A crystalline form of 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid

Abstract

Described herein are 3-phenylbenzo[b]thiophene carboxylic acid and 3-phenylbenzo[b]furan carboxylic acid derivatives and uses thereof in therapy. A crystalline form of 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid is also disclosed. The compounds disclosed herein can be used as a branched-chain alpha keto acid dehydrogenase kinase inhibitor or a degrader to treat conditions, for example, diabetes, kidney disease, nonalcoholic steatohepatitis, and heart failure.

Description

[0001] A CRYSTALLINE FORM OF -FLUORO-3-(2,4,5-TRIFLUORO-3-METHOXYPHENYL)-1-BENZOTHIOPHENE-2-CARBOXYLIC ACID

[0002] BACKGROUND OF THE INVENTION

[0003] Branched-chain amino acids (BCAAs) account for about 40% of the essential amino acids in healthy subjects and are required for protein synthesis and cellular signaling processes. BCAAs are transaminated by branched-chain aminotransferase (BCAT), and the resulting branched-chain keto acids (BCKAs) are oxidatively decarboxylated by the branched- chain ketoacid dehydrogenase (BCKDH) enzyme complex. The BCKDH enzyme complex is regulated by inhibitory phosphorylation, which is mediated by BCKDH kinase (BCKDK). Inhibition of complex phosphorylation promotes BCKDH activity and thus the irreversible catabolism of BCKA. There remains a need for pharmaceutical agents that have BCKDK inhibiting or BCKDK degrading activity to treat conditions associated with disordered BCAA catabolism, such as heart failure.

[0004] SUMMARY OF THE INVENTION

[0005] Disclosed herein is a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°.

[0006] Further disclosed herein is a pharmaceutical composition comprising a crystalline compound of the disclosure and a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, or a pharmaceutically acceptable diluent. Disclosed herein is a pharmaceutical composition comprising: a) a first therapeutically effective amount of a crystalline compound of the disclosure; and b) a second therapeutically effective amount of a therapeutic agent selected from the group consisting of an anti-diabetic agent, a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent, a kidney disease treatment agent, and an anti-heart failure treatment agent.

[0007] Disclosed herein is a method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of the disclosure, wherein the condition is selected from a group consisting of fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis or nonalcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma.

[0008] A method of treating a condition or reducing a risk of hospitalization from the condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of the disclosure, wherein the condition is selected from a group consisting of heart failure, cardiovascular death, cardiovascular death, coronary heart disease, unstable angina, peripheral arterial disease, peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, and acute coronary syndrome.

[0009] A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of the disclosure, wherein the condition is selected from a group consisting of Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, a skin and connective tissue disorder, a foot ulceration, ulcerative colitis, endothelial dysfunction, impaired vascular compliance, hyper apo B lipoproteinemia, kidney disease, end-stage kidney disease, chronic kidney disease, and maple syrup urine disease.

[0010] A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of the disclosure, wherein the condition is selected from a group consisting of hepatocellular carcinoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, stomach adenocarcinoma, adrenocortical carcinoma, kidney papillary cell carcinoma, cervical and endocervical carcinoma, bladder urothelial carcinoma, and lung adenocarcinoma.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 is a characteristic X-ray powder diffraction pattern showing 6-fluoro-3-(2,4,5- trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid (Example 9), Form 4 Anhydrous (Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)).

[0013] DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0015] Definitions

[0016] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art. The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0017] “Compounds of the invention” include compounds of Formula I and the novel intermediates used in the preparation thereof. In one embodiment, the compound is a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°. One of ordinary skill in the art will appreciate that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed.

[0018] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0019] The term “and / or” means one or more. For example, "X and / or Y" shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning. Similarly, when more than 2 expressions are listed, such as in “X, Y and / or Z”, it shall be understood to mean either i) “X and Y”, “X, Y and Z”, “X and Z”, or “Y and Z”, or ii) “X or Y or Z” and shall be taken to provide explicit support for all meanings.

[0020] As used herein, the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e. , it may vary between 4.5 mg and 5.5 mg.

[0021] The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.

[0022] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0023] "Excipient" as used herein describes any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0024] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0025] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

[0026] As used herein, the term, “subject, “individual” or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0027] As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following:

[0028] (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;

[0029] (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and

[0030] (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology or both).

[0031] Solid Form

[0032] The compounds of the invention may exist in a continuum of solid states ranging from amorphous to crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

[0033] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO'Na+, -COO'K+, or -SO3'Na+) or non-ionic (such as -N-N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0034] Pharmaceutical Compositions

[0035] In another embodiment, the invention comprises pharmaceutical compositions comprising a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°.

[0036] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[0037] Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0038] In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents.

[0039] In another embodiment, the invention comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e. , sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents.

[0040] In another embodiment, the invention comprises a topical dosage form. "Topical administration" includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci. , vol. 88, pp. OSS- OSS, 1000.

[0041] Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e. , absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0042] For intranasal administration, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0043] In another embodiment, the invention comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0044] Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well- known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 2011 ; and Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

[0045] Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[0046] Liposome containing compounds of the invention may be prepared by methods known in the art (See, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49- 60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0047] Compounds or crystalline compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and polymethylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0048] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0049] The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0050] Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0051] For example, the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsions comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0052] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0053] A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the invention may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co-precipitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the invention and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the invention are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0054] Disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°; and a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, or a pharmaceutically acceptable diluent.

