Polymorphic forms of compounds and methods for producing polymorphic forms

Abstract

Disclosed herein are thyroid receptor agonist compounds, their polymorphic forms, pharmaceutical compositions, methods of use and preparation. Some embodiments relate to crystalline forms of Compound 1 and its salts. JPEG2025508746000043.jpg35170

Description

[Technical field]

[0001] This application relates to the fields of chemistry and medicine. In particular, this application relates to thyroid agonist compounds, their polymorphic forms, pharmaceutical compositions, and their use as therapeutic agents. [Background technology]

[0002] Thyroid hormones (TH) are synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH), which is secreted by the pituitary gland in response to various stimuli (e.g., thyrotropin-releasing hormone (TRH) from the hypothalamus). Thyroid hormones are iodinated O-aryl tyrosine analogs excreted into the circulation primarily as 3,3',5,5'-tetraiodothyronine (T4). T4 is rapidly deiodinated in local tissues by thyroxine 5'-deiodinase to 3,3',5'-triiodothyronine (T3), the most potent TH. T3 is metabolized to inactive metabolites via various pathways, including those involving deiodination, glucuronidation, sulfation, deamination, and decarboxylation. Most of the circulating T4 and T3 are eliminated by the liver.

[0003] The biological activity of TH is largely mediated by the thyroid hormone receptor (TR). TR belongs to the nuclear receptor superfamily, which, together with its common partner, the retinoid X receptor, forms a heterodimer that acts as a ligand-inducible transcription factor. Like other nuclear receptors, TR has a ligand-binding domain and a DNA-binding domain and regulates gene expression by ligand-dependent interaction with DNA response elements (thyroid response elements, TREs). Currently, the literature indicates that TR is encoded by two distinct genes (TRα and TRβ), which generate several isoforms by alternative splicing (Williams, Mol. Cell. Biol. 20(22):8329-42 (2000); Nagaya et al., Biochem. Biophys. Res. Commun. 226(2):426-30 (1996)). The major isoforms identified so far are TRα-1, TRα-2, TRβ-1 and TRβ-2. TRα-1 is ubiquitously expressed in rats, with highest expression in skeletal muscle and brown lipids. TRβ-1 is also ubiquitously expressed, with highest expression in liver, brain, and kidney. TRβ-2 is expressed in specific regions of the anterior pituitary gland and hypothalamus, as well as in the developing brain and inner ear. In rat and mouse liver, TRβ-1 is the predominant isoform (80%). The TR isoforms found in humans and rats are highly homologous in terms of their amino acid sequences, suggesting that each fulfills specialized functions.

[0004] THs affect the growth, metabolism and physiological functions of almost all organs. THs lower serum cholesterol and serum triglycerides. However, side effects of TH action include cardiac arrhythmias, bone loss, nervousness and anxiety. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Williams, Mol. Cell. Biol. 20(22):8329~42 (2000)

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

[0006] TRβ agonists may be useful as therapeutic agents for conditions such as hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), and various fibrotic diseases and disorders. Thus, there is a need to provide TRβ agonist compounds with suitable stability characteristics for therapeutic use. [Means for solving the problem]

[0007] In a first aspect of the disclosure, provided herein is a crystalline form of Compound 1:

[0008] [ka]

[0009] or a solvate thereof.

[0010] In some embodiments of the first aspect, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein said characteristic peak is selected from the group consisting of about 5.1, 7.4, 10.1, 12.1, 16.4, 17.3, 18.5, 20.5, 21.4, 21.7, 22.1, 23.8, 24.1, 25.5, and 25.9 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from the group consisting of 5.1, 7.4, 10.1, 12.1, 16.4, 17.3, 18.5, 20.5, 21.4, 21.7, 22.1, 23.8, 24.1, 25.5, and 25.9 degrees 2θ. In some embodiments, the crystalline form may have a melting point of about 161°C.

[0011] In some embodiments, provided herein is a crystalline form of Compound 1, wherein the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 7.5, 8.1, 10.0, 15.4, 16.7, 18.3, 18.8, 20.2, 21.0, 22.3, 24.1, 25.1, and 26.4 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein the characteristic peaks are selected from the group consisting of 7.5, 8.1, 10.0, 15.4, 16.7, 18.3, 18.8, 20.2, 21.0, 22.3, 24.1, 25.1, and 26.4 degrees 2θ.

[0012] In some embodiments, provided herein is a crystalline form of Compound 1, wherein the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of about 4.0, 8.0, 11.0, 12.0, 14.4, 14.6, 17.1, 18.5, 19.2, 21.1, 21.7, 24.9, and 25.7 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein the characteristic peaks are selected from the group consisting of 4.0, 8.0, 11.0, 12.0, 14.4, 14.6, 17.1, 18.5, 19.2, 21.1, 21.7, 24.9, and 25.7 degrees 2θ. In some embodiments, the crystalline form may exhibit a DSC endotherm at about 70° C. or 158° C.

[0013] In some embodiments, provided herein are crystalline forms of Compound 1, wherein the crystalline forms may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 76.1, 7.6, 11.3, 12.2, 16.5, 17.0, 17.3, 18.4, 18.6, 19.5, 19.7, 20.7, 21.2, 22.5, 26.0, and 26.3 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from the group consisting of 6.1, 7.6, 11.3, 12.2, 16.5, 17.0, 17.3, 18.4, 18.6, 19.5, 19.7, 20.7, 21.2, 22.5, 26.0, and 26.3 degrees 2θ. In some embodiments, the crystalline form may exhibit a DSC endotherm at about 166° C.

[0014] In some embodiments, provided herein is a crystalline form of Compound 1, wherein the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 3.3, 5.0, 7.5, 14.9, 16.3, 17.2, 19.4, 21.7, 24.7, 25.5, and 26.6 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein the characteristic peaks are selected from the group consisting of 3.3, 5.0, 7.5, 14.9, 16.3, 17.2, 19.4, 21.7, 24.7, 25.5, and 26.6 degrees 2θ. In some embodiments, the crystalline form may exhibit a DSC endotherm at about 96°C or 166°C.

[0015] In some embodiments, provided herein are crystalline forms of Compound 1, wherein the crystalline forms may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 8.3, 15.5, 15.6, 15.9, 17.0, 17.3, 17.9, 18.6, 20.8, 22.0, 23.0, 23.6, 23.8, 25.5, 25.7, 26.0, and 26.7 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from the group consisting of 8.3, 15.5, 15.6, 15.9, 17.0, 17.3, 17.9, 18.6, 20.8, 22.0, 23.0, 23.6, 23.8, 25.5, 25.7, 26.0, and 26.7 degrees 2θ. In some embodiments, the crystalline form may exhibit a DSC endotherm at about 96° C.

[0016] In some embodiments of the first aspect provided herein, the crystalline form may be in a non-solvated state. In other embodiments, the crystalline form may be in a solvated state.

[0017] In a second aspect of the disclosure, provided herein is a crystalline form of compound 1-A:

[0018] [ka]

[0019] or a solvate thereof.

[0020] In some embodiments, the crystalline form of compound 1-A may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 6.0, 13.3, 14.4, 14.8, 16.1, 17.8, 17.9, 18.7, 20.5, 20.8, 21.7, 22.9, 23.8, 24.9, 25.1, and 26.6 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein the characteristic peaks are selected from the group consisting of 6.0, 13.3, 14.4, 14.8, 16.1, 17.8, 17.9, 18.7, 20.5, 20.8, 21.7, 22.9, 23.8, 24.9, 25.1, and 26.6 degrees 2θ. In some embodiments, the crystalline form may have a melting point of about 148°C. In some embodiments, the crystalline form may have a melting point of about 152°C. In some embodiments, the crystalline form may have a melting point of about 156°C. In some embodiments, the crystalline form may have a melting point of about 146°C to about 158°C. In some embodiments, the crystalline form may have a melting point of about 148°C to about 156°C. In some embodiments, the crystalline form may have a DSC melting point of about 146°C to about 150°C. In some embodiments, the crystalline form may have a melting point of about 152°C to about 156°C.

[0021] In some embodiments, the crystalline form of compound 1-A may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 6.1, 12.2, 13.3, 13.6, 16.5, 17.3, 18.3, 19.9, 20.2, 20.5, 21.4, 21.9, 22.5, 22.8, 23.0, and 25.6 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein the characteristic peaks are selected from the group consisting of 6.1, 12.2, 13.3, 13.6, 16.5, 17.3, 18.3, 19.9, 20.2, 20.5, 21.4, 21.9, 22.5, 22.8, 23.0, and 25.6 degrees 2θ. In some embodiments, the crystalline form may have a melting point of about 139°C.

[0022] In some embodiments, the crystalline form of compound 1-A may exhibit an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 5.7, 6.2, 15.5, 16.4, 17.0, 18.5, 20.6, 21.2, 22.0, 23.3, and 26.1 degrees 2θ. In some embodiments, the crystalline form may exhibit an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein the characteristic peaks are selected from the group consisting of 5.7, 6.2, 15.5, 16.4, 17.0, 18.5, 20.6, 21.2, 22.0, 23.3, and 26.1 degrees 2θ. In some embodiments, the crystalline form may have a melting point of about 117°C.

[0023] In some embodiments, the crystalline form of compound 1-A may have an X-ray powder diffraction pattern comprising at least one characteristic peak, wherein the characteristic peak is selected from the group consisting of approximately 6.2, 12.9, 14.0, 14.5, 16.5, 17.6, 18.0, 18.6, 20.3, 21.2, 22.7, 23.3, 24.0, and 26.1 degrees 2θ. In some embodiments, the crystalline form may have an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein the characteristic peaks are selected from the group consisting of 6.2, 12.9, 14.0, 14.5, 16.5, 17.6, 18.0, 18.6, 20.3, 21.2, 22.7, 23.3, 24.0, and 26.1 degrees 2θ. In some embodiments, the crystalline form may have a melting point of about 114°C.

[0024] In some embodiments of the first aspect provided herein, the crystalline form of compound 1-A can be in a non-solvated state.In other embodiments, the crystalline form of compound 1-A can be in a solvated state.In some specific embodiments, the crystalline form of compound 1-A can be a hydrate.In some specific embodiments, the crystalline form of compound 1-A can be a monohydrate.

[0025] Also provided herein are pharmaceutical compositions comprising a therapeutically effective amount of one or more crystalline forms described herein and one or more pharma- ceutically acceptable excipients.

[0026] Also provided herein is a method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form described herein, wherein the disease or disorder is selected from the group consisting of steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, and idiopathic fibrosis.

[0027] In some embodiments, the method may result in the prevention, treatment or amelioration of fibrosis, fibrotic conditions or fibrotic symptoms. In some embodiments, the method may result in a reduction in the amount of extracellular matrix protein present in one or more tissues of the subject. In some embodiments, the method may result in a reduction in the amount of collagen present in one or more tissues of the subject. In some embodiments, administration of the crystalline forms described herein may result in a reduction in the amount of type I, type Ia or type III collagen present in one or more tissues of the subject.

[0028] In some embodiments, described herein are methods of treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a solution prepared by dissolving a crystalline form described herein in a pharma- ceutically acceptable solvent, wherein the disease or disorder is selected from the group consisting of steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, and idiopathic fibrosis.

[0029] In another aspect of the disclosure, described herein is a compound having the structure

[0030] [ka]

[0031] or a solvate thereof. [Brief description of the drawings]

[0032] [Figure 1] 1 is an X-ray powder diffraction pattern of crystalline form A of Compound 1. [Diagram 2] FIG. 2 shows differential scanning calorimetry and thermogravimetry overlays for crystalline Form A of Compound 1 compound. [Diagram 3] FIG. 2 shows the moisture sorption / desorption curve of crystalline form A of Compound 1 compound. [Figure 4] 1 is an X-ray powder diffraction pattern of crystalline form B of Compound 1. [Diagram 5] 1 is an X-ray powder diffraction pattern of crystalline form C of Compound 1. [Figure 6] FIG. 2 shows differential scanning calorimetry and thermogravimetry overlays for crystalline Form C of Compound 1 compound. [Figure 7] 1 is an X-ray powder diffraction pattern of crystalline form D of Compound 1. [Figure 8] FIG. 2 shows differential scanning calorimetry and thermogravimetry overlays for crystalline Form D of Compound 1 compound. [Figure 9] 1 is an X-ray powder diffraction pattern of crystalline form E of Compound 1. [Figure 10] FIG. 2 shows differential scanning calorimetry and thermogravimetry overlays for crystalline Form E of Compound 1 compound. [Figure 11] 1 is an X-ray powder diffraction pattern of crystalline form F of Compound 1. [Figure 12] FIG. 2 shows differential scanning calorimetry and thermogravimetry overlays for crystalline Form F of Compound 1 compound. [Figure 13] 1 is an X-ray powder diffraction pattern of crystalline Form 1 of Compound 1-A. [Figure 14] 1 is an X-ray powder diffraction pattern of crystalline Form 2 of Compound 1-A. [Figure 15] 1 is an X-ray powder diffraction pattern of crystalline Form 3 of Compound 1-A. [Figure 16] FIG. 2 shows differential scanning calorimetry and thermogravimetry overlays for crystalline Form 3 of Compound 1-A. [Figure 17] 1 is an X-ray powder diffraction pattern of crystalline Form 4 of Compound 1-A. [Figure 18] FIG. 2 shows differential scanning calorimetry and thermogravimetry overlays for crystalline Form 4 of Compound 1-A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Disclosed herein are crystalline forms of Compound 1 or solvates thereof, and methods of crystallizing the compound. Compound 1 is shown below.

