Polymorphic forms of autotaxin inhibitors

Abstract

Disclosed herein are autotaxin inhibitor compounds, polymorphic forms thereof, pharmaceutical compositions, and methods of use and preparation. Some embodiments relate to crystalline forms of Compound 1 and salts thereof. 【Chemical 1】 JPEG2025516335000046.jpg7689

Description

Technical Field

[0001] This application relates to the fields of chemistry and medicine. More particularly, this application relates to autotaxin inhibitors and salts, polymorphs, pharmaceutical compositions thereof, and their use as therapeutic agents.

Background Art

[0002] Autotaxin (ATX), also known as ectonucleotide pyrophosphatase / phosphodiesterase family member 2 or ENNP2, is a lysophospholipase D secreted by adipocytes that catalyzes the formation of the lipid mediator, lysophosphatidic acid (LPA). Autotaxin expression is enhanced in individuals with certain diseases or disorders.

[0003] Autotaxin inhibitors may be therapeutically useful for various fibrotic diseases and disorders, as well as diseases such as cancer. Accordingly, there is a need to provide autotaxin compounds having properties suitable for therapeutic use.

Summary of the Invention

[0004] In some embodiments, a crystalline form of a compound of formula (I):

[0005]

Chemical formula

[0006] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, and the characteristic peak is selected from the group consisting of approximately 7.2, 10.4, 12.0, 14.5, 17.9, 21.5, 21.8, 22.3, 23.5, 25.0, 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 degrees 2θ.

[0007] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, said characteristic peaks being selected from the group consisting of approximately 7.2, 10.4, 12.0, 14.5, 17.9, 21.5, 21.8, 22.3, 23.5, 25.0, 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 degrees 2θ.

[0008] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks characteristic of approximately 7.2, 10.4, 17.9, 21.5, 21.8, and 25.8 degrees 2θ.

[0009] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, said characteristic peak being selected from the group consisting of approximately 6.1, 7.1, 8.8, 10.5, 12.1, 14.0, 14.4, 15.0, 17.0, 18.3, 21.1, 21.9, 23.1, 24.1, 24.4, 25.4, 27.0, 27.5, and 28.2 degrees 2θ.

[0010] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, said characteristic peaks being selected from the group consisting of approximately 6.1, 7.1, 8.8, 10.5, 12.1, 14.0, 14.4, 15.0, 17.0, 18.3, 21.1, 21.9, 23.1, 24.1, 24.4, 25.4, 27.0, 27.5, and 28.2 degrees 2θ.

[0011] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks characteristic of approximately 6.1, 7.1, 8.8, 14.4, 17.0, 18.3, 21.1, 21.9, 23.1, 25.4, and 28.2 degrees 2θ.

[0012] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, and the characteristic peak is selected from the group consisting of approximately 6.7, 9.6, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, 24.5, 24.9, 27.5, 28.3, 33.7, and 33.9 degrees 2θ.

[0013] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, and the characteristic peak is selected from the group consisting of approximately 6.7, 9.6, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, 24.5, 24.9, 27.5, 28.3, 33.7, and 33.9 degrees 2θ.

[0014] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks characteristic of approximately 6.7, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, and 24.9 degrees 2θ.

[0015] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, and the characteristic peak is selected from the group consisting of approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.0, 20.4, 21.4, 22.9, 24.1, 24.7, 25.1, 25.7, 26.1, 27.3, 27.7, 28.3, 28.8, 29.9, 30.3, 30.8, 33.8, 34.3, 35.4, and 38.1 degrees 2θ.

[0016] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, said characteristic peaks being selected from the group consisting of approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.0, 20.4, 21.4, 22.9, 24.1, 24.7, 25.1, 25.7, 26.1, 27.3, 27.7, 28.3, 28.8, 29.9, 30.3, 30.8, 33.8, 34.3, 35.4, and 38.1 degrees 2θ.

[0017] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising characteristic peaks at approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.4, 21.4, 22.9, 24.1, 24.7, 29.9, 30.3, and 30.8 degrees 2θ.

[0018] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, said characteristic peak being selected from the group consisting of approximately 6.7, 7.3, 9.9, 12.0, 13.3, 15.0, 17.3, 18.6, 19.9, 20.5, 21.3, 23.2, 23.8, 24.6, 25.8, 26.3, 26.7, 28.3, 29.2, 29.8, 31.6, 33.5, 35.0, and 38.7 degrees 2θ.

[0019] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, said characteristic peaks being selected from the group consisting of approximately 6.7, 7.3, 9.9, 12.0, 13.3, 15.0, 17.3, 18.6, 19.9, 20.5, 21.3, 23.2, 23.8, 24.6, 25.8, 26.3, 26.7, 28.3, 29.2, 29.8, 31.6, 33.5, 35.0, and 38.7 degrees 2θ.

[0020] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern that includes peaks characteristic of approximately 6.7, 9.9, 12.0, 13.3, 17.3, 18.6, 19.9, 23.2, 24.6, 26.3, 29.2, 29.8, 35.0, and 38.7 degrees 2θ.

[0021] In some embodiments, the crystalline form is a hydrate.

[0022] In some embodiments, the crystalline form is anhydrous.

[0023] In some embodiments, the crystalline form is a solvate.

[0024] In some embodiments, the crystalline form is an ethanol solvate.

[0025] In some embodiments, the crystalline form is a chloroform solvate.

[0026] In some embodiments, more than 50% by weight of the total amount of the compound of formula (I) in the composition is in said crystalline form.

[0027] In some embodiments, more than 85% by weight of the total amount of the compound of formula (I) in the composition is in said crystalline form.

[0028] In some embodiments, more than 90% by weight of the total amount of the compound of formula (I) in the composition is in said crystalline form.

[0029] Some embodiments provide

[0030]

Chemical formula

[0031] In some embodiments, the arginine salt is in crystalline form.

[0032] In some embodiments, the arginine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, and the characteristic peak is selected from the group consisting of approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, 19.4, 20.7, 25.7, 27.0, and 28.1 degrees 2θ.

[0033] In some embodiments, the arginine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, and the characteristic peaks are selected from the group consisting of approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, 19.4, 20.7, 25.7, 27.0, and 28.1 degrees 2θ.

[0034] In some embodiments, the arginine salt crystal form exhibits an X-ray powder diffraction pattern comprising characteristic peaks at approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, and 19.4 degrees 2θ.

[0035] In some embodiments, the arginine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, and the characteristic peak is selected from the group consisting of approximately 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, 16.9, 17.8, 19.3, 20.0, 20.5, 25.1, and 25.6 degrees 2θ.

[0036] In some embodiments, the arginine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, and the characteristic peaks are selected from the group consisting of 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, 16.9, 17.8, 19.3, 20.0, 20.5, 25.1, and 25.6 degrees 2θ.

[0037] In some embodiments, the arginine salt crystal form exhibits an X-ray powder diffraction pattern comprising peaks characteristic of approximately 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, and 16.9 degrees 2θ.

[0038] In some embodiments, the arginine salt crystal is anhydrous.

[0039] In some embodiments, more than 50% by weight of the total amount of the compound of formula (I) in the composition is the arginine salt.

[0040] In some embodiments, more than 85% by weight of the total amount of the compound of formula (I) in the composition is the arginine salt.

[0041] In some embodiments, more than 90% by weight of the total amount of the compound of formula (I) in the composition is the arginine salt.

[0042] Some embodiments relate to formula (I)

[0043] [Chemical formula] and provide the N-methylglucamine salt thereof, or a solvate thereof.

[0044] In some embodiments, the N-methylglucamine salt is in crystalline form.

[0045] In some embodiments, the N-methylglucamine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak, and the characteristic peak is selected from the group consisting of approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, 18.4, 18.6, 19.0, 20.3, and 25.4 degrees 2θ.

[0046] In some embodiments, the N-methylglucamine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, 18.4, 18.6, 19.0, 20.3, and 25.4 degrees 2θ.

[0047] In some embodiments, the N-methylglucamine crystal form exhibits an X-ray powder diffraction pattern comprising characteristic peaks at approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, and 18.6 degrees 2θ.

[0048] In some embodiments, the N-methylglucamine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak selected from the group consisting of approximately 8.5, 9.6, 11.6, 14.1, 16.1, 16.6, 19.1, 19.4, 19.7, 24.2, and 25.4 degrees 2θ.

[0049] In some embodiments, the N-methylglucamine salt crystal form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of approximately 8.5, 9.6, 11.6, 14.1, 16.1, 16.6, 19.1, 19.4, 19.7, 24.2, and 25.4 degrees 2θ.

[0050] In some embodiments, the N-methylglucamine salt crystal form exhibits an X-ray powder diffraction pattern comprising characteristic peaks at approximately 8.5, 9.6, 11.6, 16.1, 16.6, 19.1, 19.4, 24.2, and 25.4 degrees 2θ.

[0051] In some embodiments, the N-methylglucamine salt is anhydrous.

[0052] In some embodiments, more than 50% by weight of the total amount of the compound of formula (I) in the composition is the N-methylglucamine salt.

[0053] In some embodiments, more than 85% by weight of the total amount of the compound of formula (I) in the composition is the N-methylglucamine salt.

[0054] In some embodiments, more than 90% by weight of the total amount of the compound of formula (I) in the composition is the N-methylglucamine salt.

[0055] Some embodiments provide a pharmaceutical composition comprising the composition and a pharmaceutically acceptable excipient.

[0056] Some embodiments provide a method of treating fibrosis, comprising the step of administering a pharmaceutical composition to a subject in need of treatment for fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0057]

Figure 1

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Figure 13

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Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Mode for Carrying Out the Invention

[0058] Disclosed herein are salts and crystalline forms of the compound of formula (I), or hydrates or solvates thereof, and a method for crystallizing the compound of formula (I). Formula (I) is shown below.

[0059]

Chemical formula

[0060] The compound of formula (I) is also referred to herein as Compound 1.

[0061] As described below, the crystalline forms of the compound of formula (I) include Forms A, B, C, D, and E, as described below.

[0062] Also disclosed herein are various salts of formula (I) and the polymorphic forms of these salts. Salts described herein include the arginine salt, N-methylglucamine salt, sodium salt, potassium salt, choline salt, magnesium salt, lysine salt, ammonium salt, betaine salt, TMA salt, proline salt, DEA salt, zinc salt, and calcium salt of formula (I). Some embodiments include these salts in crystalline, semicrystalline, or amorphous forms.

[0063] One embodiment includes the arginine salt of the compound of formula (I), which is referred to herein as Compound 1-A.

[0064]

Chemical formula

[0065] Also disclosed herein is the crystalline form of the arginine salt of the compound of formula (I).

[0066] As described below, the crystalline forms of Compound 1-A include Form 1 and Form 2.

[0067] Furthermore, disclosed herein is the N-methylglucamine salt of the compound of formula (I), which is referred to herein as Compound 1-B.

[0068]

Chemical formula

[0069] Also disclosed herein is the crystalline form of the N-methylglucamine salt of the compound of formula (I).

[0070] As described below, the crystalline forms of Compound 1-B include Form 3 and Form 4.

[0071] In various embodiments, the salts and crystal forms provided herein advantageously exhibit improved solubility, bioavailability, stability, processability and / or ease of manufacture. Accordingly, such crystal forms provide important clinical improvements as autotaxin inhibitors.

[0072] This application also relates to methods of using the crystal forms described herein for treating diseases and disorders by administering to a patient a therapeutically effective amount of a composition comprising one or more crystal forms of Compound 1, Compound 1-A, and / or Compound 1-B and one or more pharmaceutically acceptable excipients.

[0073] Crystal forms of Compound 1 Disclosed herein are crystal forms of Compound 1, specifically, Crystal Form A, Crystal Form B, Crystal Form C, Crystal Form D, and Crystal Form E, as otherwise specified herein. Unless otherwise specified, the X-ray powder diffraction data provided herein were obtained using a Cu Kα radiation source.

[0074] Crystal Form A Some embodiments include a solvated crystal form of Compound 1, referred to herein as Crystal Form A. The exact conditions for forming Crystal Form A can be determined empirically, and it is only possible to present some methods that have been found to be appropriate in practice.

[0075] Crystalline Form A was characterized using various techniques described in more detail in the Experimental Methods section. Figure 1 shows the crystal structure of Form A determined by X-ray powder diffraction (XRPD). Crystalline Form A obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 7.2, 10.4, 12.0, 14.5, 17.9, 21.5, 21.8, 22.3, 23.5, 25.0, 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 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, 13, 14, or 15 characteristic peaks) selected from approximately 7.2, 10.4, 12.0, 14.5, 17.9, 21.5, 21.8, 22.3, 23.5, 25.0, 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from approximately 7.2, 10.4, 12.0, 14.5, 17.9, 21.5, 21.8, 22.3, 23.5, 25.0, 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 degrees 2θ. In some embodiments, the crystalline form of Compound 1 exhibits prominent peaks at approximately 7.2, 10.4, 12.0, 17.9, 21.5, 21.8, and 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 degrees 2θ.

[0076] As is well understood in the art, due to experimental variability when X-ray diffraction patterns are measured with different instruments, the peak positions are considered equal when the 2-theta (2θ) values fall within a certain degree of variability. For example, the United States Pharmacopeia states that identity is recognized when the angular placement of the 10 most intense diffraction peaks conforms to that of the reference substance within ±0.2 degrees and the relative intensities of the peaks do not differ by more than 20%. Thus, in some embodiments, the peak positions described herein include variability within ±0.5 degrees 2θ. In other embodiments, the peak positions described herein include variability within ±0.2 degrees 2θ. As disclosed herein, the term "approximately" when referring to values of 2θ is defined as ±0.5 degrees 2θ.

[0077] Figure 2 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of crystalline form A. The DSC results show endotherms at approximately 109 °C, approximately 133 °C, and approximately 183 °C and an exotherm at approximately 153 °C. The DSC results represent a peak at a temperature of approximately 183 °C for crystalline form A, which represents the melting point of the crystal. Accordingly, in some embodiments, crystalline form A exhibits a melting point of about 177 °C to 200 °C, about 180 °C to about 195 °C, or about 183 °C. When crystalline form A was analyzed by thermogravimetric analysis (TG), in one example, it showed a weight loss of 4.29% when carried out from 27 °C to 110 °C.

[0078] Crystalline form A exhibits good crystallinity and its melting point is relatively high (approximately 183 °C). Crystalline form A shows evidence of hydrate formation.

[0079] Crystalline form B Some embodiments include a solvated crystalline form of Compound 1 referred to herein as crystalline form B. The precise conditions for forming crystalline form B can be determined empirically, and it is only possible to present some methods that have been found to be appropriate in practice.

[0080] Crystalline Form B was characterized using various techniques described in more detail in the Experimental Methods section. Figure 3 shows the crystal structure of Form B determined by X-ray powder diffraction (XRPD). Crystalline Form B obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 6.1, 7.1, 8.8, 10.5, 12.1, 14.0, 14.4, 15.0, 17.0, 18.3, 21.1, 21.9, 23.1, 24.1, 24.4, 25.4, 27.0, 27.5, and 28.2 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 approximately 6.1, 7.1, 8.8, 10.5, 12.1, 14.0, 14.4, 15.0, 17.0, 18.3, 21.1, 21.9, 23.1, 24.1, 24.4, 25.4, 27.0, 27.5, and 28.2 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from approximately 6.1, 7.1, 8.8, 10.5, 12.1, 14.0, 14.4, 15.0, 17.0, 18.3, 21.1, 21.9, 23.1, 24.1, 24.4, 25.4, 27.0, 27.5, and 28.2 degrees 2θ. In some embodiments, the crystalline form of Compound 1 exhibits prominent peaks at approximately 6.1, 7.1, 8.8, 14.4, 17.0, 18.3, 21.1, 21.9, 23.1, 25.4, and 28.2 degrees 2θ.

[0081] Figure 4 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of Crystalline Form B. The DSC results represent a peak at a temperature of approximately 203 °C for Crystalline Form B, which represents the melting point of the crystal. Accordingly, in some embodiments, Crystalline Form B exhibits a melting point of about 191 °C to 222 °C, about 199 °C to about 212 °C, or about 203 °C. When Crystalline Form B was analyzed by thermogravimetric analysis (TG), in one example, it showed a weight loss of 4.03% when carried out from 31 °C to 180 °C.

[0082] Crystal form B exhibits good crystallinity and has a relatively high melting point (approximately 203 °C). Crystal form B shows evidence of solvate formation and is probably a solvate of ethyl alcohol.

[0083] Crystal form C Some embodiments include an anhydrous crystal form of Compound 1, referred to herein as crystal form C. The precise conditions for forming crystal form C can be determined empirically, and it is only possible to present some methods that have been found to be appropriate in practice.

[0084] Crystal form C was characterized using various techniques described in more detail in the Experimental Methods section. Figure 5 shows the crystal structure of form C determined by X-ray powder diffraction (XRPD). Crystal form C obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 6.7, 9.6, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, 24.5, 24.9, 27.5, 28.3, 33.7, and 33.9 degrees 2θ. Accordingly, in some embodiments, the crystal 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 approximately 6.7, 9.6, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, 24.5, 24.9, 27.5, 28.3, 33.7, and 33.9 degrees 2θ. In some embodiments, the crystal form of Compound 1 has at least three characteristic peaks selected from approximately 6.7, 9.6, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, 24.5, 24.9, 27.5, 28.3, 33.7, and 33.9 degrees 2θ. In some embodiments, the crystal form of Compound 1 exhibits prominent peaks at 6.7, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, and 24.9 degrees 2θ.

[0085] Figure 6 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of crystalline form C. The DSC results show a peak at a temperature of about 204 °C for crystalline form C, which represents the melting point of the crystal. Accordingly, in some embodiments, crystalline form C exhibits a melting point of about 189 °C to 219 °C, about 197 °C to about 211 °C, or about 204 °C. When crystalline form C was analyzed by thermogravimetric analysis (TG), in one example, a weight loss of 1.64% was shown when carried out from 26 °C to 220 °C.

[0086] Crystalline form C exhibits good crystallinity and has a relatively high melting point (approximately 204 °C). Crystalline form C does not show any traces of hydrate formation.

[0087] Crystalline form D Some embodiments include a solvated crystalline form of Compound 1, referred to herein as crystalline form D. The precise conditions for forming crystalline form D can be determined empirically, and it is only possible to present some methods that have been found to be appropriate in practice.

[0088] Crystalline Form D was characterized using various techniques described in more detail in the Experimental Methods section. Figure 7 shows the crystal structure of Form D determined by X-ray powder diffraction (XRPD). Crystalline Form D obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.0, 20.4, 21.4, 22.9, 24.1, 24.7, 25.1, 25.7, 26.1, 27.3, 27.7, 28.3, 28.8, 29.9, 30.3, 30.8, 33.8, 34.3, 35.4, and 38.1 degrees 2θ. 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, 13, 14, 15, or 16 characteristic peaks) selected from approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.0, 20.4, 21.4, 22.9, 24.1, 24.7, 25.1, 25.7, 26.1, 27.3, 27.7, 28.3, 28.8, 29.9, 30.3, 30.8, 33.8, 34.3, 35.4, and 38.1 degrees 2θ. In some embodiments, the crystalline form of Compound 1 has at least three characteristic peaks selected from approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.0, 20.4, 21.4, 22.9, 24.1, 24.7, 25.1, 25.7, 26.1, 27.3, 27.7, 28.3, 28.8, 29.9, 30.3, 30.8, 33.8, 34.3, 35.4, and 38.1 degrees 2θ. In some embodiments, the crystalline form of Compound 1 exhibits prominent peaks at 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.4, 21.4, 22.9, 24.1, 24.7, 29.9, 30.3, and 30.8 degrees 2θ.

[0089] Figure 8 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of crystalline form D. The DSC results show a peak at a temperature of about 203 °C for crystalline form D, which represents the melting point of the crystal. Accordingly, in some embodiments, crystalline form D exhibits a melting point of about 189 °C to 220 °C, about 196 °C to about 211 °C, or about 203 °C. When crystalline form D was analyzed by thermogravimetric analysis (TG), in one example, a weight loss of 10.47% was shown when carried out from 28 °C to 220 °C.

[0090] Crystalline form D exhibits good crystallinity and has a relatively high melting point (approximately 203 °C). Crystalline form D shows evidence of solvate formation and is probably a solvate of chloroform.

[0091] Crystalline form E Some embodiments include a crystalline form of Compound 1 referred to herein as crystalline form E. The precise conditions for forming crystalline form E can be determined empirically, and it is only possible to present some methods that have been found to be appropriate in practice.