[0055] In some embodiments, a pharmaceutical composition of the disclosure comprises a first therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°; and b) a second therapeutically effective amount of a therapeutic agent selected from the group consisting of an anti-diabetic agent, a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent, a kidney disease treatment agent, and an anti-heart failure treatment agent. In some embodiments, the therapeutic agent is an agent for treating kidney disease (e.g., acute kidney disease and / or chronic kidney disease). In some embodiments, the non-alcoholic steatohepatitis treatment agent or non-alcoholic fatty liver disease treatment agent is an ACC inhibitor, a KHK inhibitor, a DGAT-2 inhibitor, an FXR agonist, a GLP-1R agonist, metformin, incretin analogs, or an incretin receptor modulator. In some embodiments, the anti-diabetic agent is an SGLT-2 inhibitor, metformin, incretin analogs, an incretin receptor modulator, a DPP-4 inhibitor, or a PPAR agonist. In some embodiments, the anti-diabetic agent is metfomin, sitagliptin or ertuglifozin. In some embodiments, the antiheart failure agent is an ACE inhibitor, an angiotensin receptor blocker, an angiotensin-receptor neprilysin inhibitor, a beta adrenergic receptor blocker, a calcium channel blocker, or a vasodilator.

[0056] Administration and Dosing Typically, a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° is administered in an amount effective to treat a condition as described herein. A crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

[0057] The crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[0058] The crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be administered orally. Oral administration may involve swallowing, so that the crystalline compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0059] In another embodiment, the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0060] In another embodiment, the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be administered rectally or vaginally. In another embodiment, the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may also be administered directly to the eye or ear.

[0061] The dosage regimen for the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or compositions containing said crystalline compound is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely.

[0062] In one embodiment, the total daily dose of a crystalline compound that is 6-fluoro-3- (2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X- ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° is typically from about 0.01 mg / kg to about 100 mg / kg (i.e. , mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein. In another embodiment, total daily dose of the crystalline compound that is 6- fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° is from about 0.1 to about 50 mg / kg, and in another embodiment, from about 0.5 to about 30 mg / kg.

[0063] In one embodiment, a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be administered orally in the form of a tablet or a capsule. The dosage of the crystalline compound may be adjusted based on the patient’s response and symptoms. In some embodiments, the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or pharmaceutical composition may provide the crystalline compound in an amount of from about 0.01 mg to about 150 mg, from about 150 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 750 mg, from about 750 mg to about 1000 mg, from about 1250 mg to about 1500 mg, from about 1500 mg to about 1750 mg, from about 1750 mg to about 2000 mg, from about 2000 mg to about 2250 mg, from about 2250 mg to about 2500 mg, from about 2500 mg to about 2750 mg, from about 2750 mg to about 3000 mg, from about 3000 mg to about 3250 mg, from about 3250 mg to about 3500 mg, from about 3500 mg to about 3750 mg, from about 3750 mg to about 4000 mg, from about 4000 mg to about 4250 mg, from about 4250 mg to about 4500 mg, from about 4500 mg to about 4750 mg, or from about 4750 mg to about 5000 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 1 mg to about 2500 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 1 mg to about 100 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 150 mg to about 2500 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 150 mg to about 500 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 100 mg to about 1000 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 500 mg to about 1500 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 1500 mg to about 2500 mg. In one embodiment, the crystalline compound may be provided in an amount of from about 2500 mg to about 5000 mg.

[0064] A crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be provided in an amount of about 0.01 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3200 mg, about 3400 mg, about 3600 mg, about 3800 mg, about 4000 mg, about 4200 mg, about 4400 mg, about 4600 mg, about 4800 mg, or about 5000 mg. In one embodiment, the crystalline compound may be provided in an amount of about 25 mg. In one embodiment, the crystalline compound may be provided in an amount of about 50 mg. In one embodiment, the crystalline compound may be provided in an amount of about 75 mg. In one embodiment, the crystalline compound may be provided in an amount of about 100 mg. In one embodiment, the crystalline compound may be provided in an amount of about 250 mg. In one embodiment, the crystalline compound may be provided in an amount of about 500 mg. In one embodiment, the crystalline compound may be provided in an amount of about 1000 mg. In one embodiment, the crystalline compound may be provided in an amount of about 1200 mg. In one embodiment, the crystalline compound may be provided in an amount of about 1500 mg. In one embodiment, a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or compositions containing said crystalline compound is administered once a day. Multiple doses per day typically may be used to increase the total daily dose, if desired. In one embodiment, a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or compositions containing said crystalline compound is administered twice a day. In one embodiment, a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°° or compositions containing said crystalline compound is administered three times a day.

[0065] Therapeutic Methods and Uses

[0066] The crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may inhibit the activity of BCKDH or degrade BCKDH and may be useful in the treatment of a condition selected from the group consisting of fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis or nonalcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma comprising administering to a subject in need of a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or a pharmaceutically acceptable salt of said crystalline compound. In one embodiment, a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° is administered to treat nonalcoholic steatohepatitis.

[0067] In another embodiment, disclosed herein is a method of treating or reducing the risk of hospitalization for heart failure, cardiovascular death, congestive heart failure, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), cardiovascular death, heart failure in patients with Type II diabetes mellitus, coronary heart disease, peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, acute coronary syndromes and modification of cardiovascular risk comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or a pharmaceutically acceptable salt of said crystalline compound. In one embodiment, a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° can be administered to treat heart failure.

[0068] In another embodiment, disclosed herein is a method of treating a condition selected from the group consisting of Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, hyper apo B lipoproteinemia, kidney disease, end-stage kidney disease, chronic kidney disease at risk of progression, and maple syrup urine disease comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or a pharmaceutically acceptable salt of said crystalline compound. In one embodiment, a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° can be administered to treat kidney disease.

[0069] In another embodiment, disclosed herein is a method of treating a condition selected from the group consisting of hepatocellular carcinoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, stomach adenocarcinoma, adrenocortical carcinoma, kidney papillary cell carcinoma, cervical and endocervical carcinoma, bladder urothelial carcinoma, and lung adenocarcinoma comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or a pharmaceutically acceptable salt thereof. In one embodiment, a therapeutically effective amount of a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° can be administered to treat hepatocellular carcinoma.

