Pyruvate kinase R (PKR) activation composition

Abstract

The present disclosure provides crystalline solid forms, spray-dried dispersions, and pharmaceutical compositions, including solid oral dosage forms, of (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one ("Compound 1"), and methods for preparing the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Patent Application No. 16 / 576,720 filed on September 19, 2019; U.S. Patent Application No. 16 / 576,360 filed on September 19, 2019; U.S. Patent Application No. 62 / 902,887 filed on September 19, 2019; U.S. Patent Application No. 62 / 906,437 filed on September 26, 2019; International Application No. PCT / US2019 filed on September 19, 2019 / 052024; U.S. Patent Application No. 63 / 024,432, filed on May 13, 2020; U.S. Patent Application No. 63 / 024,441, filed on May 13, 2020; U.S. Patent Application No. 62 / 704,785, filed on May 28, 2020; and U.S. Patent Application No. 62 / 705,106, filed on June 11, 2020, each of which is incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to solid forms, dispersions and pharmaceutical compositions of pyruvate kinase R (PKR) activating compounds. More specifically, the present disclosure relates to crystalline solid forms, spray-dried dispersions and pharmaceutical compositions of (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one, and methods for their preparation. Background Art

[0004] Chemical compounds can form one or more different pharmaceutically acceptable solid forms, including amorphous and crystalline forms. Amorphous solid forms include dispersions of amorphous and crystalline chemical compounds, such as spray-dried dispersions. Individual solid forms of biologically active chemical compounds can have different properties. It is necessary to identify and select the appropriate solid form of the biologically active chemical compound (including appropriate crystalline form, when applicable) to develop a pharmaceutically acceptable dosage form for the treatment of various diseases or disorders.

[0005] Compound (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one ("Compound 1"),

[0006]

[0007] It is a small molecule PKR activator that modulates pyruvate kinase activity. Compound 1 is described in International Publication No. WO 2018 / 175474 as one of many compounds suitable as small molecule modulators of pyruvate kinase activity. There is still a need to identify solid forms of Compound 1 that can be used for various therapeutic applications. Summary of the invention

[0008] One aspect of the present disclosure relates to a solid oral dosage form comprising a stabilized amorphous pharmaceutical composition of compound (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one (also referred to as "stabilized amorphous Compound 1"). As used herein, the term "stabilized amorphous Compound 1" refers to an amorphous solid form of Compound 1 that has been stabilized (e.g., by combination with certain stabilizing polymers and / or by other manufacturing methods) to prevent the formation of a crystalline form of Compound 1 or solid phase separation of Compound 1 under certain storage conditions described herein (e.g., showing no crystalline diffraction peaks according to XRPD analysis (Method D) after storage at 60°C / 75% RH (exposed) for 2 weeks, and / or showing a single glass transition temperature (Tg) according to DSC analysis (Method B) after storage at 60°C / 75% RH (exposed) for 2 weeks). G ) and having no melting endotherm).

[0009] In some embodiments, the stabilized amorphous compound 1 is obtained by spray drying a solution of compound 1 and a stabilizing polymer. The inventors have found that amorphous compound 1 has higher oral bioavailability than certain crystalline forms of compound 1, including crystalline form A. Therefore, in some embodiments, compared with solid oral dosage forms containing certain crystalline forms of compound 1, solid oral dosage forms containing stabilized amorphous compound 1 advantageously provide excellent oral bioavailability of compound 1.

[0010] Also disclosed herein are amorphous spray-dried dispersions (SDDs) of Compound 1, methods for preparing the same, and pharmaceutical compositions containing the same. The present disclosure provides various solid forms of Compound 1, including one or more pharmaceutically acceptable crystalline and amorphous forms of Compound 1 that can be used for therapeutic oral administration of Compound 1. Various solid forms of Compound 1 can be identified by certain characteristic properties. For example, certain crystalline forms of Compound 1 have different characteristic XRPD peaks.

[0011] Another aspect of the present disclosure relates to a solid form of Compound 1. The solid forms of Compound 1 disclosed herein include various crystalline forms of Compound 1 (including Type A, Type B, Type C, Type D, Type E, Type F, Type G, Type H, Type I, Type J, Type K, Type L, and Type M), methods for preparing the same, and pharmaceutical compositions containing the same.

[0012] One aspect of the present disclosure relates to a novel crystalline solid form of Compound 1:

[0013]

[0014] The novel Compound 1 crystalline Form A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.61, 15.66, 23.19, and 24.76. The novel Compound 1 crystalline Form A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.6, 15.7, 23.2, and 24.8. The novel Compound 1 crystalline Form A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8.

[0015] The novel Compound 1 crystalline Form B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13. The novel Compound 1 crystalline Form B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 15.6, 22.9, 23.3, and 25.1. The novel Compound 1 crystalline Form B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1.

[0016] The novel Compound 1 crystalline Form C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.55, 18.85, 23.02, and 24.65. The novel Compound 1 crystalline Form C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 18.9, 23.0, and 24.7. The novel Compound 1 crystalline Form C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7.

[0017] The novel Compound 1 Crystalline Form D can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 9.72, 13.08, 15.74, 21.90, and 23.59. The novel Compound 1 Crystalline Form D can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 9.7, 13.1, 15.7, 21.9, and 23.6. The novel Compound 1 Crystalline Form D can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 and no diffraction at an angle (2θ±0.2) of 23.3.

[0018] The novel Compound 1 crystalline Form E can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72. The novel Compound 1 crystalline Form E can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7. The novel Compound 1 crystalline Form E can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7.

[0019] The novel Compound 1 crystalline Form F can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45. The novel Compound 1 crystalline Form F can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5. The novel Compound 1 crystalline Form F can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.4, 14.7, 16.0, 16.8, and 21.4.

[0020] The novel Compound 1 crystalline Form G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.36, 14.34, 16.58, and 21.35. The novel Compound 1 crystalline Form G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.4, 14.3, 16.6, and 21.4. The novel Compound 1 crystalline Form G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3.

[0021] The novel Compound 1 crystalline Form H can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffraction patterns at angles (2θ±0.2) of 5.8, 14.7, 16.6, 20.0, 21.3 and 25.4.

[0022] The novel Compound 1 crystalline Form I can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffraction patterns at angles (2θ±0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1.

[0023] The novel Compound 1 crystalline Form J can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffraction patterns at angles (2θ±0.2) of 4.5, 5.7, 22.8, 23.1 and 24.5.

[0024] The novel Compound 1 crystalline Form K can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffraction patterns at angles (2θ±0.2) of 4.6, 15.4, 15.6, 16.1, 23.2 and 27.4.

[0025] The novel Compound 1 crystalline Form L can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffraction patterns at angles (2θ±0.2) of 5.9, 11.9, 17.8, 21.6, 23.9 and 36.1.

[0026] The novel Compound 1 crystalline Form M can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffraction patterns at angles (2θ±0.2) of 4.5, 5.8, 9.7, 15.6, 21.9 and 26.7.

[0027] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of any crystalline solid form of Compound 1 described above and one or more pharmaceutically acceptable excipients.

[0028] Yet another aspect of the present disclosure relates to a novel amorphous solid dispersion of Compound 1. The novel amorphous solid form of Compound 1 can be prepared by spray drying a mixture comprising Compound 1 and a polymer.

[0029] Yet another aspect of the present disclosure relates to a pharmaceutical composition comprising the novel amorphous solid form of the above-mentioned Compound 1. The pharmaceutical composition can be an oral dosage form, such as a tablet.

[0030] Another aspect of the present disclosure relates to a tablet dosage form comprising Compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 A reaction scheme for the preparation of compound 1 is depicted.

[0032] Figure 2 An alternative reaction scheme for the preparation of compound 1 is depicted.

[0033] Figure 3 Depicted is an XRPD pattern of Compound 1 crystalline Form A.

[0034] Figure 4 Depicted are a thermogravimetric analysis (TGA) curve (upper curve) and a differential scanning calorimetry (DSC) thermogram (lower curve) of Compound 1 crystalline Form A.

[0035] Figure 5 Depicted is a DSC cycle thermogram of Compound 1 crystalline Form A.

[0036] Figure 6 The dynamic vapor adsorption (DVS) isotherm of Compound 1 crystalline Form A is depicted.

[0037] Figure 7 An XRPD pattern of Compound 1 crystalline Form B is depicted.

[0038] Figure 8 Depicted are a thermogravimetric analysis (TGA) curve (upper curve) and a differential scanning calorimetry (DSC) thermogram (lower curve) of Compound 1 crystalline Form B.

[0039] Fig. 9 Depicted is a DSC cycle thermogram of Compound 1 crystalline Form B.

[0040] Fig.10 Two thermogravimetric analysis (TGA) curves of Compound 1 crystalline Form B are depicted.

[0041] Fig.11 The dynamic vapor adsorption (DVS) isotherm of Compound 1 crystalline Form B is depicted.

[0042] Fig.12 An XRPD pattern of Compound 1 crystalline Form C is depicted.

[0043] Fig.13 Depicted are a thermogravimetric analysis (TGA) curve (upper curve) and a differential scanning calorimetry (DSC) thermogram (lower curve) of Compound 1 crystalline Form C.

[0044] Fig.14 Depicted is a DSC cycle thermogram of Compound 1 crystalline Form C.

[0045] Fig.15 Thermogravimetric analysis (TGA) curve of Compound 1 crystalline Form C is depicted.

[0046] Fig.16 The dynamic vapor adsorption (DVS) isotherm of Compound 1 crystalline Form C is depicted.

[0047] Fig.17 An XRPD pattern of Compound 1 crystalline Form D is depicted.

[0048] Fig.18 Depicted are a thermogravimetric analysis (TGA) curve (upper curve) and a differential scanning calorimetry (DSC) thermogram (lower curve) of Compound 1 crystalline Form D.

[0049] Fig.19 Depicted are Form A (upper curve) and Form D (lower curve) crystalline forms of Compound 1. 1 H NMR spectroscopy.

[0050] Fig. 20 An XRPD pattern of Compound 1 crystalline Form E is depicted.

[0051] Fig.21 Depicted is an XRPD pattern of Compound 1 crystalline Form F.

[0052] Fig. 22 Thermogravimetric analysis (TGA) curve (upper curve) and differential scanning calorimetry (DSC) thermogram (lower curve) of Compound 1 crystalline Form F.

[0053] Fig.23 An XRPD pattern of Compound 1 crystalline Form G is depicted.

[0054] Fig.24 Depicted is an XRPD pattern of Compound 1 crystalline Form H.

[0055] Fig.25 An XRPD pattern of Compound 1 crystalline Form I is depicted.

[0056] Fig.26 An XRPD pattern of Compound 1 crystalline Form J is depicted.

[0057] Fig. 27 An XRPD pattern of Compound 1 crystalline Form K is depicted.

[0058] Fig.28 Depicted is the XRPD pattern of Compound 1 crystalline Form L.

[0059] Fig.29 An XRPD pattern of Compound 1 crystalline Form M is depicted.

[0060] Fig.30 The XRPD pattern of a spray dried dispersion (SDD) of Compound 1 is depicted.

[0061] Fig.31 Depicted is a differential scanning calorimetry (DSC) thermogram of a spray dried dispersion (SDD) of Compound 1.

[0062] Fig.32 Depicted are graphs of plasma concentrations over time following administration of three formulations of Compound 1 in rats.

[0063] Fig.33 Depicted are graphs of plasma concentrations over time following administration of four formulations of Compound 1 in monkeys.

[0064] Fig.34 Depicted is a graph of the time-dependent solubility of Form A of Compound 1 in biologically relevant media.

[0065] Fig.35 Depicted is a graph of the time-dependent solubility of a spray dried dispersion (SDD) of Compound 1 in a biorelevant medium.

[0066] Fig.36 Depicted are overlaid XRPD patterns of five spray dried dispersions (SDD) of Compound 1 overlaid with the XRPD pattern of crystalline Compound 1 (Form A).

[0067] Fig.37 Overlaid differential scanning calorimetry (DSC) thermograms of five spray dried dispersions (SDD) of Compound 1 are depicted.

[0068] Fig.38 Graph depicting the kinetic solubility profiles of five SDDs of compound 1 at different drug loadings.

[0069] Fig.39 Depicted are superimposed XRPD patterns of a spray-dried dispersion of Compound 1 (SDD0) superimposed with the XRPD pattern of crystalline Compound 1 (Form A) after storage under the following conditions: (a) storage at 60°C for 2 weeks in a sealed vial, (b) storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial, and (c) storage at 60°C and 75% relative humidity for 2 weeks in an unsealed vial.

[0070] Fig.40 Depicted are superimposed XRPD patterns of a spray-dried dispersion of Compound 1 (SDD1) superimposed with the XRPD pattern of crystalline Compound 1 (Form A) after storage under the following conditions: (a) storage at 60°C for 2 weeks in a sealed vial, (b) storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial, and (c) storage at 60°C and 75% relative humidity for 2 weeks in an unsealed vial.

[0071] Fig.41 Depicted are superimposed XRPD patterns of a spray-dried dispersion of Compound 1 (SDD2) superimposed with the XRPD pattern of crystalline Compound 1 (Form A) after storage under the following conditions: (a) storage at 60°C for 2 weeks in a sealed vial, (b) storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial, and (c) storage at 60°C and 75% relative humidity for 2 weeks in an unsealed vial.

[0072] Fig.42 Depicted are superimposed XRPD patterns of a spray-dried dispersion of Compound 1 (SDD3) superimposed with the XRPD pattern of crystalline Compound 1 (Form A) after storage under the following conditions: (a) storage at 60°C for 2 weeks in a sealed vial, (b) storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial, and (c) storage at 60°C and 75% relative humidity for 2 weeks in an unsealed vial.

[0073] Fig.43Depicted are superimposed XRPD patterns of a spray-dried dispersion of Compound 1 (SDD4) superimposed with the XRPD pattern of crystalline Compound 1 (Form A) after storage under the following conditions: (a) storage at 60°C for 2 weeks in a sealed vial, (b) storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial, and (c) storage at 60°C and 75% relative humidity for 2 weeks in an unsealed vial.

[0074] Fig.44 Depicted are overlaid XRPD patterns of two spray-dried dispersions of Compound 1 (SDD 5 and 6) overlaid with the XRPD pattern of crystalline Compound 1 (Form A).

[0075] Fig.45 Overlaid DSC thermograms of two spray dried dispersions of Compound 1 (SDD 5 and 6) are depicted.

[0076] Fig.46 Depicted are superimposed XRPD patterns of a spray-dried dispersion of Compound 1 (SDD 5) after storage under the following conditions: (a) storage at 60°C for 1 week in a sealed vial, (b) storage at 25°C and 60% relative humidity for 1 week in an unsealed vial, and (c) storage at 40°C and 75% relative humidity for 1 week in an unsealed vial.

[0077] Fig.47 Depicted are superimposed DSC thermograms of a spray-dried dispersion of Compound 1 (SDD 5) after storage under the following conditions: (a) storage at 60°C for 1 week in a sealed vial, (b) storage at 25°C and 60% relative humidity for 1 week in an unsealed vial, and (c) storage at 40°C and 75% relative humidity for 1 week in an unsealed vial.

[0078] Fig.48 Depicted are superimposed DSC thermograms of a spray-dried dispersion of Compound 1 (SDD 5) after storage under the following conditions: (a) storage at 60°C for 2 weeks in a sealed vial, (b) storage at 25°C and 60% relative humidity for 2 weeks in an unsealed vial, and (c) storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial.

[0079] Fig.49 Depicted are superimposed XRPD patterns of a spray-dried dispersion of Compound 1 (SDD 6) after storage under the following conditions: (a) storage at 60°C for 1 week in a sealed vial, (b) storage at 25°C and 60% relative humidity for 1 week in an unsealed vial, and (c) storage at 40°C and 75% relative humidity for 1 week in an unsealed vial.

[0080] Fig.50Depicted are superimposed DSC thermograms of a spray-dried dispersion of Compound 1 (SDD 6) after storage under the following conditions: (a) storage at 60°C for 1 week in a sealed vial, (b) storage at 25°C and 60% relative humidity for 1 week in an unsealed vial, and (c) storage at 40°C and 75% relative humidity for 1 week in an unsealed vial.

[0081] Fig.51 Depicted are superimposed DSC thermograms of a spray-dried dispersion of Compound 1 (SDD 6) after storage under the following conditions: (a) storage at 60°C for 2 weeks in a sealed vial, (b) storage at 25°C and 60% relative humidity for 2 weeks in an unsealed vial, and (c) storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial.

[0082] Fig.52 Graph depicting the dissolution profile of Compound 1 tablet formulation. DETAILED DESCRIPTION

[0083] Chemical compound (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one ("Compound 1"),

[0084]

[0085] It is a small molecule modulator of pyruvate kinase. The present disclosure provides various solid forms of compound 1, pharmaceutical compositions thereof, and methods for preparing these novel solid forms of compound 1. The solid forms described herein (e.g., crystalline solid forms and amorphous solid forms) are associated with favorable features, such as favorable or improved solubility, dissolution, bioavailability, stability, and formulation convenience relative to other forms of compound 1. For example, certain amorphous solid dispersions described herein advantageously have high drug loading (e.g., ≥25%, ≥40%, ≥50%, etc.), are free of or substantially free of crystalline compound 1, are physically stable (i.e., remain free of or substantially free of crystalline compound 1 over time in accelerated stability studies), are highly soluble, and / or do not require a large amount of drying to remove residual solvents. In addition, certain tablet dosage forms described herein advantageously have a high drug load (e.g., ≥10% by weight of the core, ≥15% by weight of the core, ≥30% by weight of the core), a small tablet size (e.g., each core weighs ≤1200 mg, ≤1000 mg, ≤800 mg, ≤700 mg, etc.), contain no or substantially no crystalline Compound 1, and / or are physically stable (i.e., remain free or substantially free of crystalline Compound 1 over time in an accelerated stability study).

[0086] In some embodiments, compound 1 is a crystalline solid form (e.g., type A, type B, type C, type D, type E, type F, or type G). In some embodiments, compound 1 is a crystalline solid form (e.g., type A, type B, type C, type D, type E, type F, type G, type H, type I, type J, type K, type L, or type M). In some embodiments, the crystalline solid form is type A. In some embodiments, the crystalline solid form is type B. In some embodiments, the crystalline solid form is type C. In some embodiments, the crystalline solid form is type D. In some embodiments, the crystalline solid form is type E. In some embodiments, the crystalline solid form is type F. In some embodiments, the crystalline solid form is type G. In some embodiments, the crystalline solid form is type H. In some embodiments, the crystalline solid form is type I. In some embodiments, the crystalline solid form is type J. In some embodiments, the crystalline solid form is type K. In some embodiments, the crystalline solid form is type L. In some embodiments, the crystalline solid form is type M.

[0087] In some embodiments, Compound 1 is in an amorphous form (eg, an amorphous solid dispersion). In some embodiments, the amorphous solid dispersion comprises Compound 1 and a polymer.

[0088] Compound 1 Crystalline Form A

[0089] The novel Compound 1 Crystalline Form A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.61, 15.66, 23.19, and 24.76. The novel Compound 1 Crystalline Form A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.6, 15.7, 23.2, and 24.8. In some embodiments, Compound 1 Crystalline Form A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.61, 15.66, 23.19, and 24.76, corresponding to d spacings (angstroms ± 0.2) of 19.19, 5.66, 3.84, and 3.60, respectively. In some embodiments, Compound 1 crystalline Form A can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.6, 15.7, 23.2, and 24.8, corresponding to d-spacings (Angstroms ± 0.2) of 19.2, 5.7, 3.8, and 3.6, respectively.

[0090] In some embodiments, Compound 1 crystalline Form A can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ±0.2) of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8. In some embodiments, Compound 1 crystalline Form A can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ±0.2) of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8, corresponding to d-spacings (Angstroms±0.2) of 19.2, 12.3, 5.7, 4.2, 3.8, and 3.6, respectively.

[0091] In some embodiments, Compound 1 crystalline Form A can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.61, 7.22, 15.66, 20.48, 21.35, 21.66, 22.47, 23.19, 24.76, and 26.73. In some embodiments, Compound 1 crystalline Form A can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.6, 7.2, 15.7, 20.5, 21.4, 21.7, 22.5, 23.2, 24.8, and 26.7. In some embodiments, Compound 1 Crystalline Form A can be identified by an XRPD having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.61, 7.22, 15.66, 20.48, 21.35, 21.66, 22.47, 23.19, 24.76, and 26.73, corresponding to d-spacings (Angstroms ± 0.2) of 19.19, 12.25, 5.66, 4.34, 4.16, 4.10, 3.96, 3.84, 3.60, and 3.34, respectively. In some embodiments, Compound 1 Crystalline Form A Type can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.6, 7.2, 15.7, 20.5, 21.4, 21.7, 22.5, 23.2, 24.8, and 26.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.2, 12.2, 5.7, 4.3, 4.2, 4.1, 4.0, 3.8, 3.6, and 3.3, respectively.

[0092] In some embodiments, Compound 1 crystalline Form A is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.61 5.80 7.22 7.68 11.21 12.31 14.44 15.66 16.95 18.02 19.20 20.48 21.35 21.66 22.47 23.19 24.76 26.73 28.01 28.49 29.35 30.25 32.14 34.12 36.46

[0118] In some embodiments, Compound 1 crystalline Form A is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.6 5.8 7.2 7.7 11.2 12.3 14.4 15.7 16.9 18.0 19.2 20.5 21.3 21.7 22.5 23.2 24.8 26.7 28.0 28.5 29.4 30.3 32.1 34.1 36.5

[0144] In some embodiments, Compound 1 Crystalline Form A is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0145]

[0146] In some embodiments, Compound 1 Crystalline Form A is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0147]

[0148] In some embodiments, Compound 1 Crystalline Form A Type A is characterized by a thermogravimetric analysis (TGA) thermogram with a weight loss of about 1.9% at 100°C. In some embodiments, Compound 1 Crystalline Form A Type A is characterized by a differential scanning calorimetry (DSC) endotherm with a peak temperature of about 85.9°C and an onset temperature of about 146.0°C. In some embodiments, Compound 1 Crystalline Form A Type A is characterized by a dynamic vapor sorption (DVS) with a water uptake of about 3.4 wt % at 40% relative humidity. In some embodiments, Compound 1 Crystalline Form A Type A is characterized by a dynamic vapor sorption (DVS) with a water uptake of about 1.0 wt % at 40% to 80% relative humidity.

[0149] Compound 1 Crystalline Form B

[0150] The novel Compound 1 Crystalline Form B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13. The novel Compound 1 Crystalline Form B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 15.6, 22.9, 23.3, and 25.1. In some embodiments, Compound 1 Crystalline Form B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13, corresponding to d spacings (angstroms ± 0.2) of 19.53, 5.69, 3.89, 3.81, and 3.54, respectively. In some embodiments, Compound 1 crystalline Form B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.5, 15.6, 22.9, 23.3, and 25.1, corresponding to d-spacings (Angstroms ± 0.2) of 19.5, 5.7, 3.9, 3.8, and 3.5, respectively.

[0151] In some embodiments, Compound 1 crystalline Form B can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1. In some embodiments, Compound 1 crystalline Form B can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1, corresponding to d-spacings (Angstroms ± 0.2) of 19.5, 5.7, 4.0, 3.9, 3.8, and 3.5, respectively.

[0152] In some embodiments, Compound 1 crystalline Form B can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.52, 9.86, 15.57, 19.93, 22.19, 22.89, 23.34, 25.13, and 28.30. In some embodiments, Compound 1 crystalline Form B can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.5, 9.9, 15.6, 19.9, 22.2, 22.9, 23.3, 25.1, and 28.3. In some embodiments, Compound 1 Crystalline Form B can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.52, 9.86, 15.57, 19.93, 22.19, 22.89, 23.34, 25.13, and 28.30, corresponding to d-spacings (Angstroms ± 0.2) of 19.53, 8.97, 5.69, 4.45, 4.00, 3.89, 3.81, 3.54, and 3.15, respectively. In some embodiments, Compound 1 Crystalline Form B can be identified by an XRPD having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 9.9, 15.6, 19.9, 22.2, 22.9, 23.3, 25.1, and 28.3, corresponding to d-spacings (Angstroms ± 0.2) of 19.5, 9.0, 5.7, 4.5, 4.0, 3.9, 3.8, 3.5, and 3.2, respectively.

[0153] In some embodiments, Compound 1 crystalline Form B is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.52 8.98 9.86 12.37 13.18 15.57 16.86 18.21 19.11 19.93 20.92 22.19 22.89 23.34 25.13 25.80 26.71 28.30 29.39

[0173] In some embodiments, Compound 1 crystalline Form B is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.5 9.0 9.9 12.4 13.2 15.6 16.9 18.2 19.1 19.9 20.9 22.2 22.9 23.3 25.1 25.8 26.7 28.3 29.4

[0193] In some embodiments, Compound 1 Crystalline Form B is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0194]

[0195] In some embodiments, Compound 1 Crystalline Form B is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0196]

[0197] In some embodiments, Compound 1 crystalline Form B is characterized by a thermogravimetric analysis (TGA) thermogram with a weight loss of about 1.8% at 100° C. and / or a thermogravimetric analysis (TGA) thermogram with a weight loss of about 2.3% at 120° C. In some embodiments, Compound 1 crystalline Form B is characterized by a differential scanning calorimetry (DSC) endotherm with an onset temperature of about 138.2° C.-139.2° C. In some embodiments, Compound 1 crystalline Form B is characterized by a dynamic vapor sorption (DVS) with a water uptake of about 2.9 wt % at 60% relative humidity and a dynamic vapor sorption (DVS) with a water uptake of about 0.4 wt % at 60% to 80% relative humidity.

[0198] Compound 1 Crystalline Form C

[0199] The novel Compound 1 crystalline Form C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.55, 18.85, 23.02, and 24.65. The novel Compound 1 crystalline Form C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 18.9, 23.0, and 24.7. In some embodiments, Compound 1 crystalline Form C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.55, 18.85, 23.02, and 24.65, corresponding to d spacings (angstroms ± 0.2) of 19.43, 4.71, 3.86, and 3.61, respectively. In some embodiments, Compound 1 crystalline Form C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 18.9, 23.0, and 24.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.4, 4.7, 3.9, and 3.6, respectively.

[0200] In some embodiments, Compound 1 crystalline Form C can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7. In some embodiments, Compound 1 crystalline Form C can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.4, 12.0, 7.9, 4.7, 3.9, and 3.6, respectively.

[0201] In some embodiments, Compound 1 Crystalline Form C can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.55, 7.34, 9.07, 11.17, 18.34, 18.85, 19.57, 21.66, 23.02, and 24.65. In some embodiments, Compound 1 Crystalline Form C can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.5, 7.3, 9.1, 11.2, 18.34, 18.9, 19.6, 21.7, 23.0, and 24.7. In some embodiments, Compound 1 Crystalline Form C can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.55, 7.34, 9.07, 11.17, 18.34, 18.85, 19.57, 21.66, 23.02, and 24.65, corresponding to d-spacings (Angstroms ± 0.2) of 19.43, 12.05, 9.75, 7.92, 4.84, 4.71, 4.54, 4.10, 3.86, and 3.61, respectively. In some embodiments, Compound 1 Crystalline Form C can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.5, 7.3, 9.1, 11.2, 18.3, 18.9, 19.6, 21.7, 23.0, and 24.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.4, 12.0, 9.8, 7.9, 4.8, 4.7, 4.5, 4.1, 3.9, and 3.6, respectively.

