Compounds and methods for treating fungal infections

Abstract

Provided herein are compounds and methods for treating fungal infections. Provided herein are compositions for treating fungal infections and diseases and methods of using the same.

Description

[0001] This application is a divisional application of an application filed on August 30, 2019, with application number 201980072614.1 and invention name “Compounds and methods for treating fungal infections”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 725,971, filed August 31, 2018, which is considered a part of the disclosure of this application and is incorporated by reference into the disclosure of this application. Background Art

[0004] Fungi infect humans and are a major cause of human health problems. They also infect plants and cause significant losses in agricultural productivity. The present disclosure generally relates to the treatment and / or prevention of fungal infections and diseases. Summary of the Invention

[0005] In one aspect, provided herein is a pharmaceutical composition comprising:

[0006] (i) Compound of formula (I):

[0007]

[0008] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0009] (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or application.

[0010] In another aspect, a pharmaceutical composition is provided, comprising:

[0011] (i) fine particles of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0012] (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or application or in a dosage form for delivery by inhalation.

[0013] 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.

[0014] In some embodiments, the particles are nanomilled. In some embodiments, at least about 10% of the particles have a particle size of about 1 nm 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.

[0015] 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.

[0016] In some embodiments, the dosage form is a self-microemulsifying drug delivery system (SMEDDS). In some embodiments, the dosage form is a self-emulsifying drug delivery system (SEDDS). In some embodiments, the dosage form is a suspension or solution. In some embodiments, the dosage form is a nanosuspension. In some embodiments, the dosage form is a solid dosage form. In some embodiments, the dosage form is a spray-dried dispersion dosage form. In some embodiments, the dosage form is a hot-melt granulation dosage form. In some embodiments, the dosage form is a hot-melt extrusion dosage form. In some embodiments, the dosage form is a microprecipitated bulk powder (MBP) dosage form. In some embodiments, the dosage form is a liquid. In some embodiments, the dosage form is a suspension, solution, syrup or elixir. In some embodiments, the pharmaceutical composition is a dosage form for oral administration or application.

[0017] In some embodiments, the dosage form is a tablet or capsule. In some embodiments, the tablet or capsule has an enteric coating. In some embodiments, the dosage form is a tablet. In some embodiments, the tablet is an osmotic floating tablet. In some embodiments, the capsule is a liquid-filled hard capsule. In some embodiments, the capsule is a soft gelatin capsule.

[0018] In some embodiments, the dosage form is a modified release dosage form. In some embodiments, the modified release dosage form is a delayed release dosage form, an extended release (ER) dosage form, or a targeted release dosage form. In some embodiments, the ER dosage form is a sustained release (SR) dosage form or a controlled release (CR) dosage form. In some embodiments, the dosage form is an immediate release dosage form.

[0019] In some embodiments, the pharmaceutical composition comprises from about 10 mg to about 1,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical composition comprises from about 50 mg to about 600 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, from about 50 mg to about 150 mg, from about 150 mg to about 250 mg, from about 250 mg to about 350 mg, from about 350 mg to about 450 mg, from about 450 mg to about 550 mg, from about 550 mg to about 650 mg, from about 650 mg to about 750 mg, from about 850 mg to about 950 mg, or from about 950 mg to about 1050 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0020] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg or about 1,000 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0021] 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0022] 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0023] In some embodiments, the at least one pharmaceutically acceptable excipient is a filler, a disintegrant, a binder, a glidant, a lubricant, or any combination thereof. In some embodiments, the at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate, colloidal silicon dioxide, or any combination thereof.

[0024] In some embodiments, the pharmaceutical composition is stable at a temperature of about 2°C to about 25°C for up to 36 months. In some embodiments, the pharmaceutical composition is stable at a temperature of about 2°C to about 8°C for a period of about 24 months to about 36 months. In some embodiments, when stored as a solid, the pharmaceutical composition is stable at a temperature of about 2°C to about 25°C for up to 36 months. In some embodiments, when stored as a solid, the pharmaceutical composition is stable at a temperature of about 2°C to about 8°C for a period of about 24 months to about 36 months. In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0025] In one aspect, provided herein is a pharmaceutical composition comprising:

[0026] (i) a compound of formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0027] (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for administration or application by injection.

[0028] In some embodiments, the pharmaceutical composition is in a dosage form for intravenous (IV) injection or infusion, or intramuscular, subcutaneous, or intradermal injection.

[0029] In some embodiments, the pharmaceutical composition is a dosage form for intravenous injection or infusion. In some embodiments, the dosage form is an intravenous dosage form. In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the dosage form comprises a cosolvent.

[0030] In some embodiments, the cosolvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremephor, glycerol, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert-butyl alcohol, or any combination thereof. In some embodiments, the dosage form further comprises an oil. In some embodiments, the oil comprises sesame oil, soybean oil, vegetable oil, poppy seed oil, safflower oil, or a combination thereof.

[0031] In some embodiments, the dosage form further comprises a buffer. In some embodiments, the intravenous dosage form 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.

[0032] In some embodiments, the pH of the pharmaceutical composition is from about 2.5 to about 11.0. In some embodiments, the pH of the pharmaceutical composition is from about 2.5 to about 5.0 or from about 6.5 to about 10.5. In some embodiments, the pH of the pharmaceutical composition is from about 2.5 to about 4.5 or from about 7.0 to about 9.0.

[0033] In some embodiments, the pharmaceutical composition is formulated for intravenous administration with its pH adjusted with hydrochloric acid and / or sodium hydroxide.

[0034] In some embodiments, the pharmaceutical composition comprises about 5 mg / mL to about 250 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg / mL to about 50 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0035] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 40 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof. 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 a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for up to about 24 months. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C for a period of about 12 months to about 24 months. In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0036] In some embodiments, the compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is crystalline, microcrystalline, amorphous, or lyophilized.

[0037] 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 lyophilized.

[0038] In some embodiments, the pharmaceutical composition is substantially free of 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 up to about 10% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition comprises less than about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition comprises less than about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition comprises less than 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) of at least one impurity.

[0039] In some embodiments, the at least one impurity is a degradant: In some embodiments, the at least one impurity is:

[0040] or any combination thereof.

[0041] In some embodiments, the at least one impurity is:

[0042]

[0043] In some embodiments, the pharmaceutical composition comprises up to about 4.0% (w / w) total impurities.

[0044] In some embodiments, the pharmaceutical composition comprises no more than about 0.5% (w / w) of any individual impurity. In some embodiments, the pharmaceutical composition comprises no more than about 1.5% (w / w) of the following compounds:

[0045]

[0046] In another aspect, a compound composition is provided, comprising:

[0047] (i) a compound of formula (I); or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one antifungal agent.

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

[0049] In one aspect, the present invention provides a compound composition comprising:

[0050] (i) Compound of formula (I):

[0051]

[0052] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0053] (ii) Compounds of formula (II)

[0054]

[0055] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0056] In some embodiments, the compounded composition further comprises at least one pharmaceutically acceptable excipient.

[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 both crystalline.

[0058] 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.

[0059] In one aspect, provided herein is a method for treating or preventing a fungal infection or disease, comprising administering to a subject in need thereof a therapeutically effective amount of any pharmaceutical composition or combination of compositions described herein.

[0060] In some embodiments of the methods provided herein, the subject is administered from about 10 mg to about 8,000 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the subject is administered from about 10 mg to about 2,400 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the subject is administered about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, about 1,500 mg, about 1,800 mg, about 2,000 mg, about 2,100 mg, about 2,400 mg, about 2,500 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, or about 8,000 mg of a compound of Formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0061] In some embodiments of the methods 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to the subject. In some embodiments of the methods 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to the subject.

[0062] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject once a day, twice a day, three times a day, or four times a day. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject once a day. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject twice a day.

[0063] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of up to about 12 weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of at least one week. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of at least two weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of up to about 2 weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of one week, two weeks, 6 weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks.

[0064] In some embodiments of the methods provided herein, the subject is administered about 10 mg to about 8,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the subject is administered about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, or about 2,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0065] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous 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.

[0066] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous infusion over a period of up to about 3 hours.

[0067] In some embodiments of the methods provided herein, a loading dose is administered to the subject, followed by a maintenance dose. In some embodiments of the methods provided herein, the loading dose comprises about 1,000 mg to about 8,000 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg to about 2,400 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the methods provided herein, the loading dose comprises about 1,000 mg to about 2,000 mg. In some embodiments of the methods provided herein, the loading dose is administered by intravenous infusion over a period of about 2 hours to about 3 hours. In some embodiments of the methods provided herein, the loading dose is administered twice on the first day of treatment. In some embodiments of the methods provided herein, a second loading dose is administered about 9 hours after the first loading dose.

[0068] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg, about 700 mg, about 800 mg, about 900 mg or about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof. In some embodiments of the methods provided herein, the maintenance dose comprises about 800 mg or about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof, and is administered orally.

[0069] In some embodiments of the methods provided herein, the maintenance dose comprises administering about 600 mg or about 900 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof by intravenous infusion over a period of about 1 hour to about 3 hours.

[0070] In some embodiments of the methods provided herein, the method of any one of embodiments 157-164, wherein about 600 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 3 hours.

[0071] In some embodiments of the methods provided herein, the maintenance dose is administered once daily.

[0072] In some embodiments of the methods provided herein, the maintenance dose is administered once daily starting on the second day of treatment.

[0073] In some embodiments of the methods provided herein, about 600 mg or about 800 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of about 3 hours, starting on the second, third or fourth day of treatment.

[0074] In some embodiments of the methods provided herein, about 800 mg or about 1,000 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is orally administered starting on the second, third or fourth day of treatment.

[0075] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 800 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments of the methods provided herein, the subject is administered to about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments of the methods provided herein, the subject is administered to about 800 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments of the methods provided herein, about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is administered by intravenous infusion over a period of about 1 hour to about 3 hours, and / or about 800 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is administered orally. In some embodiments of the methods provided herein, the maintenance dose is administered once a day. In some embodiments of the methods provided herein, the maintenance dose is administered once a day starting from the second day of treatment. In some embodiments of the methods provided herein, about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by intravenous infusion over a period of about 3 hours.

[0076] In some embodiments of the methods provided herein, about 600 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of about 3 hours, beginning on the second day of treatment.

[0077] In some embodiments of the methods provided herein, about 800 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is orally administered, starting on the fourth day of treatment.

