, approx. 890 mg, approx. 900 mg, 910 mg, approx. 920 mg, approx. 930 mg, approx. 940 mg, approx. 950 mg, approx. 960 mg, approx. 970 mg, approx. 980 mg, approx. 990 mg, approx. 1,000 mg, approx. 1,100 mg, approx. 1,200 mg, approx. 1,300 mg, approx. 1,400 mg, approx. 1,500 mg, approx. 1,600 mg, approx. 1,700 mg, approx. 1,800 mg, approx. 1,900 mg, approx. 2,000 mg, approx. 2,100 mg, approx. 2,200 mg, approx. 2,300 mg, approx. 2,400 mg, approx. 2,500 mg, approx. 2,600 mg,It is administered in amounts of approximately 2,700 mg, approximately 2,800 mg, approximately 3,000 mg, approximately 4,000 mg, approximately 5,000 mg, approximately 6,000 mg, approximately 7,000 mg, or approximately 8,000 mg, or any range derivable from these values.

[0303] In certain embodiments, the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates or hydrates, is 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 120, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, Approx. 165 mg, Approx. 170 mg, Approx. 175 mg, Approx. 180 mg, Approx. 185 mg, Approx. 190 mg, Approx. 195 mg, Approx. 200 mg, Approx. 205 mg, Approx. 210 mg, Approx. 215 mg, Approx. 220 mg, Approx. 225 mg, Approx. 230 mg, Approx. 240 mg, Approx. 250 mg, Approx. 260 mg, Approx. 270 mg, Approx. 275 mg, Approx. 280 mg, Approx. 290 mg, Approx. 300 mg, Approx. 310 mg, Approx. 320 mg, Approx. 330 mg, Approx. 340 mg, Approx. 350 mg, Approx. 360 mg, Approx. 370 mg, Approx. 380 mg, Approx. 390 mg, Approx. 400 mg, 410 mg, Approx. 420 mg, Approx. 430 mg, Approx. 440 mg, approx. 450 mg, approx. 460 mg, approx. 470 mg, approx. 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 580 mg, approx. 590 mg, approx. 600 mg, approx. 610 mg, approx. 620 mg, approx. 630 mg, approx. 640 mg, approx. 650 mg, approx. 660 mg, approx. 670 mg, approx. 680 mg, approx. 690 mg, approx. 700 mg,710 mg, approx. 720 mg, approx. 730 mg, approx. 740 mg, approx. 750 mg, approx. 760 mg, approx. 770 mg, approx. 780 mg, approx. 790 mg, approx. 800 mg, approx. 810 mg, approx. 820 mg, approx. 830 mg, approx. 840 mg, approx. 850 mg, approx. 860 mg, approx. 870 mg, approx. 880 mg, approx. 890 mg, approx. 900 mg, 910 mg, approx. 920 mg, approx. 930 mg, approx. 940 mg, approx. 950 mg, approx. 960 mg, approx. 970 mg, approx. 980 mg, approx. 990 mg, approx. 1,000 mg, approx. 1,100 mg, approx. 1,200 mg, approx. 1,300 mg, approx. 1,400 mg, It is administered to the subject in amounts of approximately 1,500 mg, approximately 1,600 mg, approximately 1,700 mg, approximately 1,800 mg, approximately 1,900 mg, approximately 2,000 mg, approximately 2,100 mg, approximately 2,200 mg, approximately 2,300 mg, approximately 2,400 mg, approximately 2,500 mg, approximately 2,600 mg, approximately 2,700 mg, approximately 2,800 mg, approximately 3,000 mg, approximately 4,000 mg, approximately 5,000 mg, approximately 6,000 mg, approximately 7,000 mg, and approximately 8,000 mg.

[0304] In certain embodiments, the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates or hydrates, is given per day 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, 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, approx. 165 mg, approx. 170 mg, approx. 175 mg, approx. 180 mg, approx. 185 mg, approx. 190 mg, approx. 195 mg, approx. 200 mg, approx. 205 mg, approx. 210 mg, approx. 215 mg, approx. 220 mg, approx. 225 mg, approx. 230 mg, approx. 240 mg, approx. 250 mg, approx. 260 mg, approx. 270 mg, approx. 275 mg, approx. 280 mg, approx. 290 mg, approx. 300 mg, approx. 310 mg, approx. 320 mg, approx. 330 mg, approx. 340 mg, approx. 350 mg, approx. 360 mg, approx. 370 mg, approx. 380 mg, approx. 390 mg, approx. 400 mg, 410 mg, approx. 420 mg, approx. 430 mg, approx. 440 mg, approx. 450 mg, approx. 460 mg, approx. 470 mg, approx. 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 540 mg, approx. 550 mg, approx. 560 mg, approx. 570 mg, approx. 580 mg, approx. 590 mg, approx. 600 mg, approx. 610 mg, approx. 620 mg, approx. 630 mg, approx. 640 mg, approx. 650 mg, approx. 660 mg, approx. 670 mg, approx. 680 mg, approx. 690 mg,Approx. 700 mg, 710 mg, Approx. 720 mg, Approx. 730 mg, Approx. 740 mg, Approx. 750 mg, Approx. 760 mg, Approx. 770 mg, Approx. 780 mg, Approx. 790 mg, Approx. 800 mg, Approx. 810 mg, Approx. 820 mg, Approx. 830 mg, Approx. 840 mg, Approx. 850 mg, Approx. 860 mg, Approx. 870 mg, Approx. 880 mg, Approx. 890 mg, Approx. 900 mg, 910 mg, Approx. 920 mg, Approx. 930 mg, Approx. 940 mg, Approx. 950 mg, Approx. 960 mg, Approx. 970 mg, Approx. 980 mg, Approx. 990 mg, Approx. 1,000 mg, Approx. 1,100 mg, Approx. 1,200 mg, Approx. 1,300 mg, Approx. It is administered in amounts of 1,400 mg, approximately 1,500 mg, approximately 1,600 mg, approximately 1,700 mg, approximately 1,800 mg, approximately 1,900 mg, approximately 2,000 mg, approximately 2,100 mg, approximately 2,200 mg, approximately 2,300 mg, approximately 2,400 mg, approximately 2,500 mg, approximately 2,600 mg, approximately 2,700 mg, approximately 2,800 mg, approximately 3,000 mg, approximately 4,000 mg, approximately 5,000 mg, approximately 6,000 mg, approximately 7,000 mg, and approximately 8,000 mg.