[0070] In one embodiment, disclosed herein is a use of a crystalline compound that is 6-fluoro- 3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X- ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° for the manufacture of a medicament in treating fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis or nonalcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline compound.

[0071] In another embodiment, disclosed herein is a use of a crystalline compound that is 6- fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° for the manufacture of a medicament in treating or reducing the risk of hospitalization for heart failure, cardiovascular death, congestive heart failure, heart failure with New York Heart Association Class l-l V symptoms, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with midrange ejection fraction (HF-mrEF), cardiovascular death, heart failure in patients with Type II diabetes mellitus, coronary heart disease, unstable angina, peripheral arterial disease peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, acute coronary syndromes and modification of cardiovascular risk comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline compound.

[0072] In another embodiment, disclosed herein is a use of a crystalline compound that is 6- fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° for the manufacture of a medicament in treating a condition selected from the group consisting of Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance, hyper apo B lipoproteinemia, kidney disease, end-stage kidney disease, chronic kidney disease at risk of progression, and maple syrup urine disease comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline compound.

[0073] In another embodiment, disclosed herein is a use of a crystalline compound that is 6- fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° for the manufacture of a medicament in treating a condition selected from the group consisting of hepatocellular carcinoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, stomach adenocarcinoma, adrenocortical carcinoma, kidney papillary cell carcinoma, cervical and endocervical carcinoma, bladder urothelial carcinoma, and lung adenocarcinoma comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline compound.

[0074] Co-administration

[0075] A crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° may be used alone, or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein.

[0076] The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

[0077] A crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° and the one or more other therapeutic agents may be administered as a fixed or nonfixed combination of the active ingredients. The term "fixed combination" means a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

[0078] In one embodiment, a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° is administered in combination with a second therapeutically effective amount of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of an anti-diabetic agent, a non-alcoholic steatohepatitis (NASH) treatment agent, a non-alcoholic fatty liver disease (NAFLD) treatment agent, a kidney disease treatment agent, and an anti-heart failure treatment agent.

[0079] In one embodiment, the therapeutic agent is an agent to treat NASH, NAFLD, and associated conditions, for example, Orlistat, thiazolidinediones (TZDs) and other insulinsensitizing agents, FGF21 analogues, Metformin, Omega-3-acid ethyl esters (e.g. Lovaza), Fibrates, HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin), ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin), ezetimibe, proprotein convertase subtilisin kexin type- 9 (PCSK9) inhibitors (e.g. evolocumab, alirocumab), probucol, ursodeoxycholic acid, TGR5 agonists, FXR agonists, Vitamin E, Betaine, pentoxifylline, CB1 antagonists, carnitine, / V- acetylcysteine, reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin, ASP-1941, THR1474, TS-071 , ISIS388626 and LX4211), Phentermine, Topiramate, GLP-1 receptor agonists, GIP receptor agonists, dual GLP-1 receptor / glucagon receptor agonists (i.e. , GPK88003, MEDI0382, JNJ-64565111 , NN9277, Bl 456906), dual GLP-1 receptor / GIP receptor agonists (i.e. , Tirzepatide (LY3298176), NN9423), angiotensin-receptor blockers an acetyl-CoA carboxylase (ACC) inhibitor, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, AZD7687 or LCQ908, a diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, a PNPLA3 inhibitor, an FGF21 analog, an FGF19 analog, a PPAR agonist, an FXR agonist, an AMPK activator, an SCD1 inhibitor or an MPO inhibitor.

[0080] In one embodiment, the therapeutic agent is a GLP-1 receptor agonists, for example, liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide, HM15211 , LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, and efpeglenatide. In one embodiment, the GLP-1 receptor agonist is selected from the group consisting of:

[0081] 2-({4-[2-(4-chloro-2-fluorophenyl)-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)- oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0082] 2-({4-[2-(4-chloro-2-fluorophenyl)-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1- [(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0083] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0084] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7- fluoro-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0085] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0086] 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0087] 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0088] 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3- (1 ,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid;

[0089] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [( 1 -ethyl- 1 H-imidazol-5-yl)methyl]-1 H-benzimidazole-6- carboxylic acid;

[0090] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- (1 ,3-oxazol-4-ylmethyl)-1 H-benzimidazole-6-carboxylic acid;

[0091] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- (pyridin-3-ylmethyl)-1 H-benzimidazole-6-carboxylic acid;

[0092] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- (1 ,3-oxazol-5-ylmethyl)-1 H-benzimidazole-6-carboxylic acid;

[0093] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [(1-ethyl-1 H-1,2,3-triazol-5-yl)methyl]-1 H-benzimidazole-6-carboxylic acid;

[0094] 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- (1 ,3-oxazol-2-ylmethyl)-1 H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0095] 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- (1 ,3-oxazol-2-ylmethyl)-1 H-benzimidazole-6- carboxylic acid;

[0096] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0097] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0098] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0099] 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0100] 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0101] 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-[(1-ethyl-1 H-imidazol-5-yl)methyl]-1 H-benzimidazole-6-carboxylic acid;

[0102] 2-({4-[(2R)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0103] 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0104] 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1- yljmethyl)- 1 -[(1 -ethyl- 1 H-imidazol-5-yl)methyl]-1 H-benzimidazole-6-carboxylic acid;

[0105] 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0106] 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0107] 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-

[0108] 1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid;

[0109] 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1- [(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid, DIAST-X2; and

[0110] 2-[(4-{6-[(4-Cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-

[0111] 2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid, or pharmaceutically acceptable salts thereof.

[0112] In one embodiment, the therapeutic agent is an ACC inhibitor, for example, 4-(4-[(1- isopropyl-7-oxo-1 ,4,6,7-tetrahydro-TH-spiro[indazole-5,4'-piperidin]-T-yl)carbonyl]-6- methoxypyridin-2-yl)benzoic acid; and firsocostat (GS-0976) and pharmaceutically acceptable salts thereof.