[0092] Crystal form E was characterized using various techniques described in more detail in the Experimental Methods section. Figure 9 shows the crystal structure of form E determined by X-ray powder diffraction (XRPD). Crystal form E obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 6.7, 7.3, 9.9, 12.0, 13.3, 15.0, 17.3, 18.6, 19.9, 20.5, 21.3, 23.2, 23.8, 24.6, 25.8, 26.3, 26.7, 28.3, 29.2, 29.8, 31.6, 33.5, 35.0, and 38.7 degrees 2θ. Thus, in some embodiments, the crystal 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 6.7, 7.3, 9.9, 12.0, 13.3, 15.0, 17.3, 18.6, 19.9, 20.5, 21.3, 23.2, 23.8, 24.6, 25.8, 26.3, 26.7, 28.3, 29.2, 29.8, 31.6, 33.5, 35.0, and 38.7 degrees 2θ. In some embodiments, the crystal form of Compound 1 exhibits at least three characteristic peaks selected from approximately 6.7, 7.3, 9.9, 12.0, 13.3, 15.0, 17.3, 18.6, 19.9, 20.5, 21.3, 23.2, 23.8, 24.6, 25.8, 26.3, 26.7, 28.3, 29.2, 29.8, 31.6, 33.5, 35.0, and 38.7 degrees 2θ. In some embodiments, the crystal form of Compound 1 exhibits prominent peaks at 6.7, 9.9, 12.0, 13.3, 17.3, 18.6, 19.9, 23.2, 24.6, 26.3, 29.2, 29.8, 35.0, and 38.7 degrees 2θ.

[0093] In some embodiments, the crystal form of Compound 1 is a hydrate. In some embodiments, crystal form A is a hydrate. In some embodiments, crystal form E is a hydrate.

[0094] In some embodiments, the crystal form of Compound 1 is anhydrous. In some embodiments, crystal form C is anhydrous. In some embodiments, crystal form E is anhydrous.

[0095] In some embodiments, the crystalline form of Compound 1 is not solvated. In some embodiments, Crystal Form C is not solvated. In some embodiments, Crystal Form E is not solvated.

[0096] In some embodiments, the crystalline form of Compound 1 is a solvate. In some embodiments, Crystal Form B is a solvate. In some embodiments, Crystal Form C is a solvate. In some embodiments, Crystal Form D is a solvate. In some embodiments, Crystal Form E is a solvate.

[0097] In some embodiments, the crystalline form of Compound 1 is an ethanol solvate. In some embodiments, Crystal Form B is an ethanol solvate. In some embodiments, Crystal Form E is an ethanol solvate.

[0098] In some embodiments, the crystalline form of Compound 1 is a chloroform solvate. In some embodiments, Crystal Form D is a chloroform solvate. In some embodiments, Crystal Form E is a chloroform solvate.

[0099] Some embodiments of the present disclosure include a composition of a compound of formula (I), or a hydrate or solvate thereof. In some embodiments, the composition comprises one or more crystalline forms of Compound 1. In some embodiments, the composition comprises Crystal Form A, Crystal Form B, Crystal Form C, Crystal Form D, Crystal Form E, and any combination of the foregoing. In some embodiments, the composition comprises Crystal Form A. In some embodiments, the composition comprises Crystal Form B. In some embodiments, the composition comprises Crystal Form C. In some embodiments, the composition comprises Crystal Form D. In some embodiments, the composition comprises Crystal Form E. In some embodiments, more than 50% by weight of the total amount of Compound 1 in the composition is in said crystalline form. In some embodiments, more than 85% by weight of the total amount of Compound 1 in the composition is in said crystalline form. In some embodiments, more than 90% by weight of the total amount of Compound 1 in the composition is in said crystalline form.

[0100] Compound 1-A and its crystalline forms Disclosed herein is Compound 1-A, which is the arginine salt form of Compound 1. The structure of Compound 1-A is provided below.

[0101]

Chemical formula

[0102] Also disclosed herein are crystalline forms of Compound 1-A, particularly crystalline form 1 and crystalline form 2. (As described below). Unless otherwise specified, the X-ray powder diffraction data provided herein were obtained using a Cu Kα radiation source.

[0103] Crystalline form 1 Some embodiments include the unsolvated 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 present some methods that have been found to be suitable in practice.

[0104] Crystal Form 1 was characterized using various techniques described in more detail in the Experimental Methods section. Figure 10 shows the crystal structure of Form 1 determined by X-ray powder diffraction (XRPD). Crystal Form 1 obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, 19.4, 20.7, 25.7, 27.0, and 28.1 degrees 2θ. Thus, in some embodiments, the crystal 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 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, 19.4, 20.7, 25.7, 27.0, and 28.1 degrees 2θ. In some embodiments, the crystal form of Compound 1-A has at least three characteristic peaks selected from approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, 19.4, 20.7, 25.7, 27.0, and 28.1 degrees 2θ. In some embodiments, the crystal form of Compound 1-A exhibits prominent peaks at 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, and 19.4 degrees 2θ.

[0105] Figure 11 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of Crystal Form 1. The DSC results represent a peak at a temperature of approximately 227 °C for Crystal Form 1, which represents the melting point of the crystal. Accordingly, in some embodiments, Crystal Form 1 exhibits a melting point of about 210 °C to 245 °C, about 218 °C to about 235 °C, or about 227 °C. 1 The results of 1H-NMR are consistent with a 1:1 molar salt of Compound 1 and L-arginine. When Crystal Form 1 was analyzed by thermogravimetric analysis (TG), in one example, it showed a 1.0% weight loss when performed from 29 °C to 200 °C.

[0106] Figure 12 shows the results obtained by Dynamic Vapor Sorption (DVS), which represents that Crystal Form 1 showed a moisture absorption of 0.32% at 25 °C / 80% RH, indicating that Crystal Form 1 was slightly hygroscopic. Therefore, Crystal Form 1 can be characterized as being slightly hygroscopic and stable over a wide range of humidity.

[0107] Crystal Form 1 exhibits good crystallinity, has a relatively high melting point (approximately 227 °C), and shows no trace of hydrate formation.

[0108] Crystal Form 2 Some embodiments include a crystal form of Compound 1-A referred to herein as Crystal Form 2. The precise conditions for forming Crystal Form 2 can be determined empirically, and it is only possible to present some methods that have been found to be appropriate in practice.

[0109] Crystal Form 2 was characterized using various techniques described in more detail in the Experimental Methods section. Figure 13 shows the crystal structure of Form 2 determined by X-ray powder diffraction (XRPD). Crystal Form 2 obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, 16.9, 17.8, 19.3, 20.0, 20.5, 25.1, and 25.6 degrees 2θ. Accordingly, in some embodiments, the crystal 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, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, 16.9, 17.8, 19.3, 20.0, 20.5, 25.1, and 25.6 degrees 2θ. In some embodiments, the crystal form of Compound 1-A has at least three characteristic peaks selected from approximately 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, 16.9, 17.8, 19.3, 20.0, 20.5, 25.1, and 25.6 degrees 2θ. In some embodiments, the crystal form of Compound 1-A exhibits prominent peaks at 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, and 16.9 degrees 2θ.

[0110] Figure 14 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of Crystal Form 2. The DSC results represent a peak at a temperature of approximately 229 °C for Crystal Form 2, which represents the melting point of the crystal. Accordingly, in some embodiments, Crystal Form 2 exhibits a melting point of about 210 °C to 245 °C, about 218 °C to about 235 °C, or about 229 °C.

[0111] In some embodiments, the crystal form of Compound 1-A is anhydrous. In some embodiments, Crystal Form 1 is anhydrous. In some embodiments, Crystal Form 2 is anhydrous.

[0112] Some embodiments of the present disclosure include compositions of compounds of formula (I) comprising the arginine salt form of Compound 1 (i.e., Compound 1-A). In some embodiments, more than 50% by weight of the total amount of the compound of formula (I) in the composition is Compound 1-A. In some embodiments, more than 85% by weight of the total amount of the compound of formula (I) in the composition is Compound 1-A. In some embodiments, more than 90% by weight of the total amount of the compound of formula (I) in the composition is Compound 1-A.

[0113] In some embodiments, the composition comprises a crystalline form of Compound 1-A. In some embodiments, the composition comprises crystalline form 1, crystalline form 2, and any combination of the foregoing. In some embodiments, the composition comprises crystalline form 1. In some embodiments, the composition comprises crystalline form 2. In some embodiments, more than 50% by weight of the total amount of Compound 1-A in the composition is the crystalline form. In some embodiments, the composition comprises crystalline form 2. In some embodiments, more than 85% by weight of the total amount of Compound 1-A in the composition is the crystalline form. In some embodiments, the composition comprises crystalline form 2. In some embodiments, more than 90% by weight of the total amount of Compound 1-A in the composition is the crystalline form.

[0114] Compound 1-B and its crystalline forms Compound 1-B, which is the N-methylglucamine salt form of Compound 1, is disclosed herein. The structure of Compound 1-B is provided below.

[0115]

Chemical formula

[0116] Also disclosed herein are crystalline forms of Compound 1-B, particularly crystalline form 3 and crystalline form 4. (As described below). Unless otherwise specified, the X-ray powder diffraction data provided herein were obtained using a Cu Kα radiation source.

[0117] Crystalline form 3 Some embodiments include an unsolvated crystalline form of Compound 1-B, referred to herein as Crystal Form 3. The precise conditions for forming Crystal Form 3 can be determined empirically, and it is only possible to present some methods that have been found to be suitable in practice.

[0118] Crystal Form 3 was characterized using various techniques described in more detail in the Experimental Methods section. Figure 15 shows the crystal structure of Form 3 determined by X-ray powder diffraction (XRPD). Crystal Form 3 obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, 18.4, 18.6, 19.0, 20.3, and 25.4 degrees 2θ. Accordingly, in some embodiments, the crystalline form of Compound 1-B 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 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, 18.4, 18.6, 19.0, 20.3, and 25.4 degrees 2θ. In some embodiments, the crystalline form of Compound 1-B has at least three characteristic peaks selected from approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, 18.4, 18.6, 19.0, 20.3, and 25.4 degrees 2θ. In some embodiments, the crystalline form of Compound 1-B exhibits prominent peaks at 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, and 18.6 degrees 2θ.

[0119] Figure 16 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of Crystal Form 3. The DSC results show a peak at a temperature of approximately 165°C for Crystal Form 3, which represents the melting point of the crystal. Accordingly, in some embodiments, Crystal Form 3 exhibits a melting point of about 150°C to 180°C, about 157°C to about 173°C, or about 165°C. 1The results of 1H-NMR are consistent with a 1:1 molar salt of Compound 1 and N-methylglucamine. When crystalline Form 3 was analyzed by thermogravimetric analysis (TG), in certain examples, a 1.0% weight loss was shown when carried out from 29 °C to 150 °C.

[0120] Figure 17 shows the results obtained by dynamic vapor sorption (DVS), which represents that crystalline Form 1 showed 0.1% moisture absorption at 25 °C / 80% RH, indicating that crystalline Form 1 was non-hygroscopic. Therefore, crystalline Form 3 can be characterized as non-hygroscopic and stable over a wide range of humidity.

[0121] Crystalline Form 3 shows good crystallinity, has a relatively high melting point (approximately 165 °C), and shows no trace of hydrate formation.

[0122] Crystalline Form 4 Some embodiments include a crystalline form of Compound 1-B referred to herein as crystalline Form 4. The precise conditions for forming crystalline Form 4 can be determined empirically, and it is only possible to present some methods that have been found to be appropriate in practice.

[0123] Crystal Form 4 was characterized using various techniques described in more detail in the Experimental Methods section. Figure 18 shows the crystal structure of Form 4 determined by X-ray powder diffraction (XRPD). Crystal Form 4 obtainable by the methods disclosed herein exhibits characteristic peaks at approximately 8.5, 9.6, 11.6, 14.1, 16.1, 16.6, 19.1, 19.4, 19.7, 24.2, and 25.4 degrees 2θ. Thus, in some embodiments, the crystal form of Compound 1-B 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 8.5, 9.6, 11.6, 14.1, 16.1, 16.6, 19.1, 19.4, 19.7, 24.2, and 25.4 degrees 2θ. In some embodiments, the crystal form of Compound 1-B has at least three characteristic peaks selected from approximately 8.5, 9.6, 11.6, 14.1, 16.1, 16.6, 19.1, 19.4, 19.7, 24.2, and 25.4 degrees 2θ. In some embodiments, the crystal form of Compound 1-B exhibits prominent peaks at 8.5, 9.6, 11.6, 16.1, 16.6, 19.1, 19.4, 24.2, and 25.4 degrees 2θ.

[0124] Figure 19 shows the results obtained by differential scanning calorimetry (DSC) and thermogravimetric analysis of Crystal Form 4. The DSC results represent a peak at a temperature of approximately 159 °C for Crystal Form 4, which represents the melting point of the crystal. Accordingly, in some embodiments, Crystal Form 4 exhibits a melting point of about 138 °C to 173 °C, about 147 °C to about 167 °C, or about 159 °C.

[0125] In some embodiments, the crystal form of Compound 1-B is anhydrous. In some embodiments, Crystal Form 3 is anhydrous. In some embodiments, Crystal Form 4 is anhydrous.

[0126] Some embodiments of the present disclosure include compositions of compounds of formula (I) comprising the N-methylglucamine salt form of Compound 1 (i.e., Compound 1-B). In some embodiments, more than 50% by weight of the total amount of the compound of formula (I) in the composition is Compound 1-B. In some embodiments, more than 85% by weight of the total amount of the compound of formula (I) in the composition is Compound 1-B. In some embodiments, more than 90% by weight of the total amount of the compound of formula (I) in the composition is Compound 1-B.

[0127] In some embodiments, the composition comprises a crystalline form of Compound 1-B. In some embodiments, the composition comprises crystalline form 3, crystalline form 4, and any combination of the foregoing. In some embodiments, the composition comprises crystalline form 3. In some embodiments, the composition comprises crystalline form 4. In some embodiments, more than 50% by weight of the total amount of Compound 1-B in the composition is the crystalline form. In some embodiments, the composition comprises crystalline form 2. In some embodiments, more than 85% by weight of the total amount of Compound 1-B in the composition is the crystalline form. In some embodiments, the composition comprises crystalline form 2. In some embodiments, more than 90% by weight of the total amount of Compound 1-B in the composition is the crystalline form.

[0128] Methods for Crystallizing Compounds 1, 1-A, and 1-B A method for crystallizing Compound 1 is disclosed. The crystalline forms of Compound 1 can generally be obtained or produced by crystallizing Compound 1 under controlled conditions. In some embodiments, the method can produce a non-solvated crystalline form. In some embodiments, the method can produce a solvated crystalline form. In some embodiments, the method can produce a hydrated crystalline form. In some embodiments, the method can produce crystalline form A. In some embodiments, the method can produce crystalline form B. In some embodiments, the method can produce crystalline form C. In some embodiments, the method can produce crystalline form D. In some embodiments, the method can produce crystalline form E. In some embodiments, the method can produce a mixture of any of the foregoing crystalline forms.

[0129] Also disclosed is a method for crystallizing Compound 1-A. The crystalline forms of Compound 1-A can generally be obtained or produced by crystallizing Compound 1-A under controlled conditions. In some embodiments, the method can produce an unsolvated crystalline form. In some embodiments, the method can produce a solvated crystalline form. In some embodiments, the method can produce a hydrated crystalline form. In some embodiments, the method can produce Crystal Form 1. In some embodiments, the method can produce Crystal Form 2. In some embodiments, the method can produce a mixture of any of the aforementioned crystalline forms.

[0130] Also disclosed is a method for crystallizing Compound 1-B. The crystalline forms of Compound 1-B are generally obtained or produced by crystallizing Compound 1-B under controlled conditions. In some embodiments, the method can produce an unsolvated crystalline form. In some embodiments, the method can produce a solvated crystalline form. In some embodiments, the method can produce a hydrated crystalline form. In some embodiments, the method can produce Crystal Form 3. In some embodiments, the method can produce Crystal Form 4. In some embodiments, the method can produce a mixture of any of the aforementioned crystalline forms.

[0131] In some embodiments, the method may include dissolving the compound 1, compound 1-A, compound 1-B, or a combination thereof in an amorphous form in a first solvent to prepare a first solution. In some embodiments, the method may include dissolving the crystalline form of compound 1, compound 1-A, compound 1-B, or a combination thereof in a first solvent to prepare a first solution. In some embodiments, the method may include dissolving a mixture of the amorphous and crystalline forms of compound 1, compound 1-A, compound 1-B, or a combination thereof in a first solvent to prepare a first solution. In some embodiments, the method may include adding a second solvent to the first solution to produce 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, to any range between any of these values, or below -25 °C.

[0132] In some embodiments, the method may include isolating the crystalline form of compound 1, compound 1-A, compound 1-B, or a combination thereof. In some embodiments, the isolation may be performed by filtration such as hot filtration. In some embodiments, the isolated product may be dried by air drying or the like.

[0133] 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.

[0134] In some embodiments, the second solvent can be a single solvent. In some embodiments, the second solvent can be a mixture of two or more solvents. In some embodiments, the first solvent can include acetone, acetonitrile, 1,4-dioxane, dichloromethane, diethyl ether, dimethylformamide, ethanol, ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyltetrahydrofuran, isopropanol, n-propanol, isopropyl acetate, tetrahydrofuran, water, or a mixture thereof. In some embodiments, the second solvent can include toluene, hexane, water, dichloromethane, or a combination thereof.

[0135] In some embodiments, the method can further include stirring. In some embodiments, agitation can be performed by stirring. In some embodiments, agitation can be performed by sonication.

[0136] In some embodiments, parts of the method can be performed at the same temperature. In some embodiments, parts of the method can be performed at different temperatures. In some embodiments, parts of the method can be performed at room temperature. In some embodiments, parts of the method can be performed at -40°C to 200°C. In some embodiments, parts of the method can be performed at -40°C to 25°C. In some embodiments, parts of the method can be performed at -25°C to -10°C. In some embodiments, parts of the method can be performed at 2°C to 8°C. In some embodiments, parts of the method can be performed at 50°C to 60°C. In some embodiments, parts of the method can be performed at 65°C to 75°C. In some embodiments, parts of the method can be performed at 75°C to 150°C. In some embodiments, parts of the method can include the first solution, the second mixture, the seed-added mixture, the isolation of the crystalline form, and stirring.

[0137] In some embodiments, the crystalline form 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 acetonitrile. In other embodiments, the solvent can be dichloromethane. In other embodiments, the solvent can be acetone. In still other embodiments, the solvent can be isopropyl acetate. In other embodiments, the solvent can be methyl isobutyl ketone. In some embodiments, the first temperature is from 40°C to 60°C, or from 45°C to 55°C. In some embodiments, the first temperature is about 50°C. In some embodiments, the first solvent can be cooled to a second temperature. In some embodiments, the second temperature can be from -5°C to -25°C, or from -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 antisolvent can be added to the first solution before cooling. In some embodiments, the antisolvent is selected from hexane, n-heptane, toluene, water, or combinations thereof. In some embodiments, the antisolvent is hexane. In other embodiments, the antisolvent is toluene. In other embodiments, the antisolvent is n-heptane. In other embodiments, the antisolvent is water. The methods described herein can be used to prepare crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or combinations of the foregoing. In some embodiments, the methods described herein can be used to prepare crystalline form A. In some embodiments, the methods described herein can be used to prepare crystalline form B. In some embodiments, the methods described herein can be used to prepare crystalline form C. In some embodiments, the methods described herein can be used to prepare crystalline form D. In some embodiments, the methods described herein can be used to prepare crystalline form E.

[0138] In some embodiments, the crystalline form of Compound 1 can be prepared by adding Compound 1 to a solvent to form a slurry. In some embodiments, the solvent is acetone, acetonitrile, ethanol, ethyl acetate, methanol, methyl ethyl ketone, tetrahydrofuran, water, or a combination thereof. In some embodiments, the solvent is acetone. In other embodiments, the solvent is water. In some embodiments, the solvent is a combination of acetone and water. In some embodiments, the solvent is a combination of methanol and water. In some embodiments, the solvent combination is selected from a volume-to-volume (v / v) solvent ratio of 99 / 1, 95 / 5, 9 / 1, 85 / 15, 8 / 2, 7 / 3, 6 / 4, 1 / 1, 4 / 6, 3 / 7, 2 / 8, 15 / 85, 1 / 9, 5 / 95, or 1 / 99, or a range between any two of these values. In some embodiments, the slurry can be stirred at 20, 25, 30, 35, 40, 45, or 50 °C, or a range between any two of these values. In some embodiments, the slurry can be stirred for 1, 2, 3, 4, 5, 6 days, or 7 days or more. The methods described herein can be used to prepare crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or a combination of the foregoing. In some embodiments, the methods described herein can be used to prepare crystalline form A. In some embodiments, the methods described herein can be used to prepare crystalline form B. In some embodiments, the methods described herein can be used to prepare crystalline form C. In some embodiments, the methods described herein can be used to prepare crystalline form D. In some embodiments, the methods described herein can be used to prepare crystalline form E.