[0202] In some embodiments, Compound 1 Crystalline Form C is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.55 7.34 9.07 11.17 12.29 14.51 15.66 18.34 18.85 19.57 20.38 21.66 23.02 24.65 26.39 28.28 30.09 32.31 33.91 37.19

[0223] In some embodiments, Compound 1 Crystalline Form C is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.5 7.3 9.1 11.2 12.3 14.5 15.7 18.3 18.9 19.6 20.4 21.7 23.0 24.7 26.4 28.3 30.1 32.3 33.9 37.2

[0244] In some embodiments, Compound 1 Crystalline Form C is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0245]

[0246] In some embodiments, Compound 1 Crystalline Form C is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0247]

[0248]

[0249] In some embodiments, Compound 1 crystalline Form C is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.0% at 100° C. and / or a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% at 130° C. In some embodiments, Compound 1 crystalline Form C is characterized by a differential scanning calorimetry (DSC) endotherm having an onset temperature of about 152.2° C.-154.2° C. In some embodiments, Compound 1 crystalline Form C is characterized by a dynamic vapor sorption (DVS) having a water uptake of about 1.8 wt % at 60% relative humidity and a dynamic vapor sorption (DVS) having a water uptake of about 0.5 wt % at 60% to 80% relative humidity.

[0250] Compound 1 Crystalline Form D

[0251] The novel Compound 1 Crystalline Form D can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 9.72, 13.08, 15.74, 21.90, and 23.59. The novel Compound 1 Crystalline Form D can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 9.7, 13.1, 15.7, 21.9, and 23.6. In some embodiments, Compound 1 Crystalline Form D can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 9.72, 13.08, 15.74, 21.90, and 23.59, corresponding to d spacings (angstroms ± 0.2) of 9.10, 6.77, 5.63, 4.06, and 3.77, respectively. In some embodiments, Compound 1 Crystalline Form D can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 9.7, 13.1, 15.7, 21.9, and 23.6, corresponding to d-spacings (Angstroms ± 0.2) of 9.1, 6.8, 5.6, 4.1, and 3.8, respectively.

[0252] In some embodiments, Compound 1 crystalline Form D can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ±0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6, and no diffraction at an angle (2θ±0.2) of 23.3. In some embodiments, Compound 1 crystalline Form D can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ±0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6, corresponding to d-spacings (angstroms±0.2) of 14.4, 9.1, 6.8, 5.6, 4.1, and 3.8, respectively, and no diffraction at an angle (2θ±0.2) of 23.3.

[0253] In some embodiments, Compound 1 Crystalline Form D can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.27, 6.15, 8.71, 9.72, 12.31, 13.08, 13.76, 15.74, 18.02, 21.90, 23.59, and 26.71. In some embodiments, Compound 1 Crystalline Form D can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.3, 6.2, 8.7, 9.7, 12.3, 13.1, 13.8, 15.7, 18.0, 21.9, 23.6, and 26.7. In some embodiments, Compound 1 Crystalline Form D can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.27, 6.15, 8.71, 9.72, 12.31, 13.08, 13.76, 15.74, 18.02, 21.90, 23.59, and 26.71, corresponding to d-spacings (Angstroms ± 0.2) of 20.68, 14.36, 10.16, 9.10, 7.19, 6.77, 6.44, 5.63, 4.92, 4.06, 3.77, and 3.34, respectively. In some embodiments, Compound 1 Crystalline Form D can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.3, 6.2, 8.7, 9.7, 12.3, 13.1, 13.8, 15.7, 18.0, 21.9, 23.6, and 26.7, corresponding to d-spacings (Angstroms ± 0.2) of 20.7, 14.4, 10.2, 9.1, 7.2, 6.8, 6.4, 5.6, 4.9, 4.1, 3.8, and 3.3, respectively.

[0254] In some embodiments, Compound 1 Crystalline Form D is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.27 6.15 8.71 9.72 12.31 13.08 13.76 15.74 18.02 19.55 21.90 23.59 24.79 26.71 29.50 30.82 31.74 35.40 37.84 38.61

[0275] In some embodiments, Compound 1 Crystalline Form D is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.3 6.2 8.7 9.7 12.3 13.1 13.8 15.7 18.0 19.5 21.9 23.6 24.8 26.7 29.5 30.8 31.7 35.4 37.8 38.6

[0296] In some embodiments, Compound 1 Crystalline Form D is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0297]

[0298] In some embodiments, Compound 1 Crystalline Form D is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0299]

[0300]

[0301] In some embodiments, Compound 1 crystalline Form D is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 9.6% at 130° C. In some embodiments, Compound 1 crystalline Form D is characterized by a differential scanning calorimetry (DSC) endotherm having an onset temperature of about 91.9° C.

[0302] Compound 1 Crystalline Form E

[0303] The novel Compound 1 crystalline Form E can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72. The novel Compound 1 crystalline Form E can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7. In some embodiments, Compound 1 Crystalline Form E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2θ ± 0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72, corresponding to d spacings (angstroms ± 0.2) of 5.86, 5.63, 5.07, 4.43, 4.05, and 3.34, respectively. In some embodiments, Compound 1 Crystalline Form E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2θ ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7, corresponding to d spacings (angstroms ± 0.2) of 5.9, 5.6, 5.1, 4.4, 4.1, and 3.3, respectively.

[0304] In some embodiments, Compound 1 crystalline Form E can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7. In some embodiments, Compound 1 crystalline Form E can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 15.1, 15.8, 17.5, 19.0, 20.1, 21.9, and 26.7, corresponding to d spacings (angstroms ± 0.2) of 5.9, 5.6, 5.1, 4.7, 4.4, 4.1, and 3.3, respectively.

[0305] In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.59, 15.12, 15.75, 17.48, 20.05, 21.93, 23.18, 23.70, and 26.72. In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.6, 15.1, 15.8, 17.5, 20.1, 21.9, 23.2, 23.7, and 26.7. In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.59, 15.12, 15.75, 17.48, 20.05, 21.93, 23.18, 23.70, and 26.72, corresponding to d-spacings (Angstroms ± 0.2) of 19.27, 5.86, 5.63, 5.07, 4.43, 4.05, 3.84, 3.75, and 3.34, respectively. In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD having one or more characteristic diffractions at angles (2θ ± 0.2) of 4.6, 15.1, 15.8, 17.5, 20.1, 21.9, 23.2, 23.7, and 26.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.3, 5.9, 5.6, 5.1, 4.4, 4.1, 3.8, 3.8, and 3.3, respectively.

[0306] In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.59, 9.76, 12.36, 13.12, 15.12, 15.75, 16.84, 17.48, 18.06, 19.02, 20.05, 21.93, 23.18, 23.70, 26.72, and 27.81. In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 4.6, 9.8, 12.4, 13.1, 15.1, 15.8, 16.8, 17.5, 18.1, 19.0, 20.1, 21.9, 23.2, 23.7, 26.7, and 27.8. In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.59, 9.76, 12.36, 13.12, 15.12, 15.75, 16.84, 17.48, 18.06, 19.02, 20.05, 21.93, 23.18, 23.70, 26.72, and 27.81, corresponding to d-spacings (Angstroms ± 0.2) of 19.27, 9.06, 7.16, 6.75, 5.86, 5.63, 5.27, 5.07, 4.91, 4.67, 4.43, 4.05, 3.84, 3.75, 3.34, and 3.21, respectively. In some embodiments, Compound 1 Crystalline Form E can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 4.6, 9.8, 12.4, 13.1, 15.1, 15.8, 16.8, 17.5, 18.1, 19.0, 20.1, 21.9, 23.2, 23.7, 26.7, and 27.8, corresponding to d-spacings (Angstroms ± 0.2) of 19.3, 9.1, 7.2, 6.7, 5.9, 5.6, 5.3, 5.1, 4.9, 4.7, 4.4, 4.1, 3.8, 3.8, 3.3, and 3.2, respectively.

[0307] In some embodiments, Compound 1 Crystalline Form E is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.59 8.76 9.76 12.36 13.12 13.83 15.12 15.75 16.84 17.48 18.06 19.02 20.05 21.93 23.18 23.70 24.82 26.72 27.81 29.51 30.76 31.74 33.03 34.52 35.39 36.72 37.77 38.66

[0336] In some embodiments, Compound 1 Crystalline Form E is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.6 8.8 9.8 12.4 13.1 13.8 15.1 15.8 16.8 17.5 18.1 19.0 20.1 21.9 23.2 23.7 24.8 26.7 27.8 29.5 30.8 31.7 33.0 34.5 35.4 36.7 37.8 38.7

[0365] In some embodiments, Compound 1 Crystalline Form E is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0366]

[0367]

[0368] In some embodiments, Compound 1 Crystalline Form E is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0369]

[0370]

[0371] Compound 1 Crystalline Form F

[0372] The novel Compound 1 crystalline Form F can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45. The novel Compound 1 crystalline Form F can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5. In some embodiments, Compound 1 crystalline Form F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2θ ± 0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45, corresponding to d spacings (angstroms ± 0.2) of 16.23, 6.04, 5.54, 5.28, 4.44, 4.16, and 3.96, respectively. In some embodiments, Compound 1 crystalline Form F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5, corresponding to d spacings (angstroms ± 0.2) of 16.2, 6.0, 5.5, 5.3, 4.4, 4.2, and 4.0, respectively.

[0373] In some embodiments, Compound 1 crystalline Form F can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, and 21.4. In some embodiments, Compound 1 crystalline Form F can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, and 21.4, corresponding to d-spacings (Angstroms ± 0.2) of 16.2, 6.0, 5.5, 5.3, and 4.2, respectively.

[0374] In some embodiments, Compound 1 Crystalline Form F can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.45, 14.66, 16.00, 16.79, 18.99, 20.01, 21.36, 22.45, 23.25, and 25.32. In some embodiments, Compound 1 Crystalline Form F can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, 19.0, 20.0, 21.4, 22.5, 23.2, and 25.3. In some embodiments, Compound 1 crystalline Form F can be identified by an XRPD having one or more characteristic diffractions at angles (2θ ± 0.2) of 5.45, 14.66, 16.00, 16.79, 18.99, 20.01, 21.36, 22.45, 23.25, and 25.32, corresponding to d-spacings (Angstroms ± 0.2) of 16.23, 6.04, 5.54, 5.28, 4.67, 4.44, 4.16, 3.96, 3.83, and 3.52, respectively. In some embodiments, Compound 1 crystalline Form F can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, 19.0, 20.0, 21.4, 22.5, 23.2, and 25.3, corresponding to d-spacings (Angstroms ± 0.2) of 16.2, 6.0, 5.5, 5.3, 4.7, 4.4, 4.2, 4.0, 3.8, and 3.5, respectively.

[0375] In some embodiments, Compound 1 Crystalline Form F can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.45, 12.87, 14.66, 16.00, 16.79, 17.36, 18.99, 20.01, 20.57, 21.36, 22.45, 23.25, 25.32, 26.57, 27.25, 27.97, and 30.02. In some embodiments, Compound 1 Crystalline Form F can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.4, 12.9, 14.7, 16.0, 16.8, 17.4, 19.0, 20.0, 20.6, 21.4, 22.5, 23.2, 25.3, 26.6, 27.2, 28.0, and 30.0. In some embodiments, Compound 1 crystalline Form F can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 5.45, 12.87, 14.66, 16.00, 16.79, 17.36, 18.99, 20.01, 20.57, 21.36, 22.45, 23.25, 25.32, 26.57, 27.25, 27.97, and 30.02, corresponding to d-spacings (Angstroms ± 0.2) of 16.23, 6.88, 6.04, 5.54, 5.28, 5.11, 4.67, 4.44, 4.32, 4.16, 3.96, 3.83, 3.52, 3.35, 3.27, 3.19, and 2.98, respectively. In some embodiments, Compound 1 Crystalline Form F can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 5.4, 12.9, 14.7, 16.0, 16.8, 17.4, 19.0, 20.0, 20.6, 21.4, 22.5, 23.2, 25.3, 26.6, 27.2, 28.0, and 30.0, corresponding to d-spacings (Angstroms ± 0.2) of 16.2, 6.9, 6.0, 5.5, 5.3, 5.1, 4.7, 4.4, 4.3, 4.2, 4.0, 3.8, 3.5, 3.4, 3.3, 3.2, and 3.0, respectively.

[0376] In some embodiments, Compound 1 Crystalline Form F is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 5.45 10.92 12.87 14.66 16.00 16.79 17.36 18.99 20.01 20.57 21.36 22.45 23.25 25.32 26.57 27.25 27.97 30.02 31.98 32.89 38.29 39.09

[0399] In some embodiments, Compound 1 Crystalline Form F is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 5.4 10.9 12.9 14.7 16.0 16.8 17.4 19.0 20.0 20.6 21.4 22.5 23.2 25.3 26.6 27.2 28.0 30.0 32.0 32.9 38.3 39.1

[0422] In some embodiments, Compound 1 Crystalline Form F is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0423]

[0424]

[0425] In some embodiments, Compound 1 Crystalline Form F is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0426]

[0427] In some embodiments, Compound 1 crystalline Form F is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 6.2% at 120° C. In some embodiments, Compound 1 crystalline Form F is characterized by a differential scanning calorimetry (DSC) endotherm having a peak temperature of about 100.4° C. and an onset temperature of 125.9° C.

[0428] Compound 1 Crystalline Form G

[0429] The novel Compound 1 Crystalline Form G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 5.36, 14.34, 16.58, and 21.35. The novel Compound 1 Crystalline Form G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 5.4, 14.3, 16.6, and 21.4. In some embodiments, Compound 1 Crystalline Form G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ ± 0.2) of 5.36, 14.34, 16.58, and 21.35, corresponding to d spacings (angstroms ± 0.2) of 16.48, 6.18, 5.35, and 4.16, respectively. In some embodiments, Compound 1 crystalline Form G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2θ ± 0.2) of 5.4, 14.3, 16.6, and 21.4, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.2, 5.3, and 4.2, respectively.

[0430] In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3. In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.2, 5.3, 4.2, and 4.0, respectively.

[0431] In some embodiments, Compound 1 Crystalline Form G can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 16.58, 19.78, 21.35, 22.35, 25.33, and 26.43. In some embodiments, Compound 1 Crystalline Form G can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.4, 12.8, 14.3, 15.0, 16.6, 19.8, 21.3, 22.3, 25.3, and 26.4. In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 16.58, 19.78, 21.35, 22.35, 25.33, and 26.43, corresponding to d-spacings (Angstroms ± 0.2) of 16.48, 6.90, 6.18, 5.91, 5.35, 4.49, 4.16, 3.98, 3.52, and 3.37, respectively. In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 5.4, 12.8, 14.3, 15.0, 16.6, 19.8, 21.3, 22.3, 25.3, and 26.4, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.9, 6.2, 5.9, 5.3, 4.5, 4.2, 4.0, 3.5, and 3.4, respectively.

[0432] In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 15.79, 16.58, 19.78, 21.35, 22.35, 25.33, 26.43, 27.35, and 30.21. In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD pattern having one or more characteristic diffraction at angles (2θ ± 0.2) of 5.34, 12.8, 14.3, 15.0, 15.8, 16.6, 19.8, 21.3, 22.3, 25.3, 26.4, 27.4, and 30.2. In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 15.79, 16.58, 19.78, 21.35, 22.35, 25.33, 26.43, 27.35, and 30.21, corresponding to d-spacings (Angstroms ± 0.2) of 16.48, 6.90, 6.18, 5.91, 5.61, 5.35, 4.49, 4.16, 3.98, 3.52, 3.37, 3.26, and 2.96, respectively. In some embodiments, Compound 1 crystalline Form G can be identified by an XRPD having one or more characteristic diffraction patterns at angles (2θ ± 0.2) of 5.4, 12.8, 14.3, 15.0, 15.8, 16.6, 19.8, 21.3, 22.3, 25.3, 26.4, 27.4, and 30.2, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.9, 6.2, 5.9, 5.6, 5.3, 4.5, 4.2, 4.0, 3.5, 3.4, 3.3, and 3.0, respectively.

[0433] In some embodiments, Compound 1 Crystalline Form G is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 5.36 8.73 12.83 14.34 15.00 15.79 16.58 18.54 19.78 21.35 22.35 23.38 25.33 26.43 27.35 30.21 32.32 38.04

[0452] In some embodiments, Compound 1 Crystalline Form G is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 5.4 8.7 12.8 14.3 15.0 15.8 16.6 18.5 19.8 21.3 22.3 23.4 25.3 26.4 27.4 30.2 32.3 38.0

[0471] In some embodiments, Compound 1 Crystalline Form G is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0472]

[0473]

[0474] In some embodiments, Compound 1 Crystalline Form G is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0475]

[0476] Compound 1 Crystalline Form H

[0477] The novel Compound 1 crystalline Form H can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4. In some embodiments, Compound 1 crystalline Form H can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4, corresponding to d spacings (angstroms ±0.2) of 15.3, 6.0, 5.4, 4.4, 4.2, and 3.5, respectively.

[0478] In some embodiments, Compound 1 Crystalline Form H is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 5.8 8.4 11.5 12.4 13.1 13.7 14.7 14.9 16.0 16.2 16.6 16.9 17.3 17.7 18.3 19.5 20.0 21.3 21.9 23.1 23.6 23.9 24.4 24.9 25.1 25.4 26.2 27.4 28.1 28.4 29.3 29.7 30.4 31.0 32.7 33.4 34.1 34.8 35.5 35.8 36.4 37.1 38.5

[0522] In some embodiments, Compound 1 Crystalline Form H is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0523]

[0524]

[0525] Compound 1 Crystalline Form I

[0526] The novel Compound 1 crystalline Form I can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1. In some embodiments, Compound 1 crystalline Form I can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1, corresponding to d spacings (angstroms ±0.2) of 17.1, 6.1, 5.7, 4.4, and 4.2, respectively.

[0527] In some embodiments, Compound 1 Crystalline Form I is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 5.2 8.8 10.3 12.6 14.6 15.5 16.1 16.3 16.6 17.1 17.6 18.7 18.9 20.2 20.5 20.7 21.1 21.5 22.0 22.3 23.7 24.8 25.2 26.0 26.3 26.5 26.8 27.0 27.5 27.7 28.1 29.6 30.0 30.4 31.3 32.0 32.5 33.2 34.0 34.6 36.9 38.2 38.9 39.5

[0572] In some embodiments, Compound 1 Crystalline Form I is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0573]

[0574]

[0575] Compound 1 Crystalline Form J

[0576] The novel Compound 1 crystalline Form J can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 5.7, 22.8, 23.1, and 24.5. In some embodiments, Compound 1 crystalline Form J can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 5.7, 22.8, 23.1, and 24.5 corresponding to d spacings (angstroms ±0.2) of 19.5, 15.4, 3.9, 3.8, and 3.6, respectively.

[0577] In some embodiments, Compound 1 crystalline Form J is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.5 5.7 7.1 7.7 9.1 10.5 11.2 11.7 12.3 12.9 14.3 14.5 15.4 15.7 16.3 17.3 18.3 18.7 19.3 19.6 20.5 21.2 21.5 22.8 23.1 23.6 24.1 24.5 25.2 25.9 26.4 27.8 29.3 36.2 37.0

[0613] In some embodiments, Compound 1 Crystalline Form J is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0614]

[0615]

[0616] Compound 1 Crystalline Form K

[0617] The novel Compound 1 crystalline Form K can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4. In some embodiments, Compound 1 crystalline Form K can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4, corresponding to d spacings (angstroms ±0.2) of 19.2, 5.7, 5.7, 5.5, 3.8, and 3.3, respectively.

[0618] In some embodiments, Compound 1 crystalline Form K is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.6 9.3 10.1 12.9 13.9 14.7 15.4 15.6 16.1 17.8 18.3 18.6 19.3 20.0 20.7 21.6 21.9 22.9 23.2 24.4 25.0 25.5 26.0 27.4 28.8 29.2 30.7 31.1 32.7 36.3

[0649] In some embodiments, Compound 1 Crystalline Form K is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0650]

[0651]

[0652] Compound 1 Crystalline Form L

[0653] The novel Compound 1 crystalline Form L can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1. In some embodiments, Compound 1 crystalline Form L can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1, corresponding to d spacings (angstroms ±0.2) of 14.9, 7.5, 5.0, 4.1, 3.7, and 2.5, respectively.

[0654] In some embodiments, Compound 1 crystalline Form L is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 5.9 8.4 11.9 13.3 14.7 15.0 16.2 16.7 16.9 17.8 18.9 20.4 21.2 21.6 22.2 23.9 24.6 25.5 25.7 26.1 26.8 28.1 28.8 29.9 30.6 31.9 32.4 33.6 34.2 35.6 36.1 38.2

[0687] In some embodiments, Compound 1 Crystalline Form L is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0688]

[0689]

[0690] Compound 1 Crystalline Form M

[0691] The novel Compound 1 Crystalline Form M can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7. In some embodiments, Compound 1 Crystalline Form M can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2θ±0.2) of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7, corresponding to d spacings (angstroms ±0.2) of 19.5, 15.3, 9.1, 5.7, 4.1, and 3.3, respectively.

[0692] In some embodiments, Compound 1 Crystalline Form M is characterized by an X-ray powder diffraction having one or more characteristic diffractions at the following angles (2θ±0.2): 4.5 5.8 6.1 8.7 9.0 9.7 12.3 13.1 13.7 14.5 15.1 15.6 16.8 17.4 18.0 18.5 19.5 20.0 21.4 21.9 22.3 22.9 23.3 23.5 24.1 25.0 25.8 26.3 26.7 27.8 28.1 29.4 30.8 31.7 33.0 35.3 37.8 38.6

[0731] In some embodiments, Compound 1 Crystalline Form M is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2θ ± 0.2) and corresponding d-spacings (Angstroms ± 0.2):

[0732]

[0733]

[0734] Pharmaceutical compositions comprising a crystalline form of Compound 1

[0735] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of any crystalline solid form of compound 1 as discussed above (Type A, Type B, Type C, Type D, Type E, Type F, or Type G) and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of any crystalline solid form of compound 1 as discussed above (Type A, Type B, Type C, Type D, Type E, Type F, Type G, Type H, Type I, Type J, Type K, Type L, or Type M) and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form of compound 1 as discussed above (Type A, Type B, Type C, Type D, Type E, Type F, or Type G) and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form (Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L or Form M) of Compound 1 as discussed above and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration.

[0736] In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form of Compound 1 (Type A, Type B, Type C, Type D, Type E, Type F or Type G) as discussed above, and having a water content of about 0.5 wt%-5.0 wt%, preferably about 1.0 wt%-4.5 wt%, more preferably about 1.5 wt%-4.0 wt%, even more preferably about 2.0 wt%-3.5 wt%, and still more preferably about 2.5 wt%-3.0 wt%, relative to the weight of the pharmaceutical composition. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form of Compound 1 as discussed above (Type A, Type B, Type C, Type D, Type E, Type F, Type G, Type H, Type I, Type J, Type K, Type L or Type M), and having a water content of about 0.5 wt %-5.0 wt %, preferably about 1.0 wt %-4.5 wt %, more preferably about 1.5 wt %-4.0 wt %, even more preferably about 2.0 wt %-3.5 wt %, and still more preferably about 2.5 wt %-3.0 wt %, relative to the weight of the pharmaceutical composition. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form of Compound 1 (Type A, Type B, Type C, Type D, Type E, Type F, or Type G) as discussed above, and having a water content selected from the following ranges relative to the weight of the pharmaceutical composition: about 0.5 wt%-1.0 wt%, about 1.0 wt%-1.5 wt%, about 1.5 wt%-2.0 wt%, about 2.5 wt%-3.0 wt%, about 3.0 wt%-3.5 wt%, about 3.5-4.0 wt%, about 4.0 wt%-4.5 wt%, and about 4.5 wt%-5.0 wt%. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form of Compound 1 as discussed above (Type A, Type B, Type C, Type D, Type E, Type F, Type G, Type H, Type I, Type J, Type K, Type L, or Type M), and having a water content selected from the following ranges relative to the weight of the pharmaceutical composition: about 0.5 wt %-1.0 wt %, about 1.0 wt %-1.5 wt %, about 1.5 wt %-2.0 wt %, about 2.5 wt %-3.0 wt %, about 3.0 wt %-3.5 wt %, about 3.5-4.0 wt %, about 4.0 wt %-4.5 wt %, and about 4.5 wt %-5.0 wt %.In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form of Compound 1 (Type A, Type B, Type C, Type D, Type E, Type F, or Type G) as discussed above, and having a water content in an amount selected from the following weight percentages relative to the weight of the pharmaceutical composition: about 0.5 weight %, about 1.0 weight %, about 1.5 weight %, about 2.0 weight %, about 2.5 weight %, about 3.0 weight %, about 3.5 weight %, about 4.0 weight %, about 4.5 weight % and about 5.0 weight %. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any crystalline solid form of Compound 1 as discussed above (Type A, Type B, Type C, Type D, Type E, Type F, Type G, Type H, Type I, Type J, Type K, Type L, or Type M), and having a water content in an amount selected from the following weight percentages relative to the weight of the pharmaceutical composition: about 0.5 weight %, about 1.0 weight %, about 1.5 weight %, about 2.0 weight %, about 2.5 weight %, about 3.0 weight %, about 3.5 weight %, about 4.0 weight %, about 4.5 weight % and about 5.0 weight %.

[0737] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 Crystalline Form A and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Crystalline Form A and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is substantially free of other crystalline forms of Compound 1. In some embodiments, the pharmaceutical composition is substantially free of amorphous Compound 1.

[0738] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 Crystalline Form B and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Crystalline Form B and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is substantially free of other crystalline forms of Compound 1. In some embodiments, the pharmaceutical composition is substantially free of amorphous Compound 1.

[0739] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 Crystalline Form C and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Crystalline Form C and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is substantially free of other crystalline forms of Compound 1. In some embodiments, the pharmaceutical composition is substantially free of amorphous Compound 1.

[0740] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 Crystalline Form D and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Crystalline Form D and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is substantially free of other crystalline forms of Compound 1. In some embodiments, the pharmaceutical composition is substantially free of amorphous Compound 1.

[0741] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 Crystalline Form E and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Crystalline Form E and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is substantially free of other crystalline forms of Compound 1. In some embodiments, the pharmaceutical composition is substantially free of amorphous Compound 1.

[0742] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 Crystalline Form F and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Crystalline Form F and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is substantially free of other crystalline forms of Compound 1. In some embodiments, the pharmaceutical composition is substantially free of amorphous Compound 1.

[0743] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Compound 1 Crystalline Form G and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Crystalline Form G and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is substantially free of other crystalline forms of Compound 1. In some embodiments, the pharmaceutical composition is substantially free of amorphous Compound 1.

