Pyruvate kinase R (PKR) activating composition

Abstract

The present disclosure provides a pharmaceutical composition comprising (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one (“Compound 1”) in a crystalline solid form, a spray-drying dispersion, and a solid oral administration form, and a method for preparing the same.

Description

Technology Field

[0001] Cross-reference regarding related applications

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

[0003] Technology field

[0004] 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]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one, and methods for preparing the same. Background Technology

[0005] Chemical compounds can form one or more different pharmaceutically acceptable solid forms, including amorphous and crystalline forms. Amorphous solid forms include dispersions such as spray-dry dispersions of amorphous and crystalline chemical compounds. Individual solid forms of bioactive chemical compounds may possess different characteristics. To develop pharmaceutically acceptable dosage forms for the treatment of various diseases or pathological conditions, it is necessary to identify and select appropriate solid forms of bioactive chemical compounds (including appropriate crystalline forms where applicable).

[0006] Compound (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one("Compound 1 "),

[0007]

[0008] is a small molecule PKR activator that regulates pyruvate kinase activity. Compound 1 It is described in International Publication No. WO 2018 / 175474 as one of many compounds suitable as small molecule modulators of pyruvate kinase activity. It is a compound useful for various therapeutic applications. 1 There remains a need to identify the solid form of.

[0009] One aspect of the present disclosure is a compound (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one("stabilized amorphous compound 1 This relates to a solid oral dosage form (solid oral formulation) comprising a stabilized amorphous pharmaceutical composition of (also referred to as "stabilized amorphous compound"). As used herein, the term "stabilized amorphous compound" 1 "is a compound under the specified storage conditions described in this specification 1A compound stabilized to prevent solid phase separation or the formation of a crystalline form of compound 1 (e.g., by a combination with a specified stabilizing polymer and / or other manufacturing methods). 1 amorphous solid form (e.g., not exhibiting crystalline diffraction peaks by XRPD analysis (Method D) after 2 weeks of storage at 60°C / 75% RH (exposed), and / or a single glass transition temperature (T) with no melt endotherm by DSC analysis (Method B) after 2 weeks of storage at 60°C / 75% RH (exposed)). G The invention relates to a stabilized amorphous pharmaceutical composition comprising a compound 1 representing ) and one or more additional components.

[0010] In some embodiments, stabilized amorphous compound 1 silver compounds 1 It is obtained by spray-drying a solution of with a stabilizing polymer. The inventors of the amorphous compound 1 Compounds including this crystalline form type A 1 It was discovered that it has a higher oral bioavailability than a predetermined crystalline form. Accordingly, in some embodiments, a stabilized amorphous compound 1 A solid oral dosage form containing is advantageously a compound 1 Compared to a solid oral administration form containing a specific crystalline form of a compound 1 It provides excellent oral bioavailability.

[0011] In addition, regarding compounds in this specification 1 An amorphous spray-dried dispersion (SDD), a method for preparing the same, and a pharmaceutical composition containing the same are disclosed. The present disclosure relates to a compound 1 Compounds useful for therapeutic oral administration 1 Compounds, including one or more pharmaceutically acceptable crystalline and amorphous forms 1It provides various solid forms of compounds. 1 of Various solid forms can be identified by certain characteristic properties. For example, compounds 1 A specific crystalline form of has a distinct characteristic XRPD peak.

[0012] Another aspect of the present disclosure is a compound 1 This relates to the solid form of the compound disclosed in this specification. 1 The solid form of is a compound 1 of It includes various crystalline forms (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), a method for manufacturing the same, and a pharmaceutical composition containing the same.

[0013] One aspect of the present disclosure is the following compound 1 This relates to a novel crystalline solid form of:

[0014]

[0015] novel compounds 1 Crystalline form type A can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.61, 15.66, 23.19, and 24.76 (2 theta ± 0.2). Novel compound 1 Crystalline form type A can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.6, 15.7, 23.2, and 24.8 (2 theta ± 0.2). Novel compound 1 Crystalline form type A can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8 (2 theta ± 0.2).

[0016] novel compounds 1Crystalline form type B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.52, 15.57, 22.89, 23.34, and 25.13 (2 theta ± 0.2). Novel compound 1 Crystalline form type B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 15.6, 22.9, 23.3, and 25.1 (2 theta ± 0.2). Novel compound 1 Crystalline form type B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1 (2 theta ± 0.2).