[0078] In some embodiments of the methods provided herein, the fungal infection is caused by an invasive fungus. In some embodiments of the methods provided herein, the method further comprises administering to the subject at least one antifungal agent in combination with the pharmaceutical composition comprising a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0079] In some embodiments of the methods provided herein, the at least one antifungal agent is an azole, an echinocandin, amphotericin B deoxycholate, amphotericin B lipid coil, 5-flucytosine, terbinafine, griseofulvin, VL-2397, ibrexafungerp, orotomide F901318, or a combination thereof. In some embodiments of the methods provided herein, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavuconazole, or miconazole. In some embodiments of the methods provided herein, the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin, or a combination thereof.

[0080] In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate and the antifungal agent are administered simultaneously, approximately simultaneously or sequentially in any order. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate and the antifungal agent are administered simultaneously or approximately simultaneously. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate and the antifungal agent are administered sequentially. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate or its pharmaceutically acceptable salt is administered before the at least one antifungal agent. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutically acceptable salt thereof is administered after the at least one antifungal agent.

[0081] In some embodiments of the methods provided herein, the fungal infection or disease is caused by Aspergillus fumigatus, Blastomyces, Ajellomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Rhizopus Muco, Cunninghamell, Apophysomyces, Absidia, Saksenaea, Entomophthora, Conidiobolus, Basidiobolus, Sporothrix, Pneumocystis, Talaromyces, Asclepias, Fusarium, Scedosporium, or Mucorales fungi, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus, Aspergillus, Candida, Fusarium, Scedosporium, or Mucorales fungi, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Histoplasma dermatitidis, Candida albicans, Candida glabrata, Candida rugosa, Candida auris, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus graminearum, Rhizopus arrhizus, Mucor indica, Cunninghamella griseus, Elegant scale mold, Absidia species, Bottle mold species, Rhizomucor microti, Entomophthora species, Ear mold species, Frog feces species, Sporothrix schenckii, Pneumocystis jiroveci, Marneffei blue-shaped fungi, Asclepias albicans, Fusarium solani, Scedosporium apex, Rhizomucor microti, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus fungi or Candida fungi. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gattii, or Candida auris.

[0082] In some embodiments of the methods provided herein, the fungal infection or disease is azole-resistant and / or echinocandin-resistant.

[0083] In some embodiments of the methods provided herein, the subject is immunocompromised. In some embodiments of the methods provided herein, the subject is infected with HIV / AIDS or suffers from cancer. In some embodiments of the methods provided herein, the subject suffers from cancer. In some embodiments of the methods provided herein, the cancer is acute myeloid leukemia (AML). In some embodiments of the methods provided herein, the subject suffers from neutropenia. In some embodiments of the methods provided herein, the subject is experiencing or has experienced cancer chemotherapy treatment. In some embodiments of the methods provided herein, the subject is experiencing or has experienced corticosteroid treatment. In some embodiments of the methods provided herein, the subject is experiencing or has experienced TNF inhibitor treatment. In some embodiments of the methods provided herein, the subject is a transplant recipient. In some embodiments of the methods provided herein, the fungal infection or disease is in the bloodstream of the subject. In some embodiments of the methods provided herein, the subject reduces pulmonary fungal colony counts after administering the pharmaceutical composition.

[0084] In some embodiments of the methods provided herein, the plasma concentration versus time curve of the compound of Formula (I) in the subject has a t of less than about 30 minutes to about 180 minutes. max In some embodiments of the methods provided herein, the subject has a maximum plasma concentration (C ) of the compound of Formula (I) of about 12,000 ng / mL to about 25,000 ng / mL. max ).

[0085] Incorporation by reference

[0086] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Figures 1A-1B The geometric mean plasma concentration of Compound 1A after intravenous infusion of 10 to 1000 mg of Compound 1 in healthy subjects over 3 hours - Linear ( Figure 1A ) and semi-logarithm ( Figure 1B )axis.

[0088] Figures 2A-2B The geometric mean plasma concentration of Compound 1A following intravenous infusion of 1000 mg in healthy subjects over 0.5 to 3 hours was linear ( Figure 2A ) and semi-logarithm ( Figure 2B )axis.

[0089] Figures 3A-3B . The geometric mean plasma concentration of compound 1A was linear after intravenous infusion of 50, 150, 300 and 600 mg of compound 1 to healthy subjects within 3 hours according to qd×14 days. Figure 3A ) and semi-logarithm ( Figure 3B )axis.

[0090] Figures 4A-4B The geometric mean plasma concentration of Compound 1A was linear ( Figure 4A ) and semi-logarithm ( Figure 4B )axis.

[0091] Figures 5A-5B The geometric mean plasma concentration of Compound 1 after intravenous infusion of 10 to 350 mg of Compound 1 within 3 hours and administration of 1000 mg within 0.5 to 3 hours to healthy subjects - linear ( Figure 5A ) and semi-logarithm ( Figure 5B )axis.

[0092] Figures 6A-6B . The geometric mean plasma concentration of Compound 1 was linear ( Figure 6A ) and semi-logarithm ( Figure 6B )axis.

[0093] Figures 7A-7B The geometric mean plasma concentration of Compound 1 was linear ( Figure 7A ) and semi-logarithm ( Figure 7B )axis.

[0094] Figures 8A-8B The geometric mean plasma concentration of Compound 1A after intravenous infusion of 200 mg of Compound 1 and oral doses of 100 to 500 mg in healthy subjects in the fasting state within 3 hours - Linear ( Figure 8A ) and semi-logarithm ( Figure 8B )axis.

[0095] Figures 9A-9B After oral administration of 400 mg of Compound 1 to healthy subjects in the fasting and fed states, the geometric mean plasma concentration of Compound 1A - Linear ( Figure 9A ) and semi-logarithm ( Figure 9B )axis.

[0096] Figures 10A-10B . Geometric mean plasma concentration of Compound 1A after oral administration of 500 and 1000 mg of Compound 1 to healthy subjects in the fed state QD×14 days - Linear ( Figure 10A ) and semi-logarithm ( Figure 10B )axis.

[0097] Figure 11 .Dissolution profile of 400 mg Compound 1 tablets. DETAILED DESCRIPTION

[0098] Provided herein are, for example, compositions for treating and / or preventing fungal infections or diseases. Also provided herein are, for example, methods for treating and / or preventing fungal infections or diseases.

[0099] I. Definition

[0100] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.Chemical structures and formulae depicted herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0101] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0102] It will be apparent to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present invention. Unless otherwise indicated, structures shown herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, in addition to the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by 13 C- or 14 Compounds having the present structure other than C-enriched carbon substitutions are also within the scope of the invention.

[0103] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be treated with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0104] The term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more atoms that constitute the compound. In some embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to 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 I). In some embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In some embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen-14 ( 14N), 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 I). In some embodiments, an "isotopic variant" of a compound is in an unstable form, i.e., radioactive. In some embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to 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 I) It is understood that in the compounds provided herein, for example, any hydrogen may be 2 H, or any carbon can be 13 C, or for example any nitrogen may be 15 N, or any oxygen, for example, may be 18 O, as is feasible according to the judgment of one skilled in the art. In some embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium (D).

[0105] It should be noted that throughout the application, alternatives are written as Markush groups, e.g., each amino acid position contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately to include another embodiment, and that the Markush group should not be construed as a single unit.

[0106] As used herein, the term "a" or "an" refers to one or more (one or more). In addition, as used herein, the phrase "substituted with" means that the specified group may be substituted with one or more of any or all of the substituents. For example, in the case of a group such as an alkyl or heteroaryl group, "substituted with unsubstituted C1-C 20 When "substituted by alkyl or unsubstituted 2 to 20 membered heteroalkyl", the group may contain one or more unsubstituted C1-C 20 Alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl.As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.

[0107] As used herein, the term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts, i.e., salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or 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 compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine salts and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts, or to exist as zwitterions.

[0108] Therefore, the compound of the present invention can exist in salt form, for example, the salt formed with a pharmaceutically acceptable acid. The present invention includes this type of salt. The limiting examples of this type of salt include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (for example (+)-tartrate, (-)-tartrate or its mixture, including racemic mixture), succinate, benzoate, and the salt formed with amino acids such as glutamic acid, and quaternary ammonium salts (for example, methyl iodide, ethyl iodide etc.). These salts can be prepared by methods well known to those skilled in the art.

[0109] Preferably, the neutral form of the compound is regenerated by contacting the salt with an alkali or acid and separating the parent compound in a conventional manner. The parent form of the compound may be different from various salt forms in terms of certain physical properties (such as solubility in polar solvents). In some embodiments, the compound of the present invention comprises both alkaline and acidic functionality, which allows the compound to be converted into base addition salts or acid addition salts. The neutral form of the compound can be regenerated by contacting the salt with an alkali or acid and separating the parent compound in a conventional manner. The parent form of the compound is different from various salt forms in terms of certain physical properties (such as solubility in polar solvents), but, unless otherwise stated, for the present invention, salt disclosed herein is equivalent to the parent form of the compound.

[0110] In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein can be converted in vivo following administration. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, upon contact with an appropriate enzyme or chemical reagent.

[0111] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the intended use of the present invention and are intended to fall within the scope of the present invention.

[0112] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of a compound to a subject and absorption by the subject and that can be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solution, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such preparations can be sterile and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, colorants and / or aromatic substances that do not react adversely with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0113] The term "article of manufacture" is intended to include the formulation of the active compound with an encapsulating material as a carrier, providing a capsule in which the active component, with or without other carriers, is surrounded by the carrier, thereby being in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0114] The term "disease" or "condition" refers to a state or health condition of a patient or subject that can be treated with the compounds or methods provided herein. The disease can be a fungal infection. In other cases, "fungal infection or disease" refers to a fungal infection or disease in humans, including Cryptococcus, Aspergillus, or Candida diseases or infections.

[0115] As used herein, the term "fungal infection" or "fungal disease" refers to a disease caused by a pathogenic fungus. Fungal infection can be an opportunistic infection or a primary infection and can be caused by fungi such as yeast and / or mold.

[0116] The terms "treat" or "treatment" refer to any marker of success in the treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as alleviation, remission, reduction of symptoms, or making the patient more tolerant to the injury, pathology, or condition; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; and improving the patient's physical or mental well-being. Treatment or improvement of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treat" and variations thereof can include prevention of an injury, pathology, condition, or disease. In some embodiments, treatment is prevention. In other embodiments, treatment does not include prevention.