[0744] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a crystalline form of Compound 1. In some embodiments, the pharmaceutical composition comprises a crystalline form of Compound 1 and an amorphous form of Compound 1, wherein the amorphous form of Compound 1 is present in an amount selected from the following ranges: about 90% to about 99%, about 80% to about 89%, about 70% to about 79%, about 60% to about 69%, about 50% to about 59%, about 40% to about 49%, about 30% to about 39%, about 20% to about 29%, about 10% to about 19%, about 1% to about 9%, and about 0% to about 0.99%. In some embodiments, the pharmaceutical composition comprising a crystalline form of Compound 1 is substantially free of amorphous Compound 1.

[0745] In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 and its enantiomer ("Compound 2"). In some embodiments, the pharmaceutical composition comprises Compound 1 and its enantiomer Compound 2, wherein Compound 1 has an enantiomeric excess selected from the following ranges: at least about 99%, at least about 95%, at least about 90%, at least about 80%, about 90% to about 99%, about 80% to about 89%, about 70% to about 79%, about 60% to about 69%, about 50% to about 59%, about 40% to about 49%, about 30% to about 39%, about 20% to about 29%, about 10% to about 19%, about 1% to about 9%, and about 0% to about 0.99%. In some embodiments, the pharmaceutical composition comprises Compound 1 and its enantiomer Compound 2, wherein the weight percentage of Compound 1 relative to the total weight of Compound 1 and Compound 2 is a percentage selected from the following ranges: about 90% to about 99%, about 80% to about 89%, about 70% to about 79%, about 60% to about 69%, about 50% to about 59%, about 40% to about 49%, about 30% to about 39%, about 20% to about 29%, about 10% to about 19%, about 1% to about 9% and about 0% to about 0.99%.

[0746] The pharmaceutical compositions described herein may include a pharmaceutically acceptable carrier or one or more excipients. In some embodiments, the pharmaceutical compositions described herein may be provided in a unit dosage container (e.g., a vial or bag, etc.). In some embodiments, the pharmaceutical compositions described herein may be provided in an oral dosage form. In some embodiments, the oral dosage form is a tablet.

[0747] Amorphous solid dispersion containing compound 1

[0748] The present disclosure also provides an amorphous solid dispersion comprising Compound 1:

[0749]

[0750] and polymers. In some embodiments, the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol (macrogol) 15 hydroxystearate (e.g., HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS), including any grade thereof (e.g., HPMC AS MG).

[0751] Various amounts of compound 1 and polymer can be used in amorphous solid dispersions. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion can be selected from the following ranges: about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1: 1, about 1: 2, about 1: 3, about 1: 4, about 1: 5, about 1: 6, about 1: 7, about 1: 8, about 1: 9, and about 1: 10. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion is in the range of about 3: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion is in the range of about 2: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion is about 1: 3. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion is about 1: 1. In some embodiments, the weight ratio of Compound 1 to polymer in the amorphous solid dispersion is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3: 1. In some embodiments, the weight ratio of Compound 1 to polymer in the amorphous solid dispersion is about 1:3, about 2:3, about 1:1, about 1.5:1, or about 2:1.

[0752] In some embodiments, the amorphous solid dispersion contains no or substantially no crystalline Compound 1. In some embodiments, no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion. In some embodiments, no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion. In some embodiments, a single glass transition temperature (T ) is observed by DSC analysis (Method B) of the amorphous solid dispersion. G ) and no melting endotherm.

[0753] In some embodiments, the amorphous solid dispersion is physically stable in that it remains free or substantially free of crystalline Compound 1 over time in an accelerated stability study. In some embodiments, no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a container as described in Example 20 at 2°C-8°C and ambient relative humidity for 5 months, at 25°C and 60% relative humidity for 5 months, at 2°C-8°C and ambient relative humidity for 1 month, at 25°C and 60% relative humidity for 1 month, or at 40°C and 75% relative humidity for 1 month. In some embodiments, a single glass transition temperature (Tg) is observed by DSC analysis of the amorphous solid dispersion (Method B) after storage in a container as described in Example 20 at 2°C-8°C and ambient relative humidity for 5 months, at 25°C and 60% relative humidity for 5 months, at 2°C-8°C and ambient relative humidity for 1 month, at 25°C and 60% relative humidity for 1 month, or at 40°C and 75% relative humidity for 1 month. G ) and no melting endotherm. In some embodiments, no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage at 60°C for 1 week in a sealed vial, storage at 60°C for 2 weeks in a sealed vial, storage at 25°C and 60% relative humidity in an unsealed vial for 1 week, storage at 25°C and 60% relative humidity in an unsealed vial for 2 weeks, storage at 40°C and 75% relative humidity in an unsealed vial for 1 week, storage at 40°C and 75% relative humidity in an unsealed vial for 2 weeks, storage at 60°C and 75% relative humidity in an unsealed vial for 1 week, or storage at 60°C and 75% relative humidity in an unsealed vial for 2 weeks. In some embodiments, a single glass transition temperature (Tg) is observed by DSC analysis of the amorphous solid dispersion (Method B) after storage at 60°C for 1 week in a sealed vial, storage at 60°C for 2 weeks in a sealed vial, storage at 25°C and 60% relative humidity for 1 week in an unsealed vial, storage at 25°C and 60% relative humidity for 2 weeks in an unsealed vial, storage at 40°C and 75% relative humidity for 1 week in an unsealed vial, storage at 40°C and 75% relative humidity for 2 weeks in an unsealed vial, storage at 60°C and 75% relative humidity for 1 week in an unsealed vial, or storage at 60°C and 75% relative humidity in an unsealed vial for 2 weeks. G ) and no melting endotherm.

[0754] In some embodiments, the amorphous solid dispersion is highly soluble, for example, compound 1 dissolves quickly and easily in a biologically relevant medium. In some embodiments, in the kinetic solubility experiment described in Example 23, after 30 minutes, compound 1 has a concentration of at least 150 μg / mL, at least 200 μg / mL, at least 250 μg / mL, at least 300 μg / mL, or at least 350 μg / mL. In some embodiments, in the kinetic solubility experiment described in Example 23, compound 1 has a Cmax of at least 300 μg / mL, at least 350 μg / mL, at least 400 μg / mL, at least 450 μg / mL, at least 500 μg / mL, at least 550 μg / mL, at least 600 μg / mL, at least 650 μg / mL, or at least 700 μg / mL. In some embodiments, Compound 1 has a concentration of at least 200 μg / mL, at least 250 μg / mL, at least 300 μg / mL, at least 350 μg / mL, at least 400 μg / mL, at least 450 μg / mL, at least 500 μg / mL, at least 550 μg / mL, or at least 600 μg / mL after 4 hours in the kinetic solubility experiment described in Example 23. In some embodiments, Compound 1 has a concentration of at least 150 μg / mL, at least 200 μg / mL, at least 250 μg / mL, or at least 300 μg / mL after 16 hours in the kinetic solubility experiment described in Example 23.

[0755] Pharmaceutical composition comprising amorphous solid dispersion of compound 1

[0756] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of an amorphous solid dispersion comprising Compound 1, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration.

[0757] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an amorphous solid dispersion containing compound 1 and having a water content of about 0.5%-5.0% by weight, preferably about 1.0%-4.5% by weight, more preferably about 1.5%-4.0% by weight, even more preferably about 2.0%-3.5% by weight, and still more preferably about 2.5%-3.0% by weight relative to the weight of the pharmaceutical composition. In some embodiments, the present disclosure provides a pharmaceutical composition comprising an amorphous solid dispersion containing compound 1 and having a water content selected from the following ranges relative to the weight of the pharmaceutical composition: about 0.5%-1.0% by weight, about 1.0%-1.5% by weight, about 1.5%-2.0% by weight, about 2.5%-3.0% by weight, about 3.0%-3.5% by weight, about 3.5-4.0% by weight, about 4.0%-4.5% by weight, and about 4.5%-5.0% by weight. In some embodiments, the present disclosure provides a pharmaceutical composition comprising an amorphous solid dispersion containing Compound 1 and having a water content in an amount selected from the following weight percentages relative to the weight of the pharmaceutical composition: about 0.5 weight %, about 1.0 weight %, about 1.5 weight %, about 2.0 weight %, about 2.5 weight %, about 3.0 weight %, about 3.5 weight %, about 4.0 weight %, about 4.5 weight % and about 5.0 weight %.

[0758] In some embodiments, the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 25 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1.

[0759] The pharmaceutical compositions described herein may include a pharmaceutically acceptable carrier or one or more excipients. In some embodiments, the pharmaceutical compositions described herein may be provided in a unit dosage container (e.g., a vial or bag, etc.). In some embodiments, the pharmaceutical compositions described herein may be provided in an oral dosage form. In some embodiments, the oral dosage form is a tablet.

[0760] In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, the excipients comprising one or more of a filler, a dry binder, a glidant, a lubricant, a disintegrant, and a film coating agent. In some embodiments, one or more pharmaceutically acceptable excipients comprise a filler, and the filler comprises microcrystalline cellulose. In some embodiments, one or more pharmaceutically acceptable excipients comprise a filler, and the filler comprises lactose monohydrate. In some embodiments, one or more pharmaceutically acceptable excipients comprise a dry binder, and the dry binder comprises crospovidone. In some embodiments, one or more pharmaceutically acceptable excipients comprise a glidant, and the glidant comprises colloidal silicon dioxide. In some embodiments, one or more pharmaceutically acceptable excipients comprise a lubricant, and the lubricant comprises magnesium stearate. In some embodiments, one or more pharmaceutically acceptable excipients comprise a disintegrant, and the disintegrant comprises cross-linked sodium carboxymethyl cellulose. In some embodiments, one or more pharmaceutically acceptable excipients comprise a lubricant, and the lubricant comprises magnesium stearate.

[0761] In some embodiments, the pharmaceutical composition comprises a tablet core. In some embodiments, the tablet core comprises an intragranular portion comprising an amorphous solid dispersion, and an extragranular portion blended with the intragranular portion. In some embodiments, the pharmaceutical composition further comprises a coating disposed on the tablet core.

[0762] Different amounts of Compound 1 relative to the core can be used in a pharmaceutical composition comprising an amorphous solid dispersion containing Compound 1. In some embodiments, the amorphous solid dispersion containing Compound 1 may be about 10% by weight, about 20% by weight, about 30% by weight, about 40% by weight, about 50% by weight, about 60% by weight, about 70% by weight, about 80% by weight, or about 90% by weight of the core. In some embodiments, the amorphous solid dispersion containing Compound 1 is at least about 30% by weight of the core. In some embodiments, the amorphous solid dispersion containing Compound 1 is at least about 50% by weight of the core. In some embodiments, the amorphous solid dispersion containing Compound 1 is at least about 60% by weight of the core. In some embodiments, the amorphous solid dispersion containing Compound 1 is about 50% by weight of the core. In some embodiments, the amorphous solid dispersion containing Compound 1 is about 50% by weight of the core. In some embodiments, the amorphous solid dispersion containing Compound 1 is about 50% by weight of the core. In some embodiments, the amorphous solid dispersion containing Compound 1 is about 50% to about 70% by weight of the core. In some embodiments, the amorphous solid dispersion comprising Compound 1 is about 60% to about 65% by weight of the tablet core.

[0763] In some embodiments, the intragranular portion further comprises one or more of a filler, a dry binder, a glidant, and a lubricant. In some embodiments, the extragranular portion further comprises one or more of a filler, a disintegrant, and a lubricant.

[0764] In some embodiments, the core has the following composition:

[0765] Function % Preparation (weight) Exemplary components API 30％-70％ Amorphous solid dispersion of compound 1 Fillers 15％-40％ Microcrystalline Cellulose Dry adhesive 2％-10％ Crospovidone Glidants 0.25％-1.25％ Colloidal Silica Lubricants 0.25％-1.00％ Magnesium Stearate

[0766] In some embodiments, the core has the following composition:

[0767] Function % Preparation (weight) Exemplary components API 30％-70％ Amorphous solid dispersion of compound 1 Fillers 15％-50％ Microcrystalline cellulose, lactose monohydrate Dry adhesive 2％-10％ Crospovidone Glidants 0.25％-1.25％ Colloidal Silica Disintegrants 2％-3％ Croscarmellose Sodium Lubricants 0.25％-1.00％ Magnesium Stearate

[0768] In some embodiments, the core has the following composition:

[0769] Components Function scope SDD (1:1 drug:polymer w / w) Active ingredients 50％-75％ Microcrystalline Cellulose Fillers 15％-30％ Lactose monohydrate Fillers 0％-20％ Cross-linked polyvinyl pyrrolidone Dry adhesive 2％-10％ Colloidal Silica Glidants <2％ Croscarmellose Sodium Disintegrants 2％-10％ Magnesium Stearate Lubricants <2％

[0770] In some embodiments, the core has the following composition:

[0771] Components Function scope SDD (1.5:1 drug:polymer w / w) Active ingredients 50％-75％ Microcrystalline Cellulose Fillers 15％-30％ Lactose monohydrate Fillers 0％-20％ Cross-linked polyvinyl pyrrolidone Dry adhesive 2％-10％ Colloidal Silica Glidants <2％ Croscarmellose Sodium Disintegrants 2％-10％ Magnesium Stearate Lubricants <2％

[0772] In some embodiments, the oral unit dosage form of Compound 1 may be a tablet containing a total of about 10%-35% by weight of Compound 1, with a total dose of about 100 mg or 200 mg and a total weight of less than about 800 mg. In one embodiment, the tablet having the composition described in the table above contains about 50% of the API formed as an amorphous solid dispersion of Compound 1 obtained from the 1:3 SDD process described in the examples below (e.g., about 12.5% ​​of Compound 1 in the tablet). In one embodiment, the tablet having the composition described in the table above contains about 30% of the API formed as an amorphous solid dispersion of Compound 1 obtained from the 1:1 SDD process described in the examples below (e.g., about 15% of Compound 1 in the tablet, and a total of about 100 mg of Compound 1 in the tablet). In one embodiment, the tablet having the composition described in the table above contains about 62% of the API formed as an amorphous solid dispersion of Compound 1 obtained from the 1:1 SDD process described in the examples below (e.g., about 31% of Compound 1 in the tablet, and a total of about 200 mg of Compound 1 in the tablet).

[0773] Method for preparing amorphous solid dispersion of compound 1

[0774] The present disclosure also provides a method for preparing an amorphous solid dispersion comprising the following compound 1:

[0775]

[0776] In some embodiments, the method comprises mixing Compound 1, a polymer, and a solvent to obtain a mixture, and spray drying the mixture to obtain an amorphous solid dispersion comprising Compound 1.

[0777] In some embodiments, the polymer used in the method is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS), including any grade thereof (e.g., HPMC AS MG).

[0778] Various amounts of compound 1 and polymer can be used in the method for preparing an amorphous solid dispersion. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion used in the method for preparing an amorphous solid dispersion can be selected from the following ranges: about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1: 1, about 1: 2, about 1: 3, about 1: 4, about 1: 5, about 1: 6, about 1: 7, about 1: 8, about 1: 9, and about 1: 10. In some embodiments, the weight ratio of compound 1 used in the method for preparing an amorphous solid dispersion to polymer is in the range of about 3: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 used in the method for preparing an amorphous solid dispersion to polymer is in the range of about 2: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 used in the method for preparing an amorphous solid dispersion to polymer is about 1: 3. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 1. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 3, about 2: 3, about 1: 1, about 1.5: 1, about 2: 1, or about 3: 1. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 3, about 2: 3, about 1: 1, about 1.5: 1, or about 2: 1.

[0779] Various solvents can be used in the method of preparing the amorphous solid dispersion. In some embodiments, the solvent is dichloromethane and methanol.

[0780] The present disclosure also provides a product prepared by the following process, the process comprising mixing compound 1, a polymer and a solvent to obtain a mixture, and spray drying the mixture to obtain an amorphous solid dispersion comprising the following compound 1

[0781]

[0782] In some embodiments, the polymer used in the process is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS), including any grade thereof (e.g., HPMC AS MG).

[0783] Various amounts of compound 1 and polymer can be used in the process of preparing amorphous solid dispersions. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion used in the process of preparing an amorphous solid dispersion can be selected from the following ranges: about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1: 1, about 1: 2, about 1: 3, about 1: 4, about 1: 5, about 1: 6, about 1: 7, about 1: 8, about 1: 9 and about 1: 10. In some embodiments, the weight ratio of compound 1 used in the process of preparing an amorphous solid dispersion to polymer is in the range of about 3: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 used in the process of preparing an amorphous solid dispersion to polymer is in the range of about 2: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 used in the process of preparing an amorphous solid dispersion to polymer is about 1: 3. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 1. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 3, about 2: 3, about 1: 1, about 1.5: 1, about 2: 1, or about 3: 1. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 3, about 2: 3, about 1: 1, about 1.5: 1, or about 2: 1.

[0784] Various solvents can be used in the process of preparing the amorphous solid dispersion. In some embodiments, the solvent is dichloromethane and methanol.

[0785] Pharmaceutical composition comprising compound 1

[0786] The present disclosure provides a pharmaceutical composition, which comprises compound 1:

[0787]

[0788] The pharmaceutical composition is obtained by a process comprising mixing Compound 1 in a solid form, a polymer, and a solvent to obtain a mixture, and spray-drying the mixture to obtain an amorphous solid dispersion containing Compound 1.

[0789] In some embodiments, the solid form is Form A of Compound 1. In some embodiments, the solid form is Form B of Compound 1. In some embodiments, the solid form is Form C of Compound 1. In some embodiments, the solid form is Form D of Compound 1. In some embodiments, the solid form is Form E of Compound 1. In some embodiments, the solid form is Form F of Compound 1. In some embodiments, the solid form is Form G of Compound 1. In some embodiments, the solid form is Form H of Compound 1. In some embodiments, the solid form is Form I of Compound 1. In some embodiments, the solid form is Form J of Compound 1. In some embodiments, the solid form is Form K of Compound 1. In some embodiments, the solid form is Form L of Compound 1. In some embodiments, the solid form is Form M of Compound 1. In some embodiments, the solid form is selected from the group consisting of Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, and Form M of Compound 1. In some embodiments, the solid form is an amorphous form of Compound 1.

[0790] In some embodiments, the pharmaceutical composition obtained by the process has a water content of about 0.5%-5.0% by weight relative to the weight of the pharmaceutical composition, preferably about 1.0%-4.5% by weight, more preferably about 1.5%-4.0% by weight, even more preferably about 2.0%-3.5% by weight, and still more preferably about 2.5%-3.0% by weight. In some embodiments, the pharmaceutical composition obtained by the process has a water content selected from the following ranges relative to the weight of the pharmaceutical composition: about 0.5%-1.0% by weight, about 1.0%-1.5% by weight, about 1.5%-2.0% by weight, about 2.5%-3.0% by weight, about 3.0%-3.5% by weight, about 3.5-4.0% by weight, about 4.0%-4.5% by weight, and about 4.5%-5.0% by weight. In some embodiments, the pharmaceutical composition obtained by the process has a water content in an amount selected from the following weight percentages relative to the weight of the pharmaceutical composition: about 0.5 weight %, about 1.0 weight %, about 1.5 weight %, about 2.0 weight %, about 2.5 weight %, about 3.0 weight %, about 3.5 weight %, about 4.0 weight %, about 4.5 weight % and about 5.0 weight %.

[0791] In some embodiments, the polymer used in the process is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS), including any grade thereof (e.g., HPMC AS MG).

[0792] Various amounts of compound 1 and polymer can be used in the process of preparing amorphous solid dispersions. In some embodiments, the weight ratio of compound 1 to polymer in the amorphous solid dispersion used in the process of preparing an amorphous solid dispersion can be selected from the following ranges: about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1: 1, about 1: 2, about 1: 3, about 1: 4, about 1: 5, about 1: 6, about 1: 7, about 1: 8, about 1: 9 and about 1: 10. In some embodiments, the weight ratio of compound 1 used in the process of preparing an amorphous solid dispersion to polymer is in the range of about 3: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 used in the process of preparing an amorphous solid dispersion to polymer is in the range of about 2: 1 to about 1: 3. In some embodiments, the weight ratio of compound 1 used in the process of preparing an amorphous solid dispersion to polymer is about 1: 3. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 1. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 3, about 2: 3, about 1: 1, about 1.5: 1, about 2: 1, or about 3: 1. In some embodiments, the weight ratio of Compound 1 used in the method of preparing an amorphous solid dispersion to the polymer is about 1: 3, about 2: 3, about 1: 1, about 1.5: 1, or about 2: 1.

[0793] Various solvents can be used in the process of preparing the amorphous solid dispersion. In some embodiments, the solvent is dichloromethane and methanol.

[0794] Solid oral dosage form of compound 1

[0795] The present disclosure also provides solid oral dosage forms of Compound 1, such as tablets and capsules. In some embodiments, the solid oral dosage form comprises a stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxin-[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one, wherein the stabilized amorphous compound does not show crystallinity after storage at 60°C / 75% RH (exposed) for 2 weeks according to PXRD (Method D). In some embodiments, the stabilized amorphous compound shows a single glass transition temperature (T) after storage at 60°C / 75% RH (exposed) for 2 weeks according to DSC (Method B). G ) and no melting endotherm.

[0796] In some embodiments, the solid oral dosage form contains a total of about 100 mg or about 200 mg of (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one. In some embodiments, the solid dosage form has a total weight of no more than 700 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg. In some embodiments, the solid oral dosage form is a tablet or capsule.

[0797] In some embodiments, the stabilized amorphous compound in the solid oral dosage form is in a spray-dried dispersion with a polymer. In some embodiments, the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG) and combinations thereof. In some embodiments, the polymer is HPMC AS. In some embodiments, (S)-1-(5-[2H,3H-[1,4]dioxin-[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one and HPMC AS are spray dried in a weight ratio of 1:3 to 2:1. In some embodiments, (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one and HPMC AS are spray dried in a weight ratio of 1:1.

[0798] The present disclosure also relates to a (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one active pharmaceutical ingredient (API) composition comprising 0.05%-5.0% of (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one according to HPLC.

[0799] The present disclosure also relates to tablets comprising about 100 mg or about 200 mg of a stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one as an active pharmaceutical ingredient (API), wherein the stabilized amorphous compound shows no crystallinity after the tablets are stored at 60°C / 75% RH (exposed) for 2 weeks according to PXRD (Method D). In some embodiments, the API contains less than 5.0% (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one by HPLC. In some embodiments, the API contains less than 0.05% (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one by HPLC. In some embodiments, the tablet has a total weight of less than 700 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg.

[0800] Tablet dosage form of compound 1

[0801] The present disclosure also provides a tablet dosage form of Compound 1. In some embodiments, the tablet dosage form comprises a tablet core comprising at least 10% by weight of an amorphous form of Compound 1:

[0802]

[0803] wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the tablet core (Method D). In some embodiments, wherein the tablet core comprises at least 15 wt%, at least 20 wt%, at least 25 wt%, or at least 30 wt% of amorphous form of Compound 1. In some embodiments, the tablet core comprises about 200 mg of Compound 1 per tablet and has a total weight of no more than about 1200 mg, about 1100 mg, about 1000 mg, about 900 mg, about 800 mg, or about 700 mg per tablet.

[0804] In some embodiments, the tablet dosage form comprises a tablet core having a total weight of no more than about 1000 mg and comprising about 200 mg of amorphous form of Compound 1 per tablet, wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the tablet core (Method D). In some embodiments, the tablet core has a total weight of no more than about 800 mg per tablet.

[0805] In some embodiments, the tablet core comprises a highly enantiomerically pure form of Compound 1. In some embodiments, the tablet core comprises 0.05%-5.0% of Compound 2:

[0806]

[0807] Based on the total amount of Compound 1 and Compound 2. In some embodiments, the tablet core contains 0.05%-3.0% of Compound 2, based on the total amount of Compound 1 and Compound 2. In some embodiments, the tablet core contains 0.05%-2.0% of Compound 2, based on the total amount of Compound 1 and Compound 2. In some embodiments, the tablet core contains 0.05%-1.0% of Compound 2, based on the total amount of Compound 1 and Compound 2.

[0808] In some embodiments, the tablet dosage form is physically stable in that it remains free or substantially free of crystalline Compound 1 over time in an accelerated stability study. In some embodiments, no crystalline Compound 1 (Form A) is observed by XRPD analysis (Method D) of the tablet cores after storage for 1 month at 25°C and 60% relative humidity in a sealed container as described in Example 29, 2 months at 25°C and 60% relative humidity in a sealed container as described in Example 29, 3 months at 25°C and 60% relative humidity in a sealed container as described in Example 29, 1 month at 40°C and 75% relative humidity in a sealed container as described in Example 29, 2 months at 40°C and 75% relative humidity in a sealed container as described in Example 29, and 3 months at 40°C and 75% relative humidity in a sealed container as described in Example 29.

[0809] In some embodiments, Compound 1 is present in an amorphous solid dispersion comprising Compound 1 and a polymer. In some embodiments, the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS), including any grade thereof (e.g., HPMC AS MG).

[0810] In some embodiments, the weight ratio of Compound 1 to polymer is in the range of about 3:1 to about 1:3. In some embodiments, the weight ratio of Compound 1 to polymer is in the range of about 2:1 to about 1:3. In some embodiments, the weight ratio of Compound 1 to polymer is about 1:3. In some embodiments, the weight ratio of Compound 1 to polymer is about 1:1. In some embodiments, the weight ratio of Compound 1 to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1. In some embodiments, the weight ratio of Compound 1 to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, or about 2:1.

[0811] In some embodiments, the core of the tablet dosage form further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients comprise one or more of a filler, a dry binder, a glidant, a lubricant, a disintegrant, and a film coating agent.

[0812] In some embodiments, the tablet core comprises an intragranular portion comprising Compound 1; and an extragranular portion blended with the intragranular portion. In some embodiments, the intragranular portion comprises an amorphous solid dispersion comprising Compound 1 and a polymer and one or more of a filler, a dry binder, a glidant, and a lubricant, and the extragranular portion comprises one or more of a filler, a disintegrant, and a lubricant. In some embodiments, the intragranular portion comprises:

[0813] An amorphous solid dispersion of Compound 1 in an amount of 30% to 70% by weight of the tablet core;

[0814] One or more fillers in an amount of 15% to 50% by weight of the tablet core;

[0815] One or more dry binders in an amount of 2.50% to 10% by weight of the core;

[0816] one or more glidants in an amount of 0.50% to 1.50% by weight of the tablet core; and

[0817] One or more lubricants in an amount of 0.25% to 1% by weight of the tablet core; and

[0818] The extragranular portion contains:

[0819] One or more fillers in an amount of 5% to 15% by weight of the tablet core;

[0820] one or more disintegrants in an amount of 1.25% to 5% by weight of the tablet core; and

[0821] One or more lubricants are present in an amount of 0.25% to 1% by weight of the tablet core.