[0305] In the case of oral administration, the pharmaceutical composition provided herein, for symptomatic adjustment of the dosage to a patient to be treated, comprises 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; In one embodiment, 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, Approx. 220 mg, Approx. 230 mg, Approx. 240 mg, Approx. 250 mg, Approx. 260 mg, Approx. 270 mg, Approx. 280 mg, Approx. 290 mg, Approx. 300 mg, Approx. 310 mg, Approx. 320 mg, Approx. 330 mg, Approx. 340 mg, Approx. 350 mg, Approx. 360 mg, Approx. 370 mg, Approx. 380 mg, Approx. 390 mg, Approx. 400 mg, 410 mg, Approx. 420 mg, Approx. 430 mg, Approx. 440 mg, Approx. 450 mg, Approx. 460 mg, Approx. 470 mg, Approx. 480 mg,Approx. 490 mg, Approx. 500 mg, Approx. 510 mg, Approx. 520 mg, Approx. 530 mg, Approx. 540 mg, Approx. 550 mg, Approx. 560 mg, Approx. 570 mg, Approx. 580 mg, Approx. 590 mg, Approx. 600 mg, Approx. 610 mg, Approx. 620 mg, Approx. 630 mg, Approx. 640 mg, Approx. 650 mg, Approx. 660 mg, Approx. 670 mg, Approx. 680 mg, Approx. 690 mg, Approx. 700 mg, 710 mg, Approx. 720 mg, Approx. 730 mg, Approx. 740 mg, Approx. 750 mg, Approx. 760 mg, Approx. 770 mg, Approx. 780 mg, Approx. 790 mg, Approx. 800 mg, Approx. 810 mg, Approx. 820 mg, Approx. 830 mg, Approx. It may be formulated in the form of tablets or capsules containing 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1,000 mg, or about 2,000 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0306] In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of 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 its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0307] In some embodiments, the pharmaceutical composition provided herein may be formulated to contain about 200 mg of the compound of formula (I), or its isotope variant, for oral administration; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated to contain about 300 mg of the compound of formula (I), or its isotope variant, for oral administration; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated to contain about 400 mg of the compound of formula (I), or its isotope variant, for oral administration; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may contain about 500 mg of the compound of formula (I), or its isotope variant, for oral administration; Alternatively, it may be formulated to contain pharmaceutically acceptable salts, solvates, hydrates, or prodrugs.

[0308] In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 200 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 300 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 400 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated in the form of a tablet containing about 500 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0309] The pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion for symptomatic adjustment of the dosage to a patient to be treated, and may be 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, about 950 to about 1,050 mg; In one embodiment, 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, Approx. 220 mg, Approx. 230 mg, Approx. 240 mg, Approx. 250 mg, Approx. 260 mg, Approx. 270 mg, Approx. 280 mg, Approx. 290 mg, Approx. 300 mg, Approx. 310 mg, Approx. 320 mg, Approx. 330 mg, Approx. 340 mg, Approx. 350 mg, Approx. 360 mg, Approx. 370 mg, Approx. 380 mg, Approx. 390 mg, Approx. 400 mg, 410 mg, Approx. 420 mg,Approx. 430 mg, Approx. 440 mg, Approx. 450 mg, Approx. 460 mg, Approx. 470 mg, Approx. 480 mg, Approx. 490 mg, Approx. 500 mg, Approx. 510 mg, Approx. 520 mg, Approx. 530 mg, Approx. 540 mg, Approx. 550 mg, Approx. 560 mg, Approx. 570 mg, Approx. 580 mg, Approx. 590 mg, Approx. 600 mg, Approx. 610 mg, Approx. 620 mg, Approx. 630 mg, Approx. 640 mg, Approx. 650 mg, Approx. 660 mg, Approx. 670 mg, Approx. 680 mg, Approx. 690 mg, Approx. 700 mg, 710 mg, Approx. 720 mg, Approx. 730 mg, Approx. 740 mg, Approx. 750 mg, Approx. 760 mg, Approx. 770 mg, Approx. It contains 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1,000 mg, or about 2,000 mg of a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0310] In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion and contains 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 its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0311] In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion, containing about 200 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion, containing about 300 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion, containing about 400 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion, containing about 500 mg of the compound of formula (I) or its isotope variant; Alternatively, it may be formulated for administration by IV injection or infusion containing a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion containing about 600 mg of the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion containing about 700 mg of the compound of formula (I), or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion, containing about 800 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion, containing about 900 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug. In some embodiments, the pharmaceutical composition provided herein may be formulated for administration by IV injection or infusion, containing about 1,000 mg of the compound of formula (I) or its isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0312] In some embodiments, the pharmaceutical composition provided herein is 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, 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, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, about 130 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 It may be formulated in the form of an injection or IV infusion solution containing a compound of formula (I) of mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, or its isotopic isoforms, tautomeric isomers, pharmaceutically acceptable salts, solvates or hydrates.

[0313] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 40 mg / mL of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the pharmaceutical composition comprises about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL of the compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates.

[0314] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. The daily dose described herein may be provided once daily or multiple times daily in the form of partial doses provided as bid, tid, qid, etc., wherein the number of partial doses is equal to the daily dose. The pharmaceutical composition may be administered in a regimen of 1 to 4 times per day, including once, twice, three, 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, a loading dose, followed by a maintenance dose, of a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered.

[0315] In some embodiments, the pharmaceutical composition provided herein is administered as a tablet. In some embodiments, the pharmaceutical composition provided herein is administered as a capsule. In some embodiments, the pharmaceutical composition provided herein is administered as an injection. In some embodiments, the pharmaceutical composition provided herein is administered as an IV injection or infusion.

[0316] In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 10 minutes. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 15 minutes. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 20 minutes. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 30 minutes. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 45 minutes. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 1 hour. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 90 minutes. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 2 hours. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of about 3 hours. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of up to about 3 hours. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of at least about 3 hours. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of at least 30 minutes. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of at least 2 hours. In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of up to 2 hours.

[0317] In some embodiments, the pharmaceutical composition provided herein is administered by IV infusion over a period of up to 30 minutes.