[0117] "Treat," "treat," "alleviate," or "improve" are used interchangeably herein. These terms, as used herein (and as known in the art), also broadly include any method for obtaining a beneficial or desired result (including a clinical result) in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviating or improving one or more symptoms or conditions, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread or spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, reducing recurrence of the disease, and remission, whether partial or complete, and whether detectable or undetectable. In other words, "treating," as used herein, includes any cure, improvement, or prevention of a disease. Treatment can prevent the occurrence of the disease; inhibit the spread of the disease; alleviate the symptoms of the disease (e.g., itching, swelling, burning, coughing, fever, chest pain, difficulty breathing), completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or a combination of these.

[0118] As used herein, "treatment" and "treating" include prophylactic treatment. The treatment method comprises administering to the subject a therapeutically effective amount of a compound described herein. The administration step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, 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 understood that the effective dose of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. Changes in dosage can be determined and become apparent by standard diagnostic tests known in the art. In some cases, long-term administration may be required. For example, the composition is administered to the subject in an amount and for a duration sufficient to treat the patient.

[0119] The terms "prevention" and "prevention" refer to reducing the occurrence of disease symptoms in a patient. Prevention or prevention can be complete (no detectable symptoms) or partial, so that the observed symptoms are fewer than those that would occur without treatment. In some embodiments, prevention refers to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state. "Patient" or "subject in need" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals, including but not limited to fish and birds. In some embodiments, the patient is a human.

[0120] Treating as referred to herein also refers to the systemic delivery of the compounds disclosed herein to any type of plant, including trees, shrubs, flowering plants, foliage plants, houseplants, groundcovers and grasses, as well as agronomic plants (including crops of agronomic plants).

[0121] As used herein, a "hydrate" is a compound that contains water in stoichiometric or non-stoichiometric amounts and, in some embodiments, is formed during crystallization with water.

[0122] As used herein, the term "agronomic plant" refers to a plant that is or has been harvested or cultivated on a commercial scale, in part or in whole, or used as a significant source of feed, food, fiber, or other chemical compounds.

[0123] An "effective amount" is an amount sufficient to enable the compound to achieve the stated purpose relative to the absence of the compound (e.g., to achieve the effect to which it is administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce an enzyme signaling pathway, or to alleviate one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." "Alleviating" one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of one or more symptoms, or eliminating one or more symptoms. A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has the intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete prophylactic effect does not necessarily occur by administering one dose, but may also occur only after administering a series of doses. Thus, a prophylactic effective amount may be administered by one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce enzyme activity relative to the absence of the antagonist. As used herein, "function-destroying amount" refers to the amount of antagonist required for the function of an enzyme or protein relative to the absence of an antagonist. The exact amount will depend on the purpose of the treatment, and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be determined by measuring the relevant physiological effects, and can be adjusted according to the diagnostic analysis of the dosage regimen and subject's condition, etc. For example, measuring serum levels of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof (e.g., or a metabolite thereof) at a particular time after administration can indicate whether a therapeutically effective amount has been administered.

[0124] For any compound described herein, the therapeutically effective amount can be determined initially from cell culture assays.The target concentration will be that concentration of active compound that is capable of achieving the methods described herein as measured using methods described herein or known in the art.

[0125] As is known in the art, therapeutically effective amounts for humans can also be determined from animal models. For example, a dosage for humans can be formulated to achieve a concentration that has been found to be effective in animals. As described above, the dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward. Adjusting the dosage to achieve maximum efficacy in humans based on the above methods and other methods is well within the capabilities of ordinary technicians. Adjusting the dosage to achieve maximum therapeutic window efficacy or toxicity in humans based on the above methods and other methods is well within the capabilities of ordinary technicians.

[0126] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to alleviate a condition as described above. For example, for a given parameter, a therapeutically effective amount 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 can also be expressed as an increase or decrease "fold." For example, a therapeutically effective amount can have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to a control.

[0127] The dosage can vary depending on the needs of the patient and the compound being used. In the context of the present invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature, and extent of any adverse side effects. Determination of the appropriate dosage for a particular situation is within the skill of the skilled person. Typically, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect in these circumstances is achieved. The dosage and interval can be individually adjusted to provide a level of the administered compound that is effective for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0128] As used herein, the term "administer" means parenteral or enteral administration. Therefore, as used herein, the term "administer" refers to subject administration, including but not limited to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, inhalation, atomization, intralesional, intrathecal, intracranial, intranasal, subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump. Administration is carried out by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal) administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Other delivery methods include, but are not limited to, the use of liposome preparations, intravenous infusion, transdermal patches, by eye route, by ear route, etc. So-called "co-administered" means that compositions as described herein are administered while, before or immediately after administering one or more additional therapies (e.g., antifungal, antibacterial, antiviral and / or chemotherapeutic agents). The compound of the present invention can be administered alone or can be administered to the patient in combination. Co-administration is intended to include simultaneous, approximately simultaneous, or sequential administration of the compounds, alone or in combination (more than one compound or agent). Thus, the preparations may also be combined with other active substances, as desired (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally, topically, and formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for patient ingestion. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present invention may further comprise components that provide sustained release and / or comfort. Such components include high molecular weight, anionic mucosimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices. These components are discussed in more detail in U.S. Patents 4,911,920, 5,403,841, 5,212,162 and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered in the form of microspheres for slow release in vivo. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); as a biodegradable and injectable gel formulation (see, for example, Gao Pharm. Res. 12: 857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997).In another embodiment, the preparation of the composition of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, that is, by using a receptor ligand attached to the liposome that binds to the cell's surface membrane protein receptor, thereby causing endocytosis. By using liposomes, especially when the liposome surface carries a receptor ligand specific for a target cell or preferentially targets a specific organ, the delivery of the composition of the present invention to the target cell in vivo can be focused. (See, for example, Al-Muhammed, J. Microencapsul. 13: 293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6: 698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989). The composition of the present invention can also be delivered as nanoparticles.

[0129] By "co-administration" is meant that the compositions described herein are administered simultaneously with, immediately before, or after the administration of one or more additional therapies. The compounds of the present invention may be administered alone or co-administered to the patient. Co-administration is intended to include simultaneous or sequential administration of the compounds alone or in combination (more than one compound). The compositions of the present invention may be delivered transdermally, topically, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0130] For any compound described herein, the therapeutically effective amount can be determined initially from cell culture assays.The target concentration will be that concentration of active compound that is capable of achieving the methods described herein as measured using methods described herein or known in the art.

[0131] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dosage for use in humans can be formulated to achieve a concentration that has been found to be effective in animals. As described above, the dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward. Adjusting the dosage to achieve maximum efficacy in humans based on the above methods and other methods is well within the capabilities of ordinary skill.

[0132] The dosage can vary depending on the needs of the patient and the compound being used. In the context of the present invention, the dosage administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature, and extent of any adverse side effects. Determination of the appropriate dosage for a particular situation is within the skill of the skilled artisan. Typically, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect under the circumstances is achieved.

[0133] Dosage amount and interval can be adjusted individually to provide levels of the administered compound that are effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0134] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity but effectively treats the clinical symptoms exhibited by a particular patient. Such a plan should involve careful selection of the active compound by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred route of administration, and the toxicity profile of the selected agent.

[0135] The compounds described herein can be used in combination with each other and with other active agents known to be useful in treating infections (eg, fungal infections).

[0136] In some embodiments, co-administration includes administering an active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other) or in any order. In some embodiments, co-administration can be accomplished by co-formulating, i.e., preparing a single pharmaceutical composition comprising two active agents. In other embodiments, active agents can be formulated separately. In another embodiment, active agents and / or adjuvants can be connected or conjugated to each other. In some embodiments, the compounds described herein can be combined with the treatment for infection (e.g., fungal infection, bacterial infection, viral infection, etc.).

[0137] The compounds described herein can be administered to treat fungal infections or diseases. In this regard, the compounds disclosed herein can be administered alone to treat such infections or diseases, or can be co-administered with another therapeutic agent to treat such infections or diseases.

[0138] The compounds disclosed herein can be co-administered with antifungal agents such as polyenes, azoles, nucleoside analogs, echinocandins, and allylamines.

[0139] "Antifungal agent" is used in its ordinary sense to refer to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has antifungal properties or the ability to inhibit fungal growth or proliferation. In some embodiments, an antifungal agent is an agent identified herein as useful in a method for treating a fungal infection or disease. In some embodiments, an antifungal agent is an agent approved by the FDA or 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, a "cell" as used herein, which refers to a cell that performs metabolic or other functions sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a specific dye, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable offspring. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammals, insects (e.g., Spodoptera litura) and human cells. Cells may be useful when they are naturally non-adhesive or have been treated to be non-adhesive to a surface (e.g., by trypsinization).

[0140] "Control" or "controlled experiment" is used in its ordinary sense to refer to an experiment in which the subjects or reagents of the experiment are treated the same as in a parallel experiment, except that the experimental procedures, reagents, or variables are omitted. In some cases, the control is used as a comparison standard for evaluating the effects of the experiment. In some embodiments, the control is a measurement of protein activity in the absence of a compound described herein, including embodiments and examples.

[0141] The phrase "in an amount sufficient to effect a change" means that there is a detectable difference between the level of an indicator measured before (e.g., baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject's sense of well-being).

[0142] "Substantially pure" means that the composition comprises more than about 75% of the total content of the composition except the excipient, and is generally greater than about 85% of the total content. More typically, "substantially pure" refers to a composition in which at least 90%, at least 95%, at least 96%, at least 97% or more of the total composition except the excipient is a component of interest. In some cases, the component of interest will comprise greater than about 90%, greater than about 95% or greater than about 96% (percentage on a weight / weight basis) of the total content of the composition except the excipient. "Substantially pure" means that the composition contains less than, up to or no more than about 25%, 15%, 10%, 5% or 4% known or unknown impurities. Impurities do not include excipients (e.g., binders, fillers, diluents, glidants, lubricants, disintegrants, etc.).

[0143] I. Composition

[0144] In one aspect, provided herein is a pharmaceutical composition comprising:

[0145] (i) Compound of formula (I):

[0146]

[0147] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0148] (ii) at least one pharmaceutically acceptable excipient,

[0149] at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or application.