[0822] In some embodiments, the tablet dosage form comprises:

[0823] an amorphous solid dispersion of Compound 1 in an amount of 50% to 75% by weight of the tablet core;

[0824] One or more fillers in an amount of 15% to 50% by weight of the tablet core;

[0825] One or more dry binders in an amount of 2% to 10% by weight of the core;

[0826] One or more glidants in an amount of <2% by weight of the tablet core;

[0827] one or more disintegrants in an amount of 2% to 10% by weight of the tablet core; and

[0828] One or more lubricants in an amount of <2% by weight of the tablet core.

[0829] In some embodiments, the amorphous solid dispersion comprises compound 1 and a polymer (as described in any embodiment set forth herein). In some embodiments, one or more fillers comprise microcrystalline cellulose or lactose monohydrate. In some embodiments, one or more dry binders comprise crospovidone or cross-linked polyvinyl pyrrolidone. In some embodiments, one or more glidants comprise colloidal silicon dioxide or fumed silicon dioxide. In some embodiments, one or more lubricants comprise magnesium stearate. In some embodiments, one or more disintegrants comprise cross-linked sodium carboxymethyl cellulose.

[0830] Medical uses of solid forms and pharmaceutical compositions

[0831] In some embodiments, the disclosure relates to methods of treating a disease associated with decreased PKR activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I in any form described herein, including any embodiments thereof.

[0832] Implementation

[0833] In some embodiments, the present disclosure relates to one or more of the following listed embodiments:

[0834] 1. A crystalline solid form of Compound 1:

[0835]

[0836] 2. A crystalline solid form as described in embodiment 1, wherein the crystalline solid form is Form A of (S)-1-(5-[2H,3H-[1,4]dioxin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one ("Compound 1").

[0837] 3. The crystalline solid form of Embodiment 1 or 2, wherein Form A of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.61, 15.66, 23.19, and 24.76.

[0838] 4. The crystalline solid form of any one of embodiments 1-3, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.61, 15.66, 23.19, and 24.76, corresponding to d-spacings (Angstroms±0.2) of 19.19, 5.66, 3.84, and 3.60, respectively.

[0839] 5. The crystalline solid form of any one of embodiments 1-4, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.61, 7.22, 15.66, 20.48, 21.35, 21.66, 22.47, 23.19, 24.76, and 26.73.

[0840] 6. The crystalline solid form of any one of embodiments 1-5, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.61, 7.22, 15.66, 20.48, 21.35, 21.66, 22.47, 23.19, 24.76, and 26.73, corresponding to d-spacings (Angstroms ± 0.2) of 19.19, 12.25, 5.66, 4.34, 4.16, 4.10, 3.96, 3.84, 3.60, and 3.34, respectively.

[0841] 7. The crystalline solid form of any one of embodiments 1-6, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.61 5.80 7.22 7.68 11.21 12.31 14.44 15.66 16.95 18.02 19.20 20.48 21.35 21.66 22.47 23.19 24.76 26.73 28.01 28.49 29.35 30.25 32.14 34.12 36.46

[0867] 8. The crystalline solid form of any one of embodiments 1-7, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[0868]

[0869] 9. The crystalline solid form of any one of embodiments 1-8, wherein Form A of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.9% at 100°C.

[0870] 10. The crystalline solid form of any one of embodiments 1-9, wherein Form A of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm having a peak temperature of about 85.9°C and an onset temperature of about 146.0°C.

[0871] 11. The crystalline solid form of any one of embodiments 1-10, wherein Form A of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 3.4 wt% water uptake at 40% relative humidity.

[0872] 12. The crystalline solid form of any one of embodiments 1-11, wherein Form A of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 1.0 wt. % water uptake at 40% to 80% relative humidity.

[0873] 13. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form B of Compound 1.

[0874] 14. The crystalline solid form of Embodiment 1 or 13, wherein Form B of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13.

[0875] 15. The crystalline solid form of any of embodiments 1 and 13-14, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13, corresponding to d-spacings (Angstroms ± 0.2) of 19.53, 5.69, 3.89, 3.81, and 3.54, respectively.

[0876] 16. The crystalline solid form of any one of embodiments 1 and 13-15, wherein Form B of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.52, 9.86, 15.57, 19.93, 22.19, 22.89, 23.34, 25.13, and 28.30.

[0877] 17. The crystalline solid form of any one of embodiments 1 and 13-16, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.52, 9.86, 15.57, 19.93, 22.19, 22.89, 23.34, 25.13, and 28.30, corresponding to d-spacings (Angstroms ± 0.2) of 19.53, 8.97, 5.69, 4.45, 4.00, 3.89, 3.81, 3.54, and 3.15, respectively.

[0878] 18. The crystalline solid form of any one of embodiments 1 and 13-17, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.52 8.98 9.86 12.37 13.18 15.57 16.86 18.21 19.11 19.93 20.92 22.19 22.89 23.34 25.13 25.80 26.71 28.30 29.39

[0898] 19. The crystalline solid form of any one of embodiments 1 and 13-18, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[0899]

[0900]

[0901] 20. The crystalline solid form of any one of embodiments 1 and 13-19, wherein Form B of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.8% at 100°C.

[0902] 21. The crystalline solid form of any one of embodiments 1 and 13-20, wherein Form B of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% at 120°C.

[0903] 22. The crystalline solid form of any one of embodiments 1 and 13-21, wherein Form B of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm with an onset temperature of about 138.2°C-139.2°C.

[0904] 23. The crystalline solid form of any one of embodiments 1 and 13-22, wherein Form B of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 2.9 wt% water uptake at 60% relative humidity.

[0905] 24. The crystalline solid form of any one of embodiments 1 and 13-23, wherein Form B of Compound 1 is characterized by a dynamic vapor sorption (DVS) having a water uptake of about 0.4 wt % at 60% to 80% relative humidity.

[0906] 25. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form C of Compound 1.

[0907] 26. The crystalline solid form of Embodiment 1 or 25, wherein Form C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.55, 18.85, 23.02, and 24.65.

[0908] 27. The crystalline solid form of any one of embodiments 1 and 25-26, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.55, 18.85, 23.02, and 24.65, corresponding to d-spacings (Angstroms ± 0.2) of 19.43, 4.71, 3.86, and 3.61, respectively.

[0909] 28. The crystalline solid form of any one of embodiments 1 and 25-27, wherein Form C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.55, 7.34, 9.07, 11.17, 18.34, 18.85, 19.57, 21.66, 23.02, and 24.65.

[0910] 29. The crystalline solid form of any one of embodiments 1 and 25-28, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.55, 7.34, 9.07, 11.17, 18.34, 18.85, 19.57, 21.66, 23.02, and 24.65, corresponding to d-spacings (Angstroms ± 0.2) of 19.43, 12.05, 9.75, 7.92, 4.84, 4.71, 4.54, 4.10, 3.86, and 3.61, respectively.

[0911] 30. The crystalline solid form of any one of embodiments 1 and 25-29, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.55 7.34 9.07 11.17 12.29 14.51 15.66 18.34 18.85 19.57 20.38 21.66 23.02 24.65 26.39 28.28 30.09 32.31 33.91 37.19

[0932] 31. The crystalline solid form of any one of embodiments 1 and 25-30, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[0933]

[0934] 32. The crystalline solid form of any one of embodiments 1 and 25-31, wherein Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.0% at 100°C.

[0935] 33. The crystalline solid form of any one of embodiments 1 and 25-32, wherein Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% at 130°C.

[0936] 34. The crystalline solid form of any one of embodiments 1 and 25-33, wherein Form C of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm with an onset temperature of about 152.2°C-154.2°C.

[0937] 35. The crystalline solid form of any one of embodiments 1 and 25-34, wherein Form C of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 1.8 wt% water uptake at 60% relative humidity.

[0938] 36. The crystalline solid form of any one of embodiments 1 and 25-35, wherein Form C of Compound 1 is characterized by a dynamic vapor sorption (DVS) having a water uptake of about 0.5 wt % at 60% to 80% relative humidity.

[0939] 37. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form D of Compound 1.

[0940] 38. The crystalline solid form of Embodiment 1 or 37, wherein Form D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 9.72, 13.08, 15.74, 21.90, and 23.59.

[0941] 39. The crystalline solid form of any one of embodiments 1 and 37-38, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 9.72, 13.08, 15.74, 21.90, and 23.59, corresponding to d-spacings (Angstroms ± 0.2) of 9.10, 6.77, 5.63, 4.06, and 3.77, respectively.

[0942] 40. The crystalline solid form of any one of embodiments 1 and 37-39, wherein Form D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 4.27, 6.15, 8.71, 9.72, 12.31, 13.08, 13.76, 15.74, 18.02, 21.90, 23.59, and 26.71.

[0943] 41. The crystalline solid form of any one of embodiments 1 and 37-40, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.27, 6.15, 8.71, 9.72, 12.31, 13.08, 13.76, 15.74, 18.02, 21.90, 23.59, and 26.71, corresponding to d-spacings (Angstroms ± 0.2) of 20.68, 14.36, 10.16, 9.10, 7.19, 6.77, 6.44, 5.63, 4.92, 4.06, 3.77, and 3.34, respectively.

[0944] 42. The crystalline solid form of any one of embodiments 1 and 37-41, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.27 6.15 8.71 9.72 12.31 13.08 13.76 15.74 18.02 19.55 21.90 23.59 24.79 26.71 29.50 30.82 31.74 35.40 37.84 38.61

[0965] 43. The crystalline solid form of any one of embodiments 1 and 37-42, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[0966]

[0967]

[0968] 44. The crystalline solid form of any one of embodiments 1 and 37-43, wherein Form D of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 9.6% at 130°C.

[0969] 45. The crystalline solid form of any one of embodiments 1 and 37-44, wherein Form D of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm with an onset temperature of about 91.9°C.

[0970] 46. ​​The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form E of Compound 1.

[0971] 47. The crystalline solid form of Embodiment 1 or 46, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72.

[0972] 48. A crystalline solid form as described in any of embodiments 1 and 46-47, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72, corresponding to d-spacings (Angstroms±0.2) of 5.86, 5.63, 5.07, 4.43, 4.05, and 3.34, respectively.

[0973] 49. The crystalline solid form of any one of embodiments 1 and 46-48, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.59, 15.12, 15.75, 17.48, 20.05, 21.93, 23.18, 23.70, and 26.72.

[0974] 50. A crystalline solid form as described in any of embodiments 1 and 46-49, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.59, 15.12, 15.75, 17.48, 20.05, 21.93, 23.18, 23.70 and 26.72, corresponding to d-spacings (Angstroms±0.2) of 19.27, 5.86, 5.63, 5.07, 4.43, 4.05, 3.84, 3.75 and 3.34, respectively.

[0975] 51. The crystalline solid form of any one of embodiments 1 and 46-50, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 4.59, 9.76, 12.36, 13.12, 15.12, 15.75, 16.84, 17.48, 18.06, 19.02, 20.05, 21.93, 23.18, 23.70, 26.72, and 27.81.

[0976] 52. A crystalline solid form as described in any of embodiments 1 and 46-51, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.59, 9.76, 12.36, 13.12, 15.12, 15.75, 16.84, 17.48, 18.06, 19.02, 20.05, 21.93, 23.18, 23.70, 26.72, and 27.81, corresponding to d-spacings (Angstroms±0.2) of 19.27, 9.06, 7.16, 6.75, 5.86, 5.63, 5.27, 5.07, 4.91, 4.67, 4.43, 4.05, 3.84, 3.75, 3.34, and 3.21, respectively.

[0977] 53. The crystalline solid form of any one of embodiments 1 and 46-52, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.59 8.76 9.76 12.36 13.12 13.83 15.12 15.75 16.84 17.48 18.06 19.02 20.05 21.93 23.18 23.70 24.82 26.72 27.81 29.51 30.76 31.74 33.03 34.52 35.39 36.72 37.77 38.66

[1006] 54. The crystalline solid form of any one of embodiments 1 and 46-53, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1007]

[1008]

[1009] 55. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form F of Compound 1.

[1010] 56. The crystalline solid form of embodiment 1 or 55, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45.

[1011] 57. A crystalline solid form as described in any of embodiments 1 and 55-56, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36 and 22.45, corresponding to d-spacings (Angstroms±0.2) of 16.23, 6.04, 5.54, 5.28, 4.44, 4.16 and 3.96, respectively.

[1012] 58. The crystalline solid form of any one of embodiments 1 and 55-57, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.45, 14.66, 16.00, 16.79, 18.99, 20.01, 21.36, 22.45, 23.25, and 25.32.

[1013] 59. A crystalline solid form as described in any of embodiments 1 and 55-58, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 5.45, 14.66, 16.00, 16.79, 18.99, 20.01, 21.36, 22.45, 23.25, and 25.32, corresponding to d-spacings (Angstroms±0.2) of 16.23, 6.04, 5.54, 5.28, 4.67, 4.44, 4.16, 3.96, 3.83, and 3.52, respectively.

[1014] 60. The crystalline solid form of any one of embodiments 1 and 55-59, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 5.45, 12.87, 14.66, 16.00, 16.79, 17.36, 18.99, 20.01, 20.57, 21.36, 22.45, 23.25, 25.32, 26.57, 27.25, 27.97, and 30.02.

[1015] 61. The crystalline solid form of any one of embodiments 1 and 55-60, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.45, 12.87, 14.66, 16.00, 16.79, 17.36, 18.99, 20.01, 20.57, 21.36, 22.45, 23.25, 25.32, 26.57, 27.25, 27.97, and 30.02, corresponding to d-spacings (Angstroms ± 0.2) of 16.23, 6.88, 6.04, 5.54, 5.28, 5.11, 4.67, 4.44, 4.32, 4.16, 3.96, 3.83, 3.52, 3.35, 3.27, 3.19, and 2.98, respectively.

[1016] 62. The crystalline solid form of any one of embodiments 1 and 55-61, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 5.45 10.92 12.87 14.66 16.00 16.79 17.36 18.99 20.01 20.57 21.36 22.45 23.25 25.32 26.57 27.25 27.97 30.02 31.98 32.89 38.29 39.09

[1039] 63. The crystalline solid form of any one of embodiments 1 and 55-62, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1040]

[1041] 64. The crystalline solid form of any one of embodiments 1 and 55-63, wherein Form F of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 6.2% at 120°C.

[1042] 65. The crystalline solid form of any one of embodiments 1 and 55-64, wherein Form F of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm having a peak temperature of about 100.4°C and an onset temperature of 125.9°C.

[1043] 66. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form G of Compound 1.

[1044] 67. The crystalline solid form of Embodiment 1 or 66, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.36, 14.34, 16.58, and 21.35.

[1045] 68. The crystalline solid form of any one of embodiments 1 and 66-67, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.36, 14.34, 16.58, and 21.35, corresponding to d-spacings (Angstroms ± 0.2) of 16.48, 6.18, 5.35, and 4.16, respectively.

[1046] 69. The crystalline solid form of any one of embodiments 1 and 66-68, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 16.58, 19.78, 21.35, 22.35, 25.33, and 26.43.

[1047] 70. A crystalline solid form as described in any of embodiments 1 and 66-69, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 16.58, 19.78, 21.35, 22.35, 25.33 and 26.43, corresponding to d-spacings (Angstroms ± 0.2) of 16.48, 6.90, 6.18, 5.91, 5.35, 4.49, 4.16, 3.98, 3.52 and 3.37, respectively.

[1048] 71. The crystalline solid form of any one of embodiments 1 and 66-70, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 15.79, 16.58, 19.78, 21.35, 22.35, 25.33, 26.43, 27.35, and 30.21.

[1049] 72. The crystalline solid form of any one of embodiments 1 and 66-71, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.36, 12.83, 14.34, 15.00, 15.79, 16.58, 19.78, 21.35, 22.35, 25.33, 26.43, 27.35, and 30.21, corresponding to d-spacings (Angstroms ± 0.2) of 16.48, 6.90, 6.18, 5.91, 5.61, 5.35, 4.49, 4.16, 3.98, 3.52, 3.37, 3.26, and 2.96, respectively.

[1050] 73. The crystalline solid form of any one of embodiments 1 and 66-72, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 5.36 8.73 12.83 14.34 15.00 15.79 16.58 18.54 19.78 21.35 22.35 23.38 25.33 26.43 27.35 30.21 32.32 38.04

[1069] 74. The crystalline solid form of any one of embodiments 1 and 66-73, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1070]

[1071] 75. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline solid form of any one of embodiments 1-74 and one or more pharmaceutically acceptable excipients.

[1072] 76. The pharmaceutical composition of embodiment 75, wherein the pharmaceutical composition is for oral administration.

[1073] 77. The pharmaceutical composition of embodiment 75 or 76, wherein the pharmaceutical composition has a water content of about 0.5 wt%-5.0 wt%.

[1074] 78. The pharmaceutical composition of any one of embodiments 75-77, wherein the pharmaceutical composition has a water content of about 1.5 wt%-4.0 wt%.

[1075] 79. The pharmaceutical composition of any one of embodiments 75-78, wherein the pharmaceutical composition has a water content of about 2.5 wt%-3.0 wt%.

[1076] 80. An amorphous solid dispersion comprising Compound 1:

[1077]

[1078] and polymers.

[1079] 81. An amorphous solid dispersion as described in embodiment 80, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof.

[1080] 82. The amorphous solid dispersion of embodiment 80 or 81, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1081] 83. The amorphous solid dispersion of any one of embodiments 80-82, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3.

[1082] 84. The amorphous solid dispersion of any one of embodiments 80-83, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1083] 85. A pharmaceutical composition comprising a therapeutically effective amount of the amorphous solid dispersion of any one of embodiments 80-84 and one or more pharmaceutically acceptable excipients.

[1084] 86. The pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition is for oral administration.

[1085] 87. The pharmaceutical composition of embodiment 85 or 86, wherein the pharmaceutical composition is in tablet dosage form.

[1086] 88. The pharmaceutical composition of any one of embodiments 85-87, wherein the pharmaceutical composition has a water content of about 0.5 wt%-5.0 wt%.

[1087] 89. The pharmaceutical composition of any one of embodiments 85-88, wherein the pharmaceutical composition has a water content of about 1.5 wt%-4.0 wt%.

[1088] 90. The pharmaceutical composition of any one of embodiments 85-89, wherein the pharmaceutical composition has a water content of about 2.5 wt%-3.0 wt%.

[1089] 91. The pharmaceutical composition of any one of embodiments 85-90, wherein the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of Compound 1.

[1090] 92. The pharmaceutical composition of any one of embodiments 85-91, wherein the pharmaceutical composition comprises about 25 mg of Compound 1.

[1091] 93. The pharmaceutical composition of any one of embodiments 85-91, wherein the pharmaceutical composition comprises about 100 mg of Compound 1.

[1092] 94. The pharmaceutical composition of any one of embodiments 85-93, wherein the one or more pharmaceutically acceptable excipients comprise one or more of a filler, a dry binder, a glidant, a lubricant, a disintegrant, and a film coating agent.

[1093] 95. The pharmaceutical composition of any one of embodiments 85-94, wherein the one or more pharmaceutically acceptable excipients comprises a filler, and the filler comprises microcrystalline cellulose.

[1094] 96. The pharmaceutical composition of any one of embodiments 85-95, wherein the one or more pharmaceutically acceptable excipients comprises a dry binder, and the dry binder comprises crospovidone.

[1095] 97. The pharmaceutical composition of any one of embodiments 85-96, wherein the one or more pharmaceutically acceptable excipients comprises a glidant, and the glidant comprises colloidal silicon dioxide.

[1096] 98. The pharmaceutical composition of any one of embodiments 85-97, wherein the one or more pharmaceutically acceptable excipients comprises a lubricant, and the lubricant comprises magnesium stearate.

[1097] 99. The pharmaceutical composition of any one of embodiments 85-98, wherein the one or more pharmaceutically acceptable excipients comprises a disintegrant, and the disintegrant comprises croscarmellose sodium.

[1098] 100. The pharmaceutical composition of any one of embodiments 85-99, wherein the one or more pharmaceutically acceptable excipients comprises a lubricant, and the lubricant comprises magnesium stearate.

[1099] 101. The pharmaceutical composition of any one of embodiments 85-100, comprising a tablet core comprising:

[1100] an intra-particle portion comprising an amorphous solid dispersion; and

[1101] An extragranular portion is blended with the intragranular portion.

[1102] 102. The pharmaceutical composition of embodiment 101, further comprising a coating disposed on the core.

[1103] 103. The pharmaceutical composition of embodiment 101 or 102, wherein the amorphous solid dispersion is about 50% by weight of the core.

[1104] 104. The pharmaceutical composition of any one of embodiments 101-103, wherein the intra-granular portion further comprises one or more of a filler, a dry binder, a glidant, and a lubricant.

[1105] 105. The pharmaceutical composition of any one of embodiments 101-104, wherein the extragranular portion further comprises one or more of a filler, a disintegrant, and a lubricant.

[1106] 106. A method for preparing an amorphous solid dispersion, the amorphous solid dispersion comprising compound 1:

[1107]

[1108] The method comprises:

[1109] mixing Compound 1, a polymer, and a solvent to obtain a mixture; and

[1110] The mixture was spray dried to obtain an amorphous solid dispersion comprising Compound 1.

[1111] 107. A method as described in embodiment 106, wherein the polymer is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof.

[1112] 108. The method of embodiment 106 or 107, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1113] 109. The method of any one of embodiments 106-108, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3.

[1114] 110. The method of any one of embodiments 106-109, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1115] 111. The method of any one of embodiments 106-110, wherein the solvent is dichloromethane and methanol.

[1116] 112. A product prepared by the following process, the process comprising:

[1117] mixing Compound 1, a polymer, and a solvent to obtain a mixture; and

[1118] The mixture was spray dried to obtain an amorphous solid dispersion comprising the following Compound 1:

[1119]

[1120] 113. A product as described in embodiment 112, wherein the polymer is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP) and combinations thereof.

[1121] 114. The product of embodiment 112 or 113, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1122] 115. The product of any one of embodiments 112-114, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3.

[1123] 116. The product of any one of embodiments 112-115, wherein the weight ratio of compound 1 to the polymer is about 1:3.

[1124] 117. The product of any one of embodiments 112-116, wherein the solvent is dichloromethane and methanol.

[1125] 118. A pharmaceutical composition comprising Compound 1:

[1126]

[1127] The pharmaceutical composition is obtained by the following process, which comprises:

[1128] mixing Compound 1 in solid form, a polymer, and a solvent to obtain a mixture; and

[1129] The mixture was spray dried to obtain an amorphous solid dispersion comprising Compound 1.

[1130] 119. A pharmaceutical composition as described in embodiment 118, wherein the solid form is Form A of Compound 1.

[1131] 120. A pharmaceutical composition as described in embodiment 118, wherein the solid form is Form B of Compound 1.

[1132] 121. A pharmaceutical composition as described in embodiment 118, wherein the solid form is Form C of Compound 1.

[1133] 122. A pharmaceutical composition as described in embodiment 118, wherein the solid form is Form D of Compound 1.

[1134] 123. A pharmaceutical composition as described in embodiment 118, wherein the solid form is Form E of Compound 1.

[1135] 124. A pharmaceutical composition as described in embodiment 118, wherein the solid form is Form F of Compound 1.

[1136] 125. A pharmaceutical composition as described in embodiment 118, wherein the solid form is Form G of Compound 1.

[1137] 126. A pharmaceutical composition as described in embodiment 118, wherein the solid form is an amorphous form of Compound 1.

[1138] 127. The pharmaceutical composition of any one of embodiments 118-126, wherein the pharmaceutical composition has a water content of about 0.5 wt%-5.0 wt%.

[1139] 128. The pharmaceutical composition of any one of embodiments 118-127, wherein the pharmaceutical composition has a water content of about 1.5 wt%-4.0 wt%.

[1140] 129. The pharmaceutical composition of any one of embodiments 118-128, wherein the pharmaceutical composition has a water content of about 2.5 wt%-3.0 wt%.

[1141] 130. A pharmaceutical composition as described in any of embodiments 118-129, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof.

[1142] 131. The pharmaceutical composition of any one of embodiments 118-130, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1143] 132. The pharmaceutical composition of any one of embodiments 118-131, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3.

[1144] 133. The pharmaceutical composition of any one of embodiments 118-132, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1145] 134. The pharmaceutical composition of any one of embodiments 118-133, wherein the solvent is dichloromethane and methanol.

[1146] In some embodiments, the present disclosure relates to one or more of the following listed embodiments:

[1147] 1. A crystalline solid form of Compound 1:

[1148]

[1149] 2. A crystalline solid form as described in embodiment 1, wherein the crystalline solid form is Form A of (S)-1-(5-[2H,3H-[1,4]dioxin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one ("Compound 1").

[1150] 3. The crystalline solid form of Embodiment 2, wherein Form A of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.6, 15.7, 23.2, and 24.8.

[1151] 4. The crystalline solid form of Embodiment 2 or 3, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.6, 15.7, 23.2, and 24.8, corresponding to d-spacings (Angstroms±0.2) of 19.2, 5.7, 3.8, and 3.6, respectively.

[1152] 5. The crystalline solid form of any one of embodiments 2-4, wherein Form A of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8.

[1153] 6. A crystalline solid form as described in any of embodiments 2-5, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8, corresponding to d-spacings (Angstroms±0.2) of 19.2, 12.3, 5.7, 4.2, 3.8, and 3.6, respectively.

[1154] 7. The crystalline solid form of any one of embodiments 2-6, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.6, 7.2, 15.7, 20.5, 21.3, 21.7, 22.5, 23.2, 24.8, and 26.7.

[1155] 8. The crystalline solid form of any one of embodiments 2-7, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.6, 7.2, 15.7, 20.5, 21.3, 21.7, 22.5, 23.2, 24.8, and 26.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.2, 12.2, 5.7, 4.3, 4.2, 4.1, 4.0, 3.8, 3.6, and 3.3, respectively.

[1156] 9. The crystalline solid form of any one of embodiments 2-8, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.6 5.8 7.2 7.7 11.2 12.3 14.4 15.7 16.9 18.0 19.2 20.5 21.3 21.7 22.5 23.2 24.8 26.7 28.0 28.5 29.4 30.3 32.1 34.1

[1181] 36.5.

[1182] 10. The crystalline solid form of any one of embodiments 2-9, wherein Form A of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1183]

[1184] 11. The crystalline solid form of any one of embodiments 2-10, wherein Form A of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.9% at 100°C.

[1185] 12. The crystalline solid form of any one of embodiments 2-11, wherein Form A of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm having a peak temperature of about 85.9°C and an onset temperature of about 146.0°C.

[1186] 13. The crystalline solid form of any one of embodiments 2-12, wherein Form A of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 3.4 wt% water uptake at 40% relative humidity.

[1187] 14. The crystalline solid form of any one of embodiments 2-13, wherein Form A of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 1.0 wt. % water uptake at 40% to 80% relative humidity.

[1188] 15. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form B of Compound 1.

[1189] 16. The crystalline solid form of embodiment 15, wherein Form B of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 15.6, 22.9, 23.3, and 25.1.

[1190] 17. A crystalline solid form as described in embodiment 15 or 16, wherein Form B of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.5, 15.6, 22.9, 23.3 and 25.1, corresponding to d-spacings (Angstroms±0.2) of 19.5, 5.7, 3.9, 3.8 and 3.5, respectively.