[0318] In some embodiments, a loading dose, followed by a maintenance dose, of the pharmaceutical composition provided herein is administered. In some embodiments, both the loading dose and the maintenance dose are administered by IV infusion. In some embodiments, both the loading dose and the maintenance dose are administered orally (PO). In some embodiments, the loading dose is administered by IV infusion, and the maintenance dose is administered orally (PO). In some embodiments, a loading dose comprising about 2,000 mg of the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion. In some embodiments, a loading dose comprising about 1,000 mg of the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion twice daily (BID). In some embodiments, a loading dose comprising about 1,000 mg of the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion as BID on the first day of treatment. In some embodiments, a loading dose comprising about 1,000 mg of the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion as BID only on the first day of treatment. In some embodiments, a loading dose comprising about 1,000 mg of the compound of formula (I), or its isotopic isomorph, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion as BID at 2 or 3 hours. In some embodiments, a maintenance dose comprising about 600 mg of a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered by IV injection as a QD.In some embodiments, a maintenance dose comprising about 600 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion as a QD starting on the second day of treatment. In some embodiments, a maintenance dose comprising about 600 mg of the pharmaceutical composition provided herein is administered by IV infusion as a QD over 1 or 2 hours. In some embodiments, a maintenance dose comprising about 800 mg of the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered as a QD. In some embodiments, a BID (loading dose) is administered by IV infusion of 1,000 mg, followed by a QD (maintenance dose) by IV infusion of 600 mg, the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, a compound of formula (I), or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, is administered as a 1,000 mg BID IV 2-hour or 3-hour infusion (loading dose), followed by a 600 mg IV QD 1-hour, 2-hour, or 3-hour infusion (maintenance dose). In some embodiments, a compound of formula (I), or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, is administered as a 1,000 mg BID IV 3-hour infusion (loading dose), followed by a 600 mg IV QD 3-hour infusion (maintenance dose). In some embodiments, a 1,000 mg BID IV 3-hour infusion (loading dose) is administered, followed by an 800 mg PO QD (maintenance dose) of the compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. In some embodiments, the 1,000 mg BID IV loading dose is administered at 2 or 3 hours IVIt is administered by injection, wherein the second dose is administered about 9 to 12 hours after the first dose.

[0319] 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.

[0320] In some embodiments, the pharmaceutical composition provided herein is administered daily, every other day, every 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 other week, 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.

[0321] In some cases, a method of administering multiple compounds (e.g., a compound of formula (I), or its isotopic isomorphs, tautomers, pharmaceutically acceptable salts, solvates or hydrates, and antifungal agents) involves administering the compounds within 48 hours or less of each other. In some embodiments, administration is made 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, the compounds are administered simultaneously. An example of simultaneous administration is injecting one compound immediately before, immediately after, or after the administration of a second compound, where immediately before or immediately after refers to an amount of less than 5 minutes before or after.

[0322] In some embodiments of the pharmaceutical composition described herein, the second dose is administered about 10 minutes after the first dose, or the second dose is administered about 15 minutes after the first dose, or the second dose is administered about 20 minutes after the first dose, or the second dose is administered about 30 minutes after the first dose, or the second dose is administered about 40 minutes after the first dose, or the second dose is administered about 45 minutes after the first dose, or the second dose is administered about 1 hour after the first dose, or the second dose is administered about 2 hours after the first dose, or the second dose is administered about 3 hours after the first dose, or the second dose is administered about 4 hours after the first dose, or the second dose is administered about 5 hours after the first dose, or the second dose is administered about 6 hours after the first dose, or the second dose is administered about 7 hours after the first dose, or the second dose is administered about after the first dose The second dose is administered at the 8th hour, or the second dose is administered approximately 9 hours after the first dose, or the second dose is administered approximately 10 hours after the first dose, or the second dose is administered approximately 11 hours after the first dose, or the second dose is administered approximately 12 hours after the first dose, or the second dose is administered approximately 13 hours after the first dose, or the second dose is administered approximately 14 hours after the first dose, or the second dose is administered approximately 15 hours after the first dose, or the second dose is administered approximately 16 hours after the first dose, or the second dose is administered approximately 17 hours after the first dose, or the second dose is administered approximately 18 hours after the first dose, or the second dose is administered approximately 19 hours after the first dose, or the second dose is administered approximately 20 hours after the first dose, or the second dose is administered approximately 21 hours after the first dose, or the second dose is The second dose is administered approximately 22 hours after the first dose, or the second dose is administered approximately 23 hours after the first dose, or the second dose is administered approximately 24 hours after the first dose. In some embodiments of the pharmaceutical composition described herein, the second dose is IVIt is administered at about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 22 hours, or about 48 hours after the completion of administration of the first dose by infusion. In some embodiments of the pharmaceutical composition, a second dose is administered about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 22 hours, or about 48 hours after the start of administration of the first dose by IV infusion.

[0323] 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 the antifungal agent. In some embodiments, the pharmaceutical composition described herein is administered after the antifungal agent. In some embodiments, the pharmaceutical composition described herein is administered simultaneously with the antifungal agent. In some embodiments, both the pharmaceutical composition described herein and the antifungal agent described herein are administered as IV infusions. In some embodiments, both the pharmaceutical composition described herein and the antifungal agent described herein are administered orally. In some embodiments, the pharmaceutical composition described herein is administered orally, and the antifungal agent is administered as an IV infusion. In some embodiments, the pharmaceutical composition described herein is administered as an IV infusion, and the antifungal agent is administered orally. In some embodiments, the pharmaceutical composition described herein and the antifungal agent described herein are administered orally. In some embodiments, the pharmaceutical composition described herein and the antifungal agent described herein are administered by IV infusion.

[0324] In some embodiments, the pharmaceutical formulation provided herein has a maximum plasma concentration (C) of about 12,000 ng / mL to about 25,000 ng / mL (i.e., about 12 µg / mL to about 25 µg / mL) after administration following the elapsed minimum period. maxIt is formulated to achieve ). In some embodiments, the pharmaceutical formulations provided herein, after administration following the elapsed minimum period, are 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, and 13 µg / mL to about 15 µg / mL, 13 µg / mL to about 16 µg / mL, 13 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, 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 / 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, 23 μg / mL to about 25 μg / mL, or C of 24 μg / mL to about 25 μg / mL max It is formulated to achieve.

[0325] In some embodiments, the pharmaceutical formulations provided herein after administration following the elapsed minimum period are about 1 µg / mL, about 2 µg / mL, about 3 µg / mL, about 4 µg / mL, about 5 µg / mL, about 6 µg / mL, about 7 µg / mL, about 8 µg / mL, about 9 µg / mL, 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, about 25 µg / mL, about 26 µg / mL, about 27 C at µg / mL, approximately 28 µg / mL, approximately 29 µg / mL, or approximately 30 µg / mL max It is formulated to achieve.

[0326] In some embodiments, the pharmaceutical spray formulation contains 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, and about 25 µg / mL of C after administration following the elapsed minimum period. max It is formulated to achieve.

[0327] Fungal disease

[0328] In some embodiments, fungal diseases include aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (Valley fever), cryptococcosis, histoplasmosis, mucormycosis, and Pneumocystis pneumonia (PCP: Pneumocystis It is selected from the group consisting of pneumonia), ringworm, sporotrichum, and thalaromysis.

[0329] In some embodiments, the fungal disease is aspergillosis. In some embodiments, the aspergillosis is allergic bronchopulmonary aspergillosis (abpa), allergic aspergillic sinusitis, chronic pulmonary aspergillosis, invasive aspergillosis, or cutaneous aspergillosis. In some embodiments, the subject has an aspergilloma.