[0150] In another aspect, a pharmaceutical composition is provided, comprising:

[0151] (i) fine particles of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0152] (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or application or in a dosage form for delivery by inhalation.

[0153] 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.

[0154] In some embodiments, the particles are nanomilled. In some embodiments, at least about 10% of the particles have a particle size of about 1 nm 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.

[0155] In some embodiments, the dosage form is a self-microemulsifying drug delivery system (SMEDDS). In some embodiments, the dosage form is a self-emulsifying drug delivery system (SEDDS). In some embodiments, the dosage form is a suspension or solution. In some embodiments, the suspension is a colloidal suspension. In some embodiments, the dosage form is a nanosuspension. In some embodiments, the dosage form is a solid dosage form. In some embodiments, the dosage form is a spray-dried dispersion dosage form. In some embodiments, the dosage form is a hot-melt granulation dosage form. In some embodiments, the dosage form is a hot-melt extrusion dosage form. In some embodiments, the dosage form is a microprecipitated bulk powder (MBP) dosage form. In some embodiments, the dosage form is a liquid. In some embodiments, the dosage form is a suspension, solution, syrup or elixir. In some embodiments, the pharmaceutical composition is a dosage form for oral administration or application.

[0156] In some embodiments, the dosage form is a tablet or capsule. In some embodiments, the tablet or capsule has an enteric coating. In some embodiments, the dosage form is a tablet. In some embodiments, the tablet is an osmotic floating tablet. In some embodiments, the capsule is a liquid-filled hard capsule. In some embodiments, the capsule is a soft gelatin capsule.

[0157] In some embodiments, the dosage form is a modified release dosage form. In some embodiments, the modified release dosage form is a delayed release dosage form, an extended release (ER) dosage form, or a targeted release dosage form. In some embodiments, the ER dosage form is a sustained release (SR) dosage form or a controlled release (CR) dosage form. In some embodiments, the dosage form is an immediate release dosage form.

[0158] In some embodiments, the pharmaceutical composition comprises from about 10 mg to about 1,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical composition comprises from about 50 mg to about 600 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, from about 50 mg to about 150 mg, from about 150 mg to about 250 mg, from about 250 mg to about 350 mg, from about 350 mg to about 450 mg, from about 450 mg to about 550 mg, from about 550 mg to about 650 mg, from about 650 mg to about 750 mg, from about 850 mg to about 950 mg, or from about 950 mg to about 1050 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0159] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg or about 1,000 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0160] 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0161] 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0162] In some embodiments, the at least one pharmaceutically acceptable excipient is a filler, a disintegrant, a binder, a glidant, a lubricant, or any combination thereof. In some embodiments, the at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate, colloidal silicon dioxide, or any combination thereof.

[0163] 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 months to about 36 months at a temperature of about 2° C. to about 8° C.

[0164] In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0165] In one aspect, provided herein is a pharmaceutical composition comprising:

[0166] (i) a compound of formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0167] (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for administration or administration by intravenous (IV), intramuscular, subcutaneous or intradermal injection.

[0168] In some embodiments, the compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is crystalline, microcrystalline, amorphous, or lyophilized.

[0169] 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 lyophilized.

[0170] In some embodiments, the dosage form is an intravenous dosage form. In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the dosage form comprises a cosolvent.

[0171] In some embodiments, the cosolvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremephor, glycerol, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), tert-butyl alcohol, or any combination thereof. In some embodiments, the dosage form further comprises an oil. In some embodiments, the oil comprises sesame oil, soybean oil, vegetable oil, poppy seed oil, safflower oil, or a combination thereof. In some embodiments, the dosage form further comprises a buffer. In some embodiments, the intravenous dosage form 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.

[0172] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 6.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 6.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 5.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 2.5 to about 5.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 2.5 to about 4.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 2.5 to about 4.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 2.5 to about 3.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 2.5 to about 3.0.

[0173] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 6.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 6.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 5.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 5.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 4.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 4.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.0 to about 3.5. In some embodiments of the pharmaceutical composition disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 10.5. In some embodiments of the pharmaceutical composition disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form.In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 6.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 6.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 5.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 5.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 4.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 3.5 to about 4.0.

[0174] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 6.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 6.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 5.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.0 to about 5.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 4.0 to about 4.5.

[0175] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 6.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 6.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 5.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 4.5 to about 5.0.

[0176] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 6.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 6.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.0 to about 5.5.

[0177] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 6.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 5.5 to about 6.0.

[0178] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 7.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.0 to about 6.5.

[0179] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 8.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 7.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 6.5 to about 7.0. In some embodiments of the pharmaceutical composition disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 7.0 to about 11.0. In some embodiments of the pharmaceutical composition disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 7.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.0 to about 9.0. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.0 to about 8.5. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.0 to about 8.0.In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.0 to about 7.5.

[0180] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 7.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 7.5 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 7.5 to about 8.5. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is from about 7.5 to about 8.0.

[0181] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.0 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.0 to about 9.0. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.0 to about 8.5.

[0182] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.5 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 8.5 to about 9.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.5 to about 9.0.

[0183] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 9.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 9.0 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 9.0 to about 10.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions in which the dosage form is an intravenous dosage form, the pH is from about 9.0 to about 9.5.

[0184] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions wherein the dosage form is an intravenous dosage form, the pH is from about 9.5 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions wherein the dosage form is an intravenous dosage form, the pH is from about 9.5 to about 10.5. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions wherein the dosage form is an intravenous dosage form, the pH is from about 9.5 to about 10.0.

[0185] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form. In some embodiments of the pharmaceutical compositions wherein the dosage form is an intravenous dosage form, the pH is from about 10.0 to about 11.0. In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (i.e., infusion) dosage form.

[0186] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form is an intravenous (ie, infusion) dosage form. In some embodiments of the pharmaceutical compositions wherein the dosage form is an intravenous dosage form, the pH is about 10.5 to about 11.0.

[0187] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 2.5.

[0188] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 3.0.

[0189] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 3.5.

[0190] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 4.0.

[0191] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 4.5.

[0192] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 5.0.

[0193] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 5.5.

[0194] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.0.

[0195] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.1.

[0196] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.2.

[0197] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.3.

[0198] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.4.

[0199] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.5.

[0200] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.6.

[0201] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.6.

[0202] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.8.

[0203] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 6.9.

[0204] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.0.

[0205] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.1.

[0206] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.2.

[0207] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.3.

[0208] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.4.

[0209] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.5.

[0210] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.6.

[0211] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.7.

[0212] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.8.

[0213] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 7.9.

[0214] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.0.

[0215] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.1.

[0216] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.2.

[0217] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.3.

[0218] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.4.

[0219] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.5.

[0220] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.6.

[0221] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.7.

[0222] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.8.

[0223] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 8.9.

[0224] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.0.

[0225] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.1.

[0226] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.2.

[0227] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.3.

[0228] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.4.

[0229] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.5.

[0230] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.6.

[0231] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.9.

[0232] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.8.

[0233] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 9.9.

[0234] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.0.

[0235] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.1.

[0236] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.2.

[0237] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.3.

[0238] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.4.

[0239] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.5.

[0240] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.6.

[0241] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.7.

[0242] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.8.

[0243] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 10.9.

[0244] In some embodiments of the pharmaceutical composition wherein the dosage form is an intravenous dosage form, the pH is about 11.0.

[0245] In some embodiments, the pharmaceutical composition is formulated for intravenous administration at a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is formulated for intravenous administration at 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 formulated for intravenous administration at a pH of about 2.5 to about 4.5 or about 7.0 to about 5.0. In some embodiments, the pharmaceutical composition is formulated for intravenous administration at a pH adjusted with hydrochloric acid and / or sodium hydroxide.

[0246] In some embodiments, the pharmaceutical composition comprises about 5 mg / mL to about 250 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg / mL to about 50 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0247] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 40 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof. 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 a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for up to about 24 months. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C for a period of about 12 months to about 24 months. In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0248] In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for up to about 24 months when stored as a liquid. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C for a period of about 12 months to about 24 months when stored as a liquid. In some embodiments, the pharmaceutical composition is stored in a pH-insensitive container. In some embodiments, the pH-insensitive container is composed of glass or plastic. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for up to about 24 months when stored as a liquid in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for a period of about 12 months to about 24 months when stored as a liquid in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for a period of about 12 months to about 24 months when stored as a liquid in a pH-insensitive container. In some embodiments, the pharmaceutical composition is stable at a temperature of about -20°C to 8°C for up to about 24 months when stored as a liquid at a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is stable for a period of about 12 months to about 24 months at a temperature of about -20°C when stored as a liquid at a pH of about 2.5 to about 11.0. In some embodiments, the pharmaceutical composition is stable for a period of about 12 months to about 24 months at a temperature of about -20°C to 8°C when stored as a liquid at 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 months to about 24 months at a temperature of about -20°C when stored as a liquid at a pH of about 2.5 to about 11.0 in a pH-insensitive container.

[0249] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, suitable dosage levels of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, are generally 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 1000 to about 2000 mg, or about 600 to about 800 mg, which can be administered in single or multiple doses. In certain embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is present in an amount of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450 , 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, or 8,000 mg. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof 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 an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 600 mg. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 700 mg. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 800 mg. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 900 mg.In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 1,000 mg. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 2,000 mg. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is present at 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, or 8,000 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 10 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 15 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 20 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 25 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 30 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 35 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 40 mg / day.In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 45 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 50 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 100 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 150 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 200 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 300 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 400 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 500 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 600 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 700 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 800 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 900 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 1,000 mg / day. In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered in an amount of about 2,000 mg / day.

[0250] For oral administration, the pharmaceutical compositions provided herein can be formulated into solid dosage forms containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of Formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and 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 isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for symptomatic adjustment of the dosage for the patient to be treated.

[0251] For oral administration, the pharmaceutical compositions provided herein can be formulated into solid dosage forms containing 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 an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a powder. In some embodiments, the solid dosage form is a granule.

[0252] In some embodiments, the pharmaceutical compositions provided herein can be formulated into a solid dosage form containing about 50 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into a solid dosage form containing about 100 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into a solid dosage form containing about 150 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into a solid dosage form containing about 200 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into a solid dosage form containing about 250 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into a solid dosage form containing about 300 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into a solid dosage form containing about 400 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0253] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of Formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and 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 isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for symptomatic adjustment of the dosage to the patient to be treated.