[0017] novel compounds 1 Crystalline form type C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.55, 18.85, 23.02, and 24.65 (2 theta ± 0.2). Novel compound 1 Crystalline form type C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 18.9, 23.0, and 24.7 (2 theta ± 0.2). Novel compound 1 Crystalline form type C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7 (2 theta ± 0.2).

[0018] novel compounds 1 Crystalline form type D can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 9.72, 13.08, 15.74, 21.90, and 23.59 (2 theta ± 0.2). Novel compound 1Crystalline form type D can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 9.7, 13.1, 15.7, 21.9, and 23.6 (2 theta ± 0.2). Novel compound 1 Crystalline form type D can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 (2 theta ± 0.2) and no diffraction at angle of 23.3 (2 theta ± 0.2).

[0019] novel compounds 1 Crystalline form type E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72 (2 theta ± 0.2). Novel compound 1 Crystalline form type E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7 (2 theta ± 0.2). Novel compound 1 Crystalline form type E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7 (2 theta ± 0.2).

[0020] novel compounds 1 Crystalline form type F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45 (2 theta ± 0.2). Novel compound 1Crystalline form type F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5 (2 theta ± 0.2). Novel compound 1 Crystalline form type F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.4, 14.7, 16.0, 16.8, and 21.4 (2 theta ± 0.2).

[0021] novel compounds 1 Crystalline form type G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.36, 14.34, 16.58, and 21.35 (2 theta ± 0.2). Novel compound 1 Crystalline form type G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.4, 14.3, 16.6, and 21.4 (2 theta ± 0.2). Novel compound 1 Crystalline form type G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.4, 14.3, 16.6, 21.3, and 22.3 (2 theta ± 0.2).

[0022] novel compounds 1 Crystalline form type H can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4 (2 theta ± 0.2).

[0023] novel compounds 1 Crystalline form type I can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.2, 14.6, 15.5, 20.2, and 21.1 (2 theta ± 0.2).

[0024] novel compounds 1Crystalline form type J can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 5.7, 22.8, 23.1, and 24.5 (2 theta ± 0.2).

[0025] novel compounds 1 Crystalline form type K can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4 (2 theta ± 0.2).

[0026] novel compounds 1 Crystalline form type L can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1 (2 theta ± 0.2).

[0027] novel compounds 1 Crystalline form type M can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7 (2 theta ± 0.2).

[0028] Another aspect of the present disclosure is a therapeutically effective amount of the compound described above. 1 The invention relates to a pharmaceutical composition comprising any crystalline solid form of and one or more pharmaceutically acceptable excipients.

[0029] Another aspect of the present disclosure is a compound 1 This relates to a novel amorphous solid dispersion of a compound. 1 The novel amorphous solid form of the compound 1 It can be manufactured by spray-drying a mixture containing polymers.

[0030] Further other aspects of the present disclosure are compounds described above. 1The present invention relates to a pharmaceutical composition comprising a novel amorphous solid form. The pharmaceutical composition may be in an oral administration form, such as a tablet.

[0031] Another aspect of the present disclosure is a compound 1 This relates to a tablet dosage form (tablet formulation) containing Brief explanation of the drawing