[0139] In some embodiments, the crystalline form of Compound 1 can be prepared by adding the first crystalline form of Compound 1 to a solvent to form a saturated solution, and subsequently adding an equal amount of the first crystalline form of Compound 1 and the second crystalline form of Compound 1 to the saturated solution. In some embodiments, the solvent is acetone, acetonitrile, ethanol, ethyl acetate, methanol, methyl ethyl ketone, tetrahydrofuran, water, or a combination thereof. In some embodiments, the solvent is acetone. In other embodiments, the solvent is water. In some embodiments, the solvent is a combination of acetone and water. In some embodiments, the solvent is a combination of methanol and water. In some embodiments, the solvent combination is selected from a volume-to-volume (v / v) solvent ratio of 99 / 1, 95 / 5, 9 / 1, 85 / 15, 8 / 2, 7 / 3, 6 / 4, 1 / 1, 4 / 6, 3 / 7, 2 / 8, 15 / 85, 1 / 9, 5 / 95, or 1 / 99, or a range between any two of these values. In some embodiments, the saturated solution can be stirred at 20, 25, 30, 35, 40, 45, or 50 °C, or a range between any two of these values. In some embodiments, the saturated solution can be stirred for 1, 2, 3, 4, 5, 6 days, or 7 days or more. In some embodiments, the first crystalline form of Compound 1 is selected from crystalline form A, crystalline form B, crystalline form C, crystalline form D, and crystalline form E. In some embodiments, the second crystalline form of Compound 1 is selected from crystalline form A, crystalline form B, crystalline form C, crystalline form D, and crystalline form E. The methods described herein can be used to prepare crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or a combination of the foregoing. In some embodiments, the methods described herein can be used to prepare crystalline form A. In some embodiments, the methods described herein can be used to prepare crystalline form B. In some embodiments, the methods described herein can be used to prepare crystalline form C. In some embodiments, the methods described herein can be used to prepare crystalline form D. In some embodiments, the methods described herein can be used to prepare crystalline form E.

[0140] In some embodiments, the crystalline form of Compound 1-A can be prepared by forming a suspension of Compound 1 in a solvent and an amount of arginine. In some embodiments, the arginine can be a single enantiomer. In some embodiments, the arginine can be L-arginine. In other embodiments, the arginine can be D-arginine. In some embodiments, the amount of arginine is sufficient to provide a molar ratio of arginine to Compound 1 of 1:1, 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 3:1, or in the range between any two of these values. In some embodiments, the molar ratio of arginine to Compound 1 is from 1:1 to 1.1:1. In some specific embodiments, the molar ratio of arginine to Compound 1 is from 1.0:1.0 to 1.05:1.0. In some specific embodiments, the molar ratio of arginine to Compound 1 is 1.0:1.0. The suspension can be stirred at room temperature for 1, 2, 3, 4, 5 days, or more days. In some embodiments, the suspension can be sonicated prior to the addition of arginine. In some embodiments, the solvent is acetone. In other embodiments, the solvent is acetonitrile. In other embodiments, the solvent is 1,4-dioxane. In still 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. In some embodiments, the solvent is ethanol. In other embodiments, the solvent is water. In some embodiments, the solvent is a combination of acetone and water. In some embodiments, the solvent is a combination of methanol and water. In some embodiments, the solvent combination is selected from a volume-to-volume (v / v) solvent ratio of 99 / 1, 95 / 5, 9 / 1, 85 / 15, 8 / 2, 7 / 3, 6 / 4, 1 / 1, 4 / 6, 3 / 7, 2 / 8, 15 / 85, 1 / 9, 5 / 95, or 1 / 99, or in the range between any two of these values. In some embodiments, the solvent is a combination of acetone / water (95:5 v / v).The methods described herein can be used to prepare crystalline form 1, crystalline form 2, or combinations of the foregoing. In some embodiments, the method is used to prepare crystalline form 1. In some embodiments, the method is used to prepare crystalline form 2.

[0141] In some embodiments, the crystalline form of Compound 1-A can be prepared by combining Compound 1 with a first solvent and an amount of arginine to form a first mixture. In some embodiments, the arginine can be a single enantiomer. In some embodiments, the arginine can be L-arginine. In other embodiments, the arginine can be D-arginine. In some embodiments, the amount of arginine is sufficient to provide a molar ratio of arginine to Compound 1 of 1:1, 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 3:1, or in the range between any two of these values. In some embodiments, the molar ratio of arginine to Compound 1 is from 1:1 to 1.1:1. In some specific embodiments, the molar ratio of arginine to Compound 1 is from 1.0:1.0 to 1.05:1.0. In some specific embodiments, the molar ratio of arginine to Compound 1 is 1.0:1.0. In some embodiments, the first solvent is ethanol. In some embodiments, the first solvent is acetone. In some embodiments, the first solvent is ethyl acetate. In some embodiments, the first solvent is acetonitrile. In other embodiments, the first solvent is tetrahydrofuran. In some embodiments, the first solvent is methyl ethyl ketone. In other embodiments, the first solvent is water. In some embodiments, the first solvent is a combination of acetone and water. In some embodiments, the first solvent is a combination of methanol and water. In some embodiments, the combination of the first solvents is selected from a volume-to-volume (v / v) solvent ratio of 99 / 1, 95 / 5, 9 / 1, 85 / 15, 8 / 2, 7 / 3, 6 / 4, 1 / 1, 4 / 6, 3 / 7, 2 / 8, 15 / 85, 1 / 9, 5 / 95, or 1 / 99, or in the range between any two of these values. In some embodiments, the first solvent is a combination of acetone / water (95:5 v / v). In some embodiments, the first mixture can be stirred at 20, 25, 30, 35, 40, 45, or 50 °C, or in the range between any two of these values. In some embodiments, the first mixture is stirred for 1, 2, 3, 4, 5, 6 days, or for 7 days or more.In some embodiments, a second solvent can be added to the first mixture to form a suspension. In some embodiments, the second solvent is selected from ethanol, ethyl acetate, acetonitrile, tetrahydrofuran, methyl ethyl ketone, and water. In some embodiments, the second solvent is a combination of acetone and water. In some embodiments, the second solvent is a combination of methanol and water. In some embodiments, the combination of the second solvents includes a solvent ratio similar to the solvent ratio of the combination of the first solvents. In some embodiments, the combination of the second solvents includes the same solvent ratio as the solvent ratio of the combination of the first solvents. In some embodiments, the second solvent can be added to the first mixture over a period of 5, 10, 15, 20, 25 minutes, or 30 minutes or more. In some embodiments, a slurry is formed by the addition of the second solvent that can be added to the first mixture. The methods described herein can be used to prepare crystalline form 1, crystalline form 2, or a combination of the foregoing. In some embodiments, the method is used to prepare crystalline form 1. In some embodiments, the method is used to prepare crystalline form 2.

[0142] In some embodiments, the crystalline form of Compound 1-B can be prepared by forming a suspension of Compound 1 in a solvent and a certain amount of N-methylglucamine. In some embodiments, N-methylglucamine can be a single enantiomer. In some embodiments, N-methylglucamine can be a mixture of stereoisomers. In some embodiments, the amount of N-methylglucamine is sufficient to provide a molar ratio of N-methylglucamine to Compound 1 of 1:1, 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 3:1, or in the range between any two of these values. In some embodiments, the molar ratio of N-methylglucamine to Compound 1 is from 1:1 to 1.1:1. In some specific embodiments, the molar ratio of N-methylglucamine to Compound 1 is from 1.0:1.0 to 1.05:1.0. In some specific embodiments, the molar ratio of N-methylglucamine to Compound 1 is 1.0:1.0. The suspension can be stirred at room temperature for 1, 2, 3, 4, 5 days, or more days. In some embodiments, the suspension can be sonicated prior to the addition of N-methylglucamine. In some embodiments, the solvent is acetone. In other embodiments, the solvate is acetonitrile. In other embodiments, the solvent is 1,4-dioxane. In still 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. In some embodiments, the solvent is ethanol. In other embodiments, the solvent is water. In some embodiments, the solvent is a combination of acetone and water. In some embodiments, the solvent is a combination of methanol and water. In some embodiments, the solvent combination is selected from a volume-to-volume (v / v) solvent ratio of 99 / 1, 95 / 5, 9 / 1, 85 / 15, 8 / 2, 7 / 3, 6 / 4, 1 / 1, 4 / 6, 3 / 7, 2 / 8, 15 / 85, 1 / 9, 5 / 95, or 1 / 99, or in the range between any two of these values. In some embodiments, the solvent is a combination of acetone / water (95:5 v / v).The methods described herein can be used to prepare crystalline form 3, crystalline form 4, or combinations of the foregoing. In some embodiments, the method is used to prepare crystalline form 3. In some embodiments, the method is used to prepare crystalline form 4.

[0143] In some embodiments, the crystalline form of Compound 1-B can be prepared by combining Compound 1 with a first solvent and an amount of N-methylglucamine to form a first mixture. In some embodiments, N-methylglucamine can be a single enantiomer. In some embodiments, N-methylglucamine can be a mixture of stereoisomers. In some embodiments, the amount of N-methylglucamine is sufficient to provide a molar ratio of N-methylglucamine to Compound 1 of 1:1, 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, or 1.5:1 to 1. In some embodiments, the molar ratio of N-methylglucamine to Compound 1 is from 1:1 to 1.1:1. In some specific embodiments, the molar ratio of N-methylglucamine to Compound 1 is from 1.0:1.0 to 1.05:1.0. In some specific embodiments, the molar ratio of N-methylglucamine to Compound 1 is 1.0:1.0. In some embodiments, the first solvent is ethanol. In some embodiments, the first solvent is acetone. In some embodiments, the first solvent is ethyl acetate. In some embodiments, the first solvent is acetonitrile. In other embodiments, the first solvent is tetrahydrofuran. In some embodiments, the first solvent is methyl ethyl ketone. In other embodiments, the first solvent is water. In some embodiments, the first solvent is a combination of acetone and water. In some embodiments, the first solvent is a combination of methanol and water. In some embodiments, the combination of the first solvents is selected from a volume-to-volume (v / v) solvent ratio of 99 / 1, 95 / 5, 9 / 1, 85 / 15, 8 / 2, 7 / 3, 6 / 4, 1 / 1, 4 / 6, 3 / 7, 2 / 8, 15 / 85, 1 / 9, 5 / 95, or 1 / 99, or a range between any two of these values. In some embodiments, the first solvent is a combination of acetone / water (95:5 v / v). In some embodiments, the first mixture can be stirred at 20, 25, 30, 35, 40, 45, or 50 °C, or within a range between any two of these values. In some embodiments, the first mixture is stirred for 1, 2, 3, 4, 5, 6 days, or for 7 days or more.In some embodiments, a second solvent can be added to the first mixture to form a suspension. In some embodiments, the second solvent is selected from ethanol, ethyl acetate, acetonitrile, tetrahydrofuran, methyl ethyl ketone, and water. In some embodiments, the second solvent is a combination of acetone and water. In some embodiments, the second solvent is a combination of methanol and water. In some embodiments, the combination of the second solvents includes a solvent ratio similar to that of the combination of the first solvents. In some embodiments, the combination of the second solvents includes the same solvent ratio as that of the combination of the first solvents. In some embodiments, the second solvent can be added to the first mixture over a period of 5, 10, 15, 20, 25 minutes, or 30 minutes or more. In some embodiments, a slurry is formed by the addition of the second solvent that can be added to the first mixture. The methods described herein can be used to prepare crystalline form 3, crystalline form 4, or a combination of the foregoing. In some embodiments, the method is used to prepare crystalline form 3. In some embodiments, the method is used to prepare crystalline form 4.

[0144] Definitions As used herein, "subject" means a human or non-human mammal, and includes, but is not limited to, dogs, cats, horses, donkeys, rabbits, cows, domestic pigs, camels, llamas, alpacas, bison, yaks, goats, sheep, pigs, elk, deer, domesticated anthropoid apes, or non-human primates selected for treatment or therapy.

[0145] "Subject in need (thereof)" means a subject determined to be in need of treatment or therapy.

[0146] As used herein, "treating", "treatment", or "to treat" refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a patient who does not yet have a related disease or disorder but is susceptible to or at risk of a particular disease or disorder, whereby the treatment reduces the likelihood that the patient will develop the disease or disorder. The term "therapeutic treatment" refers to treating a patient who already has a disease or disorder.

[0147] "Prevent" or "prevention" refers to delaying or stopping the onset, manifestation, or progression of a condition or disease over a period of time, including weeks, months, or years.

[0148] "Improve" means reducing the severity of at least one indicator of a condition or disease. In certain embodiments, improve includes delaying or slowing the progression of one or more indicators of a disease or disorder. The severity of an indicator can be determined by subjective or objective measures known to those of skill in the art.

[0149] "Administer" means providing a pharmaceutical or composition to a subject and includes, but is not limited to, administration by a medical professional and self-administration.

[0150] The term "agent" includes any substance, molecule, element, compound, entity, or combination thereof. It includes, but is not limited to, for example, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0151] "Pharmaceutical agent" means a substance that provides a therapeutic effect when administered to a subject.

[0152] "Pharmaceutical composition" means a mixture of substances that includes a pharmaceutical agent suitable for administration to an individual.

[0153] “Solvate” refers to a compound formed by the interaction of a solvent with an API, metabolite, or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0154] Pharmaceutical composition Compound 1, Compound 1-A, Compound 1-B, and their crystalline forms described herein can be formulated into pharmaceutical compositions for use in the treatment of the diseases described herein. Standard pharmaceutical formulation techniques such as those disclosed in Remington’s The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), which is incorporated herein by reference in its entirety, are used. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described herein; (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0155] In some embodiments, the crystalline forms of Compound 1, Compound 1-A, and Compound 1-B described herein can be formulated into a single pharmaceutical composition for use in the treatment of the diseases described herein. In some embodiments, formulations comprising Compound 1, Compound 1-A, and / or Compound 1-B, and their crystalline forms described herein can be administered in combination with one or more second pharmaceuticals.

[0156] In some embodiments, Compound 1, Compound 1-A, and / or Compound 1-B, and their crystalline forms described herein can be dissolved in a solvent prior to administration to a subject in need thereof.

[0157] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include 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 the preparation of pharmaceutical formulations. The use of such media and agents for pharmaceutically active substances is well known in the art. The use in therapeutic compositions is contemplated unless any conventional media or agent is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants as commonly used in the art may be included. These compounds and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.)(1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0158] Some examples of substances that can function as a pharmaceutically acceptable carrier or its components include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; tragacanth powder; 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; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; coloring agents, flavors, medicaments, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0159] The selection of a pharmaceutically acceptable carrier to be used in combination with the compound of interest is determined by the manner in which the compound is to be administered.

[0160] 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 the compound suitable for administration to a subject in a single dose in accordance with a suitable medical practice. However, the preparation of a single-dose or unit dosage form does not imply that the dosage form is administered once a day or once during the course of treatment. A unit dosage form may include a single daily dose or a divided sub-dose, and several unit dosage forms may be administered over the course of a day to complete a daily dose. According to the present disclosure, a unit dosage form may be administered more or less than once a day and may be administered multiple times during the course of treatment. Such dosage forms can be administered in any manner appropriate for those formulations, including orally, parenterally, and can be administered as an infusion over a period (e.g., about 30 minutes to about 2 to 6 hours). Although single administration is specifically contemplated, the compositions administered according to the methods described herein can also be administered as a continuous infusion or via an implanted infusion pump.

[0161] The methods described herein can utilize any of a variety of suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. One of ordinary skill in the art will understand that oral and nasal compositions include compositions that are administered by inhalation and prepared using available methodologies. Depending on the particular desired route of administration, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Any pharmaceutically active substance that does not substantially interfere with the activity of the compound can be included. The amount of carrier used with the compound is sufficient to provide the actual amount of the substance 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 Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0162] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compression tablets, tablet triturates, enteric-coated tablets, sugar-coated tablets, film-coated tablets, or multiple compression tablets, containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorants, flowability-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-tacky granules, and / or suspensions, and foaming preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening agents, melting agents, colorants, and flavorants.

[0163] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants such as, as inert diluents, calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; as binders, starch, gelatin and sucrose; as disintegrants, starch, alginic acid and croscarmellose; as lubricants, magnesium stearate, stearic acid, microcrystalline cellulose, carboxymethyl cellulose and talc. Tablets may also contain solubilizing or emulsifying agents such as poloxamer, Cremophor / Kolliphor® / Lutrol® methylcellulose, hydroxypropylmethylcellulose, or others known in the art. Flow promoting agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Colorants such as FD&C dyes can be added for appearance. Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The choice of carrier components depends on secondary considerations such as taste, cost, and storage stability, which can be readily made by those skilled in the art.

[0164] Oral (PO) compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for the preparation of 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. In the case of 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, flavoring agents, and coloring agents disclosed above.

[0165] Such compositions can also be coated by conventional methods, typically using pH- or time-dependent coatings, so that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application or is released at various times to extend the desired action. 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.

[0166] The compositions described herein may optionally contain other pharmaceutically active substances.

[0167] 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 substances such as sucrose, sorbitol and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Also included may be the flow promoters, lubricants, sweeteners, colorants, antioxidants and flavorants disclosed above.

[0168] Liquid compositions formulated for topical ophthalmic use are formulated so as to be capable of being topically administered to the eye. Comfort can be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. If comfort cannot be maximized, the liquid can be formulated such that it is tolerable for the patient for topical ophthalmic use. Additionally, the ophthalmically acceptable liquid can either be packaged for single use or contain a preservative to prevent contamination over multiple uses.

[0169] For ophthalmic use, solutions or medicaments are often prepared using physiological saline as the main vehicle. Ophthalmic solutions can preferably be maintained at a comfortable pH using an appropriate buffer system. The formulation may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0170] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenyl mercaptan, acetate and phenyl mercaptan nitrate. A useful surfactant is, for example, Tween 80. Similarly, various useful vehicles may be used in the ophthalmic formulations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, purified water, and the like.

[0171] Tonicity adjusters can be added as needed or conveniently. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0172] As long as the resulting preparation is ophthalmically acceptable, various buffers and means for adjusting pH can be used. For many compositions, the pH is between 4 and 9. Thus, examples of buffers include acetate buffer, citrate buffer, phosphate buffer and borate buffer. An acid or base can be used to adjust the pH of these formulations as needed.

[0173] Examples of ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0174] Other excipient components that can be included in ophthalmic formulations are chelating agents. A useful chelating agent is sodium edetate, although other chelating agents can also be used instead of, or in combination with, it.

[0175] For topical use including transdermal administration, creams, ointments, gels, solutions or suspensions containing the compounds disclosed herein are used. Topical formulations can generally be composed of a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and a skin softener.

[0176] For intravenous administration, the compounds 1, 1-A, and / or 1-B described herein, and their crystalline forms and compositions described herein, can be dissolved or dispersed in a pharmaceutically acceptable diluent such as physiological saline or dextrose solution. Suitable excipients including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid can be included to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, and preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further 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, 65 287-33, both of which are incorporated herein by reference in their entirety. An antibacterial agent may also be included to achieve a bacteriostatic or fungistatic solution and includes, but is not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0177] Compositions for intravenous administration can be provided to healthcare providers in one or more solid forms, which are reconstituted with a suitable diluent such as sterile water, saline, or dextrose in water immediately prior to administration. In other embodiments, the composition is provided as a solution ready for parenteral administration. In still other embodiments, the composition is provided as a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein with another agent, the combination may be provided to the healthcare provider as a mixture, or the healthcare provider may mix the two agents prior to administration, or may administer the two agents separately.

[0178] The actual unit dosage of Compound 1, Compound 1-A, and / or Compound 1-B described in this specification, and their crystalline forms, depends on the specific compound and the condition being treated. In some embodiments, the dosage can be from about 0.01 mg / kg to about 120 mg / kg or more of body weight, from about 0.05 mg / kg or less to about 70 mg / kg of body weight, from about 0.1 mg / kg to about 50 mg / kg of body weight, from about 1.0 mg / kg to about 10 mg / kg of body weight, from about 5.0 mg / kg to about 10 mg / kg of body weight, or from about 10.0 mg / kg to about 20.0 mg / kg of body weight. In some embodiments, the dosage can be 100 mg / kg, 90 mg / kg, 80 mg / kg, 70 mg / kg, 60 mg / kg, 50 mg / kg, 40 mg / kg, 30 mg / kg, 25 mg / kg, 20 mg / kg, 10 mg / kg, 7.5 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2.5 mg / kg, 1 mg / kg, 0.5 mg / kg, 0.1 mg / kg, 0.05 mg / kg, or less than 0.005 mg / kg of body weight. In some embodiments, the actual unit dosage is 0.05, 0.07, 0.1, 0.3, 1.0, 3.0, 5.0, 10.0, or 25.0 mg / kg of body weight, or in the range between any two of these values. Thus, for administration to a 70 kg person, the dosage range would be from about 0.1 mg to 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 more than 700 mg, 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 dosage is 0.1 mg. In some embodiments, the actual unit dosage is 0.5 mg. In some embodiments, the actual unit dosage is 1 mg. In some embodiments, the actual unit dosage is 1.5 mg. In some embodiments, the actual unit dosage is 2 mg. In some embodiments, the actual unit dosage is 2.5 mg. In some embodiments, the actual unit dosage is 3 mg. In some embodiments, the actual unit dosage is 3.5 mg. In some embodiments, the actual unit dosage is 4 mg. In some embodiments, the actual unit dosage 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.

