Formulations of Compounds and Their Use

Abstract

The present disclosure relates to a formulation of an FXR agonist, such as a tablet, and its use in therapy.The present disclosure also relates to a method for obtaining such a formulation.The present disclosure relates to a formulation of a compound that binds to the NR1H4 receptor (FXR) and acts as an agonist or modulator of FXR.The present disclosure further relates to the use of such a formulation of a compound for the treatment and / or prevention of diseases and / or conditions due to the binding of this nuclear receptor by these compounds.

Description

Technical Field

[0001] Citation of Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 816,771, filed on Mar. 11, 2019, the content of which is hereby incorporated by reference in its entirety.

[0002] Field The present disclosure relates to formulations of FXR agonists, such as tablets, and their use in therapy.

Background Art

[0003] Background The present disclosure relates to formulations of compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The present disclosure further relates to the use of such formulations of compounds for the treatment and / or prevention of diseases and / or conditions by binding of these compounds to this nuclear receptor.

[0004] Compounds that bind to the NR1H4 receptor (FXR) can act as agonists or modulators of FXR. FXR agonists are useful for the treatment and / or prevention of diseases and conditions by binding to the NR1H4 receptor. One such FXR agonist has the following structure:

Chemical Formula

[0005] Compound 1 is also known as GS-9674 or cilofexor.

Summary of the Invention

Means for Solving the Problems

[0006] Abstract The present disclosure provides, in some embodiments, a pharmaceutical composition containing Compound 1 (also known as GS-9674 or selofexor).

[0007] Some embodiments provided herein relate to tablets containing less than about 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, where the percentage by weight is relative to the total weight of the tablet.

[0008] In some embodiments, a method for treating a condition mediated by the non-steroidal farnesoid X receptor (FXR) is provided herein in a patient in need of treating a condition mediated by the non-steroidal farnesoid X receptor (FXR), the method comprising administering a tablet containing less than about 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, where the percentage by weight is relative to the total weight of the tablet.

[0009] Some embodiments provided herein relate to tablets containing from 3% w / w to 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, where the percentage by weight is relative to the total weight of the tablet.

[0010] In some embodiments, a method for treating a condition mediated by the non-steroidal farnesoid X receptor (FXR) is provided herein in a patient in need of treating a condition mediated by the non-steroidal farnesoid X receptor (FXR), the method comprising administering a tablet containing from 3% w / w to 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, where the percentage by weight is relative to the total weight of the tablet.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description Definitions As used in this disclosure, the following terms and phrases are generally intended to have the following meanings, unless the context in which they are used indicates otherwise.

[0021] Unless the context requires otherwise, throughout this specification and the claims, the term "comprise" and its variations, such as "comprises" and "comprising", are to be construed in an open, inclusive sense, i.e., "including but not limited to".

[0022] References to "one embodiment" or "an embodiment" in this specification mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "one embodiment" or "an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0023] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic bases or inorganic acids, and organic bases or organic acids). When the compounds described herein contain one or more acidic or basic groups, the present disclosure also encompasses their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically available salts. Thus, a compound described herein that contains an acidic group may exist in these groups, for example, as an alkali metal salt, an alkaline earth metal salt, or an ammonium salt, and may be used, according to the present disclosure, for example, as an alkali metal salt, an alkaline earth metal salt, or an ammonium salt. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (such as ethylamine, ethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane (i.e., tromethamine) or amino acids). A compound described herein that contains one or more basic groups, i.e., groups that can be protonated, may exist in the form of their addition salts with inorganic or organic acids and may be used, according to the present invention, in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. When the compounds of the present disclosure contain both an acidic group and a basic group within their molecule, the present invention also encompasses internal salts or betaines (zwitterions) in addition to the described salt forms. Representative salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with an organic or inorganic acid, or an organic or inorganic base, in a solvent or a dispersant, or by anion exchange or cation exchange with other salts.The present disclosure also encompasses all salts of the compounds of the present disclosure that, due to their low physiological compatibility, are not directly suitable for use in drugs but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0024] "Pharmaceutical composition" refers to a formulation of a compound described herein (e.g., Compound 1) and a medium generally approved in the art for the delivery of biologically active compounds to mammals (e.g., humans). Such media include all pharmaceutically acceptable excipients therefor.

[0025] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound according to the present disclosure that is sufficient to effect treatment of a disease state, condition or disorder for which the compound according to the present disclosure is useful when administered to a patient in need thereof. Such amount is sufficient to elicit a biological or medical response of a tissue system or patient as determined by a researcher or clinician. The amount of the compound according to the present disclosure that constitutes a therapeutically effective amount will vary depending on the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, the drugs used in combination with or concurrently with the compounds of the present disclosure, and factors such as the age, weight, general health, sex and diet of the patient. Such therapeutically effective amount can be routinely determined by one of ordinary skill in the art in view of their knowledge, level of skill, and the present disclosure.

[0026] "Prevention" or "preventing" or "prophylaxis" means any treatment of a disease or condition that prevents the clinical symptoms of the disease or condition from occurring. The compound can, in some embodiments, be administered to a subject (including a human) at risk of or having a family history of the disease or condition.

[0027] "Treatment" and "treating" of a disease are as follows: (1) Preventing the onset of a disease or reducing the risk thereof, i.e., preventing the onset of the clinical symptoms of the disease in a subject who may be exposed to or is susceptible to the disease but has not yet experienced or manifested the symptoms of the disease; (2) Inhibiting a disease, i.e., arresting or reducing the onset of the disease or its clinical symptoms, and (3) Alleviating a disease, i.e., causing regression of the disease or its clinical symptoms and include.

[0028] The terms "subject" or "patient" refer to an animal, e.g., a mammal (including a human), that has been or is intended to be the subject of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, a domestic animal (e.g., a dog and a cat), a farm animal (e.g., a cow, a horse, a sheep, a goat, and a pig), and / or a laboratory animal (e.g., a mouse, a rat, a hamster, a guinea pig, a pig, a rabbit, a dog, and a monkey). In some embodiments, the subject (or patient) is a human.

[0029] "A human (or patient) in need thereof" refers to a human who may have or is suspected of having a disease or condition that would benefit from a particular treatment, e.g., treatment according to the present application using a compound disclosed herein.

[0030] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0031] As used herein, the term "about" when used in the context of a quantitative measurement means the indicated amount ± 10%. For example, "about 2:8" means 1.8 to 2.2:7.2 to 8.8.

[0032] The recitation of numerical ranges of values throughout this disclosure is intended to serve as a shortened description that refers individually to each separate value that falls within that range, including the values that define that range, and each separate value is incorporated herein as if it were individually recited herein.

[0033] The term "% w / w" as used herein refers to the weight of a component based on the total weight of the composition containing the component. For example, if component A is present in a 100 mg composition in an amount of 50% w / w, component A is present in an amount of 50 mg.

[0034] The terms "carrier" or "pharmaceutically acceptable carrier" or "excipient" or "pharmaceutically acceptable excipient" refer to diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, and other excipients and vehicles with which a compound is administered together. Carriers are generally described herein and also in "Remington’s Pharmaceutical Sciences" by E.W. Martin. Examples of carriers can include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. However, it should be understood that the carrier selected for a pharmaceutical composition and the amount of such carrier in the composition can vary depending on the method of formulation (e.g., dry granulation formulation, solid dispersion formulation).

[0035] The term "diluent" refers to a compound used to dilute the compound of interest prior to delivery. The diluent can also act to solubilize the compound. Non-limiting examples of diluents include starch, sugars, disaccharides, sucrose, lactose, lactose monohydrate, polysaccharides, cellulose, cellulose ethers, hydroxypropylcellulose, microcrystalline cellulose, sugar alcohols, xylitol, sorbitol, maltitol, compressible sugar, calcium carbonate or sodium carbonate, dicalcium phosphate, calcium hydrogen phosphate dihydrate, mannitol, and tricalcium phosphate.

[0036] The term "binder" as used herein refers to any pharmaceutically acceptable film that can be used to bind together the active and inactive components of a carrier to maintain cohesive discrete portions. Non-limiting examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, copovidone, and ethylcellulose.

[0037] The term "disintegrant" refers to a substance that, when added to a solid preparation, facilitates its break-up or disintegration after administration and enables the release of the active ingredient as efficiently as possible and its rapid dissolution. Non-limiting examples of disintegrants include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, α-starch, and arginine.

[0038] The term "lubricant" refers to a substance added to a powder blend to prevent the compressed powder mass from sticking to equipment during the tableting or encapsulation process. The lubricant can assist in the ejection of tablets from the die and can improve the flow of the powder. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc; and lauric acid, oleic acid, and C8 / C10 Solubilizing agents such as fatty acids include fatty acids and the like.

[0039] The term "film coating" refers to a thin, uniform film on the surface of a substrate (e.g., a tablet). Film coatings are particularly useful for protecting the active ingredient(s) from degradation by photolysis. Non-limiting examples of film coatings include those based on polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate film coatings.

[0040] The term "glidant" refers to a substance used in tablet and capsule formulations to improve flow characteristics during tablet compression and to produce an anti-caking effect. Examples of glidants can include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0041] Pharmaceutical composition Provided herein are pharmaceutical compositions containing an FXR agonist.

[0042] Some embodiments provided herein relate to pharmaceutical compositions containing Compound 1 or a pharmaceutically acceptable salt thereof.

[0043] Compound 1 can be synthesized and characterized using methods known to those skilled in the art, such as the methods described in U.S. Patent Application Publication No. 2014 / 0221659.

[0044] In some embodiments, the pharmaceutical compositions described herein exhibit improved dissolution properties. In some embodiments, the pharmaceutical compositions described herein exhibit a drug load-dependent decrease in the variability of drug exposure in a subject population. For example, in some embodiments, the effect of a decrease in drug load on the percent increase in exposure to Compound 1 is greater for one or more subjects with lower drug exposure from a higher drug load of Compound 1 compared to one or more subjects with higher drug exposure from a lower drug load of Compound 1.

[0045] In some embodiments, administration of Compound 1 with a high-fat meal results in increased exposure to Compound 1 compared to administration in a fasting state or with a low-fat or moderate-fat meal.

[0046] In some embodiments, the effect of a high-fat meal on the percent increase in exposure to Compound 1 is greater for subjects who exhibit higher drug exposure when Compound 1 is taken with a fasting condition or a low-fat meal compared to subjects who exhibit lower drug exposure when Compound 1 is taken under a fasting condition or with a low-fat meal.

[0047] Some embodiments provided herein are pharmaceutical compositions containing less than about 20% w / w Compound 1:

Chemical formula

[0048] Some embodiments provided herein are pharmaceutical compositions containing 3% w / w to 20% w / w Compound 1:

Chemical formula

[0049] Some embodiments provided herein are less than about 25% w / w of Compound 1:

Chem.

[0050] Some embodiments provided herein are 5% w / w to 25% w / w of Compound 1:

Chem.

[0051] In certain embodiments, the pharmaceutical compositions described herein contain the tromethamine salt of Compound 1, such as Form I, which has been shown to confer improved bioavailability compared to the zwitterion and has appropriate chemical and physical stability in pharmaceutical products.

[0052] Some embodiments provided herein are less than about 25% w / w of the tromethamine salt of Compound 1:

Chem.

[0053] In some embodiments, the pharmaceutical composition contains from about 1% w / w to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 3% w / w to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 5% w / w to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 5% w / w to about 20% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 5% w / w to about 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 5% w / w to about 12% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 5% w / w to about 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 5% w / w to about 8% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains from about 8% w / w to about 12% w / w of Compound 1 or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the pharmaceutical composition contains 1% w / w to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 3% w / w to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 5% w / w to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 5% w / w to 20% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 5% w / w to 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 5% w / w to 12% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 5% w / w to 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 5% w / w to 8% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 8% w / w to 12% w / w of Compound 1 or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the pharmaceutical composition contains from about 3% w / w to about 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains from about 5% w / w to about 25% w / w of a pharmaceutically acceptable salt of Compound 1.

[0056] In some embodiments, the pharmaceutical composition contains 3% w / w to 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 5% w / w to 25% w / w of a pharmaceutically acceptable salt of Compound 1.

[0057] In some embodiments, the pharmaceutical composition contains less than about 30% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 3% w / w of a pharmaceutically acceptable salt of Compound 1.

[0058] In some embodiments, the pharmaceutical composition contains 1% w / w to 30% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w to 3% w / w of a pharmaceutically acceptable salt of Compound 1.

[0059] In some embodiments, the pharmaceutical composition contains about 30% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 14% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 12% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains about 1% w / w of a pharmaceutically acceptable salt of Compound 1.

[0060] In some embodiments, the pharmaceutical composition contains 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 14% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 12% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w of a pharmaceutically acceptable salt of Compound 1.

[0061] In some embodiments, this pharmaceutical composition contains from about 3% w / w to about 25% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from about 5% w / w to about 25% w / w of Compound 1 or its tromethamine. In some embodiments, this pharmaceutical composition contains from about 5% w / w to about 20% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from about 5% w / w to about 15% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from about 5% w / w to about 12% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from about 5% w / w to about 10% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from about 5% w / w to about 8% w / w of Compound 1 or its tromethamine. In some embodiments, this pharmaceutical composition contains from about 8% w / w to about 12% w / w of Compound 1 or its tromethamine salt.

[0062] In some embodiments, this pharmaceutical composition contains from 3% w / w to 25% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from 5% w / w to 25% w / w of Compound 1 or its tromethamine. In some embodiments, this pharmaceutical composition contains from 5% w / w to 20% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from 5% w / w to 15% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from 5% w / w to 12% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from 5% w / w to 10% w / w of Compound 1 or its tromethamine salt. In some embodiments, this pharmaceutical composition contains from 5% w / w to 8% w / w of Compound 1 or its tromethamine. In some embodiments, this pharmaceutical composition contains from 8% w / w to 12% w / w of Compound 1 or its tromethamine salt.

[0063] In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at about 3% to about 25% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at about 5% to about 25% w / w.

[0064] In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 3% to 25% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 5% to 25% w / w.

[0065] In some embodiments, the pharmaceutical composition contains less than about 25% w / w of tromethamine salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 20% w / w of tromethamine salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 18% w / w of tromethamine salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 15% w / w of tromethamine salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 10% w / w of tromethamine of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 8% w / w of tromethamine salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 7% w / w of tromethamine salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 6% w / w of tromethamine salt of Compound 1. In some embodiments, the pharmaceutical composition contains less than about 5% w / w of tromethamine salt of Compound 1.

[0066] In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 25% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 20% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 18% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 15% w / w. In some embodiments, the pharmaceutical composition contains tromethamine of Compound 1 at 1% - 10% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 8% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 7% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 6% w / w. In some embodiments, the pharmaceutical composition contains tromethamine salt of Compound 1 at 1% - 5% w / w.

[0067] In some embodiments, the pharmaceutical composition contains Compound 1 at about 3% w / w to about 25% w / w. In some embodiments, the pharmaceutical composition contains Compound 1 at about 5% w / w to about 25% w / w. In some embodiments, the pharmaceutical composition contains Compound 1 at about 5% w / w to about 20% w / w. In some embodiments, the pharmaceutical composition contains Compound 1 at about 5% w / w to about 15% w / w. In some embodiments, the pharmaceutical composition contains Compound 1 at about 5% w / w to about 12% w / w. In some embodiments, the pharmaceutical composition contains Compound 1 at about 5% w / w to about 10% w / w. In some embodiments, the pharmaceutical composition contains Compound 1 at about 5% w / w to about 8% w / w.