[0032] Figure 1 shows a compound 1 The reaction equation for manufacturing is illustrated. Figure 2 shows a compound 1 An alternative reaction equation for manufacturing is illustrated. Figure 3 shows a compound 1 Illuminates the XRPD pattern of crystalline form type A. Figure 4 shows a compound 1 The thermogravimetric analysis (TGA) curve (top curve) and differential scanning calorimetry (DSC) thermogram (bottom curve) for crystalline form type A are plotted. Figure 5 shows a compound 1 Illuminates the DSC cycling thermogram for crystalline form type A. Figure 6 shows a compound 1 Plot the dynamic vapor sorption (DVS) isotherm for crystalline form type A. Figure 7 shows a compound 1 Illuminates the XRPD pattern of crystalline form type B. Figure 8 shows a compound 1 The thermogravimetric analysis (TGA) curve (top curve) and differential scanning calorimetry (DSC) thermogram (bottom curve) for crystalline form type B are plotted. Figure 9 shows a compound 1 Illuminates the DSC cycling thermogram for crystalline form type B. Figure 10 shows a compound 1 Two thermogravimetric analysis (TGA) curves for crystalline form type B are plotted. Figure 11 shows a compound 1Plot the dynamic vapor sorption (DVS) isotherm for crystalline form type B. Figure 12 shows a compound 1 The XRPD pattern for the crystalline form type C is illustrated. Figure 13 shows a compound 1 The thermogravimetric analysis (TGA) curve (top curve) and differential scanning calorimetry (DSC) thermogram (bottom curve) for crystalline form type C are plotted. Figure 14 shows a compound 1 Illuminates the DSC cycling thermogram for the crystalline form type C. Figure 15 shows a compound 1 The thermogravimetric analysis (TGA) curve for crystalline form type C is plotted. Figure 16 shows a compound 1 Plot the dynamic vapor sorption (DVS) isotherm for crystalline form type C. Figure 17 shows a compound 1 The XRPD pattern for crystalline form type D is illustrated. Figure 18 shows a compound 1 The thermogravimetric analysis (TGA) curve (top curve) and differential scanning calorimetry (DSC) thermogram (bottom curve) for crystalline form type D are plotted. Figure 19 shows a compound 1 Type A (upper curve) and Type D (lower curve) crystalline forms 1 Plot the H NMR spectrum. Figure 20 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type E. Figure 21 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type F. Figure 22 shows a compound 1 The thermogravimetric analysis (TGA) curve (upper curve) and differential scanning calorimetry (DSC) thermogram (lower curve) for crystalline form type F are plotted. Figure 23 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type G. Figure 24 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type H. Figure 25 shows a compound 1 Illuminates the XRPD pattern of crystalline form type I. Figure 26 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type J. Figure 27 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type K. Figure 28 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type L. Figure 29 shows a compound 1 Illuminates the XRPD pattern of the crystalline form type M. Figure 30 shows a compound 1 of The XRPD pattern of the spray-dry dispersion (SDD) is illustrated. Figure 31 shows a compound 1 A differential scanning calorimetry (DSC) thermogram for the spray-dry dispersion (SDD) is plotted. Figure 32 shows a compound in rats 1 Graphs of plasma concentrations over time after administration of the three formulations are shown. Figure 33 shows a compound in monkeys 1 Graphs of plasma concentrations over time after administration of the four formulations are shown. Figure 34 shows a graph of the time-dependent solubility of type A of compound 1 in biorelevant media. Fig. 35 shows compounds in a biological medium. 1 Graph of the time-dependent solubility of the spray-dry dispersion (SDD) is plotted. Figure 36 shows a crystalline compound 1 Compounds overlaid with the XRPD pattern of (Type A) 1 The superimposed XRPD patterns of five spray-dry dispersions (SDD) are illustrated. Figure 37 shows a compound 1Superimposed differential scanning calorimetry (DSC) thermograms of five spray-dry dispersions (SDD) are shown. Figure 38 shows a graph of the kinetic solubility profiles of five SDDs of compound 1 at different drug loads. Fig. 39 shows a crystalline compound 1 Compounds after storage superimposed with the XRPD pattern of (Type A), in (a) a sealed vial for 2 weeks at 60°C, (b) an unsealed vial for 2 weeks at 40°C and 75% relative humidity, and (c) an unsealed vial for 2 weeks at 60°C and 75% relative humidity. 1 Superimposed XRPD patterns of the spray-dried dispersion (SDD 0) are shown. Fig. 40 is a crystalline compound 1 Compounds after storage superimposed with the XRPD pattern of (Type A), in (a) a sealed vial for 2 weeks at 60°C, (b) an unsealed vial for 2 weeks at 40°C and 75% relative humidity, and (c) an unsealed vial for 2 weeks at 60°C and 75% relative humidity. 1 The superimposed XRPD pattern of the spray-dried dispersion (SDD 1) is illustrated. Fig. 41 shows a crystalline compound 1 Compounds after storage superimposed with the XRPD pattern of (Type A), in (a) a sealed vial for 2 weeks at 60°C, (b) an unsealed vial for 2 weeks at 40°C and 75% relative humidity, and (c) an unsealed vial for 2 weeks at 60°C and 75% relative humidity. 1 The superimposed XRPD pattern of the spray-dried dispersion (SDD 2) is illustrated. Fig. 42 shows a crystalline compound 1Compounds after storage superimposed with the XRPD pattern of (Type A), in (a) a sealed vial for 2 weeks at 60°C, (b) an unsealed vial for 2 weeks at 40°C and 75% relative humidity, and (c) an unsealed vial for 2 weeks at 60°C and 75% relative humidity. 1 The superimposed XRPD pattern of the spray-dried dispersion (SDD 3) is illustrated. Fig. 43 shows a crystalline compound 1 Compounds after storage superimposed with the XRPD pattern of (Type A), in (a) a sealed vial for 2 weeks at 60°C, (b) an unsealed vial for 2 weeks at 40°C and 75% relative humidity, and (c) an unsealed vial for 2 weeks at 60°C and 75% relative humidity. 1 The superimposed XRPD pattern of the spray-dried dispersion (SDD 4) is illustrated. Fig. 44 shows a crystalline compound 1 Compounds superimposed with the XRPD pattern of (Type A) 1 The superimposed XRPD patterns of two spray-dried dispersions (SDD 5 and 6) are shown. Figure 45 shows a compound 1 Superimposed DSC thermograms of two spray-dried dispersions (SDD 5 and 6) are shown. FIG. 46 shows the compounds after storage in (a) a sealed vial at 60°C for 1 week, (b) an unsealed vial at 25°C and 60% relative humidity for 1 week, and (c) an unsealed vial at 40°C and 75% relative humidity for 1 week. 1 The superimposed XRPD pattern of the spray-dried dispersion (SDD 5) is illustrated. FIG. 47 shows the compounds after storage in (a) a sealed vial at 60°C for 1 week, (b) an unsealed vial at 25°C and 60% relative humidity for 1 week, and (c) an unsealed vial at 40°C and 75% relative humidity for 1 week. 1Superimposed DSC thermogram of the spray-dried dispersion (SDD 5) is shown. FIG. 48 shows the compounds after storage in (a) a sealed vial at 60°C for 2 weeks, (b) an unsealed vial at 25°C and 60% relative humidity for 2 weeks, and (c) an unsealed vial at 40°C and 75% relative humidity for 2 weeks. 1 Superimposed DSC thermogram of the spray-dried dispersion (SDD 5) is shown. FIG. 49 shows the compounds after storage in (a) a sealed vial at 60°C for 1 week, (b) an unsealed vial at 25°C and 60% relative humidity for 1 week, and (c) an unsealed vial at 40°C and 75% relative humidity for 1 week. 1 The superimposed XRPD pattern of the spray-dried dispersion (SDD 6) is illustrated. FIG. 50 shows the compounds after storage in (a) a sealed vial at 60°C for 1 week, (b) an unsealed vial at 25°C and 60% relative humidity for 1 week, and (c) an unsealed vial at 40°C and 75% relative humidity for 1 week. 1 Superimposed DSC thermogram of the spray-dried dispersion (SDD 6) is shown. FIG. 51 shows the compounds after storage in (a) a sealed vial at 60°C for 2 weeks, (b) an unsealed vial at 25°C and 60% relative humidity for 2 weeks, and (c) an unsealed vial at 40°C and 75% relative humidity for 2 weeks. 1 Superimposed DSC thermogram of the spray-dried dispersion (SDD 6) is shown. Figure 52 shows a compound 1 Graph of the dissolution profile of the tablet formulation is shown. Specific details for implementing the invention

