Crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole

Abstract

The present disclosure relates to polymorphic forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole for treating mitochondrial-related disorders or conditions. In some embodiments, crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for regulating mitochondrial activity, reducing obesity, treating diseases including metabolic disorders, diabetes, or diabetes-related complications such as heart disease and kidney failure, and slowing or controlling weight gain in a subject.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 384,478, filed November 21, 2022, the entire contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present disclosure relates to polymorphic forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole for treating mitochondrial-related disorders or conditions. [Background technology]

[0003] background The present disclosure provides polymorphic forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole for treating a subject suffering from a mitochondrial-related disorder or condition, such as obesity, diabetes, or a metabolic disorder, including diabetes-related complications.

[0004] Mitochondria control metabolism in individual cells by burning sugars and fats. Mitochondrial uncoupling is a powerful, natural process the body uses to generate heat. Heat is generated by mitochondria through uncoupling of respiration (complexes I-IV) from ATP phosphorylation (complex V). In fact, 20-40% of calories consumed are used to generate body heat. Mitochondrial-related disorders or conditions occur when mitochondria cannot produce enough energy for the body to function properly and can affect nearly every part of the body, including cells of the brain, adipose tissue, nerves, muscles, heart, lungs, liver, kidneys, pancreas, eyes, and ears.

[0005] 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is a novel small molecule uncoupler. This uncoupler acts as a controlled metabolic enhancer (CMA). It is designed to effectively address the accumulation of fat and sugar in the body, which is the underlying cause of metabolic disease. CMA improves cellular metabolism, increases energy expenditure and calorie expenditure, and reduces fat accumulation. Using a novel, controlled targeting approach, 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole can increase mitochondrial proton leak, a continuous process in the body that dissipates energy and accounts for 20% to 40% of daily calorie intake. 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole utilizes the mitochondrial uncoupling mechanism to increase substrate utilization.

[0006] A primary concern in the manufacture of pharmaceutical compounds is the stability of the active substance. An active substance with stable crystalline morphology can provide consistent processing parameters and pharmaceutical quality. An unstable active substance can affect the reproducibility of the manufacturing process and therefore lead to a final formulation that does not meet the high quality and other strict requirements imposed on the formulation of pharmaceutical compositions.

[0007] Therefore, there is a continuing need for polymorphic forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole and manufacturing processes for preparing same. Summary of the Invention [Means for solving the problem]

[0008] overview In one embodiment, the present disclosure provides a compound having the following structure: [ka] wherein Compound (I) is in substantially crystalline form.

[0009] In another embodiment, the present disclosure provides polymorphic Form A of free base Compound (I) having an X-ray powder diffraction pattern with characteristic peaks expressed in degrees two-theta at approximately 17.6±0.2, 24.9±0.2, 26.1±0.2, and 30.0±0.2.

[0010] In another embodiment, the disclosure provides polymorphic Form A of free base Compound (I) having an X-ray powder diffraction pattern with characteristic peaks expressed in degrees two-theta at approximately 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 24.9±0.2, 26.1±0.2, and 30.0±0.2.

[0011] In another embodiment, the disclosure provides polymorphic Form A of free base Compound (I) having an X-ray powder diffraction pattern with characteristic peaks expressed in degrees two-theta at approximately 13±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 24.9±0.2, 26.1±0.2, and 30.0±0.2.

[0012] In another embodiment, the present disclosure provides polymorphic Form A of free base Compound (I) having the XRPD pattern shown in FIG.

[0013] In another embodiment, the present disclosure provides polymorphic Form B of free base Compound (I) having an X-ray powder diffraction pattern with characteristic peaks expressed in degrees two-theta at approximately 8.9±0.2, 13.30±0.2, and 26.2±0.2.

[0014] In another embodiment, the present disclosure provides polymorphic Form B of free base Compound (I) having an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2-theta at approximately 8.9±0.2, 9.8±0.2, 13.3±0.2, 21.6±0.2, 23.8±0.2, and 26.2±0.2.

[0015] In another embodiment, the disclosure provides polymorphic Form B of free base Compound (I) having an X-ray powder diffraction pattern with characteristic peaks expressed in degrees two-theta at approximately 8.9±0.2, 9.8±0.2, 13.3±0.2, 14.0±0.2, 15.7±0.2, 21.6±0.2, 23.8±0.2, 26.2±0.2, 27.3±0.2, and 31.1±0.2.

[0016] In certain embodiments, the present disclosure provides polymorphic Form B of free base Compound (I) having the XRPD pattern shown in FIG.

[0017] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for regulating mitochondrial activity, reducing obesity, treating diseases including metabolic disorders, diabetes, or diabetes-related complications such as heart disease and kidney failure, and slowing or controlling weight gain in a subject.

[0018] In some embodiments, the disorder is a metabolic disorder, diabetes, or diabetes-related complications such as heart disease and kidney failure, and the alleviation or control of weight gain in a subject.

[0019] In some embodiments, the disorder is obesity or excess body fat, diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, insulin resistance or insulin intolerance, dyslipidemia, cardiovascular disease, or atherosclerosis.

[0020] In some embodiments, a crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is used to reduce obesity, control or prevent weight gain in a subject, and / or stimulate oxygen consumption rate (OCR) in a subject, and / or treat inflammation and fibrosis that lead to NASH in a subject. [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole form A.

[0022] [Figure 2] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole form B.

[0023] [Figure 3] FIG. 3 shows the differential scanning calorimetry (DSC) profile of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole Form A.

[0024] [Figure 4] FIG. 4 shows the thermogravimetric analysis (TGA) profile of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole Form A.

[0025] [Figure 5] FIG. 5 shows the 1H NMR of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole form A.

[0026] [Figure 6]FIG. 6 shows the differential scanning calorimetry (DSC) profile of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole Form B.

[0027] [Figure 7] FIG. 7 shows the thermogravimetric analysis (TGA) profile of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole form B.

[0028] [Figure 8] FIG. 8 shows the H NMR of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole form B.

[0029] [Figure 9] FIG. 9 shows the 13C NMR spectrum of Form B.

[0030] [Figure 10] FIG. 10 shows an overlay of the XRPD pattern of Form A obtained by slow evaporation.

[0031] [Figure 11] FIG. 11 shows an overlay of the XRPD patterns of Forms A and B obtained by slow evaporation.

[0032] [Figure 12] FIG. 12 shows an overlay of the XRPD pattern of Form A obtained by slow cooling.

[0033] [Figure 13] FIG. 13 shows an overlay of the XRPD pattern of Form A obtained by slow cooling.

[0034] [Figure 14] FIG. 14 shows an overlay of XRPD patterns of samples obtained by adding antisolvent.

[0035] [Figure 15] FIG. 15 shows an ortep image of the single crystal structure of Form A.

[0036] [Figure 16] FIG. 16 shows the asymmetric unit image of Form A.

[0037] [Figure 17] FIG. 17 shows a 3D packing image of Form A.

[0038] [Figure 18] FIG. 18 shows an ortep image of the single crystal structure of Form B.

[0039] [Figure 19] FIG. 19 shows the asymmetric unit image of Form B.

[0040] [Figure 20] FIG. 20 shows a 3D packing image of Form B.

[0041] [Figure 21] FIG. 21 shows the plasma concentrations of 2,4-dinitrophenol after administration of micronized and non-micronized Compound (I).

[0042] [Figure 22A] FIG. 22A shows the mean (±SD) plasma Compound (I) concentration-time plot (linear scale).

[0043] [Figure 22B] FIG. 22B shows the mean (±SD) plasma Compound (I) concentration-time plot (semi-logarithmic scale).

[0044] [Figure 23A] FIG. 23A shows the mean (±SD) plasma 2-4-dinitrophenol concentration-time plot (linear scale).

[0045] [Figure 23B] FIG. 23B shows the mean (±SD) plasma 2-4-dinitrophenol concentration-time plot (semi-logarithmic scale).

[0046] [Figure 24A] FIG. 24A shows the mean (±SD) plasma Compound (I) concentration-time plot (linear scale).

[0047] [Figure 24B] FIG. 24B shows the mean (±SD) plasma Compound (I) concentration-time plot (semi-log scale).

[0048] [Figure 25A] FIG. 25A shows the mean (±SD) plasma 2-4-dinitrophenol concentration-time plot (linear scale).

[0049] [Figure 25B] FIG. 25B shows the mean (±SD) plasma 2-4-dinitrophenol concentration-time plot (semi-logarithmic scale).

[0050] [Figure 26A] FIG. 26A compares plasma Compound (I) concentrations (linear scale) following oral administration of 1050 mg of micronized and non-micronized Compound (I).

[0051] [Figure 26B] FIG. 26B compares plasma Compound (I) concentrations (semi-log scale) following oral administration of 1050 mg of micronized and non-micronized Compound (I).

[0052] [Figure 27A] FIG. 27A compares plasma 2,4-dinitrophenol concentrations (linear scale) following oral administration of 1050 mg of micronized and non-micronized Compound (I).

[0053] [Figure 27B] FIG. 27B compares plasma 2,4-dinitrophenol concentrations (semi-logarithmic scale) following oral administration of 1050 mg of micronized and non-micronized Compound (I).

[0054] [Figure 28] FIG. 28 shows the effect of particle size distribution of Compound (I).

[0055] [Figure 29] FIG. 29 shows the AUC of micronized and non-micronized Compound (I).

[0056] [Figure 30A] FIG. 30A shows the simulated dissolution data for non-micronized Compound (I).

[0057] [Figure 30B] FIG. 30B shows the simulated dissolution data for micronized Compound (I).

[0058] [Figure 30C] FIG. 30C shows the absorption rate of non-micronized Compound (I) and micronized Compound (I). DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed Description Disclosed herein is a crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole (Compound (I)). Compound (I) has the following structure: [ka] It has.

[0060] definition

[0061] 5-[(2,4-Dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole can be prepared by the procedures described in WO2018 / 129258, entitled "Novel Phenyl Derivatives," published July 12, 2018, and U.S. Pat. No. 10,618,875, entitled "Novel Phenyl Derivatives," published April 14, 2020, each of which is hereby incorporated by reference in its entirety.

[0062] In this disclosure, "Compound 1," "Compound (I)," "CM1," "Compound of the invention," and "Compound of the present invention" are interchangeable and each refer to 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole.

[0063] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0064] As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated subject, and is typically determined based on the subject's age, body surface area, weight, and condition.

[0065] As used herein, the terms "mammal," "patient," or "subject" refer to any animal, including humans, livestock, and companion animals.

[0066] As used herein, the terms "control," "treat," or "treatment" of a disorder, disease, or condition means (1) to decrease, prevent, alleviate, inhibit, attenuate, reduce, or stabilize the onset of a disease or its clinical symptoms / signs, or (2) to cause regression of a disease or its clinical symptoms / signs.

[0067] As used herein, "pharmaceutically acceptable" means suitable for use in humans, companion animals and livestock animals.

[0068] As used herein, the term "metabolic disorder" refers to a condition characterized by an alteration or disruption of metabolic function.

[0069] As used herein, "crystalline" refers to a solid having a highly regular chemical structure, i.e., long-range structural order in a crystal lattice. The molecules are arranged in a regular, periodic manner in the three-dimensional space of the lattice. In particular, a crystalline form can be produced in one or more single crystalline forms. For purposes of this application, the terms "crystalline form," "single crystalline form," "crystalline solid form," "solid form," and "polymorph" are synonymous and used interchangeably. These terms distinguish between crystals with different properties (e.g., different XRPD patterns and / or different DSC scan results).

[0070] As used herein, the term "substantially crystalline form" means that at least a specified weight percent of Compound (I) is crystalline, including at least about 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, and 99.9%.

[0071] The term "substantially pure" refers to the composition of a particular crystalline solid form of Compound (I), which may be free of impurities and / or other solid forms of Compound (I) in at least a particular weight percentage. The particular weight percentage may be 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, Compound (I) may be a substantially pure sample of any of the crystalline solid forms described herein (e.g., Form A or B). In some embodiments, Compound (I) may be substantially pure Form A. In some embodiments, Compound (I) may be substantially pure Form B.

[0072] For purposes of this application, the terms "form" and "pattern" are used interchangeably when referring to a particular crystalline form of Compound (I). For example, "Form B" and "Pattern B" refer to the same crystalline form of Compound (I).

[0073] As used herein, when a crystalline form of a compound is identified using one or more XRPD peaks expressed in degrees two-theta (2θ), each 2θ value is understood to mean a given value ±0.2 degrees, unless otherwise specified, such as a given value ±0.3. The term "characteristic peaks," when referring to peaks in an XRPD pattern of a crystalline form of Compound (I), refers to a particular set of peaks whose 2θ values, ranging from 0° to 40°, are collectively assigned uniquely to one of the crystalline forms of Compound (I).