[0330] In some embodiments, the fungal disease is blastomycosis. In some embodiments, the fungal disease is candidiasis. In some embodiments, the 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 disseminated coccidioidomycosis, including acute coccidioidomycosis (primary pulmonary coccidioidomycosis), chronic coccidioidomycosis, or primary cutaneous coccidioidomycosis. In some embodiments, the fungal disease is cryptococcosis. In some embodiments, cryptococcosis is wound or cutaneous cryptococcosis, pulmonary cryptococcosis, or cryptococcal meningitis. In some embodiments, the fungal disease is a fungal eye infection. In some embodiments, the fungal eye infection is fungal keratitis, fungal exogenous endophthalmitis, or fungal endogenous endophthalmitis. In some embodiments, the fungal disease is histoplasmosis. In some embodiments, the histoplasmosis is acute histoplasmosis. In some embodiments, the histoplasmosis is chronic histoplasmosis. In some embodiments, the fungal disease is mucormycosis. In some embodiments, the mucormycosis is nasocervical mucormycosis, pulmonary mucormycosis, gastrointestinal mucormycosis, cutaneous mucormycosis, or disseminated mucormycosis. In some embodiments, the fungal disease is Pneumocystis pneumonia (PCP). In some embodiments, the fungal disease is tinea. In some embodiments, the tinea is tinea pedis, tinea cruris, tinea capitis, tinea manus, tinea unguis, or tinea corporis. In some embodiments, ringworm is trichophyton ( Trichophyton ), mi...