[0033] The chemical compound (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one("compound 1 ")

[0034]

[0035] is a small molecule modifier of pyruvate kinase. The present disclosure describes a compound 1 Various solid forms of, pharmaceutical compositions thereof, and compounds 1 A method for preparing a novel solid form of is provided. The solid forms described herein (e.g., crystalline solid form and amorphous solid form) are compounds 1 It relates to advantageous features compared to other forms, such as advantageous or improved solubility, dissolution, bioavailability, stability, and ease of formulation. For example, a certain amorphous solid dispersion described herein advantageously has a high drug loading (e.g., ≥ 25%, ≥ 40%, ≥ 50%, etc.), and crystalline compounds 1 It is absent or practically absent, and physically stable (i.e., crystalline compounds over time in accelerated stability studies) 1 It is maintained without or substantially without), is highly soluble, and / or does not require extensive drying to remove residual solvent. Additionally, the specified tablet dosage forms described herein advantageously have a high drug load (e.g., 10% by weight or more of the tablet core, 15% by weight or more of the tablet core, 30% by weight or more of the tablet core), a small tablet size (e.g., tablet core weight per tablet ≤ 1200 mg, ≤ 1000 mg, ≤ 800 mg, ≤ 700 mg, etc.), and a crystalline compound 1 It is absent or substantially absent, and / or physically stable (i.e., crystalline compounds over time in accelerated stability studies). 1 It remains without or practically absent).