[0074] The crystalline forms of Compound (I) described herein, such as Form A, may melt at a particular temperature or over a temperature range. Such a particular temperature or temperature range may be determined by the onset temperature of the melting endotherm (T) in a DSC trace of the crystalline form. onset) In some embodiments, at such onset temperatures, a sample of the crystalline form of Compound (I) melts and undergoes a concomitant secondary process, such as recrystallization or chemical decomposition. In some embodiments, at such onset temperatures, the crystalline form of Compound (I) melts in the absence of other concomitant processes.

[0075] As used herein, when a crystalline form of a compound is identified using one or more temperatures (e.g., endothermic transition, onset of melting, etc.) from a DSC profile, each of the temperature values ​​is understood to mean the given value ±2°C unless otherwise specified.

[0076] As used herein, the terms "anhydrous" or "anhydrate," when referring to a crystalline form of Compound (I), mean that solvent molecules, including water molecules, do not form part of the unit cell of the crystalline form. Nevertheless, a sample of the anhydrous crystalline form may contain solvent molecules that do not form part of the unit cell of the anhydrous crystalline form, for example, as residual solvent molecules remaining from the production of the crystalline form. In a preferred embodiment, the solvent may constitute 0.5% by weight of the total composition of the sample of the anhydrous form. In a more preferred embodiment, the solvent may constitute 0.2% by weight of the total composition of the sample of the anhydrous form. In some embodiments, a sample of the anhydrous crystalline form of Compound (I) does not contain solvent molecules, for example, does not contain detectable amounts of solvent. The term "solvate," when referring to a crystalline form of Compound (I), means that solvent molecules, for example, organic solvents and water, form part of the unit cell of the crystalline form. A solvate containing water as the solvent is also referred to herein as a "hydrate." The term "isomorphic," when referring to a crystalline form of Compound (I), means that the forms may contain different chemical components, for example, different solvent molecules within the unit cell, but have the same XRPD pattern. Isomorphic crystalline forms are sometimes referred to herein as "isomorphs."

[0077] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material.

[0078] "Particles," as used herein, are solid forms of Compound (I) having a measurable particle size distribution. The particle size distribution can be calculated by the software of the measuring device and is generally reported as D10, D50, and D90.

[0079] The terms D10, D50, and D90 are commonly used to describe the particle size distribution of a given sample. "D10" is the value at which 10% of the particles are equal to or smaller than a defined measurement, such as particle diameter. "D50" is the value at which 50% of the particles are equal to or smaller than a defined measurement, such as particle diameter. "D60" is the value at which 60% of the particles are equal to or smaller than a defined measurement, such as particle diameter. "D70" is the value at which 70% of the particles are equal to or smaller than a defined measurement, such as particle diameter. "D80" is the value at which 80% of the particles are equal to or smaller than a defined measurement, such as particle diameter. "D90" is the value at which 90% of the particles are equal to or smaller than a defined measurement, such as particle diameter.

[0080] "Micronized" Compound (I) has been subjected to micronization using any technique known in the art, including, but not limited to, mechanical grinding or chopping, cryogenic grinding, milling, ball milling, wet milling, high pressure homogenization, emulsification and precipitation, precipitation with a compressed fluid antisolvent, spray freezing into a liquid, rapid expansion from a liquefied gas solution, evaporative precipitation into an aqueous solution, and air-jet atomization.

[0081] As used herein, the term "SDD" refers to spray-drying dispersion technology. SDD is a single-phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution in which the compound is molecularly "dissolved" in a solid matrix. As the name suggests, SDD is obtained by dissolving the drug and polymer in an organic solvent and then spray-drying the solution.

[0082] Crystalline forms of compound (I)

[0083] 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole (compound (I)) has the following structure: [ka] It has.

[0084] In certain embodiments, the present disclosure provides the free base 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole compound (I) in substantially crystalline form.

[0085] In some embodiments, the crystalline Compound (I) is polymorphic Form A.

[0086] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 17.6±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.2.

[0087] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 16.4±0.2, 17.9±0.2, and 20.7±0.2.

[0088] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising four or more peaks at 2-theta values ​​selected from 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.7±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.2.

[0089] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 13.0±0.2, 16.1±0.2, 20.4±0.2, and 24.3±0.2.

[0090] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising six or more peaks at 2-theta values ​​selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.2.

[0091] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising eight or more peaks at 2-theta values ​​selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.2.

[0092] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 22.8±0.2, 26.2±0.2, 31.1±0.2, and 33.6±0.2.

[0093] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 10 or more peaks at 2-theta values ​​selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 22.8±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, 26.2±0.2, 30.0±0.2, 31.1±0.2, and 33.6±0.2.

[0094] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 12 or more peaks at 2-theta values ​​selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 22.8±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, 26.2±0.2, 30.0±0.2, 31.1±0.2, and 33.6±0.2.

[0095] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 21.7±0.2, 29.1±0.2, 29.6±0.2, 30.7±0.2, and 37.2±0.2.

[0096] In some embodiments, polymorph Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 15 or more peaks at 2-theta values ​​selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 21.7±0.2, 22.8±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, 26.2±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1±0.2, 33.6±0.2, and 37.2±0.2.

[0097] In some embodiments, polymorph Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 18 or more peaks at 2-theta values ​​selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 21.7±0.2, 22.8±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, 26.2±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1±0.2, 33.6±0.2, and 37.2±0.2.

[0098] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 16.6±0.2, 24.1±0.2, 25.5±0.2, and 28.8±0.2.

[0099] In some embodiments, polymorphic Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 20 or more peaks at 2-theta values ​​of 13.0±0.2, 16.1±0.2, 16.4±0.2, 16.6±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2. 2, 21.7±0.2, 22.8±0.2, 24.1±0.2, 24.3±0.2, 24.9±0.2, 25.5±0.2, 26.0±0.2, 26.2±0.2, 28.8±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1±0.2, 33.6±0.2, and 37.2±0.2.

[0100] In some embodiments, polymorphic Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 22 or more peaks at 2-theta values ​​of 13.0±0.2, 16.1±0.2, 16.4±0.2, 16.6±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2. 2, 21.7±0.2, 22.8±0.2, 24.1±0.2, 24.3±0.2, 24.9±0.2, 25.5±0.2, 26.0±0.2, 26.2±0.2, 28.8±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1±0.2, 33.6±0.2, and 37.2±0.2.

[0101] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 14.4±0.2, 19.0±0.2, 28.5±0.2, 35.7±0.2, 36.2±0.2, and 38.9±0.2.

[0102] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 25 or more peaks at 2-theta values ​​of 13.0±0.2, 14.4±0.2, 16.1±0.2, 16.4±0.2, 16.6±0.2, 17.6±0.2, 17.9±0.2, 19.0±0.2, 20.4±0.2, 20.7±0.2, 21.7±0.2. 2, 22.8±0.2, 24.1±0.2, 24.3±0.2, 24.9±0.2, 25.5±0.2, 26.0±0.2, 26.2±0.2, 28.5±0.2, 28.8±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1±0.2, 33.6±0.2, 35.7±0.2, 36.2±0.2, 37.2±0.2, and 38.9±0.2.

[0103] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 28 or more peaks at 2-theta values ​​of 13.0±0.2, 14.4±0.2, 16.1±0.2, 16.4±0.2, 16.6±0.2, 17.6±0.2, 17.9±0.2, 19.0±0.2, 20.4±0.2, 20.7±0.2, 21.7±0.2. 2, 22.8±0.2, 24.1±0.2, 24.3±0.2, 24.9±0.2, 25.5±0.2, 26.0±0.2, 26.2±0.2, 28.5±0.2, 28.8±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1±0.2, 33.6±0.2, 35.7±0.2, 36.2±0.2, 37.2±0.2, and 38.9±0.2.

[0104] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 30 or more peaks at 2-theta values ​​of 7.4±0.2, 10.2±0.2, 13.0±0.2, 14.4±0.2, 14.7±0.2, 15.37±0.2, 16.1±0.2, 16.4±0.2, 16.6±0.2, 17.6±0.2, 17.9±0.2, 19.0±0.2, 19.3±0.2, 20.4±0.2, 20.7±0.2, 21.7±0.2, 21.9±0.2, 22.8±0.2, 23.3±0.2, 23.9±0.2 , 24.1±0.2, 24.3±0.2, 24.9±0.2, 25.5±0.2, 26.0±0.2, 26.2±0.2, 27.6±0.2, 28.1±0.2, 28.5±0.2, 28.8±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1± 0.2, 31.8±0.2, 33.6±0.2, 34.1±0.2, 35.0±0.2, 35.5±0.2, 35.7±0.2, 36.2±0.2, 36.9±0.2, 37.2±0.2, 38.0±0.2, 38.51±0.2, 38.9±0.2, and 39.43±0.2.

[0105] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 35 or more peaks at 2-theta values, wherein the 35 or more peaks are at the following 2-theta values: 7.4±0.2, 10.2±0.2, 13.0±0.2, 14.4±0.2, 14.7±0.2, 15.37±0.2, 16.1±0.2, 16.4±0.2, 16.6±0.2, 17.6±0.2, 17.9±0.2, 19.0±0.2, 19.3±0.2, 20.4±0.2, 20.7±0.2, 21.7±0.2, 21.9±0.2, 22.8±0.2, 23.3±0.2, 23.9±0.2 , 24.1±0.2, 24.3±0.2, 24.9±0.2, 25.5±0.2, 26.0±0.2, 26.2±0.2, 27.6±0.2, 28.1±0.2, 28.5±0.2, 28.8±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1± 0.2, 31.8±0.2, 33.6±0.2, 34.1±0.2, 35.0±0.2, 35.5±0.2, 35.7±0.2, 36.2±0.2, 36.9±0.2, 37.2±0.2, 38.0±0.2, 38.51±0.2, 38.9±0.2, and 39.43±0.2.

[0106] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 40 or more peaks at 2-theta values ​​of 7.4±0.2, 10.2±0.2, 13.0±0.2, 14.4±0.2, 14.7±0.2, 15.37±0.2, 16.1±0.2, 16.4±0.2, 16.6±0.2, 17.6±0.2, 17.9±0.2, 19.0±0.2, 19.3±0.2, 20.4±0.2, 20.7±0.2, 21.7±0.2, 21.9±0.2, 22.8±0.2, 23.3±0.2, 23.9±0.2 , 24.1±0.2, 24.3±0.2, 24.9±0.2, 25.5±0.2, 26.0±0.2, 26.2±0.2, 27.6±0.2, 28.1±0.2, 28.5±0.2, 28.8±0.2, 29.1±0.2, 29.6±0.2, 30.0±0.2, 30.7±0.2, 31.1± 0.2, 31.8±0.2, 33.6±0.2, 34.1±0.2, 35.0±0.2, 35.5±0.2, 35.7±0.2, 36.2±0.2, 36.9±0.2, 37.2±0.2, 38.0±0.2, 38.51±0.2, 38.9±0.2, and 39.43±0.2.

[0107] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 17.56±0.2, 24.95±0.2, 26.03±0.2, and 29.98±0.2.

[0108] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 16.36±0.2, 17.94±0.2, and 20.70±0.2.

[0109] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising four or more peaks at 2-theta values ​​selected from 16.36±0.2, 17.56±0.2, 17.94±0.2, 20.70±0.2, 24.95±0.2, 26.03±0.2, and 29.98±0.2.

[0110] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 12.95±0.2, 16.09±0.2, 20.36±0.2, and 24.29±0.2.

[0111] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising six or more peaks at 2-theta values ​​selected from 12.95±0.2, 16.09±0.2, 16.36±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.70±0.2, 24.29±0.2, 24.95±0.2, 26.03±0.2, and 29.98±0.2.

[0112] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising eight or more peaks at 2-theta values ​​selected from 12.95±0.2, 16.09±0.2, 16.36±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.70±0.2, 24.29±0.2, 24.95±0.2, 26.03±0.2, and 29.98±0.2.

[0113] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 22.78±0.2, 26.25±0.2, 31.15±0.2, and 33.56±0.2.

[0114] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 10 or more peaks at 2-theta values ​​selected from 12.95±0.2, 16.09±0.2, 16.36±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.70±0.2, 22.78±0.2, 24.29±0.2, 24.95±0.2, 26.03±0.2, 26.25±0.2, 29.98±0.2, 31.15±0.2, and 33.56±0.2.

[0115] In some embodiments, polymorphic Form A of free base Compound (I) has an X-ray powder diffraction pattern comprising 12 or more peaks at 2-theta values ​​selected from 12.95±0.2, 16.09±0.2, 16.36±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.70±0.2, 22.78±0.2, 24.29±0.2, 24.95±0.2, 26.03±0.2, 26.25±0.2, 29.98±0.2, 31.15±0.2, and 33.56±0.2.

[0116] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 21.66±0.2, 29.07±0.2, 29.63±0.2, 30.67±0.2, and 37.25±0.2.

[0117] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 15 or more peaks at 2-theta values, wherein the 15 or more peaks are 12.95±0.2, 16.09±0.2, 16.36±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.8 ... 0.70±0.2, 21.66±0.2, 22.78±0.2, 24.29±0.2, 24.95±0.2, 26.03±0.2, 26.25±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15±0.2, 33.56±0.2, and 37.25±0.2.