[0179] In some embodiments, Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, are about 1 to 50 mg / body surface area m 2It is administered at a dosage within the range. In some embodiments, Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, are about 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 - 11, 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 - 12, 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 to 30, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 7 to 12, 7 to 13, 7 to 13.75, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to 18, 7 to 19, 7 to 20, 7 to 22.5, 7 to 25, 7 to 27.5, 7 to 30, 7.5 to 12.5, 7.5 to 13.5, 7.5 to 15, 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to 13.75, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 22.5, 8 to 25, 8 to 27.5, 8 to 30, 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 13.75, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 22.5, 9 to 25, 9 to 27.5, 9 to 30, 10 to 11, 10 to 12, 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 / body surface area m 2 It can be administered at a dose in the range of. In some embodiments, Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, are about 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 / body surface area m 2It can be administered at a dose of. In some embodiments, Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, are about 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 / body surface area m 2 It can be administered at a dose less than. In some embodiments, Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, are about 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, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg / body surface area m 2 It can be administered at a dose exceeding.

[0180] In some embodiments, the dosages of Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, 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 dosages of Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, may be 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 dosages of Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, 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 dosages of the crystalline forms of Compound 1, Compound 1-A, and Compound 1-B described herein may be 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, 5 mg to 40 mg, 5 mg to 42 mg, 5 mg to 44 mg, 5 mg to 46 mg, 5 mg to 48 mg, 5 mg to 50 mg, 5 mg to 52 mg, 5 mg to 54 mg, 5 mg to 56 mg, 5 mg to 58 mg, 5 mg to 60 mg, 7 mg to 7.7 mg, 7 mg to 9 mg, 7 mg to 10 mg, 7 mg to 12 mg, 7 mg to 14 mg, 7 mg to 15 mg, 7 mg to 16 mg,7 mg to 18 mg, 7 mg to 20 mg, 7 mg to 22 mg, 7 mg to 24 mg, 7 mg to 26 mg, 7 mg to 28 mg, 7 mg to 30 mg, 7 mg to 32 mg, 7 mg to 34 mg, 7 mg to 36 mg, 7 mg to 38 mg, 7 mg to 40 mg, 7 mg to 42 mg, 7 mg to 44 mg, 7 mg to 46 mg, 7 mg to 48 mg, 7 mg to 50 mg, 7 mg to 52 mg, 7 mg to 54 mg, 7 mg to 56 mg, 7 mg to 58 mg, 7 mg to 60 mg, 9 mg to 10 mg, 9 mg to 12 mg, 9 mg to 14 mg, 9 mg to 15 mg, 9 mg to 16 mg, 9 mg to 18 mg, 9 mg to 20 mg, 9 mg to 22 mg, 9 mg to 24 mg, 9 mg to 26 mg, 9 mg to 28 mg, 9 mg to 30 mg, 9 mg to 32 mg, 9 mg to 34 mg, 9 mg to 36 mg, 9 mg to 38 mg, 9 mg to 40 mg, 9 mg to 42 mg, 9 mg to 44 mg, 9 mg to 46 mg, 9 mg to 48 mg, 9 mg to 50 mg, 9 mg to 52 mg, 9 mg to 54 mg, 9 mg to 56 mg, 9 mg to 58 mg, 9 mg to 60 mg, 10 mg to 12 mg, 10 mg to 14 mg, 10 mg to 15 mg, 10 mg to 16 mg, 10 mg to 18 mg, 10 mg to 20 mg, 10 mg to 22 mg, 10 mg to 24 mg, 10 mg to 26 mg, 10 mg to 28 mg, 10 mg to 30 mg, 10 mg to 32 mg, 10 mg to 34 mg, 10 mg to 36 mg, 10 mg to 38 mg, 10 mg to 40 mg, 10 mg to 42 mg, 10 mg to 44 mg, 10 mg to 46 mg, 10 mg to 48 mg, 10 mg to 50 mg, 10 mg to 52 mg, 10 mg to 54 mg, 10 mg to 56 mg, 10 mg to 58 mg, 10 mg to 60 mg, 12 mg to 14 mg, 12 mg to 15 mg, 12 mg to 16 mg, 12 mg to 18 mg, 12 mg to 20 mg, 12 mg to 22 mg, 12 mg to 24 mg, 12 mg to 26 mg, 12 mg to 28 mg, 12 mg to 30 mg, 12 mg to 32 mg, 12 mg to 34 mg, 12 mg to 36 mg, 12 mg to 38 mg, 12 mg to 40 mg, 12 mg to 42 mg, 12 mg to 44 mg, 12 mg to 46 mg, 12 mg to 48 mg, 12 mg to 50 mg, 12 mg to 52 mg, 12 mg to 54 mg, 12 mg to 56 mg, 12 mg to 58 mg, 12 mg to 60 mg, 15 mg to 16 mg, 15 mg to 18 mg, 15 mg to 20 mg, 15 mg to 22 mg, 15 mg to 24 mg,15 mg to 26 mg, 15 mg to 28 mg, 15 mg to 30 mg, 15 mg to 32 mg, 15 mg to 34 mg, 15 mg to 36 mg, 15 mg to 38 mg, 15 mg to 40 mg, 15 mg to 42 mg, 15 mg to 44 mg, 15 mg to 46 mg, 15 mg to 48 mg, 15 mg to 50 mg, 15 mg to 52 mg, 15 mg to 54 mg, 15 mg to 56 mg, 15 mg to 58 mg, 15 mg to 60 mg, 17 mg to 18 mg, 17 mg to 20 mg, 17 mg to 22 mg, 17 mg to 24 mg, 17 mg to 26 mg, 17 mg to 28 mg, 17 mg to 30 mg, 17 mg to 32 mg, 17 mg to 34 mg, 17 mg to 36 mg, 17 mg to 38 mg, 17 mg to 40 mg, 17 mg to 42 mg, 17 mg to 44 mg, 17 mg to 46 mg, 17 mg to 48 mg, 17 mg to 50 mg, 17 mg to 52 mg, 17 mg to 54 mg, 17 mg to 56 mg, 17 mg to 58 mg, 17 mg to 60 mg, 20 mg to 22 mg, 20 mg to 24 mg, 20 mg to 26 mg, 20 mg to 28 mg, 20 mg to 30 mg, 20 mg to 32 mg, 20 mg to 34 mg, 20 mg to 36 mg, 20 mg to 38 mg, 20 mg to 40 mg, 20 mg to 42 mg, 20 mg to 44 mg, 20 mg to 46 mg, 20 mg to 48 mg, 20 mg to 50 mg, 20 mg to 52 mg, 20 mg to 54 mg, 20 mg to 56 mg, 20 mg to 58 mg, 20 mg to 60 mg, 22 mg to 24 mg, 22 mg to 26 mg, 22 mg to 28 mg, 22 mg to 30 mg, 22 mg to 32 mg, 22 mg to 34 mg, 22 mg to 36 mg, 22 mg to 38 mg, 22 mg to 40 mg, 22 mg to 42 mg, 22 mg to 44 mg, 22 mg to 46 mg, 22 mg to 48 mg, 22 mg to 50 mg, 22 mg to 52 mg, 22 mg to 54 mg, 22 mg to 56 mg, 22 mg to 58 mg, 22 mg to 60 mg, 25 mg to 26 mg, 25 mg to 28 mg, 25 mg to 30 mg, 25 mg to 32 mg, 25 mg to 34 mg, 25 mg to 36 mg, 25 mg to 38 mg, 25 mg to 40 mg, 25 mg to 42 mg, 25 mg to 44 mg, 25 mg to 46 mg, 25 mg to 48 mg, 25 mg to 50 mg, 25 mg to 52 mg, 25 mg to 54 mg, 25 mg to 56 mg, 25 mg to 58 mg, 25 mg to 60 mg, 27 mg to 28 mg, 27 mg to 30 mg, 27 mg to 32 mg,27 mg to 34 mg, 27 mg to 36 mg, 27 mg to 38 mg, 27 mg to 40 mg, 27 mg to 42 mg, 27 mg to 44 mg, 27 mg to 46 mg, 27 mg to 48 mg, 27 mg to 50 mg, 27 mg to 52 mg, 27 mg to 54 mg, 27 mg to 56 mg, 27 mg to 58 mg, 27 mg to 60 mg, 30 mg to 32 mg, 30 mg to 34 mg, 30 mg to 36 mg, 30 mg to 38 mg, 30 mg to 40 mg, 30 mg to 42 mg, 30 mg to 44 mg, 30 mg to 46 mg, 30 mg to 48 mg, 30 mg to 50 mg, 30 mg to 52 mg, 30 mg to 54 mg, 30 mg to 56 mg, 30 mg to 58 mg, 30 mg to 60 mg, 33 mg to 34 mg, 33 mg to 36 mg, 33 mg to 38 mg, 33 mg to 40 mg, 33 mg to 42 mg, 33 mg to 44 mg, 33 mg to 46 mg, 33 mg to 48 mg, 33 mg to 50 mg, 33 mg to 52 mg, 33 mg to 54 mg, 33 mg to 56 mg, 33 mg to 58 mg, 33 mg to 60 mg, 36 mg to 38 mg, 36 mg to 40 mg, 36 mg to 42 mg, 36 mg to 44 mg, 36 mg to 46 mg, 36 mg to 48 mg, 36 mg to 50 mg, 36 mg to 52 mg, 36 mg to 54 mg, 36 mg to 56 mg, 36 mg to 58 mg, 36 mg to 60 mg, 40 mg to 42 mg, 40 mg to 44 mg, 40 mg to 46 mg, 40 mg to 48 mg, 40 mg to 50 mg, 40 mg to 52 mg, 40 mg to 54 mg, 40 mg to 56 mg, 40 mg to 58 mg, 40 mg to 60 mg, 43 mg to 46 mg, 43 mg to 48 mg, 43 mg to 50 mg, 43 mg to 52 mg, 43 mg to 54 mg, 43 mg to 56 mg, 43 mg to 58 mg, 42 mg to 60 mg, 45 mg to 48 mg, 45 mg to 50 mg, 45 mg to 52 mg, 45 mg to 54 mg, 45 mg to 56 mg, 45 mg to 58 mg, 45 mg to 60 mg, 48 mg to 50 mg, 48 mg to 52 mg, 48 mg to 54 mg, 48 mg to 56 mg, 48 mg to 58 mg, 48 mg to 60 mg, 50 mg to 52 mg, 50 mg to 54 mg, 50 mg to 56 mg, 50 mg to 58 mg, 50 mg to 60 mg, 52 mg to 54 mg, 52 mg to 56 mg, 52 mg to 58 mg, or 52 mg to 60 mg. In some embodiments, Compound 1, Compound 1-A, as described herein,The dosage of compound 1, compound 1-A, and / or compound 1-B, and their crystalline forms can be more than about 5 mg, more than about 10 mg, more than about 12.5 mg, more than about 13.5 mg, more than about 15 mg, more than about 17.5 mg, more than about 20 mg, more than about 22.5 mg, more than about 25 mg, more than about 27 mg, more than about 30 mg, more than about 40 mg, more than about 50 mg, more than about 60 mg, more than about 70 mg, more than about 80 mg, more than about 90 mg, more than about 100 mg, more than about 125 mg, more than about 150 mg, or more than about 200 mg. In some embodiments, the dosage of compound 1, compound 1-A, and / or compound 1-B, and their crystalline forms described herein can be less than about 5 mg, less than about 10 mg, less than about 12.5 mg, less than about 13.5 mg, less than about 15 mg, less than about 17.5 mg, less than about 20 mg, less than about 22.5 mg, less than about 25 mg, less than about 27 mg, less than about 30 mg, less than about 40 mg, less than about 50 mg, less than about 60 mg, less than about 70 mg, less than about 80 mg, less than about 90 mg, less than about 100 mg, less than about 125 mg, less than about 150 mg, or less than about 200 mg. In some embodiments, the dosage of compound 1, compound 1-A, and / or compound 1-B, and their crystalline forms described herein can 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, or in a range between any two of these values.,

[0181] Compound 1, compound 1-A, and / or compound 1-B, and their crystalline forms described herein can also be incorporated into formulations for delivery outside of the systemic circulation. Such formulations include enteric-coated capsules, tablets, soft gels, spray-dried powders, polymeric matrices, hydrogels, enteric-coated solids, crystalline solids, amorphous solids, glassy solids, coated micronized particles, liquids, atomized liquids, aerosols, or microcapsules.

[0182] Method of Administration The above composition can be administered by any suitable route of administration, for example, by injection such as subcutaneous, intramuscular, intraperitoneal, intravenous, or intraarterial; topically by creams, lotions, or patches; orally by tablets, solutions, oral suspensions, buccal films, or mouth rinses; nasally by nasal aerosols, powders, or sprays; or ophthalmically by eye drops. In some embodiments, the composition can be administered once, twice, three times, or four times a day. In other embodiments, the composition can be administered once, twice, or three times a week. In other embodiments, the composition is administered every other day, every three days, or every four days. In other embodiments, the composition is every other week, every three weeks, or every four weeks. In other embodiments, the composition is administered once or twice a month.

[0183] In some embodiments, Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, can be administered simultaneously with one or more second pharmaceuticals. In other embodiments, Compound 1, Compound 1-A, and / or Compound 1-B described herein, and their crystalline forms, can be administered sequentially with one or more second pharmaceuticals.

[0184] Method of Treatment Some embodiments relate to methods for preventing, treating, or ameliorating one or more diseases or disorders associated with autotaxin activity by administering a compound or composition described herein.

[0185] Fibrosis In some embodiments, methods for treating fibrosis using a compound or composition described herein are disclosed herein. In some embodiments, methods for preventing fibrosis using a compound or composition described herein are disclosed herein. In some embodiments, methods for attenuating, reversing, or inhibiting the signs or symptoms of fibrosis are disclosed herein.

[0186] In some embodiments, methods are disclosed herein that include administering a compound or composition described herein to a subject with fibrosis. In some embodiments, methods are disclosed herein that include the step of administering a compound or composition described herein to a subject susceptible to fibrosis.

[0187] In some embodiments, methods are described herein for reducing fibrosis in a tissue, the method including contacting the fibrotic cells or tissue with a sufficient amount of a compound or composition described herein to reduce and / or inhibit fibrosis. In some embodiments, fibrosis includes a fibrotic condition. Optionally, the amount sufficient to reduce and / or inhibit fibrosis is a therapeutically effective amount.

[0188] In some embodiments, reducing fibrosis, or treating a fibrotic condition, includes reducing or inhibiting one or more of the following: formation or deposition of extracellular matrix proteins; the number of profibrotic cell types (e.g., the number of fibroblasts or immune cells); the collagen or hydroxyproline content of cells within a fibrotic lesion; the expression or activity of profibrotic proteins; reducing fibrosis associated with an inflammatory response; or combinations thereof.

[0189] "Fibrosis," as used herein, refers to the accumulation of extracellular matrix components that occurs following trauma, inflammation, tissue repair, immune responses, hyperplasia of cells, and / or tumor formation. Examples of tissue fibrosis include, but are not limited to, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, liver cirrhosis and fibrosis, ocular fibrosis, skin scars and keloids, renal fibrosis, peritoneal fibrosis, adhesions, fibromatosis, atherosclerosis, and amyloidosis.

[0190] In some embodiments, the fibrotic condition is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic condition is idiopathic. In some embodiments, the fibrotic condition is associated with (e.g., secondary to) a disease (such as an infectious disease, an inflammatory disease, an autoimmune disease, a malignant or cancerous disease, and / or a connective tissue disease); a toxin; an insult (such as an environmental hazard (e.g., asbestos, coal dust, polycyclic aromatic hydrocarbons), tobacco smoke, trauma); a medical treatment (e.g., a surgical incision, chemotherapy, or radiation), or a combination thereof.

[0191] In some embodiments, the fibrotic condition is a fibrotic condition of the lung, a fibrotic condition of the liver, a fibrotic condition of the heart or vascular system, a fibrotic condition of the kidney, a fibrotic condition of the skin, a fibrotic condition of the gastrointestinal tract, a fibrotic condition of the eye, a fibrotic condition of the bone marrow or hematopoietic tissue, a fibrotic condition of the nervous system, a fibrotic condition of the peritoneum, or a combination thereof.

[0192] In some embodiments, the fibrotic condition affects one or more tissues selected from muscle, tendon, cartilage, skin (e.g., the epidermis or endothelium of the skin), heart tissue, vascular tissue (e.g., arteries, veins), pancreatic tissue, lung tissue, liver tissue, kidney tissue, uterine tissue, ovarian tissue, nerve tissue, testicular tissue, peritoneal tissue, colon, small intestine, bile duct, intestine, bone marrow, or hematopoietic tissue.

[0193] In some embodiments, the fibrotic condition is a fibrotic condition of the liver. In certain embodiments, the fibrotic condition of the liver is selected from one or more of the following: fatty liver disease, steatosis (e.g., non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced hepatic fibrosis, bile duct injury, biliary fibrosis, cholestasis, or biliary disease. In some embodiments, hepatic fibrosis or liver fibrosis includes, but is not limited to, fibrosis associated with alcoholism, viral infection, such as hepatitis (e.g., hepatitis C, hepatitis B, or hepatitis D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, and exposure to toxins or irritants (e.g., alcohol, pharmaceuticals, and environmental toxins).

[0194] In some embodiments, methods for treating or preventing fibrosis of a subject's liver are described herein, the methods comprising administering to the subject a compound or composition described herein. In some examples, the fibrosis is chronic or acute. In some cases, administration of the compound or composition described herein results in attenuation, delay, or prevention of signs, symptoms, and / or complications of liver fibrosis. For example, the method attenuates, delays, or prevents the onset of cirrhosis, liver failure, portal hypertension, and / or complications. Typical complications of cirrhosis include ascites, renal failure, hepatic encephalopathy, and bleeding from varices. In some cases, administration of the compound or composition described herein inhibits the accumulation of fibrogenic cells and / or prevents the deposition of extracellular matrix proteins (e.g., collagen) in the liver. The autotaxin inhibitors used in the methods provided herein are useful for treating liver fibrosis caused by any source of liver injury. Examples of liver fibrosis include, but are not limited to, viral infection (e.g., hepatitis C), autoimmune hepatitis, congenital hepatic fibrosis, bacterial infection (e.g., brucellosis), parasitic infection (e.g., hydatidosis), alcohol abuse, primary sclerosing cholangitis, pharmaceuticals (e.g., amiodarone hydrochloride, chlorpromazine, isoniazid, methotrexate, methyldopa, oxyphenisatin, tolbutamide), mechanical obstruction (e.g., surgery), non-alcoholic steatohepatitis (NASH), and combinations thereof.

[0195] In some cases, methods for the recovery or regression of fibrosis of a subject's liver are described herein, the methods comprising administering to the subject a compound or composition described herein.

[0196] In some embodiments, any method provided herein that includes administration of a compound or composition described herein further includes administering one or more additional fibrosis treatments. The additional fibrosis treatments include, for example, administration of an angiotensin inhibitor, colchicine, corticosteroid, endothelin inhibitor, interferon alpha, interleukin 10, antioxidant, hepatic stellate cell (HSC) inhibitor, or combinations thereof.

[0197] In some embodiments, the fibrotic condition is a fibrotic condition of the kidney. In some embodiments, the fibrotic condition of the kidney is selected from one or more of the following: renal fibrosis (e.g., chronic renal fibrosis), nephropathy associated with injury / fibrosis (e.g., chronic nephropathy associated with diabetes (e.g., diabetic nephropathy)), lupus, scleroderma of the kidney, glomerulonephritis, focal segmental glomerulosclerosis, nephropathy renal fibrosis of IgA nephropathy associated with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephritis (PGN), endothelial / thrombotic microvascular injury, nephropathy associated with HIV or fibrosis associated with exposure to toxins, stimulants, or chemotherapeutic agents.

[0198] In some embodiments, methods for treating or preventing fibrosis of a subject's kidney are described herein, the methods comprising administering to the subject a compound or composition described herein. In some examples, administering to the subject a compound or composition described herein attenuates, delays, or inhibits the progression of renal fibrosis. In some cases, administering a compound or composition described herein results in attenuation, delay, or prevention of signs, symptoms, and / or complications of renal fibrosis. In some examples, administering a compound or composition described herein decreases the accumulation of extracellular matrix in the kidney or the rate of extracellular matrix accumulation. In some cases, renal fibrosis is the result of acute or chronic persistent injury to kidney tissue. In some cases, renal fibrosis is characterized by glomerulosclerosis. In some cases, renal fibrosis is characterized by tubulointerstitial fibrosis.

[0199] In some cases, methods for the recovery or regression of fibrosis of a subject's kidney are described herein, the methods comprising administering to the subject a compound or composition described herein.

[0200] In some embodiments, any of the methods provided herein that involve administration of a compound or composition described herein further comprises administering one or more additional treatments for fibrosis and / or for kidney disease. The additional treatment can include, for example, inhibiting TGF-β / Smad signaling that drives fibrosis. As another example, the additional treatment can include increasing the concentration of anti-fibrotic factors in the kidney (e.g., hepatocyte growth factor (HGF) and bone morphogenetic protein-7 (BMP-7)), which can antagonize the fibrogenic action of TGF-β. Exemplary fibrosis treatments include, but are not limited to, administration of one or more of the following: pirfenidone (5-methyl-N-phenyl-2-(1H)-pyridone), tranilast, fluorophenidone, renin-angiotensin-aldosterone blockade, ACE inhibitors, ADAM inhibitors, and anti-CTGF monoclonal antibodies.