[1191] 18. The crystalline solid form of any one of embodiments 15-17, wherein Form B of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1.

[1192] 19. The crystalline solid form of any one of embodiments 15-18, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1, corresponding to d-spacings (Angstroms ± 0.2) of 19.5, 5.7, 4.0, 3.9, 3.8, and 3.5, respectively.

[1193] 20. The crystalline solid form of any one of embodiments 15-19, wherein Form B of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 9.9, 15.6, 19.9, 22.2, 22.9, 23.3, 25.1, and 28.3.

[1194] 21. The crystalline solid form of any one of embodiments 15-20, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.5, 9.9, 15.6, 19.9, 22.2, 22.9, 23.3, 25.1, and 28.3, corresponding to d-spacings (Angstroms ± 0.2) of 19.5, 9.0, 5.7, 4.5, 4.0, 3.9, 3.8, 3.5, and 3.2, respectively.

[1195] 22. The crystalline solid form of any one of embodiments 15-21, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.5 9.0 9.9 12.4 13.2 15.6 16.9 18.2 19.1 19.9 20.9 22.2 22.9 23.3 25.1 25.8 26.7 28.3

[1214] 29.4.

[1215] 23. The crystalline solid form of any one of embodiments 15-22, wherein Form B of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1216]

[1217] 24. The crystalline solid form of any one of embodiments 15-23, wherein Form B of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.8% at 100°C.

[1218] 25. The crystalline solid form of any one of embodiments 15-24, wherein Form B of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% at 120°C.

[1219] 26. The crystalline solid form of any one of embodiments 15-25, wherein Form B of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm with an onset temperature of about 138.2°C-139.2°C.

[1220] 27. The crystalline solid form of any one of embodiments 15-26, wherein Form B of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 2.9 wt% water uptake at 60% relative humidity.

[1221] 28. The crystalline solid form of any one of embodiments 15-27, wherein Form B of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 0.4 wt. % water uptake at 60% to 80% relative humidity.

[1222] 29. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form C of Compound 1.

[1223] 30. The crystalline solid form of Embodiment 29, wherein Form C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 18.9, 23.0, and 24.7.

[1224] 31. The crystalline solid form of Embodiment 29 or 30, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.5, 18.9, 23.0, and 24.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.4, 4.7, 3.9, and 3.6, respectively.

[1225] 32. The crystalline solid form of any one of embodiments 29-31, wherein Form C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7.

[1226] 33. A crystalline solid form as described in any of embodiments 29-32, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7, corresponding to d-spacings (Angstroms±0.2) of 19.4, 12.0, 7.9, 4.7, 3.9, and 3.6, respectively.

[1227] 34. The crystalline solid form of any one of embodiments 29-33, wherein Form C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 7.3, 9.1, 11.2, 18.3, 18.9, 19.6, 21.7, 23.0, and 24.7.

[1228] 35. The crystalline solid form of any one of embodiments 9-34, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.5, 7.3, 9.1, 11.2, 18.3, 18.9, 19.6, 21.7, 23.0, and 24.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.4, 12.0, 9.8, 7.9, 4.8, 4.7, 4.5, 4.1, 3.9, and 3.6, respectively.

[1229] 36. The crystalline solid form of any one of embodiments 29-35, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.5 7.3 9.1 11.2 12.3 14.5 15.7 18.3 18.9 19.6 20.4 21.7 23.0 24.7 26.4 28.3 30.1 32.3 33.9 37.2

[1250] 37. The crystalline solid form of any one of embodiments 29-36, wherein Form C of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1251]

[1252]

[1253] 38. The crystalline solid form of any one of embodiments 29-37, wherein Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.0% at 100°C.

[1254] 39. The crystalline solid form of any one of embodiments 29-38, wherein Form C of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% at 130°C.

[1255] 40. The crystalline solid form of any one of embodiments 29-39, wherein Form C of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm with an onset temperature of about 152.2°C-154.2°C.

[1256] 41. The crystalline solid form of any one of embodiments 29-40, wherein Form C of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 1.8 wt% water uptake at 60% relative humidity.

[1257] 42. The crystalline solid form of any one of embodiments 29-41, wherein Form C of Compound 1 is characterized by a dynamic vapor sorption (DVS) of about 0.5 wt% water uptake at 60% to 80% relative humidity.

[1258] 43. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form D of Compound 1.

[1259] 44. The crystalline solid form of embodiment 43, wherein Form D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 9.7, 13.1, 15.7, 21.9, and 23.6.

[1260] 45. The crystalline solid form of embodiment 43 or 44, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 9.7, 13.1, 15.7, 21.9, and 23.6, corresponding to d-spacings (Angstroms ± 0.2) of 9.1, 6.8, 5.6, 4.1, and 3.8, respectively.

[1261] 46. ​​The crystalline solid form of any one of embodiments 43-45, wherein Form D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 and no diffraction at an angle (2θ±0.2) of 23.3.

[1262] 47. A crystalline solid form as described in any of embodiments 43-46, wherein Form D of Compound 1 is characterized by an XRPD pattern with diffraction at angles (2θ±0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6, corresponding to d-spacings (Angstroms±0.2) of 14.4, 9.1, 6.8, 5.6, 4.1, and 3.8, respectively, and no diffraction at an angle (2θ±0.2) of 23.3.

[1263] 48. The crystalline solid form of any one of embodiments 43-47, wherein Form D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.3, 6.2, 8.7, 9.7, 12.3, 13.1, 13.8, 15.7, 18.0, 21.9, 23.6, and 26.7.

[1264] 49. The crystalline solid form of any one of embodiments 43-48, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.3, 6.2, 8.7, 9.7, 12.3, 13.1, 13.8, 15.7, 18.0, 21.9, 23.6, and 26.7, corresponding to d-spacings (Angstroms ± 0.2) of 20.7, 14.4, 10.2, 9.1, 7.2, 6.8, 6.4, 5.6, 4.9, 4.1, 3.8, and 3.3, respectively.

[1265] 50. The crystalline solid form of any one of embodiments 43-49, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.3 6.2 8.7 9.7 12.3 13.1 13.8 15.7 18.0 19.5 21.9 23.6 24.8 26.7 29.5 30.8 31.7 35.4 37.8

[1285] 38.6.

[1286] 51. The crystalline solid form of any one of embodiments 43-50, wherein Form D of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1287]

[1288]

[1289] 52. The crystalline solid form of any one of embodiments 43-51, wherein Form D of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 9.6% at 130°C.

[1290] 53. The crystalline solid form of any one of embodiments 43-52, wherein Form D of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm with an onset temperature of about 91.9°C.

[1291] 54. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form E of Compound 1.

[1292] 55. The crystalline solid form of embodiment 54, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7.

[1293] 56. The crystalline solid form of embodiment 54 or 55, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7, corresponding to d-spacings (Angstroms ± 0.2) of 5.9, 5.6, 5.1, 4.4, 4.1, and 3.3, respectively.

[1294] 57. The crystalline solid form of any one of embodiments 54-56, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7.

[1295] 58. A crystalline solid form as described in any of embodiments 54-57, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 15.1, 15.8, 17.5, 19.0, 20.1, 21.9, and 26.7, corresponding to d-spacings (Angstroms±0.2) of 5.9, 5.6, 5.1, 4.7, 4.4, 4.1, and 3.3, respectively.

[1296] 59. The crystalline solid form of any one of embodiments 54-56, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.6, 15.1, 15.8, 17.5, 20.1, 21.9, 23.2, 23.7, and 26.7.

[1297] 60. The crystalline solid form of any one of embodiments 54-56, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.6, 15.1, 15.8, 17.5, 20.1, 21.9, 23.2, 23.7, and 26.7, corresponding to d-spacings (Angstroms ± 0.2) of 19.3, 5.9, 5.6, 5.1, 4.4, 4.1, 3.8, 3.8, and 3.3, respectively.

[1298] 61. The crystalline solid form of any one of embodiments 54-60, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 4.6, 9.8, 12.4, 13.1, 15.1, 15.8, 16.8, 17.5, 18.1, 19.0, 20.1, 21.9, 23.2, 23.7, 26.7, and 27.8.

[1299] 62. The crystalline solid form of any one of embodiments 54-61, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.6, 9.8, 12.4, 13.1, 15.1, 15.8, 16.8, 17.5, 18.1, 19.0, 20.1, 21.9, 23.2, 23.7, 26.7, and 27.8, corresponding to d-spacings (Angstroms ± 0.2) of 19.3, 9.1, 7.2, 6.7, 5.9, 5.6, 5.3, 5.1, 4.9, 4.7, 4.4, 4.1, 3.8, 3.8, 3.3, and 3.2, respectively.

[1300] 63. The crystalline solid form of any one of embodiments 54-62, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.6 8.8 9.8 12.4 13.1 13.8 15.1 15.8 16.8 17.5 18.1 19.0 20.1 21.9 23.2 23.7 24.8 26.7 27.8 29.5 30.8 31.7 33.0 34.5 35.4 36.7 37.8

[1328] 38.7.

[1329] 64. The crystalline solid form of any one of embodiments 54-63, wherein Form E of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1330]

[1331]

[1332] 65. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form F of Compound 1.

[1333] 66. The crystalline solid form of embodiment 65, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.4, 14.7, 16.0, 16.8, and 21.4.

[1334] 67. The crystalline solid form of embodiment 65 or 66, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, and 21.4, corresponding to d-spacings (Angstroms ± 0.2) of 16.2, 6.0, 5.5, 5.3, and 4.2, respectively.

[1335] 68. The crystalline solid form of any one of embodiments 65-67, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5.

[1336] 69. The crystalline solid form of any one of embodiments 65-68, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5, corresponding to d-spacings (Angstroms ± 0.2) of 16.2, 6.0, 5.5, 5.3, 4.4, 4.2, and 4.0, respectively.

[1337] 70. The crystalline solid form of any one of embodiments 65-69, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.4, 14.7, 16.0, 16.8, 19.0, 20.0, 21.4, 22.5, 23.2, and 25.3.

[1338] 71. The crystalline solid form of any one of embodiments 65-70, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 14.7, 16.0, 16.8, 19.0, 20.0, 21.4, 22.5, 23.2, and 25.3, corresponding to d-spacings (Angstroms ± 0.2) of 16.2, 6.0, 5.5, 5.3, 4.7, 4.4, 4.2, 4.0, 3.8, and 3.5, respectively.

[1339] 72. The crystalline solid form of any one of embodiments 65-71, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 5.4, 12.9, 14.7, 16.0, 16.8, 17.4, 19.0, 20.0, 20.6, 21.4, 22.5, 23.2, 25.3, 26.6, 27.2, 28.0, and 30.0.

[1340] 73. The crystalline solid form of any one of embodiments 65-72, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 12.9, 14.7, 16.0, 16.8, 17.4, 19.0, 20.0, 20.6, 21.4, 22.5, 23.2, 25.3, 26.6, 27.2, 28.0, and 30.0, corresponding to d-spacings (Angstroms ± 0.2) of 16.2, 6.9, 6.0, 5.5, 5.3, 5.1, 4.7, 4.4, 4.3, 4.2, 4.0, 3.8, 3.5, 3.4, 3.3, 3.2, and 3.0, respectively.

[1341] 74. The crystalline solid form of any one of embodiments 65-73, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 5.4 10.9 12.9 14.7 16.0 16.8 17.4 19.0 20.0 20.6 21.4 22.5 23.2 25.3 26.6 27.2 28.0 30.0 32.0 32.9 38.3 39.1

[1364] 75. The crystalline solid form of any one of embodiments 65-74, wherein Form F of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1365]

[1366] 76. The crystalline solid form of any one of embodiments 65-75, wherein Form F of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 6.2% at 120°C.

[1367] 77. The crystalline solid form of any one of embodiments 65-76, wherein Form F of Compound 1 is characterized by a differential scanning calorimetry (DSC) endotherm having a peak temperature of about 100.4°C and an onset temperature of 125.9°C.

[1368] 78. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form G of Compound 1.

[1369] 79. The crystalline solid form of embodiment 78, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.4, 14.3, 16.6, and 21.3.

[1370] 80. The crystalline solid form of embodiment 78 or 79, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 14.3, 16.6, and 21.3, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.2, 5.3, and 4.2, respectively.

[1371] 81. The crystalline solid form of any one of embodiments 78-80, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3.

[1372] 82. The crystalline solid form of any one of embodiments 78-81, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.2, 5.3, 4.2, and 4.0, respectively.

[1373] 83. The crystalline solid form of any one of embodiments 78-82, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 5.4, 12.8, 14.3, 15.0, 16.6, 19.8, 21.3, 22.3, 25.3, and 26.4.

[1374] 84. The crystalline solid form of any one of embodiments 78-83, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 12.8, 14.3, 15.0, 16.6, 19.8, 21.3, 22.3, 25.3, and 26.4, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.9, 6.2, 5.9, 5.3, 4.5, 4.2, 4.0, 3.5, and 3.4, respectively.

[1375] 85. The crystalline solid form of any one of embodiments 78-84, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ ± 0.2) of 5.4, 12.8, 14.3, 15.0, 15.8, 16.6, 19.8, 21.3, 22.3, 25.3, 26.4, 27.4, and 30.2.

[1376] 86. The crystalline solid form of any one of embodiments 78-85, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.4, 12.8, 14.3, 15.0, 15.8, 16.6, 19.8, 21.3, 22.3, 25.3, 26.4, 27.4, and 30.2, corresponding to d-spacings (Angstroms ± 0.2) of 16.5, 6.9, 6.2, 5.9, 5.6, 5.3, 4.5, 4.2, 4.0, 3.5, 3.4, 3.3, and 3.0, respectively.

[1377] 87. The crystalline solid form of any one of embodiments 78-86, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 5.4 8.7 12.8 14.3 15.0 15.8 16.6 18.5 19.8 21.3 22.3 23.4 25.3 26.4 27.4 30.2 32.3 38.0

[1396] 88. The crystalline solid form of any one of embodiments 78-87, wherein Form G of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1397]

[1398]

[1399] 89. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form H of Compound 1.

[1400] 90. The crystalline solid form of embodiment 89, wherein Form H of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4.

[1401] 91. The crystalline solid form of embodiment 89 or 90, wherein Form H of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4, corresponding to d-spacings (Angstroms ± 0.2) of 15.3, 6.0, 5.4, 4.4, 4.2, and 3.5, respectively.

[1402] 92. The crystalline solid form of any one of embodiments 89-91, wherein Form H of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 5.8 8.4 11.5 12.4 13.1 13.7 14.7 14.9 16.0 16.2 16.6 16.9 17.3 17.7 18.3 19.5 20.0 21.3 21.9 23.1 23.6 23.9 24.4 24.9 25.1 25.4 26.2 27.4 28.1 28.4 29.3 29.7 30.4 31.0 32.7 33.4 34.1 34.8 35.5 35.8 36.4 37.1 38.5

[1446] 93. The crystalline solid form of any one of embodiments 89-92, wherein Form H of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1447]

[1448]

[1449] 94. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form I of Compound 1.

[1450] 95. The crystalline solid form of embodiment 94, wherein Form I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1.

[1451] 96. The crystalline solid form of Embodiment 94 or 95, wherein Form I of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1, corresponding to d-spacings (Angstroms ± 0.2) of 17.1, 6.1, 5.7, 4.4, and 4.2, respectively.

[1452] 97. The crystalline solid form of any one of embodiments 94-96, wherein Form I of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 5.2 8.8 10.3 12.6 14.6 15.5 16.1 16.3 16.6 17.1 17.6 18.7 18.9 20.2 20.5 20.7 21.1 21.5 22.0 22.3 23.7 24.8 25.2 26.0 26.3 26.5 26.8 27.0 27.5 27.7 28.1 29.6 30.0 30.4 31.3 32.0 32.5 33.2 34.0 34.6 36.9 38.2 38.9 39.5

[1497] 98. The crystalline solid form of any one of embodiments 94-97, wherein Form I of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1498]

[1499]

[1500] 99. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form J of Compound 1.

[1501] 100. The crystalline solid form of Embodiment 99, wherein Form J of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 5.7, 22.8, 23.1, and 24.5.

[1502] 101. The crystalline solid form of Embodiment 99 or 100, wherein Form J of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.5, 5.7, 22.8, 23.1, and 24.5, corresponding to d-spacings (Angstroms ± 0.2) of 19.5, 15.4, 3.9, 3.8, and 3.6, respectively.

[1503] 102. The crystalline solid form of any one of embodiments 99-101, wherein Form J of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.5 5.7 7.1 7.7 9.1 10.5 11.2 11.7 12.3 12.9 14.3 14.5 15.4 15.7 16.3 17.3 18.3 18.7 19.3 19.6 20.5 21.2 21.5 22.8 23.1 23.6 24.1 24.5 25.2 25.9 26.4 27.8 29.3 36.2 37.0

[1539] 103. The crystalline solid form of any one of embodiments 99-102, wherein Form J of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1540]

[1541] 104. The crystalline solid form of embodiment 1, wherein the crystalline solid form is Form K of Compound 1.

[1542] 105. The crystalline solid form of embodiment 104, wherein Form K of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4.

[1543] 106. The crystalline solid form of embodiment 104 or 105, wherein Form K of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4, corresponding to d-spacings (Angstroms ± 0.2) of 19.2, 5.7, 5.7, 5.5, 3.8, and 3.3, respectively.

[1544] 107. The crystalline solid form of any one of embodiments 104-106, wherein Form K of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.6 9.3 10.1 12.9 13.9 14.7 15.4 15.6 16.1 17.8 18.3 18.6 19.3 20.0 20.7 21.6 21.9 22.9 23.2 24.4 25.0 25.5 26.0 27.4 28.8 29.2 30.7 31.1 32.7 36.3

[1575] 108. The crystalline solid form of any one of embodiments 104-107, wherein Form K of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1576]

[1577] 109. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form L of Compound 1.

[1578] 110. The crystalline solid form of embodiment 109, wherein Form L of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1.

[1579] 111. The crystalline solid form of embodiment 109 or 110, wherein Form L of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ ± 0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1, corresponding to d-spacings (Angstroms ± 0.2) of 14.9, 7.5, 5.0, 4.1, 3.7, and 2.5, respectively.

[1580] 112. The crystalline solid form of any one of embodiments 109-111, wherein Form L of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 5.9 8.4 11.9 13.3 14.7 15.0 16.2 16.7 16.9 17.8 18.9 20.4 21.2 21.6 22.2 23.9 24.6 25.5 25.7 26.1 26.8 28.1 28.8 29.9 30.6 31.9 32.4 33.6 34.2 35.6 36.1 38.2

[1613] 113. The crystalline solid form of any one of embodiments 109-112, wherein Form L of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1614]

[1615]

[1616] 114. The crystalline solid form of Embodiment 1, wherein the crystalline solid form is Form M of Compound 1.

[1617] 115. The crystalline solid form of embodiment 114, wherein Form M of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7.

[1618] 116. A crystalline solid form as described in embodiment 114 or 115, wherein Form M of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.5, 5.8, 9.7, 15.6, 21.9 and 26.7, corresponding to d-spacings (Angstroms±0.2) of 19.5, 15.3, 9.1, 5.7, 4.1 and 3.3, respectively.

[1619] 117. The crystalline solid form of any one of embodiments 114-116, wherein Form M of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ±0.2): 4.5 5.8 6.1 8.7 9.0 9.7 12.3 13.1 13.7 14.5 15.1 15.6 16.8 17.4 18.0 18.5 19.5 20.0 21.4 21.9 22.3 22.9 23.3 23.5 24.1 25.0 25.8 26.3 26.7 27.8 28.1 29.4 30.8 31.7 33.0 35.3 37.8 38.6

[1658] 118. The crystalline solid form of any one of embodiments 114-117, wherein Form M of Compound 1 is characterized by an XRPD pattern having diffraction at the following angles (2θ ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2):

[1659]

[1660]

[1661] 119. The crystalline solid form of embodiment 1, wherein the crystalline solid form is selected from the group consisting of:

[1662] 1) Form A of Compound 1, wherein Form A of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.6, 7.2, 15.7, 21.4, 23.2, and 24.8;

[1663] 2) Form B of Compound 1, wherein Form B of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1;

[1664] 3) Form C of Compound 1, wherein Form C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7;

[1665] 4) Form D of Compound 1, wherein Form D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 and no diffraction at an angle (2θ±0.2) of 23.3;

[1666] 5) Form E of Compound 1, wherein Form E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7;

[1667] 6) Form F of Compound 1, wherein Form F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.5, 14.7, 16.0, 16.8, and 21.4;

[1668] 7) Form G of Compound 1, wherein Form G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3;

[1669] 8) Form H of Compound 1, wherein Form H of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4;

[1670] 9) Form I of Compound 1, wherein Form I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1;

[1671] 10) Form J of Compound 1, wherein Form J of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 5.7, 22.8, 23.1, and 24.5;

[1672] 11) Form K of Compound 1, wherein Form K of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4;

[1673] 12) Form L of Compound 1, wherein Form L of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1; and

[1674] 13) Form M of Compound 1, wherein Form M of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2θ±0.2) of 4.5, 5.8, 9.7, 15.6, 21.9 and 26.7.

[1675] 120. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline solid form of any one of embodiments 1-119 and one or more pharmaceutically acceptable excipients.

[1676] 121. The pharmaceutical composition of embodiment 120, wherein the pharmaceutical composition is for oral administration.

[1677] 122. The pharmaceutical composition of embodiment 120 or 121, wherein the pharmaceutical composition has a water content of about 0.5 wt%-5.0 wt%.

[1678] 123. The pharmaceutical composition of any one of embodiments 120-122, wherein the pharmaceutical composition has a water content of about 1.5 wt%-4.0 wt%.

[1679] 124. The pharmaceutical composition of any one of embodiments 120-123, wherein the pharmaceutical composition has a water content of about 2.5 wt%-3.0 wt%.

[1680] 125. An amorphous solid dispersion, comprising Compound 1:

[1681]

[1682] and polymers.

[1683] 126. An amorphous solid dispersion as described in embodiment 125, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof.

[1684] 127. The amorphous solid dispersion of embodiment 125 or 126, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1685] 128. The amorphous solid dispersion of any one of embodiments 125-127, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMC AS).

[1686] 129. The amorphous solid dispersion of any one of embodiments 125-128, wherein the weight ratio of Compound 1 to the polymer is in a range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[1687] 130. The amorphous solid dispersion of any one of embodiments 125-129, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1688] 131. The amorphous solid dispersion of any one of embodiments 125-129, wherein the weight ratio of Compound 1 to the polymer is about 1:1.

[1689] 132. The amorphous solid dispersion of any one of embodiments 125-129, wherein the weight ratio of Compound 1 to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[1690] 133. The amorphous solid dispersion of any one of embodiments 125-132, wherein no crystalline diffraction peak is observed by XRPD analysis (Method D) of the amorphous solid dispersion.

[1691] 134. The amorphous solid dispersion of any one of embodiments 125-133, wherein no crystalline diffraction peaks are observed by XRPD analysis of the amorphous solid dispersion (Method D) after storage for 5 months at 2°C-8°C and ambient relative humidity in the container as described in Example 20.

[1692] 135. The amorphous solid dispersion of any one of embodiments 125-134, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage at 25° C. and 60% relative humidity for 5 months in the container as described in Example 20.

[1693] 136. The amorphous solid dispersion of any one of embodiments 125-135, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage for 1 month at 2°C-8°C and ambient relative humidity in the container of Example 20.

[1694] 137. The amorphous solid dispersion of any one of embodiments 125-136, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage at 25° C. and 60% relative humidity for 1 month in the container as described in Example 20.

[1695] 138. The amorphous solid dispersion of any one of embodiments 125-137, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage at 40° C. and 75% relative humidity for 1 month in the container as described in Example 20.

[1696] 139. An amorphous solid dispersion as described in any one of embodiments 125-138, wherein a single glass transition temperature (T G ) and no melting endotherm.

[1697] 140. An amorphous solid dispersion as described in any one of embodiments 125-139, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage at 2°C-8°C and ambient relative humidity for 5 months in the container as described in Example 20. G ) and no melting endotherm.

[1698] 141. An amorphous solid dispersion as described in any one of embodiments 125-140, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage at 25°C and 60% relative humidity for 5 months in the container as described in Example 20. G ) and no melting endotherm.

[1699] 142. An amorphous solid dispersion as described in any one of embodiments 125-141, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage at 2°C-8°C and ambient relative humidity for 1 month in the container as described in Example 20. G ) and no melting endotherm.

[1700] 143. An amorphous solid dispersion as described in any one of embodiments 125-142, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage at 25 °C and 60% relative humidity for 1 month in the container as described in Example 20. G ) and no melting endotherm.

[1701] 144. An amorphous solid dispersion as described in any one of embodiments 125-143, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage at 40°C and 75% relative humidity for 1 month in the container as described in Example 20. G ) and no melting endotherm.

[1702] 145. The amorphous solid dispersion of any one of embodiments 125-144, wherein no crystalline diffraction peak is observed by XRPD analysis (Method D) of the amorphous solid dispersion.

[1703] 146. The amorphous solid dispersion of any one of embodiments 125-145, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage at 60° C. for 1 week in a sealed vial.

[1704] 147. The amorphous solid dispersion of any one of embodiments 125-146, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage at 60° C. for 2 weeks in a sealed vial.

[1705] 148. The amorphous solid dispersion of any one of embodiments 125-147, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 25° C. and 60% relative humidity for 1 week.

[1706] 149. The amorphous solid dispersion of any one of embodiments 125-148, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 25° C. and 60% relative humidity for 2 weeks.

[1707] 150. The amorphous solid dispersion of any one of embodiments 125-149, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 40° C. and 75% relative humidity for 1 week.

[1708] 151. The amorphous solid dispersion of any one of embodiments 125-150, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 40°C and 75% relative humidity for 2 weeks.

[1709] 152. The amorphous solid dispersion of any one of embodiments 125-151, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 60°C and 75% relative humidity for 1 week.

[1710] 153. The amorphous solid dispersion of any one of embodiments 125-152, wherein no crystalline diffraction peaks are observed by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 60° C. and 75% relative humidity for 2 weeks.

[1711] 154. An amorphous solid dispersion as described in any one of embodiments 125-136, wherein a single glass transition temperature (T G ) and no melting endotherm.

[1712] 155. An amorphous solid dispersion as described in any one of embodiments 125-154, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage at 60°C for 1 week or 2 weeks in a sealed vial. G ) and no melting endotherm.

[1713] 156. An amorphous solid dispersion as described in any one of embodiments 125-155, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage in an unsealed vial at 25°C and 60% relative humidity for 1 week or 2 weeks. G ) and no melting endotherm.

[1714] 157. An amorphous solid dispersion as described in any one of embodiments 125-156, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage in an unsealed vial at 40°C and 75% relative humidity for 1 week or 2 weeks. G ) and no melting endotherm.

[1715] 158. An amorphous solid dispersion as described in any one of embodiments 125-157, wherein a single glass transition temperature (Tg) is observable by DSC analysis (Method B) of the amorphous solid dispersion after storage in an unsealed vial at 60°C and 75% relative humidity for 1 week or 2 weeks. G ) and no melting endotherm.