[0068] In some embodiments, this pharmaceutical composition contains 3% w / w to 20% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains 5% w / w to 20% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains 5% w / w to 15% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains 5% w / w to 12% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains 5% w / w to 10% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains 5% w / w to 8% w / w of Compound 1.

[0069] In some embodiments, this pharmaceutical composition contains less than about 25% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains less than about 20% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains less than about 18% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains less than about 15% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains less than about 12% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains less than about 10% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains less than about 8% w / w of Compound 1. In some embodiments, this pharmaceutical composition contains less than about 5% w / w of Compound 1.

[0070] In some embodiments, the pharmaceutical composition contains 1% to 25% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains less than 20% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 1% to 18% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 1% to 15% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 1% to 12% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 1% to 10% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 1% to 8% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 1% to 5% w / w of Compound 1.

[0071] In some embodiments, the pharmaceutical composition contains about 20% w / w of Compound 1. About 20% w / w of Compound 1 also refers to the tromethamine salt of about 24% w / w of Compound 1.

[0072] In some embodiments, the pharmaceutical composition contains 20% w / w of Compound 1. 20% w / w of Compound 1 also refers to the tromethamine salt of 24% w / w of Compound 1.

[0073] In some embodiments, the pharmaceutical composition contains about 18% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains about 15% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains about 12% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains about 10% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains about 8% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains about 5% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains about 2.5% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains about 1% w / w of Compound 1.

[0074] In some embodiments, the pharmaceutical composition contains 18% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 15% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 12% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 10% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 8% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 5% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 2.5% w / w of Compound 1. In some embodiments, the pharmaceutical composition contains 1% w / w of Compound 1.

[0075] In some embodiments, the pharmaceutical composition contains from about 200 mg to about 1 mg of Compound 1. In some embodiments, the pharmaceutical composition contains from about 150 mg to about 10 mg of Compound 1. In some embodiments, the pharmaceutical composition contains from about 125 mg to about 15 mg of Compound 1. In some embodiments, the pharmaceutical composition contains from about 100 mg to about 30 mg of Compound 1. In some embodiments, the pharmaceutical composition contains from about 100 mg to about 20 mg of Compound 1. In some embodiments, the pharmaceutical composition contains from about 50 mg to about 200 mg of Compound 1. In some embodiments, the pharmaceutical composition contains from about 50 mg to about 150 mg of Compound 1. In some embodiments, the pharmaceutical composition contains from about 10 mg to about 50 mg of Compound 1.

[0076] In some embodiments, this pharmaceutical composition contains from 200 mg to 1 mg of Compound 1. In some embodiments, this pharmaceutical composition contains from 150 mg to 10 mg of Compound 1. In some embodiments, this pharmaceutical composition contains from 125 mg to 15 mg of Compound 1. In some embodiments, this pharmaceutical composition contains from 100 mg to 30 mg of Compound 1. In some embodiments, this pharmaceutical composition contains from 100 mg to 20 mg of Compound 1. In some embodiments, this pharmaceutical composition contains from 50 mg to 200 mg of Compound 1. In some embodiments, this pharmaceutical composition contains from 50 mg to 150 mg of Compound 1. In some embodiments, this pharmaceutical composition contains from 10 mg to 50 mg of Compound 1.

[0077] In some embodiments, this pharmaceutical composition contains about 150 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 100 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 90 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 80 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 70 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 60 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 50 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 40 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 30 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 20 mg of Compound 1. In some embodiments, this pharmaceutical composition contains about 10 mg of Compound 1.

[0078] In some embodiments, this pharmaceutical composition contains 150 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 100 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 90 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 80 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 70 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 60 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 50 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 40 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 30 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 20 mg of Compound 1. In some embodiments, this pharmaceutical composition contains 10 mg of Compound 1.

[0079] In some embodiments, this pharmaceutical composition contains 100 mg of Compound 1, wherein Compound 1 is present in an amount of about 5% to about 12% w / w, or from about 8% to about 12% w / w. In some embodiments, this pharmaceutical composition contains 30 mg of Compound 1, wherein Compound 1 is present in an amount of about 5% to about 12% w / w, or for example from about 8% to about 12% w / w.

[0080] In some embodiments, this pharmaceutical composition contains 100 mg of Compound 1, wherein Compound 1 is present in an amount of 5% to 12% w / w, or from 8% to 12% w / w. In some embodiments, this pharmaceutical composition contains 30 mg of Compound 1, wherein Compound 1 is present in an amount of 5% to 12% w / w, or for example from 8% to 12% w / w.

[0081] In some embodiments, this pharmaceutical composition contains 100 mg of Compound 1, where Compound 1 is present in an amount of about 12% w / w. In some embodiments, this pharmaceutical composition contains 30 mg of Compound 1, where Compound 1 is present in an amount of about 12% w / w.

[0082] In some embodiments, this pharmaceutical composition contains 100 mg of Compound 1, where Compound 1 is present in an amount of 12% w / w. In some embodiments, this pharmaceutical composition contains 30 mg of Compound 1, where Compound 1 is present in an amount of 12% w / w.

[0083] In some embodiments, this pharmaceutical composition contains 100 mg of Compound 1, where Compound 1 is present in an amount of about 8% w / w. In some embodiments, this pharmaceutical composition contains 30 mg of Compound 1, where Compound 1 is present in an amount of about 8% w / w.

[0084] In some embodiments, this pharmaceutical composition contains 100 mg of Compound 1, where Compound 1 is present in an amount of 8% w / w. In some embodiments, this pharmaceutical composition contains 30 mg of Compound 1, where Compound 1 is present in an amount of 8% w / w.

[0085] Excipient / Carrier As discussed above, the pharmaceutical compositions disclosed herein contain Compound 1 or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions disclosed herein may further contain pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Such compositions can be prepared in a manner well known in the pharmaceutical art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0086] In some embodiments, the pharmaceutical composition contains a diluent selected from the group consisting of dicalcium phosphate, cellulose, compressible sugar, calcium hydrogen phosphate dihydrate, lactose, lactose monohydrate, mannitol, microcrystalline cellulose, starch, tricalcium phosphate, and combinations thereof.

[0087] In one embodiment, this pharmaceutical composition contains lactose monohydrate in an amount ranging from about 0 to about 50% w / w, about 5% to about 45% w / w, about 10% to about 40% w / w, about 15% to about 35% w / w, or about 20% to about 30% w / w. In a specific embodiment, this lactose monohydrate is present in this pharmaceutical composition at about 0% w / w, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 22% w / w, about 25% w / w, about 27% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or about 50%. In one exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at about 22.3% w / w. In another exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at about 28% w / w. In yet another embodiment, lactose monohydrate is present in this pharmaceutical composition at about 20% w / w. In a further exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at about 24% w / w. In a further exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at about 26% w / w. In another exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at about 30% w / w. In a further exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at about 30.8%.

[0088] In one embodiment, this pharmaceutical composition contains lactose monohydrate in an amount ranging from 0 to 50% w / w, 5% - 45% w / w, 10% - 40% w / w, 15% - 35% w / w, or 20% - 30% w / w. In a specific embodiment, this lactose monohydrate is present in this pharmaceutical composition at 0.1% w / w, 5% w / w, 10% w / w, 15% w / w, 20% w / w, 22% w / w, 25% w / w, 27% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, or 50%. In one exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at 22.3% w / w. In another exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at 28% w / w. In yet another embodiment, lactose monohydrate is present in this pharmaceutical composition at 20% w / w. In a further exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at 24% w / w. In a further exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at 26% w / w. In another exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at 30% w / w. In a further exemplary embodiment, lactose monohydrate is present in this pharmaceutical composition at 30.8%.

[0089] In another embodiment, this pharmaceutical composition contains microcrystalline cellulose in an amount in the range of about 0% to about 70% w / w, about 5% to about 65% w / w, about 10% to about 65% w / w, about 10% to about 60% w / w, about 15% to about 60% w / w, about 20% to about 60% w / w, or about 15% to about 60% w / w. In a specific embodiment, this microcrystalline cellulose is present in this pharmaceutical composition at about 0% w / w, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 22% w / w, about 25% w / w, about 27% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, or about 60% w / w, or about 65% w / w. In one exemplary embodiment, microcrystalline cellulose is present in this pharmaceutical composition at about 27% w / w. In another exemplary embodiment, microcrystalline cellulose is present in this pharmaceutical composition at about 28.4% w / w. In yet another embodiment, microcrystalline cellulose is present in this pharmaceutical composition at about 45% w / w. In yet another embodiment, microcrystalline cellulose is present in this pharmaceutical composition at about 25.5% w / w. In yet another embodiment, microcrystalline cellulose is present in this pharmaceutical composition at about 62% w / w. In a further exemplary embodiment, microcrystalline cellulose is present in this pharmaceutical composition at about 57.5% w / w.

[0090] In another embodiment, the pharmaceutical composition contains microcrystalline cellulose in an amount in the range of 0 to 70% w / w, 5 to 65% w / w, 10 to 65% w / w, 10 to 60% w / w, 15 to 60% w / w, 20 to 60% w / w, or 15 to 60% w / w. In a specific embodiment, the microcrystalline cellulose is present in the pharmaceutical composition at 0.1% w / w, 5% w / w, 10% w / w, 15% w / w, 20% w / w, 22% w / w, 25% w / w, 27% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, 55% w / w, 60% w / w, or 65% w / w. In one exemplary embodiment, the microcrystalline cellulose is present in the pharmaceutical composition at 27% w / w. In another exemplary embodiment, the microcrystalline cellulose is present in the pharmaceutical composition at 28.4% w / w. In yet another embodiment, the microcrystalline cellulose is present in the pharmaceutical composition at 45% w / w. In yet another embodiment, the microcrystalline cellulose is present in the pharmaceutical composition at 25.5% w / w. In yet another embodiment, the microcrystalline cellulose is present in the pharmaceutical composition at 62% w / w. In a further exemplary embodiment, the microcrystalline cellulose is present in the pharmaceutical composition at 57.5% w / w.

[0091] In one embodiment, this pharmaceutical composition contains mannitol in an amount in the range of about 0% to about 70% w / w, about 10% to about 65% w / w, about 15% to about 65% w / w, about 15% to about 60% w / w, or about 20% to about 60% w / w. In a specific embodiment, this mannitol is present in this pharmaceutical composition at about 0% w / w, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 22% w / w, about 25% w / w, about 27% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 57% w / w, about 60% w / w, or about 65% w / w. In one exemplary embodiment, mannitol is present in this pharmaceutical composition at about 54.6% w / w. In another exemplary embodiment, mannitol is present in this pharmaceutical composition at about 56.8% w / w. In yet another embodiment, mannitol is present in this pharmaceutical composition at about 51.4% w / w. In yet another embodiment, mannitol is present in this pharmaceutical composition at about 22.4% w / w. In a further exemplary embodiment, mannitol is present in this pharmaceutical composition at about 21.7% w / w.

[0092] In one embodiment, this pharmaceutical composition contains mannitol in an amount in the range of 0 to 70% w / w, 10% to 65% w / w, 15% to 65% w / w, 15% to 60% w / w, or 20% to 60% w / w. In a specific embodiment, this mannitol is present in this pharmaceutical composition at 0% w / w, 5% w / w, 10% w / w, 15% w / w, 20% w / w, 22% w / w, 25% w / w, 27% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, 55% w / w, 57% w / w, 60% w / w, or 65% w / w. In one exemplary embodiment, mannitol is present in this pharmaceutical composition at 54.6% w / w. In another exemplary embodiment, mannitol is present in this pharmaceutical composition at 56.8% w / w. In yet another embodiment, mannitol is present in this pharmaceutical composition at 51.4% w / w. In yet another embodiment, mannitol is present in this pharmaceutical composition at 22.4% w / w. In a further exemplary embodiment, mannitol is present in this pharmaceutical composition at 21.7% w / w.

[0093] In yet another embodiment, this pharmaceutical composition contains a mixture of lactose monohydrate and microcrystalline cellulose in an amount in the range of about 0 to about 95% w / w, about 20 to about 95% w / w, about 30 to about 95% w / w, about 40 to about 95% w / w, about 50% to about 95% w / w, about 55% to about 95% w / w, or about 60% to about 95% w / w. In a specific embodiment, this mixture of lactose monohydrate and microcrystalline cellulose is present in this pharmaceutical composition at about 20% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 62%, about 65%, about 67%, about 70%, about 72%, about 75%, about 77%, about 80%, about 82%, about 85%, about 87%, about 90% w / w, or about 95% w / w.

[0094] In yet another embodiment, the pharmaceutical composition contains a mixture of lactose monohydrate and microcrystalline cellulose in an amount in the range of 0 to 95% w / w, 20 to 95% w / w, 30 to 95% w / w, 40 to 95% w / w, 50% to 95% w / w, 55% to 95% w / w, or 60% to 95% w / w. In a specific embodiment, the mixture of lactose monohydrate and microcrystalline cellulose is present in the pharmaceutical composition at 20% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, 55% w / w, 60% w / w, 62%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 82%, 85%, 87%, 90% w / w, or 95% w / w.

[0095] In yet another embodiment, the pharmaceutical composition contains a mixture of mannitol and microcrystalline cellulose in an amount in the range of about 0 to about 90% w / w, about 20 to about 90% w / w, about 30 to about 90% w / w, about 40 to about 90% w / w, about 50% to about 90% w / w, about 55% to about 90% w / w, or about 60% to about 90% w / w. In a specific embodiment, the mixture of mannitol and microcrystalline cellulose is present in the pharmaceutical composition at about 20% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 62%, about 65%, about 67%, about 70%, about 72%, about 75%, about 77%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, or about 90% w / w.

[0096] In yet another embodiment, this pharmaceutical composition contains a mixture of mannitol and microcrystalline cellulose in an amount in the range of 0 to 90% w / w, 20 to 90% w / w, 30 to 90% w / w, 40 to 90% w / w, 50% to 90% w / w, 55% to 90% w / w, or 60% to 90% w / w. In a specific embodiment, this mixture of mannitol and microcrystalline cellulose is present in this pharmaceutical composition at 20% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, 55% w / w, 60% w / w, 62%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, or 90% w / w.

[0097] In some embodiments, this pharmaceutical composition contains a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, povidone, α-starch, sodium starch glycolate, and combinations thereof.

[0098] In one embodiment, this pharmaceutical composition contains crospovidone in an amount in the range of about 1 to about 30% w / w, about 1 to about 25% w / w, about 1 to about 20% w / w, about 1 to about 15% w / w, about 2.5 to about 15% w / w, or about 5 to about 15% w / w. In a specific embodiment, this crospovidone is present in this pharmaceutical composition at about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, or about 15% w / w. In one exemplary embodiment, this crospovidone is present in this pharmaceutical composition at about 7% w / w. In another exemplary embodiment, this crospovidone is present in this pharmaceutical composition at about 10% w / w. In yet another embodiment, this crospovidone is present in this pharmaceutical composition at about 5% w / w.