Claims

Claim 1 A pharmaceutical composition comprising: (i) a compound of the following formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition exists in a formulation for oral administration or administration: . Claim 2 A pharmaceutical composition comprising: (i) a compound of the following formula (I), or a particulate of its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition exists as an oral dosage or administration formulation or an inhalation delivery formulation: . Claim 3 A pharmaceutical composition according to claim 1 or 2, wherein the compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline, microcrystalline, amorphous, or freeze-dried. Claim 4 A pharmaceutical composition in which the compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline, in accordance with paragraph 3. Claim 5 In paragraph 3, a pharmaceutical composition in which the compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are amorphous. Claim 6 A pharmaceutical composition according to claim 3, wherein the compound of formula (I), or its isotopic isoforms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are freeze-dried. Claim 7 A pharmaceutical composition in which the particles are micronized in any one of paragraphs 2 to 6. Claim 8 A pharmaceutical composition according to claim 7, wherein the particles have a particle size of about 1 μm to about 750 μm. Claim 9 A pharmaceutical composition according to claim 7 or 8, wherein at least about 10% of the particles have a particle size of about 1 μm to about 750 μm. Claim 10 A pharmaceutical composition according to any one of claims 7 to 9, wherein at least about 20% of the particles have a particle size of about 1 μm to about 750 μm. Claim 11 A pharmaceutical composition according to any one of claims 7 to 10, wherein at least about 30% of the particles have a particle size of about 1 μm to about 750 μm. Claim 12 A pharmaceutical composition according to any one of claims 7 to 11, wherein at least about 40% of the particles have a particle size of about 1 μm to about 750 μm. Claim 13 A pharmaceutical composition according to any one of claims 7 to 12, wherein at least about 50% of the particles have a particle size of about 1 μm to about 750 μm. Claim 14 A pharmaceutical composition according to any one of claims 7 to 13, wherein at least about 60% of the particles have a particle size of about 1 μm to about 750 μm. Claim 15 A pharmaceutical composition according to any one of claims 7 to 14, wherein at least about 70% of the particles have a particle size of about 1 μm to about 750 μm. Claim 16 A pharmaceutical composition according to any one of claims 7 to 15, wherein at least about 80% of the particles have a particle size of about 1 μm to about 750 μm. Claim 17 A pharmaceutical composition according to any one of claims 7 to 16, wherein at least about 90% of the particles have a particle size of about 1 μm to about 750 μm. Claim 18 A pharmaceutical composition according to any one of claims 7 to 17, wherein at least about 95% of the particles have a particle size of about 1 μm to about 750 μm. Claim 19 A pharmaceutical composition according to any one of paragraphs 2 to 6, wherein the particles are nano-ground. Claim 20 A pharmaceutical composition according to claim 19, wherein the particles have a particle size of about 1 nm to about 750 nm. Claim 21 A pharmaceutical composition according to claim 19 or 20, wherein at least about 10% of the particles have a particle size of 1 nm to about 750 nm. Claim 22 A pharmaceutical composition according to any one of claims 19 to 21, wherein at least about 20% of the particles have a particle size of 1 nm to about 750 nm. Claim 23 A pharmaceutical composition according to any one of claims 19 to 22, wherein at least about 30% of the particles have a particle size of 1 nm to about 750 nm. Claim 24 A pharmaceutical composition according to any one of claims 19 to 23, wherein at least about 40% of the particles have a particle size of 1 nm to about 750 nm. Claim 25 A pharmaceutical composition according to any one of claims 19 to 24, wherein at least about 50% of the particles have a particle size of 1 nm to about 750 nm. Claim 26 A pharmaceutical composition according to any one of claims 19 to 25, wherein at least about 60% of the particles have a particle size of 1 nm to about 750 nm. Claim 27 A pharmaceutical composition according to any one of claims 19 to 26, wherein at least about 70% of the particles have a particle size of 1 nm to about 750 nm. Claim 28 A pharmaceutical composition according to any one of claims 19 to 27, wherein at least about 80% of the particles have a particle size of 1 nm to about 750 nm. Claim 29 A pharmaceutical composition according to any one of claims 19 to 28, wherein at least about 90% of the particles have a particle size of 1 nm to about 750 nm. Claim 30 A pharmaceutical composition according to any one of claims 19 to 29, wherein at least about 95% of the particles have a particle size of 1 nm to about 750 nm. Claim 31 A pharmaceutical composition according to any one of claims 1 to 30, wherein the formulation is a self-microemulsifying drug delivery system (SMEDDS). Claim 32 A pharmaceutical composition according to any one of claims 1 to 30, wherein the formulation is a self-emulsifying drug delivery system (SEDDS). Claim 33 A pharmaceutical composition according to any one of claims 1 to 30, wherein the formulation is a spray-dried dispersed formulation. Claim 34 A pharmaceutical composition according to any one of claims 1 to 30, wherein the formulation is a high-temperature melt granule formulation. Claim 35 A pharmaceutical composition according to any one of claims 1 to 30, wherein the formulation is a high-temperature melt extrusion formulation. Claim 36 A pharmaceutical composition according to any one of claims 1 to 30, wherein the formulation is a finely precipitated bulk powder (MBP) formulation. Claim 37 A pharmaceutical composition according to any one of claims 1 to 30, wherein the formulation is a liquid formulation. Claim 38 A pharmaceutical composition in which the formulation is a suspension, liquid, syrup, or elixir in paragraph 37. Claim 39 A pharmaceutical composition according to claim 37 or 38, wherein the formulation is a nanosuspension. Claim 40 A pharmaceutical composition in which the formulation is a suspension, in any one of paragraphs 37 to 39. Claim 41 A pharmaceutical composition in which the formulation is a colloidal suspension in paragraph 40. Claim 42 A pharmaceutical composition according to any one of claims 1 to 36, wherein the formulation is a solid formulation. Claim 43 A pharmaceutical composition according to any one of claims 1 to 36 or 42, wherein the formulation is a granule or a powder. Claim 44 A pharmaceutical composition according to any one of claims 1 to 36 or 42 to 43, wherein the formulation is a tablet or a capsule. Claim 45 A pharmaceutical composition according to claim 44, wherein the tablet or capsule has an enteric coating. Claim 46 A pharmaceutical composition in which the formulation is a tablet, as described in paragraph 44. Claim 47 A pharmaceutical composition in which the tablet is an osmotic suspension tablet, as described in paragraph 44. Claim 48 A pharmaceutical composition according to claim 44, wherein the capsule is a hard capsule or a soft gelatin capsule filled with liquid. Claim 49 A pharmaceutical composition according to any one of claims 1 to 48, wherein the formulation is a modified-release formulation. Claim 50 A pharmaceutical composition according to claim 49, wherein the modified-release formulation is a delayed-release formulation, an extended-release (ER) formulation, or a targeted-release formulation. Claim 51 A pharmaceutical composition according to claim 50, wherein the ER formulation is a sustained-release (SR) formulation or a controlled-release (CR) formulation. Claim 52 A pharmaceutical composition according to any one of claims 1 to 