[0254] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets containing 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, 1,500, 1,600, 1,700, 1,800, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 1,800, 1,900, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 1,900, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 1,900, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 1,900, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 8,000, 9,000,

[0255] In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 50 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 100 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 150 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 200 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 250 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 300 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 400 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. For oral administration, the pharmaceutical compositions provided herein can be formulated into a liquid form (e.g., a solution, suspension or syrup) containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of Formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and 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 isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, for symptomatic adjustment of the dosage for the patient to be treated.For oral administration, the pharmaceutical compositions provided herein can be formulated into a liquid form (e.g., a solution, suspension or syrup) containing 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, 1,500, 1,100, 1,200, 1,300, 1,400, or 1,500 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0256] In some embodiments, provided herein are pharmaceutical compositions that can be formulated into liquid forms (e.g., solutions, suspensions, or syrups) containing approximately 50 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein are pharmaceutical compositions that can be formulated into liquid forms (e.g., solutions, suspensions, or syrups) containing approximately 100 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein are pharmaceutical compositions that can be formulated into liquid forms (e.g., solutions, suspensions, or syrups) containing approximately 150 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein are pharmaceutical compositions that can be formulated into liquid forms (e.g., solutions, suspensions, or syrups) containing approximately 200 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein are pharmaceutical compositions that can be formulated into liquid forms (e.g., solutions, suspensions, or syrups) containing approximately 250 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein are pharmaceutical compositions that can be formulated into liquid forms (e.g., solutions, suspensions, or syrups) containing approximately 300 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in a liquid form (e.g., a solution, suspension, or syrup) containing about 400 mg of a compound of Formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0257] In some embodiments, the pharmaceutical compositions provided herein can be formulated as liquid (e.g., intravenous) dosage forms containing about 1.0 to about 1,500 mg or about 1.0 to about 1,000 mg of a compound of Formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and 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 isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for symptomatic adjustment of the dosage to the patient to be treated.

[0258] For oral administration, the pharmaceutical compositions provided herein can be formulated as liquid (e.g., intravenous) dosage forms containing 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 an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0259] In some embodiments, the pharmaceutical compositions provided herein can be formulated into liquid (e.g., intravenous) dosage forms containing about 50 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into liquid (e.g., intravenous) dosage forms containing about 100 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into liquid (e.g., intravenous) dosage forms containing about 150 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated into liquid (e.g., intravenous) dosage forms containing about 200 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein is a pharmaceutical composition that can be formulated into a liquid (e.g., intravenous) dosage form containing about 250 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein is a pharmaceutical composition that can be formulated into a liquid (e.g., intravenous) dosage form containing about 300 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, provided herein is a pharmaceutical composition that can be formulated into a liquid (e.g., intravenous) dosage form containing about 400 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The pharmaceutical composition can be administered in a regimen of 1-4 times a day, including once, twice, three times, and four times a day. In certain embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for one day, followed by 600 mg once a day during the treatment period. In other embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for one day, followed by 800 mg once a day during the treatment period.

[0260] In other embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for one day, followed by 900 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for one day, followed by 1000 mg once a day during the treatment period.

[0261] In certain embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for two days, followed by 600 mg once a day during the treatment period. In other embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for two days, followed by 800 mg once a day during the treatment period. In other embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for two days, followed by 900 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice daily for two days, followed by 1000 mg once daily during the treatment period.

[0262] In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for three days, followed by 600 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for three days, followed by 800 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for three days, followed by 900 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice daily for three days, followed by 1000 mg once daily during the treatment period.

[0263] In certain embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for four days, followed by 600 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for four days, followed by 800 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice a day for four days, followed by 900 mg once a day during the treatment period. In other embodiments, the compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 1,000 mg twice daily for four days, followed by 1000 mg once daily during the treatment period.

[0264] In certain embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 1,000 mg once daily. In certain embodiments, a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is administered to a patient in need thereof in an amount of about 40 mg to about 145 mg, about 40 to about 1,000, about 600 to about 1,000, or about 600 mg to about 2,000 mg per day until disease remission, recovery, or intolerable toxicity.

[0265] In another aspect, a compound composition is provided, comprising:

[0266] (i) a compound of formula (I); or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0267] (ii) at least one antifungal agent.

[0268] In some embodiments, the at least one antifungal agent is an azole, an echinocandin, amphotericin B deoxycholate, amphotericin B lipid coil, 5-flucytosine, terbinafine, griseofulvin, VL-2397, ibrexafungerp, orotomide F901318, or a combination thereof. In some embodiments, the azole is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavuconazole, or miconazole. In some embodiments, the echinocandin is caspofungin, anidulafungin, micafungin, or rezafungin.

[0269] In one aspect, the present invention provides a compound composition comprising:

[0270] (i) Compound of formula (I):

[0271]

[0272] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and

[0273] (ii) Compounds of formula (II)

[0274]

[0275] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0276] In some embodiments, the compounded composition further comprises at least one pharmaceutically acceptable excipient.

[0277] 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 both crystalline.

[0278] 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.

[0279] In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate in the pharmaceutical composition is about 40: 1. In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate in the pharmaceutical composition is about 1:80. In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate in the pharmaceutical composition is about 0.01:100.

[0280] In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate 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, 45:1, 50:1, 60:1, 70:1, 8 ... 0.1:100 or about 0.01:100. In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate 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, 0.1:100 or about 0.01:100.

[0281] In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate in the pharmaceutical composition is about 0.8: 10. In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate in the pharmaceutical composition is about 0.01: 10.

[0282] In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate 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, 10:0.10, 10:0.11, 10:0.12, 10:0.13, 10:0.14, 10:0.15, 10:0.16, 10:0.17, 10:0.18, 10:0.19, 10:0.20, 10:0.21, 10:0.22, 10:0.23, 10:0.24, 10:0.25, 10:0.26, 10:0.27, 10:0.28, 10:0.29, 10:0.30, 10:0.31, 10:0.32, 10:0.33, 10:0.34, 10:0.35, 10:0.36, 10:0.37, 10:0.38, 10:0.39, 10:0.39, 10:0.31 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate 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, 10:0.10, 10:0.11, 10:0.12, 10:0.13, 10:0.14, 10:0.15, 10:0.16, 10:0.17, 10:0.18, 10:0.19, 10:0.20, 10:0.21, 10:0.22, 10:0.23, 10:0.24, 10:0.25, 10:0.26, 10:0.27, 10:0.28, 10:0.29, 10:0.29, 10:0.29, 10:0.2 10, 0.5:10, 0.4:10, 0.3:10, 0.2:10, or about 0.1:10.

[0283] In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate in the pharmaceutical composition is about 1:5.

[0284] In certain embodiments, the ratio of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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 (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate to the compound of formula (II) or its isotopic variant, 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. In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is substantially pure. In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is substantially free of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 10.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 9.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 8.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 7.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 6.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 5.0%. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 4.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 3.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 3.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 3.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 3.6% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 3.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 3.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 3.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 3.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 3.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 3.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 2.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 2.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of less than about 2.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.6% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 1.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.1%. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of less than about 0.05% (w / w).

[0285] In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is substantially free of impurities. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 10.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 9.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 8.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 7.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 6.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 5.0%. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 4.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 3.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 3.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 3.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 3.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 3.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 3.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 3.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 3.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 3.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 3.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 2.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of at most about 2.8% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 2.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.8% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 1.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of no more than about 1.1% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of no more than about 1.0% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of no more than about 0.9% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as having an impurity content of no more than about 0.8% (w / w).In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.7% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.6% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.5% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.4% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.3% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.2% (w / w). In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.1%. In some embodiments of the pharmaceutical compositions disclosed herein, substantially free of impurities is defined as an impurity content of no more than about 0.05% (w / w).

[0286] In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 90% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 91% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 92% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 93% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 94% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 95% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 96% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 97% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 98% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at least about 99% pure. In some embodiments of the pharmaceutical compositions 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.

[0287] In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 90% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 91% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 92% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 93% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 94% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 95% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 96% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 97% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 98% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are at most about 99% pure. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is at most 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.

[0288] In some embodiments of the pharmaceutical compositions disclosed herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate contains less than about 10% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 9% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 8% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 7% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 6% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 5% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 4% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 3% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 2% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition contains less than about 1% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.9% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.8% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.7% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.6% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.5% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.4% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.3% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.2% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises less than about 0.1% of at least one impurity.

[0289] In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 10% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 9% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 8% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 7% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 6% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 5% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 4% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 3% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 2% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 1% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions contain up to about 0.9% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.8% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.7% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.6% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.5% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.4% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.3% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.2% of at least one impurity. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises at most about 0.1% of at least one impurity.

[0290] In some embodiments, the pharmaceutical composition is substantially free of 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 up to about 10% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition comprises less than about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition comprises less than about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), or about 1% (w / w) of at least one impurity. In some embodiments, the pharmaceutical composition comprises less than 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) of at least one impurity.

[0291] In some embodiments, the at least one impurity is a degradant: In some embodiments, the at least one impurity is:

[0292]

[0293]

[0294] or any combination thereof.

[0295] In some embodiments, the at least one impurity is:

[0296]

[0297] In some embodiments, the pharmaceutical composition comprises up to about 4.0% (w / w) total impurities. In some embodiments, the pharmaceutical composition comprises up to about 0.5% (w / w) of any individual impurity. In some embodiments, the pharmaceutical composition comprises up to about 1.5% (w / w) of the following compounds:

[0298]

[0299] In some embodiments, the impurities in the pharmaceutical compositions disclosed herein are:

[0300]

[0301] The disclosed formula (I) compound or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate can be in the form of a composition suitable for administration to a subject. Typically, such a composition is a "pharmaceutical composition", which comprises a formula (I) compound or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate, and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In certain embodiments, the formula (I) compound or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is present in a therapeutically acceptable amount. The pharmaceutical composition can be used in the method of the present invention; therefore, for example, the pharmaceutical composition can be administered to a subject in vitro or in vivo to achieve therapeutic and preventive methods and uses as described herein.

[0302] The pharmaceutical compositions of the invention may be formulated to be compatible with an intended method or route of administration; exemplary routes of administration are described herein.