[0118] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 18 or more peaks at 2-theta values, wherein the 18 or more peaks are 12.95±0.2, 16.09±0.2, 16.36±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.8 ... 0.70±0.2, 21.66±0.2, 22.78±0.2, 24.29±0.2, 24.95±0.2, 26.03±0.2, 26.25±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15±0.2, 33.56±0.2, and 37.25±0.2.

[0119] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 16.63±0.2, 24.11±0.2, 25.49±0.2, and 28.77±0.2.

[0120] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 20 or more peaks at 2-theta values, wherein the 20 or more peaks are at the following 2-theta values: 12.95±0.2, 16.09±0.2, 16.36±0.2, 16.63±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.70±0.2, 21.06±0.2, 22.04±0.2, 23.03±0.2, 24.08±0.2, 25.06±0.2, 26.09±0.2, 27.04±0.2, 28.05±0.2, 29.04±0.2, 30.02±0.2, 31.01±0.2, 32.01±0.2, 33.02±0.2, 34.01±0.2, 35.02±0.2, 36.02±0.2, 37.02±0.2, 38.02±0.2, 39.02±0.2, 40.02±0.2, 41.02±0.2, 42.02±0.2, 43.02±0.2, 44.02±0.2, 45.02±0.2, 46.02±0.2, 47.02±0.2, 48.02±0.2, 49.02±0.2, 50.02±0.2, 51.02±0.2, 52.02±0.2, 53.02±0.2, 0.66±0.2, 22.78±0.2, 24.11±0.2, 24.29±0.2, 24.95±0.2, 25.49±0.2, 26.03±0.2, 26.25±0.2, 28.77±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15±0.2, 33.56±0.2, and 37.25±0.2.

[0121] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 22 or more peaks at 2-theta values ​​of 12.95±0.2, 16.09±0.2, 16.36±0.2, 16.63±0.2, 17.56±0.2, 17.94±0.2, 20.36±0.2, 20.70±0.2, 21.06±0.2, 22.04±0.2, 23.03±0.2, 24.08±0.2, 25.06±0.2, 26.09±0.2, 27.06±0.2, 28.05±0.2, 29.04±0.2, 30.04±0.2, 31.02±0.2, 32.01±0.2, 33.01±0.2, 34.01±0.2, 35.01±0.2, 36.01±0.2, 37.01±0.2, 38.01±0.2, 39.01±0.2, 40.01±0.2, 41.01±0.2, 42.01±0.2, 43.01±0.2, 44.01±0.2, 45.01±0.2, 46.01±0.2, 47.01±0.2, 48.01±0.2, 49.01±0.2, 50.01±0.2, 51.01±0.2, 52.01±0.2, 53.01±0.2, 54.01±0.2, 55.01±0. 0.66±0.2, 22.78±0.2, 24.11±0.2, 24.29±0.2, 24.95±0.2, 25.49±0.2, 26.03±0.2, 26.25±0.2, 28.77±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15±0.2, 33.56±0.2, and 37.25±0.2.

[0122] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 14.44±0.2, 19.05±0.2, 28.50±0.2, 35.70±0.2, 36.22±0.2, and 38.92±0.2.

[0123] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 25 or more peaks at 2-theta values, wherein the 25 or more peaks are: 12.95±0.2, 14.44±0.2, 16.09±0.2, 16.36±0.2, 16.63±0.2, 17.56±0.2, 17.94±0.2, 19.05±0.2, 20.36±0.2, 20.70±0.2, 21.66±0.2, 22.7 8±0.2, 24.11±0.2, 24.29±0.2, 24.95±0.2, 25.49±0.2, 26.03±0.2, 26.25±0.2, 28.50±0.2, 28.77±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15±0.2, 33.56±0.2, 35.70±0.2, 36.22±0.2, 37.25±0.2, and 38.92±0.2.

[0124] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 28 or more peaks at 2-theta values ​​of 12.95±0.2, 14.44±0.2, 16.09±0.2, 16.36±0.2, 16.63±0.2, 17.56±0.2, 17.94±0.2, 19.05±0.2, 20.36±0.2, 20.70±0.2, 21.66±0.2, 22.06±0.2, 23.04±0.2, 24.02±0.2, 25.01±0.2, 26.01±0.2, 27.02±0.2, 28.01±0.2, 29.02±0.2, 30.02±0.2, 31.02±0.2, 32.02±0.2, 33.02±0.2, 34.02±0.2, 35.02±0.2, 36.02±0.2, 37.02±0.2, 38.02±0.2, 39.02±0.2, 40.02±0.2, 41.02±0.2, 42.02±0.2, 43.02±0.2, 44.02±0.2, 45.02±0.2, 46.02±0.2, 47.02±0.2, 48.02±0.2, 49.02±0.2, 50.02±0.2, 51.02±0.2, 52.02±0.2, 53.02±0. 0.78±0.2, 24.11±0.2, 24.29±0.2, 24.95±0.2, 25.49±0.2, 26.03±0.2, 26.25±0.2, 28.50±0.2, 28.77±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15±0.2, 33.56±0.2, 35.70±0.2, 36.22±0.2, 37.25±0.2, and 38.92±0.2.

[0125] In some embodiments, polymorphic Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 30 or more peaks at 2-theta values, wherein the 30 or more peaks are at the following 2-theta values: 7.37±0.2, 10.25±0.2, 12.95±0.2, 14.44±0.2, 14.71±0.2, 15.37±0.2 , 16.09±0.2, 16.36±0.2, 16.63±0.2, 17.56±0.2, 17.94±0.2, 19.05±0.2, 19.28±0.2, 20.36±0.2, 20.70±0.2, 21.66±0.2, 21.90±0.2, 22.78±0.2, 23.26±0.2, 23.89±0.2, 24. 11±0.2, 24.29±0.2, 24.95±0.2, 25.49±0.2, 26.03±0.2, 26.25±0.2, 27.58±0.2, 28.09±0.2, 28.50±0.2, 28.77±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15± 0.2, 31.80±0.2, 33.56±0.2, 34.08±0.2, 34.96±0.2, 35.47±0.2, 35.70±0.2, 36.22±0.2, 36.93±0.2, 37.25±0.2, 37.97±0.2, 38.51±0.2, 38.92±0.2, and 39.43±0.2.

[0126] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 35 or more peaks at 2-theta values, wherein the 35 or more peaks are at the following 2-theta values: 7.37±0.2, 10.25±0.2, 12.95±0.2, 14.44±0.2, 14.71±0.2, 15.37±0.2 , 16.09±0.2, 16.36±0.2, 16.63±0.2, 17.56±0.2, 17.94±0.2, 19.05±0.2, 19.28±0.2, 20.36±0.2, 20.70±0.2, 21.66±0.2, 21.90±0.2, 22.78±0.2, 23.26±0.2, 23.89±0.2, 24. 11±0.2, 24.29±0.2, 24.95±0.2, 25.49±0.2, 26.03±0.2, 26.25±0.2, 27.58±0.2, 28.09±0.2, 28.50±0.2, 28.77±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15± 0.2, 31.80±0.2, 33.56±0.2, 34.08±0.2, 34.96±0.2, 35.47±0.2, 35.70±0.2, 36.22±0.2, 36.93±0.2, 37.25±0.2, 37.97±0.2, 38.51±0.2, 38.92±0.2, and 39.43±0.2.

[0127] In some embodiments, polymorph Form A of the free base Compound (I) has an X-ray powder diffraction pattern comprising 40 or more peaks at 2-theta values, the 40 or more peaks being at the following 2-theta values: 7.37±0.2, 10.25±0.2, 12.95±0.2, 14.44±0.2, 14.71±0.2, 15.37±0.2 , 16.09±0.2, 16.36±0.2, 16.63±0.2, 17.56±0.2, 17.94±0.2, 19.05±0.2, 19.28±0.2, 20.36±0.2, 20.70±0.2, 21.66±0.2, 21.90±0.2, 22.78±0.2, 23.26±0.2, 23.89±0.2, 24. 11±0.2, 24.29±0.2, 24.95±0.2, 25.49±0.2, 26.03±0.2, 26.25±0.2, 27.58±0.2, 28.09±0.2, 28.50±0.2, 28.77±0.2, 29.07±0.2, 29.63±0.2, 29.98±0.2, 30.67±0.2, 31.15± 0.2, 31.80±0.2, 33.56±0.2, 34.08±0.2, 34.96±0.2, 35.47±0.2, 35.70±0.2, 36.22±0.2, 36.93±0.2, 37.25±0.2, 37.97±0.2, 38.51±0.2, 38.92±0.2, and 39.43±0.2.

[0128] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by at least four peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 7.3±0.2, 16.0±0.2, 16.3±0.2, and 24.7±0.2.

[0129] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ as shown in Table 1 below.

[0130] [Table 1-1] [Table 1-2]

[0131] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ as shown in Table 2 below.

[0132] [Table 2-1] [Table 2-2] [Table 2-3]

[0133] In some embodiments, polymorphic Form A of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ as shown in Table 3 below.

[0134] [Table 3-1] [Table 3-2]

[0135] In some embodiments, the present disclosure provides polymorphic Form A of free base Compound (I) having the XRPD pattern shown in FIG.

[0136] In some embodiments, polymorphic Form A of free base Compound (I) has a differential scanning calorimetry thermogram (DSC) profile characterized by an endothermic transition at a temperature between 157°C ± 3 and 162°C ± 3 and a second endothermic transition at 183°C ± 3.

[0137] In some embodiments, polymorphic Form A of free base Compound (I) has a thermogravimetric analysis (TGA) profile characterized by a weight loss of about 0.704% at 175°C ± 3°C.

[0138] In some embodiments, the crystalline Compound (I) is polymorphic Form B.

[0139] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 13.3±0.2, 23.8±0.2, and 26.3±0.2.

[0140] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 9.8±0.2, 21.6±0.2, 27.3±0.2, and 28.1±0.2.

[0141] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising four or more peaks at 2-theta values ​​selected from 9.8±0.2, 13.3±0.2, 21.6±0.2, 23.8±0.2, 26.3±0.2, 27.3±0.2, and 28.1±0.2.

[0142] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 14.0±0.2, 25.8±0.2, 26.6±0.2, and 31.1±0.2.

[0143] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising six or more peaks at 2-theta values ​​selected from 9.8±0.2, 13.3±0.2, 14.0±0.2, 21.6±0.2, 23.8±1 0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, and 31.1±0.2.

[0144] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising eight or more peaks at 2-theta values ​​selected from 9.8±0.2, 13.3±0.2, 14.0±0.2, 21.6±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, and 31.1±0.2.

[0145] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 9.0±0.2, 21.2±0.2, 23.2±0.2, 31.8±0.2, and 33.0±0.2.

[0146] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 10 or more peaks at 2-theta values ​​selected from 9.8±0.2, 9.0±0.2, 13.3±0.2, 14.0±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 31.1±0.2, 31.8±0.2, and 33.0±0.2.

[0147] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 12 or more peaks at 2-theta values ​​selected from 9.8±0.2, 9.0±0.2, 13.3±0.2, 14.0±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 31.1±0.2, 31.8±0.2, and 33.0±0.2.

[0148] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 17.7±0.2, 19.1±0.2, 30.0±0.2, and 34.7±0.2.

[0149] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 14 or more peaks at 2-theta values ​​selected from 9.8±0.2, 9.0±0.2, 13.3±0.2, 14.0±0.2, 17.7±0.2, 19.1±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 30.0±0.2, 31.1±0.2, 31.8±0.2, 33.0±0.2, and 34.7±0.2.

[0150] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 16 or more peaks in 2-theta values ​​selected from 9.8±0.2, 9.0±0.2, 13.3±0.2, 14.0±0.2, 17.7±0.2, 19.1±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 30.0±0.2, 31.1±0.2, 31.8±0.2, 33.0±0.2, and 34.7±0.2.

[0151] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 10.2±0.2, 17.2±0.2, 18.5±0.2, 28.7±0.2, and 35.3±0.2.

[0152] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 18 or more peaks at 2-theta values, wherein the 18 or more peaks are at the following 2-theta values: 9.8±0.2, 9.0±0.2, 10.2±0.2, 13.3±0.2, 14.0±0.2, 17.2±0.2, 17.7±0.2, 18.5±0.2, 19.1±0.2, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0.2, 55.0±0.2, 56 ±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 28.7±0.2, 30.0±0.2, 31.1±0.2, 31.8±0.2, 33.0±0.2, 34.7±0.2, and 35.3±0.2.

[0153] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 20 or more peaks at 2-theta values, wherein the 20 or more peaks are at the following 2-theta values: 9.8±0.2, 9.0±0.2, 10.2±0.2, 13.3±0.2, 14.0±0.2, 17.2±0.2, 17.7±0.2, 18.5±0.2, 19.1±0.2, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0.2, 55.0±0.2, 56 ±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 28.7±0.2, 30.0±0.2, 31.1±0.2, 31.8±0.2, 33.0±0.2, 34.7±0.2, and 35.3±0.2.