[0113] In one embodiment, the therapeutic agent is an FXR agonists, for example, tropifexor (2-[(1 R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1 ,2-oxazol-4-yl}methoxy)-8- azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid); cilofexor (GS-9674); obeticholic acid; LY2562175; Met409; TERN-101; and EDP-305 and pharmaceutically acceptable salts thereof.

[0114] In one embodiment, the therapeutic agent is a DGAT2 inhibitor, for example, (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5- carboxamide;

[0115] 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)- / \ / -((3R,4S)-4-fluoropiperidin-3- yl)pyrimidine-5-carboxamide;

[0116] 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)- / \ / -((3S,5S)-5-fluoropiperidin-3- yl)pyrimidine-5-carboxamide;

[0117] 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)- / \ / -((3R,4S)-4-fluoropiperidin-3-yl)pyrimidine- 5-carboxamide;

[0118] 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)- / \ / -((3R,4R)-4-fluoropiperidin-3-yl)pyrimidine- 5-carboxamide;

[0119] 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)- / \ / -((3R,4R)-4-fluoropiperidin-3- yl)pyrimidine- 5-carboxamide; and

[0120] 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-((3S,5S)-5-fluoropiperidin-3-yl)pyrimidine- 5-carboxamide, or a pharmaceutically acceptable salt thereof.

[0121] In one embodiment, the therapeutic agent is a KHK inhibitor, for example, [(1 R,5S,6R)- 3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6- yl]acetic acid or a pharmaceutically acceptable salt thereof.

[0122] In one embodiment, the therapeutic agent is an anti-diabetic agent. In some embodiments, the anti-diabetic agent is insulin, metformin, a GLP-1 receptor agonist disclosed herein, an ACC inhibitor disclosed herein, an SGLT2 inhibitor disclosed herein, a monoacylglycerol O-acyltransferase inhibitor, a phosphodiesterase (PDE)-10 inhibitors, an AMPK activator, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinides, a-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688), an a- glucoside hydrolase inhibitor (e.g., acarbose), a-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPARy agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), PPAR a / y agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), protein tyrosine phosphatase-1 B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Today, 12(9 / 10), 373-381 (2007)), SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidease IV (DPP-IV) inhibitors (e.g., those in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secreatagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, glucokinase activators (GKa) such as those described in W02010103437, WG201010343f8, WG2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g. GSK1362885), VPAC2 receptor agonists, glucagon receptor modulators such as those described in Demong, D.E. et al. Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described in WG2010140092, WO2010128425, WG2010128414, WG2010106457, Jones, R.M. et al. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J.C., Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of this application can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611.

[0123] In one embodiment, the antidiabetic agent is an inhibitor or modulator of a carnitine palmitoyl transferase enzyme, an inhibitor of fructose 1,6-diphosphatase, an inhibitor of aldose reductase, a mineralocorticoid receptor inhibitor, an inhibitor of TORC2, inhibitor of CCR2 and / or CCR5, inhibitor of PKC isoforms (e.g. PKCa, PKCp, PKCy), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81 , GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILIbeta, modulators of RXRalpha. In addition, suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

[0124] In one embodiment, the therapeutic agent is an anti-heart failure agent, for example, ACE inhibitors (e.g. captopril, enalapril, fosinopril, Lisinopril, perindopril, quinapril, Ramipril, trandolapril), Angiotensin II receptor blockers (e.g., Candesartan, Losartan, Valsartan), Angiotensin-receptor neprilysin inhibitors (sacubitril / valsartan), ^channel blocker Ivabradine, Beta-Adrenergic blocking agents (e.g., bisoprolol, metoprolol succinate, carvedilol), SGLT2 inhibitors, Aldosterone antagonists (e.g., spironolactone, eplerenone), cardiac myosin activator (e.g. omecamtiv mecarbil), guanylate cyclase stimulator (e.g. vericiguat), cardiac myosin inhibitor (e.g. mavacamten), SERCA2a activator (e.g. istaroxime), hydralazine and isosorbide dinitrate, diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, Indapamide, Metolazone, Triamterene), or digoxin. In one embodiment, the therapeutic agent is an antihypertensive agent, for example, an alpha adrenergic blocker; a beta adrenergic blocker; a calcium channel blocker (e.g., diltiazem, verapamil, nifedipine and amlodipine); a vasodilator (e.g., hydralazine), a diuretic (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); a renin inhibitor; an ACE inhibitor (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonist (e.g., losartan, irbesartan, valsartan); ET receptor antagonist (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); Dual ET / AII antagonist (e.g., compounds disclosed in WO 00 / 01389); neutral endopeptidase (NEP) inhibitor; vasopepsidase inhibitor (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). In one embodiment, the antihypertensive agent is ivabradine.

[0125] In one embodiment, the therapeutic agent is a calcium channel blocker (L-type or T- type), for example, an L-type calcium channel blocker or a T-type calcium channel blocker. In some embodiments, the calcium channel blocker is diltiazem, verapamil, nifedipine, amlodipine, or mybefradil.

[0126] In one embodiment, the therapeutic agent is a cardiac glycoside, for example, digitalis and ouabain.