[0036] In some embodiments, compounds 1 It is in a crystalline solid form (e.g., Type A, Type B, Type C, Type D, Type E, Type F, or Type G). In some embodiments, the compound 1 It 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.

[0037] In some embodiments, compounds 1 It is in an amorphous form (e.g., an amorphous solid dispersion). In some embodiments, the amorphous solid dispersion is a compound 1 It includes polymers.

[0038] compound 1 Crystalline form type A

[0039] novel compounds 1 Crystalline form type A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.61, 15.66, 23.19, and 24.76 (2 theta ± 0.2). Novel compound 1Crystalline form type A can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.6, 15.7, 23.2, and 24.8 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type A can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.61, 15.66, 23.19, and 24.76, respectively, and corresponding d-spacings (angstroms ± 0.2) of 19.19, 5.66, 3.84, and 3.60. In some embodiments, the compound 1 Crystalline form type A can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.6, 15.7, 23.2, and 24.8 (2 theta ± 0.2) corresponding to d-interplanar distances (angstrom ± 0.2) of 19.2, 5.7, 3.8, and 3.6, respectively.

[0040] In some embodiments, compounds 1 Crystalline form type A can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type A can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8, corresponding to d-interplanar distances (angstrom ± 0.2) of 19.2, 12.3, 5.7, 4.2, 3.8, and 3.6, respectively.

[0041] In some embodiments, compounds 1Crystalline form type A can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type A can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type A can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (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, the compound 1 Crystalline form type A can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 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.

[0042] In some embodiments, compounds 1 Crystalline form type A is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0043]

[0044] In some embodiments, compounds 1Crystalline form type A is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0045]

[0046] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0047]

[0048] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0049]

[0050] In some embodiments, compounds 1 Crystalline form type A is characterized by a thermogravimetric analysis (TGA) thermogram with a weight loss of about 1.9% at up to 100°C. In some embodiments, the compound 1 Crystalline form type A is characterized by differential scanning calorimetry (DSC) endothermy having a peak temperature of about 85.9°C and an onset temperature of about 146.0°C. In some embodiments, the compound 1 Crystalline form type A is characterized by dynamic vapor adsorption (DVS) of about 3.4% by weight of moisture absorption at up to 40% relative humidity. In some embodiments, the compound 1 Crystalline form type A is characterized by kinetic vapor adsorption (DVS) of about 1.0% by weight of moisture absorption at relative humidity from 40% to 80%.

[0051] compound 1 Crystalline form type B

[0052] novel compounds 1 Crystalline form type B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.52, 15.57, 22.89, 23.34, and 25.13 (2 theta ± 0.2). Novel compound 1 Crystalline form type B can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.5, 15.6, 22.9, 23.3, and 25.1 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13, corresponding to d-interplanar distances (angstroms ± 0.2) of 19.53, 5.69, 3.89, 3.81, and 3.54, respectively. In some embodiments, the compound 1 Crystalline form type B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.5, 15.6, 22.9, 23.3, and 25.1, corresponding to d-interplanar distances (angstrom ± 0.2) of 19.5, 5.7, 3.9, 3.8, and 3.5, respectively.

[0053] In some embodiments, compounds 1 Crystalline form type B can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type B can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1, corresponding to d-interplanar distances (angstrom ± 0.2) of 19.5, 5.7, 4.0, 3.9, 3.8, and 3.5, respectively.

[0054] In some embodiments, compounds 1 Crystalline form type B can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type B can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type B can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (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, the compound 1 Crystalline form type B can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 0.2) of 19.5, 9.0, 5.7, 4.5, 4.0, 3.9, 3.8, 3.5, and 3.2, respectively.