[0154] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 22 or more peaks at 2-theta values ​​of 9.8±0.2, 9.0±0.2, 10.2±0.2, 13.3±0.2, 14.0±0.2, 17.2±0.2, 17.7±0.2, 18.5±0.2, 19.1±0.2, 20.4±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2. 2, 24.6±0.2, 25.0±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 28.7±0.2, 30.0±0.2, 30.4±0.2, 31.1±0.2, 31.8±0.2, 32.4±0.2, 33.0±0.2, 33.5±0.2, 34.1±0.2, 34.7±0.2, 35.3±0.2, 36.2±0.2, 37.3±0.2, 38.1±0.2, 38.8±0.2.

[0155] In some embodiments, polymorphic Form B of the free base Compound (I) has an X-ray powder diffraction pattern comprising 25 or more peaks at 2-theta values ​​of 9.8±0.2, 9.0±0.2, 10.2±0.2, 13.3±0.2, 14.0±0.2, 17.2±0.2, 17.7±0.2, 18.5±0.2, 19.1±0.2, 20.4±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2. 2, 24.6±0.2, 25.0±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 28.7±0.2, 30.0±0.2, 30.4±0.2, 31.1±0.2, 31.8±0.2, 32.4±0.2, 33.0±0.2, 33.5±0.2, 34.1±0.2, 34.7±0.2, 35.3±0.2, 36.2±0.2, 37.3±0.2, 38.1±0.2, 38.8±0.2.

[0156] In some embodiments, polymorphic Form B of the free base Compound (I) has an X-ray powder diffraction pattern comprising 30 or more peaks at 2-theta values ​​of 9.8±0.2, 9.0±0.2, 10.2±0.2, 13.3±0.2, 14.0±0.2, 17.2±0.2, 17.7±0.2, 18.5±0.2, 19.1±0.2, 20.4±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2. 2, 24.6±0.2, 25.0±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 28.7±0.2, 30.0±0.2, 30.4±0.2, 31.1±0.2, 31.8±0.2, 32.4±0.2, 33.0±0.2, 33.5±0.2, 34.1±0.2, 34.7±0.2, 35.3±0.2, 36.2±0.2, 37.3±0.2, 38.1±0.2, 38.8±0.2.

[0157] In some embodiments, polymorphic Form B of the free base Compound (I) has an X-ray powder diffraction pattern comprising 34 or more peaks at 2-theta values ​​of 9.8±0.2, 9.0±0.2, 10.2±0.2, 13.3±0.2, 14.0±0.2, 17.2±0.2, 17.7±0.2, 18.5±0.2, 19.1±0.2, 20.4±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2. 2, 24.6±0.2, 25.0±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 28.7±0.2, 30.0±0.2, 30.4±0.2, 31.1±0.2, 31.8±0.2, 32.4±0.2, 33.0±0.2, 33.5±0.2, 34.1±0.2, 34.7±0.2, 35.3±0.2, 36.2±0.2, 37.3±0.2, 38.1±0.2, 38.8±0.2.

[0158] In some embodiments, the polymorphic Form B of the free base Compound (I) has a molecular weight of approximately 9.8±0.2, 9.0±0.2, 10.2±0.2, 13.3±0.2, 14.0±0.2, 17.2±0.2, 17.7±0.2, 18.5±0.2, 19.1±0.2, 20.4±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 24.6±0.2, 25.0±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.6±0.2, 28.6±0.2, 29.6±0.2, 30.6±0.2, 31.6±0.2, 32.6±0.2, 33.6±0.2, 34.6±0.2, 35.0±0.2, 35.8±0.2, 36.6±0.2, 37.6±0.2, 38.6±0.2, 39.6±0.2, 40.6±0.2, 41.6±0.2, 42.6±0.2, 43.6±0.2, 44.6±0.2, 45.0±0.2, 46.6±0.2, 47.6±0.2, 48.6±0.2, 49.6±0.2, 50.6±0.2, 51.6±0.2, 52.6±0.2, 53.6±0.2, 54.6±0.2, 55.6±0.2 Characterized by an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2θ at 0.2, 27.3±0.2, 28.1±0.2, 28.7±0.2, 30.0±0.2, 30.4±0.2, 31.1±0.2, 31.8±0.2, 32.4±0.2, 33.0±0.2, 33.5±0.2, 34.1±0.2, 34.7±0.2, 35.3±0.2, 36.2±0.2, 37.3±0.2, 38.1±0.2, 38.8±0.2.

[0159] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern with characteristic peaks expressed in degrees two-theta at approximately 13.26±0.2, 23.78±0.2, and 26.26±0.2.

[0160] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern with characteristic peaks expressed in degrees two-theta at approximately 9.81±0.2, 21.58±0.2, 27.27±0.2, and 28.10±0.2.

[0161] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising four or more peaks at 2-theta values ​​selected from 9.81±0.2, 13.26±0.2, 21.58±0.2, 23.78±0.2, 26.26±0.2, 27.27±0.2, and 28.10±0.2.

[0162] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 13.99±0.2, 25.78±0.2, 26.63±0.2, and 31.08±0.2.

[0163] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising six or more peaks at 2-theta values ​​selected from 9.81±0.2, 13.26±0.2, 13.99±0.2, 21.58±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, and 31.08±0.2.

[0164] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising eight or more peaks at 2-theta values ​​selected from 9.81±0.2, 13.26±0.2, 13.99±0.2, 21.58±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, and 31.08±0.2.

[0165] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 8.95±0.2, 21.23±0.2, 23.20±0.2, 31.77±0.2, and 32.95±0.2.

[0166] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 10 or more peaks at 2-theta values ​​selected from 9.81±0.2, 8.95±0.2, 13.26±0.2, 13.99±0.2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 31.08±0.2, 31.77±0.2, and 32.95±0.2.

[0167] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 12 or more peaks at 2-theta values ​​selected from 9.81±0.2, 8.95±0.2, 13.26±0.2, 13.99±0.2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 31.08±0.2, 31.77±0.2, and 32.95±0.2.

[0168] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 17.66±0.2, 19.15±0.2, 30.0±0.2, and 34.74±0.2.

[0169] In some embodiments, polymorphic Form B of the free base Compound (I) has an X-ray powder diffraction pattern comprising 14 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 13.26±0.2, 13.99±0.2, 17.66±0.2, 19.15±0.2, 21. 58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 30.00±0.2, 31.08±0.2, 31.77±0.2, 32.95±0.2, and 34.74±0.2.

[0170] In some embodiments, polymorphic Form B of the free base Compound (I) has an X-ray powder diffraction pattern comprising 16 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 13.26±0.2, 13.99±0.2, 17.66±0.2, 19.15±0.2, 21. 58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 30.00±0.2, 31.08±0.2, 31.77±0.2, 32.95±0.2, and 34.74±0.2.

[0171] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 10.20±0.2, 17.21±0.2, 18.55±0.2, 28.71±0.2, and 35.27±0.2.

[0172] In some embodiments, polymorphic Form B of the free base Compound (I) has an X-ray powder diffraction pattern comprising 18 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 10.20±0.2, 13.26±0.2, 13.99±0.2, 17.21±0.2, 17.66±0.2, 18.55±0.2, 19.15±0.2. 2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 28.71±0.2, 30.00±0.2, 31.08±0.2, 31.77±0.2, 32.95±0.2, 34.74±0.2, and 35.27±0.2.

[0173] In some embodiments, polymorphic Form B of the free base Compound (I) has an X-ray powder diffraction pattern comprising 20 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 10.20±0.2, 13.26±0.2, 13.99±0.2, 17.21±0.2, 17.66±0.2, 18.55±0.2, 19.15±0.2. 2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 28.71±0.2, 30.00±0.2, 31.08±0.2, 31.77±0.2, 32.95±0.2, 34.74±0.2, and 35.27±0.2.

[0174] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 22 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 10.20±0.2, 13.26±0.2, 13.99±0.2, 17.21±0.2, 17.66±0.2, 18.55±0.2, 19.15±0.2, 20.42±0.2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 24. 0.58±0.2, 25.00±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 28.71±0.2, 30.00±0.2, 30.41±0.2, 31.08±0.2, 31.77±0.2, 32.42±0.2, 32.95±0.2, 33.50±0.2, 34.09±0.2, 34.74±0.2, 35.27±0.2, 36.21±0.2, 37.30±0.2, 38.11±0.2, 38.77±0.2.

[0175] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 25 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 10.20±0.2, 13.26±0.2, 13.99±0.2, 17.21±0.2, 17.66±0.2, 18.55±0.2, 19.15±0.2, 20.42±0.2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 24. 0.58±0.2, 25.00±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 28.71±0.2, 30.00±0.2, 30.41±0.2, 31.08±0.2, 31.77±0.2, 32.42±0.2, 32.95±0.2, 33.50±0.2, 34.09±0.2, 34.74±0.2, 35.27±0.2, 36.21±0.2, 37.30±0.2, 38.11±0.2, 38.77±0.2.

[0176] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 30 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 10.20±0.2, 13.26±0.2, 13.99±0.2, 17.21±0.2, 17.66±0.2, 18.55±0.2, 19.15±0.2, 20.42±0.2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 24.06±0.2, 25.04±0.2, 26.02±0.2, 27.01±0.2, 28.01±0.2, 29.02±0.2, 30.01±0.2, 31.01±0.2, 32.01±0.2, 33.01±0.2, 34.01±0.2, 35.01±0.2, 36.01±0.2, 37.01±0.2, 38.01±0.2, 39.01±0.2, 40.01±0.2, 41.01±0.2, 42.01±0.2, 43.01±0.2, 44.01±0.2, 45.01±0.2, 46.01±0.2, 47.01±0.2, 48.01±0.2, 49.01±0.2, 50.01±0.2, 51.01±0.2, 52.01±0.2, 0.58±0.2, 25.00±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 28.71±0.2, 30.00±0.2, 30.41±0.2, 31.08±0.2, 31.77±0.2, 32.42±0.2, 32.95±0.2, 33.50±0.2, 34.09±0.2, 34.74±0.2, 35.27±0.2, 36.21±0.2, 37.30±0.2, 38.11±0.2, 38.77±0.2.

[0177] In some embodiments, polymorphic Form B of free base Compound (I) has an X-ray powder diffraction pattern comprising 34 or more peaks at 2-theta values ​​of 9.81±0.2, 8.95±0.2, 10.20±0.2, 13.26±0.2, 13.99±0.2, 17.21±0.2, 17.66±0.2, 18.55±0.2, 19.15±0.2, 20.42±0.2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 24.06±0.2, 24.04±0.2, 24.06 ... 0.58±0.2, 25.00±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.27±0.2, 28.10±0.2, 28.71±0.2, 30.00±0.2, 30.41±0.2, 31.08±0.2, 31.77±0.2, 32.42±0.2, 32.95±0.2, 33.50±0.2, 34.09±0.2, 34.74±0.2, 35.27±0.2, 36.21±0.2, 37.30±0.2, 38.11±0.2, 38.77±0.2.

[0178] In some embodiments, the polymorphic Form B of the free base Compound (I) has a molecular weight of approximately 9.81±0.2, 8.95±0.2, 10.20±0.2, 13.26±0.2, 13.99±0.2, 17.21±0.2, 17.66±0.2, 18.55±0.2, 19.15±0.2, 20.42±0.2, 21.58±0.2, 21.23±0.2, 23.20±0.2, 23.78±0.2, 24.58±0.2, 25.00±0.2, 25.78±0.2, 26.26±0.2, 26.63±0.2, 27.63±0.2, 28.63±0.2, 29.63±0.2, 30.63±0.2, 31.63±0.2, 32.63±0.2, 33.63±0.2, 34.63±0.2, 35.63±0.2, 36.63±0.2, 37.63±0.2, 38.63±0.2, 39.63±0.2, 40.63±0.2, 41.63±0.2, 42.63±0.2, 43.63±0.2, 44.63±0.2, 45.63±0.2, 46.63±0.2, 47.63±0.2, 48.63±0.2, 49.63±0.2, 50.63±0.2, 51.63±0.2, 52.6 The sample is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at: 27.27±0.2, 28.10±0.2, 28.71±0.2, 30.00±0.2, 30.41±0.2, 31.08±0.2, 31.77±0.2, 32.42±0.2, 32.95±0.2, 33.50±0.2, 34.09±0.2, 34.74±0.2, 35.27±0.2, 36.21±0.2, 37.30±0.2, 38.11±0.2, 38.77±0.2.

[0179] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by at least eight peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 8.8±0.2, 9.7±0.2, 10.1±0.2, 13.1±0.2, 13.9±0.2, 15.6±0.2, 18.4±0.2, and 21.4±0.2.

[0180] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ as shown in Table 4 below.

[0181] [Table 4-1] [Table 4-2]

[0182] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ as shown in Table 5 below.