[0201] In some embodiments, the fibrotic condition is a fibrotic condition of the skin. In some embodiments, the fibrotic condition of the skin is selected from one or more of the following: scleroderma, systemic sclerosis, nephrogenic systemic fibrosis (e.g., resulting from exposure to gadolinium, which is frequently used as a contrast agent for MRI in patients with severe renal insufficiency), scars, and keloids.

[0202] In some embodiments, methods for treating or preventing fibrosis of a subject's skin are described herein, the methods comprising administering to the subject a compound or composition described herein. In some instances, administering to the subject a compound or composition described herein attenuates, delays, or inhibits the progression of skin fibrosis. In some cases, administering a compound or composition described herein results in attenuation, delay, or prevention of signs, symptoms, and / or complications of skin fibrosis. In some instances, administering a compound or composition described herein reduces the accumulation or the rate of accumulation of extracellular matrix in the skin. In some cases, skin fibrosis is persistent damage to acute or chronic skin tissue.

[0203] In some embodiments, after administration of the compounds or compositions described herein to a subject having scleroderma, the skin thickness of the sclerotic skin decreases. For example, administration of the compounds or compositions described herein decreases the skin thickness of scleroderma skin by at least about 5%, 10%, 20%, 30%, 40%, or 50% compared to the skin thickness before administration of the compounds or compositions described herein.

[0204] In some embodiments, methods for the recovery of fibrosis or fibrotic regression of a subject's skin are described herein, the method comprising administration of the compounds or compositions described herein to the subject.

[0205] In some embodiments, any method provided herein comprising administration of the compounds or compositions described herein further comprises administering one or more additional fibrosis treatments and / or dermatological treatments. Treatments for scleroderma include, but are not limited to, administration of D-penicillamine, bovine collagen, methotrexate, mycophenolate mofetil, human relaxin, interferon alpha, anti-transforming growth factor beta antibody, or combinations thereof.

[0206] In some embodiments, the fibrotic condition is an ocular fibrotic condition. In some embodiments, the ocular fibrotic condition is selected from one or more of the following: glaucoma, subretinal fibrosis, age-related macular degeneration (ARMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), fibrosis after eye surgery (glaucoma surgery, cataract surgery, LASIK surgery).

[0207] In some embodiments, methods for treating or preventing fibrosis of the eye of a subject are described herein, the methods comprising administering to the subject a compound or composition described herein. In some examples, administering to the subject a compound or composition described herein attenuates, delays, or inhibits the progression of eye fibrosis. In some cases, administering a compound or composition described herein results in attenuation, delay, or prevention of signs, symptoms, and / or complications of eye fibrosis. In some examples, administering a compound or composition described herein reduces the accumulation of extracellular matrix in the eye or the rate of accumulation of extracellular matrix. In some cases, eye fibrosis is a persistent injury to acute or chronic eye tissue.

[0208] In some embodiments, after administering a compound or composition described herein to a subject having eye fibrosis, the degree of eye fibrosis decreases. For example, administering a compound or composition described herein reduces fibrosis of bleb protrusion after trabeculectomy and reduces the defect rate of bleb protrusion due to fibrosis by about 5%, 10%, 20%, 30%, 40%, or 50% compared to a patient who does not receive treatment with a compound or composition described herein.

[0209] In some embodiments, methods for the recovery or regression of fibrosis of the eye of a subject are described herein, the methods comprising administering to the subject a compound or composition described herein.

[0210] In some embodiments, any method provided herein that comprises administering a compound or composition described herein further comprises performing one or more additional fibrosis treatments and / or eye disease treatments. Treatments for eye fibrosis include, but are not limited to, administration of mitomycin, 5-fluorouracil, corticosteroids, antibiotics, anti-transforming growth factor beta antibodies, or combinations thereof.

[0211] In some embodiments, the fibrotic state is the fibrotic state of the peritoneum. In some embodiments, methods for treating or preventing peritoneal fibrosis in a subject are described herein, the methods comprising administering to the subject a compound or composition described herein. In some examples, administering to the subject a compound or composition described herein attenuates, delays, or inhibits the progression of peritoneal fibrosis. In some cases, administering a compound or composition described herein results in attenuation, delay, or prevention of signs, symptoms, and / or complications of peritoneal fibrosis. In some examples, administering a compound or composition described herein reduces the accumulation of extracellular matrix in the peritoneum or the rate of extracellular matrix accumulation.

[0212] In some embodiments, peritoneal fibrosis is caused by long-term peritoneal dialysis. In some embodiments, the compounds or compositions described herein are administered to subjects with peritonitis. In some embodiments, peritoneal fibrosis is caused by one or more of the following episodes: biocompatible dialysate, peritonitis, uremia, and / or chronic inflammation.

[0213] In some cases, methods for the recovery or regression of peritoneal fibrosis in a subject are described herein, the methods comprising administering to the subject a compound or composition described herein.

[0214] In some embodiments, any method provided herein that comprises administering a compound or composition described herein further comprises administering an anti-inflammatory agent or an immunosuppressive agent.

[0215] In some embodiments, the fibrotic state is the fibrotic state of the gastrointestinal tract. In some embodiments, the fibrotic state is selected from one or more of fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory disorders such as Barrett's esophagus and chronic gastritis, and / or fibrosis associated with hindgut inflammatory disorders such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease.

[0216] In some embodiments, the fibrotic condition is a fibrotic condition of the lung. In some embodiments, the fibrotic condition of the lung is selected from one or more of the following: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, or bronchiectasis. In some embodiments, the pulmonary fibrosis is secondary to a disease, toxin, episode, medical treatment, or combination thereof. In some embodiments, the pulmonary fibrosis is associated with one or more of the following: disease processes such as asbestosis and silicosis; occupational hazards; environmental pollutants; smoking; autoimmune connective tissue disorders (e.g., rheumatoid arthritis, scleroderma, and systemic lupus erythematosus (SLE)); connective tissue disorders such as sarcoidosis; infectious diseases, e.g., infections, especially chronic infections; medical treatments including radiation therapy and drug therapy, e.g., chemotherapy (e.g., treatment with bleomycin, methotrexate, amiodarone, busulfan, and / or nitrofurantoin), but not limited thereto. In some embodiments, the fibrotic condition of the lung treated by the methods of the present invention is associated with (e.g., secondary to) cancer treatment, e.g., treatment of cancer (e.g., treatment of squamous cell carcinoma, testicular cancer, Hodgkin's disease with bleomycin).

[0217] In some embodiments, the fibrotic condition is a fibrotic condition of the heart. In one embodiment, the fibrotic condition of the heart is cardiomyopathy (e.g., radiation myocarditis, surgical complications (e.g., postoperative fibrosis of the myocardium), infectious diseases (e.g., Chagas disease, bacteria, trichinosis, or fungal myocarditis); granulomatous metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis); developmental disorders (e.g., endocardial fibroelastosis); atherosclerosis, or cardiomyopathy associated with exposure to toxins or stimulants (e.g., drug-induced cardiomyopathy, drug-induced cardiotoxicity, alcoholic cardiomyopathy, cobalt poisoning or exposure). In some embodiments, the cardiomyopathy is associated with an inflammatory disorder of the heart tissue (e.g., sarcoidosis of the myocardium).

[0218] In some embodiments, the fibrotic condition is an adhesion. In some embodiments, the adhesion is selected from one or more of the following: abdominal adhesion, peritoneal adhesion, pelvic adhesion, pericardial adhesion, epidural adhesion, peritendinous, or adhesive capsulitis.

[0219] In some embodiments, the fibrotic condition is a fibrotic condition of the eye. In some embodiments, the fibrotic condition of the eye includes anterior eye diseases such as glaucoma and corneal opacification. In some embodiments, the fibrotic condition of the eye includes posterior eye diseases such as age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma. In some embodiments, the fibrotic condition of the eye is due to fibrosis after eye surgery.

[0220] In some embodiments, the fibrotic condition is a fibrotic condition of the bone marrow or hematopoietic tissue. In some embodiments, the fibrotic condition of the bone marrow is a characteristic feature of chronic myeloproliferative neoplasms of the bone marrow such as primary myelofibrosis (also referred to herein as primary myelofibrosis or chronic idiopathic myelofibrosis). In some embodiments, myelofibrosis is associated with (e.g., secondary to) a malignant disease caused by a clonal proliferative disorder. In some embodiments, myelofibrosis is associated with (e.g., secondary to) a blood disorder selected from one or more of the following: polycythemia vera, essential thrombocythemia, myelodysplasia, hairy cell leukemia, lymphoma (e.g., Hodgkin's lymphoma or non-Hodgkin's lymphoma), multiple myeloma, or chronic myelogenous leukemia (CML). In some embodiments, myelofibrosis is associated with (e.g., secondary to) a non-blood disorder selected from the following secondary epitheliomas associated with non-blood disorders such as metastasis of a solid tumor to the bone marrow, autoimmune disorders (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disorder, or polymyositis), infection (e.g., tuberculosis), or vitamin D deficiency.

[0221] Colitis In some embodiments, methods of treating colitis using the compounds disclosed herein are disclosed herein. In some embodiments, methods of preventing colitis using the compounds disclosed herein are disclosed herein. In some embodiments, methods of attenuating, alleviating, or inhibiting the signs or symptoms of colitis are disclosed herein.

[0222] In some embodiments, methods are disclosed herein that include administering a compound or composition described herein to a subject having colitis. In some embodiments, methods are disclosed herein that include administering a compound or composition described herein to a subject susceptible to colitis.

[0223] In some embodiments, methods of reducing colitis in a tissue are disclosed herein, the method comprising contacting the tissue with a compound or composition described herein in an amount sufficient to reduce or inhibit colitis. Optionally, the amount sufficient to reduce and / or inhibit colitis is a therapeutically effective amount.

[0224] "Colitis", as used herein, refers to inflammation of the large intestine tissue. Colitis includes acute self-limiting and chronic colitis. Colitis includes autoimmune colitis, idiopathic colitis, iatrogenic colitis, vascular disease, and infectious colitis. The autoimmune type of colitis includes inflammatory bowel disease and ulcerative colitis. The idiopathic type of colitis includes microscopic colitis, lymphocytic colitis, and collagenous colitis. The iatrogenic type of colitis includes diversion colitis and chemical colitis. Colitis caused by vascular disease includes ischemic colitis. Infectious colitis includes colitis caused by Escherichia coli, Clostridium difficile, Shigella dysenteriae, or Shigatoxigenic group. In some embodiments, colitis includes ulcerative colitis.

[0225] In some embodiments, methods of treating colitis in a subject by administering to the subject a compound or composition described herein are disclosed. In some embodiments, one or more signs or symptoms of colitis are reduced in the subject after administration of the compound or composition described herein. Signs or symptoms of colitis include, but are not limited to, abdominal pain, loss of appetite, fatigue, diarrhea, mucus in the stool, muscle spasms, urgency, abdominal distension, abdominal tenderness, weight loss, changes in bowel habits such as increased frequency, fever, bleeding, bloody stools, distension, erythema of the colonic mucosa, and ulcers.

[0226] In some embodiments, after administration of the compound or composition described herein to a subject with colitis, the subject shows improvement in the clinical signs, symptoms, or histopathology of colitis. In one example, after administration of an autotaxin inhibitor, colonic inflammation decreases. In another example, after administration of an autotaxin inhibitor, tissue damage is reversed. In another example, after administration of an autotaxin inhibitor, tissue damage progression is attenuated. In yet another example, after administration of an autotaxin inhibitor, tissue damage is inhibited. Tissue damage can be visualized by histological examination using staining such as Masson's trichrome staining.

[0227] In some embodiments, after administration of an autotaxin inhibitor to a subject with ulcerative colitis, the ulcer area decreases, for example, by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 50%, 90%, 99% of the size before administration of the autotaxin inhibitor. In another example, after administration of the autotaxin inhibitor, the ulcer area is at least about 2-fold, 3-fold, or 5-fold smaller than the size before administration of the autotaxin inhibitor compared to administration of a control.

[0228] In some embodiments, after administration of an autotaxin inhibitor to a subject with colitis, the subject's weight does not increase or decrease by more than about 2%, 5%, or 10%.

[0229] In some embodiments, after administration of an autotaxin inhibitor to a subject with colitis, the subject increases the consistency of bowel movements.

[0230] In some embodiments, a subject with colitis is treated by administration of a compound or composition described herein and by administering one or more additional treatments. Additional treatments include hydration therapy, and administration of steroids, anti-inflammatory agents, and / or immunosuppressive agents. In one example, the additional treatment is cyclosporine A (CsA). In another example, the additional treatment is sulfasalazine.

[0231] In some embodiments, an animal model of induced colitis (e.g., colitis induced by DSS, or colitis induced by DNBS) is administered a compound or composition described herein (preventively or therapeutically), and after administration of the compound or composition described herein, the animal shows an increase in colon length, or an increase in colon weight, or an increase in both colon length and weight. For example, after administration of a compound or composition described herein to a mouse or rat with induced colitis, the colon length increases by at least about 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 1 cm, 2 cm, or 3 cm compared to administration of a vehicle or control. In another example, after administration of a compound or composition described herein to a mouse or rat with induced colitis, the colon weight increases by at least about 0.05 g compared to administration of a vehicle or control. In some embodiments, after treatment of a mouse or rat with induced colitis with an autotaxin inhibitor, the mouse or rat reduces the ulcer area by at least about 10%, 20%, 50%, or 90% compared to the ulcer area before administration. In some embodiments, after treatment of a mouse or rat with induced colitis with an autotaxin inhibitor, the mouse or rat has an ulcer area of less than about 90%, 80%, 70%, 50%, 20%, or 10% of the size of the ulcer area in an untreated or control mouse or rat with induced colitis.

[0232] Pruritus In some embodiments, methods for treating pruritus using the compounds or compositions disclosed herein are disclosed herein. In some embodiments, methods for preventing pruritus using the compounds or compositions disclosed herein are disclosed herein. In some embodiments, methods for attenuating, alleviating, or inhibiting at least one sign or symptom of pruritus are disclosed herein.

[0233] In some embodiments, methods are disclosed herein that include administering to a subject suffering from pruritus a compound or composition described herein. In some embodiments, methods are disclosed herein that include administering to a subject prone to pruritus a compound or composition described herein.

[0234] In some embodiments, methods for reducing pruritus in a tissue are disclosed herein, the method comprising contacting the tissue with a compound or composition described herein in an amount sufficient to reduce or inhibit pruritus.

[0235] Pruritus is a disease that includes local or general itching, which is a common and debilitating symptom in various diseases. Pruritus usually occurs on the skin, but may also occur at sites other than the skin, such as mucous membranes. Pruritus is a common sign of local skin disorders induced by insect bites or allergic reactions to environmental allergens, urticaria, skin diseases of fungal and bacterial origin, external parasite infections, and hemorrhoids. In some embodiments, methods for treating pruritus caused by systemic diseases, such as, for example, hypothyroidism, hyperthyroidism, mucocandiasis in true diabetes, and Hodgkin's disease, are disclosed herein. In some embodiments, methods for treating persistent or recurrent pruritus associated with many systemic diseases and skin disorders are disclosed herein. Pruritus includes, but is not limited to, renal pruritus, cholestatic pruritus, pruritus of the blood, and pruritus of endocrine glands.

[0236] In some embodiments, methods for treating pruritus associated with liver disease and intrahepatic or posthepatic cholestasis are disclosed herein. Liver diseases that cause pruritus include primary biliary cirrhosis, hepatitis B and C virus, primary sclerosing cholangitis, cholangiocarcinoma, alcoholic cirrhosis, autoimmune hepatitis, and the like.

[0237] In some embodiments, methods for treating pruritus resulting from various causes are disclosed herein, such as xerosis, skin conditions (psoriasis, eczema, sunburn, athlete's foot, etc.), insect bites, poisonous plants (Urushi tata, American ivy, urushiol, etc.), Hodgkin's disease, jaundice, polycythemia, scabies, lice, mites, thyroid diseases, diabetes mellitus, drug-induced pityriasis capitis, iron deficiency anemia, parasitic infections, drugs, cholestasis, pruritus associated with pregnancy, HIV infection, other causes of itching or pruritus, or combinations thereof.

[0238] In some embodiments, methods for treating or preventing pruritus in a subject are disclosed herein, the method comprising administering to the subject a compound or composition described herein. In some embodiments, administration of the compound or composition described herein reduces pruritus by at least about 10%, 20%, 30%, 50%, or 90%.

[0239] In some embodiments, after administration of an autotaxin inhibitor to a subject suffering from pruritus, the subject reduces the total number of scratching movements compared to the number of scratching movements before administration of the autotaxin inhibitor. For example, the scratching movement decreases by at least about 10%, 20%, 50%, or 90%. In some embodiments, pruritus is prevented or treated by administration of a compound or composition described herein and one or more additional pruritus treatments or therapeutics. Pruritus treatments include, but are not limited to, the use of skin creams and lotions to prevent skin dryness and the use of antihistamines, steroids, or antibiotics. Pruritus therapeutics include doxepin, mirtazapine, gabapentin, aprepitant, capsaicin, tacrolimus, gamma-linolenic acid, cholestyramine, rifampin, opioid antagonists, ondansetron, and activated charcoal.

[0240] In some embodiments, methods for preventing or treating pruritus of renal origin in a subject are described herein, the method comprising administering to the subject a compound or composition described herein. In some embodiments, methods for preventing or treating cholestatic pruritus in a subject are described herein, the method comprising administering to the subject a compound or composition described herein. In some embodiments, methods for preventing or treating hematologic pruritus in a subject are described herein, the method comprising administering to the subject a compound or composition described herein. In some embodiments, methods for preventing or treating pruritus of endocrine gland origin in a subject are described herein, the method comprising administering to the subject a compound or composition described herein.

[0241] Nervous system diseases In some embodiments, methods of treating a neurological disease, disorder, or condition using a compound or composition described herein are disclosed herein. In some embodiments, methods of preventing a neurological disease, disorder, or condition using a compound or composition described herein are disclosed herein. In some embodiments, methods of attenuating, restoring, or inhibiting the signs or symptoms of a neurological disease, disorder, or condition are disclosed herein.

[0242] In some embodiments, methods are disclosed herein that include administering a compound or composition described herein to a subject having a neurological disease, disorder, or condition. In some embodiments, methods are disclosed herein that include administering a compound or composition described herein to a subject susceptible to a neurological disease, disorder, or condition.

[0243] In some embodiments, the neurological disease is multiple sclerosis. In some examples, the neurological disease is caused by a genetic disorder. In some examples, the neurological disease is a developmental disease, such as split cord malformation. In some examples, the neurological disease is a degenerative disease, such as Parkinson's disease or Alzheimer's disease. In some examples, the neurological disease is due to a stroke. Neurological diseases, disorders, and conditions suitable for treatment with an ATX inhibitor, or characteristics of neurological diseases, disorders, and conditions include, but are not limited to, amyotrophic lateral sclerosis (ALS), arteriovenous malformation (AVM), cerebral aneurysm, brain tumor, dural arteriovenous fistula, epilepsy, headache, memory impairment, Parkinson's disease, peripheral neuropathy, postherpetic neuralgia, spinal cord tumor, and stroke. In one example, autotaxin activity is increased in the CSF (cerebrospinal fluid) and serum of patients with relapsing / remitting multiple sclerosis compared to patients with other neurological diseases.

[0244] In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis, relapsing multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis.

[0245] In some embodiments, multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS). People with this type of MS have clearly defined attacks of worsening neurological function. These attacks are followed by periods of partial or complete recovery called remissions. During remission, symptoms often improve and there is no obvious worsening or progression of the disease. Approximately 85% of people with MS are initially diagnosed with RRMS.

[0246] In some embodiments, multiple sclerosis is relapsing multiple sclerosis (RMS). RMS includes several forms of MS with relapsing characteristics, including relapsing-remitting MS, progressive-relapsing MS, and secondary progressive MS.

[0247] In some embodiments, multiple sclerosis is primary progressive multiple sclerosis (PPMS). In this form, neurological function gradually worsens, but there are no distinct periods of relapse or remission. The rate of progression for an individual varies over time and may sometimes stabilize or temporarily improve, but the progression is continuous. 10% of people are diagnosed with this type of MS.

[0248] In some embodiments, multiple sclerosis is secondary progressive multiple sclerosis (SPMS). After an initial period of relapsing-remitting MS (RRMS), many people transition to SPMS. This disease steadily worsens and may or may not relapse, remit, or stabilize.

[0249] In some embodiments, a method for treating damage to a subject's nervous system, such as damage to the brain, spinal cord, and / or nerve tissue, is disclosed herein, the method comprising administering to the subject a compound or composition described herein.

[0250] In some embodiments, a method for treating cancer that affects a subject's nervous system is disclosed herein, the method comprising administering to the subject a compound or composition described herein. In some examples, the cancer is a brain cancer.

[0251] In some embodiments, methods for treating demyelination induced by an injury to a subject are disclosed herein, the methods comprising administering to the subject a compound or composition described herein.