[0034] [ka]

[0035] Crystalline forms of Compound 1 include Forms A, B, C, D, E and F (described herein).

[0036] Disclosed herein is the (2-dimethylamino)ethanol ("deanol") salt of Compound 1, referred to herein as Compound 1-A.

[0037] [ka]

[0038] A crystalline form of the deanol salt of Compound 1 is also disclosed herein.

[0039] Crystalline forms of Compound 1-A include Forms 1, 2, 3 and 4 (described herein).

[0040] The present application relates to a first crystalline form of Compound 1, and methods for crystallizing various crystalline forms of Compound 1.

[0041] The present application relates to a first crystalline form of compound 1-A, and methods for crystallizing various crystalline forms of compound 1-A.

[0042] The crystalline forms provided herein advantageously exhibit improved solubility, bioavailability, stability, processability and ease of manufacture.As a result, compound 1, particularly crystalline form A, and compound 1-A, particularly crystalline form 3, provide improved long-term stability.Therefore, the crystalline forms provide significant clinical improvement as TRβ agonists.

[0043] The present application also relates to methods of using the crystalline forms described herein to treat diseases and disorders by administering to a patient a therapeutically effective amount of a composition comprising one or more crystalline forms of Compound 1 and / or Compound 1-A and one or more pharma- ceutically acceptable excipients.

[0044] Crystalline form of compound 1 Disclosed herein are crystalline forms of Compound 1, and in particular crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, and crystalline form F (described below). Unless otherwise noted, X-ray powder diffraction data provided herein was determined using a Cu Kα radiation source.

[0045] Crystal form A Some embodiments include a non-solvated crystalline form of Compound 1, referred to herein as crystalline Form A. The exact conditions for forming crystalline Form A can be determined empirically, and it is only possible to give some methods that have been found to be suitable for practice.

[0046] Crystalline Form A was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 1 shows the crystal structure of Form A as determined by X-ray powder diffraction (XRPD). Crystalline Form A obtainable by the methods disclosed herein exhibits prominent peaks at approximately 5.1, 7.4, 10.1, 12.1, 16.4, 17.3, 18.5, 20.5, 21.4, 21.7, 22.1, 23.8, 24.1, 25.5 and 25.9 degrees 2θ. Thus, in some embodiments, a crystalline form of Compound 1 has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 characteristic peaks) selected from approximately 5.1, 7.4, 10.1, 12.1, 16.4, 17.3, 18.5, 20.5, 21.4, 21.7, 22.1, 23.8, 24.1, 25.5, and 25.9 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from approximately 5.1, 7.4, 10.1, 12.1, 16.4, 17.3, 18.5, 20.5, 21.4, 21.7, 22.1, 23.8, 24.1, 25.5, and 25.9 degrees 2θ.

[0047] As is well understood in the art, due to experimental variability when X-ray diffraction patterns are measured on different instruments, peak positions are presumed to be equal if the 2-theta (2θ) values ​​match within some variability. For example, the United States Pharmacopeia states that identity is confirmed if the angular settings of the 10 strongest diffraction peaks match those of a reference material within ±0.2 degrees, and the relative intensities of the peaks do not vary by more than 20%. Thus, in some embodiments, the peak positions listed herein include a variability within ±0.5 degrees 2θ. In other embodiments, the peak positions listed herein include a variability within ±0.2 degrees 2θ. As disclosed herein, the term "approximately" is defined as ±0.5 degrees 2θ when referring to 2θ values.

[0048] FIG. 2 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis for crystalline form A. The DSC results show a peak at a temperature of about 161° C. for crystalline form A, which indicates the melting point of the crystal. Thus, in some embodiments, crystalline form A exhibits a melting point of about 158° C. to 164° C., about 158° C. to about 166° C., or about 161° C. Crystalline form A was analyzed by thermogravimetric analysis (TG), and in one case exhibited a mass loss of 1.78% when run from 25° C. to 160° C. Meanwhile, FIG. 3 shows the dynamic vapor sorption (DVS) results for crystalline form A, indicating moderate water uptake.

[0049] Thus, crystalline form A may be characterized as being moderately hygroscopic and stable over a wide range of humidity. Crystalline form A also exhibits good crystallinity, has a relatively high melting point (approximately 161° C.), and crystalline form A does not show any evidence of hydrate formation.

[0050] Crystal form B Some embodiments include a solvated crystalline form of Compound 1, referred to herein as crystalline Form B. The exact conditions for forming crystalline Form B can be determined empirically, and it is only possible to give some methods that have been found to be suitable for practice.

[0051] Crystalline form B was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 4 shows the crystal structure of form B as determined by X-ray powder diffraction (XRPD). Crystalline form B obtainable by the methods disclosed herein exhibits prominent peaks at approximately 7.5, 8.1, 10.0, 15.4, 16.7, 18.3, 18.8, 20.2, 21.0, 22.3, 24.1, 25.1 and 26.4 degrees 2θ. Thus, in some embodiments, the crystalline form of Compound 1 has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 characteristic peaks) selected from about 7.5, 8.1, 10.0, 15.4, 16.7, 18.3, 18.8, 20.2, 21.0, 22.3, 24.1, 25.1, and 26.4 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from about 7.5, 8.1, 10.0, 15.4, 16.7, 18.3, 18.8, 20.2, 21.0, 22.3, 24.1, 25.1, and 26.4 degrees 2θ.

[0052] Crystalline form B shows evidence of solvate formation, most likely a solvate of isopropyl alcohol.

[0053] Crystal form C Some embodiments include a crystalline form of Compound 1, referred to herein as crystalline form C. The exact conditions for forming crystalline form C can be determined empirically, and it is only possible to provide some methods that have been found to be suitable for practice.

[0054] Crystalline form C was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 5 shows the crystal structure of form C as determined by X-ray powder diffraction (XRPD). Crystalline form C, obtainable by the methods disclosed herein, exhibits prominent peaks at approximately 4.0, 8.0, 11.0, 12.0, 14.4, 14.6, 17.1, 18.5, 19.2, 21.1, 21.7, 24.9 and 25.7 degrees 2θ. Thus, in some embodiments, the crystalline form of Compound 1 has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 characteristic peaks) selected from about 4.0, 8.0, 11.0, 12.0, 14.4, 14.6, 17.1, 18.5, 19.2, 21.1, 21.7, 24.9, and 25.7 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from about 4.0, 8.0, 11.0, 12.0, 14.4, 14.6, 17.1, 18.5, 19.2, 21.1, 21.7, 24.9, and 25.7 degrees 2θ.

[0055] Figure 6 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis for crystalline form C. The DSC results show endotherms at 70°C and 158°C for crystalline form C. Crystalline form C was analyzed by thermogravimetric analysis (TG) and in one case exhibited a mass loss of 4.4% when run from 25°C to 110°C. Crystalline form C becomes amorphous when heated to 115°C.

[0056] Crystal form D Some embodiments include a crystalline form of Compound 1, referred to herein as crystalline form D. The exact conditions for forming crystalline form D can be determined empirically, and it is only possible to provide some methods that have been found to be suitable for practice.

[0057] Crystalline form D was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 7 shows the crystal structure of form D as determined by X-ray powder diffraction (XRPD). Crystalline form D, obtainable by the methods disclosed herein, exhibits prominent peaks at approximately 6.1, 7.6, 11.3, 12.2, 16.5, 17.0, 17.3, 18.4, 18.6, 19.5, 19.7, 20.7, 21.2, 22.5, 26.0 and 26.3 degrees 2θ. Thus, in some embodiments, a crystalline form of Compound 1 has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 characteristic peaks) selected from approximately 6.1, 7.6, 11.3, 12.2, 16.5, 17.0, 17.3, 18.4, 18.6, 19.5, 19.7, 20.7, 21.2, 22.5, 26.0, and 26.3 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from approximately 6.1, 7.6, 11.3, 12.2, 16.5, 17.0, 17.3, 18.4, 18.6, 19.5, 19.7, 20.7, 21.2, 22.5, 26.0, and 26.3 degrees 2θ.

[0058] Figure 8 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis for crystalline form D. The DSC results show an endotherm at 166°C for crystalline form D, indicating the crystalline melting point. Crystalline form D was analyzed by thermogravimetric analysis (TG) and in one case exhibited a mass loss of 3.875% when run from 25°C to 140°C, indicating a possible hydrate.

[0059] Crystal form E Some embodiments include a non-solvated crystalline form of Compound 1, referred to herein as crystalline form E. The exact conditions for forming crystalline form E can be determined empirically, and it is only possible to give some methods that have been found to be suitable for practice.

[0060] Crystalline form E was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 9 shows the crystal structure of form E as determined by X-ray powder diffraction (XRPD). Crystalline form E obtainable by the methods disclosed herein exhibits prominent peaks at approximately 3.3, 5.0, 7.5, 14.9, 16.3, 17.2, 19.4, 21.7, 24.7, 25.5 and 26.6 degrees 2θ. Thus, in some embodiments, the crystalline form of compound 1 has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 characteristic peaks) selected from approximately 3.3, 5.0, 7.5, 14.9, 16.3, 17.2, 19.4, 21.7, 24.7, 25.5 and 26.6 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from approximately 3.3, 5.0, 7.5, 14.9, 16.3, 17.2, 19.4, 21.7, 24.7, 25.5, and 26.6 degrees 2θ.

[0061] Figure 10 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis for crystalline form E. The DSC results show endotherms at 96°C and 166°C for crystalline form E. Crystalline form E was analyzed by thermogravimetric analysis (TG) and in one case exhibited a 2.5% mass loss when run from 25°C to 125°C, although the mass loss was not attributable to the solvent.

[0062] Crystal form F Some embodiments include a solvated crystalline form of Compound 1, referred to herein as crystalline form F. The exact conditions for forming crystalline form F can be determined empirically, and it is only possible to provide some methods that have been found to be suitable for practice.

[0063] Crystalline form F was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 11 shows the crystal structure of form E as determined by X-ray powder diffraction (XRPD). Crystalline form E, obtainable by the methods disclosed herein, exhibits prominent peaks at approximately 8.3, 15.5, 15.6, 15.9, 17.0, 17.3, 17.9, 18.6, 20.8, 22.0, 23.0, 23.6, 23.8, 25.5, 25.7, 26.0 and 26.7 degrees 2θ. Thus, in some embodiments, a crystalline form of Compound 1 has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 characteristic peaks) selected from approximately 8.3, 15.5, 15.6, 15.9, 17.0, 17.3, 17.9, 18.6, 20.8, 22.0, 23.0, 23.6, 23.8, 25.5, 25.7, 26.0, and 26.7 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from approximately 8.3, 15.5, 15.6, 15.9, 17.0, 17.3, 17.9, 18.6, 20.8, 22.0, 23.0, 23.6, 23.8, 25.5, 25.7, 26.0, and 26.7 degrees 2θ.

[0064] Figure 12 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis for crystalline form F. The DSC results show an endotherm at 96°C for crystalline form F. Crystalline form F was analyzed by thermogravimetric analysis (TG) and in one case exhibited a mass loss of 2.75% when run from 25°C to 90°C. 1 H-NMR results (not shown) indicate the formation of a dimethylformamide solvate.

[0065] Compound 1-A and its crystalline form Disclosed herein is Compound 1-A, which is the (2-dimethylamino)ethanol ("deanol") salt of Compound 1. The structure of Compound 1-A is provided below.

[0066] [ka]

[0067] Also disclosed herein are crystalline forms of Compound 1-A, and in particular crystalline Form 1, crystalline Form 2, crystalline Form 3, and crystalline Form 4 (described below). Unless otherwise noted, X-ray powder diffraction data provided herein was determined using a Cu Kα radiation source.