[0127] In one embodiment, the therapeutic agent is a diuretic. In some embodiments, the diuretic is a loop diuretic, for example, furosemide (such as LASIX™), torsemide (such as DEMADEX™), bemetanide (such as BUMEX™), and ethacrynic acid (such as EDECRIN™). In some embodiments, the diuretic is a thiazide-type diuretic, for example, chlorothiazide (e.g., DIURIL™, ESIDRIX™ or HYDRODIURIL™), hydrochlorothiazide (e.g., MICROZIDE™ or ORETIC™), benzthiazide, hydroflumethiazide (e.g., SALURON™), bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (e.g., LOZOL™). In some embodiments, a compound of the disclosure can be co-administered with chlorothiazide or hydrochlorothiazide. In some embodiments, a compound of the disclosure can be coadministered with chlorothiazide. In some embodiments, a compound of the disclosure can be co-administered with hydrochlorothiazide. In some embodiments, the diuretic is a phthalimidine- type diuretic, for example, chlorthalidone (e.g., HYGROTON™) and metolazone (e.g., ZAROXOLYN™). In some embodiments, a compound of the disclosure can be co-administered with chlorthalidone. In some embodiments, the diuretic is a quinazoline-type diuretic such as quinethazone. In some embodiments, the diuretic is a potassium-sparing diuretic such as triamterene (e.g., DYRENIUM™) and amiloride (e.g., MIDAMOR™ or MODURETIC™). In one embodiment, a compound of the disclosure can be co-administered with a loop diuretic. In one embodiment, a compound of the disclosure can be co-administered with furosemide or torsemide. In one embodiment, a compound of the disclosure can be co-administered with furosemide. In one embodiment, a compound of the disclosure can be co-administered with torsemide, which may optionally be a controlled or modified release form of torsemide.

[0128] In one embodiment, the therapeutic agent is a mineralocorticoid receptor antagonist, for example, spironolactone and eplerenone.

[0129] In one embodiment, the therapeutic agent is a phosphodiesterase (PDE) inhibitor, for example, a PDE III inhibitor (e.g., cilostazol) or a PDE V inhibitor (e.g., sildenafil).

[0130] In one embodiment, the therapeutic agent is a drug used in the management of chronic kidney disease, for example, phosphate binders (e.g. sucroferric oxyhydroxide, sevelamer, calcium acetate), sodium bicarbonate, erythropoietin-stimulating agents, oral or intravenous iron agents (e.g. iron sucrose, ferric carboxymaltose, ferumoxytol), potassium binders, calcitriol, or SGLT2 inhibitors (e.g. dapagliflozin, empagliflozin, or other SGLT2 inhibitors recited herein).

[0131] In some embodiments, a compound of the disclosure is used in conjunction with other cardiovascular or cerebrovascular treatments including percutaneous coronary intervention (PCI), stenting, drug-eluting stents, stem cell therapy and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

[0132] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° and a second therapeutic agent are combined in a single dosage unit they may be formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that effects a sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and / or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. These as well as other ways of minimizing contact between the components of combination products, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

[0133] In combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to mammals (e.g., humans, male or female) by conventional methods.

[0134] In one embodiment, the present invention provides a pharmaceutical composition comprising a) a first therapeutically effective amount of the crystalline compound of the disclosure; and b) a second therapeutically effective amount of a therapeutic agent selected from the group consisting of an anti-diabetic agent, a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent, a kidney disease treatment agent, and an anti-heart failure treatment agent. In some embodiments, the non-alcoholic steatohepatitis treatment agent or the non-alcoholic fatty liver disease treatment agent is an acetyl-CoA carboxylase (ACC) inhibitor, glucagon-like peptide 1 (GLP-1) receptor agonist, a diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, an farnesoid X receptor (FXR) agonist, metformin, incretin analogs, or an incretin receptor modulator. In some embodiments, the antidiabetic agent is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, metformin, incretin analogs, an incretin receptor modulator, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a peroxisome prol iterator-activated receptor (PPAR) agonist. In some embodiments, the antidiabetic agent is metformin, sitagliptin, or ertuglifozin. In some embodiments, the anti-heart failure agent is an angiotensin-converting enzyme (ACE) inhibitor, an SGLT-2 inhibitor, an angiotensin receptor blocker, an angiotensin-receptor neprilysin inhibitor, a beta adrenergic receptor blocker, a calcium channel blocker, or a vasodilator. In some embodiments, the antiheart failure agent is valsartan, sacubitril, dapagliflozin, empagliflozin, canagliflozin or ertuglifozin.

[0135] These agents and compounds of the invention may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e. , dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

[0136] Kits

[0137] Another aspect of the invention provides kits comprising the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or pharmaceutical compositions comprising the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°. A kit may include, in addition to the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes the crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° or a pharmaceutical composition thereof and one or more therapeutic agents, such as an anti-diabetic agent, a non-alcoholic steatohepatitis treatment agent, a nonalcoholic fatty liver disease treatment agent, a kidney disease treatment agent, and an antiheart failure treatment agent.

[0138] In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising a crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises the crystalline compound that is 6-fluoro-3-(2,4,5- trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2° in quantities sufficient to carry out the methods of the invention and a container for the dosage and a container for the dosage.

[0139] EXAMPLES

[0140] Example 1 : Compounds of the invention

[0141] Compounds of the invention were prepared as previously described inW02020 / 261144A1 (Table 1).

[0142] Table 1. Compounds of the invention

[0143]

[0144]

[0145] EXAMPLE 2: Biological activity of compounds of the invention

[0146] Protein Generation

[0147] BCKDK protein was generated using a pET vector containing from N- to C-terminus: 6xHis, MBP, a TEV protease site (ENLYFQG), a biotin acceptor peptide (GLNDIFEAQKIEWHE), and human BCKDK (residues 31-412 of the protein pre-processing, NP 005872.2). Protein was co-expressed with GroEL-GroES in BL21 (DE3) E. coli in LB media, and protein production was induced with 0.5 mM IPTG and 0.5 mg / mL L-arabinose at an ODeoo of 1 and grown for 16 h at 26 °C. Bacteria were lysed using a Microfluidizer in 100 mM potassium phosphate pH 7.5, 500 mM NaCI, 0.1 mM EDTA, 1% Tween-20, 0.25% Triton X- 100, 10% glycerol, 1 mM DTT, and protease inhibitors. M BP-tagged protein was purified by affinity chromatography using amylose resin, and MBP was removed from BCKDK by TEV protease incubation followed by gel filtration chromatography in 50 mM HEPES pH 7.5, 500 mM NaCI, 300 mM L-Arginine, 2 mM MgCh, 1 mM DTT, and 10% glycerol. A pET vector containing E. coli LplA was expressed in BL21 (DE3) E. coli in LB media, and protein production was induced with 0.75 mM IPTG at an ODeoo of 1 and grown for 16 h at 30 °C. Bacteria were lysed using a Microfluidizer in 50 mM sodium phosphate buffer pH 7.5, 350 mM NaCI, 1.5 mM MgCl2, and 1 mM DTT. LplA protein was precipitated from clarified lysate with 1 M ammonium sulfate and further purified by gel filtration chromatography in 50 mM sodium phosphate pH 7.5, 350 mM NaCI, 1.5 mM MgCh, 1 mM DTT, and 10% glycerol.