[0099] In one embodiment, this pharmaceutical composition contains crospovidone in an amount in the range of 1 to 30% w / w, 1 to 25% w / w, 1 to 20% w / w, 1 to 15% w / w, 2.5 to 15% w / w, or 5 to 15% w / w. In a specific embodiment, this crospovidone is present in this pharmaceutical composition in an amount of 1% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, or 15% w / w. In one exemplary embodiment, this crospovidone is present in this pharmaceutical composition in an amount of 7% w / w. In another exemplary embodiment, this crospovidone is present in this pharmaceutical composition in an amount of 10% w / w. In yet another embodiment, this crospovidone is present in this pharmaceutical composition in an amount of 5% w / w.

[0100] In some embodiments, this pharmaceutical composition contains a glidant selected from the group consisting of colloidal silicon dioxide, talc, starch, starch derivatives, and combinations thereof.

[0101] In one embodiment, this pharmaceutical composition contains colloidal silicon dioxide in an amount in the range of about 0 to about 5% w / w, about 0.1 to about 4.5% w / w, about 0.1 to about 4% w / w, about 0.5 to about 5.0% w / w, about 0.5 to about 3% w / w, about 0.5 to about 2% w / w, or about 0.5 to about 1.5% w / w. In a specific embodiment, this colloidal silicon dioxide is present in an amount of about 0% w / w, about 0.1% w / w, about 0.5% w / w, about 0.75% w / w, about 1% w / w, about 1.25% w / w, about 1.5% w / w, or about 2% w / w. In one exemplary embodiment, this colloidal silicon dioxide is present in this pharmaceutical composition in an amount of about 1% w / w.

[0102] In one embodiment, this pharmaceutical composition contains colloidal silicon dioxide in an amount in the range of 0 to 5% w / w, 0.1 to 4.5% w / w, 0.1 to 4% w / w, 0.5 to 5.0% w / w, 0.5 to 3% w / w, 0.5 to 2% w / w, or 0.5 to 1.5% w / w. In a specific embodiment, this colloidal silicon dioxide is present in an amount of 0% w / w, 0.1% w / w, 0.5% w / w, 0.75% w / w, 1% w / w, 1.25% w / w, 1.5% w / w, or 2% w / w. In one exemplary embodiment, this colloidal silicon dioxide is present in this pharmaceutical composition in an amount of 1% w / w.

[0103] In some embodiments, this pharmaceutical composition contains a lubricant selected from the group consisting of calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and combinations thereof.

[0104] In one embodiment, this pharmaceutical composition contains magnesium stearate in an amount in the range of about 0 to about 3% w / w, about 0.1 to about 2.5% w / w, about 0.5 to about 3% w / w, about 0.5 to about 2.5% w / w, about 0.5 to about 2% w / w, about 1 to about 3% w / w, or about 1 to about 2% w / w. In a specific embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of about 0.1%, about 0.5% w / w, about 0.75% w / w, about 1% w / w, about 1.25% w / w, about 1.5% w / w, about 1.75% w / w, about 2% w / w, about 2.5% w / w, or about 3% w / w. In one exemplary embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of about 1.75% w / w. In another exemplary embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of about 1.5% w / w. In yet another embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of about 1% w / w.

[0105] In one embodiment, this pharmaceutical composition contains magnesium stearate in an amount in the range of 0 to 3% w / w, 0.1 to 2.5% w / w, 0.5 to 3% w / w, 0.5 to 2.5% w / w, 0.5 to 2% w / w, 1 to 3% w / w, or 1 to 2% w / w. In a specific embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of 0.1%, 0.5% w / w, 0.75% w / w, 1% w / w, 1.25% w / w, 1.5% w / w, 1.75% w / w, 2% w / w, 2.5% w / w, or 3% w / w. In one exemplary embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of 1.75% w / w. In another exemplary embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of 1.5% w / w. In yet another embodiment, this magnesium stearate is present in this pharmaceutical composition in an amount of 1% w / w.

[0106] Some embodiments provided herein relate to a pharmaceutical composition containing (a) about 5% to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 40% to about 60% w / w of microcrystalline cellulose, (c) about 20% to about 30% w / w of lactose monohydrate, (d) about 5% to about 10% w / w of crospovidone, and about 1% to about 2% w / w of magnesium stearate.

[0107] Some embodiments provided herein relate to a pharmaceutical composition containing (a) 5% to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 40% to 60% w / w of microcrystalline cellulose, (c) 20% to 30% w / w of lactose monohydrate, (d) 5% to 10% w / w of crospovidone, and 1% to 2% w / w of magnesium stearate.

[0108] Some embodiments provided herein relate to pharmaceutical compositions comprising (a) from about 0.5% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 55% to about 65% w / w of microcrystalline cellulose, (c) from about 25% to about 35% w / w of lactose monohydrate, (d) from about 1% to about 10% w / w of crospovidone, and from about 0.5% to about 1.5% w / w of magnesium stearate.

[0109] Some embodiments provided herein relate to pharmaceutical compositions comprising (a) from 0.5% to 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from 55% to 65% w / w of microcrystalline cellulose, (c) from 25% to 35% w / w of lactose monohydrate, (d) from 1% to 10% w / w of crospovidone, and from 0.5% to 1.5% w / w of magnesium stearate.

[0110] Some embodiments provided herein relate to pharmaceutical compositions comprising (a) from about 20% to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 40% to about 50% w / w of microcrystalline cellulose, (c) from about 20% to about 30% w / w of mannitol, (d) from about 5% to about 10% w / w of crospovidone, and from about 1% to about 2% w / w of magnesium stearate.

[0111] Some embodiments provided herein relate to pharmaceutical compositions comprising (a) from 20% to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from 40% to 50% w / w of microcrystalline cellulose, (c) from 20% to 30% w / w of mannitol, (d) from 5% to 10% w / w of crospovidone, and from 1% to 2% w / w of magnesium stearate.

[0112] Some embodiments provided herein relate to pharmaceutical compositions containing (a) from about 5% to about 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 20% to about 30% w / w of microcrystalline cellulose, (c) from about 50% to about 60% w / w of mannitol, (d) from about 5% to about 10% w / w of crospovidone, and from about 1% to about 2% w / w of magnesium stearate.

[0113] Some embodiments provided herein relate to pharmaceutical compositions containing (a) 5% to 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 20% to 30% w / w of microcrystalline cellulose, (c) 50% to 60% w / w of mannitol, (d) 5% to 10% w / w of crospovidone, and 1% to 2% w / w of magnesium stearate.

[0114] Some embodiments provided herein relate to pharmaceutical compositions containing (a) from about 5% to about 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 5% to about 10% w / w of crospovidone, (c) from about 50% to about 60% w / w of mannitol, (d) from about 20% to about 30% w / w of microcrystalline cellulose, and (e) from about 1% to about 2% w / w of magnesium stearate.

[0115] Some embodiments provided herein relate to pharmaceutical compositions containing (a) 5% to 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 5% to 10% w / w of crospovidone, (c) 50% to 60% w / w of mannitol, (d) 20% to 30% w / w of microcrystalline cellulose, and (e) 1% to 2% w / w of magnesium stearate.

[0116] Some embodiments provided herein relate to pharmaceutical compositions containing (a) about 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 7% w / w of crospovidone, (c) about 55% w / w of mannitol, (d) about 27% w / w of microcrystalline cellulose, and (e) about 1.75% w / w of magnesium stearate.

[0117] Some embodiments provided herein relate to a pharmaceutical composition comprising (a) 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 7% w / w of crospovidone, (c) 55% w / w of mannitol, (d) 27% w / w of microcrystalline cellulose, and (e) 1.75% w / w of magnesium stearate.

[0118] Some embodiments provided herein relate to a pharmaceutical composition comprising (a) from about 5% to about 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 5% to about 10% w / w of crospovidone, (c) from about 50% to about 60% w / w of mannitol, (d) from about 20% to about 30% w / w of microcrystalline cellulose, and (e) from about 1% to about 2% w / w of magnesium stearate.

[0119] Some embodiments provided herein relate to a pharmaceutical composition comprising (a) 5% - 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 5% - 10% w / w of crospovidone, (c) 50% - 60% w / w of mannitol, (d) 20% - 30% w / w of microcrystalline cellulose, and (e) 1% - 2% w / w of magnesium stearate.

[0120] Some embodiments provided herein relate to a pharmaceutical composition comprising (a) about 14% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 7% w / w of crospovidone, (c) about 51% w / w of mannitol, (d) about 25.5% w / w of microcrystalline cellulose, and (e) about 1.75% w / w of magnesium stearate.

[0121] Some embodiments provided herein relate to a pharmaceutical composition comprising (a) 14% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 7% w / w of crospovidone, (c) 51% w / w of mannitol, (d) 25.5% w / w of microcrystalline cellulose, and (e) 1.75% w / w of magnesium stearate.

[0122] Mode of Administration The pharmaceutical compositions disclosed herein can be administered in either a single dose or multiple doses, for example, by rectal, buccal, intranasal and transdermal routes, by intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or by means of implanted or coated devices, such as stents, for example, via a cylindrical polymer inserted into an artery, by various methods.

[0123] One mode of administration is parenteral, for example, by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for parenteral administration include, for example, aqueous, or oily suspensions or emulsions in sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0124] Another mode of administration is by inhalation. Compositions for inhalation or ventilation can include solutions and suspensions, and powders, in pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof. This liquid or solid composition can contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, these compositions are administered by the oral or nasal respiratory route for local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent can be nebulized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent, or an intermittent positive pressure breathing machine. The solution, suspension, or powder composition can preferably be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0125] In some embodiments, the pharmaceutical compositions disclosed herein can be administered orally. Administration can be, for example, via tablets, capsules, or enteric-coated tablets. When preparing solid pharmaceutical compositions containing at least one of the compounds described herein, the active ingredient is usually diluted by an excipient and / or enclosed in a carrier such as can be in the form of a capsule, sachet, paper, or other container. When this excipient acts as a diluent, it can be in the form of a solid, semi-solid, or liquid substance, which acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, these compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0126] To prepare solid pharmaceutical compositions such as tablets, the principal active ingredient(s) can be mixed with a pharmaceutical excipient to form a solid pre-formulated composition containing a homogeneous mixture of the compounds described herein. When these pre-formulated compositions are referred to as homogeneous, the active ingredient(s) can be uniformly dispersed throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0127] In some embodiments, the pharmaceutical compositions disclosed herein can be formulated to provide rapid release, sustained release, or delayed release of the active ingredient(s) after administration to a subject by using procedures known in the art. A "sustained release formulation" is a formulation designed to slowly release a therapeutic agent over an extended period of time within the body, while an "immediate release formulation" is a formulation designed to rapidly release a therapeutic agent within a short period of time within the body. Optionally, the immediate release formulation can be coated so that the therapeutic agent is released only when it reaches a desired target (e.g., the stomach) within the body.

[0128] In some embodiments where the pharmaceutical compositions disclosed herein are formulated into tablets or pills, the tablets or pills can be coated or otherwise formulated to provide a dosage form that confers the advantage of extended / sustained action or to protect from gastric acid conditions. For example, the tablets or pills can contain a time-delay substance such as glyceryl monostearate or glyceryl distearate, used alone or with wax. Further, the tablets or pills can include an inner dosage component and an outer dosage component, where the outer dosage component can be in the form of an envelope that covers the inner dosage component. These two components can be separated by an enteric layer that resists degradation in the stomach and serves to allow the inner component to enter the duodenum intact or to delay release. A variety of substances can be used for the enteric layer or coating, such substances including numerous polymeric acids, as well as mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0129] In some embodiments where the pharmaceutical compositions disclosed herein are formulated into tablets or pills, the tablets or pills can be coated or otherwise formulated for immediate release.

[0130] In some embodiments where the pharmaceutical compositions disclosed herein are formulated into tablets or pills, the tablets or pills can have a film coating. In some embodiments, the film coating is configured to limit degradation by photolysis. A suitable film coating can be selected by conventional screening of commercially available preparations. In one embodiment, the film coating comprises a polyvinyl alcohol-based coating. In another embodiment, the film coating comprises polyvinyl alcohol combined with one or more of titanium dioxide, polyethylene glycol, and talc. In yet another embodiment, the film coating is present in the pharmaceutical composition at about 3.0% w / w, or 3.0% w / w.

[0131] In some embodiments, the pharmaceutical compositions disclosed herein can be formulated as single-layer tablets. Such single-layer tablets generally contain an active ingredient (i.e., Compound 1 or additional therapeutic agents described herein) mixed in a single, homogeneous phase. Exemplary methods for making single-layer tablets include, but are not limited to, co-dry granulation and bi-granulation. Co-dry granulation of the pharmaceutical compositions disclosed herein involves dry granulating all of the active ingredients (i.e., Compound 1 or additional therapeutic agents described herein) and excipients together. Bi-granulation of the pharmaceutical compositions disclosed herein is a multi-step process that includes (i) co-dry granulating two of the active ingredients (e.g., Compound 1 and additional therapeutic agents described herein) and excipients together to form Granule A, (ii) dry granulating a third active ingredient (e.g., another additional therapeutic agent described herein) and excipients to form Granule B, and (iii) mixing / blending Granule A and Granule B together.

[0132] Some embodiments provided herein relate to tablets containing Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is the tromethamine salt.

[0133] Some embodiments provided herein are tablets containing less than about 20% w / w Compound 1:

Chemical formula

[0134] Some embodiments provided herein are tablets containing 3% w / w to 20% w / w Compound 1:

Chemical formula

[0135] Some embodiments provided herein are tablets containing less than about 25% w / w of Compound 1:

Chemical formula

[0136] Some embodiments provided herein are tablets containing 3% w / w to 25% w / w of Compound 1:

Chemical formula

[0137] Some embodiments provided herein are tablets containing less than about 25% w / w of Compound 1:

Chemical formula

[0138] Some embodiments provided herein are tablets containing 3% w / w to 20% w / w of Compound 1:

Chemical formula

[0139] In some embodiments, the tablets contain from about 1% w / w to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain from about 3% w / w to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain from about 5% w / w to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain from about 5% w / w to about 20% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain from about 5% w / w to about 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain from about 5% w / w to about 12% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain from about 5% w / w to about 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain from about 5% w / w to about 8% w / w of Compound 1 or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the tablet contains from 1% w / w to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 3% w / w to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 5% w / w to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 5% w / w to 20% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 5% w / w to 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 5% w / w to 12% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 8% w / w to 12% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 5% w / w to 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains from 5% w / w to 8% w / w of Compound 1 or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the tablet contains from about 3% to about 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains from about 5% to about 25% w / w of a pharmaceutically acceptable salt of Compound 1.

[0142] In some embodiments, the tablet contains from 3% to 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains from 5% to 25% w / w of a pharmaceutically acceptable salt of Compound 1.

[0143] In some embodiments, the tablet contains from about 3% to about 25% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains from about 5% to about 25% w / w of the tromethamine salt of Compound 1.

[0144] In some embodiments, the tablet contains 3% to 25% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 5% to 25% w / w of the tromethamine salt of Compound 1.

[0145] In some embodiments, the tablet contains less than about 30% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains less than about 3% w / w of a pharmaceutically acceptable salt of Compound 1.