[1716] 159. The amorphous solid dispersion of any one of embodiments 125-158, wherein in the kinetic solubility experiment described in embodiment 23, Compound 1 has a concentration of at least 300 μg / mL after 30 minutes.

[1717] 160. The amorphous solid dispersion of any one of embodiments 125-159, wherein Compound 1 has a Cmax of at least 600 μg / mL in the kinetic solubility experiment described in Embodiment 23.

[1718] 161. The amorphous solid dispersion of any one of embodiments 125-160, wherein in the kinetic solubility experiment described in embodiment 23, Compound 1 has a concentration of at least 450 μg / mL after 4 hours.

[1719] 162. The amorphous solid dispersion of any one of embodiments 125-158, wherein in the kinetic solubility experiment described in embodiment 23, Compound 1 has a concentration of at least 200 μg / mL after 16 hours.

[1720] 163. A pharmaceutical composition comprising a therapeutically effective amount of the amorphous solid dispersion of any one of embodiments 125-162 and one or more pharmaceutically acceptable excipients.

[1721] 164. The pharmaceutical composition of embodiment 163, wherein the pharmaceutical composition is for oral administration.

[1722] 165. The pharmaceutical composition of embodiment 163 or 164, wherein the pharmaceutical composition is in tablet dosage form.

[1723] 166. The pharmaceutical composition of any one of embodiments 163-165, wherein the pharmaceutical composition has a water content of about 0.5 wt%-5.0 wt%.

[1724] 167. The pharmaceutical composition of any one of embodiments 163-166, wherein the pharmaceutical composition has a water content of about 1.5 wt%-4.0 wt%.

[1725] 168. The pharmaceutical composition of any one of embodiments 163-167, wherein the pharmaceutical composition has a water content of about 2.5 wt%-3.0 wt%.

[1726] 169. The pharmaceutical composition of any one of embodiments 163-168, wherein the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of Compound 1.

[1727] 170. The pharmaceutical composition of any one of embodiments 163-169, wherein the pharmaceutical composition comprises about 25 mg of Compound 1.

[1728] 171. The pharmaceutical composition of any one of embodiments 163-169, wherein the pharmaceutical composition comprises about 100 mg of Compound 1.

[1729] 172. The pharmaceutical composition of any one of embodiments 163-169, wherein the pharmaceutical composition comprises about 200 mg of Compound 1.

[1730] 173. The pharmaceutical composition of any one of embodiments 163-172, wherein the one or more pharmaceutically acceptable excipients comprise one or more of a filler, a dry binder, a glidant, a lubricant, a disintegrant, and a film coating agent.

[1731] 174. The pharmaceutical composition of any one of embodiments 163-173, wherein the one or more pharmaceutically acceptable excipients comprises a filler, and the filler comprises microcrystalline cellulose.

[1732] 175. The pharmaceutical composition of any one of embodiments 163-174, wherein the one or more pharmaceutically acceptable excipients comprises a filler, and the filler comprises lactose monohydrate.

[1733] 176. The pharmaceutical composition of any one of embodiments 163-175, wherein the one or more pharmaceutically acceptable excipients comprises a dry binder, and the dry binder comprises crospovidone.

[1734] 177. The pharmaceutical composition of any one of embodiments 163-176, wherein the one or more pharmaceutically acceptable excipients comprises a glidant, and the glidant comprises colloidal silicon dioxide.

[1735] 178. The pharmaceutical composition of any one of embodiments 163-177, wherein the one or more pharmaceutically acceptable excipients comprises a lubricant, and the lubricant comprises magnesium stearate.

[1736] 179. The pharmaceutical composition of any one of embodiments 163-178, wherein the one or more pharmaceutically acceptable excipients comprises a disintegrant, and the disintegrant comprises croscarmellose sodium.

[1737] 180. The pharmaceutical composition of any one of embodiments 163-179, comprising a tablet core comprising:

[1738] an intra-particle portion comprising an amorphous solid dispersion; and

[1739] An extragranular portion is blended with the intragranular portion.

[1740] 181. The pharmaceutical composition of embodiment 180, further comprising a coating disposed on the core.

[1741] 182. The pharmaceutical composition of embodiment 180 or 181, wherein the amorphous solid dispersion is at least about 30% by weight of the core.

[1742] 183. The pharmaceutical composition of any one of embodiments 180-182, wherein the amorphous solid dispersion is at least about 50% by weight of the core.

[1743] 184. The pharmaceutical composition of any one of embodiments 180-183, wherein the amorphous solid dispersion is at least about 60% by weight of the core.

[1744] 185. The pharmaceutical composition of any one of embodiments 180-184, wherein the amorphous solid dispersion is about 50% by weight of the core.

[1745] 186. The pharmaceutical composition of any one of embodiments 180-185, wherein the amorphous solid dispersion is about 50% to about 70% by weight of the core.

[1746] 187. The pharmaceutical composition of any one of embodiments 180-186, wherein the amorphous solid dispersion is about 60% to about 65% by weight of the core.

[1747] 188. The pharmaceutical composition of any one of embodiments 180-187, wherein the intra-granular portion further comprises one or more of a filler, a dry binder, a glidant, and a lubricant.

[1748] 189. The pharmaceutical composition of any one of embodiments 180-188, wherein the extragranular portion further comprises one or more of a filler, a disintegrant, and a lubricant.

[1749] 190. A method for preparing an amorphous solid dispersion, the amorphous solid dispersion comprising compound 1:

[1750]

[1751] The method comprises:

[1752] mixing Compound 1, a polymer, and a solvent to obtain a mixture; and

[1753] The mixture was spray dried to obtain an amorphous solid dispersion comprising Compound 1.

[1754] 191. The method of embodiment 190, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof.

[1755] 192. The method of embodiment 190 or 191, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1756] 193. The method of any one of embodiments 190-192, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMC AS).

[1757] 194. The method of any one of embodiments 190-193, wherein the weight ratio of Compound 1 to the polymer is in a range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[1758] 195. The method of any one of embodiments 190-194, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1759] 196. The method of any one of embodiments 190-194, wherein the weight ratio of Compound 1 to the polymer is about 1:1.

[1760] 197. The method of any one of embodiments 190-194, wherein the weight ratio of Compound 1 to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[1761] 198. The method of any one of embodiments 190-197, wherein the solvent is dichloromethane and methanol.

[1762] 199. A product prepared by the following process, the process comprising:

[1763] mixing Compound 1, a polymer, and a solvent to obtain a mixture; and

[1764] The mixture was spray dried to obtain an amorphous solid dispersion comprising the following Compound 1:

[1765]

[1766] 200. The product of embodiment 199, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly(methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof.

[1767] 201. The product of embodiment 199 or 200, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1768] 202. The product of any one of embodiments 199-201, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMC AS).

[1769] 203. The product of any one of embodiments 199-202, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[1770] 204. The product of any one of embodiments 199-203, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1771] 205. The product of any one of embodiments 199-203, wherein the weight ratio of Compound 1 to the polymer is about 1:1.

[1772] 206. The product of any one of embodiments 199-203, wherein the weight ratio of Compound 1 to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[1773] 207. The product of any one of embodiments 199-206, wherein the solvent is dichloromethane and methanol.

[1774] 208. A pharmaceutical composition comprising Compound 1:

[1775]

[1776] The pharmaceutical composition is obtained by the following process, which comprises:

[1777] mixing Compound 1 in solid form, a polymer, and a solvent to obtain a mixture; and

[1778] The mixture was spray dried to obtain an amorphous solid dispersion comprising Compound 1.

[1779] 209. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form A of Compound 1.

[1780] 210. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form B of Compound 1.

[1781] 211. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form C of Compound 1.

[1782] 212. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form D of Compound 1.

[1783] 213. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form E of Compound 1.

[1784] 214. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form F of Compound 1.

[1785] 215. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form G of Compound 1.

[1786] 216. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form H of Compound 1.

[1787] 217. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form I of Compound 1.

[1788] 218. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form J of Compound 1.

[1789] 219. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form K of Compound 1.

[1790] 220. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form L of Compound 1.

[1791] 221. A pharmaceutical composition as described in embodiment 208, wherein the solid form is Form M of Compound 1.

[1792] 222. A pharmaceutical composition as described in embodiment 208, wherein the solid form is selected from the group consisting of: Type A, Type B, Type C, Type D, Type E, Type F, Type G, Type H, Type I, Type J, Type K, Type L and Type M of Compound 1.

[1793] 223. A pharmaceutical composition as described in embodiment 208, wherein the solid form is an amorphous form of Compound 1.

[1794] 224. The pharmaceutical composition of any one of embodiments 208-223, wherein the pharmaceutical composition has a water content of about 0.5 wt%-5.0 wt%.

[1795] 225. The pharmaceutical composition of any one of embodiments 208-224, wherein the pharmaceutical composition has a water content of about 1.5 wt%-4.0 wt%.

[1796] 226. The pharmaceutical composition of any one of embodiments 208-225, wherein the pharmaceutical composition has a water content of about 2.5 wt%-3.0 wt%.

[1797] 227. A pharmaceutical composition as described in any of embodiments 208-226, wherein the polymer is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of: polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof.

[1798] 228. The pharmaceutical composition of any one of embodiments 208-227, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1799] 229. The pharmaceutical composition of any one of embodiments 208-228, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMC AS).

[1800] 230. The pharmaceutical composition of any one of embodiments 208-229, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[1801] 231. The pharmaceutical composition of any one of embodiments 208-230, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1802] 232. The pharmaceutical composition of any one of embodiments 208-230, wherein the weight ratio of Compound 1 to the polymer is about 1:1.

[1803] 233. A pharmaceutical composition as described in any of embodiments 208-230, wherein the weight ratio of Compound 1 to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1 or about 3:1.

[1804] 234. The pharmaceutical composition of any one of embodiments 208-233, wherein the solvent is dichloromethane and methanol.

[1805] 235. A tablet dosage form comprising a tablet core comprising at least 10% by weight of Compound 1 in an amorphous form:

[1806]

[1807] Wherein no crystalline Compound 1 (Form A) was observed by XRPD analysis (Method D) of the tablet core.

[1808] 236. A tablet dosage form as described in embodiment 235, wherein the core comprises at least 15% by weight of Compound 1 in an amorphous form.

[1809] 237. A tablet dosage form as described in embodiment 235 or 236, wherein the core comprises at least 30% by weight of Compound 1 in an amorphous form.

[1810] 238. A tablet dosage form as described in any one of embodiments 235-237, wherein the tablet core comprises about 200 mg of Compound 1 per tablet and has a total weight of no more than about 1200 mg per tablet.

[1811] 239. A tablet dosage form as described in embodiment 238, wherein the tablet core has a total weight of no more than about 1100 mg, about 1000 mg, about 900 mg, about 800 mg or about 700 mg per tablet.

[1812] 240. A tablet dosage form comprising a tablet core having a total weight of no more than about 1000 mg and comprising about 200 mg per tablet of an amorphous form of Compound 1:

[1813]

[1814] Wherein no crystalline Compound 1 (Form A) was observed by XRPD analysis of the tablet cores (Method D).

[1815] 241. A tablet dosage form as described in embodiment 240, wherein the core has a total weight of no more than about 800 mg per tablet.

[1816] 242. A tablet dosage form as described in any one of embodiments 235-241, wherein the core comprises 0.05%-5.0% of Compound 2:

[1817]

[1818]

[1819] Based on the total amount of Compound 1 and Compound 2.

[1820] 243. A tablet dosage form as described in embodiment 242, wherein the core comprises 0.05%-3.0% of Compound 2, based on the total amount of Compound 1 and Compound 2.

[1821] 244. A tablet dosage form as described in embodiment 242 or 243, wherein the core comprises 0.05%-2.0% of Compound 2, based on the total amount of Compound 1 and Compound 2.

[1822] 245. The tablet dosage form of any one of embodiments 242-244, wherein the core comprises 0.05%-1.0% of Compound 2, based on the total amount of Compound 1 and Compound 2.

[1823] 246. A tablet dosage form as described in any one of embodiments 235-245, wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the core after storage at 25°C and 60% relative humidity for 1 month in a sealed container as described in Example 29 (Method D).

[1824] 247. A tablet dosage form as described in any one of embodiments 235-246, wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the core (Method D) after storage at 25°C and 60% relative humidity for 2 months in a sealed container as described in Example 29.

[1825] 248. A tablet dosage form as described in any one of embodiments 235-247, wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the core (Method D) after storage at 25°C and 60% relative humidity for 3 months in a sealed container as described in Example 29.

[1826] 249. The tablet dosage form of any one of embodiments 235-248, wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the tablet core (Method D) after storage at 40°C and 75% relative humidity for 1 month in a sealed container as described in Example 29.

[1827] 250. A tablet dosage form as described in any one of embodiments 235-249, wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the core after storage at 40°C and 75% relative humidity for 2 months in a sealed container as described in Example 29 (Method D).

[1828] 251. The tablet dosage form of any one of embodiments 235-250, wherein no crystalline Compound 1 (Form A) is observed by XRPD analysis of the tablet core (Method D) after storage at 40°C and 75% relative humidity for 3 months in a sealed container as described in Example 29.

[1829] 252. The tablet dosage form of any one of embodiments 235-251, wherein Compound 1 is present in an amorphous solid dispersion comprising Compound 1 and a polymer.

[1830] 253. The tablet dosage form of embodiment 252, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly(methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof.

[1831] 254. The tablet dosage form of embodiment 252 or 253, wherein the polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1832] 255. The tablet dosage form of any one of embodiments 252-254, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMC AS).

[1833] 256. The tablet dosage form of any one of embodiments 252-255, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[1834] 257. The tablet dosage form of any one of embodiments 252-256, wherein the weight ratio of Compound 1 to the polymer is about 1:3.

[1835] 258. The tablet dosage form of any one of embodiments 252-256, wherein the weight ratio of Compound 1 to the polymer is about 1:1.

[1836] 259. The tablet dosage form of any one of embodiments 252-256, wherein the weight ratio of Compound 1 to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[1837] 260. The tablet dosage form of any one of embodiments 235-259, further comprising one or more pharmaceutically acceptable excipients.

[1838] 261. The tablet dosage form of embodiment 260, wherein the one or more pharmaceutically acceptable excipients comprise one or more of a filler, a dry binder, a glidant, a lubricant, a disintegrant, and a film coating agent.

[1839] 262. The tablet dosage form of any one of embodiments 235-261, wherein the core comprises:

[1840] an intragranular portion comprising Compound 1; and

[1841] An extragranular portion is blended with the intragranular portion.

[1842] 263. A tablet dosage form as described in embodiment 262, wherein the intragranular portion comprises an amorphous solid dispersion containing Compound 1 and a polymer and one or more of a filler, a dry binder, a glidant, and a lubricant, and the extragranular portion comprises one or more of a filler, a disintegrant, and a lubricant.

[1843] 264. The tablet dosage form of any one of embodiments 235-263, wherein the intra-granular portion comprises:

[1844] an amorphous solid dispersion of Compound 1 in an amount of 30% to 70% by weight of the tablet core;

[1845] One or more fillers in an amount of 15% to 50% by weight of the core;

[1846] One or more dry binders in an amount of 2.50% to 10% by weight of the core;

[1847] one or more glidants in an amount of 0.50% to 1.50% by weight of the tablet core; and

[1848] One or more lubricants in an amount of 0.25% to 1% by weight of the core; and

[1849] The extragranular portion comprises:

[1850] One or more fillers in an amount of 5% to 15% by weight of the core;

[1851] one or more disintegrants in an amount of 1.25% to 5% by weight of the tablet core; and

[1852] One or more lubricants in an amount of 0.25% to 1% by weight of the core; or

[1853] Wherein the tablet dosage form comprises:

[1854] an amorphous solid dispersion of Compound 1 in an amount of 50% to 75% by weight of the tablet core;

[1855] One or more fillers in an amount of 15% to 50% by weight of the core;

[1856] One or more dry binders in an amount of 2% to 10% by weight of the core;

[1857] one or more glidants in an amount of <2% by weight of the tablet core;

[1858] one or more disintegrants in an amount of 2% to 10% by weight of the tablet core; and

[1859] One or more lubricants in an amount of <2% by weight of the tablet core.

[1860] 265. The tablet dosage form of embodiment 264, wherein the amorphous solid dispersion comprises Compound 1 and a polymer.

[1861] 266. The tablet dosage form of embodiment 265, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly(methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof.

[1862] 267. A tablet dosage form as described in embodiment 265 or 266, wherein the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC AS).

[1863] 268. A tablet dosage form as described in any one of embodiments 265-267, wherein the weight ratio of Compound 1 to the polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[1864] 269. The tablet dosage form of any one of embodiments 265-268, wherein the weight ratio of Compound 1 to polymer is about 1:3.

[1865] 270. The tablet dosage form of any one of embodiments 265-269, wherein the weight ratio of Compound 1 to polymer is about 1:1.

[1866] 271. The tablet dosage form of any one of embodiments 265-270, wherein the weight ratio of Compound 1 to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[1867] 272. The tablet dosage form of any one of embodiments 264-271, wherein the one or more fillers comprise microcrystalline cellulose or lactose monohydrate.

[1868] 273. The tablet dosage form of any one of embodiments 264-272, wherein the one or more dry binders comprises crospovidone or cross-linked polyvinyl pyrrolidone.

[1869] 274. The tablet dosage form of any one of embodiments 264-273, wherein the one or more glidants comprise colloidal silicon dioxide or fumed silicon dioxide.

[1870] 275. The tablet dosage form of any one of embodiments 264-274, wherein the one or more lubricants comprises magnesium stearate.

[1871] 276. The tablet dosage form of any one of embodiments 264-275, wherein the one or more disintegrants comprises croscarmellose sodium.

[1872] 277. A solid oral dosage form comprising a stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one, wherein the stabilized amorphous compound shows no crystallinity after storage at 60°C / 75% RH (exposed) for 2 weeks according to PXRD (Method D).

[1873] 278. A solid oral dosage form as described in embodiment 277, wherein the stabilized amorphous compound exhibits a single glass transition temperature (Tg) after storage at 60°C / 75%RH (exposed) for 2 weeks according to DSC (Method B). G ) and no melting endotherm.

[1874] 279. A solid oral dosage form as described in embodiment 277 or 278, wherein the solid oral dosage form contains a total of 200 mg of (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one.

[1875] 280. The solid oral dosage form of any one of embodiments 277-279, wherein the solid oral dosage form has a total weight of no more than 800 mg.

[1876] 281. The solid oral dosage form of any one of embodiments 277-280, wherein the solid oral dosage form is a tablet or a capsule.

[1877] 282. A solid oral dosage form as described in any one of embodiments 277-281, wherein the stabilized amorphous compound is in a spray-dried dispersion with a polymer.

[1878] 283. A solid oral dosage form as described in embodiment 282, wherein the polymer is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone (PVP), and combinations thereof, or selected from the group consisting of: polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), hydroxyethyl cellulose (HEC), poly (methacrylic acid-methyl methacrylate copolymer) (e.g., L100-55), polyethylene glycol 15 hydroxystearate (for example, HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (for example, ), polyethylene glycol (PEG), and combinations thereof.

[1879] 284. A solid oral dosage form as described in embodiment 283, wherein the polymer is HPMC AS.

[1880] 285. A solid oral dosage form as described in embodiment 284, wherein the (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one and HPMC AS are spray dried in a weight ratio of 1:3 to 2:1.

[1881] 286. A solid oral dosage form as described in embodiment 284, wherein the (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one and HPMC AS are spray dried in a weight ratio of 1:1.

[1882] 287. A (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one active pharmaceutical ingredient (API) composition comprising 0.05%-5.0% of (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one according to HPLC.

[1883] 288. A tablet comprising 200 mg of a stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxin-[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one as an active pharmaceutical ingredient (API), wherein the stabilized amorphous compound shows no crystallinity after the tablet is stored at 60°C / 75% RH (exposed) for 2 weeks according to PXRD (Method D).

[1884] 289. A tablet as described in embodiment 288, wherein the API contains less than 5.0% of (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one according to HPLC.

[1885] 290. A tablet as described in embodiment 288 or 289, wherein the API contains less than 0.05% of (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one according to HPLC.

[1886] 291. The tablet of any one of embodiments 288-290, having a total weight of less than 800 mg.

[1887] Example

[1888] The present teachings include the descriptions provided in the examples, which are not intended to limit the scope of any claims. The following non-limiting examples are provided to further illustrate the present teachings. According to the present application, it will be appreciated by those skilled in the art that many changes may be made in the specific embodiments provided herein without departing from the spirit and scope of the present teachings, and similar or similar results may still be obtained.

[1889] abbreviation

[1890]

[1891]

[1892] Instruments and methods

[1893] Unless otherwise indicated, the following instruments and methods were used in the working examples described herein.

[1894] X-ray powder diffraction (XRPD or PXRD)

[1895] Method A. XRPD analysis was performed with a Panalytical X'Pert3 Powder XRPD on a Si zero background stand. The 2θ position was calibrated relative to a Panalytical 640Si powder standard. Details of the XRPD method used in the experiments are listed in Table 1.

[1896] Table 1

[1897]

[1898] Method B. XRPD analysis was performed using a Rigaku X-ray powder diffractometer MiniFlex 600 with the parameters listed in Table 2.

[1899] Table 2

[1900] parameter set up Soller (incident) 5.0 degrees IHS 10.0 mm SS 1.250 degrees DS 1.250 degrees Soller (receive) 5.0 degrees RS 0.3 mm Scan axis θ / 2θ model continuous Start (degrees) 2.0000 Stop (degrees) 40.0000 Step length (degrees) 0.020 Speed ​​(degrees / minute) 2.5 Rotation yes Voltage(kV) 40 Current (mA) 15

[1901] Method C. XRPD analysis was performed using a Panalytical X'Pert3 powder diffractometer in reflection mode. Details of the XRPD method used in the experiment are as follows:

[1902]

[1903] Method D. XRPD analysis was performed using the following parameters:

[1904]

[1905] Thermal analysis (TGA and DSC)

[1906] Method A. TGA was performed using a TA Q500 TGA from TA Instruments. DSC was performed using a TA Q2000 DSC from TA Instruments. The detailed parameters used are listed in Table 3.

[1907] Table 3

[1908]

[1909]

[1910] Method B. DSC analysis was performed using the following program: DSC modulation at 1.00°C for 60 seconds, ramping to 250°C at a ramp rate of 2°C / min. An alternate temperature range of 20°C to 25°C was used.

[1911] Dynamic gas adsorption

[1912] Dynamic vapor adsorption (DVS) was measured using a Surface Measurement System (SMS) DVS Intrinsic. The parameters for the DVS analysis are listed in Table 4.

[1913] Table 4

[1914]

[1915] High pressure liquid chromatography (HPLC)

[1916] Method A. The HPLC parameters and gradient listed in Table 5 and Table 6, respectively, were used for sample analysis.

[1917] Table 5

[1918]

[1919]

[1920] Table 6

[1921] Time (minutes) Flow rate (mL / min) % Mobile phase A % Mobile phase B 0.0 1.0 100.0 0.0 5.0 1.0 80.0 20.0 18.0 1.0 40.0 60.0 20.0 1.0 0.0 100.0 24.0 1.0 0.0 100.0 25.0 1.0 100.0 0.0 35.0 1.0 100.0 0.0

[1922] Ultra-high performance liquid chromatography

[1923] The UPLC parameters and linear method gradient disclosed in Table 7 and Table 8, respectively, were used for sample analysis.

[1924] Table 7

[1925]

[1926]

[1927] Table 8

[1928] Time (minutes) Flow rate (mL / min) % Mobile phase A % Mobile phase B 0.00 0.500 100.0 0.0 1.00 0.500 100.0 0.0 3.50 0.500 0.0 100.0 4.00 0.500 0.0 100.0 4.01 0.500 100.0 0.0 6.50 0.500 100.0 0.0

[1929] Water content

[1930] By USP <921> Method 1c Determination of water content.

[1931] Dissolution

[1932] Unless otherwise indicated, according to USP <711> Dissolution of the tablets was performed using USP Apparatus 2 (Paddles). Assay confirmation was achieved by quantification relative to an external reference standard using a reversed phase gradient UPLC method. The UPLC method utilized an Acquity UPLC BEH Shield column using two mobile phases, both consisting of acetonitrile, water, and phosphate buffer.

[1933] Example 1-(S)-1-(5-[2H,3H-[1,4]dioxin-7-yl]pyridine-7-sulfonyl]- Synthesis of 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one (1)

[1934] PKR activating compound 1 can be prepared by the methods described herein and Figure 1 and Figure 2 The molecular weight of compound 1 is 457.50 Da.

[1935] Step 1. 2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride (3)

[1936] Into a purged 100 mL round-bottom flask maintained under an inert nitrogen atmosphere were placed a hexane solution of n-BuLi (2.5 M, 2 mL, 5.0 mmol, 0.54 eq) and n-Bu 2Mg in heptane solution (1.0M, 4.8mL, 4.8mmol, 0.53 equiv). The resulting solution was stirred at RT (20°C) for 10min. A solution of 7-bromo-2H, 3H-[1,4]dioxadiene [2,3-b]pyridine (2g, 9.26mmol, 1.00 equiv) in tetrahydrofuran (16mL) was then added dropwise and stirred at -10°C for 10min. The resulting mixture was stirred at -10°C for 1h. The reaction mixture was slowly added to a sulfonyl chloride solution (16mL) at -10°C. The resulting mixture was stirred at -10°C for 0.5h. The reaction was then quenched by carefully adding 30mL saturated ammonium chloride solution at 0°C. The resulting mixture was extracted with 3x50 mL dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (1:3). 1.3 g (60%) of 2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride was obtained as a white solid. LCMS m / z: C 7 H 6 ClNO 4 S calculated: 235.64; found: 236 [M+H] + .

[1937] Step 2. 5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (4)

[1938] Into a 100 mL round-bottom flask was placed 2H, 3H-[1,4] dioxin [2,3-b] pyridine-7-sulfonyl chloride (1.3 g, 5.52 mmol, 1.00 equiv), 1H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3, 4-c] pyrrole-2-carboxylic acid tert-butyl ester (1.16 g, 5.52 mmol), dichloromethane (40 mL) and triethylamine (1.39 g, 13.74 mmol, 2.49 equiv). The solution was stirred at 20 ° C for 2 h and then diluted with 40 mL of water. The resulting mixture was extracted with 3x30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane / methanol (10: 1). 1.2 g (53%) of tert-butyl 5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate was obtained as a yellow solid. LCMS m / z: C 18 H 23 N3 O 6 S calculated: 409.46; found: 410 [M+H] + .