[0055] In some embodiments, compounds 1 Crystalline form type B is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0056]

[0057] In some embodiments, compounds 1Crystalline form type B is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0058]

[0059] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0060]

[0061] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0062]

[0063]

[0064] In some embodiments, compounds 1 Crystalline form type B is characterized by a thermogravimetric analysis (TGA) thermogram with a weight loss of about 1.8% up to 100°C and / or a thermogravimetric analysis (TGA) thermogram with a weight loss of about 2.3% at 120°C. In some embodiments, the compound 1 Crystalline form type B is characterized by having differential scanning calorimetry (DSC) endothermy with an onset temperature of about 138.2 to 139.2°C. In some embodiments, the compound 1 Crystalline form type B is characterized by dynamic vapor absorption (DVS) of about 2.9% by weight of moisture absorption up to 60% relative humidity, and dynamic vapor absorption (DVS) of about 0.4% by weight of moisture absorption at 60% to 80% relative humidity.

[0065] compound 1 Crystalline form type C

[0066] novel compounds 1 Crystalline form type C can be identified by X-ray powder diffraction (XRPD) patterns having one or more characteristic diffractions at angles of 4.55, 18.85, 23.02, and 24.65 (2 theta ± 0.2). Novel compound 1 Crystalline form type C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.5, 18.9, 23.0, and 24.7 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.55, 18.85, 23.02, and 24.65, corresponding to d-interplanar distances (angstroms ± 0.2) of 19.43, 4.71, 3.86, and 3.61, respectively. In some embodiments, the compound 1 Crystalline form type C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 18.9, 23.0, and 24.7 (2 theta ± 0.2), corresponding to d-interplanar distances (angstrom ± 0.2) of 19.4, 4.7, 3.9, and 3.6, respectively.

[0067] In some embodiments, compounds 1 Crystalline form type C can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type C can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7, corresponding to d-interplanar distances (angstrom ± 0.2) of 19.4, 12.0, 7.9, 4.7, 3.9, and 3.6, respectively.

[0068] In some embodiments, compounds 1 Crystalline form type C can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 4.55, 7.34, 9.07, 11.17, 18.34, 18.85, 19.57, 21.66, 23.02, and 24.65 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type C can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 4.5, 7.3, 9.1, 11.2, 18.34, 18.9, 19.6, 21.7, 23.0, and 24.7 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type C can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (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, the compound 1 Crystalline form type C can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 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.

[0069] In some embodiments, compounds 1 Crystalline form type C is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0070]

[0071]

[0072] In some embodiments, compounds 1 Crystalline form type C is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0073]

[0074] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0075]

[0076] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0077]

[0078]

[0079] In some embodiments, compounds 1 The crystalline form type C is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.0% up to 100°C, and / or a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% up to 130°C. In some embodiments, the compound 1 Crystalline form type C is characterized by having differential scanning calorimetry (DSC) endothermy with an onset temperature of about 152.2 to 154.2°C. In some embodiments, the compound 1Crystalline form type C is characterized by dynamic vapor absorption (DVS) of about 1.8% by weight of moisture absorption up to 60% relative humidity, and dynamic vapor absorption (DVS) of about 0.5% by weight of moisture absorption at 60% to 80% relative humidity.

[0080] compound 1 Crystalline form type D

[0081] novel compounds 1 Crystalline form type D can be identified by X-ray powder diffraction (XRPD) patterns having one or more characteristic diffractions at angles of 9.72, 13.08, 15.74, 21.90, and 23.59 (2 theta ± 0.2). Novel compound 1 Crystalline form type D can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 9.7, 13.1, 15.7, 21.9, and 23.6 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type D can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 9.72, 13.08, 15.74, 21.90, and 23.59, corresponding to d-interplanar distances (angstroms ± 0.2) of 9.10, 6.77, 5.63, 4.06, and 3.77, respectively. In some embodiments, the compound 1 Crystalline form type D can be identified by one or more characteristic diffracted X-ray powder diffraction (XRPD) at angles (2 theta ± 0.2) of 9.7, 13.1, 15.7, 21.9, and 23.6, corresponding to d-interplanar distances (angstrom ± 0.2) of 9.1, 6.8, 5.6, 4.1, and 3.8, respectively.

[0082] In some embodiments, compounds 1Crystalline form type D can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 (2 theta ± 0.2) and no diffraction at angle of 23.3 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type D can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 corresponding to d-interplanar distances (angstrom ± 0.2) of 14.4, 9.1, 6.8, 5.6, 4.1, and 3.8, respectively, and having no diffraction at angle 23.3 (2 theta ± 0.2).

[0083] In some embodiments, compounds 1 Crystalline form type D can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type D can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1Crystalline form type D can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (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, the compound 1 Crystalline form type D can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 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.