[0183] [Table 5-1] [Table 5-2]

[0184] In some embodiments, polymorphic Form B of free base Compound (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ as shown in Table 6 below.

[0185] [Table 6-1] [Table 6-2]

[0186] In some embodiments, polymorphic Form B of the free base Compound (I) has the XRPD pattern shown in FIG.

[0187] In some embodiments, polymorphic Form B of free base Compound (I) has a differential scanning calorimetry (DSC) thermogram profile characterized by an initial endothermic transition at about 182.3°C ± 3°C and a peak temperature at about 184°C ± 3°C.

[0188] In some embodiments, polymorphic Form B of free base Compound (I) has a thermogravimetric analysis (TGA) profile characterized by a weight loss of about 0.584% at 175°C ± 3°C.

[0189] In some embodiments, polymorphic Form B of the free base Compound (I) exhibits 1H NMR (DMSO-d6): δ 8.792 (d, J=2.5 Hz, 1H), 8.572 (dd, J=9.5, 2.5 Hz, 1H); 7.832 (D, J=9.5 Hz, 1H, 7.399 (s, 1H), 5.663 (s, 2H), 3.957 (s, 3H).

[0190] In some embodiments, polymorphic Form B of the free base Compound (I) has the 13C NMR spectrum shown in FIG.

[0191] In some embodiments, polymorphic Form B of free base Compound (I) is substantially free of impurities. In some embodiments, polymorphic Form B of free base Compound (I) contains less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3 ppm, less than 2 ppm, or less than 1 ppm of residual DNFB. In some embodiments, polymorphic Form B of free base Compound (I) contains 1 ppm to 6 ppm, 1 ppm to 5 ppm, 1 ppm to 4 ppm, 1 ppm to 3 ppm, or 1 ppm to 2 ppm of residual DNFB.

[0192] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by crystallization by slow evaporation at room temperature.

[0193] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by crystallization by slow cooling from a heated saturated solution.

[0194] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by crystallization by the addition of one or more anti-solvents.

[0195] In some embodiments, polymorphic Form B of free base Compound (I) can be prepared by crystallization by heating a solution of polymorphic Form A.

[0196] In some embodiments, polymorphic Form B of free base Compound (I) can be prepared by crystallization from thermal cycling of a solution of polymorphic Form A.

[0197] In some embodiments, a small amount of a polymorphic form of the free base Compound (I) is added to the above method as a seeding material.

[0198] In some embodiments, suitable solvents include, but are not limited to, alcoholic solvents, acetone, acetonitrile, THF, ethyl acetate, isopropyl acetate, DCM, MEK, MTBE, n-heptane, 2-MeTHF, toluene, 1,4-dioxane, DMF, DMSO, or mixtures thereof.

[0199] In some embodiments, the alcohol solvent includes methanol, ethanol, propanol, and the like.

[0200] In some embodiments, the solvent is DMSO.

[0201] In some embodiments, the solvent is DMF.

[0202] In some embodiments, a suitable anti-solvent is HO, isopropyl acetate, MTBE, n-heptane, toluene, ethanol, or a mixture thereof.

[0203] In some embodiments, the solvent is DMF.

[0204] In some embodiments, the solvent is acetonitrile.

[0205] In some embodiments, the solvent is ethanol.

[0206] In some embodiments, one or more acids are added to the solvent.

[0207] In some embodiments, the acid includes, but is not limited to, HBr, HCl, or H2SO4.

[0208] In some embodiments, the mixed solution is heated to a temperature greater than 35°C, greater than 40°C, greater than 45°C, greater than 50°C, greater than 55°C, greater than 60°C, greater than 65°C, greater than 70°C, greater than 75°C, greater than 80°C, greater than 100°C, greater than 120°C, greater than 140°C, greater than 160°C, or greater than 180°C.

[0209] In some embodiments, the mixed solution containing the polymorphic form is heated to a temperature between 35°C and 60°C, or between 35°C and 50°C, or between 40°C and 60°C, or between 60°C and 80°C, or between 65°C and 70°C.

[0210] In some embodiments, polymorphic Form A of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with a solvent to form a mixture; ii. optionally, adding one or more anti-solvents to the mixture; iii. Collect the crystalline Form A by filtration or slow evaporation, or by heating the mixture to elevated temperature and then cooling the mixture to room temperature or 5°C.

[0211] In some embodiments of the above method, the solvent is selected from acetone, acetonitrile, THF, DCM, MEK, 1,4-dioxane, DMF, DMSO, or a mixture thereof; the anti-solvent is selected from HO, isopropyl acetate, MTBE, n-heptane, toluene, or ethanol; and the elevated temperature is greater than 50°C, greater than 60°C, greater than 70°C, greater than 80°C, greater than 100°C, greater than 120°C, greater than 140°C, or greater than 160°C.

[0212] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with a solvent to form a mixture; ii. filtering the mixture; iii. Collecting crystalline Form A from the mixture by slow evaporation.

[0213] In some embodiments of the above method, the solvent can be selected from acetone, acetonitrile, THF, DCM, MEK, 1,4-dioxane, DMF, DMSO, or a mixture thereof.

[0214] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with 1,4-dioxane to form a mixture; ii. filtering the mixture; iii. Collecting crystalline Form B from the mixture by slow evaporation.

[0215] In some embodiments, polymorphic Form A of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with a solvent to form a mixture; ii. Heat the mixture to an elevated temperature and then cool the mixture to 5°C.

[0216] In some embodiments, the solvent can be selected from acetone, acetonitrile, THF, DCM, MEK, 1,4-dioxane, DMF, DMSO, water, or a mixture thereof. In some embodiments, the elevated temperature is greater than 50° C.

[0217] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with a solvent to form a mixture; ii. optionally, adding one or more anti-solvents to the mixture; iii. heating the mixture to an elevated temperature and then collecting crystalline Form B by filtration; iv. Then cool and immediately filter the mixture.

[0218] In some embodiments of the above method, the solvent can be selected from acetone, acetonitrile, THF, DCM, MEK, 1,4-dioxane, DMF, DMSO, or a mixture thereof, the anti-solvent can be selected from HO, isopropyl acetate, MTBE, n-heptane, toluene, or ethanol, the elevated temperature is 50°C, and stirring can be performed at elevated temperature, room temperature, or 5°C.

[0219] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with a solvent to form a mixture; ii. adding one or more anti-solvents to the mixture; iii. Collect crystalline Form A or B by filtration.

[0220] In some embodiments, the solvent can be selected from acetone, acetonitrile, THF, DCM, MEK, 1,4-dioxane, DMF, DMSO, or a mixture thereof, the anti-solvent can be selected from HO, isopropyl acetate, MTBE, n-heptane, toluene, or ethanol, and the elevated temperature is 50°C.

[0221] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with a solvent to form a mixture; ii. optionally, adding one or more anti-solvents to the mixture; iii. collecting crystalline Form A by filtration or slow evaporation; iv. combining Form A with a second solvent to form a second mixture and heating the second mixture to an elevated temperature; v. Cooling and filtering to collect crystalline Form A; vi. Repeat steps iv and v as necessary.

[0222] In some embodiments of the above method, the solvent can be selected from acetone, acetonitrile, THF, DCM, MEK, 1,4-dioxane, DMF, DMSO, or a mixture thereof, the second solvent can be selected from HO, isopropyl acetate, MTBE, n-heptane, toluene, or ethanol, the elevated temperature is greater than 50° C., greater than 60° C., greater than 70° C., greater than 80° C., greater than 100° C., greater than 120° C., greater than 140° C., or greater than 160° C., and stirring can be performed at elevated temperature or at room temperature. In some embodiments, the solvent in step iv can be a different solvent than step i.

[0223] In some embodiments, polymorphic forms of the free base Compound (I) can be prepared by the following method: i. combining the free base compound (I) with a heated solvent to form a mixture; ii. Allow the mixture to slowly cool to room temperature; iii. adding a solvent to the mixture to precipitate Form B; iv. collecting crystalline Form B by filtration; iv. combining Form A with a solvent to form a second mixture and heating the second mixture to an elevated temperature; v. Cool and filter to collect crystalline Form B.

[0224] In some embodiments of the above method, the solvent can be selected from acetone, acetonitrile, THF, DCM, MEK, 1,4-dioxane, DMF, DMSO, or a mixture thereof; the anti-solvent can be selected from HO, ethyl acetate, or ethanol; the elevated temperature is greater than 50° C., greater than 60° C., greater than 70° C., greater than 80° C., greater than 100° C., greater than 120° C., greater than 140° C., or greater than 160° C.; and stirring can be performed at elevated temperature or at room temperature.

[0225] In some embodiments, the solvent used in step iv can be a different solvent than in step i.

[0226] In some embodiments, the solvent mixture in step i is acetonitrile and DMSO. In some embodiments, the solvent in step iv is acetonitrile.

[0227] Micronized crystalline compound (I)

[0228] Another aspect of the present disclosure is a compound having the following structure: [ka] The present invention provides a micronized crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole having the formula:

[0229] In some embodiments, the micronized crystalline form is micronized crystalline form B.

[0230] In some embodiments, the micronized crystalline form is micronized crystalline form A.

[0231] In some embodiments, crystalline Forms A and B are micronized. In some embodiments, the micronized crystalline form of Compound (I) is micronized crystalline Form A. In some embodiments, crystalline Form B is micronized.

[0232] In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D10) of less than 4 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D10) of between about 0.5 μm and about 4 μm, between about 0.5 μm and 3 μm, between about 0.5 μm and 2 μm, or between about 0.5 μm and 1.5 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D10) of about 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1.0 μm, 1.1 μm, or 1.2 μm.

[0233] In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of less than 50 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of less than 20 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of less than 15 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of less than 10 μm.

[0234] In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 0.5 μm to about 50 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 1 μm to 20 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 1 μm to 15 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 1 μm to 10 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 1 μm to 5 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 2 μm to 4 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 10 μm to 45 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of between about 10 μm and 20 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 12 μm.

[0235] In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, or 4 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 3.5 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 3 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 1.8 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D50) of about 1.2 μm. In some embodiments, micronized crystalline Forms A and B are about 1.24 μm, 1.75 μm, 12.06 μm, 19.63 μm, or 41.9 μm.

[0236] In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D90) of less than 70 μm, less than 60 μm, less than 50 μm, less than 30 μm, or less than 20 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D90) of between about 2 μm and about 60 μm, between about 2 μm and 55 μm, between about 1.0 μm and 10 μm, or between about 2.0 μm and 5.0 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D90) of about 2.0 μm, 4.0 μm, 8.5 μm, or 53 μm.

[0237] In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D90) of about 5 μm to about 15 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D90) of about 8 μm to about 13 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D90) of about 8, 9, 10, 11, 12, or 13 μm. In some embodiments, micronized crystalline Forms A and B have a particle size distribution (D90) of about 9 μm.

[0238] Treatment method

[0239] In some embodiments, the present disclosure provides a method for treating a mitochondrial-associated disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of any of the crystalline forms of Compound (I) described herein.

[0240] In some embodiments, the mitochondrial-related disorder or condition is a metabolic disorder, diabetes, or a diabetes-related complication.

[0241] In some embodiments, the disorder is obesity or excess body fat.

[0242] In some embodiments, the disorder is diabetes. In some embodiments, the disorder is type 2 diabetes mellitus (T2DM).

[0243] In some embodiments, the disorder is non-alcoholic fatty liver disease (NAFLD).

[0244] In some embodiments, the patient with NAFLD has elevated obesity or elevated HbA1c.

[0245] In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH).

[0246] In some embodiments, the disorder is fatty liver.

[0247] In some embodiments, the disorder is insulin resistance or insulin intolerance.

[0248] In some embodiments, the disorder is dyslipidemia.

[0249] In some embodiments, the disorder is a cardiovascular disease.

[0250] In some embodiments, the disorder is atherosclerosis.

[0251] In some embodiments, the present disclosure provides a method for reducing obesity, controlling or preventing weight gain in a subject in need thereof, comprising administering to the subject an effective amount of any of the crystalline forms of Compound (I) described herein.

[0252] In some embodiments, the present disclosure provides a method for stimulating the oxygen consumption rate (OCR) in a subject in need thereof, comprising administering to the subject an effective amount of any of the crystalline forms of Compound (I) described herein.

[0253] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating mitochondrial-related disorders, including but not limited to, obesity, diabetes, insulin resistance, and heart or kidney failure, in a subject in need thereof.

[0254] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating mitochondrial-related disorders, including metabolic disorders, diabetes, or diabetes-related complications.

[0255] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for controlling or preventing obesity or excess body fat in a subject in need thereof.

[0256] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating or reducing obesity in a subject in need thereof.

[0257] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating diabetes. In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating type 2 diabetes mellitus (T2DM).

[0258] In some embodiments, the crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is useful for treating non-alcoholic fatty liver disease (NAFLD). In some embodiments, the crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is useful for treating non-alcoholic fatty liver disease (NAFLD), wherein the subject has elevated obesity or elevated HbA1c.