[0148] The human BCKDHE1a-E2 fusion substrate was cloned into a pET vector and contained from N- to C-terminus: the lipoyl binding domain of E2 (residues 62-160 preprocessing, NP 001909.4), a TEV protease site (LENLYFQG), residues 331-345 (preprocessing, NP 000700.1) from E1a, and 6xHis (Tso, S. C. et al., J Biol Chem 2014, 289 (30), 20583-20593). The fusion substrate was expressed in BL21(DE3) E. coli in LB media, and protein production was induced with 0.75 mM IPTG at an ODeoo of 1 and grown for 16 h at 30 °C. Bacteria were lysed using a Microfluidizer in 50 mM sodium phosphate pH 7.5, 350 mM NaCI, 10 mM imidazole, 10% glycerol, 1 mM DTT, and protease inhibitors. Fusion substrate was purified by Ni-NTA affinity chromatography followed gel filtration chromatography in 50 mM sodium phosphate pH 7.5, 350 mM NaCI, 1.5 mM MgCh, 1 mM DTT, and 10% glycerol. For lipoylation, fusion substrate was incubated with LplA at a 10:1 (substrate: LplA) ratio in 20 mM sodium phosphate pH 7.4, 6 mM MgCh, 4 mM ATP, 2 mM DTT, 3 mM DL-6,8-thioctic acid at 37 °C. The reaction was monitored using an Agilent 6530 Q-TOF coupled to an Agilent 1290 UPLC. The final lipoylated fusion substrate was purified by gel filtration chromatography in 50 mM HEPES pH 7.5, 350 mM NaCI, 1.5 mM MgCI2, 1 mM DTT, 10% glycerol.

[0149] In Vitro FRET

[0150] BCKDK activity was monitored by phosphorylation of a HIS-tagged fusion BCKDHEIa- E2 substrate protein as described above and was detected using a time resolved-fluorescence resonance energy transfer (TR-FRET) assay system. Compounds were spotted into a 384 well plate, and purified human BCKDK protein was added to the plated compound. After incubation, the LBD-linker-E1 phosphorylation sequence was added in the presence of 15 pM ATP. The reaction was terminated with EDTA. Phosphorylated substrate was recognized by the addition of rabbit anti-E1 phospho Ser293 antibodies (Bethyl Laboratories - A304-672A), and the TR- FRET signal was developed by addition of anti-HIS donor molecules (Europium; Perkin Elmer - AD0205 , AD0110 , AD0111) and anti-Rabbit acceptor molecules (Ulight; Perkin Elmer - TRF502D , TRF502M , TRF502R). Recognition of phosphorylated E1 brought donor and acceptor molecules into close proximity, and excitation at 320 nm caused energy transfer from the Europium donor to the Ulight acceptor dye, which in turn generated light at 665 nm. Signal intensity was proportional to the level of BCKDK-mediated substrate phosphorylation. Reactions were normalized to zero percent effect with DMSO and one hundred percent effect with 600 pM Radicicol, a known BCKDK inhibitor. IC50 curves were generated using ABASE software (I DBS, Boston MA).

[0151] In Table 2 assay data (IC50S) are presented for the Examples below in accordance with the above-described assay.

[0152] Table 2: In Vitro FRET Assay Data

[0153] 1. Biological data obtained on the neutral acid, rather than the ammonium salt.

[0154] Phospho BCKDHA Alpha Surefire Cell Assay

[0155] Prior to conducting the assay, BCKDH antibodies (Bethyl A303-790A) were biotinylated using the ChromaLink™ One-Shot Antibody Biotinylation Kit (TriLink Technologies B-9007- 009K) and phospho (S293) BCKDHA antibodies (Bethyl A303-672A) were CaptSure™ tagged using the Lightning-Link® CaptSure™ Conjugation Kit (TGR Biosciences 6300007). Human skeletal myocytes (Gibco A11440) were previously immortalized via the introduction of hTERT into the cells.

[0156] Human skeletal myocytes (Gibco A11440) were plated in a 384 well plate at a density of 15,000 live cells / well and grown in skeletal muscle growth media containing the media supplement and chick embryo extract (Promocell C-23060 and C-23160, MP92850145). After overnight incubation, media was removed, and BCKDK inhibitors were added in assay media (growth media diluted 10-fold in PBS). After 60 minutes, the media was removed, the cells were washed with PBS and lysed in 10 pL of buffer (Cell Signaling #9803) containing 2 nM biotinylated total BCKDH antibodies and 1X protease / phosphatase inhibitor cocktail (Cell Signaling 5872). Samples were incubated for 60 minutes, and 5 pL of diluted CaptSure tagged Phospho BCKDHA Antibody (1:400) and anti-CaptSure acceptor beads (40 pg / pL) in 1X immunoassay buffer (Perkin Elmer AL000F) were added to the lysates. After a 60 minute incubation, 5 pL streptavidin donor beads (40 pg / pL) beads were added in 1X immunoassay buffer while protecting from light. Fluorescence was emitted when the phospho and total BCKDH antibodies were within proximity, signifying phosphorylation of S293 BCKDH. Fluorescence was monitored on the Envision plate reader. The zero percent effect was determined from DMSO treatment and the maximal effect was assessed relative to the BCKDK inhibitor BT2. (Tso, S. C.; Gui, W. J.; Wu, C. Y.; et al. Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain alpha-ketoacid dehydrogenase kinase. J Biol Chem 2014, 289, 20583-20593.). IC50 curves were generated using ActivityBase software (I DBS, Boston MA).