[0068] Crystal form 1 Some embodiments include a non-solvated crystalline form of Compound 1-A, referred to herein as crystalline Form 1. The exact conditions for forming crystalline Form 1 can be determined empirically, and it is only possible to provide some methods that have been found to be suitable for practice.

[0069] Crystalline Form 1 was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 13 shows the crystal structure of Form 1 as determined by X-ray powder diffraction (XRPD). Crystalline Form 1 obtainable by the methods disclosed herein exhibits prominent peaks at approximately 6.1, 12.2, 13.3, 13.6, 16.5, 17.3, 18.3, 19.9, 20.2, 20.5, 21.4, 21.9, 22.5, 22.8, 23.0 and 25.6 degrees 2θ. Thus, in some embodiments, the crystalline form of compound 1-A has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 characteristic peaks) selected from approximately 6.1, 12.2, 13.3, 13.6, 16.5, 17.3, 18.3, 19.9, 20.2, 20.5, 21.4, 21.9, 22.5, 22.8, 23.0, and 25.6 degrees 2θ. In some embodiments, the crystalline form of compound 1-A has at least three characteristic peaks selected from approximately 6.1, 12.2, 13.3, 13.6, 16.5, 17.3, 18.3, 19.9, 20.2, 20.5, 21.4, 21.9, 22.5, 22.8, 23.0, and 25.6 degrees 2θ.

[0070] DVS results (not shown) indicate that crystalline form 1 is moderately hygroscopic. DSC analysis indicates a melting point of about 139° C. for crystalline form 1.

[0071] Crystal form 2 Some embodiments include a non-solvated crystalline form of compound 1-A, referred to herein as crystalline Form 2. The exact conditions for forming crystalline Form 1 can be determined empirically, and it is only possible to provide some methods that have been found to be suitable for practice.

[0072] Crystalline Form 2 was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 14 shows the crystal structure of Form 2 as determined by X-ray powder diffraction (XRPD). Crystalline Form 2 obtainable by the methods disclosed herein exhibits prominent peaks at approximately 5.7, 6.2, 15.5, 16.4, 17.0, 18.5, 20.6, 21.2, 22.0, 23.3 and 26.1 degrees 2θ. Thus, in some embodiments, the crystalline form of Compound 1-A has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 characteristic peaks) selected from approximately 5.7, 6.2, 15.5, 16.4, 17.0, 18.5, 20.6, 21.2, 22.0, 23.3 and 26.1 degrees 2θ. In some embodiments, the crystalline form of compound 1-A has at least three characteristic peaks selected from approximately 5.7, 6.2, 15.5, 16.4, 17.0, 18.5, 20.6, 21.2, 22.0, 23.3, and 26.1 degrees 2θ.

[0073] DVS results (not shown) indicate that crystalline form 2 is moderately hygroscopic. DSC analysis indicates a melting point of about 117° C. for crystalline form 2.

[0074] Crystal form 3 Some embodiments include a crystalline form of compound 1-A, referred to herein as crystalline form 3. The exact conditions for forming crystalline form 3 can be determined empirically, and it is only possible to provide some methods that have been found to be suitable for practice.

[0075] Crystalline Form 3 was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 15 shows the crystal structure of Form 3 as determined by X-ray powder diffraction (XRPD). Crystalline Form 3 obtainable by the methods disclosed herein exhibits prominent peaks at approximately 6.0, 13.3, 14.4, 14.8, 16.1, 17.8, 17.9, 18.7, 20.5, 20.8, 21.7, 22.9, 23.8, 24.9, 25.1, and 26.6 degrees 2θ. Thus, in some embodiments, the crystalline form of compound 1-A has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 characteristic peaks) selected from approximately 6.0, 13.3, 14.4, 14.8, 16.1, 17.8, 17.9, 18.7, 20.5, 20.8, 21.7, 22.9, 23.8, 24.9, 25.1, and 26.6 degrees 2θ. In some embodiments, the crystalline form of the compound of Formula (I) has at least three characteristic peaks selected from approximately 6.0, 13.3, 14.4, 14.8, 16.1, 17.8, 17.9, 18.7, 20.5, 20.8, 21.7, 22.9, 23.8, 24.9, 25.1, and 26.6 degrees 2θ.

[0076] 16 shows the DSC and TGA results for crystalline form 3. The DSC results show two endotherms, the first indicating the loss of water at a temperature of about 117° C., and 156° C. indicating the melting point of the crystals. Thus, in some embodiments, crystalline form 3 exhibits a melting point of about 148° C. to about 152° C. or about 156° C. In some embodiments, crystalline form 3 may have a melting point of about 146° C. to about 158° C. or about 148° C. to about 156° C. In some embodiments, crystalline form 3 may have a DSC melting point of about 146° C. to about 150° C. or about 152° C. to about 156° C.1 H-NMR results are consistent with a 1:1 molar salt of compound 1 and deanol. Crystalline form 3 was analyzed by thermogravimetry (TG) and in one case exhibited a mass loss of 3.85% when run from 25° C. to 90° C. and a mass loss of 2.09% when run from 90° C. to 150° C. DVS data (not shown) indicate negligible water uptake. Karl Fischer titration indicates that crystalline form 3 is a monohydrate.

[0077] Crystal form 4 Some embodiments include a non-solvated crystalline form of compound 1-A, referred to herein as crystalline form 4. The exact conditions for forming crystalline form 4 can be determined empirically, and it is only possible to provide some methods that have been found to be suitable for practice.

[0078] Crystalline Form 4 was characterized using various techniques, which are described in more detail in the Experimental Methods section. Figure 17 shows the crystal structure of Form 4 as determined by X-ray powder diffraction (XRPD). Crystalline Form 4 obtainable by the methods disclosed herein exhibits prominent peaks at approximately 6.2, 12.9, 14.0, 14.5, 16.5, 17.6, 18.0, 18.6, 20.3, 21.2, 22.7, 23.3, 24.0 and 26.1 degrees 2θ. Thus, in some embodiments, the crystalline form of compound 1-A has at least one characteristic peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 characteristic peaks) selected from about 6.2, 12.9, 14.0, 14.5, 16.5, 17.6, 18.0, 18.6, 20.3, 21.2, 22.7, 23.3, 24.0, and 26.1 degrees 2θ. In some embodiments, the crystalline form of the compound of formula (I) has at least three characteristic peaks selected from about 6.2, 12.9, 14.0, 14.5, 16.5, 17.6, 18.0, 18.6, 20.3, 21.2, 22.7, 23.3, 24.0, and 26.1 degrees 2θ.

[0079] 17 shows the DSC and TGA results for crystalline Form 4. The DSC results show an endotherm at 114° C., which indicates the crystalline melting point. Thus, in some embodiments, crystalline Form 4 exhibits a melting point of about 111° C. to 117° C., about 106° C. to about 116° C., or about 114° C. 1 H-NMR results are consistent with a 1:1 molar salt of compound 1 and deanol. Crystalline form 4 was analyzed by thermogravimetry (TG) and in one case exhibited a mass loss of 0.44% when run from 25° C. to 120° C.

[0080] Methods for crystallizing compounds 1 and 1-A Disclosed are methods of crystallizing Compound 1. Crystalline forms of Compound 1 may generally be obtained or produced by crystallizing Compound 1 under controlled conditions. In some embodiments, the methods may produce a non-solvated crystal form. In some embodiments, the methods may produce a solvated crystal form. In some embodiments, the methods may produce crystalline form A. In some embodiments, the methods may produce crystalline form B. In some embodiments, the methods may produce crystalline form C. In some embodiments, the methods may produce crystalline form D. In some embodiments, the methods may produce crystalline form E. In some embodiments, the methods may produce crystalline form F. In some embodiments, the methods may produce a mixture of any of the aforementioned crystalline forms.

[0081] Also disclosed are methods of crystallizing compound 1-A. Crystalline forms of compound 1 may generally be obtained or produced by crystallizing compound 1-A under controlled conditions. In some embodiments, the methods may produce a non-solvated crystal form. In some embodiments, the methods may produce a solvated crystal form. In some embodiments, the methods may produce crystalline form 1. In some embodiments, the methods may produce crystalline form 2. In some embodiments, the methods may produce crystalline form 3. In some embodiments, the methods may produce crystalline form 4. In some embodiments, the methods may produce a mixture of any of the aforementioned crystalline forms.

[0082] In some embodiments, the method may include dissolving an amorphous form of Compound 1 or Compound 1-A in a first solvent to create a first solution. In some embodiments, the method may include dissolving a crystalline form of Compound 1 or Compound 1-A in a first solvent to create a first solution. In some embodiments, the method may include dissolving a mixture of amorphous and crystalline forms of Compound 1 or Compound 1-A in a first solvent to create a first solution. In some embodiments, the method may include adding a second solvent to the first solution to create a second mixture. In some embodiments, the method may include evaporating the second mixture. In some embodiments, the method may include cooling the second mixture. In some embodiments, the second mixture may be cooled to 25°C, 20°C, 15°C, 10°C, 5°C, 0°C, -5°C, -10°C, -20°C, -25°C, any range between any of these values, or below -25°C.

[0083] In some embodiments, the method may include isolating the crystalline form of Compound 1 or Compound 1-A. In some embodiments, the isolation may be performed by filtration, such as hot filtration. In some embodiments, the isolated product may be dried, such as by air drying.

[0084] In some embodiments, the first solvent may be a single solvent. In some embodiments, the first solvent may be a mixture of two or more solvents. In some embodiments, the first solvent may be acetone, acetonitrile, 1,4-dioxane, dimethylformamide, ethanol, ethyl acetate, diethyl ether, methanol, methyl ethyl ketone, 2-methyltetrahydrofuran, isopropanol, n-propanol, isopropyl acetate, tetrahydrofuran, water, or a mixture thereof.

[0085] In some embodiments, the second solvent may be a single solvent. In some embodiments, the second solvent may be a mixture of two or more solvents. In some embodiments, the second solvent may include acetone, acetonitrile, 1,4-dioxane, dimethylformamide, ethanol, ethyl acetate, diethyl ether, methanol, methyl ethyl ketone, 2-methyltetrahydrofuran, isopropanol, n-propanol, isopropyl acetate, tetrahydrofuran, water, or a mixture thereof. In some embodiments, the second solvent may include toluene, hexane, water, dichloromethane, or a combination thereof.

[0086] In some embodiments, the method may further include agitation. In some embodiments, the agitation may be performed by stirring. In some embodiments, the agitation may be performed by sonication.

[0087] In some embodiments, the portions of the method may be performed at the same temperature. In some embodiments, the portions of the method may be performed at various temperatures. In some embodiments, the portions of the method may be performed at room temperature. In some embodiments, the portions of the method may be performed at -40°C to 200°C. In some embodiments, the portions of the method may be performed at -40°C to 25°C. In some embodiments, the portions of the method may be performed at -25°C to -10°C. In some embodiments, the portions of the method may be performed at 2°C to 8°C. In some embodiments, the portions of the method may be performed at 50°C to 60°C. In some embodiments, the portions of the method may be performed at 65°C to 75°C. In some embodiments, the portions of the method may be performed at 75°C to 150°C. In some embodiments, the portions of the method may include the first solution, the second mixture, the seeded mixture, isolating the crystalline form, and agitating.

[0088] In some embodiments, the crystalline form of compound 1-A may be prepared by dissolving a crystalline or amorphous form of compound 1 in a first solvent to form a first solution, dissolving one molar equivalent of (2-dimethylamino)ethanol in a second solvent to form a second solution, and combining the first and second solutions to form a combined solution. In some embodiments, the first solvent may include acetone, acetonitrile, 1,4-dioxane, dimethylformamide, ethanol, ethyl acetate, diethyl ether, methanol, methyl ethyl ketone, 2-methyltetrahydrofuran, isopropanol, n-propanol, isopropyl acetate, tetrahydrofuran, water, or a mixture thereof. In some embodiments, the second solvent may include acetone, acetonitrile, 1,4-dioxane, dimethylformamide, ethanol, ethyl acetate, diethyl ether, methanol, methyl ethyl ketone, 2-methyltetrahydrofuran, isopropanol, n-propanol, isopropyl acetate, tetrahydrofuran, water, or a mixture thereof. In some embodiments, the first solvent and the second solvent can be the same. In some embodiments, the first solvent and the second solvent can be different. In some embodiments, the combined solution can be further agitated, evaporated, and / or cooled as described herein.