[0303] Pharmaceutical compositions comprising a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates can be in a form suitable for oral use, for example as tablets, capsules, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more agents, such as sweeteners, flavorings, coloring agents and preservatives, so as to provide pharmaceutically refined and palatable products. Tablets, capsules, etc. contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for preparing them. These excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binding agents such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.

[0304] The tablets, capsules etc. that are suitable for oral administration can be uncoated or coated by known technology, to postpone disintegration and absorption in the gastrointestinal tract, thereby provide lasting effect.For example, time delay material can be adopted, as glyceryl monostearate or glyceryl distearate.They also can be coated by technology known in the art, to form the osmotic therapeutic tablet for controlled release.Other reagents comprise biodegradable or biocompatible granule or polymeric substance, as polyester, polyamino acid, hydrogel, polyvinyl pyrrolidone, polyanhydride, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethyl cellulose, protamine sulfate or lactide / glycolide copolymer, polylactide / glycolide copolymer or ethylene-vinyl acetate copolymer, to control the sending of the composition used.For example, oral medicament can be embedded in microcapsule or colloidal drug delivery system, and this microcapsule is respectively prepared by using hydroxymethyl cellulose or gelatin-microcapsule or poly (methyl methacrylate) microcapsule, by coacervation technology or by interfacial polymerization. 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 above formulations will be apparent to those skilled in the art.

[0305] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active substance in admixture with excipients suitable for their preparation. Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic; dispersants or wetting agents, such as naturally occurring phosphatides (such as lecithin), or condensation products of alkylene oxide and fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (such as heptadecanol), or condensation products of ethylene oxide and the partial ester derived from fatty acids and hexitol (such as polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide and the partial ester derived from fatty acids and hexitol anhydrides (such as polyethylene sorbitan monooleate). Aqueous suspensions can also contain one or more preservatives.

[0306] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those mentioned above, and flavorings may be added to provide a palatable oral preparation.

[0307] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersant or wetting agent and optionally one or more suspending agents and / or a preservative. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0308] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or gum tragacanth; naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0309] Pharmaceutical compositions generally include a therapeutically effective amount of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and one or more pharmaceutically and physiologically acceptable formulations. 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 paraben), emulsifiers, suspending agents, dispersants, solvents, fillers, loosening agents, detergents, buffers, vehicles, diluents and / or adjuvants. For example, suitable vehicles may be physiological saline solutions or citrate-buffered saline, which may be supplemented with other substances commonly found in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin is a further exemplary vehicle. Those skilled in the art will readily recognize the various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, the buffer component can be a water-soluble material such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid and salts thereof (e.g., potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.). Acceptable buffers include, for example, Tris buffer; N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-morpholino)ethanesulfonic acid (MES); 2-(N-morpholino)ethanesulfonic acid sodium salt (MES); 3-(N-morpholino)propanesulfonic acid (MOPS); and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS), potassium dihydrogen phosphate and dipotassium hydrogen phosphate.

[0310] After the pharmaceutical composition is formulated, it can be stored in a sterile vial in the form of a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such a formulation can be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a disposable container (e.g., a disposable vial, ampoule, syringe, or autoinjector (similar to, for example, )), while in other embodiments, a container for multiple use (e.g., a vial for multiple use) is provided. The formulation can also include a carrier to protect the composition from rapid degradation or removal from the body, such as a controlled dilution formulation, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone or in combination with a wax can be used. Any drug delivery device can be used to deliver a compound of formula (I) or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates; including implants (e.g., implantable pumps) and catheter systems, slow injection pumps, and devices, all of which are well known to those skilled in the art.

[0311] Depot injections, typically administered subcutaneously or intramuscularly, can also be used to release a compound disclosed herein (e.g., a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate) over a limited period of time. Depot injections are typically solid-based or oil-based and typically comprise at least one of the formulation components described herein. Those of ordinary skill in the art are familiar with the possible formulations and uses of depot injections.

[0312] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. Such suspensions may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents such as those mentioned herein. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Injectable preparations include, for example, EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile, fixed oils are conventionally used as solvents or suspending media; for this purpose, any non-irritating, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. Prolonged absorption of certain injectable formulations may be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).

[0313] The present invention contemplates the administration of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate in the form of a suppository for rectal administration. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0314] The compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate may be in the form of any other suitable pharmaceutical composition currently known or developed in the future (eg, a spray for nasal or inhalation use).

[0315] II. How to use

[0316] In one aspect, provided herein is a method for treating and / or preventing a fungal infection or disease, comprising administering to a subject in need thereof a therapeutically effective amount of any pharmaceutical composition or combination of compositions described herein.

[0317] In one aspect, provided herein is a method for treating and / or preventing fungal infection or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: (i) a compound of formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or application.

[0318] In another aspect, provided herein is a method for treating and / or preventing fungal infection or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: (i) fine particles of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or application or in a dosage form for inhalation delivery.

[0319] In some embodiments of the methods provided herein, the dosage form is a self-microemulsifying drug delivery system (SMEDDS). In some embodiments of the methods provided herein, the dosage form is a self-emulsifying drug delivery system (SEDDS). In some embodiments of the methods provided herein, the dosage form is a suspension or solution. In some embodiments of the methods provided herein, the dosage form is a nanosuspension. In some embodiments of the methods provided herein, the dosage form is a solid dosage form. In some embodiments of the methods provided herein, the dosage form is a spray-dried dispersed dosage form. In some embodiments of the methods provided herein, the dosage form is a hot-melt granulated dosage form. In some embodiments of the methods provided herein, the dosage form is a hot-melt extruded dosage form. In some embodiments of the methods provided herein, the dosage form is a microprecipitated bulk powder (MBP) dosage form. In some embodiments of the methods provided herein, the dosage form is a liquid. In some embodiments of the methods provided herein, the dosage form is a suspension, solution, syrup or elixir. In some embodiments of the methods provided herein, the pharmaceutical composition is a dosage form for oral administration or application.

[0320] In some embodiments of the methods described herein, the dosage form is a tablet or capsule. In some embodiments of the methods described herein, the tablet or capsule has an enteric coating. In some embodiments of the methods described herein, the dosage form is a tablet. In some embodiments of the methods described herein, the tablet is an osmotic floating tablet. In some embodiments of the methods described herein, the capsule is a liquid-filled hard capsule. In some embodiments of the methods described herein, the capsule is a soft gelatin capsule.

[0321] In some embodiments of the methods described herein, the dosage form is a modified release dosage form. In some embodiments of the methods described herein, the modified release dosage form is a delayed release dosage form, an extended release (ER) dosage form, or a targeted release dosage form. In some embodiments of the methods described herein, the ER dosage form is a sustained release (SR) dosage form or a controlled release (CR) dosage form. In some embodiments of the methods described herein, the dosage form is an immediate release dosage form.

[0322] In one aspect, provided herein is a method for treating and / or preventing a fungal infection or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: (i) a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for administration or administration by intravenous (IV), intramuscular, subcutaneous, or intradermal injection. In some embodiments of the methods described herein, the form is an intravenous dosage form.

[0323] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous 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.

[0324] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous infusion over a period of up to about 1 hour. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous infusion over a period of up to about 2 hours. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous infusion over a period of up to about 3 hours.

[0325] In another aspect, a method for treating a fungal infection or disease is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound composition comprising: (i) a compound of formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one antifungal agent.

[0326] In one aspect, the present invention provides a method for treating and / or preventing fungal infection or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound composition comprising:

[0327] (i) Compound of formula (I):

[0328]

[0329] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or water thereof

[0330] compounds; and

[0331] (ii) Compounds of formula (II):

[0332]

[0333] or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0334] In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is crystalline, microcrystalline, amorphous or lyophilized. In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is crystalline. In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is amorphous. In some embodiments of the methods described herein, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is lyophilized.

[0335] In some embodiments of the methods provided herein, the subject is administered from about 10 mg to about 8,000 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the subject is administered from about 10 mg to about 2,400 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the subject is administered about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, about 1,500 mg, about 1,800 mg, about 2,000 mg, about 2,100 mg, about 2,400 mg, about 2,500 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, or about 8,000 mg of a compound of Formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0336] In some embodiments of the methods 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to the subject. In some embodiments of the methods 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 an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to the subject.

[0337] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject daily. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject once a day, twice a day, three times a day, or four times a day. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject once a day. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject twice a day.

[0338] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of up to about 12 weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of at least one week. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of at least two weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of up to about 2 weeks. In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject for a period of one week, two weeks, 6 weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 52 weeks.

[0339] In some embodiments of the methods provided herein, the subject is administered about 10 mg to about 8,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the methods provided herein, the subject is administered about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, or about 2,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0340] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous 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.

[0341] In some embodiments of the methods provided herein, the pharmaceutical composition is administered to the subject by intravenous infusion over a period of up to about 3 hours.

[0342] In some embodiments of the methods provided herein, a loading dose is administered to the subject, followed by a maintenance dose. In some embodiments of the methods provided herein, the loading dose comprises about 1,000 mg to about 8,000 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg to about 2,400 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments of the methods provided herein, the loading dose comprises about 1,000 mg to about 2,000 mg. In some embodiments of the methods provided herein, the loading dose is administered by intravenous infusion over a period of about 2 hours to about 3 hours. In some embodiments of the methods provided herein, the loading dose is administered twice on the first day of treatment. In some embodiments of the methods provided herein, a second loading dose is administered about 9 hours after the first loading dose.

[0343] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg, about 700 mg, about 800 mg, about 900 mg or about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof. In some embodiments of the methods provided herein, the maintenance dose comprises about 800 mg or about 1,000 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof. In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 900 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof, and is administered orally.

[0344] In some embodiments of the methods provided herein, the maintenance dose comprises administering about 600 mg or about 900 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof by intravenous infusion over a period of about 1 hour to about 3 hours.

[0345] In some embodiments of the methods provided herein, the method of any one of embodiments 157-164, wherein about 600 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 3 hours.

[0346] In some embodiments of the methods provided herein, the maintenance dose is administered once daily.

[0347] In some embodiments of the methods provided herein, the maintenance dose is administered once daily starting on the second day of treatment.

[0348] In some embodiments of the methods provided herein, about 600 mg or about 800 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of about 3 hours, starting on the second, third or fourth day of treatment.

[0349] In some embodiments of the methods provided herein, about 800 mg or about 1,000 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is orally administered starting on the second, third or fourth day of treatment.