[1939] Step 3. 2-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole (5)

[1940] Into a 100 mL round-bottom flask was placed 5-[2H,3H-[1,4]dioxadiene [2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo [3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.2 g, 2.93 mmol, 1.00 equiv), dichloromethane (30 mL) and trifluoroacetic acid (6 mL). The solution was stirred at 20 ° C for 1 h. The resulting mixture was concentrated in vacuo. The residue was dissolved in 10 mL of methanol and the pH was adjusted to 8 with sodium bicarbonate (2 mol / L). The resulting solution was extracted with 3x10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with dichloromethane / methanol (10:1). 650 mg (72%) of 2-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole were obtained as a yellow solid. LCMS m / z: C 13 H 15 N 3 O 4 S calculated: 309.34; found: 310 [M+H] + .

[1941] Step 4. (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one (1) and (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one (2)

[1942] Into a 100 mL round bottom flask was placed 2-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole (150 mg, 0.48 mmol, 1.00 equiv), 3-hydroxy-2-phenylpropionic acid (97 mg, 0.58 mmol, 1.20 equiv), dichloromethane (10 mL), HATU (369 mg, 0.97 mmol, 2.00 equiv) and DIEA (188 mg, 1.46 mmol, 3.00 equiv). The resulting solution was stirred at 20 °C overnight. The reaction mixture was diluted with 20 mL of water and then extracted with 3x20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC eluting with dichloromethane / methanol (20:1) and by preparative HPLC (column: XBridge C18 OBD preparative column, 5μm, 19mm x 250mm; mobile phase A: water (10mmol / L NH 4 HCO 3 ), mobile phase B: MeCN; gradient: 15% B to 45% B over 8 min; flow rate: 20 mL / min; UV detector: 254 nm). IF, 2.0cm x 25cm, 5μm; Mobile phase A: DCM, phase B: MeOH (maintain 60% MeOH for 15min); Flow rate: 16mL / min; Detector, UV 254&220nm) to separate the two enantiomers. Produced peak 1 (2, Rt: 8.47min) 9.0mg (4%) of (R)-1-(5-[2H,3H-[1,4]dioxadiene [2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo [3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one as a yellow solid; and Peak 2 (1, Rt: 11.83 min) 10.6 mg (5%) of (S)-1-(5-[2H,3H-[1,4]dioxin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one as a yellow solid.

[1943] (1): 1 H NMR (400 MHz, DMSO-d 6)δ8.13(d,J=2.0Hz,1H),7.61(d,J=2.0Hz,1H),7.31-7.20(m,5H),4.75(t,J=5.2Hz,1H),4.50-4.47( m,2H),4.40-4.36(m,1H),4.32-4.29(m,2H),4.11-3.87(m,8H),3.80-3.77(m,1H),3.44-3.41(m,1H). LC-MS(ESI)m / z:C 22 H 23 N 3 O 6 S: Calculated value: 457.13; Found: 458.0 [M+H] + .

[1944] (2): 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(d,J=2.0Hz,1H),7.60(d,J=2.0Hz,1H),7.31-7.18(m,5H),4.75(t,J=5.2Hz,1H),4.52-4.45( m,2H),4.40-4.36(m,1H),4.34-4.26(m,2H),4.11-3.87(m,8H),3.80-3.78(m,1H),3.44-3.43(m,1H). LC-MS(ESI)m / z:C 22 H 23 N 3 O 6 S: Calculated value: 457.13; Found: 458.0 [M+H] + .

[1945] Step 5. (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one (1)

[1946] Alternatively, compound 1 can be synthesized using the procedure described as step 5 herein.

[1947] 3-Hydroxy-2-phenylpropionic acid (1 g) was separated by preparative SFC under the following conditions: Instrument name: SHIMADZULC-20AD, LC parameters: Pump mode: binary gradient, Pump B starting concentration: 100.0%, total flow rate: 170 mL / min, Phase A, Phase B: MeOH (0.1% HAC), Column name: CHIRALPAK AD-H, Length: 100 mm, Internal diameter: 4.6 mm, Particle size: 5 μm, Column temperature: 20° C., PDA model: SPD-M20A, Wavelength: 190 nm to 500 nm. Peak 1: (Rt=5.76 min) 380 mg of (S)-3-hydroxy-2-phenylpropionic acid as a white solid and Peak 2: (Rt=6.87 min) 370 mg of (R)-3-hydroxy-2-phenylpropionic acid as a white solid were obtained. 1 H NMR (300 MHz, DMSO-d 6 ): δ pp m 12.31 (br s, 1H), 7.40-7.20 (m, 5H), 4.94 (br s, 1H), 3.92 (t, J = 9 Hz, 1H), 3.67-3.54 (m, 2H). S-enantiomer: (C 0.02, water); [Reference: -79] R-enantiomer: (C 0.02, water).

[1948] A solution of 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (130.9 mg, 0.423 mmol) in DMF (2.5 ml) was cooled in an ice bath and then treated with (S)-3-hydroxy-2-phenylpropionic acid (84.8 mg, 0.510 mmol), HATU (195.5 mg, 0.514 mmol) and DIEA (0.30 mL, 1.718 mmol) and stirred overnight at ambient temperature. The solution was diluted with EtOAc (20 mL), washed sequentially with water (20 mL) and brine (2 x 20 mL), and dried (MgSO 4), filtered, treated with silica gel, and evaporated under reduced pressure. The material was chromatographed by Biotage MPLC (10 g silica gel column, 0% to 5% MeOH in DCM) to give a white, slightly sticky solid. The sample was re-adsorbed onto silica gel and chromatographed (10 g silica gel column, 0% to 100% EtOAc in hexane) to give (2S)-1-(5-[2H, 3H-[1,4] dioxin-[2,3-b] pyridine-7-sulfonyl]-1H, ​​2H, 3H, 4H, 5H, 6H-pyrrolo[3,4-c] pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one (106.5 mg, 0.233 mmol, 55% yield) as a white solid.

[1949] Example 2 - Preparation and Characterization of Form A of Compound 1

[1950] Preparation of Form A of Compound 1

[1951] To an overhead stirred, temperature probe and N 2 A 1 L round bottom flask with an inlet was charged with 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (33.24 g, 96 mmol), (S)-3-hydroxy-2-phenylpropanoic acid (19.08 g, 115 mmol) and DMF (361 ml). The mixture was cooled to 0°C, HATU (43.7 g, 115 mmol) was added, and a slight exotherm of about 5°C was observed. DIEA (70.2 ml, 402 mmol) was added dropwise over 20 minutes, and the pot was kept near 0°C. The reaction mixture was sampled after 2 h and then after 3 h. After 3 h, another 50 mL of DMF was added to dilute the reaction mixture.

[1952] After 3.5 h at 0 °C, 37 volumes of DCM were added to the reaction mixture and the solution was transferred to a 4 L separatory funnel and washed with water (2060 mL). The organic layer was then washed with 3X 2060 mL of brine (26% W / W NaCl) and MgSO 4 Dry overnight.The solution was concentrated on a rotary evaporator to give a waxy white solid (>80 g).

[1953] The solid was triturated with 500 mL of 5:4 EtOAc / hexanes, filtered, washed with 100 mL of 1 :1 EtOAc / hexanes, and dried in a vacuum oven at ambient temperature to afford 50.3 g of a white solid.

[1954] The resulting material was ground in a mortar, charged into a 3 L round bottom flask with overhead stirring and slurried with 1900 mL of ethanol. The slurry was heated to 76 °C and water was added dropwise. After adding 40 mL of water, the mixture was filtered using a Buchner funnel. The filtrate was returned to the round bottom flask, stirred overnight, and slowly cooled to room temperature.

[1955] The resulting slurry was cooled to 10°C, stirred for 1 hour, and filtered. The round-bottom flask and the filter cake were washed with 100 mL of ethanol. The filter cake was dried on the funnel for 1 hour and left overnight in a vacuum oven at room temperature to obtain 38.43 g of compound 1 as a white solid, which was named Compound 1 Type A.

[1956] Characterization of Form A of Compound 1

[1957] Form A was characterized by XRPD (Method A), TGA (Method A), DSC (Method A) and DVS analysis.

[1958] The XRPD pattern of Form A is depicted in Figure 3 , and the corresponding data are summarized in the following table:

[1959]

[1960]

[1961] The above XRPD data for Form A may also be rounded to one decimal place as summarized in the following table:

[1962]

[1963]

[1964] The TGA and DSC curves of type A are shown in Figure 4 In. Figure 4 As shown, Form A exhibits a 1.9% weight loss at 100°C as measured by TGA, and exhibits two endotherms at 85.9°C (peak temperature) and 146.0°C (onset temperature) as measured by DSC.

[1965] Through Figure 5 In the DSC cycle shown, Form A was heated to 120°C and cooled to 25°C, followed by heating to 300°C. No endotherm was observed below 100°C in the second heating cycle. XRPD analysis after the DSC cycle showed no form change compared to Form A ( Figure 3 ).

[1966] The DVS results showed a water absorption of 3.4% at 40% RH (ambient conditions) and 1.0% at 40% RH to 80% RH at RT, indicating that Form A is hygroscopic ( Figure 6). As determined by XRPD, no form change of Form A was observed before and after DVS testing at RT.

[1967] Based on the above analytical data, Form A is considered to be a channel hydrate.

[1968] Example 3 - Polymorph Screening of Compound 1

[1969] Polymorph screening experiments were performed using a series of crystallization and solid state transformation methods.

[1970] Solid vapor diffusion

[1971] Solid vapor diffusion experiments were performed using 13 different solvents. About 15 mg of compound 1 (Type A) was weighed into a 4 mL vial and placed into a 20 mL vial with 3 mL of a volatile solvent. The 20 mL vial was sealed with a cap and stored at RT for 7 days to allow the solvent vapor to interact with the sample. Solids were characterized by XRPD analysis (Method A), and the results summarized in Table 9 showed that a mixture of Type A or Type A and Type D was obtained.

[1972] Table 9

[1973]

[1974] Slurry transformation at 4°C, RT or 50°C

[1975] Slurry experiments were performed at RT in different solvent systems. Approximately 15 mg of Compound 1 (Form A) was suspended in 0.3 mL of solvent in a 2 mL glass vial. After the suspension was magnetically stirred at 4°C, RT or 50°C for 7 days, the residual solid was isolated for XRPD analysis (Method A). The results summarized in Table 10 indicate that Form A, Form B, Form C and Form D or mixtures thereof were obtained.

[1976] Table 10

[1977]

[1978]

[1979] Liquid vapor diffusion

[1980] About 15 mg of Compound 1 (Type A) was dissolved in a suitable solvent to obtain a clear solution in a 4 mL vial. This solution was then placed in a 20 mL vial containing 3 mL of anti-solvent. The 20 mL vial was sealed with a cap and kept at RT for a time sufficient for the organic vapor to interact with the solution. After 7 days, the solid was isolated for XRPD analysis (Method A). The results summarized in Table 11 indicate that Type A and Type B were produced.

[1981] Table 11

[1982]

[1983] Another series of liquid vapor diffusion experiments were performed under the conditions listed in Table 12. Compound 1 (Form A) was weighed into a 3 mL glass vial and the corresponding solvent or solvent mixture was added. After vortexing and ultrasonic shaking, the suspension was filtered and the filtrate was transferred to a clean 4 mL shell vial. A small amount of Compound 1 (Form A) was added as a seed. Subsequently, the shell vial was sealed with a polyethylene stopper with a pinhole and packaged in a 20 mL glass vial containing 3 mL anti-solvent for liquid vapor diffusion at room temperature. The solid form produced by the experiment was characterized by XRPD analysis (Method C).

[1984] Table 12

[1985]

[1986] Slow evaporation

[1987] Slow evaporation experiments were performed under 4 conditions. Briefly, approximately 15 mg of compound 1 (Form A) was mixed with 1.0-2.5 mL of solvent in a 4 mL glass vial. If the solid was not completely dissolved, the suspension was filtered using a PTFE membrane (pore size of 0.2 μm) and the filtrate was used for subsequent steps. The visually clear solution was subjected to evaporation at RT by (3-5 pinholes) The vial was sealed. The solid was isolated for XRPD analysis (Method A) and the results summarized in Table 13 indicate that only Form A was obtained.

[1988] Table 13

[1989]

[1990] Another series of slow evaporation experiments were performed under the conditions listed in Table 14. Compound 1 (Form A) was weighed into a 3 mL glass vial and the corresponding solvent or solvent mixture was added. After vortexing and ultrasonic shaking, the suspension was filtered and the filtrate was transferred to a clean 4 mL shell vial. A small amount of Compound 1 (Form A) was added as a seed. Subsequently, the shell vial was sealed with a polyethylene stopper with a pinhole and placed in a fume hood at room temperature for slow evaporation. The solid form produced by the experiment was characterized by XRPD analysis (Method C).

[1991] Table 14

[1992]

[1993]

[1994] Antisolvent addition

[1995] A total of 8 anti-solvent addition experiments were performed. About 15 mg of Compound 1 (Form A) was dissolved in 0.2-4.0 mL of solvent to obtain a clear solution. The solution was stirred magnetically, and 0.2 mL of anti-solvent was added in each step until precipitation occurred or the total amount of anti-solvent reached 15.0 mL. The resulting precipitate was isolated for XRPD analysis (Method A). The results in Table 15 show that Form A and amorphous material were produced.

[1996] Table 15

[1997]

[1998] Reverse antisolvent addition

[1999] A total of 2 reverse anti-solvent addition experiments were performed. Approximately 15 mg of Compound 1 (Form A) was dissolved in 0.2 mL of solvent to give a clear solution. The solution was added to 2 mL of anti-solvent. The resulting precipitate was isolated for XRPD analysis (Method A). The results summarized in Table 16 indicate that Form A or a mixture of Form A and amorphous material was produced.

[2000] Table 16

[2001]

[2002] Slow cooling

[2003] Slow cooling experiments were performed under the conditions listed in Table 17. Compound 1 (Form A) was weighed into a 3 mL glass vial and the corresponding solvent or solvent mixture was added. After vortexing and ultrasonic shaking to accelerate dissolution, the suspension was placed in a biochemical incubator and equilibrated at 50 ° C for 30 minutes. The hot suspension was then filtered with a syringe filter (0.045 μm PTFE filter membrane) and the hot filtrate was transferred to a clean 3 mL vial (preheated at 50 ° C). The vial was sealed and placed in an incubator and slowly cooled from 50 ° C to 5 ° C at a rate of 0.01 ° C / min. The solid form produced by the experiment was characterized by XRPD analysis (Method C).

[2004] Table 17

[2005]

[2006] *After slow cooling, only a few small crystals were observed. The system was kept at 5°C for 22 days, at which time plate-like crystals (L-type) were observed.

[2007] Example 4 - Preparation and Characterization of Form B of Compound 1

[2008] Preparation of Form B of Compound 1

[2009] Form B was prepared on a 100 mg scale from a slurry of Form A in methanol at 50°C by a method similar to the slurry conversion method described in Example 3.

[2010] Characterization of Form B of Compound 1

[2011] Form B was characterized by XRPD (Method A), TGA (Method A), DSC (Method A) and DVS analysis.

[2012] The XRPD pattern of Form B is depicted in Figure 7 , and the corresponding data are summarized in the following table:

[2013]

[2014] The above XRPD data for Form B may also be rounded to one decimal place as summarized in the following table:

[2015]

[2016]

[2017] The TGA and DSC curves of type B are shown in Figure 8 In. Figure 8 As shown, Form B exhibits a 1.8% weight loss up to 100°C and an endotherm at 138.2°C (onset temperature), which may be due to melting.

[2018] like Fig. 9 As shown, through the DSC cycle (RT-120°C-RT-250°C), only one melting endotherm was observed at 139.2°C (onset temperature), and there was no extensive endotherm below 120°C in the second heating cycle.

[2019] like Fig.10 As shown, Form B shows a 1.7% weight loss at 120°C based on an immediate TGA test after being heated to 120°C and exposed to ambient conditions for only one minute. The normal TGA curve for Form B shows a 2.3% weight loss at 120°C without preheat treatment.

[2020] No form change was observed by XRPD analysis after DSC cycles of heating to 120 °C and cooling to RT.

[2021] According to DVS analysis ( Fig.11 ), showing that Form B has a water absorption of 2.9% at 60% RH (ambient conditions) and 0.4% at 60% RH to 80% RH at RT, indicating that Form B is hygroscopic. As determined by XRPD analysis, no form change of Form B was observed before and after DVS testing at RT.

[2022] Based on the above analytical data, form B is considered to be a channel hydrate.

[2023] Example 5 - Preparation and Characterization of Form C of Compound 1

[2024] Preparation of Form C of Compound 1

[2025] Form C was prepared on a 100 mg scale by a method analogous to the slurry conversion method described in Example 3 from a slurry of Form A in 1,4-dioxane at RT.

[2026] Characterization of Form C of Compound 1

[2027] Form C was characterized by XRPD (Method A), TGA (Method A), DSC (Method A) and DVS analysis.

[2028] The XRPD pattern of Form C is depicted in Fig.12 , and the corresponding data are summarized in the following table:

[2029]

[2030] The above XRPD data for Form C may also be rounded to one decimal place as summarized in the following table:

[2031]

[2032] The TGA and DSC curves of type C are shown in Fig.13 In. Fig.13 As shown, Form C exhibits a 1.0% weight loss up to 100°C and an endotherm at 152.2°C (onset temperature), which is probably due to melting.

[2033] By using a DSC cycle (RT-120°C-RT-250°C), only one melting endotherm was observed at 154.2°C (onset temperature), and no extensive endotherm was observed below 120°C in the second heating cycle ( Fig.14 ).

[2034] like Fig.15 As shown, Form C shows a 0.7% weight loss at 130°C based on an immediate TGA test after heating to 120°C and exposure to ambient conditions for one minute. The normal TGA curve for Form C shows a 2.3% weight loss at 130°C without preheating.

[2035] No form change was observed by XRPD analysis after heating to 120 °C and cooling to RT by DSC cycle.

[2036] According to DVS analysis ( Fig.16), showing that Form C has a water absorption of 1.8% at 60% RH (ambient conditions) and 0.5% at 60% RH to 80% RH at RT, indicating that Form C is hygroscopic. As determined by XRPD analysis, no form change of Form C was observed before and after DVS testing at RT.

[2037] Based on the above analytical data, form B is considered to be a channel hydrate.

[2038] Example 6 - Preparation and Characterization of Form D of Compound 1

[2039] Preparation of Form D of Compound 1

[2040] Form D was prepared by a method similar to the slurry conversion method described in Example 3 from a slurry of Form A in tetrahydrofuran (THF) at 4°C.

[2041] Characterization of D-form of compound 1

[2042] The results were analyzed by XRPD (Method A), TGA (Method A), DSC (Method A) and 1 H NMR analysis was used to characterize the D form.

[2043] The XRPD pattern of Form D is depicted in Fig.17 , and the corresponding data are summarized in the following table:

[2044]

[2045]

[2046] The above XRPD data for Form D may also be rounded to one decimal place as summarized in the following table:

[2047]

[2048] The TGA and DSC curves of type D are shown in Fig.18 In. Fig.18 As shown, Form D exhibited a weight loss of 9.6% at 130°C as measured by TGA, and exhibited an endotherm at 91.9°C (onset temperature) as measured by DSC.

[2049] Type A and Type D 1 H NMR spectrum is shown in Fig.19 Form D appears to be a THF solvate, such as 1 H NMR spectroscopy (600 MHz, DMSO-d6) detected the presence of THF protons at about 1.76 and about 3.60 ppm.

[2050] Example 7 - Preparation and Characterization of Form E of Compound 1

[2051] Characterization of Form E of Compound 1

[2052] Form E was characterized by XRPD (Method A) analysis.

[2053] The XRPD pattern of Form E is depicted in Fig. 20 , and the corresponding data are summarized in the following table:

[2054]

[2055] The above XRPD data for Form E may also be rounded to one decimal place as summarized in the following table:

[2056]

[2057] Example 8 - Preparation and Characterization of Form F of Compound 1

[2058] Preparation of Form F of Compound 1

[2059] Compound 1 Form F was generated by liquid vapor diffusion in 1,4-dioxane / heptane at RT.

[2060] Characterization of Form F of Compound 1

[2061] Form F was characterized by XRPD (Method A), TGA and DSC analysis (Method A).

[2062] The XRPD pattern of Form F is shown in Fig.21 , and the corresponding data are summarized in the following table:

[2063]

[2064] The above XRPD data for Form F may also be rounded to one decimal place as summarized in the following table:

[2065]

[2066]

[2067] The TGA and DSC curves of type F are shown in Fig. 22 In. Fig. 22 As shown, Form F exhibits a 6.2% weight loss to 120°C as determined by TGA, and two endotherms at 100.4°C and 125.9°C (onset temperatures) as determined by DSC.

[2068] Example 9 - Preparation and Characterization of Form G of Compound 1

[2069] Preparation of Form G of Compound 1

[2070] Form G was prepared from a slurry of Form A in methyl ethyl ketone at room temperature.

[2071] Characterization of Form G of Compound 1

[2072] Form G was characterized by XRPD (Method A) analysis.

[2073] The XRPD pattern of Form G is depicted in Fig.23 , and the corresponding data are summarized in the following table:

[2074]

[2075]

[2076] The above XRPD data for Form G may also be rounded to one decimal place as summarized in the following table:

[2077]

[2078] Example 10 - Preparation and Characterization of H Form of Compound 1

[2079] Preparation of H-form of compound 1

[2080] Form H was prepared as described in Example 3 by liquid vapor diffusion.

[2081] Characterization of H-form of compound 1

[2082] Form H was characterized by XRPD (Method C) analysis.

[2083] The XRPD pattern of Form H is depicted in Fig.24 , and the corresponding data are summarized in the following table:

[2084]

[2085]

[2086] Example 11 - Preparation and Characterization of Form I of Compound 1

[2087] Preparation of Form I of Compound 1

[2088] Form I was prepared as described in Example 3 by liquid vapor diffusion.

[2089] Characterization of Form I of Compound 1

[2090] Form I was characterized by XRPD (Method C) analysis.

[2091] The XRPD pattern of Form I is depicted at Fig.25 , and the corresponding data are summarized in the following table:

[2092]

[2093]

[2094] Example 12 - Preparation and Characterization of Form J of Compound 1

[2095] Preparation of Form J of Compound 1

[2096] Form J was prepared as described in Example 3 by liquid vapor diffusion.

[2097] Characterization of Form J of Compound 1

[2098] Form J was characterized by XRPD (Method C) analysis.

[2099] The XRPD pattern of Form J is depicted in Fig.26 , and the corresponding data are summarized in the following table:

[2100]

[2101]

[2102] Example 13 - Preparation and Characterization of Form K of Compound 1

[2103] Preparation of Form K of Compound 1

[2104] Form K was prepared as described in Example 3 by slow cooling.

[2105] Characterization of Form K of Compound 1

[2106] Form K was characterized by XRPD (Method C) analysis.

[2107] The XRPD pattern of Form K is depicted in Fig. 27 , and the corresponding data are summarized in the following table:

[2108]

[2109] Example 14 - Preparation and Characterization of L-Form of Compound 1

[2110] Preparation of L-form of compound 1

[2111] Form L was prepared as described in Example 3 by slow cooling.

[2112] Characterization of the L-form of compound 1

[2113] Form L was characterized by XRPD (Method C) analysis.

[2114] The XRPD pattern of Form L is depicted in Fig.28 , and the corresponding data are summarized in the following table:

[2115]

[2116] Single crystal X-ray analysis revealed that Form L is a THF / water cosolvate of Compound 1, wherein Compound 1, THF and water are present in a 1:1:1 ratio.

[2117] Example 15 - Preparation and Characterization of Form M of Compound 1

[2118] Preparation of M-form of compound 1

[2119] Form M was prepared as described in Example 3 by liquid vapor diffusion.

[2120] Characterization of the M-form of compound 1

[2121] Form M was characterized by XRPD (Method C) analysis.

[2122] The XRPD pattern of Form M is depicted in Fig.29 , and the corresponding data are summarized in the following table:

[2123]

[2124]

[2125] Example 16 - Preparation and Characterization of Spray-Dried Dispersion of Compound 1

[2126] A spray dried dispersion (SDD) of compound 1 was prepared. SDD consisted of compound 1 and polymer (hydroxypropyl methylcellulose AS-MG) in a weight ratio of 1:3. Compound 1 and polymer were dissolved in organic solvents (dichloromethane and methanol) and spray dried to obtain an amorphous amorphous drug substance. SDD containing compound 1 and HPMC AS (1:3) is referred to herein as SDD 0.

[2127] According to Table 18, a spray solution of 7.8% solid content (1:3 Compound 1: HPMC AS-MG) was prepared in 80:20 DCM: methanol. The spray solution was prepared using an API correction factor of 0.966. The spray solution was prepared by adding DCM and methanol to a 36L stainless steel mixing vessel. HPMC AS-MG was added to the solvent system while mixing with a top-down mixer under medium vortex. Compound 1 was then added to the solution. The solution had a yellow / brown clear appearance, but white fibrous particles were visible in the solution.

[2128] Table 18

[2129]

[2130]

[2131] Correction factor: 0.9660

[2132] The Mobile Minor spray drying apparatus was set up according to Table 19 and warmed for about one hour before spraying. A wash solution (80:20 DCM: methanol) was sprayed before the active solution to balance the nozzle. The compound 1 active solution was sprayed according to the settings in Table 19. The spray dried dispersion was dried overnight (about 20 hours) in a Shel vacuum oven at 50°C and -25 inches of Hg vacuum under a nitrogen purge of 15 scfh. The resulting spray dried dispersion was confirmed to be dry by GC analysis. About 2.1 kg of spray dried dispersion was produced in this run.

[2133] Table 19

[2134] parameter Set point Inline filter Swagelok 140μm stainless steel nozzle 0.3mm, 60° angle Intake air flow 80kg / h Inlet air temperature 104℃ Pump stroke length 5.70mm Nozzle pressure 600psi Feed rate (g / min) 184g / min Outlet temperature(℃) 36 Set condenser air temperature (℃) -10 Actual condenser air temperature (℃) -3 Cooler temperature (℃) -20 Feed temperature environment

[2135] Respectively Fig.30 and Fig.31 The SDD was characterized by XRPD (Method B) and DSC analysis (ambient to 200°C, 2°C / min ramp rate) as shown. The SDD was determined to be homogeneous and amorphous, as shown by the amorphous diffraction pattern, the absence of a crystalline melt and the absence of a single Tg at 100°C.

[2136] Example 17 - Bioavailability of Spray-dried Dispersion (SDD) of Compound 1 in Rats and Mice

[2137] Systemic exposure of Compound 1 in rats and mice was evaluated by administration of an SDD consisting of Compound 1 and HPMC AS-MG (1:3) (SDD 0, which can be prepared as described in Example 16) dispersed in an aqueous vehicle (0.5% hydroxypropylmethylcellulose in water). The SDD formulation administered to rats at 500 mg / kg ("500 mpk SDD") showed an AUC of last This is 40 times the maximum exposure obtained using the standard formulation ("300 mpk suspension" consisting of Compound 1 (Form A) in 10% propylene glycol, 10% hydrogenated castor oil (Cremophore), 80% water), as shown in Tables 20 and Fig.32 In addition, the exposure of a 500 mpk nanosuspension consisting of nanoparticles of Compound 1 (Form A) was evaluated, as shown in Fig.32 Robust exposure of the SDD formulation was also observed in mice.