[0089] In some embodiments, crystalline Form A of Compound 1 may be prepared by dissolving an amount of Compound 1 in a minimal amount of solvent at a first temperature to form a first solution. In some embodiments, the solvent may be acetonitrile. In other embodiments, the solvent may be ethyl acetate. In still other embodiments, the solvent may be acetone. In still other embodiments, the solvent may be diethyl ether. In other embodiments, the solvent may be methyl ethyl ketone. In some embodiments, the first temperature is from 40° C. to 60° C. or from 45° C. to 55° C. In some specific embodiments, the first temperature is about 50° C. In some embodiments, the first solvent may be cooled to a second temperature. In some embodiments, the second temperature may be from −5° C. to −25° C. or from −10° C. to −20° C. In other embodiments, the second temperature may be room temperature. In some specific embodiments, the second temperature is about −15° C. In some embodiments, an anti-solvent may be added to the first solution before cooling. In some embodiments, the anti-solvent is hexane. In another embodiment, the anti-solvent is toluene.

[0090] In some embodiments, crystalline Form A of Compound 1 can be prepared by combining an amount of Compound 1 with a solvent at room temperature and grinding the solid. In some embodiments, the amount of Compound 1 is 20 mg and the amount of solvent is 10 μl. In some embodiments, the solvent is acetone, acetonitrile, ethanol, ethyl acetate, methanol, methyl ethyl ketone, tetrahydrofuran, or water.

[0091] In some embodiments, crystalline Form A of Compound 1 may be prepared by adding Compound 1 to a solvent to form a slurry. In some embodiments, the solvent is dichloromethane. In other embodiments, the solvent is water. In some embodiments, the slurry may be stirred at 20, 25, 30, 35, 40, 45, or 50° C. In some embodiments, the slurry may be stirred for 1, 2, 3, 4, 5, 6, or 7 days or more.

[0092] In some embodiments, crystalline form B of Compound 1 can be prepared by combining an amount of Compound 1 with a solvent at room temperature and grinding the solid. In some embodiments, the amount of Compound 1 is 20 mg and the amount of solvent is 10 μl. In some embodiments, the solvent is isopropanol.

[0093] In some embodiments, crystalline Form C of Compound 1 can be prepared by dissolving a quantity of Compound 1 in a minimum amount of solvent at room temperature and evaporating to leave a solid. In some embodiments, the solvent is acetone, acetonitrile, 1,4-dioxane, ethanol, methanol, isopropanol, water, or a mixture thereof.

[0094] In some embodiments, crystalline form D of compound 1 can be prepared by dissolving an amount of compound 1 in a minimal amount of solvent at a first temperature to form a first solution. In some embodiments, the solvent can be acetone. In other embodiments, the solvent can be tetrahydrofuran. In still other embodiments, the solvent can be ethanol. In still other embodiments, the solvent can be water. In other embodiments, the solvent can be methanol / water (95 / 5 v / v). In some embodiments, the first temperature is 40° C. to 60° C. or 45° C. to 55° C. In some specific embodiments, the first temperature is about 50° C. In some specific embodiments, the first temperature is about 60° C. In some embodiments, the first solvent can be cooled to a second temperature. In some embodiments, the second temperature can be −5° C. to −25° C. or −10° C. to −20° C. In other embodiments, the second temperature can be room temperature. In some specific embodiments, the second temperature is about −15° C. In some embodiments, an anti-solvent may be added to the first solution before cooling. In some embodiments, the solvent is THF and the anti-solvent is water. In some embodiments, the solvent is THF and the anti-solvent is hexane. In some embodiments, the solvent is THF and the anti-solvent is dichloromethane.

[0095] In some embodiments, crystalline form E of compound 1 may be prepared by dissolving an amount of compound 1 in a minimal amount of solvent at a first temperature to form a first solution. In some embodiments, the solvent may be acetonitrile and water 95:5 (v / v). In other embodiments, the solvent may be methanol. In some embodiments, the solvent is diethyl ether. In other embodiments, the solvent is methyl ethyl ketone. In some embodiments, the solvent may be methanol. In some embodiments, the first temperature is 40° C. to 60° C. or 45° C. to 55° C. In some specific embodiments, the first temperature is about 50° C. In some specific embodiments, the first temperature is about 60° C. In some embodiments, the first solvent may be cooled to a second temperature. In some embodiments, the second temperature may be −5° C. to −25° C. or −10° C. to −20° C. In other embodiments, the second temperature may be room temperature. In some specific embodiments, the second temperature is about −15° C. In some embodiments, an anti-solvent may be added to the first solution before cooling. In some embodiments, the solvent is methanol and the anti-solvent is toluene. In some embodiments, the solvent is isopropanol and the anti-solvent is hexane. In some embodiments, the solvent is diethyl ether and the anti-solvent is dichloromethane. In some embodiments, the solvent is methanol and the anti-solvent is dichloromethane. In some embodiments, the solvent is methyl ethyl ketone and the anti-solvent is dichloromethane.

[0096] In some embodiments, crystalline form F of Compound 1 can be prepared by dissolving a quantity of Compound 1 in a minimum amount of solvent at room temperature and evaporating to leave a solid. In some embodiments, the solvent is dimethylformamide.

[0097] In some embodiments, crystalline form F of compound 1 may be prepared by dissolving an amount of compound 1 in a minimum amount of solvent at a first temperature to form a first solution. In some embodiments, the solvent may be dimethylformamide. In some embodiments, the first temperature is from 40° C. to 60° C. or from 45° C. to 55° C. In some specific embodiments, the first temperature is about 50° C. In some embodiments, the first solvent may be cooled to a second temperature. In some embodiments, the second temperature may be from −5° C. to −25° C. or from −10° C. to −20° C. In some specific embodiments, the second temperature is about −15° C. In some embodiments, an anti-solvent may be added to the first solution before cooling. In some embodiments, the anti-solvent is toluene.

[0098] In some embodiments, crystalline Form 1 of Compound 1-A may be prepared by combining Compound 1 with a solvent to form a first solution and adding said solution to one molar equivalent of (2-methylamino)ethanol to form a second solution. The second solution may be stirred at room temperature for 1, 2, 3, 4, 5 days or more. In some embodiments, the first solution may be sonicated prior to addition to the (2-methylamino)ethanol. In some embodiments, the solvent is acetone. In other embodiments, the solvent is 1,4-dioxane. In yet other embodiments, the solvent is diethyl ether. In some embodiments, the solvent is isopropanol. In other embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is methyl ethyl ketone.

[0099] In some embodiments, crystalline Form 3 of Compound 1-A may be prepared by combining Compound 1 in a first solvent to form a first solution. In some embodiments, the first solvent may be acetone. In some embodiments, the acetone may contain 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% water. In some embodiments, the first solution may be added to a second solution of 2-(dimethylamino)ethanol in a second solvent to form a third solution. In some embodiments, the second solvent may be acetone. In some embodiments, the acetone may contain 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% water. In some embodiments, the molar ratio of 2-(dimethylamino)ethanol to compound 1-A is 1:1, 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, or 1:5 to 1. In some embodiments, the molar ratio of 2-(dimethylamino)ethanol to compound 1-A is 1:1 to 1.1:1. In some specific embodiments, the molar ratio of 2-(dimethylamino)ethanol to compound 1-A is 1.05:1. In some embodiments, the first solution may be added to the second solution over 5, 10, 15, 20, 25, or 30 minutes or more. In some embodiments, a slurry is formed upon addition of the first solution to the second solution. In some embodiments, an additional solvent may be added to the slurry. In some embodiments, the additional solvent is acetone. In some embodiments, the acetone may contain 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% water.

[0100] In some embodiments, crystalline Form 3 of Compound 1-A may be prepared by combining Compound 1 with 1 molar equivalent of (2-methylamino)ethanol pre-dissolved in ethanol to form a solution. In some embodiments, the solution may be sonicated and evaporated until a solid forms. In some embodiments, the solution may be stirred at room temperature for 1, 2, 3, 4, 5 days or more.

[0101] In some embodiments, crystalline Form 4 of Compound 1-A may be prepared by combining Compound 1 with a solvent to form a first solution and adding said solution to one molar equivalent of (2-methylamino)ethanol to form a second solution. The second solution may be stirred at room temperature for 1, 2, 3, 4, 5 days or more. In some embodiments, the first solution may be sonicated prior to addition to (2-methylamino)ethanol. In some embodiments, the solvent is acetonitrile or ethyl acetate.

[0102] definition "Subject", as used herein, means a non-human mammal selected for treatment or therapy, including, but not limited to, a human, or a dog, cat, horse, donkey, mule, cow, domestic buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, moose, deer, domestic antelope, or non-human primate.

[0103] "Disease or condition in a subject" refers to a subject exhibiting one or more clinical indicators of a disease or condition. In certain embodiments, the disease or condition is one or more fibrosis, fibrotic conditions or fibrotic symptoms. In certain embodiments, the disease or condition is scleroderma. In certain embodiments, the disease or condition is non-alcoholic steatohepatitis (NASH). In certain embodiments, the disease or condition is cirrhosis. In certain embodiments, the disease or condition is non-alcoholic fatty liver disease (NAFLD). In certain embodiments, the disease or condition is idiopathic pulmonary fibrosis. In certain embodiments, the disease or condition is atherosclerosis. In certain embodiments, the disease or condition is hepatitis, alcoholic fatty liver disease, asthma, myocardial fibrosis, organ transplant fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the liver and gallbladder, splenic fibrosis, scleroderma, pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial pneumonia, and / or chronic myelopathy. Interstitial lung disease, acute interstitial pneumonia, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes mellitus, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis fibrosis), complications of surgery, fibrotic chronic allograft vasculopathy and / or chronic rejection of transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibrotic proliferative lesions of the oral cavity, fibrosing intestinal stenosis, Crohn's disease, glial scarring, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components.

[0104] As used herein, "fibrosis" refers to the abnormal deposition of extracellular matrix proteins. Such proteins include, but are not limited to, collagen, elastin, fibronectin, laminin, keratin, keratin sulfate, fibrin, perlecan, agrin, or aggrecan. As used herein, "collagen" refers to any one of the collagen subtypes, including, but not limited to, types I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, or XVIII. Exemplary collagen types and subtypes include, among others, types I, Ia, II, III, IV, and V. As used herein, fibrosis can occur by itself or as a symptom or sequela of another condition. As used herein, fibrosis may be caused by a genetic condition, a genetic predisposition, an environmental insult, an injury, injury recovery, an autoimmune condition, or another condition that leads to chronic inflammation, a chronic inflammatory condition, or an abnormal or excessive deposition of extracellular matrix components. Fibrosis, as referred to herein, may be assessed by assaying for or determining the presence or level of one or more biomarkers. Biomarkers of the presence of fibrosis include, but are not limited to, expression of Col1a1, Col3a1, ACTA2, ENPP2, and / or LGALS1 genes, or any combination or product thereof. Diagnosis or assessment of fibrosis may further be made by determining the presence or level of type I collagen and / or hydroxyproline, or any combination or product thereof. Diagnosis or assessment of fibrosis may be made by histological, histochemical, or immunohistochemical analysis of one or more samples from a subject.

[0105] "Glycogen storage disease" means any one or more of a group of disorders characterized by a malfunction in the synthesis, transport, or utilization of glycogen, generally due to the loss of a necessary enzymatic activity. Glycogen storage diseases are generally classified into types according to their symptoms and etiology. The known types are GSD type 0 (non-gluconeogenic, glycogen synthase deficiency); GSD type 1 (von Gierke disease, glucose-6-phosphatase transferase / transporter deficiency, GSD I); GSD type 2 (Pompe disease, alpha-1-4-glucosidase deficiency, GSD II); GSD type 3 (Cohri disease, Forbes disease, limit dextrin formation, debranching enzyme disease; amylo-1-6-glucosidase deficiency due to loss of glucosidase and / or transferase activity, GSD III); GSD type 4 (Andersen disease, glycogen phosphorylase deficiency, Brancher deficiency, amylopectinosis, glycogen debranching enzyme deficiency; amylo-1,4 to 1,6 transglucosidase deficiency, GSD IV); GSD type 5 (McArdle disease, glycogen phosphorylase (muscle type) deficiency, GSD V); GSD GSD type 6 (Haas disease; glycogen phosphorylase E (liver type) deficiency, GSD VI); GSD type 7 (Tarui disease; phosphofructokinase deficiency, GSD VII); GSD types 8, 9 (GSD with phosphorylase activation system defect; phosphorylase kinase (liver or muscle isoform) deficiency, GSD VIII and GSD IX); GSD type 10 (cyclic AMP-dependent kinase deficiency, GSD X); GSD type 11 (Fanconi-Bickel syndrome; glucose transporter type 2 (GLUT2) deficiency, GSD XI); and GSD type 12 (aldolase A deficiency, GSD XII). Subtypes of glycogen storage diseases are also known, in particular GSD 1a, which is caused by a mutation in the gene for glucose-6-phosphatase (G6PC) and leads to excessive accumulation of glycogen and lipids in liver tissue, hepatomegaly, hepatic adenomas and hepatocellular carcinoma, among other symptoms. Symptoms of glycogen storage diseases can include elevated or decreased blood glucose levels, insulin insensitivity, myopathy, and hepatic manifestations such as steatosis, hyperlipidemia, hypercholesterolemia, cardiac hypertrophy, hepatomegaly, fibrosis, cirrhosis, hepatocellular adenoma, and hepatocellular carcinoma.Symptoms may also include insulin insensitivity, elevated or depressed blood glucose, renal insufficiency and / or fibrosis.