[0252] In some embodiments, methods for treating an infectious disease of the nervous system of a subject are disclosed herein, the methods comprising administering to the subject a compound or composition described herein. In some examples, the infectious disease of the nervous system includes meningitis.

[0253] In some embodiments, methods for treating a nervous system disorder, impairment, or disease of a subject are disclosed herein, the methods comprising administering to the subject a compound or composition described herein. In some embodiments, methods for treating multiple sclerosis of a subject are disclosed herein, the methods comprising administering to the subject a compound or composition described herein. In some embodiments, the treatment includes inhibition or restoration of demyelination. Inhibition of demyelination includes a decrease in the rate of demyelination compared to a state in which treatment with a compound or composition described herein is not performed, the decrease in rate being at least a 5%, 10%, 20%, 30%, 40%, 50%, 80%, or 90% decrease in demyelination. In some examples, administration of a compound or composition described herein prevents, delays, and / or attenuates demyelination.

[0254] In some embodiments, methods for preventing or treating signs, symptoms, and / or complications of a neurological disorder, impairment, or disease are disclosed herein, the methods comprising administering a compound or composition described herein. In some embodiments, methods for preventing or treating signs, symptoms, and / or complications of multiple sclerosis in a subject are disclosed herein, the methods comprising the step of administering to the subject a compound or composition described herein. Signs and symptoms of multiple sclerosis include, but are not limited to, numbness or weakness in one or more limbs, partial or complete loss of vision, double vision, blurred vision, tingling, electric shock-like sensations, tremors, impaired coordination, unsteady gait, slurred speech, fatigue, dizziness, and changes in bowel and / or bladder function. Examples of multiple sclerosis complications include, but are not limited to, muscle stiffness, muscle spasm, paralysis, mental changes such as memory loss and mood swings, depression, and epilepsy.

[0255] In some embodiments, methods for reducing the frequency, severity, and / or duration of recurrence of a neurological disorder, impairment, or disease are disclosed herein, the methods comprising administering a compound or composition described herein. In some embodiments, methods for reducing the frequency, severity, and / or duration of recurrence of multiple sclerosis are disclosed herein, the methods comprising administering a compound or composition described herein. In some examples, administration of a compound or composition described herein suppresses or halts the progression of one or more symptoms in a patient with multiple sclerosis. In some examples, administration of a compound or composition described herein prevents or delays the onset of symptoms of multiple sclerosis.

[0256] In some instances, a neuropathy such as multiple sclerosis is treated with a combination of a compound or composition described herein and one or more additional treatments. The additional treatments include, but are not limited to, plasma exchange, physical therapy, muscle relaxants, exercise, rest, and, hereinafter, corticosteroids, beta interferon, glatiramer acetate, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, mitoxantrone; and administration of one or more of these combinations.

[0257] Neurological diseases, disorders, and conditions that are amenable to treatment with the compounds or compositions described herein, or characteristics of neurological diseases, disorders, and conditions, include, but are not limited to, agenesis of the septum pellucidum, acid lipase diseases, acid maltase deficiency, acquired epileptic aphasia, acute disseminated encephalomyelitis, ADHD, Adie's pupil, Adie's syndrome, adrenoleukodystrophy, agenesis of the corpus callosum, cognitive impairment, Aicardi syndrome, neurological complications due to AIDS, Alexander disease, Alpers' disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anencephaly, aneurysm, Angelman syndrome, angiomatosis, anoxia, antiphospholipid syndrome, aphasia, apraxia, arachnoid cyst, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformation, Asperger syndrome, ataxia, stroke, Barth syndrome, Batten disease, Becker's myotonia, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal atrophy, benign intracranial hypertension, Bernhardt-Roth syndrome, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury, Bradberry-Eggleston syndrome, cerebral aneurysm, brain injury, Brown-Séquard syndrome, CADASIL, Canavan disease, causalgia, cavernoma, cavernous-like angioma, cavernous vascular malformation, central cord syndrome, central pain syndrome, central pontine myelinolysis, head injury, ceramidase deficiency, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral beriberi, cerebral cavernous malformation, cerebral gigantism, cerebral hypoxia, cerebral palsy, cerebro-oculo-facial-skeletal syndrome, Chiari malformation, chorea, choreic acanthocytosis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic orthostatic intolerance, Cockayne syndrome type II, Coffin-Lowry syndrome, colpocephaly, coma, complex regional pain syndrome, congenital facial diplegiadiplegia, congenital myasthenia, congenital myopathy, congenital cavernous angioma, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, giant cell inclusion disease, cytomegalovirus infection, Dandy-Walker syndrome, Dawson disease, De Morsier syndrome, Dejerine-Klumpke paralysis, dementia, dentate cerebellar ataxia, dentatorubral atrophy, dermatomyositis, developmental coordination disorder, Devic disease, diabetic neuropathy, multiple sclerosis, Drave syndrome, autonomic neuropathy, dysgraphia, dysphagia, dyspraxia, cerebellar ataxia, dystonia, spinal muscular atrophy, encephalopathy, empty sella syndrome, encephalitis, brain tumor, cerebrovascular malformation in the trigeminal region of the brain, epilepsy, Erb-Duchenne and Dejerine-Klumpke paralysis, Erb anesthesia, extrapontine myelinolysis, Fabry disease, Fahr syndrome, familial dysautonomia, familial angioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, Farber disease, febrile convulsion, fibromuscular dysplasia, Fisher syndrome, Friedreich ataxia, and frontotemporal dementia are included.

[0258] Inflammation and inflammatory disorders In some embodiments, methods of treating inflammatory diseases, illnesses, or disorders using the compounds or compositions disclosed herein are disclosed herein. In some embodiments, methods of reducing inflammation in a subject's tissue are disclosed herein, the method comprising administering to the subject a compound or composition described herein. In some examples, the tissue is colorectal tissue.

[0259] As used in this disclosure, "inflammation" refers to the well-known local reaction to various types of injury or infection, which is characterized by redness, heat, swelling, and pain, and often includes dysfunction or decreased mobility.

[0260] In some embodiments, the methods described herein include methods for treating the following additional inflammatory diseases or disorders, reducing the risk thereof, and delaying the onset thereof, using the compounds or compositions described herein: (a) ocular inflammation associated with, for example, corneal ulcers, giant papillary conjunctivitis, blepharitis, chalazia, uveitis, dry eye, postoperative inflammation, and contact lens-related inflammation; (b) allergic diseases such as hay fever, rhinitis, seasonal allergic conjunctivitis, vernal conjunctivitis, and other eosinophil-mediated diseases; (c) skin diseases such as psoriasis, contact dermatitis, eczema, infectious skin ulcers, open wounds, and cellulitis; (d) infectious diseases including sepsis, septic shock, encephalitis, infectious arthritis, endotoxin shock, gram-negative bacterial shock, Jarisch-Herxheimer reaction, herpes zoster, toxic shock, cerebral malaria, bacterial meningitis, acute respiratory distress syndrome (ARDS), Lyme disease, and HIV infection; (e) wasting diseases such as cachexia secondary to cancer or HIV; (f) inflammation due to transplantation of organs, tissues, or cells (e.g., bone marrow, cornea, kidney, lung, liver, heart, skin, islets) including transplant rejection, and graft-versus-host disease; (g) side effects of drug therapies including side effects of amphotericin B treatment, immunosuppressive therapies such as treatment with interleukin 2, side effects of OKT3 treatment, side effects of GM-CSF treatment, side effects of cyclosporine treatment, and side effects of aminoglycoside treatment, stomatitis, and mucositis due to immunosuppression; (h) circulatory diseases including those induced or exacerbated by inflammatory responses such as ischemia, atherosclerosis, peripheral vascular disease, restenosis after angioplasty, inflammatory aortic aneurysms, vasculitis, stroke, spinal cord injury, congestive heart failure, hemorrhagic shock, ischemia / reperfusion injury, vasospasm after subarachnoid hemorrhage, cerebrovascular attack after vasospasm, pleurisy, pericarditis, and cardiovascular complications of diabetes; (i) dialysis including pericarditis due to peritoneal dialysis; (j) gout; and (k) burns, chemical agents such as acids, alkalis, or inflammation induced by heat, etc.

[0261] Autoimmune diseases The methods described herein, in some embodiments, include methods for treating, reducing the risk of, and delaying the onset of autoimmune diseases or disorders using the compounds or compositions disclosed herein. Examples of autoimmune diseases include, but are not limited to, alopecia areata, lupus erythematosus, ankylosing spondylitis, Meniere's disease, antiphospholipid antibody syndrome, mixed connective tissue disease, autoimmune Addison's disease, autoimmune hemolytic anemia, myasthenia gravis, autoimmune hepatitis, pemphigus vulgaris, Behcet's disease, pernicious anemia, bullous pemphigoid, polyarteritis nodosa, myocarditis, polychondritis, celiac sprue dermatitis, polyglandular syndrome, chronic fatigue syndrome (CFIDS), polymyalgia rheumatica, chronic inflammatory demyelinating, polymyositis and dermatomyositis, chronic inflammatory polyneuropathy, primary agammaglobulinemia, Churg-Strauss syndrome, primary biliary cirrhosis, endometriosis pemphigoid, psoriasis, CREST syndrome, Raynaud's syndrome, cold agglutinin disease, Reiter's syndrome, Crohn's disease, rheumatic fever, discoid lupus, multiple sclerosis, rheumatoid arthritis, essential mixed cryoglobulinemia, sarcoidosis, connective tissue inflammation, scleroderma, Grave's disease, Sjogren's syndrome, Guillain-Barre, stiff-person syndrome, Hashimoto's thyroiditis, Takayasu arteritis, idiopathic pulmonary fibrosis, temporal arteritis / giant cell arteritis, idiopathic thrombocytopenic purpura (ITP), ulcerative colitis, IgA nephropathy, uveitis, insulin-dependent diabetes (type I), diabetes (type II), vasculitis, lichen planus, and vitiligo vulgaris.

[0262] In some embodiments, methods for treating, reducing the risk of, and delaying the onset of autoimmune diseases or disorders further include administration of immunosuppressive agents. Examples of immunosuppressive agents include, but are not limited to, glucocorticoids, cell division inhibitors, antibodies, and agents that act on immunophilins. Examples of glucocorticoids include cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone, deoxycorticosterone, and aldosterone. Examples of cell division inhibitors include alkylating agents (e.g., nitrogen mustards such as cyclophosphamide, nitrosoureas, platinum compounds) and antimetabolites (e.g., folic acid analogs such as methotrexate, purine analogs such as azathioprine and mercaptopurine, pyrimidine analogs such as fluorouracil, protein synthesis inhibitors). Examples of drugs used in the described methods include cyclosporine, tacrolimus, sirolimus, interferon, opioid, TNF-binding protein, mycophenolate, and fingolimod. Examples of antibodies useful for co-administration with the compounds or compositions described herein in the methods described herein include antithymocyte globulin, 1D09C3, adalimumab / D2E7 (Humira; Trudexa), afelimomab, ofatumumab / GA101 (type II), alemtuzumab / Campath-1H (MabCampath), apolizumab / Hu1D10, Aselizumab, atrilizumab (Atlizumab), basiliximab (Simulect), bectumomab (Bectumomab) / IMMU-LL2, belimumab (Belimumab) (Benlysta, LymphoStat-B), Bertilimumab, BL22 / CAT-3888, brentuximab (Brentuximab) / cAC10 / SGN-35, briakinumab / ABT-874, canakinumab (Canakinumab) / ACZ885 (Ilaris), certolizumab pegol (CertolizumabPegol) / CDP870 (Cimzia), Clenoliximab, Dacetuzumab / SGN-40, Daclizumab (Zenapax), Eculizumab / 5G1.1 (Soliris), Efalizumab (Raptiva, formerly Xanelim), Epratuzumab / hLL2 / IMMU-102 (Lymphocyde(c)), Fontolizumab, Fresolimumab / GC-1008, Galiximab / IDEC-114, Gavilimomab / ABX-CBL, Gemtuzumab, Golimumab / CNTO148 (Simponi), HL2434P (IMMU-114), Ibritumomab tiuxetan (MXDPTA) / IDEC Y2B8 (Zevalin), Infliximab / chimeric A2 (cA2) (Remicade), Inolimomab / BT563, Inotuzumab, Keliximab / IDEC CE9.1, Reldelimomab / CAT-152, Lynxuzumab / HuM195 (Zamyl), LMB-2, Lorvotuzumab mertansine, Lumiliximab / IDEC-152, Lym-1 (Oncolym), MDX-060, Mepolizumab / SB-240563, Metelimumab / CAT-192, Mogamulizumab / KW-0761 / AMG-761, Moxetumomab pasudotox / CAT-8015 / HA22, Muromonab-CD3 (Orthoclone OKT3), Natalizumab (Tysabri, Antigren), Nerelimomab / CDP571, Ocrelizumab / PRO70769 (Type I), Odulimomab, Ofatumumab / 2F2 / HuMax-CD20 (Arzerra) (Type I), Omalizumab (Xolair), Otelixizumab / TRX4, Pascolizumab / SB 240683, Reslizumab / SCH 55700 (Cinquil), Rituximab / chimeric 2B8 (IDEC-C2B8) (Rituxan, MabThera) (Type I), rupulizumab (Antova), SAR-3419, secukinumab / AIN-457, SGN30, sipulizumab / MEDI-507, teplyzumab / MGA031 / hOKT3γ1(Ala-Ala), tocilizumab (Actemra), tositumomab (Type II), ustekinumab / CNTO 1275 (Stelara), vedolizumab / MNL-0002, belzutifan / IMMU-106 / hA20 (Type I), bimagrumab (Novion), zanilimumab / HuMax-CD4, zolimomab aritox / H65, abatacept / CTLA4-Ig / BMS-188667 (Orencia), belatacept / LEA29Y, atacicept / BLyS / APRIL-Ig, etanercept / TNFR-Ig (Enbrel), pegsunercept / pegylated TNFR-Ig, alefacept (Amevive), and rilonacept (Arcalyst). Immunosuppressive antibodies include antibodies that target complement-dependent proteins and interleukins.

[0263] Angiogenesis In some embodiments, methods for treating or preventing angiogenesis in a subject are described herein, the method comprising administering to the subject a compound or composition described herein. Angiogenesis includes sprouting angiogenesis and intussusceptive angiogenesis. In some examples, the method further comprises administering an angiogenesis inhibitor (e.g., a VEGF inhibitor (bevacizumab), sorafenib, sunitinib, pazopanib, everolimus, or a combination thereof).

[0264] Cancer Autotaxin has been demonstrated to increase cell motility, neovascularization, proliferation, and aggressiveness of tumors. ATX is upregulated in many tumor lineages such as breast cancer, renal cancer, liver cancer, glioblastoma, ovarian cancer, and prostate cancer.

[0265] In some embodiments, methods of treating cancer with a compound or composition disclosed herein are disclosed herein.

[0266] Autotaxin is a metastasis-promoting enzyme first isolated from the conditioned medium of human melanoma cells. In addition, overexpression of autotaxin is frequently observed in malignant tumor tissues such as breast cancer, renal cancer, Hodgkin's lymphoma, hepatocellular carcinoma, pancreatic cancer, and glioblastoma. LPA further contributes to tumorigenesis by increasing cell motility and invasiveness.

[0267] The term "cancer" as used herein refers to the abnormal growth of cells that proliferate in an uncontrolled manner and, in some cases, have a tendency to metastasize (spread). Types of cancer include, but are not limited to, solid tumors (bladder tumors, intestinal tumors, brain tumors, breast tumors, endometrial tumors, heart tumors, kidney tumors, lung tumors, liver tumors, uterine tumors, lymphoid tissue tumors (lymphomas), ovarian tumors, pancreatic tumors, or tumors of other endocrine organs (thyroid), prostate tumors, skin tumors (melanomas or basal cell carcinomas), or blood tumors (such as leukemias and lymphomas) at any stage of the disease with or without metastasis.

[0268] Non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumor, tumors of the brain and spinal cord, breast cancer, bronchial tumor, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, desmoid tumor, embryonal tumor, endometrial cancer, ependymoma, ependymoblastoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal interstitial cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, oropharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, low malignant potential ovarian tumor, pancreatic cancer, papilloma, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumor of intermediate differentiation, pineoblastoma and primitive neuroectodermal tumor supratentorial, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, primitive neuroectodermal tumor supratentorial, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms tumor.

[0269] In some embodiments, the compounds or compositions described herein, or pharmaceutically acceptable salts thereof, are used in the treatment of ovarian cancer, prostate cancer, breast cancer, lung cancer, melanoma, head and neck cancer, bowel cancer (colorectal cancer), thyroid cancer, glioblastoma, follicular lymphoma, renal cancer, Hodgkin's lymphoma, hepatocellular carcinoma, pancreatic cancer, or melanoma.

[0270] In one embodiment, the compounds or compositions described herein, or pharmaceutically acceptable salts thereof, are used in the treatment of pancreatic cancer. In some such embodiments, the compounds or compositions described herein, or pharmaceutically acceptable salts thereof, are used in the treatment of pancreatic cancer in combination with one or more chemotherapeutic agents.

[0271] In some embodiments, the compounds or compositions described and disclosed herein, or pharmaceutically acceptable salts thereof, are used in the treatment of bone metastases.

[0272] In some embodiments, the compounds or compositions described and disclosed herein, or pharmaceutically acceptable salts thereof, are used in the treatment of oral cancer, prostate cancer, rectal cancer, non-small cell lung cancer, lip and oral cavity cancer, liver cancer, lung cancer, anal cancer, renal cancer, vulvar cancer, breast cancer, oropharyngeal cancer, nasal and paranasal cavity cancer, hypopharyngeal cancer, urethral cancer, small intestine cancer, cholangiocarcinoma, bladder cancer, ovarian cancer, laryngeal cancer, hypopharyngeal cancer, gallbladder cancer, colon cancer, colorectal cancer, head and neck cancer, parathyroid cancer, penile cancer, vaginal cancer, thyroid cancer, pancreatic cancer, esophageal cancer, Hodgkin's lymphoma, disorders associated with leukemia, fungating polyps, or myelodysplastic syndromes.

[0273] In some embodiments, the compounds or compositions described and disclosed herein, or pharmaceutically acceptable salts thereof, are used in the treatment of non-small cell lung cancer, pancreatic cancer, breast cancer, ovarian cancer, colorectal cancer, or head and neck cancer.

[0274] In some embodiments, the compounds or compositions described herein, or pharmaceutically acceptable salts thereof, are used in the treatment of carcinomas, tumors, neoplasms, lymphomas, melanomas, glioblastomas, sarcomas, or blastomas.

[0275] In some embodiments, the cancer is selected from the group consisting of: carcinoma, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adrenocortical carcinoma, well-differentiated carcinoma, squamous cell carcinoma, serous carcinoma, small cell carcinoma, invasive squamous cell carcinoma, large cell carcinoma, pancreatic islet cell carcinoma, oat cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, verrucous carcinoma, renal cell carcinoma, papillary serous adenocarcinoma, Merkel cell carcinoma, hepatocellular carcinoma, soft tissue carcinoma, bronchial adenocarcinoma, capillary carcinoma, Bartholin gland adenocarcinoma, basal cell carcinoma, carcinosarcoma, papilloma / carcinoma, clear cell carcinoma, endometroid adenocarcinoma, metastatic carcinoma of the mesothelium, mucoepidermoid carcinoma, cholangiocarcinoma, actinic keratosis, cystadenoma, and hepatic adenomatosis.

[0276] In some embodiments, the tumor is selected from the group consisting of: astrocytic tumor, malignant mesothelioma, ovarian germ cell tumor, primitive neuroectodermal tumor above the tentorium, Wilms tumor, pituitary tumor, extragonadal germ cell tumor, gastrinoma, germ cell tumor, trophoblastic tumor, brain tumor, pineal and primitive neuroectodermal tumor above the tentorium, pituitary tumor, somatostatin-secreting tumor, endodermal sinus tumor, carcinoid, central cerebral astrocytoma, glucagon-producing tumor, hepatic adenoma, insulinoma, medulloepithelioma, plasmacytoma, bipoma, and pheochromocytoma.

[0277] In some embodiments, the neoplasm is selected from the group consisting of: intraepithelial neoplasm, multiple myeloma / plasma cell neoplasm, plasma cell neoplasm, epitheliomatous squamous cell neoplasm, endometrial hyperplasia, focal nodular hyperplasia, hemangioendothelioma, lymphangioleiomyomatosis, and malignant thymoma.

[0278] In some embodiments, the lymphoma is selected from the group consisting of: nervous system lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenström macroglobulinemia.

[0279] In some embodiments, melanoma is selected from the group consisting of: acral lentiginous melanoma, superficial spreading melanoma, uveal melanoma, lentigo maligna-derived melanoma, melanoma, intraocular melanoma, adenocarcinoma nodular melanoma, and hemangioma.

[0280] In some embodiments, sarcoma is selected from the group consisting of: adenoma, adenocarcinoma, chondrosarcoma, endometrial stromal sarcoma, Ewing's sarcoma, Kaposi's sarcoma, leiomyosarcoma, rhabdomyosarcoma, sarcoma, uterine sarcoma, osteosarcoma, and pseudosarcoma.