[0146] In some embodiments, the tablet contains 1% to 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% to 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% to 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% to 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% to 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% to 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% to 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% to 3% w / w of a pharmaceutically acceptable salt of Compound 1.

[0147] In some embodiments, the tablet contains less than about 30% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 25% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 20% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 18% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 15% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 10% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 8% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 7% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 6% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains less than about 5% w / w of the tromethamine salt of Compound 1.

[0148] In some embodiments, the tablet contains 1% to 30% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 25% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 20% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 18% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 15% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 14% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 10% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 8% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 7% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 6% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% to 5% w / w of the tromethamine salt of Compound 1.

[0149] In some embodiments, the tablet contains about 30% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 14% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains about 1% w / w of a pharmaceutically acceptable salt of Compound 1.

[0150] In some embodiments, the tablet contains 30% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 25% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 20% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 18% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 15% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 14% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 12% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 10% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 8% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 7% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 6% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 5% w / w of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the tablet contains 1% w / w of a pharmaceutically acceptable salt of Compound 1.

[0151] In some embodiments, the tablet contains about 30% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 25% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 20% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 18% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 15% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 14% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 10% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 8% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 7% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 6% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 5% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains about 1% w / w of the tromethamine salt of Compound 1.

[0152] In some embodiments, the tablet contains 30% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 25% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 20% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 18% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 15% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 14% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 10% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 8% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 7% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 6% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 5% w / w of the tromethamine salt of Compound 1. In some embodiments, the tablet contains 1% w / w of the tromethamine salt of Compound 1.

[0153] In some embodiments, the tablet contains from about 3% w / w to about 25% w / w of Compound 1. In some embodiments, the tablet contains from about 5% w / w to about 25% w / w of Compound 1. In some embodiments, the tablet contains from about 5% w / w to about 20% w / w of Compound 1. In some embodiments, the tablet contains from about 5% w / w to about 15% w / w of Compound 1. In some embodiments, the tablet contains from about 5% w / w to about 12% w / w of Compound 1. In some embodiments, the tablet contains from about 5% w / w to about 10% w / w of Compound 1. In some embodiments, the tablet contains from about 5% w / w to about 8% w / w of Compound 1.

[0154] In some embodiments, the tablet contains 3% w / w to 20% w / w of Compound 1. In some embodiments, the tablet contains 5% w / w to 20% w / w of Compound 1. In some embodiments, the tablet contains 5% w / w to 15% w / w of Compound 1. In some embodiments, the tablet contains 5% w / w to 12% w / w of Compound 1. In some embodiments, the tablet contains 5% w / w to 10% w / w of Compound 1. In some embodiments, the tablet contains 5% w / w to 8% w / w of Compound 1.

[0155] In some embodiments, the tablet contains less than about 25% w / w of Compound 1. In some embodiments, the tablet contains less than about 20% w / w of Compound 1. In some embodiments, the tablet contains less than about 18% w / w of Compound 1. In some embodiments, the tablet contains less than about 15% w / w of Compound 1. In some embodiments, the tablet contains less than about 12% w / w of Compound 1. In some embodiments, the tablet contains less than about 10% w / w of Compound 1. In some embodiments, the tablet contains less than about 8% w / w of Compound 1. In some embodiments, the tablet contains less than about 5% w / w of Compound 1.

[0156] In some embodiments, the tablet contains 1% to 20% w / w of Compound 1. In some embodiments, the tablet contains 1% to 18% w / w of Compound 1. In some embodiments, the tablet contains 1% to 15% w / w of Compound 1. In some embodiments, the tablet contains 1% to 12% w / w of Compound 1. In some embodiments, the tablet contains 1% to 10% w / w of Compound 1. In some embodiments, the tablet contains 1% to 8% w / w of Compound 1. In some embodiments, the tablet contains 1% to 5% w / w of Compound 1.

[0157] In some embodiments, the tablet contains about 20% w / w of Compound 1. In some embodiments, the tablet contains about 18% w / w of Compound 1. In some embodiments, the tablet contains about 15% w / w of Compound 1. In some embodiments, the tablet contains about 12% w / w of Compound 1. In some embodiments, the tablet contains about 10% w / w of Compound 1. In some embodiments, the tablet contains about 8% w / w of Compound 1. In some embodiments, the tablet contains about 5% w / w of Compound 1. In some embodiments, the tablet contains about 2.5% w / w of Compound 1. In some embodiments, the tablet contains about 1% w / w of Compound 1.

[0158] In some embodiments, the tablet contains 20% w / w of Compound 1. In some embodiments, the tablet contains 18% w / w of Compound 1. In some embodiments, the tablet contains 15% w / w of Compound 1. In some embodiments, the tablet contains 12% w / w of Compound 1. In some embodiments, the tablet contains 10% w / w of Compound 1. In some embodiments, the tablet contains 8% w / w of Compound 1. In some embodiments, the tablet contains 5% w / w of Compound 1. In some embodiments, the tablet contains 2.5% w / w of Compound 1. In some embodiments, the tablet contains 1% w / w of Compound 1.

[0159] In some embodiments, the tablet contains from about 200 mg to about 1 mg of Compound 1. In some embodiments, the tablet contains from about 150 mg to about 10 mg of Compound 1. In some embodiments, the tablet contains from about 125 mg to about 15 mg of Compound 1. In some embodiments, the tablet contains from about 100 mg to about 30 mg of Compound 1. In some embodiments, the tablet contains from about 100 mg to about 20 mg of Compound 1. In some embodiments, the tablet contains from about 50 mg to about 200 mg of Compound 1. In some embodiments, the tablet contains from about 50 mg to about 150 mg of Compound 1. In some embodiments, the tablet contains from about 10 mg to about 50 mg of Compound 1.

[0160] In some embodiments, the tablet contains 200 mg to 1 mg of Compound 1. In some embodiments, the tablet contains 150 mg to 10 mg of Compound 1. In some embodiments, the tablet contains 125 mg to 15 mg of Compound 1. In some embodiments, the tablet contains 100 mg to 30 mg of Compound 1. In some embodiments, the tablet contains 100 mg to 20 mg of Compound 1. In some embodiments, the tablet contains 50 mg to 200 mg of Compound 1. In some embodiments, the tablet contains 50 mg to 150 mg of Compound 1. In some embodiments, the tablet contains 10 mg to 50 mg of Compound 1.

[0161] In some embodiments, the tablet contains about 150 mg of Compound 1. In some embodiments, the tablet contains about 100 mg of Compound 1. In some embodiments, the tablet contains about 90 mg of Compound 1. In some embodiments, the tablet contains about 80 mg of Compound 1. In some embodiments, the tablet contains about 70 mg of Compound 1. In some embodiments, the tablet contains about 60 mg of Compound 1. In some embodiments, the tablet contains about 50 mg of Compound 1. In some embodiments, the tablet contains about 40 mg of Compound 1. In some embodiments, the tablet contains about 30 mg of Compound 1. In some embodiments, the tablet contains about 20 mg of Compound 1. In some embodiments, the tablet contains about 10 mg of Compound 1.

[0162] In some embodiments, the tablet contains 150 mg of Compound 1. In some embodiments, the tablet contains 100 mg of Compound 1. In some embodiments, the tablet contains 90 mg of Compound 1. In some embodiments, the tablet contains 80 mg of Compound 1. In some embodiments, the tablet contains 70 mg of Compound 1. In some embodiments, the tablet contains 60 mg of Compound 1. In some embodiments, the tablet contains 50 mg of Compound 1. In some embodiments, the tablet contains 40 mg of Compound 1. In some embodiments, the tablet contains 30 mg of Compound 1. In some embodiments, the tablet contains 20 mg of Compound 1. In some embodiments, the tablet contains 10 mg of Compound 1.

[0163] In some embodiments, the tablet further contains about 20% to about 70% w / w of microcrystalline cellulose. In some embodiments, the tablet further contains about 25% to about 60% w / w of microcrystalline cellulose.

[0164] In some embodiments, the tablet further contains 20% to 70% w / w of microcrystalline cellulose. In some embodiments, the tablet further contains 25% to 60% w / w of microcrystalline cellulose.

[0165] In some embodiments, the tablet further contains about 15% to about 65% w / w of lactose monohydrate, mannitol, or a combination thereof. In some embodiments, the tablet further contains about 20% to about 60% w / w of lactose monohydrate, mannitol, or a combination thereof.

[0166] In some embodiments, the tablet further contains 15% to 65% w / w of lactose monohydrate, mannitol, or a combination thereof. In some embodiments, the tablet further contains 20% to 60% w / w of lactose monohydrate, mannitol, or a combination thereof.

[0167] In some embodiments, the tablet further contains about 5% to about 10% w / w of crospovidone.

[0168] In some embodiments, the tablet further contains 5% to 10% w / w of crospovidone.

[0169] In some embodiments, the tablet further contains about 1% to about 2% w / w of magnesium stearate.

[0170] In some embodiments, the tablet further contains 1% to 2% w / w of magnesium stearate.

[0171] Some embodiments provided herein relate to tablets containing (a) from about 5% to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 40% to about 60% w / w of microcrystalline cellulose, (c) from about 20% to about 30% w / w of lactose monohydrate, (d) from about 5% to about 10% w / w of crospovidone, and (e) from about 1% to about 2% w / w of magnesium stearate.

[0172] Some embodiments provided herein relate to tablets containing (a) 5% to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 40% to 60% w / w of microcrystalline cellulose, (c) 20% to 30% w / w of lactose monohydrate, (d) 5% to 10% w / w of crospovidone, and (e) 1% to 2% w / w of magnesium stearate.

[0173] In some embodiments, the tablets contain (a) from about 5% to about 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 40% to about 60% w / w of microcrystalline cellulose, (c) from about 20% to about 30% w / w of lactose monohydrate, (d) from about 5% to about 10% w / w of crospovidone, and (e) from about 1% to about 2% w / w of magnesium stearate.

[0174] In some embodiments, the tablets contain (a) 5% to 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 40% to 60% w / w of microcrystalline cellulose, (c) 20% to 30% w / w of lactose monohydrate, (d) 5% to 10% w / w of crospovidone, and (e) 1% to 2% w / w of magnesium stearate.

[0175] In some embodiments, the tablets contain (a) about 6% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 58% w / w of microcrystalline cellulose, (c) about 28% w / w of lactose monohydrate, (d) about 7% w / w of crospovidone, and (e) about 1.5% w / w of magnesium stearate.

[0176] In some embodiments, the tablet contains (a) 6% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 58% w / w of microcrystalline cellulose, (c) 28% w / w of lactose monohydrate, (d) 7% w / w of crospovidone, and (e) 1.5% w / w of magnesium stearate.

[0177] In some embodiments, the tablet contains (a) about 5% w / w of Compound 1, (b) about 58% w / w of microcrystalline cellulose, (c) about 28% w / w of lactose monohydrate, (d) about 7% w / w of crospovidone, and (e) about 1.5% w / w of magnesium stearate.

[0178] In some embodiments, the tablet contains (a) 5% w / w of Compound 1, (b) 58% w / w of microcrystalline cellulose, (c) 28% w / w of lactose monohydrate, (d) 7% w / w of crospovidone, and (e) 1.5% w / w of magnesium stearate.

[0179] In some embodiments, the tablet contains (a) about 20% to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 40% to about 50% w / w of microcrystalline cellulose, (c) about 20% to about 30% w / w of lactose monohydrate, (d) about 5% to about 10% w / w of crospovidone, and (e) about 1% to about 2% w / w of magnesium stearate.

[0180] In some embodiments, the tablet contains (a) 20% to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 40% to 50% w / w of microcrystalline cellulose, (c) 20% to 30% w / w of lactose monohydrate, (d) 5% to 10% w / w of crospovidone, and (e) 1% to 2% w / w of magnesium stearate.

[0181] In some embodiments, the tablet contains (a) about 24% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 45% w / w of microcrystalline cellulose, (c) about 22% w / w of lactose monohydrate, (d) about 7% w / w of crospovidone, and (e) about 1.5% w / w of magnesium stearate.

[0182] In some embodiments, the tablet contains (a) 24% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 45% w / w of microcrystalline cellulose, (c) 22% w / w of lactose monohydrate, (d) 7% w / w of crospovidone, and (e) 1.5% w / w of magnesium stearate.

[0183] In some embodiments, the tablet contains (a) about 20% w / w of Compound 1, (b) about 45% w / w of microcrystalline cellulose, (c) about 22% w / w of lactose monohydrate, (d) about 7% w / w of crospovidone, and (e) about 1.5% w / w of magnesium stearate.

[0184] In some embodiments, the tablet contains (a) 20% w / w of Compound 1, (b) 45% w / w of microcrystalline cellulose, (c) 22% w / w of lactose monohydrate, (d) 7% w / w of crospovidone, and (e) 1.5% w / w of magnesium stearate.

[0185] In some embodiments, the tablet contains (a) about 0.5% to about 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 55% to about 65% w / w of microcrystalline cellulose, (c) about 25% to about 35% w / w of lactose monohydrate, (d) about 1% to about 10% w / w of crospovidone, and (e) about 0.5% to about 1.5% w / w of magnesium stearate.

[0186] In some embodiments, the tablet contains (a) 0.5% to 2% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 55% to 65% w / w of microcrystalline cellulose, (c) 25% to 35% w / w of lactose monohydrate, (d) 1% to 10% w / w of crospovidone, and (e) 0.5% to 1.5% w / w of magnesium stearate.

[0187] In some embodiments, the tablet contains (a) about 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 62% w / w of microcrystalline cellulose, (c) about 31% w / w of lactose monohydrate, (d) about 5% w / w of crospovidone, and (e) about 1% w / w of magnesium stearate.

[0188] In some embodiments, the tablet contains (a) 1% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 62% w / w of microcrystalline cellulose, (c) 31% w / w of lactose monohydrate, (d) 5% w / w of crospovidone, and (e) 1% w / w of magnesium stearate.

[0189] In some embodiments, the tablet contains (a) about 1% w / w of Compound 1, (b) about 62% w / w of microcrystalline cellulose, (c) about 31% w / w of lactose monohydrate, (d) about 5% w / w of crospovidone, and (e) about 1% w / w of magnesium stearate.

[0190] In some embodiments, the tablet contains (a) 1% w / w of Compound 1, (b) 62% w / w of microcrystalline cellulose, (c) 31% w / w of lactose monohydrate, (d) 5% w / w of crospovidone, and (e) 1% w / w of magnesium stearate.

[0191] Some embodiments provided herein relate to tablets containing (a) from about 20% to about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) from about 40% to about 50% w / w of microcrystalline cellulose, (c) from about 20% to about 30% w / w of mannitol, (d) from about 5% to about 10% w / w of crospovidone, and (e) from about 1% to about 2% w / w of magnesium stearate.

[0192] Some embodiments provided herein relate to tablets containing (a) 20% - 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 40% - 50% w / w of microcrystalline cellulose, (c) 20% - 30% w / w of mannitol, (d) 5% - 10% w / w of crospovidone, and (e) 1% - 2% w / w of magnesium stearate.

[0193] Some embodiments provided herein relate to tablets containing (a) about 24% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 45% w / w of microcrystalline cellulose, (c) about 22% w / w of mannitol, (d) about 7% w / w of crospovidone, and about (e) 1.5% w / w of magnesium stearate.