[0106] As used herein, "inflammatory disease" refers to a disease or disorder characterized by inflammation. Exemplary inflammatory diseases include acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, uterine Cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis , enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, dyslipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiac hypertrophy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, Keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, nonalcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris vularis), pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonia, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal phlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis and vulvitis.Inflammation, as referred to herein, may be assessed by assaying for or determining the presence or level of one or more biomarkers. Biomarkers of the presence of inflammation include, but are not limited to, expression of the TNF, CARD15, IL4R, IL23R, CTLA4, ANXA1, ANXA2, LGALS3 and / or PTPN22 genes or any combination or product thereof.

[0107] The term "atherosclerosis" refers to a condition characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries, which promote fibrosis and calcification. Atherosclerosis increases the risk of angina, stroke, heart attack, or other cardiac or cardiovascular conditions.

[0108] "Subject in need thereof" means a subject identified as in need of therapy or treatment.

[0109] A therapeutic effect alleviates to some extent one or more of the symptoms of a disease or disorder, including curing the disease or disorder. "Cure" means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure has been achieved (such as extensive tissue damage).

[0110] "Treat", "treatment" or "treating" as used herein refers to administering a pharmaceutical composition for preventative and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a patient who is susceptible to or otherwise at risk of a particular disease or disorder, but who does not already have the relevant disease or disorder, whereby the treatment reduces the likelihood that the patient will develop the disease or disorder. The term "therapeutic treatment" refers to administering treatment to a patient who already has a disease or disorder.

[0111] "Preventing" or "prevention" refers to delaying or forestalling the onset, development or progression of a condition or disease for a period of time, including weeks, months, or years.

[0112] "Amelioration" refers to a reduction in the severity of at least one indicator of a condition or disease. In certain embodiments, improvement includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of an indicator may be determined by subjective or objective measures known to those skilled in the art.

[0113] "Modulation" refers to the adjustment of a function or activity. In certain embodiments, modulation refers to an increase in gene expression. In certain embodiments, modulation refers to a decrease in gene expression. In certain embodiments, modulation refers to an increase or decrease in the total serum level of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the free serum level of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the total serum level of a specific non-protein factor. In certain embodiments, modulation refers to an increase or decrease in the free serum level of a specific non-protein factor. In certain embodiments, modulation refers to an increase or decrease in the total bioavailability of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the total bioavailability of a specific non-protein factor.

[0114] "Administering" means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administration by a medical professional and self-administration.

[0115] The term "agent" includes any substance, molecule, element, compound, entity, or combination thereof, including, but not limited to, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. An agent can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0116] "Pharmaceutical agent" means a substance that provides a therapeutic effect when administered to a subject.

[0117] "Pharmaceutical composition" refers to a mixture of substances containing a pharmaceutical agent suitable for administration to an individual. For example, a pharmaceutical composition may comprise a modified oligonucleotide and a sterile aqueous solution.

[0118] "Solvate" refers to a compound, its metabolite, or a salt formed by the interaction of a solvent and EPI. Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0119] Pharmaceutical Compositions Compound 1 and compound 1-A as well as their crystalline forms described herein can be formulated into pharmaceutical compositions for use in treating the conditions described herein. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington, The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), which is incorporated herein by reference in its entirety. Thus, some embodiments include pharmaceutical compositions comprising (a) a safe and therapeutically effective amount of a compound as described herein or a pharma-ceutically acceptable salt thereof, and (b) a pharma-ceutically acceptable carrier, diluent, excipient, or combination thereof.

[0120] In some embodiments, the crystalline forms of Compound 1 and Compound 1-A described herein may be formulated into a single pharmaceutical composition for use in treating the conditions described herein. In some embodiments, formulations comprising Compound 1 and / or Compound 1-A and their crystalline forms described herein may be administered in combination with one or more second pharmaceutical agents.

[0121] In some embodiments, compound 1 and / or compound 1-A and their crystalline forms described herein may be dissolved in a solvent prior to administration to a subject in need thereof.

[0122] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, diluents, emulsifiers, binders, buffers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, or any other such compounds known to those skilled in the art to be useful in preparing pharmaceutical formulations. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the composition. In addition, various adjuvants, such as those commonly used in the art, may be included. These and other such compounds are described in the literature, for example, in the Merck Index, Merck & Company, Rahway, NJ. Discussions of the inclusion of various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press.

[0123] Some examples of substances that can serve as pharma- ceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEEN®; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0124] The choice of a pharma- ceutically acceptable carrier to be used in conjunction with the subject compounds is determined by the manner in which the compound is to be administered.

[0125] The compositions described herein are preferably provided in unit dosage forms. As used herein, a "unit dosage form" is a composition containing an amount of a compound suitable for administration to a subject in a single dose according to medical practice standards. However, the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of treatment. A unit dosage form may include a single daily dose or divided subdoses, where several unit dosage forms would be administered throughout the day to complete a daily dose. According to the present disclosure, unit dosage forms may be given more or less frequently than once per day and may be administered more than once during a course of treatment. Such dosage forms may be administered in any manner consistent with their formulation, such as orally, parenterally, or over a period of time (e.g., from about 30 minutes to about 2-6 hours) as an infusion. Although single doses are specifically contemplated, compositions administered according to the methods described herein may also be administered as a continuous infusion or via an implantable infusion pump.

[0126] The methods as described herein may utilize any of a variety of forms suitable for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parental routes of administration. Those skilled in the art will appreciate that oral and nasal compositions include compositions administered by inhalation and made using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optional pharmaceutically active materials may be included that do not substantially interfere with the activity of the compound. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker and Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0127] A variety of oral dosage forms may be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets may be compressed, triturated tablets, enteric coated, sugar coated, film coated, or multiple compressed, containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings, as well as effervescent preparations reconstituted from effervescent granules.

[0128] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharma- ceutically compatible adjuvants such as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders, such as starch, gelatin and sucrose; disintegrants, such as starch, alginic acid and croscarmelose; lubricants, such as magnesium stearate, stearic acid, microcrystalline cellulose, carboxymethylcellulose and talc. Tablets may also contain solubilizers or emulsifiers, such as poloxamer, cremophor / Kolliphor® / Lutrol®, methylcellulose, hydroxypropylmethylcellulose, or others known in the art. Glidants, such as silicon dioxide, can be used to improve the flow characteristics of powder mixtures. Colorants, such as FD&C dyes, can be added for appearance. Sweeteners and flavorings, such as aspartame, saccharin, menthol, peppermint and fruit flavorings, are useful adjuvants for chewable tablets.Capsules typically contain one or more solid diluents as disclosed above.The selection of carrier components is determined by secondary considerations such as taste, cost and storage stability, which can be easily made by those skilled in the art.

[0129] Oral (PO) compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweeteners, flavorings and colorings disclosed above.

[0130] Such compositions may be coated by conventional methods, typically with a pH or time dependent coating, so that the subject compound is released in the vicinity of the desired local application in the gastrointestinal tract or at various times to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0131] The compositions described herein may optionally include other pharmacoactive agents.

[0132] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms.Such compositions typically include one or more of soluble filler materials such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.The glidants, lubricants, sweeteners, colorants, antioxidants and flavorings disclosed above may also be included.

[0133] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered locally to the eye. Comfort can be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may not require optimal comfort. If comfort cannot be maximized, liquids can be formulated so that topical ophthalmic use is tolerated by patients. In addition, ophthalmically acceptable liquids can be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0134] In ophthalmic applications, solutions or medicaments are often prepared using saline as the main vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system. The formulation may also contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0135] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.Useful surfactants are, for example, Tween 80®.Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein.These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0136] Tonicity adjusters may be added as needed or for convenience, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0137] Various buffers and means for adjusting pH may be used, so long as the resulting preparation is ophthalmically acceptable. In many compositions, the pH will be between 4 and 9. Buffers thus include acetate buffers, citrate buffers, phosphate buffers and borate buffers. The pH of these formulations can be adjusted as needed using acids or bases.

[0138] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0139] Another vehicle component that may be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may be used instead or in conjunction therewith.

[0140] For topical use, including transdermal administration, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0141] For intravenous administration, Compound 1 and / or Compound 1-A and their crystalline forms and compositions thereof described herein may be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid, may be included to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Additional acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J. Pharm. Sci. Tech. 2011, 65 287-332, both of which are incorporated herein by reference in their entireties. Antimicrobial agents, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol, may be included to achieve a bacteriostatic or fungistatic solution.

[0142] Compositions for intravenous administration may be provided to the caregiver in one or more solid forms that are reconstituted immediately prior to administration with a suitable diluent, such as sterile water, saline, or dextrose in water. In other embodiments, the compositions are provided in a liquid formulation that can be administered parenterally as is. In yet other embodiments, the compositions are provided in a liquid formulation that is further diluted prior to administration. In embodiments involving administration of a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0143] The actual unit dose of Compound 1 and / or Compound 1-A and their crystalline forms described herein depends on the specific compound and on the condition to be treated. In some embodiments, the dose may be from about 0.01 mg to about 120 mg or more per kg of body weight, from about 0.05 mg or less to about 70 mg per kg of body weight, from about 0.1 mg to about 50 mg per kg of body weight, from about 1.0 mg to about 10 mg per kg of body weight, from about 5.0 mg to about 10 mg per kg of body weight, or from about 10.0 mg to about 20.0 mg per kg of body weight. In some embodiments, the dose may be less than 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 25 mg, 20 mg, 10 mg, 7.5 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2.5 mg, 1 mg, 0.5 mg, 0.1 mg, 0.05 mg, or 0.005 mg per kg of body weight. In some embodiments, the actual unit dose is 0.05, 0.07, 0.1, 0.3, 1.0, 3.0, 5.0, 10.0, or 25.0 mg per kg of body weight. Thus, for administration to a 70 kg person, the dosage range is from about 0.1 mg to about 70 mg, from about 1 mg to about 50 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 10 mg, from about 2.5 mg to about 30 mg, from about 35 mg or less to about 700 mg or more, from about 7 mg to about 600 mg, from about 10 mg to about 500 mg, or from about 20 mg to about 300 mg, or from about 200 mg to about 2000 mg. In some embodiments, the actual unit dose is 0.1 mg. In some embodiments, the actual unit dose is 0.5 mg. In some embodiments, the actual unit dose is 1 mg. In some embodiments, the actual unit dose is 1.5 mg. In some embodiments, the actual unit dose is 2 mg. In some embodiments, the actual unit dose is 2.5 mg. In some embodiments, the actual unit dose is 3 mg. In some embodiments, the actual unit dose is 3.5 mg. In some embodiments, the actual unit dose is 4 mg. In some embodiments, the actual unit dose is 4.5 mg. In some embodiments, the actual unit dose is 5 mg. In some embodiments, the actual unit dose is 10 mg.In some embodiments, the actual unit dose is 25 mg. In some embodiments, the actual unit dose is 250 mg or less. In some embodiments, the actual unit dose is 100 mg or less. In some embodiments, the actual unit dose is 70 mg or less.