[0157] In Table 3 assay data (IC50S) are presented for the Examples below in accordance with the above-described assay (to two (2) significant figures as the geometric mean, based on the number of replicates tested (Number)).

[0158] Table 3: SureFire Alpha Assay Data

[0159] 1. N.D. - Not determined

[0160] 2. Biological data obtained on the neutral acid, rather than the ammonium salt.

[0161] Powder X-Ray Diffraction of 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid Form 4 anhydrous The powder X-ray diffraction pattern for 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid Form 4 anhydrous was generated using a Bruker AXS D8 Endeavor diffractometer equipped with a copper (Cu) radiation source. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The motorized divergence slits were set at constant illumination of 11 mm. Diffracted radiation was detected using a LYNXEYE XE-T energy dispersive X-ray detector, with the position sensitive detector (PSD) opening set at 4.00°. Data were collected on the theta-theta goniometer at the Cu wavelength from 2.0 to 55.0 degrees 2-theta (°20) using a step size of 0.019 °20 and a time per step of 0.2 s. Samples were prepared for analysis by placing them in a silicon low background small divot holder and rotated at 15 rpm during data collection.

[0162] Data were analyzed in Diffrac.Suite EVA Version 5.0.0.22. The collected powder pattern of 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid Form 4 was aligned to correct °20 positions using a Silicon reference material (NIST SRM640e). A peak list was prepared using reflections > 2% of the most intense band. A typical variability of ± 0.2 °20 in peak positions (USP-941) applies to this data.

[0163] The PXRD pattern for 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid Form 4 anhydrous is provided in Figure 1. A peak list is included in Table 1.

[0164] TABLE 1. PXRD Peak list for 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2- carboxylic acid Form 4 anhydrous

[0165] EMBODIMENTS

[0166] The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. Embodiment 1. A crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3- methoxyphenyl)-1-benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°.

[0167] Embodiment 2. The crystalline compound of embodiment 1 , wherein the X-ray powder diffraction pattern further comprises characteristic peaks expressed in degrees 20 of 11.4° ± 0.2° and 16.7° ± 0.2°.

[0168] Embodiment 3. The crystalline compound of embodiment 1 or 2, wherein the crystalline compound is anhydrous.

[0169] Embodiment 4. A pharmaceutical composition comprising the crystalline compound of any one of embodiments 1-3 and a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, or a pharmaceutically acceptable diluent. Embodiment 5. A pharmaceutical composition comprising: a) a first therapeutically effective amount of the crystalline compound of any one of embodiments 1-3; and b) a second therapeutically effective amount of a therapeutic agent selected from the group consisting of an anti-diabetic agent, a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent, a kidney disease treatment agent, and an anti-heart failure treatment agent.

[0170] Embodiment 6. The pharmaceutical composition of embodiment 5, wherein the therapeutic agent is: 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6- methoxypyridin-2-yl)benzoic acid;

[0171] [(1 R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3- azabicyclo[3.1 ,0]hex-6-yl]acetic acid;

[0172] 2-[(1 R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8- azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

[0173] (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5- carboxamide; or

[0174] 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2- ylmethyl]- 1 H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0175] Embodiment 7. The pharmaceutical composition of embodiment 5, wherein the nonalcoholic steatohepatitis treatment agent or the non-alcoholic fatty liver disease treatment agent is an acetyl-CoA carboxylase (ACC) inhibitor, glucagon-like peptide 1 (GLP-1) receptor agonist, a diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, an farnesoid X receptor (FXR) agonist, metformin, incretin analogs, or an incretin receptor modulator.

[0176] Embodiment 8. The pharmaceutical composition of embodiment 5, wherein the antidiabetic agent is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, metformin, incretin analogs, an incretin receptor modulator, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a peroxisome proliferator-activated receptor (PPAR) agonist.

[0177] Embodiment 9. The pharmaceutical composition of embodiment 5, wherein the antidiabetic agent is metformin, sitagliptin, or ertuglifozin.

[0178] Embodiment 10. The pharmaceutical composition of embodiment 5, wherein the antiheart failure agent is an angiotensin-converting enzyme (ACE) inhibitor, an SGLT-2 inhibitor, an angiotensin receptor blocker, an angiotensin-receptor neprilysin inhibitor, a beta adrenergic receptor blocker, a calcium channel blocker, or a vasodilator.

[0179] Embodiment 11. The pharmaceutical composition of embodiment 5, wherein the antiheart failure agent is valsartan, sacubitril, dapagliflozin, empagliflozin, canagliflozin or ertuglifozin. Embodiment 12. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of embodiments 1-3, wherein the condition is selected from a group consisting of fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis or nonalcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma.

[0180] Embodiment 13. The method of embodiment 12, wherein the condition is nonalcoholic steatohepatitis.

[0181] Embodiment 14. A method of treating a condition or reducing a risk of hospitalization from the condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of embodiments 1-3, wherein the condition is selected from a group consisting of heart failure, cardiovascular death, cardiovascular death, coronary heart disease, unstable angina, peripheral arterial disease, peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, and acute coronary syndrome.

[0182] Embodiment 15. The method of embodiment 14, wherein the condition is heart failure.

[0183] Embodiment 16. The method of embodiment 14, wherein the heart failure is congestive heart failure, heart failure with a New York Heart Association Class l-IV symptom, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with midrange ejection fraction (HF-mrEF), or heart failure associated with Type II diabetes mellitus.