[0281] In some embodiments, glioma is selected from the group consisting of: glioma, brainstem glioma, and glioma of the hypothalamus and optic pathway.

[0282] In some embodiments, blastoma is selected from the group consisting of: pulmonary blastoma, pleuropulmonary blastoma, retinoblastoma, neuroblastoma, medulloblastoma, glioblastoma, and hemangiblastomas.

[0283] Airway diseases Inflammatory diseases, disorders, and conditions that can be treated with the compounds or compositions disclosed herein include airway diseases, including pulmonary inflammation such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma. COPD is primarily composed of two related diseases: chronic bronchitis and emphysema. In both diseases, there is a chronic obstruction of the flow of air through and out of the airways, which is generally persistent and progressive over time.

[0284] Asthma is a chronic disease of the airways of the lungs characterized by inflammation of the bronchi and opposing narrowing. Asthma includes extrinsic asthma (allergic asthma), intrinsic asthma (non-allergic asthma), mixed asthma (extrinsic and intrinsic asthma), occupational asthma caused by agents such as toluene diisocyanate, polyvinyl chloride, phthalic anhydride, trimellitic anhydride, plicatic acid (basswood), or metal salts such as platinum or nickel, or drug-induced asthma (including asthma caused by aspirin or non-steroidal anti-inflammatory drugs (NSAIDs)), exercise-induced asthma, and T cell-mediated asthmatic diseases including cough-variant asthma. In some embodiments, asthma is an allergic or non-allergic asthmatic disease mediated by T cell function.

[0285] In some embodiments, methods of treating asthma using the compounds or compositions described herein are disclosed herein. In asthmatic individuals, the release of normal repair mediators including LPA is impaired or the action of repair mediators is inappropriately prolonged, causing inappropriate airway remodeling. The main structural features of the remodeled airways seen in asthma include thickening of the reticular lamina (a structure like the basement membrane beneath airway epithelial cells), increased number and activity of myofibroblasts, thickening of the smooth muscle layer, increased number of mucus glands and mucus secretion, and alteration of connective tissue and capillary bed throughout the airway wall. In some embodiments, autotaxin and / or LPA contribute to these structural changes in the airways. In some embodiments, autotaxin and / or LPA are involved in the acute airway hyperresponsiveness during asthma. The lumen of the remodeled asthmatic airway is narrowed by thickening of the airway wall, thereby reducing air flow. In some embodiments, LPA contributes to long-term structural remodeling and acute hyperresponsiveness of the asthmatic airway. In some embodiments, LPA contributes to the enhanced responsiveness that is a major feature of the acute exacerbation phase of asthma.

[0286] In some embodiments, methods of treating or preventing COPD using the compounds or compositions described herein are disclosed herein. The term "chronic obstructive pulmonary disease (COPD)" refers to a group of lung diseases including chronic bronchitis, emphysema, and obliterative bronchiolitis. The most common of these diseases are chronic bronchitis and emphysema. A person with COPD may have either chronic bronchitis or emphysema, or may have a mixture of the symptoms of these two diseases. Emphysema is usually caused by damage to the lungs due to the environment itself, usually as a result of long-term smoking, but can also be caused by an inherited deficiency of α1-antitrypsin in the lungs, and this type of emphysema is usually inherited.

[0287] In some embodiments, methods of treating chronic bronchitis using the compounds or compositions described herein are disclosed herein. Chronic bronchitis (CB) is an inflammation of one or more bronchi that usually occurs secondarily to an infection and is characterized by excessive production of mucus in the bronchi, accompanied by a recurrent cough that lasts at least three months out of at least two consecutive years. CB is a major non-asthmatic disease of the lungs. Various factors, including tobacco smoke, environmental pollution, chronic infections, and various genetic abnormalities, cause CB. Of these factors, tobacco smoke is the most common. The pathological changes in the lungs include, hereinafter, (1) hypertrophy and hyperplasia of the mucus-secreting glands in the bronchi, (2) an increase in goblet cells, (3) disappearance or damage of cilia, and (4) chronic inflammatory changes and narrowing of the peripheral airways.

[0288] In some embodiments, methods of treating emphysema using the compounds or compositions described herein are disclosed herein. Emphysema is a lung disease caused by damage to the alveolar sacs in the lungs, usually caused by long-term smoking. This damage results in a pathological accumulation of air in the tissue.

[0289] In vivo administration of LPA causes airway hyperresponsiveness, itch-scratch response, eosinophil and neutrophil infiltration and activation, vascular remodeling, and nociceptive flexor response. LPA further causes histamine release from mast cells in mice and rats. In acute allergic reactions, histamine causes various responses such as smooth muscle contraction, plasma exudation, and mucus production. Plasma exudation is important in the airway because leakage and subsequent airway wall edema contribute to the development of airway hyperresponsiveness. In some embodiments, methods are disclosed herein for reducing plasma leakage resulting from acute allergic reactions using the compounds or compositions described herein.

[0290] Obesity In some embodiments, methods are disclosed herein for treating obesity and / or diabetes using the compounds or compositions described herein.

[0291] Autotaxin is responsible for the lysoPLD activity released by adipocytes and exerts paracrine regulation on preadipocyte proliferation through an LPA-dependent mechanism. In addition, autotaxin is upregulated in genetic obesity during adipocyte differentiation. In one example, autotaxin mRNA is upregulated in adipocytes from db / db mice, suggesting that upregulation of autotaxin is associated with a severe type 2 diabetes phenotype and adipocyte insulin resistance. In some examples, upregulation of autotaxin in adipocytes is associated with type 2 diabetes.

[0292] The term "obesity", as used herein, refers to a medical condition in which excess body fat has accumulated to the extent that it may have side effects on health and increase health-related problems. In some embodiments, "obesity" refers to weight gain, which is at least 5% of total body weight. In some embodiments, methods are disclosed herein for treating postmenopausal obesity and / or visceral obesity using the compounds or compositions described herein.

[0293] Metabolic disorder In some embodiments, methods for treating metabolic disorders and diseases associated with metabolic disorders are disclosed herein, the methods comprising administering a compound or composition described herein. As used herein, "metabolic disorder" refers to any medical condition resulting from an alteration in the metabolism of a subject. Such disorders include those resulting from an alteration in glucose homeostasis and / or insulin dysfunction. Metabolic disorders include, but are not limited to, metabolic syndrome, high blood glucose, insulin resistance, impaired glucose tolerance, type 2 diabetes, type 1 diabetes, prediabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and obesity.

[0294] Metabolic disorders are interrelated and can lead to various disorders across different systems. By addressing central metabolic disorders, for example, in a patient, the severity of related diseases can be reduced, including cardiovascular diseases (including, for example, ischemic heart disease, angina, myocardial infarction, congestive heart failure, hypertension, abnormal cholesterol levels, deep vein thrombosis, and pulmonary embolism), neurological disorders (including, for example, stroke, neuropathic femoral pain, migraine (idiopathic), and increased intracranial pressure, depression and social stigma), rheumatic diseases and orthopedic disorders (including, for example, gout, poor mobility, osteoarthritis, and low back pain), dermatological diseases (including, for example, striae, epidermal nevus, lymphedema, and cellulitis), gastrointestinal diseases (including, for example, gastroesophageal reflux disease (GERD) and cholelithiasis (gallstones)), respiratory diseases (including, for example, obstructive sleep apnea, obesity hypoventilation syndrome, asthma, and increased complications during general anesthesia), urological and renal diseases (including, for example, erectile dysfunction, urinary incontinence, chronic kidney disease, and hypogonadism).

[0295] In some embodiments, methods of treating metabolic disorders are described herein. In some embodiments, administration of a compound or composition described herein to an individual with a metabolic disorder has various desirable results including, but not limited to, a decrease in blood glucose level, a decrease in plasma lysophosphatidic acid level, an improvement in insulin sensitivity, an increase in insulin secretion, an improvement in glucose tolerance, and a decrease in adipose tissue expansion. Any of these results can treat, delay, or prevent the onset of a metabolic disorder, where such metabolic disorders include, but are not limited to, metabolic syndrome, high blood glucose, insulin resistance, impaired glucose tolerance, type 2 diabetes, type 1 diabetes, prediabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and obesity.

[0296] In some embodiments, methods of administering a compound or composition described herein to lower fasting blood glucose levels in mice fed a high-fat diet are described. Mice fed a high-fat diet have higher fasting blood glucose levels than mice fed a normal diet, as exemplified herein. Administration of a compound or composition described herein to mice fed a high-fat diet decreased fasting blood glucose levels, thereby bringing the fasting blood glucose levels closer to the levels observed in mice fed a normal diet.

[0297] In some embodiments, the methods disclosed herein include administering a compound or composition described herein to a subject with elevated blood glucose levels. In some embodiments, an autotaxin inhibitor is used to treat underlying metabolic disorders. In some embodiments, a metabolic disorder is treated by lowering blood glucose levels. In some embodiments, the subject is overweight or obese. In some embodiments, the subject has type 2 diabetes. In some embodiments, the subject has non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis. In some embodiments, the subject does not have a metabolic disorder. In some embodiments, an autotaxin inhibitor delays or prevents the onset of a metabolic disorder by lowering high blood glucose levels.

[0298] In some embodiments, methods for reducing an individual's plasma lysophosphatidic acid level are described herein, the methods comprising administering a compound or composition described herein. In some embodiments, the plasma lysophosphatidic acid level in an individual is higher than that of a control. In some embodiments, the control is a person without a metabolic disorder. In some embodiments, the individual's high plasma lysophosphatidic acid level contributes to, or increases, the risk of developing a metabolic disorder.

[0299] In some embodiments, methods are disclosed herein that comprise administering a compound or composition described herein to a subject having an elevated plasma lysophosphatidic acid level as compared to a control. In some embodiments, methods for improving insulin sensitivity are disclosed herein, the methods comprising administering a compound or composition described herein to an individual sensitive to insulin. In some embodiments, methods are disclosed herein that comprise administering a compound or composition described herein to a subject having insulin resistance. In some embodiments, methods are disclosed herein that comprise administering a compound or composition described herein to improve insulin secretion in an individual. In some embodiments, methods are disclosed herein that comprise administering a compound or composition described herein to improve glucose tolerance in an individual having impaired glucose tolerance. In some embodiments, methods are disclosed herein for reducing the expansion of adipose tissue in a subject, the methods comprising administering a compound or composition described herein to the subject. In some embodiments, methods are disclosed herein for treating a metabolic disorder in a subject who is overweight or obese, the methods comprising administering a compound or composition described herein to the subject.

[0300] Drug-induced hyperglycemia In some embodiments, methods for treating drug-induced hyperglycemia in a subject are disclosed herein, the methods comprising administering to the subject a compound or composition described herein. In some embodiments, administration of a compound or composition described herein to a subject treats, prevents, or ameliorates symptoms of drug-induced hyperglycemia. In some embodiments, administration of a compound or composition described herein to a subject treats, prevents, or ameliorates symptoms of drug-induced hyperglycemia by reducing blood glucose levels. Drugs may sometimes confer glucose homeostasis that can result in hyperglycemia. In some embodiments, hyperglycemia occurs in the absence of a diagnosis of diabetes. High blood glucose levels, if left untreated, can lead to a medical emergency. Symptoms include, but are not limited to, fatigue, weakness, fruity-smelling breath, confusion, lack of concentration, shortness of breath in the skin, nausea, vomiting, dry skin, and flushing of the skin. Common drug categories associated with contributing to hyperglycemia include, but are not limited to, antibiotics such as fluoroquinolones including gatifloxacin; beta-blockers such as propranolol, metoprolol, or atenolol; thiazides such as hydrochlorothiazide, and thiazide-like diuretics and thiazide-like drugs (metolazone); second-generation antipsychotics (SGA), or "atypical antipsychotics" such as olanzapine or clozapine; corticosteroids; calcineurin inhibitors such as cyclosporine, sirolimus, or tacrolimus; protease inhibitors such as ritonavir.

[0301] Stress-induced hyperglycemia In some embodiments, methods for treating stress-induced hyperglycemia in a subject are disclosed herein, the methods comprising administering to the subject a compound or composition described herein. In some embodiments, administration of the compound or composition described herein to a subject treats, prevents, or delays the onset of stress-induced hyperglycemia. In some embodiments, administration of the compound or composition described herein to a subject treats, prevents, or delays the onset of stress-induced hyperglycemia by lowering blood glucose levels. Stress-induced hyperglycemia (SIH) is a transient increase in plasma glucose levels above 200 mg / dL that occurs during acute illness or injury. In some embodiments, the hyperglycemia occurs in the absence of a diagnosis of diabetes. SIH results from excessive glucose production relative to glucose removal. SIH is associated with diseases including, but not limited to, myocardial infarction, stroke, and trauma. SIH is associated with increased mortality and a high incidence of congestive heart failure and cardiac shock in patients after myocardial infarction. Persons who have suffered a stroke have a high mortality associated with SIH, and the likelihood of a desirable neurological outcome decreases as blood glucose levels increase with SIH. Hyperglycemia has also been found to be a precursor to pneumonia, urinary tract infections, wound infections, and infectious complications in the form of bacteria. Overall, published studies have consistently shown high morbidity and mortality in patients presenting with SIH.

[0302] Intraocular pressure In some embodiments, methods for treating elevated intraocular pressure associated with glaucoma in a subject are disclosed herein, the methods comprising administering to the subject a compound or composition described herein.

[0303] Glaucoma is one of the leading causes of blindness and is characterized by an increase in intraocular pressure (IOP). IOP is a major risk factor for developing glaucoma, and the risk of developing glaucoma decreases when IOP is reduced. Treatment of ocular hypotension is the mainstay of glaucoma treatment. The increase in IOP is due to a decrease in the drainage of aqueous humor (AH) through the trabecular pathway, and autotaxin activity is a protein abundant in human AH. Autotaxin is secreted by human trabecular meshwork cells, and autotaxin activity is significantly increased in glaucoma patients. Inhibition of autotaxin activity in AH by local and intracameral delivery of small molecule inhibitors results in a decrease in IOP in rabbits.

[0304] Neuropathic pain In some embodiments, methods of treating neuropathic pain using the compounds or compositions described herein are disclosed herein.

[0305] LPA causes neuropathic pain as well as demyelination, and pain-related protein expression is altered via LPA1. In some examples, heterozygous knockout mice of autotaxin show approximately 50% recovery of neuropathic pain induced by nerve injury compared to wild-type mice. Lysophosphatidylcholine (LPC) is known to cause neuropathic pain. In one example, neuropathic pain caused by LPC is partially reduced in heterozygous knockout mice of autotaxin.

[0306] Neuropathic pain results from damage to nerves. In contrast to the immediate pain caused by tissue injury, in some embodiments, neuropathic pain develops days or months after trauma. In addition, neuropathic pain is often persistent or chronic and can occur spontaneously or as a result of a stimulus that is not normally painful.

Example

[0307] Additional embodiments are disclosed in more detail in the following examples, which are not intended to limit the claims in any way.

[0308] X-ray powder diffraction X-ray powder diffraction (XRPD) experiments were carried out using a PANalytical X’Pert3 and an Empyrean X-ray powder diffractometer, using the parameters listed below.

[0309] [Table 1]

[0310] Thermogravimetric analysis and differential scanning calorimetry Thermogravimetric analysis (TGA) was carried out using a TA Instruments TA Discovery5500 / Q5000 TGA system. Differential scanning calorimetry (DSC) was carried out using a TA Instruments TA Discovery2500 / Q2000 DSC system. The parameters of the instruments used for TGA and DSC are listed below.

[0311] [Table 2]

[0312] Determination of molar ratio The molar ratio was analyzed using a Waters H-Class ultra-high performance liquid chromatography (UPLC) system, using the conditions and parameters listed below.

[0313] [Table 3]

[0314] Stability measurement Stability measurements were analyzed using a Waters H-Class ultra-high performance liquid chromatography (UPLC) system, using the conditions and parameters listed below.

[0315]

Table 4

[0316] Ion chromatography The stoichiometric ion chromatography (IC) analysis was performed using a ThermoFisher ICS-1100 machine with the conditions and parameters listed below.

[0317]

Table 5

[0318] Dynamic vapor sorption The dynamic vapor sorption (DVS) analysis was carried out using an SMS (Surface Measurement Systems) DVS Intrinsic analyzer with the parameters listed below.

[0319]

Table 6

[0320] 1 1H nuclear magnetic resonance (NMR) 1 The 1H-NMR spectra were obtained on a Bruker 400 MHz spectrometer. The sample was prepared by dissolving the material in DMSO-d 6 6.

[0321] Example 1: Compound 1 in Form A The first isolation of Form A of Compound 1 was first carried out on a 50 mg scale and then repeated on a 1 g scale. Approximately 50 mg of the sodium salt of Compound 1 was dissolved in approximately 1 mL of MeOH / H 2It was dissolved in O(1:1, v / v) at 50 °C. The solution was stirred at 50 °C for about 6 hours, and then a suspension was obtained by dropwise adding a 1 M solution of HCl to the solution. The suspension was stirred at room temperature for 6 hours, and Form A of Compound 1 was isolated by vacuum filtration, then washed with water, and subsequently dried under vacuum at room temperature overnight. About 45 mg of Form A of Compound 1 was obtained. This procedure was repeated with about 1 g of the sodium salt of Compound 1, and about 850 mg of Form A of Compound 1 was obtained.

[0322] The final isolation of Form A of Compound 1 was carried out by dissolving 4.4 g of the sodium salt of Compound 1 in 90 mL of MeOH / H 2 O(1:1, v / v) at 50 °C. The solution was stirred at 50 °C for about 6 hours, and when the pH of the solution was measured, it was 11.1. A suspension was obtained by adding 10 mL of a 1 M solution of HCl to the solution. When the pH of the suspension was measured, it was 1.7. 840 mg of the form of the compound obtained as described herein of Form A was added to the suspension, and subsequently stirred at room temperature for 6 hours. Form A of Compound 1 was isolated by vacuum filtration, then washed with 50 mL of water, and subsequently dried under vacuum at room temperature overnight to obtain 4.95 g of Form A of Compound 1. The yield was about 98.8%. This final batch of Form A of Compound 1 was used in the screening experiment.

[0323] Example 2: Polymorph Screening Experiment of Compound 1 A polymorph screening experiment using Form A of Compound 1 prepared as described in Example 1 was carried out using various solvents under various conditions. To prepare the polymorphic forms of Compound 1, one of the following crystallization methods was used.

[0324] Slurry experiment at room temperature: About 20 mg of Form A of Compound 1 was suspended in 0.5 mL of the corresponding solvent in an HPLC vial at room temperature. The suspension was magnetically stirred at room temperature for 7 days (~1000 rpm). The obtained solid was isolated for XRPD analysis.

[0325] Slurry experiment at 50 °C Approximately 20 mg of Form A of Compound 1 was suspended in 0.5 mL of the corresponding solvent in an HPLC vial. The suspension was magnetically stirred at 50 °C for 3 days (~1000 rpm). The resulting solid was isolated for XRPD analysis.

[0326] Temperature cycle: Approximately 20 mg of Form A of Compound 1 was suspended in 0.5 mL of the corresponding solvent in an HPLC vial. The suspension was magnetically stirred at a temperature cycle from 50 °C to 5 °C (0.1 °C / min, 3 cycles) for 3 days (~1000 rpm). The resulting solid was isolated for XRPD analysis.

[0327] Poor solvent precipitation: Approximately 20 mg of Form A of Compound 1 was dissolved in a minimal amount of solvent at a specific temperature. The solution was filtered to obtain a clear solution, and the solution was magnetically stirred (~1000 rpm), followed by slowly adding the poor solvent until a precipitate appeared or the total volume of the poor solvent reached 5 mL. The resulting precipitate was isolated for XRPD analysis.

[0328] The results of the polymorph screening experiment produced five crystal forms, designated as Form A, Form B, Form C, Form D, and Form E. Form E was obtained by purging Form A with nitrogen and reverted to Form A after 5 hours in the ambient environment. The experimental results for Form A, Form B, Form C, and Form D are shown in Table 1.

[0329]

Table 7-1

Table 7-2

[0330] Example 3: Competitive slurry experiment of crystal forms of Compound 1 Acetone / H 2 O solutions (~2 mL) with various water activities (pure acetone and H 2It was saturated with Form A of Compound 1 in the presence of O. Immediately after saturation, equal amounts of Form A and Form C (each approximately 10 mg) were suspended in the saturated solution, and then the sample was magnetically stirred at room temperature for 2 days. The resulting solid was isolated for XRPD analysis. The results of the interconversion slurry study are shown in Table 2.

[0331]

Table 8

[0332] Example 4: Salt Screening Experiment of Crystal Forms of Compound 1 Salt screening experiments using Compound 1 and 1 equivalent of counterion were carried out by stirring for 4 days at room temperature using various solvents. A poor solvent was added to the slurry at 5 °C, and evaporation was applied to the clear solution to induce solid formation. After centrifugation, the resulting solid was dried under vacuum at room temperature overnight and then analyzed by XRPD. The XRPD results of the salt screening experiments are shown in Table 3.