[0144] In some embodiments, Compound 1 and / or Compound 1-A and their crystalline forms described herein are administered to a subject having a body surface area of ​​1 m 2 In some embodiments, Compound 1 and / or Compound 1-A and their crystalline forms described herein are administered at a dose ranging from about 1 to 50 mg per m of body surface area. 2Approximately 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-13.75, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1 .5~2, 1.5~3, 1.5~4, 1.5~5, 1.5~6, 1.5~7, 1.5~8, 1.5~9, 1.5~10, 1.5~11, 1.5~12, 1.5~13, 1.5~13.75, 1.5~14, 1.5~15, 1.5~16, 1.5~17, 1.5~18, 1.5~ 19, 1.5~20, 1.5~22.5, 1.5~25, 1.5~27.5, 1.5~30, 2.5~2, 2.5~3, 2.5~4, 2.5~5, 2.5~6, 2.5~7, 2.5~8, 2.5~9, 2.5~10, 2.5~11, 2.5~12, 2.5~13, 2.5~13 .75, 2.5~14, 2.5~15, 2.5~16, 2.5~17, 2.5~18, 2.5~19, 2.5~20, 2.5~22.5, 2.5~25, 2.5~27.5, 2.5~30, 2.5~7.5, 3~4, 3~5, 3~6, ​​3~7, 3~8, 3~9, 3~10, 3~1 1, 3~12, 3~13, 3~13.75, 3~14, 3~15, 3~16, 3~17, 3~18, 3~19, 3~20, 3~22.5, 3~25, 3~27.5, 3~30, 3.5~6.5, 3.5~13.75, 3.5~15, 2.5~17.5, 4~5, 4~6, 4~7 , 4~8, 4~9, 4~10, 4~11, 4~12, 4~13, 4~13.75, 4~14, 4~15, 4~16, 4~17, 4~18, 4~19, 4~20, 4~22.5, 4~25, 4~27.5, 4~30, 5~6, 5~7, 5~8, 5~9, 5~10, 5~11, 5~1 2, 5~13, 5~13.75, 5~14, 5~15, 5~16, 5~17, 5~18, 5~19, 5~20, 5~22.5, 5~25, 5~27.5, 5~30, 6~7, 6~8, 6~9, 6~10, 6~11, 6~12, 6~13, 6~13.75, 6~14, 6~15, 6~16, 6~17, 6~18, 6~19, 6~20, 6~22.5, 6~25, 6~27.5, 6~30, 7~8, 7~9, 7~10, 7~11, 7~12, 7~13, 7~13.75, 7~14, 7~15, 7~16, 7~17, 7~18, 7~19, 7~20, 7~22.5, 7~25, 7~27.5, 7~30, 7.5~12.5, 7.5~13.5, 7.5~15, 8~9, 8~10, 8~11, 8~12, 8~13, 8~13.75, 8~14, 8~15, 8~16, 8~17, 8~18, 8~19, 8~20, 8~22.5, 8~25, 8~27.5, 8~30, 9~10, 9~11, 9~12, 9~13, 9~13.75, 9~14, 9~15, 9~16, 9~17, 9~18, 9~19, 9~20, 9~22.5, 9~25, 9~27.5, 9~30, 10~11, 10~12, It may be administered at a dose within the range of 10 to 13, 10 to 13.75, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 22.5, 10 to 25, 10 to 27.5, 10 to 30, 11.5 to 15.5, 12.5 to 14.5, 7.5 to 22.5, 8.5 to 32.5, 9.5 to 15.5, 15.5 to 24.5, 5 to 35, 17.5 to 22.5, 22.5 to 32.5, 25 to 35, 25.5 to 24.5, 27.5 to 32.5, 2 to 20, 2.5 to 22.5, or 9.5 to 21.5 mg. In some embodiments, Compound 1 and / or Compound 1-A and their crystalline forms described herein are administered to a patient with a body surface area of ​​1 m. 2 Approximately 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19 , 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg. In some embodiments, Compound 1 and Compound 1-A and their crystalline forms described herein may be administered at a dose of 1 mg / mL of body surface area. 2Approximately 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, In some embodiments, Compound 1 and / or Compound 1-A and their crystalline forms described herein may be administered at a dose of less than 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg per m2 of body surface area. 2 Approximately 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 22 1.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg.

[0145] In some embodiments, the dosage of Compound 1 and / or Compound 1-A and crystalline forms thereof described herein may be about 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 0.5 mg to 100 mg, 0.5 mg to 50 mg, 0.5 mg to 20 mg, 0.5 mg to 10 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 20 mg, 1 mg to 10 mg, 2.5 mg to 50 mg, 2.5 mg to 20 mg, 2.5 mg to 10 mg, or about 2.5 mg to 5 mg. In some embodiments, the dose of Compound 1 and / or Compound 1-A and crystalline forms thereof described herein may be about 5 mg to 300 mg, 5 mg to 200 mg, 7.5 mg to 200 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 30 mg to 100 mg, 40 mg to 100 mg, 10 mg to 80 mg, 15 mg to 80 mg, 20 mg to 80 mg, 30 mg to 80 mg, 40 mg to 80 mg, 10 mg to 60 mg, 15 mg to 60 mg, 20 mg to 60 mg, 30 mg to 60 mg, or about 40 mg to 60 mg. In some embodiments, the dose of Compound 1 and / or Compound 1-A and crystalline forms thereof described herein may be about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the dose of the crystalline forms of Compound 1 and Compound 1-A described herein is about 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg, 5 mg to 28 mg, 5 mg to 30 mg, 5 mg to 32 mg, 5 mg to 34 mg, 5 mg to 36 mg, 5 mg to 38 mg, 5mg~40mg, 5mg~42mg, 5mg~44mg, 5mg~46mg, 5mg~48mg, 5mg~50mg, 5mg~52mg, 5mg~54mg, 5mg~56mg, 5mg~58mg, 5mg~60mg, 7mg~ 7.7mg, 7mg~9mg, 7mg~10mg, 7mg~12mg, 7mg~14mg, 7mg~15mg, 7mg~16mg, 7mg~18mg, 7mg~20mg, 7mg~22mg, 7mg~24mg, 7mg~26mg,7mg~28mg、7mg~30mg、7mg~32mg、7mg~34mg、7mg~36mg、7mg~38mg、7mg~40mg、7mg~42mg、7mg~44mg、7mg~46mg、7mg~48mg、7mg~50mg、7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~42mg、9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~16mg、10mg~18mg、10mg~20mg、10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg, 27mg~44mg, 27mg~46mg, 27mg~48mg, 27mg~50mg, 27mg~52mg, 27mg~54mg, 27mg~56mg, 27mg~58mg, 27mg~60mg, 30mg~32mg, 30mg ~34mg, 30mg~36mg, 30mg~38mg, 30mg~40mg, 30mg~42mg, 30mg~44mg, 30mg~46mg, 30mg~48mg, 30mg~50mg, 30mg~52mg, 30mg~54mg, 30mg~56mg , 30mg~58mg, 30mg~60mg, 33mg~34mg, 33mg~36mg, 33mg~38mg, 33mg~40mg, 33mg~42mg, 33mg~44mg, 33mg~46mg, 33mg~48mg, 33mg~50mg, 33m g~52mg, 33mg~54mg, 33mg~56mg, 33mg~58mg, 33mg~60mg, 36mg~38mg, 36mg~40mg, 36mg~42mg, 36mg~44mg, 36mg~46mg, 36mg~48mg, 36mg~50m g, 36mg~52mg, 36mg~54mg, 36mg~56mg, 36mg~58mg, 36mg~60mg, 40mg~42mg, 40mg~44mg, 40mg~46mg, 40mg~48mg, 40mg~50mg, 40mg~52mg, 40 mg~54mg, 40mg~56mg, 40mg~58mg, 40mg~60mg, 43mg~46mg, 43mg~48mg, 43mg~50mg, 43mg~52mg, 43mg~54mg, 43mg~56mg, 43mg~58mg, 42mg~60 In some embodiments, the dose of Compound 1 and / or Compound 1-A and crystalline forms thereof described herein may be about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 14.5 mg, about 15.5 mg, about 16.5 mg, about 17.5 mg, about 18.5 mg, about 20 mg, about 22.5 mg, about 24.5 mg, about 25 mg, about 26.5 mg, about 27.5 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 ...It may be greater than about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the dose of Compound 1 and / or Compound 1-A and their crystalline forms described herein may be less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the dose of Compound 1 and / or Compound 1-A and their crystalline forms described herein may be about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[0146] Compound 1 and / or Compound 1-A as well as their crystalline forms described herein may be incorporated into formulations for delivery outside the systemic circulation. Such formulations may include enteric coated capsules, tablets, soft gels, spray-dried powders, polymer matrices, hydrogels, enteric coated solids, crystalline solids, amorphous solids, glassy solids, coated micronized particles, liquids, atomized liquids, aerosols, or microcapsules.

[0147] Method of administration The above-mentioned compositions may be administered via any suitable route of administration, for example, by injection, such as subcutaneously, intramuscularly, intraperitoneally, intravenously or intraarterially; topically, such as by cream, lotion or patch; orally, such as by pill, dissolved liquid, oral suspension, oral film or mouthwash; intranasally, such as by nasal aerosol, powder or spray; or ophthalmically, such as by eye drops. In some embodiments, the composition may be administered once, twice, three or four times a day. In other embodiments, the composition may be administered once, twice or three times a week. In other embodiments, the composition is administered every other day, every third day or every fourth day. In other embodiments, the composition is administered every other week, every three weeks or every four weeks. In other embodiments, the composition is administered once a month or twice a month.

[0148] In some embodiments, Compound 1 and / or Compound 1-A and their crystalline forms described herein may be administered simultaneously with one or more second pharmaceutical agents. In other embodiments, Compound 1 and / or Compound 1-A and their crystalline forms described herein may be administered sequentially with one or more second pharmaceutical agents.

[0149] Treatment Some embodiments according to the methods and compositions of the present disclosure are methods for preventing, treating or ameliorating one or more fatty liver diseases or disorders in a subject, comprising administering an effective amount of compound 1 and / or compound 1-A as described herein and their crystalline forms to a subject in need thereof. In some embodiments, the disease or disorder may be fatty liver disease. In some embodiments, the fatty liver disease may be steatosis. In other embodiments, the fatty liver disease may be non-alcoholic fatty liver disease. In some embodiments, the fatty liver disease may be non-alcoholic steatohepatitis (NASH). In some embodiments, the subject may have two or more of the above fatty liver diseases.

[0150] Some embodiments according to the methods and compositions of the present disclosure relate to a method for the reduction or prevention of deposition of an extracellular matrix protein comprising administering to a subject in need thereof an effective amount of Compound 1 and / or Compound 1-A as described herein and crystalline forms thereof. In some embodiments, the deposition of an extracellular matrix protein may comprise abnormal or excessive deposition of the protein. In some embodiments, the extracellular matrix protein may comprise one or more of collagen, keratin, elastin, or fibrin. In some embodiments, the extracellular matrix protein may comprise collagen. In some embodiments, the extracellular matrix protein may comprise type I collagen. In some embodiments, the extracellular matrix protein may comprise type Ia collagen. In some embodiments, the extracellular matrix protein may comprise type III collagen. Some embodiments according to the compositions and methods of the present disclosure relate to a method for the treatment of fibrosis or a symptom or sequelae thereof comprising administering to a subject in need thereof an effective amount of Compound 1 and / or Compound 1-A as described herein and crystalline forms thereof.

[0151] In some embodiments, the compounds and compositions described herein, Compound 1 and / or Compound 1-A and their crystalline forms can be used in a method of preventing, treating or ameliorating one or more diseases or disorders in a subject, comprising administering a compound disclosed herein or a pharma- ceutically acceptable salt thereof to a subject in need thereof.In some embodiments, the disease or disorder can be liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis.In some embodiments, the disease or disorder can be nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis or primary biliary cirrhosis.

[0152] In some embodiments, compounds and compositions comprising crystalline forms of Compound 1 and / or Compound 1-A described herein can be used to treat a variety of conditions, including those caused by fibrosis or inflammation, specifically those associated with abnormal collagen deposition. Exemplary conditions include glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), nonalcoholic steatohepatitis (NASH), liver cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, liver and gallbladder cirrhosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis. , interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonia, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, jaundice macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, complications of surgery, fibrotic chronic allograft vasculopathy and / or chronic rejection of transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibrotic proliferative lesions of the oral cavity, fibrosing intestinal stenosis, Crohn's disease, glial scarring, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components such as collagen.

[0153] In some embodiments, the disclosed methods include methods for the treatment, amelioration, or prevention of a fibrotic condition. In some embodiments, the fibrotic condition may be secondary to another condition. In some embodiments, the fibrotic condition or primary condition may further include chronic inflammation of an organ, tissue, spatial region, or fluid-connected area of ​​a subject's body. In some embodiments, the inflammation may include activation of one or more TGF-beta dependent signaling pathways. In some embodiments, the TGF-β dependent signaling pathways may include one or more elements responsive to T3 or T4. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of one or more of collagen, keratin, or elastin. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of collagen. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of type I collagen. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of type Ia collagen. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of type III collagen.In some embodiments, the fibrotic condition is Glycogen Storage Disease Type III (GSD III), Glycogen Storage Disease Type VI (GSD VI), Glycogen Storage Disease Type IX (GSD IX), nonalcoholic steatohepatitis (NASH), cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ transplant fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the liver and gallbladder, splenic fibrosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonia, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardium The conditions may include one or more of the following: fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, complications of surgery, fibrotic chronic allograft vasculopathy and / or chronic rejection of transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibrotic proliferative lesions of the oral cavity, fibrosing intestinal strictures, Crohn's disease, glial scarring, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis. In some embodiments, the fibrotic condition may include one or more of GSD III, GSD IX, non-alcoholic steatohepatitis, cirrhosis of the liver and / or pancreas, scleroderma, idiopathic pulmonary fibrosis, psoriasis, alcoholic fatty liver disease, Dupuytren's disease, and / or any combination thereof.