[0350] In some embodiments of the methods provided herein, the maintenance dose comprises about 600 mg or about 800 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments of the methods provided herein, the subject is administered to about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments of the methods provided herein, the subject is administered to about 800 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments of the methods provided herein, about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is administered by intravenous infusion over a period of about 1 hour to about 3 hours, and / or about 800 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is administered orally. In some embodiments of the methods provided herein, the maintenance dose is administered once a day. In some embodiments of the methods provided herein, the maintenance dose is administered once a day starting from the second day of treatment. In some embodiments of the methods provided herein, about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is administered by intravenous infusion over a period of about 3 hours.

[0351] In some embodiments of the methods provided herein, about 600 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of about 3 hours, beginning on the second day of treatment.

[0352] In some embodiments of the methods provided herein, about 800 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof is orally administered, starting on the fourth day of treatment.

[0353] In some embodiments of the methods provided herein, the fungal infection is caused by invasive fungi. In some embodiments of the methods provided herein, the method further comprises administering to the subject at least one antifungal agent in combination with the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments of the methods provided herein, the at least one antifungal agent is an azole drug, an echinocandin, amphotericin B deoxycholate, amphotericin B lipid roll, 5-flucytosine, terbinafine, griseofulvin, VL-2397, ibrexafungerp, orotomide F901318 or a combination thereof. In some embodiments of the methods provided herein, the azole drug is ketoconazole, fluconazole, posaconazole, itraconazole, voriconazole, isavuconazole or miconazole. In some embodiments of the methods provided herein, the echinocandin is caspofungin, anidulafungin, micafungin or rezafungin, or a combination thereof.

[0354] In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate and the antifungal agent are administered simultaneously, approximately simultaneously or sequentially in any order. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate and the antifungal agent are administered simultaneously or approximately simultaneously. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate and the antifungal agent are administered sequentially. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate or its pharmaceutically acceptable salt is administered before the at least one antifungal agent. In some embodiments of the methods provided herein, the pharmaceutical composition comprising a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, or a pharmaceutically acceptable salt thereof is administered after the at least one antifungal agent.

[0355] In some embodiments of the methods provided herein, the fungal infection or disease is caused by Aspergillus fumigatus, Blastomyces, Ajellomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Rhizopus Muco, Cunninghamell, Apophysomyces, Absidia, Saksenaea, Entomophthora, Conidiobolus, Basidiobolus, Sporothrix, Pneumocystis, Talaromyces, Asclepias, Fusarium, Scedosporium, or Mucorales fungi, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus, Aspergillus, Candida, Fusarium, Scedosporium, or Mucorales fungi, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Histoplasma dermatitidis, Candida albicans, Candida glabrata, Candida rugosa, Candida auris, Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, Rhizopus graminearum, Rhizopus arrhizus, Mucor indica, Cunninghamella griseus, Elegant scale mold, Absidia species, Bottle mold species, Rhizomucor microti, Entomophthora species, Ear mold species, Frog feces species, Sporothrix schenckii, Pneumocystis jiroveci, Marneffei blue-shaped fungi, Asclepias albicans, Fusarium solani, Scedosporium apex, Rhizomucor microti, or any combination thereof. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus fungi or Candida fungi. In some embodiments of the methods provided herein, the fungal infection or disease is caused by Cryptococcus neoformans, Cryptococcus gattii, or Candida auris.

[0356] In some embodiments of the methods provided herein, the fungal infection or disease is azole-resistant and / or echinocandin-resistant.

[0357] In some embodiments of the methods provided herein, the subject is immunocompromised. In some embodiments of the methods provided herein, the subject is infected with HIV / AIDS or suffers from cancer. In some embodiments of the methods provided herein, the subject suffers from cancer. In some embodiments of the methods provided herein, the cancer is acute myeloid leukemia (AML). In some embodiments of the methods provided herein, the subject suffers from neutropenia. In some embodiments of the methods provided herein, the subject is experiencing or has experienced cancer chemotherapy treatment. In some embodiments of the methods provided herein, the subject is experiencing or has experienced corticosteroid treatment. In some embodiments of the methods provided herein, the subject is experiencing or has experienced TNF inhibitor treatment. In some embodiments of the methods provided herein, the subject is a transplant recipient. In some embodiments of the methods described herein, a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is administered to the subject in combination with posaconazole.

[0358] In some embodiments of the methods 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 methods 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.

[0359] In some embodiments of the methods provided herein, the fungal infection or disease is in the bloodstream of the subject. In some embodiments of the methods provided herein, the subject has a decrease in pulmonary fungal colony counts after administration of the pharmaceutical composition.

[0360] In some embodiments of the methods provided herein, the plasma concentration versus time curve of the compound of Formula (I) in the subject has a t of less than about 30 minutes to about 180 minutes. max In some embodiments of the methods provided herein, the subject has a maximum plasma concentration (C ) of the compound of Formula (I) of about 12,000 ng / mL to about 25,000 ng / mL. max ).

[0361] Drug administration

[0362] In some embodiments, the pharmaceutical composition of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate as described herein is provided at the maximum tolerated dose (MTD) for the compound of formula (I). In other embodiments, the amount of the pharmaceutical composition of the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate administered 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 amount of the pharmaceutical composition of the compound of Formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, administered 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 derivable range therein.

[0363] In certain embodiments, in the treatment, prevention or amelioration of one or more symptoms of a disorder, disease or condition described herein (e.g., a fungal infection or disease), suitable dosage levels of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof are generally in the range of about 1 to 8,000 mg, about 10 to 8,000 mg, about 10 to 2,000 mg, about 1 to about 1,000 mg, about 25 to about 1,The dosage range of the invention is about 1000 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, which can be administered in a single dose or in multiple doses. In certain embodiments, the compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is administered at 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 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg 0mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, 710mg, about 720mg 0mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1,000mg, about 1,100mg, about 1,about 200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, about 2,000, about 2,100, about 2,200, about 2,300, about 2,400, about 2,500, about 2,600, about 2,700, about 2,800, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000 mg, or any range derivable therein.

[0364] In certain embodiments, a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered at 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, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 180, about 185, about 190, about 200, about 210, about 220, about 230, about 235, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 310, about 320, about 330, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400 0, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg 0mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg , 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, about 1,100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, about 2,000, about 2,100, about 2,200, about 2,300, about 2,400, about 2,500, about 2,600, about 2,700, about 2,800, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000mg was administered to the subjects.

[0365] In certain embodiments, a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered at 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, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 180, about 185, about 190, about 200, about 210, about 220, about 230, about 235, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 310, about 320, about 330, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400 0, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg 0mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg , 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, about 1,100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, about 2,000, about 2,100, about 2,200, about 2,300, about 2,400, about 2,500, about 2,600, about 2,700, about 2,800, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000mg / day.

[0366] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing about 1 to 2,000 mg, about 10 to 2,000 mg, about 1 to about 1,000 mg, about 25 to about 1,000 mg, about 25 to about 800 mg, about 25 to about 600 mg, about 50 to about 600 mg, about 50 to about 300 mg, about 50 to about 150 mg, about 150 to about 250 mg, about 250 mg to about 350 mg, about 350 to about 450 mg, about 450 to about 550 mg, about 550 to about 650 mg, about 650 to about 750 mg, 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 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 7 90 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 or about 2,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, for symptomatic adjustment of the dosage for the patient to be treated. ;

[0367] In some embodiments, the pharmaceutical compositions provided herein can be formulated into tablets or capsules containing about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg or about 800 mg of a compound of formula (I) or an isotopic variant thereof, a tautomer, a pharmaceutically acceptable salt, a solvate or a hydrate thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for oral administration containing about 200 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for oral administration containing about 300 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for oral administration containing about 400 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for oral administration containing about 500 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0368] In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 200 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 300 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 400 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein may be formulated into tablet form containing about 500 mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0369] The pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion and contain about 1 to 2,000 mg, about 10 to 2,000 mg, about 1 to about 1,000 mg, about 25 to about 1,000 mg, about 25 to about 800 mg, about 25 to about 600 mg, about 50 to about 600 mg, about 50 to about 300 mg, about 50 to about 150 mg, about 150 to about 250 mg, about 250 mg to about 350 mg, about 350 to about 450 mg, about 450 to about 550 mg, about 550 to about 650 mg, about 650 to about 750 mg, about 750 to about 850 mg, about 850 to about 950 mg, about 950 to about 1050 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 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 7 90 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 or about 2,000 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof, for symptomatic adjustment of the dosage for the patient to be treated. ;

[0370] In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion and contain about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 950 mg or about 1,000 mg of a compound of Formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0371] In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 200 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 300 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 400 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 500 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 600 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 700 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 800 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion, containing about 900 mg of a compound of formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated for administration by intravenous injection or infusion and contain about 1,000 mg of a compound of Formula (I), or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.In some embodiments, the pharmaceutical compositions provided herein can be formulated as an injection or intravenous infusion containing about 5 mg / mL to about 250 mg / mL, about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 40 mg / mL, or about 10 mg / mL to about 30 mg / mL; in one embodiment, 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. / 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 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 of a compound of Formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof.

[0372] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 40 mg / mL of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof. 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 a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0373] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. The daily dose as described herein can be given once a day or multiple times a day in the form of divided doses, and the divided doses are given twice a day (bid), three times a day (tid), four times a day (qid), etc., wherein the total amount of the divided doses is equal to the daily dose. The pharmaceutical composition can be applied in a 1-4 times a day scheme, including once a day, twice, three times and four times. In some embodiments, the pharmaceutical composition is applied once a day. In some embodiments, the pharmaceutical composition is applied twice a day. In some embodiments, the pharmaceutical composition is applied three times a day. In some embodiments, the pharmaceutical composition is applied four times a day or more. In some embodiments, a loading dose, followed by a maintenance dose of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is applied.

[0374] In some embodiments, the pharmaceutical compositions provided herein are administered as tablets. In some embodiments, the pharmaceutical compositions provided herein are administered as capsules. In some embodiments, the pharmaceutical compositions provided herein are administered as injections. In some embodiments, the pharmaceutical compositions provided herein are administered as intravenous injections or infusions.

[0375] In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 10 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 15 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 20 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 30 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 45 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 1 hour. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 90 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 2 hours. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of about 3 hours. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of up to about 3 hours. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of at least 3 hours. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of at least 30 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of at least 2 hours. In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of up to 2 hours.