[0259] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating non-alcoholic steatohepatitis (NASH).

[0260] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating fatty liver.

[0261] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating insulin resistance or insulin intolerance.

[0262] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating dyslipidemia.

[0263] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating cardiovascular disease.

[0264] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating atherosclerosis.

[0265] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating diseases, disorders, and conditions associated with defective mitochondrial function in mammals in need thereof.

[0266] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating diabetes, including but not limited to, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty liver, and type 2 diabetes mellitus (T2DM) in a subject in need of treating diabetes.

[0267] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for controlling or preventing weight gain or maintaining weight in a subject in need thereof.

[0268] In some embodiments, the crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole stimulates the oxygen consumption rate (OCR) in a subject in need thereof.

[0269] In some embodiments, the crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole are useful for treating cardiovascular disease in a subject in need thereof.

[0270] In some embodiments, the crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is useful for treating the inflammation and fibrosis that leads to NASH.

[0271] In some embodiments, the present disclosure provides a method for treating the mitochondrial-associated disorder or condition, comprising administering micronized crystalline Compound (I) to a subject in need of treatment for the mitochondrial-associated disorder or condition.

[0272] In some embodiments, administration of micronized crystalline Compound (I) reduces the half-life (t 1 / 2 ) is extended.

[0273] In some embodiments, administration of micronized crystalline Compound (I) reduces the time to reach maximum plasma concentration of Compound (I) (T) compared to administration of non-micronized crystalline Compound (I). max ) is delayed.

[0274] In some embodiments, administration of micronized crystalline Compound (I) results in a higher maximum plasma concentration (C) of Compound (I) compared to administration of non-micronized crystalline Compound (I). max ) decreases.

[0275] In some embodiments, administration of micronized crystalline Compound (I) increases the area under the curve (AUC) of Compound (I) compared to administration of non-micronized crystalline Compound (I).

[0276] In some embodiments, administration of micronized crystalline Compound (I) results in a shorter half-life (t 1 / 2 ) is extended.

[0277] In some embodiments, administration of micronized crystalline Compound (I) reduces the time to reach maximum plasma concentration of 2,4-dinitrophenol (T) compared to administration of non-micronized crystalline Compound (I). max ) is delayed.

[0278] In some embodiments, administration of micronized crystalline Compound (I) results in a higher maximum plasma concentration of 2,4-dinitrophenol (C) compared to administration of non-micronized crystalline Compound (I). max ) decreases.

[0279] In some embodiments, administration of micronized crystalline Compound (I) increases the area under the curve (AUC) of 2,4-dinitrophenol compared to administration of non-micronized crystalline Compound (I).

[0280] Pharmaceutical Composition

[0281] One aspect of the present disclosure provides a pharmaceutical composition comprising any of the crystalline forms described herein and a pharmaceutically acceptable carrier.

[0282] Pharmaceutical compositions for use according to the present disclosure can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including additives and adjuvants that facilitate the processing of active compounds into pharmaceutically usable preparations. The appropriate formulation depends on the selected route of administration. Pharmaceutically acceptable additives and carriers are generally known to those skilled in the art. Such additives and carriers can be found, for example, in Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975) or Rowe, Shesky, and Quinn, Handbook of Pharmaceutical Excipients, 6 th Ed. Pharmaceutical Press, London, UK (2009)).

[0283] In therapeutic use to control or prevent weight gain in a subject, the polymorphic forms of the free base Compound (I) are administered orally or parenterally.

[0284] In therapeutic use for treating a mitochondrial-related disorder or condition in a subject, the polymorphic forms of the free base Compound (I) are administered orally or parenterally.

[0285] In therapeutic use to stimulate oxygen consumption rate (OCR) in a subject, polymorphic forms of the free base Compound (I) are administered orally or parenterally.

[0286] In some embodiments, the polymorphic form of free base Compound (I) or a pharmaceutical composition thereof is administered once, twice, or three times daily.

[0287] The amount of polymorphic free base Compound (I) contained in compositions suitable for use in the present disclosure includes an amount sufficient to achieve the intended purpose.

[0288] Determining a therapeutically effective amount is well within the capabilities of one skilled in the art. Generally, the amount of polymorphic free base Compound (I) ranges from 0.01% to 99.9% by weight of the composition. In some embodiments, the amount of polymorphic free base Compound (I) ranges from 0.1% to 90% by weight of the composition. In some embodiments, the amount of polymorphic free base Compound (I) ranges from 1% to 70% by weight of the composition. In some embodiments, the amount of polymorphic free base Compound (I) ranges from 10% to 50% by weight of the composition.

[0289] Therapeutically effective amounts of polymorphic free base Compound (I) range from about 0.001 to about 1000 mg / kg body weight / day. The desired dosage may conveniently be presented in a single dose or in divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses daily.

[0290] In some embodiments, the effective amount of polymorphic free base Compound (I) is from about 0.01 mg / kg to about 100 mg / kg.

[0291] In some embodiments, the effective amount of polymorphic free base Compound (I) is from about 0.1 mg / kg to about 50 mg / kg and any and all whole or partial increments therebetween, including, but not limited to, about 0.1 mg / kg, about 1 mg / kg, about 10 mg / kg, about 100 mg / kg, about 200 mg / kg, or about 300 mg / kg.

[0292] In some embodiments, the effective amount of polymorphic free base Compound (I) is about 1-10 mg / kg. In some embodiments, the effective amount of polymorphic free base Compound (I) is about 2-10 mg / kg. In other embodiments, the effective amount of polymorphic free base Compound (I) is about 3-10 mg / kg. In other embodiments, the effective amount of polymorphic free base Compound (I) is about 4-10 mg / kg.

[0293] In some embodiments, the effective amount of polymorphic free base Compound (I) is about 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or 1050 mg.

[0294] In some embodiments, the effective amount of polymorphic free base Compound (I) is about 2-10 mg / kg, hi other embodiments, the effective amount of polymorphic free base Compound (I) is about 3-10 mg / kg.

[0295] In another embodiment, the effective amount of polymorphic free base Compound (I) is about 4-10 mg / kg.

[0296] Without further explanation, it is believed that one skilled in the art can use the foregoing description and illustrative examples to make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely provide a detailed description of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the present invention. [Example]

[0297] definition Compound (I): 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole MeOH: Methanol EtOH: ethanol IPA: Isopropanol MEK: Methyl ethyl ketone ACN: acetonitrile THF: tetrahydrofuran EA: Ethyl acetate MTBE: Methyl tert-butyl ether DCM: dichloromethane 2-MeTHF: 2-methyltetrahydrofuran DMSO: dimethyl sulfoxide XRPD: X-ray powder diffractometer DSC: Differential scanning calorimetry TGA: Thermogravimetric analysis DVS: Dynamic Water Vapor Sorption NMR: nuclear magnetic resonance SEM: Scanning electron microscope FT-IR: Fourier transform infrared spectrum KF: Karl Fischer HPLC: High-Performance Liquid Chromatograph

[0298] Example 1 Polymorph Screening

[0299] The goal of polymorph studies is to identify potential polymorphs and select the most suitable one in terms of stability, hygroscopicity, and feasibility for downstream development. The free base compound (I) is poorly soluble. The crystalline form can be enhanced in solubility by the addition of various solubilizing agents.

[0300] The solubility of compound (I) is comparable between pH 1 and 6.5, i.e., its solubility is pH independent. The results suggest that compound (I) is unlikely to ionize, and it was hypothesized that successful salt formation was unlikely.

[0301] However, precipitation of Compound (I) from EtOH solution with HBr and H2SO4 and HCl in acetone yields polymorphs not previously observed in the free base. Two distinct polymorphic forms, Form A and Form B, have been identified. Multiple isoforms have also been identified.

[0302] Form A is an anhydrous form. Form A can be obtained from most solvent systems by equilibration, slow evaporation, slow cooling, and addition of an antisolvent. Form A is highly crystalline. The DSC profile (Figure 3) shows a T of 156.9 °C. onset Figure 3 shows one endothermic peak at 182.9 °C with an enthalpy of 9 J / g, corresponding to the solid-solid transition from Form A to Form B. onset The melting peak at 0.25 and the enthalpy at 183.9°C. Decomposition occurs upon melting. TGA (Figure 4) shows a weight loss of about 0.7% at about 175°C. 1 H-NMR (Figure 5) shows that there was no detectable residual solvent. Form A is a thermodynamically stable anhydrate at or below 35°C.

[0303] Form B is an anhydrous form. Form B was obtained by heating Form A to 165°C or by slow evaporation in 1,4-dioxane. Form B is highly crystalline. DSC (Figure 6) shows a melting peak at Tonset of 182.3°C. Decomposition occurs upon melting. TGA (Figure 7) shows a weight loss of about 0.6% at about 175°C. 1 H-NMR (Figure 8) shows that there was no detectable residual solvent. Form B becomes the thermodynamically stable form A at 50°C or higher.

[0304] Based on the competitive equilibrium results, Forms A and B are enantiotropically related. At 35°C or below, Form A is the only or predominant polymorph in the sample, making it the thermodynamically stable Form A at 35°C or below. At 50°C, Form B is the only or predominant polymorph in the sample, making it the thermodynamically stable form at 50°C or above. At 40°C, Form A was obtained as the major product from acetone or THF, while Form B was obtained as the major product from the acetonitrile / water (v:v=85:15) system, suggesting a phase transition temperature near 40°C. Slight thermodynamic perturbations at this temperature may lead to different equilibrium outcomes.

[0305] Based on the competitive equilibrium results, the thermodynamically stable anhydrate at ambient temperature (20-25°C) is Form A.

[0306] The bulk stability of Compound (I) Forms A and B was evaluated for 1 and 2 weeks at 25° C. / 92% RH in an open container, 40° C. / 75% RH in an open container, and 60° C. in a closed container. Compound (I) Forms A and B are physically and chemically stable under these conditions.

[0307] The hygroscopicity of both Form A and Form B of Compound (I) was evaluated at 25°C by dynamic water vapor sorption (DVS) testing. Form A of Compound (I) is non-hygroscopic. Form A absorbs approximately 0.1% water at 25°C from 40% RH to 95% RH. After the DVS testing, the obtained sample was still Form A. Form B of Compound (I) is non-hygroscopic. Form B absorbs approximately 0.1% water at 25°C from 40% RH to 95% RH. After the DVS testing, the obtained sample was still Form B.

[0308] Form A is primarily formed and is stable at room temperature. Form B is more stable at temperatures above (approximately) 37°C. By heating the slurry, Form B accumulates over time. By heating the slurry, more residual dinitrofluorobenzene (DNFB) can be removed and the desired purity achieved.

[0309] Impurity removal is likely to be more effective in heated solvents, so producing Form B at higher temperatures will remove more of the remaining impurities.

[0310] Based on the results of DSC analysis and competitive equilibrium experiments, Forms A and B are enantiotropically related. Form A is the thermodynamically stable form at or below 35°C, while Form B is the thermodynamically stable form at or above 50°C. Both Forms A and B exhibit good chemical and physical stability and are non-hygroscopic at 25°C. Although Forms A and B exhibit good chemical and physical stability after a two-week bulk stability study, this result only describes the short-term kinetic stability of the two interconvertible polymorphs as bare drug substances. As revealed by competitive equilibrium experiments, given accelerated kinetic conditions and sufficient time, the two polymorphs will convert to each other as a function of temperature.

[0311] [Table 7]

[0312] Example 2 solubility studies

[0313] Approximately 5 mg of Form A was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the drug substance at 25°C. Approximately 10 mg of Form A was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the drug substance at 50°C. Sonication was applied to aid dissolution. The maximum volume of each solvent added was 1 mL. Approximate solubility was determined by visual observation.

[0314] [Table 8]

[0315] The solubility of the crystalline forms was further collected. The results showed poor solubility at 25°C and 50°C in all selected solvents except DMSO. Form A was used as the starting material in all the following studies. The results are listed in Table 9.

[0316] [Table 9]

[0317] The starting and final materials were verified by XRPD. All XRPD profiles at 25° C. and 50° C. were the same. Final material refers to the compound after recrystallization.

[0318] Several slurry experiments were performed with the crystalline forms in various solvent systems. Results showed that Form A+B converted to Form B at 50-60°C in acetone and MEK systems. Form B was stable after slurrying in various solvents at various temperatures. Solubility by HPLC is listed in Tables 10 and 11.

[0319] [Table 10]

[0320] [Table 11]

[0321] Example 3 Water sorption and desorption experiments on polymorphic form B

[0322] The water sorption and desorption behavior of Forms A and B was investigated by DVS at 25° C. in a cycle of 40-95-0-95-40% relative humidity (RH) with an equilibration time of 240 min per step. XRPD was measured after the DVS test to determine the form change.