[0194] Some embodiments provided herein relate to tablets containing (a) 24% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 45% w / w of microcrystalline cellulose, (c) 22% w / w of mannitol, (d) 7% w / w of crospovidone, and (e) 1.5% w / w of magnesium stearate.

[0195] Some embodiments provided herein relate to tablets containing (a) about 20% w / w of Compound 1, (b) about 45% w / w of microcrystalline cellulose, (c) about 22% w / w of mannitol, (d) about 7% w / w of crospovidone, and (e) about 1.5% w / w of magnesium stearate.

[0196] Some embodiments provided herein relate to tablets containing (a) 20% w / w of Compound 1, (b) 45% w / w of microcrystalline cellulose, (c) 22% w / w of mannitol, (d) 7% w / w of crospovidone, and (e) 1.5% w / w of magnesium stearate.

[0197] Some embodiments provided herein relate to tablets containing (a) about 5% to about 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 20% to about 30% w / w of microcrystalline cellulose, (c) about 50% to about 60% w / w of mannitol, (d) about 5% to about 10% w / w of crospovidone, and (e) about 1% to about 2% w / w of magnesium stearate.

[0198] Some embodiments provided herein relate to tablets containing (a) 5% - 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 20% - 30% w / w of microcrystalline cellulose, (c) 50% - 60% w / w of mannitol, (d) 5% - 10% w / w of crospovidone, and (e) 1% - 2% w / w of magnesium stearate.

[0199] Some embodiments provided herein relate to tablets containing (a) about 6% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 28% w / w of microcrystalline cellulose, (c) about 57% w / w of mannitol, (d) about 7% w / w of crospovidone, and (e) about 1.75% w / w of magnesium stearate.

[0200] Some embodiments provided herein relate to tablets containing (a) 6% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 28% w / w of microcrystalline cellulose, (c) 57% w / w of mannitol, (d) 7% w / w of crospovidone, and (e) 1.75% w / w of magnesium stearate.

[0201] Some embodiments provided herein relate to tablets containing (a) about 5% w / w of Compound 1, (b) about 28% w / w of microcrystalline cellulose, (c) about 57% w / w of mannitol, (d) about 7% w / w of crospovidone, and (e) about 1.75% w / w of magnesium stearate.

[0202] Some embodiments provided herein relate to tablets containing (a) 5% w / w of Compound 1, (b) 28% w / w of microcrystalline cellulose, (c) 57% w / w of mannitol, (d) 7% w / w of crospovidone, and (e) 1.75% w / w of magnesium stearate.

[0203] Some embodiments provided herein relate to tablets containing (a) about 5% to about 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 5% to about 10% w / w of crospovidone, (c) about 50% to about 60% w / w of mannitol, (d) about 20% to about 30% w / w of microcrystalline cellulose, and (e) about 1% to about 2% w / w of magnesium stearate.

[0204] Some embodiments provided herein relate to tablets containing (a) 5% to 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 5% to 10% w / w of crospovidone, (c) 50% to 60% w / w of mannitol, (d) 20% to 30% w / w of microcrystalline cellulose, and (e) 1% to 2% w / w of magnesium stearate.

[0205] Some embodiments provided herein relate to tablets containing (a) about 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 7% w / w of crospovidone, (c) about 55% w / w of mannitol, (d) about 27% w / w of microcrystalline cellulose, and (e) about 1.75% w / w of magnesium stearate.

[0206] Some embodiments provided herein relate to tablets containing (a) 10% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 7% w / w of crospovidone, (c) 55% w / w of mannitol, (d) 27% w / w of microcrystalline cellulose, and (e) 1.75% w / w of magnesium stearate.

[0207] Some embodiments provided herein relate to tablets containing (a) about 8% w / w of Compound 1, (b) about 7% w / w of crospovidone, (c) about 55% w / w of mannitol, (d) about 27% w / w of microcrystalline cellulose, and (e) about 1.75% w / w of magnesium stearate.

[0208] Some embodiments provided herein relate to tablets containing (a) 8% w / w of Compound 1, (b) 7% w / w of crospovidone, (c) 55% w / w of mannitol, (d) 27% w / w of microcrystalline cellulose, and (e) 1.75% w / w of magnesium stearate.

[0209] Some embodiments provided herein relate to tablets containing (a) about 5% to about 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 5% to about 10% w / w of crospovidone, (c) about 50% to about 60% w / w of mannitol, (d) about 20% to about 30% w / w of microcrystalline cellulose, and (e) about 1% to about 2% w / w of magnesium stearate.

[0210] Some embodiments provided herein relate to tablets containing (a) 5% to 15% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 5% to 10% w / w of crospovidone, (c) 50% to 60% w / w of mannitol, (d) 20% to 30% w / w of microcrystalline cellulose, and (e) 1% to 2% w / w of magnesium stearate.

[0211] Some embodiments provided herein relate to tablets containing (a) about 14% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) about 7% w / w of crospovidone, (c) about 51% w / w of mannitol, (d) about 25.5% w / w of microcrystalline cellulose, and (e) about 1.75% w / w of magnesium stearate.

[0212] Some embodiments provided herein relate to tablets containing (a) 14% w / w of Compound 1 or a pharmaceutically acceptable salt thereof, (b) 7% w / w of crospovidone, (c) 51% w / w of mannitol, (d) 25.5% w / w of microcrystalline cellulose, and (e) 1.75% w / w of magnesium stearate.

[0213] Some embodiments provided herein relate to tablets containing (a) about 5% to about 15% w / w of Compound 1, (b) about 5% to about 10% w / w of crospovidone, (c) about 50% to about 60% w / w of mannitol, (d) about 20% to about 30% w / w of microcrystalline cellulose, and (e) about 1% to about 2% w / w of magnesium stearate.

[0214] Some embodiments provided herein relate to tablets containing (a) 5% to 15% w / w of Compound 1, (b) 5% to 10% w / w of crospovidone, (c) 50% to 60% w / w of mannitol, (d) 20% to 30% w / w of microcrystalline cellulose, and (e) 1% to 2% w / w of magnesium stearate.

[0215] Some embodiments provided herein relate to tablets containing (a) about 12% w / w of Compound 1, (b) about 7% w / w of crospovidone, (c) about 51% w / w of mannitol, (d) about 25.5% w / w of microcrystalline cellulose, and (e) about 1.75% w / w of magnesium stearate.

[0216] Some embodiments provided in this specification relate to tablets containing (a) 12% w / w of Compound 1, (b) 7% w / w of crospovidone, (c) 51% w / w of mannitol, (d) 25.5% w / w of microcrystalline cellulose, and (e) 1.75% w / w of magnesium stearate.

[0217] In some embodiments, the tablet is a film-coated tablet.

[0218] In some embodiments, the tablet further contains selonsertib.

[0219] In some embodiments, the tablet further contains firsocostat.

[0220] Dosage The effective dosage of the active ingredient used may vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages can be readily determined by one of ordinary skill in the art.

[0221] When treating or preventing an FXR-mediated condition to which the compounds of the present disclosure are applicable, substantially satisfactory results are obtained when the compounds of the present disclosure are administered at a daily dosage of from about 0.1 milligram to about 100 milligrams per kilogram of body weight of the animal. In some embodiments, the compounds of the present disclosure are administered as a single daily dose, or as two to six divided doses per day, or in a sustained release form. For most large animals, the total daily dosage is from about 1 milligram to about 1000 milligrams, or from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult, the total daily dosage is generally from about 7 milligrams to about 350 milligrams. This dosage regimen can be adjusted to provide an optimal therapeutic response. In some embodiments, the total daily dosage is from about 1 milligram to about 900 milligrams, from about 10 milligrams to about 800 milligrams, from about 20 milligrams to about 700 milligrams, from about 30 milligrams to about 600 milligrams, from about 40 milligrams to about 550 milligrams, or from about 50 milligrams to about 400 milligrams. In certain embodiments, the compounds of the present disclosure are administered at a daily dosage of from 0.1 milligram to 100 milligrams per kilogram of body weight of the animal. In some embodiments, the compounds of the present disclosure are administered as a single daily dose, or as two to six divided doses per day, or in a sustained release form. For most large animals, the total daily dosage is from 1 milligram to 1000 milligrams, or from 1 milligram to 50 milligrams. In the case of a 70 kg adult, the total daily dosage is generally from 7 milligrams to 350 milligrams. This dosage regimen can be adjusted to provide an optimal therapeutic response. In some embodiments, the total daily dosage is from 1 milligram to 900 milligrams, 10 milligrams to 800 milligrams, 20 milligrams to 700 milligrams, 30 milligrams to 600 milligrams, 40 milligrams to 550 milligrams, or 50 milligrams to 400 milligrams.

[0222] The compound or composition of the present application can be administered once, twice, three times, or four times a day using any suitable one of the above-described modes. Further, the administration or treatment with the compound can be continued over several days. For example, a typical treatment is continued for at least 7 days, 14 days, or 28 days for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy and are frequently alternated with a rest period of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. Treatment cycles may be continuous in other embodiments. In some embodiments, the administration or treatment with the compound can be continued over several days. For example, a typical treatment is continued for 7 to 28 days, 14 days, or 28 days for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy and are frequently alternated with a rest period of 1 to 28 days, generally 7 days or 14 days, between cycles. Treatment cycles may be continuous in other embodiments.

[0223] In certain embodiments, the methods provided herein include administering to a subject an initial daily dose of from about 1 mg to about 800 mg, or 1 to 800 mg, of a compound described herein, and increasing this dose in an increment until clinical efficacy is achieved. Increments of about 5 mg, about 10 mg, about 25 mg, about 50 mg, or about 100 mg can be used to increase the dose. This dosage can be increased daily, every other day, twice a week, or once a week.

[0224] In some embodiments, the methods provided herein include administering to a subject a daily dosage of about 100 mg of Compound 1.

[0225] In some embodiments, the methods provided herein include administering to a subject a daily dosage of 100 mg of Compound 1.

[0226] In some embodiments, the methods provided herein include administering to a subject a daily dosage of about 30 mg of Compound 1.

[0227] In some embodiments, the methods provided herein include administering to a subject a daily dosage of 30 mg of Compound 1.

[0228] Methods of Treatment and Use "Treatment" or "treating" is an approach for obtaining a beneficial or desired result (including clinical results). Beneficial or desired clinical results can include one or more of the following: (a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the extent of the disease or condition); (b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or (c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., reducing the disease state, providing a partial or complete regression of the disease or condition, enhancing the effect of another dosage, delaying the progression of the disease, increasing the quality of life, and / or extending survival).

[0229] The present disclosure further relates to the use of the compounds described herein and the compositions described herein for the treatment and / or prevention of diseases and / or conditions by binding of these compounds to this nuclear receptor. Further, the present disclosure relates to the use of the compounds described herein and the compositions described herein for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions by binding of these compounds to this nuclear receptor.

[0230] Methods of treating a patient having a condition mediated by FXR are also provided herein. In some embodiments, the method includes administering a compound or composition disclosed herein. In some embodiments, a method of treating a patient having a condition mediated by FXR includes administering a pharmaceutical composition described herein. In some embodiments, a method of treating a patient having a condition mediated by FXR includes administering a tablet described herein.

[0231] Methods of treating or preventing a disease or condition in a patient in need thereof are also provided herein, the method including administering a pharmaceutical composition described herein, wherein the disease or condition is congenital hepatic fibrosis.

[0232] In some embodiments, a method of treating a patient having congenital hepatic fibrosis includes administering a pharmaceutical composition containing Compound 1 described herein. In some embodiments, a method of treating a patient having congenital hepatic fibrosis includes administering a tablet containing Compound 1 described herein.

[0233] In some embodiments, the compounds or compositions disclosed herein are provided for use in the treatment of a condition mediated by FXR.

[0234] In some embodiments, the compounds or compositions disclosed herein are provided for the manufacture of a medicament for the treatment of a condition mediated by FXR.

[0235] In some embodiments, the condition mediated by FXR is a chronic intrahepatic or any form of extrahepatic cholestatic condition; liver fibrosis; an obstructive inflammatory disorder of the liver; a chronic inflammatory disorder of the liver; cirrhosis; hepatic steatosis or related syndromes; cholestatic or fibrotic effects associated with alcoholic cirrhosis or viral forms of hepatitis; liver failure or hepatic ischemia after partial hepatectomy; chemotherapy-related steatohepatitis (CASH); acute liver failure; or inflammatory bowel disease.

[0236] In some embodiments, the condition mediated by FXR is a disorder of lipids and lipoproteins; type I diabetes; type II diabetes; clinical complications of type I and type II diabetes selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other effects observed in clinically developed long-term diabetes; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); obesity; a metabolic syndrome selected from the group consisting of dyslipidemia, diabetes, and an abnormally high body mass index; acute myocardial infarction; acute stroke; or thrombosis occurring as an endpoint of chronic obstructive atherosclerotic disease.

[0237] In some embodiments, the condition mediated by FXR is a non-malignant hyperproliferative disorder; and a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colonic adenoma, and polyposis; colorectal adenocarcinoma; breast cancer; pancreatic adenocarcinoma; Barrett's esophagus; or other forms of neoplastic disease of the gastrointestinal tract and liver.

[0238] In some embodiments, the condition mediated by FXR is non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

[0239] In some embodiments, the condition mediated by FXR is congenital hepatic fibrosis. In some embodiments, the condition mediated by FXR is NASH. In some embodiments, the condition mediated by FXR is PSC.

[0240] In some embodiments, the present disclosure relates to the use of the compounds and compositions disclosed herein in the preparation of a medicament for the prevention and / or treatment of chronic intrahepatic or some form of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory disorders resulting from inappropriate bile composition, gastrointestinal conditions with reduced uptake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel disease, disorders of lipids and lipoproteins, type II diabetes and clinical complications of type I and type II diabetes, chronic fatty and fibrotic degeneration of organs resulting from enhanced lipid and particularly triglyceride accumulation and subsequent activation of fibrogenic pathways, obesity and metabolic syndrome (a complex condition of dyslipidemia, diabetes, and an abnormally high body mass index), acute myocardial infarction, acute stroke, thrombosis occurring as an endpoint of chronic obstructive atherosclerotic disease, persistent infection by intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative disorders, malignant hyperproliferative disorders, colorectal adenocarcinoma and particularly hepatocellular carcinoma, hepatic steatosis and related syndromes, liver failure or hepatic insufficiency as a result of chronic liver disease or surgical hepatectomy, acute myocardial infarction, hepatitis B infection, hepatitis C infection, cholestatic and fibrotic effects associated with alcoholic cirrhosis or viral forms of hepatitis, and / or congenital hepatic fibrosis.

[0241] Some embodiments provided herein relate to a method of treating an FXR-mediated condition in a patient in need of treating an FXR-mediated condition, the method comprising administering a pharmaceutical composition comprising less than about 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0242] Some embodiments provided herein relate to methods of treating an FXR-mediated condition in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising from 1% to 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0243] Some embodiments provided herein relate to methods of treating an FXR-mediated condition in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising less than about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0244] Some embodiments provided herein relate to methods of treating an FXR-mediated condition in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising from 1% to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0245] Some embodiments provided herein relate to methods of treating an FXR-mediated condition in a patient in need thereof, the method comprising administering a tablet comprising less than about 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the tablet.

[0246] Some embodiments provided herein relate to a method of treating an FXR-mediated condition in a patient in need thereof, the method comprising administering a tablet comprising from 1% to 20% w / w of Compound 1 and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the tablet.