[0154] According to the methods and compositions of the present disclosure, the crystalline forms of Compound 1 and Compound 1-A described herein may be administered to a subject to treat, ameliorate, prevent or cure a fibrotic condition or a condition in which fibrosis is a symptom or sequelae. According to the methods and compositions as disclosed herein, the fibrotic condition or a condition in which fibrosis is a sequelae may further comprise chronic inflammation. According to the methods and compositions as disclosed herein, the fibrotic condition or a condition in which fibrosis is a sequelae may further comprise activation of one or more TGF-β-dependent signaling pathways. According to the methods and compositions as disclosed herein, the fibrotic condition or a condition in which fibrosis is a sequelae may further comprise activation and / or inhibition of one or more thyroid receptor beta (TRβ)-dependent signaling pathways. According to the methods and compositions as disclosed herein, the fibrotic condition or condition having fibrosis as a sequelae may further include the involvement of a signaling pathway responsive to triiodothyronine (T3), thyroxine (T4), any combination thereof, or a mimetic thereof. According to the methods and compositions as disclosed herein, the fibrotic condition or condition having fibrosis as a sequelae may further include the involvement of a receptor responsive to T3, T4, any combination thereof, or a mimetic thereof. In some embodiments according to the methods and compositions as disclosed herein, the fibrotic condition or condition having fibrosis as a sequelae may include the involvement of TRβ. In some embodiments according to the methods and compositions as disclosed herein, the fibrotic condition or condition having fibrosis as a sequelae may include one or more conditions that are prevented, ameliorated, or cured by administration of one or more agonists of TRβ. In some embodiments according to the methods and compositions disclosed herein, the fibrotic condition or condition having fibrosis as a sequela may include one or more conditions that are prevented, ameliorated or cured by administration of one or more of the compounds described herein. In some embodiments, the compounds disclosed herein may be co-administered with one or more excipients. In some embodiments, the compounds disclosed herein may be administered before, during or after surgical intervention, phototherapy or ultrasound therapy.

[0155] In some embodiments, the compositions and methods described herein provide compositions and methods for the treatment, amelioration, prevention or cure of collagen deposition. In some embodiments, the collagen deposition comprises abnormal or excessive deposition of collagen. In some embodiments, the collagen deposition may comprise abnormal or excessive deposition of type I collagen. In some embodiments, the collagen deposition may comprise abnormal or excessive deposition of type Ia collagen. In some embodiments, the collagen deposition may comprise abnormal or excessive deposition of type III collagen. According to the methods and compositions as disclosed herein, the collagen deposition may further comprise the involvement of a receptor responsive to T3, T4, any combination thereof, or a mimetic thereof. In some embodiments according to the methods and compositions disclosed herein, the collagen deposition may comprise the involvement of TRβ. In some embodiments according to the methods and compositions disclosed herein, the collagen deposition may be prevented, ameliorated or cured by administration of one or more agonists of TRβ. In some embodiments according to the methods and compositions disclosed herein, the collagen deposition may be prevented, ameliorated or cured by administration of one or more crystalline forms of Compound 1 and / or Compound 1-A. In some embodiments, the one or more crystalline forms of Compound 1 and Compound 1-A may be co-administered with one or more excipients. In some embodiments, the one or more crystalline forms of Compound 1 and / or Compound 1-A may be administered before, during or after surgical intervention, phototherapy or ultrasound therapy.

[0156] In some embodiments, administration of Compound 1 and / or Compound 1-A and their crystalline forms or compositions comprising Compound 1 and / or Compound 1-A and their crystalline forms as described herein results in a reduction in the expression of Cola1, Col3a1, αSMA and / or Galectin 1 genes or any combination or product thereof in a subject to whom the combination is administered, as disclosed herein. In some embodiments, administration of one or more crystalline forms of Compound 1 and / or Compound 1-A results in a reduction in the degree of fibrosis observable by histology, histochemistry, immunohistochemistry, etc., and / or a reduction in the amount, accumulation or distribution of type 1 collagen and / or hydroxyproline or any combination thereof in a subject to whom the combination is administered. In some embodiments, administration of one or more crystalline forms of Compound 1 and / or Compound 1-A results in a reduction in total serum lipids, total serum cholesterol, total serum triglycerides, total liver lipids, total liver cholesterol, total liver triglycerides, or any combination thereof. EXAMPLES

[0157] Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0158] X-ray powder diffraction (XRPD) A Rigaku Smart Lab X-ray diffractometer was configured for reflected Bragg-Brentano geometry using a line source X-ray beam. The X-ray source was a Cu Long Fine Focus tube operated at 40 kV and 44 ma. This source provides an incident beam profile that changes from a high angle thin line to a low angle wide rectangle at the sample. Beam conditioning slits are used in the line source to ensure that the maximum beam size is less than 10 mm both along the line and perpendicular to the line. The Bragg-Brentano geometry is a parafocusing geometry controlled by passive divergence and receiving slits, with the sample itself acting as the focusing component for the optics. The intrinsic resolution of the Bragg-Brentano geometry depends in part on the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart Lab is operated to give peak widths of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by 5.0° Soller slits in both the incident and diffracted beam paths.

[0159] Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surface flat and parallel to the reference plane of the sample holder. Each sample was analyzed from 2 to 40°2θ using a continuous scan of 6°2θ per minute with an effective step size of 0.02°2θ.

[0160] Thermogravimetric analysis (TG) Thermogravimetric analysis was performed using a TA Instruments Q50 instrument. The instrument balance was calibrated using class M weights and temperature calibration was performed using Alumel. The nitrogen purge was approximately 40 ml per minute during equilibration and approximately 60 ml per minute in the furnace. Each sample was placed in a pre-tared platinum pan and heated from 20°C to 350°C at a rate of 10°C per minute.

[0161] Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) analyses were performed using a TA Instruments Q2000 instrument. Temperature calibration of the instrument was performed using indium. The DSC cell was kept under a nitrogen purge of approximately 50 ml per minute during each analysis. Samples were placed in standard crimped aluminum pans and heated from 25° C. to 350° C. at a rate of 10° C. per minute.

[0162] 1 H nuclear magnetic resonance (NMR) 1 H-NMR spectra were obtained on a Bruker Avance II 400 spectrometer. Samples were prepared by dissolving the material in DMSO-d6. The solutions were filtered and placed into individual 5 mm NMR tubes for subsequent spectral acquisition. Temperature-controlled (295 K) spectra were acquired on the Avance II 400. 1 H-NMR spectra were obtained using a 5 mm cryoprobe operating at an observation frequency of 400.18 MHz.

[0163] Karl Fischer (KF) analysis Karl Fischer analysis was performed using a Mettler-Toledo C20 coulometric KF titrator. The instrument was calibrated using Hydranal water standards containing 1% water. The titrant was Hydranal in methanol. Samples were analyzed in duplicate.

[0164] Dynamic Vapor Sorption (DVS) DVS analysis was performed using a TA Instruments Q5000 Dynamic Vapor Sorption Analyzer. The instrument was calibrated using standard weights and a sodium bromide standard for humidity. Approximately 10-25 mg of sample was loaded into a metal-coated quartz pan for analysis. Samples were analyzed at 25°C with a maximum equilibration time of 1 hour in 10% relative humidity (RH) steps from 5 to 95% RH (adsorption cycle) and from 95 to 5% RH (desorption cycle). Movement from one step to the next occurred either after satisfying an equilibrium criterion of 0.01% mass change or if the equilibrium criterion was not met after 1 hour. Mass percent change values ​​were calculated using Microsoft Excel.

[0165] Example 1 Polymorph screening experiments for compound 1 Polymorph screening experiments for Compound 1 were carried out under different conditions and using different solvents. To prepare polymorphic forms of Compound 1, one of the following crystallization methods was used.

[0166] Cooling Experiment: Approximately 20 mg of compound 1 was dissolved in a minimum amount of solvent at the specified temperature. In cases where solubility was very high, an anti-solvent was used to prevent the use of too much material. The solution was then allowed to cool to room temperature. If no solids were observed within a day, the sample was moved to a refrigerator (2-8°C). If no solids were observed after being in the refrigerator for 1-2 days, the sample was moved to a freezer (-25 to -10°C). If no solids were observed after being in the freezer for several days, the sample was removed and allowed to evaporate at room temperature.

[0167] Evaporation experiments: Approximately 20 mg of compound 1 was dissolved in a glass vial in minimal solvent at room temperature. The vial was left uncapped in a fume hood at ambient temperature and allowed to evaporate.

[0168] Grinding experiments: Approximately 20 mg of compound 1 was placed in a PEEK grinding cup with a stainless steel ball. The volume in the grinding cup was approximately 2 ml. In some cases, solvent (10 μl) was added. The cup was placed in a Retsch grinder at 100% power for 20 minutes. The resulting solid was analyzed by XRPD.

[0169] Flash Precipitation: Approximately 20 mg of compound 1 was dissolved in a glass vial in a minimum amount of solvent at the specified temperature. Approximately 5-10 volumes of cold anti-solvent were then added to the vial (from either the refrigerator or freezer). If no solids formed, the sample was placed in the freezer (-25 to -10°C) for several days. If no solids formed in the freezer, the sample was removed and allowed to evaporate at ambient temperature.

[0170] Anti-solvent precipitation: Approximately 20 mg of compound 1 was dissolved in a minimum amount of solvent at the specified temperature. Anti-solvent was then added slowly until a cloudy solution formed. The solution was allowed to stir overnight. If no solids had formed the next day, additional anti-solvent was added. This was repeated daily until either a solid had precipitated or approximately 5-10 volumes of anti-solvent had been added. If no solids had formed, the sample was placed in the freezer (-25 to -10°C) for several days. If no solids had formed in the freezer, the sample was removed and allowed to evaporate at room temperature.

[0171] Slurry: Approximately 20 mg of Compound 1 was placed in a vial and a solvent was added to prevent all of the solid from dissolving. The slurry was then magnetically stirred at the specified temperature. The solid was then collected by vacuum filtration.

[0172] The results of the polymorphism screening experiments are provided in Table 1.

[0173] [Table 1A]

[0174] [Table 1B]

[0175] [Table 1C]

[0176] [Table 1D]

[0177] Example 2 Competitive slurry experiments for compound 1 The solutions (approximately 2 ml) were saturated with Form A of Compound 1. Once saturated, they were centrifuged and the mother liquor was transferred to HPLC vials containing equal amounts (approximately 10 mg each) of Forms A, C, D, and E. The samples were then magnetically stirred for 3 days at the indicated temperatures. The solids were collected by vacuum filtration. The results of these slurries are presented below in Table 2. Form A was obtained from all of the experiments, indicating that it is the most stable form under the conditions tested.

[0178] [Table 2]

[0179] Example 3 Polymorph screening experiment for compound 1-A Polymorph screening experiments for the (2-methylamino)ethanol ("deanol") salt were performed by combining Compound 1 and deanol under various conditions and with various solvents. Several polymorphs were prepared as shown below. All of the crystalline salts exhibited a 1:1 stoichiometry of Compound 1:deanol. The results are provided in Table 3 below.

[0180] [Table 3A]

[0181] [Table 3B]

[0182] [Table 3C]

[0183] [Table 3D]

[0184] Example 4 Polymorph screening experiment for compound 1-A Compound 1-A Form 3 was mixed with various solvents under various conditions. Three polymorphs were identified as Forms 1, 2, and 3. All of the crystalline salts exhibited a 1:1 stoichiometry of Compound 1:deanol.

[0185] [Table 4]

[0186] Example 5 Preparation of Form 3 of Compound 1-A To a 500 ml Erlenmeyer flask, compound 1 (16.089 g) and 40 ml of acetone (containing 2.5% water) were added. The mixture was allowed to stir magnetically at room temperature until the solids dissolved. In a separate flask, 2-(dimethylamino)ethanol ("Deanol"; 1.05 equivalents, 3.650 g) was dissolved in 10 ml of acetone (containing 2.5% water). The Deanol solution was added to the compound 1 solution over 10 minutes. Solids began to precipitate after approximately 2 ml had been added, forming a thick slurry. An additional 150 ml of acetone (containing 2.5% water) was added to the compound 1 slurry to bring the total amount of solvent in the flask to 200 ml. The slurry was allowed to stir magnetically at room temperature overnight. The slurry was then vacuum filtered through Whatman filter paper. The recovered white solid was placed on weighing paper, broken up with a spatula, and allowed to air dry for 2 days. Compound 1 deanol salt (i.e., compound 1-A) (18.817 g, 93% yield) was recovered.