[0323] [Table 12]

[0324] [Table 13]

[0325] Example 4 Crystallization by slow evaporation at room temperature

[0326] 20 mg of Compound (I) free form was dissolved in 0.2-1 mL of solvent. The resulting solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The resulting clear solution was allowed to slowly evaporate under ambient conditions (approximately 20-25°C, 40-60% RH). The solid residue was examined by XRPD as shown in Table 14. Figure 10 shows the XRPD pattern of Form A obtained by this method. Figure 11 shows the XRPD patterns of Forms A and B obtained by this method.

[0327] [Table 14]

[0328] Example 5 Crystallization by slow cooling from heated saturated solutions

[0329] 40 mg of Compound (I) free form was dissolved in a minimum amount of selected solvent at 50°C. The resulting solution was filtered by centrifugation at 14,000 rpm through a 0.45 μm nylon membrane filter. The resulting clear solution was cooled to 5°C at 0.1°C / min. The precipitate was collected by centrifugal filtration at 14,000 rpm through a 0.45 μm nylon membrane filter. The solid portion (wet cake) was examined by XRPD. Figure 12 shows XRPD patterns (SC1-SC3) of Form A obtained by this method. Figure 13 shows XRPD patterns (SC4-SC6) of Form A obtained by this method.

[0330] [Table 15]

[0331] Example 6 Crystallization by addition of antisolvent

[0332] 30 mg of Compound (I) free form was dissolved in a minimum amount of a selected good solvent at ambient temperature (approximately 20-25°C). 1 to 4 volumes of a poor solvent were slowly added to the resulting clear solution until a large amount of solid precipitated. The precipitate was collected by centrifugal filtration at 14,000 rpm through a 0.45 μm nylon membrane filter. The solid portion (wet cake) was examined by XRPD. Figure 14 shows the XRPD pattern of Form A obtained by this method.

[0333] [Table 16]

[0334] Example 7 Preparation of Form B of Compound (I)

[0335] The DMF solution of Compound (I) is charged to a reactor, polish-filtered, and stored in a clean container to obtain clarified Compound (I). Half of the clarified Compound (I) in DMF solution to be treated is charged to a reactor. Water is then added to the clarified filtrate to precipitate the crude Compound (I) product, which is stirred and isolated by filtration. This procedure is repeated for the remaining half of the clarified Compound (I). The combined crude wet cake is washed with ethanol. The crude wet cake is partially dried in the filter, added back to the reactor, reslurried in water at 35-45°C, cooled, and stirred at room temperature. The crude Compound (I) is filtered, washed with ethanol, and partially dried in the filter. The crude Compound (I) is suspended in ethanol and heated at 60-70°C for 2-3 hours, then cooled to room temperature, filtered, washed with ethanol, and partially dried. The resulting solid is dried under vacuum overnight and then recrystallized by heating in acetonitrile at 60-70°C for 16-20 hours and slowly cooling to room temperature. The resulting crystalline Form B is filtered, washed with ethanol, and dried until a constant weight is achieved. The dried crystalline Form B is then sieved through a 40-mesh sieve before packaging. 1 H NMR (DMSO-d6): δ 8.792 (d, J=2.5 Hz,1H), 8.572 (dd, J=9.5, 2.5Hz, 1H); 7.832 (D, J=9.5 Hz, 1H, 7.399 (s, 1H), 5.66.3 (s, 2H), 3.957 (s, 3H).

[0336] Example 7.1 Preparation of Form B of Compound (I)

[0337] Compound (I) Form A was dissolved in a heated ACN:DMSO mixture in a glass-lined reactor, polish filtered (preceded by an ACN rinse), and slowly cooled to 25°C over 4 hours. After cooling to room temperature, water was added over 4 hours to complete the precipitation of the product. After stirring for 1 hour or more, the solid was isolated by filtration, rinsed with EtOH, and dried to constant weight in a vacuum oven at 45°C. The dried solid was then analyzed for various critical quality attributes (row 2 of Table 17).

[0338] Acetonitrile Slurry: The dried solid was slurried in acetonitrile at 70° C. After stirring for 16 hours or more, the mixture was then cooled to 25° C. and the product was isolated by centrifugation. The solid was rinsed with EtOH and dried to constant weight to isolate Form B (65%).

[0339] As shown in Table 17, reslurrying with acetonitrile also purged impurities from Form B, particularly residual DNFB, from 12.3 to 1.9 ppm (limit 6 ppm).

[0340] [Table 17]

[0341] Example 8 Single crystal cultivation and analysis

[0342] The objective of this study was to solve the single crystal structures of Form A and Form B using single crystal analysis.

[0343] The instrumental methods are listed below. [Table 27]

[0344] Single crystalline Form A suitable for single crystal analysis was obtained by slow evaporation in DCM. Figure 1 shows the XRPD pattern of Form A.

[0345] The crystal structure of Form A was determined at 298(2) K. Based on single crystal data, the single crystal crystallized in the orthorhombic Pbca space group, with R int = 6.0%, and final R1 = [I>2σ(I)] = 4.9% at 298(2) K. An Ortep image of the Form A molecule is shown in Figure 15. The asymmetric unit of Form A is shown in Figure 16. A 3D packing image of Form A is shown in Figure 17. Table 18 provides crystal size data for Form A.

[0346] [Table 18]

[0347] A single crystalline Form B suitable for single crystal analysis was obtained from crystalline Form B, as shown in FIG. 2, which shows the XRPD pattern of Form B.

[0348] The crystal structure of Form B was determined at 298(2) K. Based on single crystal data, the single crystal crystallized in the monoclinic P21 / c space group, with R int = 12.7%, and final R1 = [I>2σ(I)] = 7.7% at 298(2) K. An Ortep image of the Form B molecule is shown in Figure 20. The asymmetric unit of Form B is shown in Figure 19. A 3D packing image of Form B is shown in Figure 20. Table 19 provides crystal size data for Form B.

[0349] [Table 19]

[0350] Example 9 Solubility-Enhancing Additive Screening for Compound (I) - Crystalline vs. Amorphous Form

[0351] The inventors evaluated the solubility enhancement of crystalline Compound (I) Form B and amorphous forms of Compound (I) present in a spray-dried dispersion formulation in suspension vehicles containing solubility-enhancing additives.

[0352] In this study, amorphous drug / polymer colloids of Compound (I) were prepared by spray-drying dispersion (SDD) using Compound (I) and hydroxypropyl methylcellulose acetate succinate (HPMCAS-M). These experiments aimed to identify a solubilizing agent for Compound (I), and TPGS was selected as the additive for the canine study. By extending the dissolution time of Compound (I), rapid uptake of Compound (I) into plasma was prevented, avoiding the risk of a high Cmax (maximum plasma concentration). High plasma concentrations, or rather, a rapid increase in concentration, confer DNP toxicity.

[0353] The SDD of this screening has the following features: Spray dried 120g 25% Compound (I): HPMCAS-M. Spray solvent: 2.5% H2O: Acetone Total solids: 6 wt% [1.5 wt% Compound (I), 4.5 wt% HPMCAS-M] 87% yield PXRD was consistent with an amorphous form A single Tg was observed at 75°C by mDSC.

[0354] [Table 20]

[0355] As shown in Table 20, there is a four- to five-fold difference in solubility between the crystalline and amorphous forms of Compound (I) after one hour. There is also a difference in solubility over time. As shown in Table 20, amorphous Compound (I) dissolves rapidly and then becomes insoluble after extended incubation, as indicated by the lower values. Instead, the concentration of crystalline Form B steadily increases in the medium. Compound (I) is a Class 2 compound with low solubility and high permeability; that is, dissolution is crucial to achieving a slow increase in Compound (I) in plasma, and highly solubilized forms and / or formulations may lead to rapid uptake. Increased solubility (as in the case of the amorphous form) can lead to a sharp increase in PK and potentially unsafe plasma concentrations. This is a prime example, as shown in Table 21.

[0356] As shown in Table 21, when Compound (I) is in amorphous form, the solubility of the free drug is increased by approximately 3-fold. The amorphous form of Compound (I) and TPGS in suspension have a combined effect on the solubility of the free drug, increasing the solubility of the free drug by approximately 9-fold. Addition of TPGS to a suspension of crystalline Compound (I) increases the solubility of the free drug by approximately 3-fold.

[0357] This result highlights that in Examples 10 and 11, unexpected results were achieved by using micronized crystalline Form B, namely, much higher bioavailability than expected.

[0358] [Table 21] All suspensions were prepared at 20 mg / mL of Compound (I). These suspensions had suitable syringability and colloidal stability for use in preclinical and clinical studies. The excipient concentration was determined based on the maximum tolerated dose in dogs.

[0359] Example 10 Comparative pharmacokinetic study of micronized compound (I) in beagle dogs after oral single-dose administration

[0360] Crystalline Form B of Compound (I) (micronized and unmicronized) was administered as a single dose via oral capsule to groups of dogs as set forth in Table 22 below.

[0361] Crystalline Form B was sieved through a 40 mesh screen and micronized by jet milling. The injector and grinder gas pressures were optimized at 5.0 bar each to achieve a D90 of the milled material of 30 μm or less.

[0362] [Table 22]

[0363] Eight serial blood samples (approximately 1 mL each) were collected from each dog at 1, 2, 4, 6, 8, 12, 16, and 24 hours post-dosing for dosing on Day 1. After the final blood sample collection on Day 2, all animals were returned to the ITR reserve colony.

[0364] For this purpose, blood was drawn from each dog by venipuncture and collected in tubes containing the anticoagulant K2EDTA. After collection, the samples were centrifuged (2500 rpm, approximately 4°C for 10 minutes), and the resulting plasma was collected, divided into two aliquots (Set A and Set B), and stored frozen (at -60°C or below) in appropriately labeled vials or tubes.

[0365] FIG. 21 shows the plasma concentrations of 2,4-dinitrophenol after administration of micronized and non-micronized Compound (I).

[0366] Particle size distribution of Compound (I), mean C after administration max and mean AUC 24h are summarized in Table 23 below.

[0367] [Table 23] *Micronized Sample 1 (Dosage Group 2) is the same batch used in Example 11 herein. Compound (I) was administered in a capsule without any additional excipients.

[0368] Example 11 Pharmacokinetics of micronized compound (I)

[0369] Drug administration

[0370] Crystalline Compound (I) or matching placebo was administered orally as a single dose. All subjects, except for the fed cohort, were dosed in the morning after an 8-hour fast, maintained a semi-recumbent position for 1 hour after dosing, and fasted for 4 hours after dosing. Capsules were swallowed with 240 mL (8 fl oz) of room temperature water.

[0371] Micronized Compound (I) was dosed at 600 mg, 1050 mg, and 1400 mg in the fasted state. Compound (I) was rapidly absorbed, with T max The median time was 1.50 to 1.75 hours, and T lag The median time was 0.25 hours. 1 / 2 The mean apparent clearance and volume of distribution remained similar with increasing dose. Compound (I) exposure was observed at C max and AUC, over the dose range of 600 mg to 1400 mg, C max The dose-proportionality was lower (31 = 0.65), and the AUC inf appears to be only slightly lower (31=0.96).

[0372] 2,4-Dinitrophenol appeared immediately after administration of Compound (I), and lag The median time was 0.25 hours, and T max The median time ranged from 6.0 to 8.0 hours. 1 / 2The mean apparent clearance and volume of distribution remained similar with increasing dose. The exposure to 2,4-dinitrophenol was max and AUC, over the dose range of 600 mg to 1400 mg, C max and AUC inf The effects appeared to be less than dose-proportional for , with slopes of 0.89 and 0.81, respectively.

[0373] Figures 22A and 22B show the mean (±SD) plasma Compound (I) concentration-time plots by dose following oral administration of non-micronized Compound (I) (linear (22A) and semi-logarithmic scale (22B)).

[0374] Figures 23A and 23B show the mean (±SD) plasma 2,4-dinitrophenol concentration-time plots by dose following oral administration of non-micronized Compound (I) (linear (23A) and semi-logarithmic scale (23B)).

[0375] Figures 24A and 24B show mean (±SD) plasma Compound (I) concentration-time plots (linear and semi-log scales) by dose following oral administration of micronized Compound (I).

[0376] Figures 25A and 25B below show mean (±SD) plasma 2,4-dinitrophenol (DNP) concentration-time plots (linear and semi-logarithmic scales) by dose following oral administration of micronized Compound (I). DNP appeared immediately after a single dose of the micronized formulation of Compound (I), and T lag The median time was 0.25 hours, and T max The median time ranged from 6.0 to 8.0 hours. 1 / 2The mean apparent clearance and volume of distribution remained similar with increasing dose. DNP exposure was less than dose-proportional for Cmax and AUCinf across the dose range of 600 to 1400 mg of micronized Compound (I), with slopes of 0.89 and 0.81, respectively.

[0377] Table 24A shows the pharmacokinetic parameters of Compound (I) after a single dose of non-micronized Compound (I). Table 24B shows the pharmacokinetic parameters of Compound (I) after a single dose of micronized crystalline Compound (I).