[0247] Some embodiments provided herein relate to a method of treating an FXR-mediated condition in a patient in need thereof, the method comprising administering a tablet comprising less than about 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the tablet.

[0248] Some embodiments provided herein relate to a method of treating an FXR-mediated condition in a patient in need thereof, the method comprising administering a tablet comprising from 1% to 25% w / w of Compound 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, wherein the percentage by weight is relative to the total weight of the tablet.

[0249] In some embodiments, the FXR-mediated condition is non-alcoholic steatohepatitis (NASH). In such embodiments, the tablets described herein contain from about 1 mg to about 200 mg, or from about 30 mg to about 100 mg of Compound 1. For example, in some embodiments, the tablets described herein contain about 30 mg or about 100 mg of Compound 1. In some embodiments, the tablets described herein contain about 1 mg or about 200 mg of Compound 1.

[0250] In some embodiments, the condition mediated by FXR is non-alcoholic steatohepatitis (NASH). In such embodiments, the tablets described herein contain from 1 mg to 200 mg, or from 30 mg to 100 mg, of Compound 1. For example, in some embodiments, the tablets described herein contain 30 mg or 100 mg of Compound 1. In some embodiments, the tablets described herein contain 1 mg or 200 mg of Compound 1.

[0251] In some embodiments, the condition mediated by FXR is primary sclerosing cholangitis (PSC). In such embodiments, the tablets described herein contain from about 1 mg to about 200 mg, or from about 30 mg to about 100 mg, of Compound 1. For example, in some embodiments, the tablets described herein contain about 30 mg or about 100 mg of Compound 1. In some embodiments, the tablets described herein contain about 1 mg or about 200 mg of Compound 1.

[0252] In some embodiments, the condition mediated by FXR is primary sclerosing cholangitis (PSC). In such embodiments, the tablets described herein contain from 1 mg to 200 mg, or from 30 mg to 100 mg, of Compound 1. For example, in some embodiments, the tablets described herein contain 30 mg or 100 mg of Compound 1. In some embodiments, the tablets described herein contain 1 mg or 200 mg of Compound 1.

[0253] In some embodiments, the condition mediated by FXR is primary biliary cirrhosis (PBC). In such embodiments, the tablets described herein contain from about 1 mg to about 200 mg, or from about 30 mg to about 100 mg, of Compound 1. For example, in some embodiments, the tablets described herein contain about 30 mg or about 100 mg of Compound 1. In some embodiments, the tablets described herein contain about 1 mg or about 200 mg of Compound 1.

[0254] In some embodiments, the condition mediated by FXR is primary biliary cirrhosis (PBC). In such embodiments, the tablets described herein contain 1 mg to 200 mg, or from 30 mg to 100 mg, of Compound 1. For example, in some embodiments, the tablets described herein contain 30 mg or 100 mg of Compound 1. In some embodiments, the tablets described herein contain 1 mg or 200 mg of Compound 1.

[0255] In some embodiments, the methods described herein further include the case where the tablets are administered with food. In some embodiments, the methods described herein further include the case where the tablets are administered with a high-fat diet. In some embodiments, the methods described herein further include the case where the tablets are administered with a moderate-fat diet. In some embodiments, the methods described herein further include the case where the tablets are administered with a low-fat diet.

[0256] As used herein, the term "low-fat diet" or "light-fat diet" is a diet having about 400 kcal, with about 20% of the calories derived from fat.

[0257] As used herein, the term "moderate-fat diet" is a diet having about 600 kcal, with about 27% of the calories derived from fat.

[0258] As used herein, the term "high-fat diet" refers to a diet having about 800 - 1000 kcal, wherein about 50% of the calories are derived from fat.

[0259] In some embodiments, the methods described herein further comprise administering a therapeutically effective amount of seroneseltib.

[0260] In some embodiments, the methods described herein further comprise administering a therapeutically effective amount of filsofostat.

[0261] Some embodiments provided herein relate to a method of treating NASH in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising less than about 20% w / w, or 1% - 20% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition contains about 30 mg, or 30 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0262] Some embodiments provided herein relate to a method of treating NASH in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising less than about 25% w / w, or 1% - 25% w / w of Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition contains about 30 mg, or 30 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0263] Some embodiments provided herein relate to methods of treating NASH in patients in need thereof, the method comprising administering a pharmaceutical composition comprising about 12% w / w, or 12% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition contains about 30 mg, or 30 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0264] Some embodiments provided herein relate to methods of treating NASH in patients in need thereof, the method comprising administering a pharmaceutical composition comprising about 8% w / w, or 8% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition contains about 30 mg, or 30 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0265] Some embodiments provided herein relate to methods of treating PSC in patients in need thereof, the method comprising administering a pharmaceutical composition comprising less than about 20% w / w, or 1% - 20% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition contains about 100 mg, or 100 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0266] Some embodiments provided herein relate to methods of treating PSC in patients in need thereof, the method comprising administering a pharmaceutical composition comprising less than about 25% w / w, or 1% - 25% w / w of Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, wherein This pharmaceutical composition contains about 100 mg, or 100 mg of Compound 1, and this percentage by weight is relative to the total weight of this pharmaceutical composition.

[0267] Some embodiments provided herein relate to a method of treating PSC in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising about 12% w / w, or 12% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein this pharmaceutical composition contains about 100 mg, or 100 mg of Compound 1, and this percentage by weight is relative to the total weight of this pharmaceutical composition.

[0268] Some embodiments provided herein relate to a method of treating PSC in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising about 8% w / w, or 8% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein this pharmaceutical composition contains about 100 mg, or 100 mg of Compound 1, and this percentage by weight is relative to the total weight of this pharmaceutical composition.

[0269] Some embodiments provided herein relate to a method of treating PSC in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising less than about 20% w / w, or 1% - 20% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein this pharmaceutical composition contains about 30 mg, or 30 mg of Compound 1, and this percentage by weight is relative to the total weight of this pharmaceutical composition.

[0270] Some embodiments provided herein relate to a method of treating PSC in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising less than about 25% w / w, or 1% - 25% w / w of Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises about 30 mg, or 30 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0271] Some embodiments provided herein relate to a method of treating PSC in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising about 12% w / w, or 12% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises about 30 mg, or 30 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0272] Some embodiments provided herein relate to a method of treating PSC in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising about 8% w / w, or 8% w / w of Compound 1, and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises about 30 mg, or 30 mg of Compound 1, and the percentage by weight is relative to the total weight of the pharmaceutical composition.

[0273] The medicaments referred to herein can be prepared by conventional processes and can contain combinations of the compounds according to the disclosure with pharmaceutically acceptable carriers.

[0274] Kit Also provided herein are kits comprising a compound or composition described herein (e.g., a tablet described herein) and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a composition of the present disclosure and instructions for use of these compounds in the treatment of a label and / or indication (including the diseases or conditions described herein).

[0275] Also provided herein are articles of manufacture comprising a compound or composition described herein within a suitable container. The container can be a vial, bottle, ampoule, pre-filled syringe, and intravenous bag.

[0276] Combination therapy In some embodiments, Compound 1:

Chemical formula

[0277] In some embodiments, the therapeutic agent, or combination of therapeutic agents, is an ACE inhibitor, an aldehyde dehydrogenase inhibitor, an acetyl-CoA carboxylase inhibitor, a diacylglycerol O-acyltransferase 2 inhibitor, an adenosine A3 receptor agonist, an adiponectin receptor agonist, an aldehyde dehydrogenase 2 stimulator, an AKT protein kinase inhibitor, an AMP-activated protein kinase (AMPK), an AMP kinase activator, an ATP citrate lyase inhibitor, an AMP-activated protein kinase stimulator, an endothelial nitric oxide synthase stimulator, an NAD-dependent deacetylase sirtuin-1 stimulator, an androgen receptor agonist, an amylin receptor agonist, an angiotensin II AT-1 receptor antagonist, an autophagy protein modulator, an autotaxin inhibitor, an Axl tyrosine kinase receptor inhibitor, a Bax protein stimulator, a bioactive lipid, a calcitonin agonist, a cannabinoid receptor modulator, a caspase inhibitor, a caspase-3 stimulator, a cathepsin inhibitor, a caveolin-1 inhibitor, a CCR2 chemokine antagonist, a CCR2 chemokine antagonist, an angiotensin II AT-1 receptor antagonist, a CCR3 chemokine antagonist, a CCR5 chemokine antagonist, a CD3 antagonist, a chloride channel stimulator, a CNR1 inhibitor, a cyclin D1 inhibitor, a cytochrome P450 7A1 inhibitor, a DGAT1 / 2 inhibitor, a diacylglycerol O-acyltransferase 1 inhibitor (DGAT1), a cytochrome P4502E1 inhibitor (CYP2E1), CXCR4 chemokine antagonist, dipeptidyl peptidase IV inhibitor, Endosialin modulator, Eotaxin ligand inhibitor, extracellular matrix protein modulator, farnesoid X receptor agonist, fatty acid synthase inhibitor, FGF1 receptor agonist, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligand, galectin-3 inhibitor, glucagon receptor agonist, glucagon-like peptide 1 agonist, G protein-coupled bile acid receptor 1 agonist, G protein-coupled receptor 84 antagonist, Hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4α modulator (HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitor, STAT-3 modulator, HMG CoA reductase inhibitor, hypoxia-inducible factor-2α inhibitor, IL-10 agonist, IL-17 antagonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, insulin ligand agonist, insulin receptor agonist, integrin modulator, integrin antagonist, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, IL-6 receptor agonist, Jak2 tyrosine kinase inhibitor, ketohexokinase (KHK) inhibitor, croto-β stimulatory factor, 5-lipoxygenase inhibitor, lipoprotein lipase inhibitor, liver X receptor, LPL gene stimulator, lysophosphatidate-1 receptor antagonist, lysyl oxidase homolog 2 inhibitor, macrophage mannose receptor 1 modulator, matrix metalloproteinase (MMP) inhibitor, MEKK-5 protein kinase inhibitor, MCH receptor-1 antagonist, membrane copper amine oxidase (VAP-1) inhibitor, methionine aminopeptidase-2 inhibitor, methyl CpG-binding protein 2 modulator, MicroRNA-21 (miR-21) inhibitor, mitochondrial uncoupler, mixed lineage kinase-3 inhibitor, myelin basic protein stimulatory factor, NACHT LRRInhibitor of PYD domain protein 3 (NLRP3), NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), nicotinic acid receptor 1 agonist, P2Y13 purinergic receptor stimulator, nuclear receptor modulator, P2X7 purinergic receptor modulator, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor β modulator, phenylalanine hydroxylase stimulator, phospholipase C inhibitor, PPARα agonist, PPARδ agonist, PPARγ agonist, peptidyl-prolyl cis-trans isomerase A inhibitor, PPARγ modulator, protease-activated receptor-2 antagonist, protein kinase modulator, Rho-associated protein kinase inhibitor, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitor, sodium glucose transporter-2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl-CoA desaturase-1 inhibitor, STK25 inhibitor, suppressor of cytokine signaling-1 stimulator, suppressor of cytokine signaling-3 stimulator, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonist, TLR-4 antagonist, transglutaminase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulator, or YAP / TAZ modulator and zonulin inhibitor.

[0278] One or more additional therapeutic agents include: ACE inhibitors, such as enalapril; Aldehyde dehydrogenase inhibitors, such as ADX-629; Acetyl-CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat (firsocostat)), DRM-01, gemcabene, PF-05175157, QLT-091382, PF-0522 1304; Acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitor, such as PF-07055341; Adenosine receptor agonist, such as CF-102 (namodenoson), CF-101, CF-502, CGS21680; Adiponectin receptor agonist, such as ADP-355, ADP-399; Aldehyde dehydrogenase 2 stimulator, such as FP-045; Amylin / calcitonin receptor agonist, such as KBP-042, KBP-089; AMP-activated protein kinase stimulator, such as PXL-770, O-304; AMP kinase activator / ATP citrate lyase inhibitor, such as bempedoic acid (ETC-1002, ESP-55016) AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulator, such as NS-0200; Androgen receptor agonist, such as LPCN-1144; Angiotensin II AT-1 receptor antagonist, such as irbesartan; Angiopoietin-related protein-3 inhibitor, such as IONIS-ANGPTL3-LRx; Autophagy protein modulator, such as A-2906; Autotaxin inhibitor, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, AM-063, BBT-877; Axl tyrosine kinase receptor inhibitor, such as bemcentinib (BGB-324, R-428); Bax protein stimulator, such as CBL-514; Bioactive lipid, such as DS-102; Cannabinoid receptor modulator, such as namacizumab, GWP-42004, REV-200, CRB-4001; Caspase inhibitors, such as emricasan; Pan-cathepsin B inhibitors, such as VBY-376; Pan-cathepsin inhibitors, such as VBY-825; CCR2 / CCR5 chemokine antagonists, such as cenicriviroc, maraviroc, CCX-872, WXSH-0213; CCR2 chemokine antagonists, such as propagermanium; CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200, DMX-250; CCR3 chemokine antagonists, such as bertilimumab; CD3 antagonists, such as NI-0401; Chloride channel stimulators, such as cobiprostone; CXCR4 chemokine antagonists, such as AD-214; Diacylglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx, PF-06865571; Diacylglycerol acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitor (CYP2E1), such as SNP-610; Dipeptidyl peptidase IV inhibitors, such as linagliptin, evogliptin; Eotaxin ligand inhibitors, such as bertilimumab, CM-101; Extracellular matrix protein modulators, such as CNX-024; Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, (MET-409), PX20606, EYP-001, TERN-101, TC-100, INT-2228; Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767; Fatty acid synthase inhibitors, such as TVB-2640; Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282; Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, BMS-986036, B-1344; Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 AKR-001; Galectin-3 inhibitors, such as GR-MD-02, GB-1107; Glucagon-like peptide 1 (GLP1R) agonists, such as AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, semaglutide; G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777; Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s020; Histone deacetylase inhibitors / STAT-3 modulators, such as SFX-01; HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; Hypoxia-inducible factor-2α inhibitors, such as PT-2567; IL-10 agonists, such as peg-ilodecakin; Ileal sodium bile acid cotransporter inhibitors, such as odevixibat (A-4250), volixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, elobixibat (A-3309); Insulin sensitizers, such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), VVP-100X, CB-4211, ETI-101; Insulin ligand / ds insulin receptor agonists, such as ORMD-0801; Integrin antagonists, such as IDL-2965; IL-6 receptor agonists, such as KM-2702; Ketoxokinase (KHK) inhibitors, such as PF-06835919; β-Klotho (KLB)-FGF1c agonists, such as MK-3655 (NGM-313); 5-Lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102); Lipoprotein lipase inhibitors, such as CAT-2003; LPL gene stimulators, such as alipogene tiparvovec; Liver X receptor (LXR) inhibitors, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238; Lysophosphatidate-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198; Lysyl oxidase homolog 2 inhibitors, such as simtuzumab, PXS-5382A (PXS-5338); Macrophage mannose receptor 1 modulators, such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); Membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201; MEKK-5 protein kinase (ASK-1) inhibitors, such as GS-4997, SRT-015, GS-444217, GST-HG-151; MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158); Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A; Methionine aminopeptidase-2 inhibitors, such as ZGN-1061, ZGN-839, ZN-1345; Methyl CpG binding protein 2 modulators, such as mercaptamine; Mineralocorticoid receptor antagonist (MCRA), such as MT-3995; Mitochondrial uncouplers, such as 2,4-dinitrophenol; Mixed lineage kinase-3 inhibitors, such as URMC-099-C; Myelin basic protein stimulators, such as olesoxime; Myeloperoxidase inhibitors, such as PF-06667272, AZM-198; NADPH oxidase inhibitors, such as GKT-831, APX-311; Nicotinic acid receptor 1 agonists, such as ARI-3037MO; NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349); Nuclear receptor modulators, such as DUR-928 (DV-928); P2X7 purinergic receptor modulators, such as SGM-1019; P2Y13 purinergic receptor agonists, such as CER-209; PDE 3 / 4 inhibitors, such as ciclesonide (MN-001); PDE 5 inhibitors, such as sildenafil, MSTM-102; PDGF receptor β modulators, such as BOT-191, BOT-509; Peptidyl-prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, NV-556 (NVP-025); Phenylalanine hydroxylase stimulators, such as HepaStem; PPAR agonists, such as elafibranor (GFT-505), seladelpar lysine (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, lanifibranor (IVA-337), CHS-131; Protease-activated receptor-2 antagonists, such as PZ-235; Protein kinase modulators, such as CNX-014; Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325), KD-025; S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891; Sodium glucose transporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, sotagliflozin, Sodium glucose transporter-1 / 2 (SGLT 1 / 2) inhibitors, such as licogliflozin bis(prolinate); SREBP transcription factor inhibitors, such as CAT-2003, MDV-4463; Stearoyl-CoA desaturase-1 inhibitors, such as aramchol; Thyroid hormone receptor beta agonists, such as resmetirom (MGL-3196), MGL-3745, VK-2809; TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201); TLR-4 antagonists, such as JKB-121; Tyrosine kinase receptor modulators, such as CNX-025; GPCR modulators, such as CNX-023; Intranuclear hormone receptor modulators, such as Px-102; Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and Zonulin inhibitors, such as lorazotide acetate (INN-202) are mentioned.