[0184] Embodiment 17. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of embodiments 1-3, wherein the condition is selected from a group consisting of Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, a skin and connective tissue disorder, a foot ulceration, ulcerative colitis, endothelial dysfunction, impaired vascular compliance, hyper apo B lipoproteinemia, kidney disease, end-stage kidney disease, chronic kidney disease, and maple syrup urine disease. Embodiment 18. The method of embodiment 17, wherein the condition is kidney disease.

[0185] Embodiment 19. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of embodiments 1-3, wherein the condition is selected from a group consisting of hepatocellular carcinoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, stomach adenocarcinoma, adrenocortical carcinoma, kidney papillary cell carcinoma, cervical and endocervical carcinoma, bladder urothelial carcinoma, and lung adenocarcinoma.

[0186] Embodiment 20. The method of embodiment 19, wherein the condition is hepatocellular carcinoma.

[0187] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiment(s) described herein. Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein.

[0188] It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0189] All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A crystalline compound that is 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1- benzothiophene-2-carboxylic acid, characterized by an X-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 20 of 8.4° ± 0.2°, 15.8° ± 0.2°, and 28.9° ± 0.2°.

2. The crystalline compound of claim 1 , wherein the X-ray powder diffraction pattern further comprises characteristic peaks expressed in degrees 20 of 11.4° ± 0.2° and 16.7° ± 0.2°.

3. The crystalline compound of claim 1 or 2, wherein the crystalline compound is anhydrous.

4. A pharmaceutical composition comprising the crystalline compound of any one of claims 1-3 and a pharmaceutically acceptable carrier, a pharmaceutically acceptable vehicle, or a pharmaceutically acceptable diluent.

5. A pharmaceutical composition comprising: a) a first therapeutically effective amount of the crystalline compound of any one of claims 1-3; and b) a second therapeutically effective amount of a therapeutic agent selected from the group consisting of an anti-diabetic agent, a non-alcoholic steatohepatitis treatment agent, a non-alcoholic fatty liver disease treatment agent, a kidney disease treatment agent, and an antiheart failure treatment agent.

6. The pharmaceutical composition of claim 5, wherein the therapeutic agent is: 4-(4-(1-isopropyl-7-oxo-1 ,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6- methoxypyridin-2-yl)benzoic acid;[(1 R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3- azabicyclo[3.1 ,0]hex-6-yl]acetic acid;2-[(1 R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1 ,2-oxazol-4-yl}methoxy)-8- azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylic acid;(S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5- carboxamide; or2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2- ylmethyl]- 1 H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 5, wherein the non-alcoholic steatohepatitis treatment agent or the non-alcoholic fatty liver disease treatment agent is an acetyl-CoA carboxylase (ACC) inhibitor, glucagon-like peptide 1 (GLP-1) receptor agonist, a diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, an farnesoid X receptor (FXR) agonist, metformin, incretin analogs, or an incretin receptor modulator.

8. The pharmaceutical composition of claim 5, wherein the anti-diabetic agent is a sodiumglucose cotransporter-2 (SGLT-2) inhibitor, metformin, incretin analogs, an incretin receptor modulator, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a peroxisome prol iterator-activated receptor (PPAR) agonist.

9. The pharmaceutical composition of claim 5, wherein the anti-diabetic agent is metformin, sitagliptin, or ertuglifozin.

10. The pharmaceutical composition of claim 5, wherein the anti-heart failure agent is an angiotensin-converting enzyme (ACE) inhibitor, an SGLT-2 inhibitor, an angiotensin receptor blocker, an angiotensin-receptor neprilysin inhibitor, a beta adrenergic receptor blocker, a calcium channel blocker, or a vasodilator.

11. The pharmaceutical composition of claim 5, wherein the anti-heart failure agent is valsartan, sacubitril, dapagliflozin, empagliflozin, canagliflozin or ertuglifozin.

12. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of claims 1-3, wherein the condition is selected from a group consisting of fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis or nonalcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma.

13. The method of claim 12, wherein the condition is nonalcoholic steatohepatitis.

14. A method of treating a condition or reducing a risk of hospitalization from the condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of claims 1-3, wherein the condition is selected from a group consisting of heart failure, cardiovascular death, cardiovascular death, coronary heart disease, unstable angina, peripheral arterial disease, peripheral vascular disease, renovascular disease, pulmonary hypertension, vasculitis, and acute coronary syndrome.

15. The method of claim 14, wherein the condition is heart failure.

16. The method of claim 14, wherein the heart failure is congestive heart failure, heart failure with a New York Heart Association Class l-l V symptom, heart failure with reduced left ventricular function (HF-rEF), heart failure with preserved left ventricular function (HF-pEF), heart failure with midrange ejection fraction (HF-mrEF), or heart failure associated with Type II diabetes mellitus.

17. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of claims 1-3, wherein the condition is selected from a group consisting of Type I diabetes, Type II diabetes mellitus, idiopathic Type I diabetes (Type lb), latent autoimmune diabetes in adults (LADA), early-onset Type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, a skin and connective tissue disorder, a foot ulceration, ulcerative colitis, endothelial dysfunction, impaired vascular compliance, hyper apo B lipoproteinemia, kidney disease, end-stage kidney disease, chronic kidney disease, and maple syrup urine disease.

18. The method of claim 17, wherein the condition is kidney disease.

19. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of any one of claims 1-3, wherein the condition is selected from a group consisting of hepatocellular carcinoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, colorectal adenocarcinoma, mesothelioma, stomach adenocarcinoma, adrenocortical carcinoma, kidney papillary cell carcinoma, cervical and endocervical carcinoma, bladder urothelial carcinoma, and lung adenocarcinoma.

20. The method of claim 19, wherein the condition is hepatocellular carcinoma.

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