[0378] [Table 24A]

[0379] [Table 24B]

[0380] As shown in Table 24B, administration of 1050 mg of a micronized formulation of crystalline Compound (I) resulted in an 8.8-fold increase in Compound (I) Cmax and a 6.9- to 7.2-fold increase in Compound (I) AUC compared to 1050 mg of a non-micronized formulation of Compound (I). Over the range of 600 to 1400 mg of micronized crystalline Compound (I), the Cmax of Compound (I) was 8.8-fold and 6.9- to 7.2-fold. max appeared to increase in a less than dose-proportional manner, and AUC inf appeared to increase in a slightly less than dose-proportional manner (slope = 0.96).

[0381] Figures 26A and 26B compare plasma Compound (I) concentrations (linear and semi-logarithmic scales) after oral administration of 1050 mg of micronized and non-micronized Compound (I). Figures 27A and 27B compare plasma 2,4-dinitrophenol concentrations (linear and semi-logarithmic scales) after oral administration of 1050 mg of micronized and non-micronized Compound (I).

[0382] FIG. 28 shows the effect of particle size distribution on the cumulative release of Compound (I).

[0383] Figure 29 compares the AUC of micronized and non-micronized Compound (I) and shows that micronizing Compound (I) increases exposure.

[0384] The data demonstrate that micronized Compound (I) was absorbed more rapidly and reached higher plasma concentrations compared to non-micronized Compound (I). The micronization and long half-life (i.e., enhancement over time) of Compound (I) results in unexpected levels of therapeutic efficacy for the treatment of a wide range of diseases and conditions.

[0385] A positive effect of food on Compound (I) absorption was evident, as was the effect of Compound (I) particle size on absorption when two formulations of Compound (I) with different particle sizes were evaluated. There was evidence of saturable absorption at a single high dose. AUC / C max The ratio was approximately 18 regardless of dose.

[0386] This study demonstrates the following: The pharmacokinetics of compound (I) is characterized by rapid absorption and rapid excretion. 2,4-Dinitrophenol appears quickly and is excreted relatively slowly. Micronization of compound (I) increased the Cmax of compound (I) and 2,4-dinitrophenol by more than 8.2 times, and the AUC of compound (I) and 2,4-dinitrophenol by more than 6.90 times. Exposure to Compound (I) and 2,4-dinitrophenol following administration of micronized Compound (I) generally increases in a less than dose-proportional manner.

[0387] Example 12 Pharmacokinetics of micronized compound (I)

[0388] A physiologically based pharmacokinetic (PBPK) analysis was developed to establish the relationship between particle size and exposure. Micronization of crystalline Compound (I) improved its absorption, with a 600 mg micronized dose having the same absorption rate as a 30 mg non-micronized dose. Dosing with micronized crystalline Compound (I) not only significantly increased plasma exposure of Compound (I) and one of its metabolites, DNP, but also showed signs of reduced hepatic metabolism, likely due to saturation of clearance. Simulations of the effect of different particle size distributions on exposure indicated little difference in exposure as long as the particle size was small.

[0389] To demonstrate the effect of reducing particle size, the output of the PBPK model for a non-micronized dose of 500 mg and a micronized dose of 600 mg are shown in Figures 30A-30C.

[0390] According to the model, the non-micronized dose resulted in a 66% absorption rate (Figure 30A), while the micronized dose resulted in nearly complete dissolution with a 98% absorption rate (Figure 30B). The correlation between absorption rate and absorption for the dose range of 30-1400 mg for the non-micronized and micronized doses is shown in Figure 30C. A non-micronized dose of 30 mg resulted in the same absorption rate (F) as a 600 mg micronized dose. a ), i.e., 98% (Table 25).

[0391] [Table 25]

[0392] The PBPK model was also used to simulate the effect on exposure for hypothetical batches of various particle size distributions (Table 26). For comparison, both the non-micronized and micronized batches from Example 11 were added. All micronized batches had comparable exposure.

[0393] [Table 26]

[0394] Micronization had at least two effects observed on the exposure of crystalline Compound (I) + DNP compared to non-micronized Compound (I): - The more compound (I) dissolved, the higher the absorption rate. - Compound (I) + DNP has higher hepatic exposure and likely saturates hepatic clearance, resulting in lower clearance.

[0395] Incorporation by Reference This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be deemed known to those of skill in the art and may therefore be excluded even if not expressly stated to be excluded herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

Claims

1. The following structure: 【Transformation 5】 A crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole having the formula:

2. 10. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 13.3±0.2, 23.8±0.2, and 26.3±0.

2.

3. 10. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 9.8±0.2, 21.6±0.2, 27.3±0.2, and 28.1±0.

2.

4. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising four or more peaks in 2-theta values ​​selected from 9.8±0.2, 13.3±0.2, 21.6±0.2, 23.8±0.2, 26.3±0.2, 27.3±0.2, and 28.1±0.

2.

5. 10. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 14.0±0.2, 25.8±0.2, 26.6±0.2, and 31.1±0.

2.

6. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising six or more peaks in 2-theta values, wherein the six or more peaks are selected from 9.8±0.2, 13.3±0.2, 14.0±0.2, 21.6±0.2, 23.8±10.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, and 31.1±0.

2.

7. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising eight or more peaks in 2-theta values, wherein the eight or more peaks are selected from 9.8±0.2, 13.3±0.2, 14.0±0.2, 21.6±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, and 31.1±0.

2.

8. 10. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 9.0±0.2, 21.2±0.2, 23.2±0.2, 31.8±0.2, and 33.0±0.

2.

9. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising ten or more peaks in 2-theta values, wherein the ten or more peaks are selected from 9.8±0.2, 9.0±0.2, 13.3±0.2, 14.0±0.2, 21.6±0.2, 21.2±0.2, 23.2±0.2, 23.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.3±0.2, 28.1±0.2, 31.1±0.2, 31.8±0.2, and 33.0±0.

2.

10. 10. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 17.7±0.2, 19.1±0.2, 30.0±0.2, and 34.7±0.

2.

11. 2. The crystalline form of claim 1, wherein said crystalline form is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

12. 10. The crystalline form of claim 1, wherein the crystalline form has a differential scanning calorimetry thermogram (DSC) characterized by an initial endothermic transition at about 182.3°C ± 3°C and a peak temperature at about 184°C ± 3°C.

13. 10. The crystalline form of claim 1, wherein the crystalline form has a thermogravimetric analysis (TGA) characterized by a weight loss of about 0.584% at 175°C ± 3°C.

14. 10. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 17.6±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.

2.

15. 10. The crystalline form of claim 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at 16.4±0.2, 17.9±0.2, and 20.7±0.

2.

16. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising four or more peaks in 2-theta values ​​selected from 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.7±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.

2.

17. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by at least three peaks in an X-ray powder diffraction pattern, expressed in degrees 2θ, at approximately 13.0±0.2, 16.1±0.2, 20.4±0.2, and 24.3±0.

2.

18. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising six or more peaks in 2-theta values, wherein the six or more peaks are selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.

2.

19. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising eight or more peaks in 2-theta values, wherein the eight or more peaks are selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, and 30.0±0.

2.

20. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by at least three peaks, expressed in degrees 2θ, at approximately 22.8±0.2, 26.2±0.2, 31.1±0.2, and 33.6±0.2 in an X-ray powder diffraction pattern.

21. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising ten or more peaks in 2-theta values, wherein the ten or more peaks are selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 22.8±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, 26.2±0.2, 30.0±0.2, 31.1±0.2, and 33.6±0.

2.

22. 2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern comprising 12 or more peaks in 2-theta values, wherein the 12 or more peaks are selected from 13.0±0.2, 16.1±0.2, 16.4±0.2, 17.6±0.2, 17.9±0.2, 20.4±0.2, 20.7±0.2, 22.8±0.2, 24.3±0.2, 24.9±0.2, 26.0±0.2, 26.2±0.2, 30.0±0.2, 31.1±0.2, and 33.6±0.

2.

23. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by at least three peaks, expressed in degrees 2θ, at approximately 21.7±0.2, 29.1±0.2, 29.6±0.2, 30.7±0.2, and 37.2±0.2 in an X-ray powder diffraction pattern.

24. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by at least three peaks, expressed in degrees 2θ, at approximately 16.6±0.2, 24.1±0.2, 25.5±0.2, and 28.8±0.2 in an X-ray powder diffraction pattern.

25. 2. The crystalline form of claim 1, wherein the crystalline form is characterized by at least three peaks, expressed in degrees 2θ, at approximately 14.4±0.2, 19.0±0.2, 28.5±0.2, 35.7±0.2, 36.2±0.2, and 38.9±0.2 in an X-ray powder diffraction pattern.

26. 2. The crystalline form of claim 1, wherein said crystalline form is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

27. 10. The crystalline form of claim 1, wherein the crystalline form has a differential scanning calorimetry thermogram (DSC) profile characterized by an endothermic transition at a temperature between 157°C ± 3 and 162°C ± 3 and a second endothermic transition at 183°C ± 3.

28. 10. The crystalline form of claim 1, wherein the crystalline form has a thermogravimetric analysis (TGA) characterized by a weight loss of about 0.704% at 175°C ± 3°C.

29. The crystalline form of any one of claims 2 to 13, which is crystalline form B.

30. 29. The crystalline form of any one of claims 14 to 28, which is crystalline form A.

31. The following structure: 【Transformation 6】 A micronized crystalline form of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole having the formula:

32. 32. The micronized crystalline form of claim 31, which is micronized crystalline form B.

33. 33. The micronized crystalline form of claim 32, wherein micronized crystalline form B is characterized by an X-ray powder diffraction pattern expressed in degrees 2θ according to any one of claims 2 to 11.

34. 32. The micronized crystalline form of claim 31, which is micronized crystalline form A.

35. 34. The micronized crystalline form of claim 33, wherein micronized crystalline form A is characterized by an X-ray powder diffraction pattern expressed in degrees 2θ according to any one of claims 14 to 28.

36. 36. The micronized crystalline form of any one of claims 31 to 35, wherein the micronized crystalline form has a particle size distribution (D50) of from about 1 μm to about 10 μm.

37. 37. The micronized crystalline form of any one of claims 31 to 36, wherein the micronized crystalline form has a particle size distribution (D50) of from about 1 μm to about 5 μm.

38. 38. The micronized crystalline form of any one of claims 31 to 37, wherein the micronized crystalline form has a particle size distribution (D50) of from about 2 μm to about 4 μm.

39. 39. The micronized crystalline form of any one of claims 31 to 38, wherein the micronized crystalline form has a particle size distribution (D50) of about 3 μm.

40. 40. The micronized crystalline form of any one of claims 31 to 39, wherein the micronized crystalline form has a particle size distribution (D90) of from about 5 μm to about 15 μm.

41. 40. The micronized crystalline form of any one of claims 31 to 39, wherein the micronized crystalline form has a particle size distribution (D90) of from about 8 μm to about 13 μm.

42. 40. The micronized crystalline form of any one of claims 31 to 39, wherein the micronized crystalline form has a particle size distribution (D90) of about 9 μm.

43. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 30 and a pharmaceutically acceptable carrier.

44. 43. A pharmaceutical composition comprising the micronized crystalline form of any one of claims 31 to 42 and a pharmaceutically acceptable carrier.

45. 43. A method of treating a mitochondrial-related disorder or condition in a subject, comprising administering to a subject in need of treatment for a mitochondrial-related disorder or condition an effective amount of the crystalline form of any one of claims 1-30 or the micronized crystalline form of any one of claims 31-42.

46. 46. ​​The method of claim 45, wherein the disorder or condition is a metabolic disorder, diabetes, or a diabetes-related complication.

47. 46. ​​The method of claim 45, wherein the disorder is obesity or excess body fat.

48. 46. ​​The method of claim 45, wherein the disorder or condition is a metabolic disorder, diabetes, or a diabetes-related complication.

49. 46. ​​The method of claim 45, wherein the disorder or condition is type 2 diabetes mellitus (T2DM).

50. 46. ​​The method of claim 45, wherein the disorder is nonalcoholic fatty liver disease (NAFLD).

51. 46. ​​The method of claim 45, wherein the disorder is nonalcoholic steatohepatitis (NASH).

52. 46. ​​The method of claim 45, wherein the disorder is fatty liver.

53. 46. ​​The method of claim 45, wherein the disorder is insulin resistance or insulin intolerance.

54. 46. ​​The method of claim 45, wherein the disorder is dyslipidemia.

55. 46. ​​The method of claim 45, wherein the disorder is a cardiovascular disease.

56. 46. ​​The method of claim 45, wherein the disorder is atherosclerosis.

57. 43. A method of reducing obesity and controlling or preventing weight gain in a subject, comprising administering to a subject in need thereof an effective amount of a crystalline form of any one of claims 1 to 30 or a micronized crystalline form of any one of claims 31 to 42.

58. 43. A method for stimulating oxygen consumption rate (OCR) in a subject, comprising administering to a subject in need thereof an effective amount of the crystalline form of any one of claims 1-30 or the micronized crystalline form of any one of claims 31-42.

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