48, wherein the formulation is an immediate-release formulation. Claim 53 A pharmaceutical composition according to any one of claims 1 to 52, wherein the pharmaceutical composition comprises about 10 mg to about 1,000 mg of a compound of formula (I), or an isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 54 A pharmaceutical composition according to any one of claims 1 to 52, wherein the pharmaceutical composition comprises about 50 mg to about 600 mg of a compound of formula (I), or an isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 55 A pharmaceutical composition according to any one of claims 1 to 52, wherein the pharmaceutical composition comprises a compound of formula (I) of 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 1,050 mg, or an isotopic dimorphism, tautomeric, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 56 A pharmaceutical composition according to any one of claims 1 to 52, wherein 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 dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 57 A pharmaceutical composition according to any one of claims 1 to 52, wherein 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, or about 500 mg of a compound of formula (I), or an isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 58 A pharmaceutical composition according to any one of claims 1 to 57, wherein at least one pharmaceutically acceptable excipient is a filler, disintegrant, binder, fluidizing agent, lubricant, or any combination thereof. Claim 59 A pharmaceutical composition according to any one of claims 1 to 58, wherein at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate, colloidal silicon dioxide, or any combination thereof. Claim 60 A pharmaceutical composition according to any one of claims 1 to 59, wherein the pharmaceutical composition is stable for up to 36 months at a temperature of about 2°C to about 25°C. Claim 61 A pharmaceutical composition according to claim 60, wherein 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. Claim 62 A pharmaceutical composition according to any one of claims 1 to 61, wherein the pharmaceutical composition substantially does not contain impurities. Claim 63 A pharmaceutical composition according to any one of claims 1 to 62, wherein the pharmaceutical composition is at least about 90% pure. Claim 64 A pharmaceutical composition according to any one of claims 1 to 63, wherein the pharmaceutical composition is at least about 95% pure. Claim 65 A pharmaceutical composition according to any one of claims 1 to 64, wherein the pharmaceutical composition is at least about 96% pure. Claim 66 A pharmaceutical composition according to any one of claims 1 to 65, wherein the pharmaceutical composition is at least about 97% pure. Claim 67 A pharmaceutical composition according to any one of claims 1 to 66, wherein the pharmaceutical composition is at least about 98% pure. Claim 68 A pharmaceutical composition according to any one of claims 1 to 67, wherein the pharmaceutical composition is at least about 99% pure. Claim 69 A pharmaceutical composition according to any one of claims 1 to 68, wherein 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% pure. Claim 70 A pharmaceutical composition according to any one of claims 1 to 62, wherein the pharmaceutical composition comprises at least one impurity of up to about 10% (w / w). Claim 71 A pharmaceutical composition according to any one of claims 1 to 62 or 70, wherein the pharmaceutical composition comprises at least one impurity of 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 less than about 1% (w / w). Claim 72 A pharmaceutical composition according to any one of claims 1 to 62 or 70 to 71, wherein the pharmaceutical composition comprises at least one impurity of about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or less than about 1% (w / w). Claim 73 A pharmaceutical composition according to any one of claims 70 to 72, wherein the pharmaceutical composition comprises at least 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). Claim 74 A pharmaceutical composition according to any one of claims 70 to 72, wherein at least one impurity is a decomposition product. Claim 75 In any one of paragraphs 70 to 72, at least one impurity A pharmaceutical composition that is, or any combination thereof. Claim 76 In any one of paragraphs 70 to 75, at least one impurity Pharmaceutical composition. Claim 77 A pharmaceutical composition according to any one of claims 1 to 62, wherein the pharmaceutical composition comprises a maximum of about 4.0% (w / w) of total impurities. Claim 78 A pharmaceutical composition according to any one of claims 1 to 62 or 77, wherein the pharmaceutical composition comprises at most about 0.5% (w / w) of any individual impurity. Claim 79 In any one of paragraphs 1 to 62 or 77 to 78, the pharmaceutical composition comprises up to about 1.5% (w / w) of a compound A pharmaceutical composition comprising Claim 80 A pharmaceutical composition according to any one of claims 77 to 79, wherein the pharmaceutical composition comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg of a compound of formula (I), or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate. Claim 81 A pharmaceutical composition comprising: (i) a compound of the following formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition exists as a dosage form for administration by injection or administration: . Claim 82 A pharmaceutical composition according to claim 81, wherein the pharmaceutical composition is present in a formulation for intravenous (IV) injection or infusion, or for intramuscular, subcutaneous, or intradermal injection. Claim 83 A pharmaceutical composition according to paragraph 82, wherein the pharmaceutical composition exists as a formulation for IV injection or infusion. Claim 84 A pharmaceutical composition in which the pharmaceutical composition is a liquid formulation, in any one of paragraphs 81 to 83. Claim 85 A pharmaceutical composition according to any one of claims 81 to 84, wherein the compound of formula (I), or its isotopic isomer, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate is crystalline, microcrystalline, amorphous, or freeze-dried. Claim 86 In paragraph 85, a pharmaceutical composition in which the compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are crystalline. Claim 87 In paragraph 85, a pharmaceutical composition in which the compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are amorphous. Claim 88 A pharmaceutical composition according to claim 85, wherein the compound of formula (I), or its isotopic isoforms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are freeze-dried. Claim 89 A pharmaceutical composition according to any one of claims 81 to 88, wherein the formulation comprises a co-solvent. Claim 90 In paragraph 89, the co-solvent is PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremophor, glycerin, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert - A pharmaceutical composition comprising butanol, or any combination thereof. Claim 91 A pharmaceutical composition according to any one of claims 81 to 90, wherein the formulation further comprises oil. Claim 92 A pharmaceutical composition according to claim 91, wherein the oil comprises sesame oil, soybean oil, vegetable oil, poppy seed oil, safflower oil, or a combination thereof. Claim 93 A pharmaceutical composition according to any one of claims 81 to 92, wherein the formulation further comprises a buffer. Claim 94 A pharmaceutical composition in which the buffer is a phosphate buffer in paragraph 93. Claim 95 A pharmaceutical composition in which the phosphate buffer in paragraph 94 is potassium phosphate. Claim 96 A pharmaceutical composition according to claim 94 or 95, wherein potassium phosphate is monobasic or dibasic. Claim 97 A pharmaceutical composition according to any one of claims 81 to 96, wherein the pharmaceutical composition has a pH of about 2.5 to about 11.