[0279] In certain specific embodiments, one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, alamchol, ARI-3037MO, ASP-8232, AZD-2693, belimumab, betaine anhydride, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fludroxycortide (ST-002), FT-4101, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HTD-1801, HST-202, HST-201, hydrochlorothiazide, icosabutate (PRC-4016), icosapent ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, Irbesarta, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452, LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namilumab, NC-101, NDI-010976, ND-L02-s0201, NGM-282, NGM-313, NGM-386, NGM-395, NP-160, norursodeoxycholic acid, NVP-022,Selected from O-304, obeticholic acid, 25HC3S, olesoxime, PAT-505, PAT-048, PB-4547, peg-ilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-45478, TQA-3526, tipelcast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, besimodegib, bolixibat potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XRx-117, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

[0280] In some embodiments, the method and composition comprise a therapeutically effective amount of an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, and a therapeutically effective amount of a farnesoid X receptor (FXR) agonist, which FXR agonist is a compound described herein.

[0281] In certain embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is of formula (II):

Chemical formula

[0282] ASK1 inhibitors, such as the compounds of formula (II), can be synthesized and characterized using methods known to those skilled in the art, such as those described in US Patent Application Publication No. 2007 / 0276050, US Patent Application Publication No. 2011 / 0009410, and US Patent Application Publication No. 2013 / 0197037.

[0283] In some embodiments, the methods and compositions include a therapeutically effective amount of an acetyl-CoA carboxylase inhibitor and a therapeutically effective amount of a farnesoid X receptor (FXR) agonist, which FXR agonist is in a solid form described herein.

[0284] In certain embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor is of formula (III):

Chemical formula

[0285] The compound of formula (III) is also known as GS-0976 or NDI-010976 or firsocostat.

[0286] In certain embodiments of the methods and pharmaceutical compositions disclosed herein, the ACC inhibitor has the structure of formula (IV):

Chemical formula

[0287] The compounds of formula (III) and formula (IV) can be synthesized and characterized using methods known to those skilled in the art, such as those described in International Publication No. 2013 / 071169.

[0288] In certain embodiments of the methods and pharmaceutical compositions disclosed herein, the ASK1 inhibitor is a compound of formula (II), the ACC inhibitor is a compound of formula (III), and the FXR agonist is a compound of formula (I).

Example

[0289] Preparation of Compound 1 Compound 1 is synthesized according to known methods, for example, the methods described in U.S. Patent No. 9,139,539. The tromethamine salt (Form I) of formula I for use in the tablets described herein can be prepared as follows.

[0290] Compound 1 tromethamine salt (tris salt) Form I was obtained by drying the compound 1 tromethamine salt ethanol solvate (at 0% RH and 25 °C). The compound 1 tromethamine salt ethanol solvate was prepared by adding approximately 1.1 equivalents of Tris (12 mg) and 1 mL of ethanol to a 4 mL vial containing 52.5 mg of the zwitterionic compound 1:

Chemical formula

[0291] The XRPD pattern was collected on a PANalytical XPERT-PRO diffractometer under ambient conditions with the following experimental settings: 45 kV, 40 mA, Kα1 = 1.5406 Å, scan range 2 - 40° 2θ, step size 0.0084 or 0.0167° 2θ, measurement time: 5 minutes. The XRPD analysis of Compound 1 tromethamine salt Form I shows an XRPD pattern that includes 2θ diffraction (±0.2° 2θ) at 5.2, 16.8, and 25.6 degrees. In some embodiments, Form I of the tromethamine salt of Formula I has an XRPD pattern that includes 2θ diffraction (±0.2° 2θ) at 5.2, 16.8, and 25.6 degrees, and one, two, or three of 2θ diffraction (±0.2° 2θ) at 10.9, 15.3, and 21.8 degrees. In some embodiments, Form I of the tromethamine salt of Formula I has an XRPD pattern that includes 2θ diffraction (±0.2° 2θ) at 5.2, 16.8, and 25.6 degrees, and one, two, or three of 2θ diffraction (±0.2° 2θ) at 10.9, 15.3, and 21.8 degrees. In some embodiments, Form I of the tromethamine salt of Formula I has an XRPD pattern that includes 2θ diffraction (±0.2° 2θ) at 5.2, 16.8, and 25.6 degrees, and one, two, three, four, or five of 2θ diffraction (±0.2° 2θ) at 13.3, 20.1, 20.4, 21.0, and 24.3 degrees. In some embodiments, Form I of the tromethamine salt of Formula I has an XRPD pattern that includes 2θ diffraction (±0.2° 2θ) at 5.2, 16.8, 25.6, 10.9, 15.3, 21.8, and 13.3, 20.1, 20.4, 21.0, and 24.3.

[0292] DSC analysis of Compound 1 tromethamine salt Form I shows the onset of melting at about 129 °C, followed by an exotherm with onset at about 150 °C, and decomposition.

[0293] TGA analysis of Compound 1 tromethamine salt Form I shows that these solids showed no weight loss below about 150 °C prior to decomposition. Example 1: Preparation and Formulation of Tablets

[0294] Representative powder formulations of Compound 1 are shown in Tables 1, 2, and 3 below. These formulations were prepared as follows. The tromethamine salt of Compound 1 was blended with microcrystalline cellulose, mannitol, and crospovidone. This blend was passed through a mill and then blended with the internal portion of the magnesium stearate granules. This powder blend was roller-compressed and then passed through a mill. The resulting granules were blended with the external portion of the magnesium stearate granules and compressed into core tablets and film-coated.

Table 1

Table 2

Table 3

[0295] Example 2: Research Protocol The research protocols discussed in Examples 3 and 4 are as follows.

[0296] Study A Cohorts of Study A: · Part A: Predetermined cohorts (Cohorts 1 - 3): Randomized, partially blinded, placebo - controlled, single - dose and multiple - dose with dose escalation. 60 unique subjects; 15 per cohort (12 of Compound 1, 3 of placebo for correspondence (「PTM」)) · Part B: Eligible cohorts (Cohorts 5 and 8): Randomized, partially blinded, placebo - controlled, single - dose and multiple - dose with dose selection and administration frequency adapted. 60 unique subjects, 15 per cohort (12 of Compound 1, 3 of PTM)

[0297] Target population: Healthy men and non - pregnant, non - lactating female subjects, 18 - 45 years old (including 18 and 45 years old).

[0298] Eligible subjects within each cohort were healthy male and non-pregnant, non-lactating female volunteers with approximately uniform distribution, with a body mass index ("BMI") of 19 ≦ BMI ≦ 30 kg / m 2 , a normal 12-lead electrocardiogram ("ECG") (or one had an abnormality clinically considered not significant by the investigator), normal renal function (estimated glomerular filtration rate calculated using the Cockcroft-Gault formula ≧ 80 mL / min), no significant medical history, and were in good health as determined by the investigator in a screening evaluation conducted within 28 days prior to the planned first dose.

[0299] Study procedure / frequency: Part A (single and multiple ascending doses, pre-specified cohorts) proceeded in four staggered, pre-specified dose escalation cohorts and was governed by study-specific stopping criteria. Within each cohort, 15 unique subjects were randomized 4:1 to receive compound 1 (N = 12) or PTM (N = 3) in a blinded fashion. All study drugs in Part A were administered in a fasting state. Within each cohort, the dose escalation from a single dose (period 1) to multiple doses (period 2) was permitted after evaluation of cumulative blinded safety data up to day 3 of the same cohort.

[0300] The cohorts and study treatments for Part A are shown in Table 4:

Table 4

[0301] Part B (adaptive cohorts) was as follows: Based on available safety, pharmacokinetics ("PK"), and / or pharmacodynamics ("PD") data from Part A, the total daily dose for Part B (cohorts 5 and 8) was selected to be between 1 - 600 mg, and the dosing frequency (once or twice daily) and dietary conditions for administration (fasting, low-fat, moderate-fat, or high-fat diet) were selected. Once determined, the dose level, dosing frequency, and dietary conditions were made consistent within the cohort.

[0302] If the dose selected in two or more eligible cohorts exceeded the dose evaluated in the previous cohort, these cohorts were run in a shifted fashion (starting with the lowest dose), applying the same stopping rules as for the cohorts in Part A. If the total dose under evaluation was the same as or lower than the dose already evaluated, the cohorts in Part B were potentially started in parallel with the cohorts in Part A.

[0303] Within each cohort, 15 unique subjects were randomized 4:1 to receive Compound 1 up to 600 mg (N = 12) or PTM (N = 3). When Compound 1 / PTM was administered twice daily, the total daily dose did not exceed 600 mg. The study treatment within each cohort was administered either once or twice daily, in either a fasting or fed (low, moderate, or high fat meal) state.

[0304] The cohorts and study treatments for Part B are as shown in Table 5:

Table 5

[0305] The study drug(s) were supplied as tablets of Compound 1 at strengths of 1 mg, 10 mg, and 100 mg. Tablets of Compound 1 without Compound 1, which were placebos for matching, were also supplied, and these were identical in size, shape, color, and appearance to the tablets of active Compound 1 of their corresponding strengths.

[0306] All study treatments were administered using 240 mL of water. For study treatments containing more than 8 tablets, up to an additional 60 mL of water was administered if necessary.

[0307] All study treatments in Part A were administered in a fasting state as follows. The study treatments in Part B were administered in either a fasting or fed state as follows.

[0308] Administration in the fasting state: The investigational drug(s) was / were administered at approximately the same time each day after an overnight fast (no food or beverages other than water for at least 10 hours). Subjects continued to fast until 2 hours after collection of the PK samples for the investigational drug administration.

[0309] On the day of intensive PK and / or PD sampling, all investigational drug(s) was / were administered at approximately the same time each day after an overnight fast (no food or beverages other than water for at least 10 hours). Subjects continued to fast until 4 hours after collection of the PK samples for the investigational drug administration. Additionally, subjects were restricted from consuming water other than that given with the investigational drug(s) from 1 hour before dosing until several hours after dosing. A standardized meal could be given to the subjects after the PK draw at 4 hours post-dose.

[0310] Administration with food: The investigational drug(s) was / were administered at approximately the same time each day and within 5 minutes of completion of a standardized meal. The meal was started 30 minutes before administration of the investigational drug. Subjects fasted until 4 hours after collection of the PK samples for the investigational drug administration. The dietary fat content (low fat, moderate fat, or high fat) was determined based on data available from subsequent cohorts.

[0311] On the day of intensive PK and / or PD sampling, all investigational drug(s) was / were administered at approximately the same time each day after an overnight fast (no food or beverages other than water for at least 10 hours) and, for administration in the fasting state, within 5 minutes of completion of a standardized meal. The meal should be started 30 minutes before administration of the investigational drug. Subjects continued to fast until 4 hours after collection of the PK samples for the investigational drug administration. Additionally, subjects were restricted from consuming water other than that given with the investigational drug(s) and the standardized meal from 1 hour before dosing until 2 hours after dosing. A standardized meal could be given to the subjects after the PK draw at 4 hours post-dose.

[0312] Study B Study B, Cohort of Part A (Relative Bioavailability (“rBA”)): · Cohort 1: A total of 20 subjects (for 18 evaluable) · Cohort 3: A total of 30 subjects (for 26 evaluable)

[0313] Target population: Healthy males and non-pregnant, non-lactating female subjects, aged 18 - 45 (including 18 and 45).

[0314] Eligible subjects were healthy males and non-pregnant, non-lactating female subjects with approximately uniform distribution, with a body mass index (BMI) of ≥19.0 and ≤30.0 kg / m 2 , normal 12-lead ECG, normal renal function, no significant medical history, and in good health as determined by the investigator in a screening evaluation conducted within 28 days before the planned first dose.

[0315] Study procedure / frequency:

[0316] For Part A, once eligibility was confirmed after completion of the approved (-2 day) study procedure, eligible subjects were randomized 1:1 to one of two treatment sequences within each cohort, and the number of subjects on -1 day was assigned to receive the study drug starting on Day 1.

[0317] The study treatments are as follows:

[0318] Cohort 1 (Seronceltiub (“SEL”) and Compound 1): · Treatment A: A single dose of 18 mg of SEL (1 × 18 mg tablet) + 30 mg of Compound 1 (1 × 30 mg tablet), orally co-administered in the morning within 5 minutes after completion of a high-fat meal · Treatment C: A single dose of 30 mg of Compound 1 (1 × 30 mg tablet), orally administered in the morning in a fasting state

[0319] Cohort 3 (Compound 1): · Treatment I: A single dose of 30 mg of Compound 1 (1 × 30 mg tablet) was orally administered in the morning within 5 minutes of the completion of a light meal.

[0320] - On Day 1, the meal timing and meal type were made to correspond to Day 1 for all except Cohort 3, for which they were made to correspond to Day 17.

[0321] Administration in the fasting state (Treatment C): The investigational drug(s) were administered in the morning after an overnight fast (no food or beverages other than water for at least 10 hours). The subjects continued fasting until 4 hours after the collection of the PK sample for the (first) investigational drug administration. Further, the subjects were restricted from consuming water other than 240 mL provided with each investigational drug administration from 1 hour before to 2 hours after each investigational drug administration. Water could be consumed by the subjects for the remainder of the collection period after blood sampling at 2 hours. A meal (standardized lunch) was provided to the subjects after blood sampling 4 hours after administration.