[2138] Table 20

[2139]

[2140] Example 18 - Bioavailability of Spray-dried Dispersion of Compound 1 in Monkeys

[2141] Several formulations of Compound 1 were evaluated in monkeys, including an SDD consisting of Compound 1 and HPMC AS-MG (1:3) (SDD 0, which can be prepared as described in Example 16). The composition of the tested formulations is listed in Table 21.

[2142] Table 21

[2143]

[2144]

[2145] The pharmacokinetic parameters of the formulation were evaluated in monkeys and are shown in Fig.33 The curve shows that the SDD formulation (formulation 4) significantly increased the overall exposure compared to the encapsulated formulations (formulations 1, 2, and 3). The bioavailability of the SDD formulation increased by about 50%-62%, which was several times higher than that of the other formulations at a dose equivalent to 100 mg.

[2146] Example 19 - Time of Compound 1 Form A and Spray-dried Dispersion of Compound 1 in Biorelevant Media Dependent solubility

[2147] The solubility of Compound 1 Form A in aqueous media was evaluated. Aqueous samples of Compound 1 Form A were saturated with solid content. The samples were shaken at 37°C for 24 hours. Each aqueous medium was also sampled after 30 minutes and filtered / diluted using the same procedure as that to be used for the t=24 hour samples. Sample pH was measured only after 24 hours of equilibrium.

[2148] After 24 hours of equilibration, the pH of the saturated samples was measured and the mixture was centrifuged through a 0.22 μm nylon filter at 15,000 rpm for approximately 2 minutes. All centrifuged samples were diluted with method diluent and analyzed by HPLC (Method A). If no solids were present after overnight equilibration, the solubility was reported as "≥" the measured value. The reported concentrations were based on a single point calibration of the nominal method and were reported as free form. The results are shown in Tables 22 and Fig.34 middle.

[2149] Table 22

[2150]

[2151] The solubility of 1:3 Compound 1:HPMC-AS-MG spray dried dispersion (SDD 0, which can be prepared as described in Example 16) in aqueous media was evaluated at different time points over a 24-hour period. A separate saturated sample was prepared for each expected time point by adding approximately 10 mg of SDD material to 1.5 mL of solvent. The samples were placed on a 600 RPM hot shaker at 37°C and pulled at t=2min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, and 24h. The mixture was centrifuged at 15,000rpm through a 0.22μm nylon filter for approximately 5 minutes. All centrifuged samples were diluted with method diluent and analyzed by HPLC (Method A). Sample pH values ​​were measured only at 24 hours. The results are shown in Tables 23 and Fig.35 middle.

[2152] Table 23

[2153]

[2154]

[2155] 1 Solids observed in centrifugal filters are resuspended in supersaturated conditions, but high values ​​indicate a malfunctioning filter. Fig.35 Deleted from the solubility curve.

[2156] The solubility of SDD was significant, especially at the earlier time points. After four hours, the solubility of SDD in FaSSIF was 72.4 μg / mL and in FeSSIF was 558.5 μg / mL. The four-hour solubility of SDD in SGF was 273.5 μg / mL. After 24 hours of equilibrium in all aqueous media tested, the solubility decreased.

[2157] Example 20 - Stability Evaluation of Spray-Dried Dispersion of Compound 1

[2158] Two different batches of 1:3 Compound 1:HPMC-AS-MG spray dried dispersion (SDD 0, prepared as described in Example 16) were subjected to stability studies under the conditions listed in Table 24. The stability study results for each batch and storage condition are reported in the table identified in Table 24. The results for Batch 1 at the 5 month time point and Batch 2 at the 1 month time point were consistent with the T=0 time point.

[2159] Table 24

[2160]

[2161] Table 25

[2162]

[2163] Table 26

[2164]

[2165] Table 27

[2166]

[2167] Table 28

[2168]

[2169] Table 29

[2170]

[2171] Example 21 - Preparation and Characterization of Spray-Dried Dispersion of Compound 1

[2172] Spray solutions with different ratios of Compound 1 to polymer (hydroxypropyl methylcellulose AS-MG) were prepared in 80:20 DCM:MeOH at 8% solids (Table 30). The spray solutions were spray dried using a Procept 4M8-Trix unit with the settings detailed in Table 31. The resulting spray dried dispersions (SDD) were dried in a nitrogen purged vacuum oven at 50°C, -25 inches Hg for 19 hours. The dispersions were analyzed by XRPD (Method D; Fig.36 ) and DSC analysis (Method B; Fig.37 ) were used to evaluate SDD. By PXRD analysis, the SDD appeared amorphous with no observed crystalline diffraction peaks. For all dispersions, a single well-defined T G No melting endotherm was observed, further confirming the amorphous nature of all spray dried dispersions. Residual solvent analysis of the spray dried dispersions dried for 19 hours showed different levels of dichloromethane. The observed trend was that the level of dichloromethane increased with increasing ratio of Compound 1 to polymer.

[2173] Table 30

[2174]

[2175] Table 31

[2176] parameter set up Nozzle orifice 1.0mm Intake speed <![CDATA[0.35–0.39m 3 / min]]> Inlet temperature 50℃-60℃ Flow rate About 10g / min Pump speed 70％-80％ Atomic gas flow 15L / min Outlet temperature 36℃

[2177] Example 22 - Preparation and Characterization of Spray-Dried Dispersion of Compound 1

[2178] Spray solutions with different ratios of Compound 1 to polymer (hydroxypropyl methylcellulose AS-MG) were prepared at 12% solid content in 80:20 DCM:MeOH (Table 32). The spray solutions were sprayed on a GEA Mobile Minor spray dryer and the SDD was collected and dried over N 2 Dry under purge at 50°C and -25 inches Hg.

[2179] Table 32

[2180]

[2181] Example 23 - Kinetic Solubility of Compound 1 SDD

[2182] Using μDISS Profiler from Pion, Inc TM The instrument quantifies concentration during equilibrium solubility experiments involving SDD 0 (which can be prepared as described in Example 16) and SDD 1-4 (which can be prepared as described in Example 21). The unit consists of six photodiode array (PDA) spectrophotometers, each with its own dedicated fiber optic dip probe, which is centered in a glass vial containing 10 mL of medium. Concentration measurements are made directly in the assay medium, and the processed results are plotted in "real time".

[2183] The probe with a 2 mm path length tip was selected for quantification of compound 1 in SDD. The developed calibration curve was used to quantify compound 1 in the samples during the kinetic solubility experiment at each time point. The 2 mm path length tip was selected for detection of the concentration of compound 1 in SGF and FaSSIF media.

[2184] Standard calibration curves were generated in the respective assay media using a continuous addition scheme. A stock solution of compound 1 was prepared at approximately 20 mg / mL in DMSO. Calculated aliquots of the stock solution were added to the respective buffers to prepare several standard solutions spanning a specific concentration range. The concentration range of the standard solutions for the channels in SGF and FaSSIF media was approximately 50 to approximately 300 μg / mL, respectively. The area under the second derivative curve was used to calculate the concentration. A wavelength range was selected for the compounds to avoid sensitivity issues. The linearity of the standard curve in the selected wavelength region was characterized by r 2 ≥0.999.

[2185] The area under the second derivative curve in the range of 285-300 nm (SGF) and 305-320 nm (FaSSIF) was used to calculate the standard curve in the corresponding medium. The corresponding standard curve was used to determine the concentration of compound 1 in the solubility assay.

[2186] Weigh the required amount of SDD material (equivalent to 20 mg of compound 1) into a 20 mL glass vial. The vial was then transferred to the instrument for analysis. A clean stirring bar was added to the vial containing the sample. 16 mL of SGF buffer was transferred to the vial before starting the experiment to reach an upper limit of approximately 1.25 mg / mL. Stirring was maintained at 220 RPM and the medium temperature was maintained at 37 ° C. Kinetic solubility data was collected for 30 minutes in SGF medium. The data showed that all SDDs exhibited very similar release curves under different loads and achieved approximately the same concentration of compound 1 (approximately 300 μg / mL).

[2187] At 30 minute intervals, the medium was switched to FaSSIF 6.5. The final volume in the vial was increased from 16 mL (1.00 mg / mL) to 20 mL. The resulting samples were then analyzed in FaSSIF using a μDiss Profiler for approximately 18 hours.

[2188] The SDD 0 formulation with a drug loading of 25% reaches a higher solubility of approximately 700 μg / mL, but does not remain in a supersaturated state for a long time. Although the solubility of SDD 0 at 4 hours is slightly lower than that of SDD 1 loaded with 40% API, the equilibrium solubility after approximately 16 hours is higher than all other SDD systems. SDD 3 and SDD 4 do not reach concentrations as high as SDD 0 (spring effect). However, compared to all other SDD systems tested, SDD 3 and SDD4 both remain in a supersaturated state for a longer time. However, the equilibrium solubility of SDD 3 and SDD 4 after 16 hours is lower than that of SDD 0. SDD 2 and SDD 3 show significantly improved solubility and prolonged supersaturation. The kinetic solubility curves are shown in Fig.38 middle.

[2189] The results are summarized in Table 33. All solubility results reported in the table are the average of n=2 replicates.

[2190] Table 33

[2191]

[2192]

[2193] Example 24 - Stability of Spray-dried Dispersion of Compound 1

[2194] Spray dried dispersions of Compound 1 (SDD 0 (which may be prepared as described in Example 16) and SDD 1-4 (which may be prepared as described in Example 21)) were subjected to short term stability studies in two different storage configurations and under different storage conditions. The samples were set up as "sealed" and "exposed". The sealed samples were placed in crimp seal vials and stored under a single storage condition; 60°C. The exposed samples were placed in a vial that was lightly covered with perforated foil to expose it to moisture. The exposed samples were stored at 40°C / 75%RH and 60°C / 75%RH. Samples were removed after T=1 and 2 weeks for PXRD analysis (Method D).

[2195] The PXRD diffraction patterns of SDD 0-4 taken after 2 weeks are provided in Figure 39 to Figure 43 The results are summarized in Table 34. SDD 0, 1, 2 and 3 showed amorphous characteristics by PXRD under all test conditions within 2 weeks. SDD 4 showed crystallinity by PXRD after storage at 60°C / 75%RH (exposed) for 2 weeks. SDD 4 also showed two glass transition temperatures by DSC (Method B) after storage at 60°C / 75%RH (exposed) for 2 weeks, indicating phase separation.

[2196] Table 34

[2197]

[2198]

[2199]

[2200] Example 25 - Stability of Spray-dried Dispersion of Compound 1

[2201] Spray dried dispersions of Compound 1 (SDD 5 and 6 (Example 22)) were stored in two different storage configurations under different storage conditions. The samples were set to "sealed" and "exposed". The sealed samples were stored in amber crimp-sealed vials under the following conditions: 2°C-8°C, 25°C / 60%RH, 40°C / 75%RH, and 60°C. The exposed samples were stored in amber crimp-sealed vials covered with foil, which were perforated to expose to humidity: 25°C / 75%RH, 40°C / 75%RH, and 60°C / 75%RH.

[2202] At T = 0, 1 and 2 weeks, the samples were analyzed by PXRD (Method D) and / or DSC (Method B) analysis. The results are summarized in Table 35. No crystalline diffraction peaks were observed in any sample by PXRD. In addition, a single T was observed by DSC in all samples. G And no melting endotherm was observed.

[2203] Table 35

[2204]

[2205]

[2206]

[2207] The kinetic dissolution of SDD 5 and SDD 6 samples at T=0 and T=1 week (40°C / 75%RH exposed; and 40°C / 75%RH sealed) was determined using the procedure described in Example 23. The results are summarized in Table 36.

[2208] Table 36

[2209]

[2210] Example 26 - Composition and preparation of tablet dosage form of compound 1

[2211] Composition of tablet dosage form

[2212] A tablet dosage form of Compound 1 was prepared, comprising an SDD consisting of Compound 1 and HPMC AS-MG (1:3), compressed into tablets and film-coated with pharmacopoeial excipients. Tablets were presented in 25 mg (white coated round tablets) and 100 mg (white coated oval tablets) dosage strengths. The composition of each dosage strength is summarized in Table 37.

[2213] Table 37

[2214]

[2215] 1 = Amount based on 25.00% (w / w) potency of Compound 1 drug substance in the spray dried intermediate.

[2216] Preparation of tablet dosage form

[2217] The manufacturing process of the compound 1 tablet formulation consists of four steps: 1) spray drying dispersion, 2) intragranular granulation, rolling / grinding / blending, 3) extragranular granulation / blending, and 4) tableting and coating. The initial step of spray drying dispersion is performed by producing an organic solution containing the compound 1 drug substance and hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate ester MG) (HPMCAS-MG). Using a method similar to that of Example 16, the solution is spray dried to produce an SDD consisting of compound 1 and HPMC AS-MG (1:3). The SDD is blended with intragranular excipients, followed by rolling / grinding and blending. The resulting granules are then mixed with extragranular components to form the final common granule blend. The final blend is compressed into tablets equivalent to 25 mg or 100 mg of active matter, followed by coating.

[2218] Example 27 - Dissolution Evaluation of Tablet Dosage Form

[2219] The dissolution of the 100 mg tablets described in Example 26 was tested. The dissolution test parameters are provided in Table 38 and the results are summarized in Table 39.

[2220] Table 38

[2221]

[2222] Table 39

[2223]

[2224] Example 28 - Release Testing of Tablet Dosage Form

[2225] Dissolution testing of 25 mg and 100 mg tablets having the composition specified in Example 26 was performed according to the dissolution parameters listed in Table 40. Dissolution was determined by UPLC analysis. The results of the dissolution testing are reported in Tables 41 and Fig.52 middle.

[2226] Table 40

[2227]

[2228] Table 41

[2229]

[2230] Example 29 - Stability Evaluation of Tablet Dosage Form

[2231] Two different batches of 25 mg and 100 mg tablets having the composition specified in Example 26 were subjected to stability studies under the conditions listed in Table 42. The stability study results for each batch and storage condition are reported in the table identified in Table 42.

[2232] Tablets were prepared for XRPD analysis (Method D) by crushing the tablets with a mortar and pestle and transferring 5-10 mg of material to a sample pan, slightly overfilling and ensuring that the powder was evenly distributed to cover the bottom of the plate. Weighing paper was placed on the powder and gently pressed down to level the powder surface. The XRPD pattern of the tablets was overlapped with the XRPD pattern of the reference standard (Compound 1, Form A). The tablets were considered to be free of diffraction peaks present in the reference standard only if there was no peak at about 15 degrees 2θ. Irregular small peaks at about 3 degrees 2θ were acceptable.

[2233] Table 42

[2234]

[2235] Table 43

[2236]

[2237] Table 44

[2238]

[2239]

[2240] Table 45

[2241]

[2242]

[2243] Table 46

[2244]

[2245]

[2246] Table 47

[2247]

[2248] Table 48

[2249]

[2250]

[2251] Table 49

[2252]

[2253] Table 50

[2254]

[2255] The results for Batch 1 at the 3-month time point and Batch 2 at the 1-month time point in the tablet batches were consistent with the T=0 time point.

[2256] Example 30 - Composition and preparation of tablet dosage form of compound 1

[2257] Tablets containing spray dried dispersion (SDD) of Compound 1 and pharmacopoeial excipients were prepared in 100 mg and 200 mg dosage strengths. The composition of the tablets is listed in Tables 51 and 52.

[2258] Tablets were prepared by first making SDD (spray drying of organic solutions of Compound 1 and HPMC-AS (1:1 w / w) (Table 51) or Compound 1 and HPMC-AS (1.5:1 w / w) (Table 52), followed by roller compaction / milling with intragranular excipients and blending with extragranular excipients. The final blend was compressed into tablets followed by film coating.

[2259] Table 51

[2260]

[2261]

[2262] Table 52

[2263]

[2264] Example 31 - Stability Evaluation of Tablet Dosage Form

[2265] Tablets having the compositions listed in Tables 51 and 52 were prepared for XRPD analysis (Method D) in the following manner: the tablets were crushed with a mortar and pestle and 5-10 mg of the material was transferred to a sample pan, slightly overfilled and ensuring that the powder was evenly distributed to cover the bottom of the plate. A weighing paper was placed on the powder and gently pressed down to level the surface of the powder. The XRPD pattern of the tablets was overlapped with the XRPD pattern of the reference standard (Compound 1, Form A). The XRPD pattern of the tablet was considered to be free of the diffraction peaks present in the reference standard only when there was no peak at about 15 degrees 2θ. An irregular small peak at about 3 degrees 2θ was acceptable. The tablets were determined to be free of crystalline Form A because the XRPD pattern did not have the diffraction peaks present in the reference standard.

[2266] Example 32 - Determination of Maximum Dose of Compound 2

[2267] Good laboratory practice (GLP) toxicology testing was performed on compound 1 test articles containing a predetermined amount of compound 2 in rats and cynomolgus monkeys. Standard toxicology techniques were used to determine the no-observed-adverse-effect level (NOAEL) for each species, and the resulting human dose level was calculated based on the dose per body surface area using the FDA human equivalent dose method. Based on these experiments and calculations, the maximum recommended starting dose (MRSD) for the first human clinical trial was determined based on the results produced by GLP toxicology testing. The API composition of compound 1 containing less than 5.0% (as determined by HPLC area percentage) of compound 2 is completely within the safe human equivalent dose range determined for compound 2.

Claims

1. A solid oral dosage form comprising a stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one, wherein the stabilized amorphous compound shows no crystallinity after storage for 2 weeks at 60°C / 75%RH, exposed conditions according to Method D, and the stabilized amorphous compound is in a spray-dried dispersion with a polymer, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS), and the compound and HPMC AS are spray-dried in a weight ratio of 3:1 to 1:3, and, The XRPD analysis was performed using the following parameters:

2. The solid oral dosage form of claim 1, wherein the stabilized amorphous compound exhibits a single glass transition temperature T after storage for 2 weeks at 60°C / 75%RH under exposed conditions according to DSC of Method B. G And there is no melting endotherm.

3. The solid oral dosage form of claim 1 or 2, wherein the solid oral dosage form contains a total of 200 mg of (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one.

4. The solid oral dosage form of claim 1 or 2, wherein the solid oral dosage form has a total weight of no more than 800 mg.

5. The solid oral dosage form of claim 4, wherein the solid oral dosage form is a tablet or a capsule.

6. The solid oral dosage form of claim 1 or 2, wherein the (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one and HPMC AS are spray dried in a weight ratio of 2:1 to 1:

3.

7. The solid oral dosage form of claim 1 or 2, wherein the (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one and HPMC AS are spray dried in a weight ratio of 1:

1.

8. A tablet comprising 200 mg of a stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one as an active pharmaceutical ingredient API, wherein the stabilized amorphous compound shows no crystallinity after the tablet is stored for 2 weeks at 60°C / 75%RH, exposed, according to XRPD of method D, and the stabilized amorphous compound is in a spray-dried dispersion with a polymer, wherein the polymer is hydroxypropylmethylcellulose acetate succinate HPMC AS, and the weight ratio of the compound to the polymer is in the range of 3:1 to 1:3, and, The XRPD analysis was performed using the following parameters:

9. The tablet of claim 8, wherein the weight ratio of the compound to the polymer is in the range of 2:1 to 1:

3.

10. The tablet of claim 8, wherein the weight ratio of the compound to the polymer is about 1:

1.

11. The tablet according to any one of claims 8 to 10, wherein the API comprises less than 5.0% of (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one according to HPLC.

12. The tablet of claim 11, wherein the API comprises less than 0.05% of (R)-1-(5-[2H,3H-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-3-hydroxy-2-phenylpropan-1-one according to HPLC.

13. The tablet according to any one of claims 8 to 10, having a total weight of less than 800 mg.

14. An amorphous solid dispersion, comprising compound 1: and hydroxypropylmethylcellulose acetate succinate HPMC AS, wherein the weight ratio of Compound 1 to HPMC AS is in the range of 3:1 to 1:3, and the amorphous solid dispersion is a spray-dried dispersion. 15 . The amorphous solid dispersion of claim 14 , wherein a weight ratio of Compound 1 to the polymer is in the range of 2:1 to 1:

3.

16. The amorphous solid dispersion of claim 15, wherein the weight ratio of Compound 1 to HPMC AS is about 1:

1.

17. The amorphous solid dispersion according to any one of claims 14 to 16, wherein no crystalline diffraction peak is observed by XRPD analysis of method D of the amorphous solid dispersion, and wherein method D performs XRPD analysis using the following parameters:

18. The amorphous solid dispersion of any one of claims 14 to 16, wherein a single glass transition temperature T is observable by DSC analysis of method B of the amorphous solid dispersion. G and no melting endotherm, wherein the DSC analysis of Method B is performed using the following program: DSC modulation at 1.00°C for 60 seconds, ramping to 250°C at a ramp rate of 2°C / min, using an alternate temperature range of 20°C to 25°C.

19. A pharmaceutical composition comprising a therapeutically effective amount of the amorphous solid dispersion according to any one of claims 14 to 18 and one or more pharmaceutically acceptable excipients.

20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is for oral administration.

21. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition is in tablet dosage form.

22. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition has a water content of 0.5 wt% to 5.0 wt%.

23. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of Compound 1.

24. The pharmaceutical composition of claim 19 or 20, comprising a tablet core comprising: an intra-particle portion comprising an amorphous solid dispersion; and An extragranular portion is blended with the intragranular portion.

25. The pharmaceutical composition of claim 24, further comprising a coating disposed on the core.

26. The pharmaceutical composition of claim 24, wherein the amorphous solid dispersion is at least 30% by weight of the core.

27. The pharmaceutical composition of claim 24, wherein the intra-granular portion further comprises one or more of a filler, a dry binder, a glidant, and a lubricant.

28. The pharmaceutical composition of claim 24, wherein the extragranular portion further comprises one or more of a filler, a disintegrant, and a lubricant.

29. A tablet dosage form comprising a tablet core comprising at least 10% by weight of Compound 1 in an amorphous form: wherein Form A crystalline Compound 1 is not observed by XRPD analysis of the core by Method D, the Form A crystalline Compound 1 being characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.61, 15.66, 23.19, and 24.76; and wherein compound 1 and a polymer are in a spray-dried dispersion, wherein the polymer is hydroxypropylmethylcellulose acetate succinate HPMC AS, and the weight ratio of compound 1 to the polymer is in the range of 3:1 to 1:3, and, The XRPD analysis was performed using the following parameters:

30. The tablet dosage form of claim 29, wherein the weight ratio of Compound 1 to the polymer is in the range of 2:1 to 1:

3.

31. The tablet dosage form of claim 29, wherein the weight ratio of Compound 1 to the polymer is about 1:

1.

32. The tablet dosage form of any one of claims 29-31, wherein the tablet core comprises at least 15% by weight of Compound 1 in an amorphous form.

33. The tablet dosage form of any one of claims 29-31, wherein the tablet core comprises at least 30% by weight of Compound 1 in an amorphous form.

34. The tablet dosage form of any one of claims 29-31, wherein the tablet core comprises about 200 mg of Compound 1 per tablet and has a total weight of no more than 1200 mg per tablet.

35. The tablet dosage form of claim 34, wherein the tablet core has a total weight of no more than 1100 mg, 1000 mg, 900 mg, 800 mg or 700 mg per tablet.

36. A tablet dosage form comprising a tablet core having a total weight of no more than 1000 mg and comprising about 200 mg per tablet of amorphous form of Compound 1: wherein Form A crystalline Compound 1 is not observed by XRPD analysis of the core by Method D, wherein Form A crystalline Compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ±0.2) of 4.61, 15.66, 23.19, and 24.76; and wherein compound 1 and a polymer are in a spray-dried dispersion, wherein the polymer is hydroxypropylmethylcellulose acetate succinate HPMC AS, and the weight ratio of compound 1 to the polymer is in the range of 3:1 to 1:3, and, The XRPD analysis was performed using the following parameters:

37. The tablet dosage form of claim 36, wherein the core has a total weight of no more than 800 mg per tablet.

38. The tablet dosage form of claim 36, wherein the core comprises 0.05%-5.0% of Compound 2: Based on the total amount of Compound 1 and Compound 2.

39. The tablet dosage form of any one of claims 36-38, wherein no crystalline Compound 1 Form A is observed by XRPD analysis of the core by Method D after storage at 25°C and 60% relative humidity for 1 month in a sealed container as described in Example 29.

40. The tablet dosage form of any one of claims 36-38, wherein the weight ratio of Compound 1 to the polymer is in the range of 2:1 to 1:

3.

41. The tablet dosage form of any one of claims 36-38, wherein the weight ratio of Compound 1 to the polymer is about 1:

1.

42. The tablet dosage form of any one of claims 36-38, further comprising one or more pharmaceutically acceptable excipients.

43. The tablet dosage form of claim 42, wherein the one or more pharmaceutically acceptable excipients comprises one or more of a filler, a dry binder, a glidant, a lubricant, a disintegrant, and a film coating agent.

44. The tablet dosage form of any one of claims 36-38, wherein the core comprises: an intragranular portion comprising Compound 1; and An extragranular portion is blended with the intragranular portion.

45. The tablet dosage form of claim 44, wherein the intragranular portion comprises an amorphous solid dispersion comprising Compound 1 and a polymer and one or more of a filler, a dry binder, a glidant, and a lubricant, and the extragranular portion comprises one or more of a filler, a disintegrant, and a lubricant.

46. ​​The tablet dosage form of any one of claims 36-38, wherein the intra-granular portion comprises: an amorphous solid dispersion of Compound 1 in an amount of 30% to 70% by weight of the tablet core; One or more fillers in an amount of 15% to 50% by weight of the core; One or more dry binders in an amount of 2.50% to 10% by weight of the core; one or more glidants in an amount of 0.50% to 1.50% by weight of the tablet core; and One or more lubricants in an amount of 0.25% to 1% by weight of the core; and The extragranular portion comprises: One or more fillers in an amount of 5% to 15% by weight of the core; one or more disintegrants in an amount of 1.25% to 5% by weight of the tablet core; and One or more lubricants in an amount of 0.25% to 1% by weight of the core; or Wherein the tablet dosage form comprises: an amorphous solid dispersion of Compound 1 in an amount of 50% to 75% by weight of the tablet core; One or more fillers in an amount of 15% to 50% by weight of the core; One or more dry binders in an amount of 2% to 10% by weight of the core; one or more glidants in an amount of <2% by weight of the tablet core; one or more disintegrants in an amount of 2% to 10% by weight of the tablet core; and One or more lubricants in an amount of <2% by weight of the tablet core.

47. The tablet dosage form of claim 46, wherein the one or more fillers comprise microcrystalline cellulose or lactose monohydrate.

48. The tablet dosage form of claim 46, wherein the one or more dry binders comprises crospovidone or cross-linked polyvinyl pyrrolidone.

49. The tablet dosage form of claim 46, wherein the one or more glidants comprises colloidal silicon dioxide or fumed silicon dioxide.

50. The tablet dosage form of claim 46, wherein the one or more lubricants comprises magnesium stearate.

51. The tablet dosage form of claim 46, wherein the one or more disintegrants comprises croscarmellose sodium.

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