0. Claim 98 A pharmaceutical composition according to any one of claims 81 to 96, wherein the pharmaceutical composition has a pH of about 2.5 to about 5.0 or about 6.5 to about 10.

5. Claim 99 A pharmaceutical composition according to any one of claims 81 to 96, wherein the pharmaceutical composition has a pH of about 2.5 to about 4.5 or about 7.0 to about 9.

0. Claim 100 A pharmaceutical composition according to any one of claims 81 to 99, wherein the pH of the pharmaceutical composition is adjusted with hydrochloric acid and / or sodium hydroxide. Claim 101 A pharmaceutical composition according to any one of claims 81 to 100, wherein the pharmaceutical composition comprises a compound of formula (I) in an amount of about 5 mg / mL to about 250 mg / mL, or an isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 102 A pharmaceutical composition according to any one of claims 81 to 101, wherein the pharmaceutical composition comprises a compound of formula (I) in an amount of about 10 mg / mL to about 50 mg / mL, or an isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 103 A pharmaceutical composition according to any one of claims 81 to 102, wherein the pharmaceutical composition comprises a compound of formula (I) in an amount of about 20 mg / mL to about 40 mg / mL, or an isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 104 A pharmaceutical composition according to any one of claims 81 to 102, wherein the pharmaceutical composition comprises a compound of formula (I) having an amount of about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, or about 30 mg / mL, or an isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 105 A pharmaceutical composition according to any one of claims 1 to 104, wherein the pharmaceutical composition comprises about 10 mg to about 1,000 mg of a compound of formula (I), or an isotopic dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 106 A pharmaceutical composition according to any one of claims 1 to 105, wherein the pharmaceutical composition comprises about 50 mg to about 600 mg of a compound of formula (I), or an isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 107 A pharmaceutical composition according to any one of claims 1 to 105, wherein the pharmaceutical composition comprises a compound of formula (I) of 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 1,050 mg, or an isotopic dimorphism, tautomeric, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 108 A pharmaceutical composition according to any one of claims 81 to 105, wherein 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 dimorphism, tautomeric, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 109 A pharmaceutical composition according to any one of claims 81 to 108, wherein the pharmaceutical composition is stable for up to about 24 months at a temperature of about -20°C to 8°C. Claim 110 A pharmaceutical composition according to claim 101, wherein the pharmaceutical composition is stable for a period of about 12 to about 24 months at a temperature of about -20°C. Claim 111 A pharmaceutical composition according to any one of claims 81 to 110, wherein the pharmaceutical composition substantially does not contain impurities. Claim 112 A pharmaceutical composition according to any one of claims 81 to 111, wherein the pharmaceutical composition is at least about 90% pure. Claim 113 A pharmaceutical composition according to any one of claims 81 to 112, wherein the pharmaceutical composition is at least about 95% pure. Claim 114 A pharmaceutical composition according to any one of claims 81 to 113, wherein the pharmaceutical composition is at least about 96% pure. Claim 115 A pharmaceutical composition according to any one of claims 81 to 114, wherein the pharmaceutical composition is at least about 97% pure. Claim 116 A pharmaceutical composition according to any one of claims 81 to 115, wherein the pharmaceutical composition is at least about 98% pure. Claim 117 A pharmaceutical composition according to any one of claims 81 to 116, wherein the pharmaceutical composition is at least about 99% pure. Claim 118 A pharmaceutical composition according to any one of claims 81 to 117, wherein 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% pure. Claim 119 A pharmaceutical composition according to any one of claims 81 to 111, wherein the pharmaceutical composition comprises at least one impurity of up to about 10% (w / w). Claim 120 A pharmaceutical composition according to any one of claims 81 to 111 or 119, wherein the pharmaceutical composition comprises at least one impurity of 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 less than about 1% (w / w). Claim 121 A pharmaceutical composition according to any one of claims 81 to 111 or 119 to 120, wherein the pharmaceutical composition comprises at least one impurity of about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or less than about 1% (w / w). Claim 122 A pharmaceutical composition according to any one of claims 81 to 111 or 119 to 121, wherein the pharmaceutical composition comprises at least 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). Claim 123 A pharmaceutical composition according to any one of claims 119 to 122, wherein at least one impurity is a decomposition product. Claim 124 In any one of paragraphs 119 to 123, at least one impurity A pharmaceutical composition that is, or any combination thereof. Claim 125 In any one of paragraphs 119 to 124, at least one impurity Pharmaceutical composition. Claim 126 A pharmaceutical composition according to any one of claims 81 to 111, wherein the pharmaceutical composition comprises a maximum of about 4.0% (w / w) of total impurities. Claim 127 A pharmaceutical composition according to any one of claims 81 to 111 or 126, wherein the pharmaceutical composition comprises at most about 0.5% (w / w) of any individual impurity. Claim 128 In any one of claims 81 to 111 or 126 to 127, the pharmaceutical composition is a compound of up to about 1.5% (w / w). A pharmaceutical composition comprising Claim 129 A pharmaceutical composition according to any one of claims 81 to 128, wherein the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I), or its isotopic isoform, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate. Claim 130 A combination composition comprising: (i) a compound of the following formula (I), or its isotopic dimorphisms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates; and (ii) at least one antifungal agent. . Claim 131 A combination composition according to claim 130, wherein the composition further comprises at least one pharmaceutically acceptable excipient. Claim 132 A combination composition according to claim 130 or 131, wherein at least one antifungal agent is an azole, echinocandin, amphotericin B deoxycholate, amphotericin B cochlyate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, iblexafungup, orotomide F901318, or a combination thereof. Claim 133 A combination composition according to claim 132, wherein the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isabuconazole, or miconazole. Claim 134 A combination composition according to claim 132, wherein the echinocandin is caspofungin, anidulafungin, micafungin, or lezafungin. Claim 135 A combination composition comprising: (i) a compound of the following formula (I), or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate; and (ii) a combination composition comprising a compound of the following formula (II), or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate: . Claim 136 A combination composition according to claim 135, wherein the composition further comprises at least one pharmaceutically acceptable excipient. Claim 137 A combination composition according to claim 135 or 136, wherein the compound of formula (I), or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate or hydrate, and the compound of formula (II), or its isotopic dimorphism, tautomeric isomer, pharmaceutically acceptable salt, solvate or hydrate, are both crystalline. Claim 138 A combination composition according to any one of claims 135 to 137, wherein the compound of formula (I), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomeric variant, pharmaceutically acceptable salt, solvate, or hydrate are present in a ratio of about 10:

1. Claim 139 A combination composition according to any one of claims 135 to 138, wherein the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate are present in a ratio of about 9:1 to about 9.99:0.

01. Claim 140 A combination composition according to any one of claims 135 to 139, wherein the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate are present in a ratio of about 9.5:0.5 to about 9.9:0.

1. Claim 141 A combination composition according to any one of claims 135 to 140, wherein the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate, and the compound of formula (II), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate are present in a ratio 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. Claim 142 A method for treating or preventing a fungal infection or disease, comprising the step of administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 129 or the composition of any one of claims 130 to 141 to a subject who requires treatment or prevention of the fungal infection or disease. Claim 143 A method according to claim 142 in which about 10 mg to about 8,000 mg of a compound of formula (I), or its isotopic amorphous form, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. Claim 144 A method according to claim 142 or 143 in which about 10 mg to about 2,400 mg of a compound of formula (I), or its isotopic amorphous form, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. Claim 145 A method according to any one of claims 142 to 144, wherein about 10 mg to about 2,000 mg of a compound of formula (I), or its isotopic amorphous form, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. Claim 146 In any one of paragraphs 142 to 144, of 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 A method in which a compound of formula (I), or its isotopic isoforms, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates are administered to a subject. Claim 147 A method in which, in any one of claims 142 to 146, a compound of formula (I) or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates is administered to a subject in an amount of 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. Claim 148 A method in which, in any one of claims 142 to 144, 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 dimorphism, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered to a subject. Claim 149 A method according to any one of claims 142 to 148, wherein the pharmaceutical composition is administered to a subject daily. Claim 150 A method according to any one of claims 142 to 149, wherein the pharmaceutical composition is administered to a subject once a day, twice a day, three times a day, or four times a day. Claim 151 A method according to any one of claims 142 to 150, wherein the pharmaceutical composition is administered to a subject for a period of up to about 12 weeks. Claim 152 A method according to any one of claims 142 to 151, wherein the pharmaceutical composition is administered to a subject for a period of at least one week. Claim 153 A method according to any one of claims 142 to 152, wherein the pharmaceutical composition is administered to a subject for a period of at least two weeks. Claim 154 A method according to any one of claims 142 to 153, wherein the pharmaceutical composition is administered to a subject for a period of 1 week, 2 weeks, 6 weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks. Claim 155 A method according to any one of claims 142 to 154, wherein the pharmaceutical composition is administered to a subject by IV infusion over a period of about 20 minutes, about 30 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours. Claim 156 A method according to any one of claims 142 to 155, wherein the pharmaceutical composition is administered to a subject by IV infusion over a period of up to about 3 hours. Claim 157 A method according to any one of claims 142 to 156, wherein a loading dose is administered to a subject, followed by the administration of a maintenance dose. Claim 158 A method according to claim 157 comprising a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, with a loading dose of about 1,000 mg to about 8,000 mg. Claim 159 A method according to claim 157 or 158 comprising a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, wherein the retention dose is about 600 mg to about 2,400 mg. Claim 160 A method according to any one of claims 157 to 159, wherein the loading dose comprises about 1,000 mg to about 2,000 mg. Claim 161 A method according to any one of claims 157 to 160, wherein the loading dose is administered by IV infusion over a period of about 2 to about 3 hours. Claim 162 A method according to any one of claims 157 to 161, wherein the loading dose is administered twice on the first day of treatment. Claim 163 A method according to paragraph 162 in which the second loading dose is administered approximately 9 hours after the first loading dose. Claim 164 A method according to any one of claims 157 to 163, comprising a compound of formula (I) or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, wherein the retention dose is about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. Claim 165 A method according to any one of claims 157 to 164, comprising a compound of formula (I), or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, with a maintenance dose of about 800 mg or about 1,000 mg, administered to a subject. Claim 166 A method according to any one of claims 157 to 164, comprising a compound of formula (I) or its isotopic dimorphisms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates having a retention dose of about 600 mg or about 900 mg. Claim 167 A method according to any one of claims 157 to 164, comprising a compound of formula (I) or its isotopic isoform, tautomer, pharmaceutically acceptable salt, solvate, or hydrate having a maintenance dose of about 600 mg or about 900 mg, administered orally. Claim 168 A method according to any one of claims 157 to 164, comprising a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, with a maintenance dose of about 600 mg or about 900 mg, administered by IV infusion over a period of about 1 hour to about 3 hours. Claim 169 A method according to any one of claims 157 to 164, wherein about 600 mg of a compound of formula (I), or its isotopic amorphous form, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by IV infusion over a period of about 3 hours. Claim 170 A method according to any one of paragraphs 157 to 169, wherein the maintenance dose is administered once daily. Claim 171 A method according to any one of claims 157 to 170, wherein the maintenance dose is administered once daily starting on the second day of treatment. Claim 172 A method according to any one of claims 157 to 164, wherein about 600 mg or about 800 mg of a compound of formula (I), or its isotopic amorphous form, tautomeric isomer, pharmaceutically acceptable salt, solvate or hydrate, is administered by IV infusion over a period of about 3 hours, starting on the second, third, or fourth day of treatment. Claim 173 A method according to any one of claims 157 to 164, wherein about 800 mg or about 1,000 mg of a compound of formula (I), or its isotopic amorphous form, tautomeric isomer, pharmaceutically acceptable salt, solvate or hydrate is administered orally starting on the second, third, or fourth day of treatment. Claim 174 A method in which, in any one of paragraphs 142 to 173, the fungal infection is caused by an invasive fungus. Claim 175 A method according to any one of claims 142 to 174, further comprising the step of administering to a subject at least one antifungal agent in combination with a pharmaceutical composition comprising a compound of formula (I), or an isotopic isomer, tautomeric isomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 176 A method according to claim 175, wherein at least one antifungal agent is an azole, echinocandin, amphotericin B deoxycholate, amphotericin B cochlyate, 5-fluorocytosine, terbinafine, griseofulvin, VL-2397, iblexafungup, orotomide F901318, or a combination thereof. Claim 177 In paragraph 176, the method in which the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isabuconazole, or miconazole. Claim 178 In paragraph 177, the method wherein the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin, or a combination thereof. Claim 179 A method according to any one of claims 175 to 178, wherein a pharmaceutical composition comprising a compound of formula (I), or its isotopic isoforms, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and an antifungal agent are administered simultaneously, nearly simultaneously, or sequentially in any order. Claim 180 A method according to claim 179 in which a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates, and an antifungal agent are administered simultaneously or nearly simultaneously. Claim 181 A method according to claim 179 in which a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorphs, tautomeric isomers, pharmaceutically acceptable salts, solvates, or hydrates, and an antifungal agent are administered sequentially. Claim 182 A method according to claim 181 in which a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate or hydrate; or its pharmaceutically acceptable salt is administered prior to at least one antifungal agent. Claim 183 A method according to claim 181 in which a pharmaceutical composition comprising a compound of formula (I), or its isotopic isomorph, tautomeric isomer, pharmaceutically acceptable salt, solvate or hydrate; or its pharmaceutically acceptable salt is administered after at least one antifungal agent. Claim 184 In any one of paragraphs 142 to 183, the fungal infection or disease is Aspergillus fumigatus ( Aspergillus fumigatus ), Blastomyces( Blastomyces ), Azelomyces( Ajellomyces ), Candida( Candida ), Coccidioides( Coccidioides ), Cryptococcus( Cryptococcus ), histoplasma( Histoplasma ), Rhizopus( Rhizopus ), Mukor( Mucor ), Kuninghamela( Cunninghamella ), Apophaisomyces( Apophysomyces ), Absidia( Absidia ), Saxenaea( Saksenaea ), Entomoptora( Entomophthora ), Conidiobolus( Conidiobolus ), Basidiobolus( Basidiobolus ), Sporotrix( Sporothrix ), Pneumocystis( Pneumocystis ), Thalaromyces( Talaromyces ), Asclepias( Asclepias ), Fusarium( Fusarium ), Sedosporium( Scedosporium ) Fungi or mucorales( Mucorales A method caused by fungi from the neck, or any combination thereof. Claim 185 A method according to any one of paragraphs 142 to 183, wherein the fungal infection or disease is caused by Cryptococcus, Aspergillus, Candida, Fusarium, Sedosporium fungi or fungi of the Mucoraleles order, or any combination thereof. Claim 186 In paragraph 185, the fungal infection or disease is Aspergillus fumigatus ( Aspergillus fumigatus ), Aspergillus flavus ( Aspergillus flavus ), Blastomyces dermatidis( Blastomyces dermatitidis ), Azelomyces dermatitidis( Ajellomyces dermatitidis ), Candida albicans( Candida albicans ), Candida glabrata( Candida glabrata ), Candida lugosa( Candida rugosa ), Candida auris( Candida auris ), Coccidioides imitis( Coccidioides immitis ), Coccidioides posadasii( Coccidioides posadasii ), Cryptococcus neoformans( Cryptococcus neoformans ), Cryptococcus gatii( Cryptococcus gattii ), histoplasma capsulatum( Histoplasma capsulatum ), Rhizopus stolonifer ( Rhizopus stolonifer ), Rhizopus arijus( Rhizopus arrhizus ), Mucor Indicus( Mucor indicus ), Kuninghamela Bertoletiae( Cunninghamella bertholletiae ), Apophysomyces elegans( Apophysomyces elegans ), Absidia species (Absidia species) , Saxenaea species (Saksenaea species) , Rhizomucor fusillus ( Rhizomucor pusillus ), Entomoptora species (Entomophthora species) , Conidiobolus species (Conidiobolus species) , Basidiobulus species (Basidiobolus species) , Sporotrix Shenkiyi( Sporothrix schenckii ), Pneumocystis jirobesii ( Pneumocystis jirovecii ), Thalaromyces marnepei( Talaromyces marneffei ), Asclepias Albicans( Asclepias albicans ), Fusarium solani( Fusarium solani ), Sedosporium apiospermum ( Scedosporium apiospermum ), Rhizomucor fusillus (Rhizomucor pusillus) A method that is caused by , or any combination thereof. Claim 187 In paragraph 185, a method in which a fungal infection or disease is caused by Cryptococcus fungus or Candida fungus. Claim 188 In paragraph 187, a method in which a fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gatii, or Candida auris. Claim 189 A method according to any one of claims 142 to 188, wherein the fungal infection or disease has azole resistance and / or echinocandin resistance. Claim 190 A method in which, in any one of paragraphs 142 to 189, the subject is immune impaired. Claim 191 A method in which, in any one of paragraphs 142 to 190, the subject is infected with HIV / AIDS or has cancer. Claim 192 In paragraph 191, a method in which the subject has cancer. Claim 193 In paragraph 192, the method in which the cancer is acute myeloid leukemia (AML). Claim 194 A method in which, in any one of paragraphs 142 to 193, the subject has neutropenia. Claim 195 A method in which, in any one of paragraphs 142 to 194, the subject is receiving or has received cancer chemotherapy treatment. Claim 196 A method in which, in any one of paragraphs 142 to 190, the subject is receiving or has received corticosteroid treatment. Claim 197 A method in which, in any one of paragraphs 142 to 190, the subject is receiving or has received TNF inhibitor treatment. Claim 198 A method in which, in any one of paragraphs 142 to 190, the subject is a transplant recipient. Claim 199 A method according to any one of claims 142 to 198, wherein a fungal infection or disease is present in the bloodstream of the subject. Claim 200 A method according to any one of claims 142 to 199, wherein the subject has a reduced fungal colony count in the lungs after administration of the pharmaceutical composition. Claim 201 In any one of claims 142 to 200, the plasma concentration versus time curve of the compound of formula (I) in the subject is less than about 30 minutes to about 180 minutes t max A method of having. Claim 202 In any one of claims 142 to 201, the subject has a maximum plasma concentration (C) of a compound of formula (I) of about 12,000 ng / mL to about 25,000 ng / mL. max A method of having ).

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