[0333]

Table 9

[0334] Example 5: Preparation of Forms 1 and 2 of Compound 1-A A 5 mL glass vial was charged with Form A of Compound 1 (298.8 mg), 108.0 mg of L-arginine, and 2.0 mL of EtOH. The resulting suspension was magnetically stirred at room temperature for 7 days (1000 rpm). The suspension was then centrifuged to isolate the solid, which was dried under vacuum at room temperature for approximately 8 hours. For Crystal Form 1 of Compound 1-A 1 1H NMR spectroscopy showed the absence of EtOH and indicated the stoichiometric presence of Compound 1 to L-arginine in a 1.0:1.0 ratio. The DVS plot of Form 1 of Compound 1-A showed a moisture uptake of 0.32% at 25 °C / 80% RH, indicating that Form 1 of Compound 1-A is slightly hygroscopic. No morphological changes were observed after the DVS test.

[0335] A 5 mL glass vial was charged with Compound 1 Form A (300 mg), 1.0 equivalent of L-arginine, and 2 mL of acetone / water (19:1, v / v). The resulting suspension was magnetically stirred at room temperature for 6 days (1000 rpm). The suspension was then centrifuged to isolate the solid, which was dried under vacuum at room temperature for approximately 8 hours. For crystalline Form 2 of Compound 1-A 1 1H NMR spectroscopy indicated the absence of acetone and a 1:1 stoichiometry of Compound 1 to L-arginine. The TGA / DSC results for Form 2 of Compound 1-A showed a 1.3% weight loss up to 200 °C.

[0336] Competitive slurry experiments for Forms 1 and 2 of Compound 1-A were carried out by preparing a saturated solution (~2 mL) of Form 1 of Compound 1-A in either EtOH or acetone. Immediately upon saturation, equal masses of Form 1 of Compound 1-A and Form 2 of Compound 1-A were suspended in the saturated solution, and the samples were then magnetically stirred at room temperature or 50 °C. The resulting solids were isolated for XRPD analysis. The results of the interconversion slurry studies are shown in Table 4.

[0337] [Table 10]

[0338] Example 6: Preparation of Forms 3 and 4 of Compound 1-B A 5 mL glass vial was charged with Compound 1 Form A (301.9 mg), 121.1 mg of N-methylglucamine, and 2.0 mL of ACN. The resulting suspension was magnetically stirred at room temperature for 7 days (1000 rpm). The suspension was then centrifuged to isolate the solid, which was dried under vacuum at room temperature for approximately 8 hours. For crystalline Form 3 of Compound 1-B 1 1H NMR spectroscopy indicated the absence of ACN and a 1.0:1.0 stoichiometry of Compound 1 to N-methylglucamine. The DVS plot for Form 3 of Compound 1-B showed 0.1% water uptake at 25 °C / 80% RH, indicating that Form 3 of Compound 1-B is non-hygroscopic. No morphological changes were observed after the DVS test.

[0339] To a 5 mL glass vial was added compound 1 Form A (300 mg), 1.0 equivalent of N-methylglucamine, and 2 mL of acetone / water (19:1, v / v). The resulting suspension was magnetically stirred at room temperature for 4 days (1000 rpm). The suspension was then centrifuged to isolate the solid, which was dried under vacuum at room temperature for about 8 hours. For crystalline form 4 of compound 1-B 1 1H NMR spectroscopy showed no presence of acetone and showed a 1.0:1.2 stoichiometry of compound 1 to N-methylglucamine. The TGA / DSC results for form 4 of compound 1A showed a 0.9% weight loss up to 150 °C.

[0340] Competitive slurry experiments for forms 3 and 4 of compound 1-B were conducted by preparing a saturated solution of form 3 of compound 1-B in acetone (~2 mL). Once saturated, equal masses of form 3 of compound 1-B and form 4 of compound 1-B were suspended in the saturated solution, and the sample was then magnetically stirred at room temperature or 50 °C. The resulting solids were isolated for XRPD analysis. The results of the interconversion slurry studies are shown in Table 5.

[0341] [Table 11]

[0342] Example 7: Characterization of Crystalline Samples Crystalline solid forms were characterized by a combination of XRPD, thermogravimetry (TG), DSC, and / or solution NMR.

[0343] Crystalline Form A of Compound 1 The XRPD results for crystalline form A (Figure 1) showed good crystallinity. A melting temperature of approximately 183 °C was observed using differential scanning calorimetry (Figure 2).

[0344] XRPD measurements were made for crystalline form A of compound 1. The observed peaks are shown in Table 6. The prominent peaks are listed in Table 7.

[0345] [Table 12]

[0346]

Table 13

[0347] Crystal Form B of Compound 1 The XRPD results (Figure 3) of Crystal Form B show good crystallinity. A melting temperature of approximately 203 °C was observed using differential scanning calorimetry (Figure 4).

[0348] The XRPD measurements of Crystal Form B of Compound 1 were taken. The observed peaks are shown in Table 8. The prominent peaks are listed in Table 9.

[0349]

Table 14

[0350]

Table 15

[0351] Crystal Form C of Compound 1 The XRPD results (Figure 5) of Crystal Form C show good crystallinity. A melting temperature of approximately 204 °C was observed using differential scanning calorimetry (Figure 6).

[0352] The XRPD measurements of Crystal Form C of Compound 1 were taken. The observed peaks are shown in Table 10. The prominent peaks are listed in Table 11.

[0353]

Table 16

[0354]

Table 17

[0355] Crystal Form D of Compound 1 The XRPD results of crystalline form D (Figure 7) show good crystallinity. A melting temperature of approximately 203 °C was observed using differential scanning calorimetry (Figure 8).

[0356] The XRPD measurements of crystalline form D of Compound 1 were taken. The observed peaks are shown in Table 12. The prominent peaks are listed in Table 13.

[0357] [Table 18]

[0358] [Table 19]

[0359] Crystalline form E of Compound 1 The XRPD results of crystalline form E (Figure 9) show poor crystallinity. The XRPD measurements of crystalline form E of Compound 1 were taken. The observed peaks are shown in Table 14. The prominent peaks are listed in Table 15.

[0360] [Table 20]

[0361] [Table 21]

[0362] Crystalline form 1 of Compound 1-A The XRPD results of crystalline form 1 of Compound 1-A (Figure 10) show good crystallinity. A melting temperature of approximately 227 °C was observed using differential scanning calorimetry (Figure 11).

[0363] The XRPD measurements of crystalline form 1 of Compound 1-A were taken. The observed peaks are shown in Table 16. The prominent peaks are listed in Table 17.

[0364] [Table 22]

[0365]

Table 23

[0366] Crystal Form 2 of Compound 1-A The XRPD results (Figure 13) of Crystal Form 2 of Compound 1-A show good crystallinity. A melting temperature of approximately 229 °C was observed using differential scanning calorimetry (Figure 14).

[0367] The XRPD measurements of Crystal Form 2 of Compound 1-A were taken. The observed peaks are shown in Table 18. The prominent peaks are listed in Table 19.

[0368]

Table 24

[0369]

Table 25

[0370] Crystal Form 3 of Compound 1-B The XRPD results (Figure 15) of Crystal Form 3 of Compound 1-B show good crystallinity. A melting temperature of approximately 165 °C was observed using differential scanning calorimetry (Figure 16).

[0371] The XRPD measurements of Crystal Form 3 of Compound 1-B were taken. The observed peaks are shown in Table 20. The prominent peaks are listed in Table 21.

[0372]

Table 26

[0373]

Table 27

[0374] Crystal Form 4 of Compound 1-B The XRPD results (Figure 18) of Crystal Form 4 of Compound 1-B show good crystallinity. A melting temperature of approximately 159 °C was observed using differential scanning calorimetry (Figure 19).

[0375] XRPD measurements of Crystal Form 4 of Compound 1-B were made. The observed peaks are shown in Table 22. The prominent peaks are listed in Table 23.

[0376] [Table 28]

[0377] [Table 29]

[0378] Example 8: Characterization of Water Solubility and Crystallization Forms The equilibrium solubilities of Form A, Form C, Form 1 of Compound 1-A, and Form 3 of Compound 1-B were measured in water at ambient temperature. A known amount of water was placed in a 1 dram glass vial and a weighed aliquot of the sample was added while stirring magnetically at room temperature. If the solid dissolved, another aliquot of the solvent was added. The solubility and characterization data for Form A, Form B, Form C, Form D, Form 1 of Compound 1-A, and Form 3 of Compound 1-B are shown in Table 24.

[0379] [Table 30]

[0380] The results showed that Form 3 of Compound 1-B is substantially more soluble than the other forms tested.

[0381] Example 9: Kinetic Solubility The kinetic solubility tests of Form A, Form C, Form 1 of Compound 1-A, and Form 3 of Compound 1-B were carried out at 37 °C with sampling times of 1, 4, and 24 hours using water, SGF, FaSSIF, and FeSSIF. Approximately 40 mg of the solid was suspended in 3 mL of each medium at a dose concentration of approximately 10 mg / mL. The prepared suspensions were equilibrated by rolling (25 rpm). Approximately 1.0 mL of the suspension was extracted at each time point and centrifuged to obtain the precipitate and supernatant. The solubility and pH of the filtered supernatant were tested, and the isolated precipitate was tested by XRPD. The results of the kinetic solubility are shown in Table 25.

[0382] When compared with Form A (0.003 mg / mL), Form C (0.002 mg / mL), and Form 1 of Compound 1-A (0.62 mg / mL), Form 3 of Compound 1-B showed the highest solubility (7.1 mg / mL) in water.

[0383] Forms A and C did not show any form changes after 24 hours of equilibration in the four buffers.

[0384] Form 1 of Compound 1-A did not show any form changes after 1 hour of equilibration in water. Form 1 of Compound 1-A transitioned to Form A after 1 hour of equilibration in SGF and FeSSIF. Form 1 of Compound 1-A transitioned to Type A after 1, 4, or 24 hours of equilibration in FaSSIF.

[0385] Form 3 of Compound 1-B transitioned to Type A after 1, 4, or 24 hours of equilibration in SGF or FaSSIF. Form 3 of Compound 1-B transitioned to Form A after 1 hour of equilibration in FeSSIF. Form 3 of Compound 1-B transitioned to Form A after 24 hours of equilibration in water.

[0386]

Table 31

[0387] Example 10: Physical and Chemical Stability The physical and chemical stabilities of Form 1 of Compound 1-A, Form 3 of Compound 1-B, and Form A were tested under 25°C / 60% RH and 40°C / 75% RH. Approximately 20 mg of the solid sample of each crystal form was added to an HPLC vial (open dish) and then stored under 25°C / 60% RH or 40°C / 75% RH. After one week, the samples were removed from the test conditions and analyzed by HPLC and XRPD to evaluate their chemical and physical stabilities, respectively. Form 1 of Compound 1-A, Form 3 of Compound 1-B, and Form A did not show significant decomposition and / or form change under the conditions of 25°C / 60% RH and 40°C / 75% RH, as shown in Table 26.

[0388]

Table 32

[0389] The above has been described in some detail for purposes of clarity and understanding as examples and illustrations, but it will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, the forms disclosed herein are merely illustrative and are not intended to limit the scope of the present disclosure. Rather, it should be clearly understood that all modifications and alternatives falling within the true scope and spirit of the present disclosure are included.

Claims

1. Equation (I) 【Chemistry 1】 The crystals of the compound, or its solvate.

2. The crystal according to claim 1, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 7.2, 10.4, 12.0, 14.5, 17.9, 21.5, 21.8, 22.3, 23.5, 25.0, 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 degrees 2θ.

3. The crystal according to claim 2, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 7.2, 10.4, 12.0, 14.5, 17.9, 21.5, 21.8, 22.3, 23.5, 25.0, 25.8, 27.2, 27.7, 29.8, 31.6, and 36.7 degrees 2θ.

4. The crystal according to claim 3, wherein the crystal exhibits an X-ray powder diffraction pattern that includes characteristic peaks at approximately 7.2, 10.4, 17.9, 21.5, 21.8, and 25.8 degrees 2θ.

5. The crystal according to claim 1, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, and the characteristic peak is selected from the group consisting of approximately 6.1, 7.1, 8.8, 10.5, 12.1, 14.0, 14.4, 15.0, 17.0, 18.3, 21.1, 21.9, 23.1, 24.1, 24.4, 25.4, 27.0, 27.5, and 28.2 degrees 2θ.

6. The crystal according to claim 5, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 6.1, 7.1, 8.8, 10.5, 12.1, 14.0, 14.4, 15.0, 17.0, 18.3, 21.1, 21.9, 23.1, 24.1, 24.4, 25.4, 27.0, 27.5, and 28.2 degrees 2θ.

7. The crystal according to claim 6, wherein the crystal exhibits an X-ray powder diffraction pattern that includes characteristic peaks at approximately 6.1, 7.1, 8.8, 14.4, 17.0, 18.3, 21.1, 21.9, 23.1, 25.4, and 28.2 degrees 2θ.

8. The crystal according to claim 1, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 6.7, 9.6, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, 24.5, 24.9, 27.5, 28.3, 33.7, and 33.9 degrees 2θ.

9. The crystal according to claim 8, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 6.7, 9.6, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, 24.5, 24.9, 27.5, 28.3, 33.7, and 33.9 degrees 2θ.

10. The crystal according to claim 9, wherein the crystal exhibits an X-ray powder diffraction pattern including characteristic peaks at approximately 6.7, 11.2, 13.3, 16.1, 17.7, 18.1, 18.9, 19.3, 20.0, 20.6, 21.5, and 24.9 degrees 2θ.

11. The crystal according to claim 1, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.0, 20.4, 21.4, 22.9, 24.1, 24.7, 25.1, 25.7, 26.1, 27.3, 27.7, 28.3, 28.8, 29.9, 30.3, 30.8, 33.8, 34.3, 35.4, and 38.1 degrees 2θ.

12. The crystal according to claim 11, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.0, 20.4, 21.4, 22.9, 24.1, 24.7, 25.1, 25.7, 26.1, 27.3, 27.7, 28.3, 28.8, 29.9, 30.3, 30.8, 33.8, 34.3, 35.4, and 38.1 degrees 2θ.

13. The crystal according to claim 12, wherein the crystal exhibits an X-ray powder diffraction pattern that includes characteristic peaks at approximately 6.7, 11.2, 12.0, 13.7, 16.0, 17.5, 17.9, 18.7, 20.4, 21.4, 22.9, 24.1, 24.7, 29.9, 30.3, and 30.8 degrees 2θ.

14. The crystal according to claim 1, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 6.7, 7.3, 9.9, 12.0, 13.3, 15.0, 17.3, 18.6, 19.9, 20.5, 21.3, 23.2, 23.8, 24.6, 25.8, 26.3, 26.7, 28.3, 29.2, 29.8, 31.6, 33.5, 35.0, and 38.7 degrees 2θ.

15. The crystal according to claim 14, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 6.7, 7.3, 9.9, 12.0, 13.3, 15.0, 17.3, 18.6, 19.9, 20.5, 21.3, 23.2, 23.8, 24.6, 25.8, 26.3, 26.7, 28.3, 29.2, 29.8, 31.6, 33.5, 35.0, and 38.7 degrees 2θ.

16. The crystal according to claim 15, wherein the crystal exhibits an X-ray powder diffraction pattern that includes characteristic peaks at approximately 6.7, 9.9, 12.0, 13.3, 17.3, 18.6, 19.9, 23.2, 24.6, 26.3, 29.2, 29.8, 35.0, and 38.7 degrees 2θ.

17. The crystal according to any one of claims 1 to 16, wherein the crystal is a hydrate.

18. The crystal according to any one of claims 1 to 16, wherein the crystal is an anhydrous.

19. The crystal according to any one of claims 1 to 16, wherein the crystal is a solvate.

20. The crystal according to any one of claims 1 to 16, wherein the crystal is an ethanol solvate.

21. The crystal according to any one of claims 1 to 16, wherein the crystal is a chloroform solvate.

22. A composition comprising the crystals described in any one of claims 1 to 16, wherein more than 50% by weight of the total amount of the compound of formula (I) in the composition is the crystals.

23. A composition comprising the crystals described in any one of claims 1 to 16, wherein more than 85% by weight of the total amount of the compound of formula (I) in the composition is the crystals.

24. A composition comprising the crystals described in any one of claims 1 to 16, wherein more than 90% by weight of the total amount of the compound of formula (I) in the composition is the crystals.

25. Equation (I) 【Chemistry 2】 The arginine salt of the compound, or its solvate.

26. The arginine salt according to claim 25, wherein the arginine salt is crystalline.

27. The arginine salt according to claim 26, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, 19.4, 20.7, 25.7, 27.0, and 28.1 degrees 2θ.

28. The arginine salt according to claim 27, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, 19.4, 20.7, 25.7, 27.0, and 28.1 degrees 2θ.

29. The arginine salt according to claim 28, wherein the crystal exhibits an X-ray powder diffraction pattern including characteristic peaks at approximately 5.9, 8.8, 10.4, 12.3, 14.6, 17.1, 17.5, and 19.4 degrees 2θ.

30. The arginine salt according to claim 26, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, 16.9, 17.8, 19.3, 20.0, 20.5, 25.1, and 25.6 degrees 2θ.

31. The arginine salt according to claim 30, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, 16.9, 17.8, 19.3, 20.0, 20.5, 25.1, and 25.6 degrees 2θ.

32. The arginine salt according to claim 31, wherein the crystal exhibits an X-ray powder diffraction pattern including characteristic peaks at approximately 5.7, 8.6, 10.3, 10.5, 12.1, 12.4, 14.2, 14.5, 16.6, and 16.9 degrees 2θ.

33. The arginine salt according to any one of claims 25 to 32, wherein the arginine salt is an anhydrous form.

34. A composition comprising an arginine salt according to any one of claims 25 to 32, wherein the arginine salt constitutes more than 50% by weight of the total amount of the compound of formula (I) in the composition.

35. A composition comprising an arginine salt according to any one of claims 25 to 32, wherein the arginine salt constitutes more than 85% by weight of the total amount of the compound of formula (I) in the composition.

36. A composition comprising an arginine salt according to any one of claims 25 to 32, wherein the arginine salt constitutes more than 90% by weight of the total amount of the compound of formula (I) in the composition.

37. Equation (I) 【Transformation 3】 The N-methylglucamine salt of the compound, or its solvate.

38. The N-methylglucamine salt according to claim 37, wherein the N-methylglucamine salt is crystalline.

39. The N-methylglucamine salt according to claim 38, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, 18.4, 18.6, 19.0, 20.3, and 25.4 degrees 2θ.

40. The N-methylglucamine salt according to claim 39, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, 18.4, 18.6, 19.0, 20.3, and 25.4 degrees 2θ.

41. The N-methylglucamine salt according to claim 40, wherein the crystal exhibits an X-ray powder diffraction pattern including characteristic peaks at approximately 8.3, 9.5, 10.5, 10.8, 12.2, 12.5, 14.2, 14.5, 16.4, 16.8, and 18.6 degrees 2θ.

42. The N-methylglucamine salt according to claim 38, wherein the crystal exhibits an X-ray powder diffraction pattern including at least one characteristic peak, the characteristic peak being selected from the group consisting of approximately 8.5, 9.6, 11.6, 14.1, 16.1, 16.6, 19.1, 19.4, 19.7, 24.2, and 25.4 degrees 2θ.

43. The N-methylglucamine salt according to claim 42, wherein the crystal exhibits an X-ray powder diffraction pattern including at least three characteristic peaks, the characteristic peaks being selected from the group consisting of approximately 8.5, 9.6, 11.6, 14.1, 16.1, 16.6, 19.1, 19.4, 19.7, 24.2, and 25.4 degrees 2θ.

44. The N-methylglucamine salt according to claim 43, wherein the crystal exhibits an X-ray powder diffraction pattern including characteristic peaks at approximately 8.5, 9.6, 11.6, 16.1, 16.6, 19.1, 19.4, 24.2, and 25.4 degrees 2θ.

45. The N-methylglucamine salt according to any one of claims 37 to 44, wherein the N-methylglucamine salt is an anhydrous form.

46. A composition comprising an N-methylglucamine salt according to any one of claims 37 to 44, wherein more than 50% by weight of the total amount of the compound of formula (I) in the composition is the N-methylglucamine salt.

47. A composition comprising an N-methylglucamine salt according to any one of claims 37 to 44, wherein more than 85% by weight of the total amount of the compound of formula (I) in the composition is the N-methylglucamine salt.

48. A composition comprising an N-methylglucamine salt according to any one of claims 37 to 44, wherein more than 90% by weight of the total amount of the compound of formula (I) in the composition is the N-methylglucamine salt.

49. A pharmaceutical composition comprising the composition according to claim 22 and a pharmaceutically acceptable excipient.

50. The pharmaceutical composition according to claim 49 for use in the treatment of fibrosis.

51. A pharmaceutical composition comprising the composition described in claim 34 and a pharmaceutically acceptable excipient.

52. The pharmaceutical composition according to claim 51, for use in the treatment of fibrosis.

53. A pharmaceutical composition comprising the composition according to claim 46 and a pharmaceutically acceptable excipient.

54. The pharmaceutical composition according to claim 53, for use in the treatment of fibrosis.

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