[0376] In some embodiments, the pharmaceutical compositions provided herein are administered as an intravenous infusion over a period of up to 30 minutes.

[0377] In some embodiments, a loading dose, followed by a maintenance dose of the pharmaceutical composition provided herein, is administered. In some embodiments, the loading dose and maintenance dose are both administered by intravenous infusion. In some embodiments, the loading dose and maintenance dose are both administered orally (PO). In some embodiments, the loading dose is administered by intravenous infusion, and the maintenance dose is administered orally (PO). In some embodiments, a loading dose is administered by intravenous infusion, comprising approximately 2,000 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, a loading dose is administered by intravenous infusion twice a day (BID), comprising approximately 1,000 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, a loading dose is administered by intravenous infusion BID on the first day of treatment, comprising approximately 1,000 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, a loading dose is administered by intravenous infusion BID only on the first day of treatment, comprising about 1,000 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, a loading dose is administered by intravenous infusion BID over 2 or 3 hours, comprising about 1,000 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, a maintenance dose is administered by intravenous infusion QD, comprising about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, starting from the second day of treatment, a maintenance dose is administered by intravenous infusion QD, comprising about 600 mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, a maintenance dose is administered by 1 hour or 2 hours intravenous infusion QD, comprising about 600mg of the pharmaceutical composition provided herein. In some embodiments, a maintenance dose is administered by oral QD, comprising about 800mg of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, 1,000mg is administered intravenously BID (loading dose), followed by 600mg intravenous infusion BID (maintenance dose) of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate.In some embodiments, 1,000 mg BID intravenous 2 hours or 3 hours infusion (loading dose) is administered, followed by 600 mg intravenous QD 1 hour, 2 hours or 3 hours infusion (maintenance dose) of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, 1,000 mg BID intravenous 3 hours infusion (loading dose) is administered, followed by 600 mg intravenous QD 3 hours infusion (maintenance dose) of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, 1,000 mg BID intravenous 3 hours infusion (loading dose) is administered, followed by 800 mg oral QD (maintenance dose) of a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate. In some embodiments, a 1,000 mg BID intravenous loading dose is administered by 2 or 3 hour intravenous infusion, with the second dose administered about 9 to about 12 hours after the first dose.

[0378] In some embodiments, the pharmaceutical compositions provided herein are 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.

[0379] In some embodiments, the pharmaceutical compositions provided herein are administered every day, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, every week, every two weeks, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months.

[0380] In some cases, the method of administering multiple compounds (e.g., a compound of formula (I) or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate and an antifungal agent) comprises administering the compounds within 48 hours or less of each other. In some embodiments, administration is performed 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 the injection of one compound immediately before, after or during oral administration of a second compound, where immediately refers to a time period of less than about 5 minutes.

[0381] In some embodiments of the pharmaceutical compositions described herein, the second dose is administered about 10 minutes after the first dose, the second dose is administered about 15 minutes after the first dose, the second dose is administered about 20 minutes after the first dose, the second dose is administered about 30 minutes after the first dose, the second dose is administered about 40 minutes after the first dose, the second dose is administered about 45 minutes after the first dose, the second dose is administered about 1 hour after the first dose, the second dose is administered about 2 hours after the first dose, the second dose is administered about 3 hours after the first dose, the second dose is administered about 4 hours after the first dose, the second dose is administered about 5 hours after the first dose, the second dose is administered about 6 hours after the first dose, the second dose is administered about 7 hours after the first dose, the second dose is administered about 8 hours after the first dose, the second dose is administered about 9 hours after the first dose. The second dose is administered at about 10 hours after the first dose, the second dose is administered at about 11 hours after the first dose, the second dose is administered at about 12 hours after the first dose, the second dose is administered at about 13 hours after the first dose, the second dose is administered at about 14 hours after the first dose, the second dose is administered at about 15 hours after the first dose, the second dose is administered at about 16 hours after the first dose, the second dose is administered at about 17 hours after the first dose, the second dose is administered at about 18 hours after the first dose, the second dose is administered at about 19 hours after the first dose, the second dose is administered at about 20 hours after the first dose, the second dose is administered at about 21 hours after the first dose, the second dose is administered at about 22 hours after the first dose, the second dose is administered at about 23 hours after the first dose, or the second dose is administered at about 24 hours after the first dose. In some embodiments of the pharmaceutical compositions described herein, the second dose is administered about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 45 minutes, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 22, or about 48 hours after completion of administration of the first dose by intravenous infusion. In some embodiments of the pharmaceutical composition, the second dose is administered about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 45 minutes, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 22, or about 48 hours after initiation of administration of the first dose by intravenous infusion.

[0382] In some embodiments, the pharmaceutical compositions described herein are administered in combination with an antifungal agent. In some embodiments, the pharmaceutical compositions described herein are administered before the antifungal agent. In some embodiments, the pharmaceutical compositions described herein are administered after the antifungal agent. In some embodiments, the pharmaceutical compositions described herein are administered simultaneously with the antifungal agent. In some embodiments, the pharmaceutical compositions described herein and the antifungal agent are both administered in the form of an intravenous infusion. In some embodiments, the pharmaceutical compositions described herein and the antifungal agent are both administered orally. In some embodiments, the pharmaceutical compositions described herein are administered orally, while the antifungal agent is administered in the form of an intravenous infusion. In some embodiments, the pharmaceutical compositions described herein are administered in the form of an intravenous infusion, while the antifungal agent is administered orally. In some embodiments, the pharmaceutical compositions described herein and the antifungal agent are administered orally. In some embodiments, the pharmaceutical compositions described herein and the antifungal agent are administered orally. In some embodiments, the pharmaceutical compositions described herein and the antifungal agent are administered by intravenous infusion.

[0383] In some embodiments, the pharmaceutical formulations provided herein are formulated to achieve 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 after a minimum period of time. max). In some embodiments, the pharmaceutical formulations provided herein are formulated to achieve an dosage of about 12 μg / mL to about 13 μg / mL, 12 μg / mL to about 14 μg / mL, 12 μg / mL to about 15 μg / mL, 12 μg / mL to about 16 μg / mL, 12 μg / mL to about 17 μg / mL, 12 μg / mL to about 18 μg / mL, 12 μg / mL to about 19 μg / mL, 12 μg / mL to about 20 μg / mL, 12 μg / mL to about 21 μg / mL, 12 μg / mL to about 22 μg / mL, 12 μg / mL to about 23 μg / mL, 12 μg / mL to about 24 μg / mL, 13 μg / mL to about 14 μg / mL, 13 μg / mL to about 15 μg / mL, 13 μg / mL to about 16 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, 2 0 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 24 μg / mL to about 25 μg / mL of C, max .

[0384] In some embodiments, the pharmaceutical formulations provided herein are formulated to achieve an expression of 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, or about 15 μg / mL after administration after a minimum period of time. C / 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 μg / mL, about 28 μg / mL, about 29 μg / mL, or about 30 μg / mL max .

[0385] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C of 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, about 25 μg / mL after administration after a minimum period of time.max .

[0386] Fungal diseases

[0387] In some embodiments, the fungal disease is selected from aspergillosis, blastomycosis, candidiasis, coccidioidomycosis (valley fever), cryptococcosis, histoplasmosis, mucormycosis, Pneumocystis pneumonia (PCP), tinea, sporotrichosis, and talaromycosis.

[0388] In some embodiments, the fungal disease is aspergillosis. In some embodiments, the aspergillosis is allergic bronchopulmonary aspergillosis (ABPA), allergic aspergillosis sinusitis, chronic pulmonary aspergillosis, invasive aspergillosis, or cutaneous aspergillosis. In some embodiments, the subject has aspergilloma.

[0389] In some embodiments, the fungal disease is blastomycosis. In some embodiments, the fungal disease is candidiasis. In some embodiments, candidiasis is oropharyngeal candidiasis (thrush), vulvovaginal candidiasis (vaginal candidiasis), fungemia or invasive candidiasis. In some embodiments, the fungal disease is coccidioidomycosis (valley fever). In some embodiments, coccidioidomycosis is acute coccidioidomycosis (primary pulmonary coccidioidomycosis), chronic co...

Claims

1. A pharmaceutical composition comprising: (i) Compounds of formula (I): or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a dosage form for oral administration or application; wherein the dosage form is a tablet; wherein the pharmaceutical composition comprises 350 mg to 450 mg of a compound of formula (I) or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; The at least one pharmaceutically acceptable excipient is microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate, colloidal silicon dioxide or any combination thereof.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is stable at a temperature of 2°C to 25°C for up to 36 months.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is stable at a temperature of 2°C to 8°C for a period of 24 months to 36 months.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises less than 5% w / w of at least one impurity; wherein the at least one impurity is:

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 350 mg to 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition comprises 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 350 mg to 450 mg of the compound of formula (I).

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition comprises 400 mg of the compound of formula (I).

10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has 40% of the compound of formula (I) in the pharmaceutical composition.

11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has 40% of the compound of formula (I) in the pharmaceutical composition, and wherein the pharmaceutical composition comprises 400 mg of the compound of formula (I).

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate and colloidal silicon dioxide as pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition comprises microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate and colloidal silicon dioxide as pharmaceutically acceptable excipients.

14. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition comprises microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate and colloidal silicon dioxide as pharmaceutically acceptable excipients.

15. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: (i) a compound of formula (I); and (ii) microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate and colloidal silicon dioxide as the pharmaceutically acceptable excipients; wherein the pharmaceutical composition is in a dosage form for oral administration or application; wherein the dosage form is a tablet; and The pharmaceutical composition comprises 400 mg of the compound of formula (I).

16. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: (i) a compound of formula (I); and (ii) microcrystalline cellulose, pregelatinized starch, povidone, magnesium stearate and colloidal silicon dioxide as the pharmaceutically acceptable excipients; wherein the pharmaceutical composition is in a dosage form for oral administration or application; wherein the dosage form is a tablet; wherein the pharmaceutical composition comprises 400 mg of a compound of formula (I); and 40% of the pharmaceutical composition is the compound of formula (I).

17. The pharmaceutical composition according to claim 15 or 16, wherein the pharmaceutical composition comprises an extragranular part and an intragranular part, wherein the amount of magnesium stearate in the intragranular part is 0.75%.

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