[0322] Administration with a light meal (Treatment I): The investigational drug(s) were administered together with food and 240 mL of water. A meal was started 30 minutes before investigational drug administration after an overnight fast (no food or beverages other than water for at least 10 hours). The dose was administered at the point when the subject had completed (100%) the provided light meal (containing approximately 400 kcal, with approximately 20% of the calories being derived from fat) within 5 minutes or less. The subjects were fasted for 4 hours after investigational drug administration. A meal (standardized lunch) was provided to the subjects after blood sampling 4 hours after administration. Further, water and other fluids were restricted for 1 hour until 2 hours after dose administration, except for the water provided with the dose and the beverages (where applicable) provided with the standardized meal. Water could be consumed by the subjects for the remainder of the collection period after blood sampling at 2 hours.

[0323] Administration with a high-fat meal (Treatment A): The investigational drug(s) was administered with food and 240 mL of water. After an overnight fast (no food or beverages other than water for at least 10 hours), a meal was started 30 minutes prior to the administration of the investigational drug. The dose was administered at 5 minutes or less after the subject had completed (100%) the provided high-fat meal (containing approximately 800 - 1000 kcal, with approximately 50% of the calories being derived from fat (approximately 150 kcal, 250 kcal, and 500 - 600 kcal being derived from protein, carbohydrates, and fat, respectively)). The subject was fasted for 4 hours after the administration of the investigational drug. A meal (standardized lunch) was provided to the subject after blood sampling at 4 hours after administration. Additionally, water and other fluids were restricted for 1 hour until 2 hours after dose administration, except for the water provided with the dose and the beverages provided with the standardized meal (if applicable). Water could be consumed by the subject for the remainder of the collection period after blood sampling at 2 hours.

[0324] Study C Total number of planned subjects: A total of approximately 40 subjects (20 of whom were white).

[0325] Eligible white subjects were healthy male and non-pregnant, non-lactating female volunteers aged 18 - 55 years (including 18 and 55 years), with an approximately uniform distribution, and a BMI of 18 - 30 kg / m 2 (18 kg / m 2 and 30 kg / m 2 (including), had no smoking habit, had a normal 12-lead ECG or an abnormality considered not clinically significant by the investigator, had normal renal function (Clcr ≧ 90 ml / min), had no significant medical history, and were in good health as determined by a screening evaluation conducted within 28 days prior to the planned administration of the study medication. White subjects had a non-Japanese, non-Asian, and non-African ethnicity. The parents and grandparents of white subjects had a non-Japanese, non-Asian, and non-African ethnicity.

[0326] Eligible subjects received the following treatments: On day 1, a single dose of 100 mg of Compound 1 (1 × 100 mg tablets) administered orally in the morning, followed by an overnight fast.

[0327] Each dose of the study drug was administered on the morning of day 1 together with 240 mL of non-carbonated (non - fizzy) water, followed by an overnight fast (for at least 10 hours, without food or beverages other than water). Subjects continued to fast and food intake was restricted until after the collection of blood samples at 4 hours. Furthermore, subjects were restricted from consuming water or other fluids except for 240 mL given with the study treatment from 1 hour before dosing until 2 hours after dosing.

[0328] Study D The cohorts for Study D are as follows:

[0329] Cohort 10 (Compound 1 at 100 mg, Formulation 9 in Table 3): · Treatment D: A single dose of Compound 1 (1 × 100 mg tablets) administered orally within 5 minutes of consuming a low - fat meal in the morning. · Treatment E: A single dose of Compound 1 (1 × 100 mg tablets) administered orally within 5 minutes of consuming a high - fat meal in the morning. · Treatment F: A single dose of Compound 1 (1 × 100 mg tablets) administered orally in a fasting state in the morning.

Table 9

[0330] Fasting and Diet All meals and / or snacks provided to subjects during their stay in the clinical research facility were standardized for all subjects, and the calorie and fat content were similar, and were consumed at approximately the same time each day. Meal components (e.g., margarine, jelly, bread) were provided to subjects in individual portions (e.g., 1 cup of table spoon) per approved meal schedule. Provision in blocks of meal components (e.g., a bottle of jelly for subjects to share) was not done. All meals were consumed at approximately the same time each day (e.g., 07:30, 12:00, and 18:00).

[0331] When investigational drug administration and intensive PK sampling were performed at the same time point, PK samples were collected at the nominal time point, and investigational drug administration was performed after PK sample collection (within 5 minutes of the nominal time point).

[0332] Administration in the fasting state: Treatment F Compound 1 was administered in the morning after an overnight fast (without food or beverages other than water for at least 10 hours). Subjects continued to fast until 4 hours after the collection of PK samples for the (first) investigational drug administration. Further, subjects were restricted from consuming water other than 240 mL given together with each investigational drug administration from 1 hour before to 2 hours after each investigational drug administration. Water was consumed as needed by the subjects after blood sampling at 2-hour intervals for the remainder of the collection period. A meal (standardized lunch) was provided to the subjects after blood sampling 4 hours after dosing.

[0333] Administration with meal (light meal): Treatment D Compound 1 was administered together with food and 240 mL of water. After an overnight fast (without food or beverages other than water for at least 10 hours), a meal was started 30 minutes before investigational drug administration. The dose was administered at the time when the subject completed (100%) the provided light meal (containing approximately 400 kcal, of which approximately 20% of the calories were derived from fat) within 5 minutes or less. The subjects were fasted for 4 hours after investigational drug administration. A meal (standardized lunch) was provided to the subjects after blood sampling 4 hours after dosing.

[0334] Furthermore, water and other moisture were withheld for 1 hour until 2 hours after dosing, except for water provided with dosing and beverages (if applicable) provided with a standardized meal. Water was consumed by the subject as needed after blood sampling at 2-hour intervals for the remainder of the collection period.

[0335] Administration with food (high-fat diet): Treatment E Compound 1 was administered with food and 240 mL of water. After an overnight fast (no food or beverages other than water for at least 10 hours), a meal was started 30 minutes before study drug administration. The dose was administered at the point when the subject had completed (100%) a high-fat diet provided (containing approximately 800 - 1,000 kcal, with approximately 50% of the calories being derived from fat (approximately 150 kcal, 250 kcal, and 500 - 600 kcal being derived from protein, carbohydrates, and fat, respectively)) within 5 minutes or less. The subject was fasted for 4 hours after study drug administration. A meal (standardized lunch) was provided to the subject after blood sampling 4 hours after dosing.

[0336] Furthermore, water and other moisture were withheld for 1 hour until 2 hours after dosing, except for water provided with dosing and beverages (if applicable) provided with a standardized meal. Water was consumed by the subject as needed after blood sampling at 2-hour intervals for the remainder of the collection period.

[0337] Example 3: Influence of drug load on the variability of exposure to Compound 1 Single-dose pharmacokinetic exposure parameters (AUC inf ) of Compound 1 from multiple Phase 1 studies in healthy volunteers using various drug loads of Compound 1 were compared to determine whether the drug load of Compound 1 affects the variability and / or absolute value of the systemic exposure of Compound 1. The data used in this analysis are presented in Table 6 below.

Table 6

[0338] The graph and statistical summary of the exposure (AUC inf ) of compound 1 obtained from the studies listed above are presented in FIGS. 1A, 1B, and Table 7 (data presented to 3 significant digits), respectively.

[0339] These data show that certain drug loads of compound 1, such as 5% and 8% (or for example about 5% to about 12% or about 12%), resulted in a decrease in variability and an increase in the exposure of compound 1 compared to that observed at a 20% drug load.

Table 7

[0340] Example 4: Evaluation of the effect of diet type on the exposure and variability of compound 1 Multiple first-phase studies in healthy volunteers administered compound 1 in the fasting state or in the fed state with various diet types were compared to determine whether food and diet type affect the variability and / or absolute value of the systemic exposure of compound 1. The data used in this analysis are presented in Table 8 below. inf )

Table 8

[0341] The exposure (AUC infThe graphs and statistical summaries of ( ) are presented in Figure 2 and Table 9 (presenting data to 3 significant figures), respectively. These data show that the effect of food on the exposure to Compound 1 depends on the type of diet, with low-fat and moderate-fat diets reducing the exposure to Compound 1, while high-fat diets increase the exposure to Compound 1. Moderate- and high-fat diets reduce the variability of Compound 1, independent of % drug load, compared to administration in the fasting state, while low-fat diets did not reduce the variability of Compound 1 exposure.

Table 9A

[0342] In cohort 1 of Study B, 30 mg of Compound 1 was administered to the same subjects in a crossover manner with a high-fat diet (+ celoncertib (SEL)) and in the fasting state.

[0343] Paired comparisons of Compound 1 exposure in these subjects showed that subjects with low exposure when Compound 1 was administered in fasting conditions or with a low-fat diet had a greater percentage increase than subjects with high exposure under fasting conditions or with a low-fat diet when Compound 1 was taken with a high-fat diet (Figure 3A, Figure 3B, Figure 4A, Figure 4B, Figure 5, Figure 6, and Figure 7).

[0344] Example 5: Effect of Acid Reducing Agents in Healthy Subjects The objective of cohort 11 was to evaluate the effect of an acid reducing agent (ARA) on the PK of a single tablet formulation of Compound 1 using famotidine, a representative H2RA. A 100 mg strength tablet of Compound 1 (equivalent in free form) was used. Famotidine was obtained from a commercial source.

[0345] Study Drug Dosage and Administration

[0346] The study treatments were as follows: · Treatment J: A single dose of Compound 1 (1 x 100 mg tablet) administered orally in the fasting state in the morning. · Treatment K: A single dose of Compound 1 (1 × 100 mg tablets) orally administered in a fasting state 2 hours after famotidine (FAM) (1 × 40 mg) in the morning.

Table 9B

[0347] When the administration of the investigational drug and intensive PK sampling were performed at the same time point, PK samples were collected at the nominal time point, and the administration of the investigational drug was performed within 5 minutes after PK sample collection (at the nominal time point).

[0348] Administration in a fasting state: Treatments J and K

[0349] The investigational drug(s) was administered in the morning after an overnight fast (no food or beverages other than water for at least 10 hours). The subjects continued to fast until 4 hours after the collection of PK samples for the (first) administration of the investigational drug. Furthermore, the subjects were restricted from consuming water other than 240 mL given together with each administration of the investigational drug from 1 hour before to 2 hours after each administration of the investigational drug. Water was consumed as needed by the subjects after blood sampling every 2 hours for the remainder of the collection period.

[0350] The results of this example show an increase in the bioavailability of Compound 1 in animals pretreated with famotidine. Figure 8 shows that there is an increase in bioavailability when Compound 1 is administered 2 hours after famotidine (a representative histamine 2 receptor antagonist (H2RA)). Figure 9 shows that there is an increase in exposure (i.e., bioavailability) with Compound 1 at a 12% drug load when using famotidine pretreatment. The data are shown in Table 10.

Table 10

[0351] Although the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications, improvements, and variations of the present invention, which are implemented in these embodiments and features disclosed herein, can be made by those skilled in the art, and such modifications, improvements, and alterations are considered to be within the scope of the present invention. The substances, methods, and examples provided herein are representative of the preferred embodiments, are illustrative, and are not intended to be limiting of the scope of the present invention.

[0352] The present invention has been broadly and generally described herein. Each of the narrower species and subgeneric groups that are within the scope of this general disclosure also forms part of the present invention. This includes the general description of the present invention from which some subject matter has been removed by a condition or negative limitation, whether or not the subject matter to be removed is specifically described herein.

[0353] Furthermore, when a feature or aspect of the present invention is described in terms of a Markush group, those skilled in the art will recognize that the present invention is thereby also described in terms of any individual member of this Markush group or a subgroup of members.

[0354] All publications, patent applications, patents, and other references mentioned herein are hereby expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control. In one embodiment, for example, the following items are provided. (Item 1) A tablet containing less than about 20% w / w of Compound 1:

Chemical formula

Chem.

Chem.

Chem.

Claims

1. A tromethamine salt of Compound 1 in an amount of about 5% w / w to about 8% w / w of Compound 1, wherein the percentage by weight is based on the total weight of the tablet, and wherein Compound 1 has the following structure: 【Chemical Formula 19】 A tromethamine salt of Compound 1 having; (b) microcrystalline cellulose; (c) lactose monohydrate, mannitol, or a combination of lactose monohydrate and mannitol; (d) crospovidone; and (e) a tablet containing magnesium stearate.

2. The tablet according to claim 1, containing about 5% w / w of Compound 1.

3. The tablet according to claim 1, containing about 8% w / w of Compound 1.

4. The tablet according to any one of claims 1 to 3, containing about 100 mg of Compound 1.

5. The tablet according to any one of claims 1 to 3, containing about 30 mg of Compound 1.

6. The tablet according to any one of claims 1 to 5, further containing about 25% to about 60% w / w of microcrystalline cellulose.

7. The tablet according to any one of claims 1 to 6, further containing about 20% to about 60% w / w of lactose monohydrate, mannitol, or a combination thereof.

8. The tablet according to any one of claims 1 to 7, further containing about 5% to about 10% w / w of crospovidone.

9. The tablet according to any one of claims 1 to 8, further containing about 1% to about 2% w / w of magnesium stearate.

10. The tablet according to any one of claims 1 to 9, wherein the tablet is a film-coated tablet.

11. The tablet according to any one of claims 1 to 10, further containing seroncelti.

12. The tablet according to any one of claims 1 to 11, further containing filsocostat.

13. A tablet for treating a condition mediated by the non-steroidal farnesoid X receptor (FXR) in a patient in need of treating a condition mediated by the non-steroidal farnesoid X receptor (FXR), (a) a tromethamine salt of Compound 1 in an amount of about 5% w / w to about 8% w / w of Compound 1, wherein the percentage by weight is based on the total weight of the tablet, and wherein Compound 1 has the following structure: 【Chemical 21】 The tromethamine salt of Compound 1 having; (b) microcrystalline cellulose; (c) lactose monohydrate, mannitol, or a combination of lactose monohydrate and mannitol; (d) crospovidone; and (e) magnesium stearate. A tablet containing.

14. The tablet according to claim 13, wherein the tablet contains about 5% w / w of Compound 1.

15. The tablet according to claim 13, wherein the tablet contains about 8% w / w of Compound 1.

16. The tablet according to any one of claims 13 to 15, wherein the state mediated by the FXR is non-alcoholic steatohepatitis (NASH).

17. The tablet according to claim 16, wherein the tablet contains about 1 mg to about 200 mg of Compound 1.

18. The tablet according to any one of claims 13 to 15, wherein the state mediated by the FXR is primary sclerosing cholangitis (PSC).

19. The tablet according to claim 18, wherein the tablet contains about 1 mg to about 200 mg of Compound 1.

20. The tablet according to any one of claims 13 to 15, wherein the state mediated by the FXR is primary biliary cirrhosis (PBC).

21. The tablet according to any one of claims 1 to 20, wherein the tablet is administered with food.

22. The tablet according to any one of claims 1 to 21, wherein the tablet is administered with a high-fat diet.

23. The tablet according to any one of claims 1 to 22, characterized in that it is administered in combination with ceronsertib.

24. The tablet according to any one of claims 1 to 23, characterized in that it is administered in combination with filsoctostat.

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