[0187] Example 6 Characterization of crystalline samples The crystalline solid forms were characterized by a combination of XRPD, thermogravimetric analysis (TG), DSC and / or solution NMR.

[0188] Crystalline Form A of Compound 1 XRPD results for crystalline form A (Figure 1) show good crystallinity. A melting temperature of approximately 161°C was observed using differential scanning calorimetry (Figure 2). Crystalline form A was moderately hygroscopic according to dynamic vapor sorption / desorption analysis (Figure 3).

[0189] XRPD measurements were performed on crystalline form A of Compound 1. The peaks observed are shown in Table 5. Prominent peaks are listed in Table 6.

[0190] [Table 5]

[0191] [Table 6]

[0192] Crystalline Form B of Compound 1 The XRPD results of crystalline form B (Figure 4) show poor crystallinity. Crystalline form B was obtained only during the IPA crushing experiment. Crystalline form B was determined to be a solvate of isopropyl alcohol.

[0193] XRPD measurements were performed on crystalline form B of Compound 1. The peaks observed are shown in Table 7. Prominent peaks are listed in Table 8.

[0194] [Table 7]

[0195] [Table 8]

[0196] Crystalline Form C of Compound 1 XRPD results for crystalline form C (Figure 5) indicate poor crystallinity. Using differential scanning calorimetry, an endotherm was observed at approximately 158°C (Figure 6), which likely represents the crystalline melting point. Crystalline form C became amorphous upon heating. Crystalline form C exhibited a 4.4% mass loss when run from 25°C to 110°C as measured by thermogravimetric analysis. However, the mass loss was found not to be due to the solvent.

[0197] XRPD measurements were performed on crystalline form C of Compound 1. The peaks observed are shown in Table 9. Prominent peaks are listed in Table 10.

[0198] [Table 9]

[0199] [Table 10]

[0200] Crystal form D of compound 1 XRPD results for crystalline form D (Figure 7) show good crystallinity. Using differential scanning calorimetry, a melting point of approximately 166°C was observed (Figure 8). Thermogravimetric analysis showed a mass loss of 3.875% when run from 25°C to 140°C, indicating a possible hydrate.

[0201] XRPD measurements were performed on crystalline form D of Compound 1. The peaks observed are shown in Table 11. Prominent peaks are listed in Table 12.

[0202] [Table 11]

[0203] [Table 12]

[0204] Crystal form E of compound 1 XRPD results for crystalline form E (Figure 9) show poor crystallinity. Endotherms at 96°C and 166°C were observed for crystalline form E by DSC (Figure 10). Crystalline form E exhibited a 2.5% mass loss when run from 25°C to 125°C, however, the mass loss was not attributable to the solvent.

[0205] XRPD measurements were performed on crystalline form E of Compound 1. The peaks observed are shown in Table 13. Prominent peaks are listed in Table 14.

[0206] [Table 13]

[0207] [Table 14]

[0208] Crystal Form F of Compound 1 XRPD results for crystalline form F (Figure 11). Crystalline form B was only obtained during the DMF evaporation experiment and was determined to be a dimethylformamide solvate. DSC results show an endotherm at 96°C for crystalline form F (Figure 12).

[0209] XRPD measurements were performed on crystalline form F of Compound 1. The peaks observed are shown in Table 15. Prominent peaks are listed in Table 16.

[0210] [Table 15]

[0211] [Table 16]

[0212] Crystalline Form 1 of Compound 1-A The XRPD results for crystalline form 1 (Figure 13) show good crystallinity. Using differential scanning calorimetry, a melting point of approximately 139°C was observed. Crystalline form A was moderately hygroscopic with a melting point of about 139°C.

[0213] XRPD measurements were performed on crystalline Form 1 of Compound 1-A. The peaks observed are shown in Table 17. Prominent peaks are listed in Table 18.

[0214] [Table 17]

[0215] [Table 18]

[0216] Crystalline Form 2 of Compound 1-A XRPD results for crystalline form 2 (Figure 14) show a degree of crystallinity. Crystalline form 2 was found to have a melting point of about 117°C and was determined to be moderately hygroscopic.

[0217] XRPD measurements were performed on crystalline Form 2 of Compound 1-A. The peaks observed are shown in Table 19. Prominent peaks are listed in Table 20.

[0218] [Table 19]

[0219] [Table 20]

[0220] Crystalline Form 3 of Compound 1-A XRPD results for crystalline form 3 (Figure 15) show good crystallinity. Using differential scanning calorimetry, a melting point of approximately 156°C was observed. Another endotherm was observed at about 107°C (Figure 16). Crystalline form 3 exhibited a mass loss of 3.85% when run from 25°C to 90°C and a mass loss of 2.09% when run from 90°C to 150°C. DVS data (not shown) shows negligible water uptake. Karl Fischer titration indicates that crystalline form 3 is a monohydrate.

[0221] XRPD measurements were performed on crystalline Form 3 of Compound 1-A. The peaks observed are shown in Table 21. Prominent peaks are listed in Table 22.

[0222] [Table 21]

[0223] [Table 22]

[0224] Crystalline Form 4 of Compound 1-A XRPD results for crystalline Form 4 are provided in Figure 17. Using differential scanning calorimetry, a melting point of approximately 114°C was observed (Figure 18). Crystalline Form 4 was moderately hygroscopic and non-solvated.

[0225] XRPD measurements were performed on crystalline Form 4 of Compound 1-A. The peaks observed are shown in Table 23. Prominent peaks are listed in Table 24.

[0226] [Table 23]

[0227] [Table 24]

[0228] Example 7 Equilibrium Aqueous Solubility Data for Compound 1 and Compound 1-A The equilibrium solubility of Compounds 1 and 1-A was measured in water at room temperature. A known volume of water was placed in a 1 dram glass vial and a mass aliquot of Compound 1 or Compound 1-A was added with magnetic stirring at room temperature. If the solid dissolved, another aliquot of solvent was added. The data is summarized below in Table 25.

[0229] [Table 25]

[0230] Example 8 Kinetic solubility studies of compound 1 and compound 1-A The kinetic solubility of Compound 1 was measured both in simulated gastric fluid (SGF) at a pH of about 1.2 and in water at 37° C. In SGF, the concentration was less than 1 μg / ml for up to 6 hours. The resulting solid was Form A. In water, a concentration of 0.3 mg / ml was achieved within 2 minutes, and after 6 hours the concentration was about 0.5 mg / ml.

[0231] Similarly, the kinetic solubility of Compound 1-A (Form 1) was measured both in SGF at a pH of about 1.2 and in water at 37° C. In SGF, the concentration was less than 1 μg / ml for up to 6 hours. The resulting solid was amorphous by XRPD. In water, a concentration of 2.3 mg / ml was achieved within 2 minutes, and after 6 hours the concentration was about 3.1 mg / ml. The resulting solid was found to be crystalline Form 3 of Compound 1-A.

[0232] [Table 26]

[0233] Although the above has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made thereto without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather are intended to cover all modifications and alternatives falling within the true scope and spirit of the present disclosure.

Claims

1. Crystalline form of Compound 1: 【Chemistry 1】 or a solvate thereof.

2. 2. The crystalline form of claim 1, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said at least three characteristic peaks are selected from the group consisting of 5.1, 7.4, 10.1, 12.1, 16.4, 17.3, 18.5, 20.5, 21.4, 21.7, 22.1, 23.8, 24.1, 25.5, and 25.9±0.2 degrees 2θ.

3. The crystalline form described in claim 2 having a melting point of 161°C.

4. 2. The crystalline form of claim 1, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of 7.5, 8.1, 10.0, 15.4, 16.7, 18.3, 18.8, 20.2, 21.0, 22.3, 24.1, 25.1, and 26.4±0.2 degrees 2θ.

5. 2. The crystalline form of claim 1, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, said at least three characteristic peaks being selected from the group consisting of 4.0, 8.0, 11.0, 12.0, 14.4, 14.6, 17.1, 18.5, 19.2, 21.1, 21.7, 24.9, and 25.7±0.2 degrees 2θ.

6. A crystalline form described in claim 5, which exhibits a DSC endotherm at 70°C or 158°C.

7. 2. The crystalline form of claim 1, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said at least three characteristic peaks are selected from the group consisting of 6.1, 7.6, 11.3, 12.2, 16.5, 17.0, 17.3, 18.4, 18.6, 19.5, 19.7, 20.7, 21.2, 22.5, 26.0, and 26.3±0.2 degrees 2θ.

8. The crystalline form of claim 7, which exhibits a DSC endotherm at 166°C.

9. 2. The crystalline form of claim 1, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of 3.3, 5.0, 7.5, 14.9, 16.3, 17.2, 19.4, 21.7, 24.7, 25.5, and 26.6±0.2 degrees 2θ.

10. The crystalline form of claim 9, which exhibits a DSC endotherm at 96°C or 166°C.

11. 2. The crystalline form of claim 1, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said at least three characteristic peaks are selected from the group consisting of 8.3, 15.5, 15.6, 15.9, 17.0, 17.3, 17.9, 18.6, 20.8, 22.0, 23.0, 23.6, 23.8, 25.5, 25.7, 26.0, and 26.7±0.2 degrees 2θ.

12. The crystalline form of claim 11, which exhibits a DSC endotherm at 96°C.

13. Crystalline form of compound 1-A: 【Chemistry 2】 or a solvate thereof.

14. 14. The crystalline form of claim 13, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said at least three characteristic peaks are selected from the group consisting of 6.0, 13.3, 14.4, 14.8, 16.1, 17.8, 17.9, 18.7, 20.5, 20.8, 21.7, 22.9, 23.8, 24.9, 25.1, and 26.6±0.2 degrees 2θ.

15. The crystalline form of claim 14 having a melting point of 156°C.

16. 14. The crystalline form of claim 13, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said at least three characteristic peaks are selected from the group consisting of 6.1, 12.2, 13.3, 13.6, 16.5, 17.3, 18.3, 19.9, 20.2, 20.5, 21.4, 21.9, 22.5, 22.8, 23.0, and 25.6±0.2 degrees 2θ.

17. The crystalline form of claim 16 having a melting point of 139°C.

18. 14. The crystalline form of claim 13, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, said at least three characteristic peaks being selected from the group consisting of 5.7, 6.2, 15.5, 16.4, 17.0, 18.5, 20.6, 21.2, 22.0, 23.3, and 26.1±0.2 degrees 2θ.

19. The crystalline form of claim 18 having a melting point of 117°C.

20. 14. The crystalline form of claim 13, exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks, said at least three characteristic peaks being selected from the group consisting of 6.2, 12.9, 14.0, 14.5, 16.5, 17.6, 18.0, 18.6, 20.3, 21.2, 22.7, 23.3, 24.0, and 26.1±0.2 degrees 2θ.

21. The crystalline form of claim 20 having a melting point of 114°C.

22. 21. The crystalline form of claim 20 which is a monohydrate.

23. 23. A pharmaceutical composition comprising a therapeutically effective amount of one or more crystalline forms of any one of claims 1 to 22 and one or more pharmaceutically acceptable excipients.

24. A composition for use in treating a disease or disorder in a subject, comprising the crystalline form of any one of claims 1 to 22, wherein the disease or disorder is selected from the group consisting of steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis and idiopathic fibrosis.

25. A composition for use according to claim 24, wherein said use results in the prevention, treatment or amelioration of fibrosis, a fibrotic condition or a fibrotic symptom.

26. A composition for use according to claim 24, wherein said use results in a reduction in the amount of extracellular matrix protein present in one or more tissues of said subject.

27. A composition for use according to claim 24, wherein said use results in a reduction in the amount of collagen present in one or more tissues of said subject.

28. 25. A composition for use according to claim 24, wherein said use results in a reduction in the amount of type I, type Ia or type III collagen present in one or more tissues of said subject.

29. A composition for use in treating a disease or disorder in a subject, comprising the crystalline form of any one of claims 1 to 22, said composition being prepared by dissolving the crystalline form of any one of claims 1 to 22 in a pharmaceutically acceptable solvent, and wherein the disease or disorder is selected from the group consisting of steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis and idiopathic fibrosis.

30. structure 【Transformation 3】 or a solvate thereof.

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