[0084] In some embodiments, compounds 1 Crystalline form type D is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0085]

[0086]

[0087] In some embodiments, compounds 1 Crystalline form type D is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0088]

[0089] In some embodiments, compounds 1Crystalline form type 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-interplanar distances (ANGS±0.2):

[0090]

[0091]

[0092] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0093]

[0094]

[0095] In some embodiments, compounds 1 Crystalline form type D is characterized by a thermogravimetric analysis (TGA) thermogram with a weight loss of about 9.6% up to 130°C. In some embodiments, the compound 1 Crystalline form type D is characterized by having differential scanning heat (DSC) endothermic with an onset temperature of about 91.9°C.

[0096] compound 1 Crystalline form type E

[0097] novel compounds 1 Crystalline form type E can be identified by X-ray powder diffraction (XRPD) patterns having one or more characteristic diffractions at angles of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72 (2 theta ± 0.2). Novel compound 1 Crystalline form type E can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7. In some embodiments, the compound1 Crystalline form type E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72, corresponding to d-interplanar distances (angstroms ± 0.2) of 5.86, 5.63, 5.07, 4.43, 4.05, and 3.34, respectively. In some embodiments, the compound 1 Crystalline form type E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7, corresponding to d-interplanar distances (angstrom ± 0.2) of 5.9, 5.6, 5.1, 4.4, 4.1, and 3.3, respectively.

[0098] In some embodiments, compounds 1 Crystalline form type E can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7. In some embodiments, the compound 1 Crystalline form type E can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 19.0, 20.1, 21.9, and 26.7, corresponding to d-interplanar distances (angstrom ± 0.2) of 5.9, 5.6, 5.1, 4.7, 4.4, 4.1, and 3.3, respectively.

[0099] In some embodiments, compounds 1 Crystalline form type E can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1Crystalline form type E can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type E can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (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, the compound 1 Crystalline form type E can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 0.2) of 19.3, 5.9, 5.6, 5.1, 4.4, 4.1, 3.8, 3.8, and 3.3, respectively.

[0100] In some embodiments, compounds 1 Crystalline form type E can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1Crystalline form type E can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type E corresponds to d-interplanar distances (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, at one or more angles (2 theta ± 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, at angles (2 theta ± 0.2), corresponding to d-interplanar distances (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. It can be identified by XRPD having characteristic diffraction. In some embodiments, the compound 1 Crystalline form type E can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 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, 3.3, and 3.2, respectively, corresponding to d-interplanar distances (angstrom ± 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, 3.3, and 3.2, respectively.

[0101] In some embodiments, compounds 1 Crystalline form type E is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0102]

[0103]

[0104] In some embodiments, compounds 1 Crystalline form type E is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0105]

[0106]

[0107] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0108]

[0109]

[0110] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0111]

[0112]

[0113] compound 1 Crystalline form type F

[0114] novel compounds 1 Crystalline form type F can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45 (2 theta ± 0.2). Novel compound 1Crystalline form type F can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45, corresponding to corresponding d-interplanar distances (angstroms ± 0.2) of 16.23, 6.04, 5.54, 5.28, 4.44, 4.16, and 3.96, respectively. In some embodiments, the compound 1 Crystalline form type F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5, corresponding to corresponding d-interplanar distances (angstrom ± 0.2) of 16.2, 6.0, 5.5, 5.3, 4.4, 4.2, and 4.0, respectively.

[0115] In some embodiments, compounds 1 Crystalline form type F can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 5.4, 14.7, 16.0, 16.8, and 21.4 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type F can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 0.2) of 5.4, 14.7, 16.0, 16.8, and 21.4, corresponding to d-interplanar distances (angstrom ± 0.2) of 16.2, 6.0, 5.5, 5.3, and 4.2, respectively.

[0116] In some embodiments, compounds 1Crystalline form type F can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type F can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type F can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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 corresponding d-interplanar distances (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, the compound 1 Crystalline form type F can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 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.

[0117] In some embodiments, compounds 1Crystalline form type F can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type F can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type F corresponds to d-interplanar distances (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, 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. It can be identified by XRPD having one or more characteristic diffraction patterns at an angle (2 theta ± 0.2). In some embodiments, the compound 1Crystalline form type F can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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 corresponding d-interplanar distances (angstrom ± 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.

[0118] In some embodiments, compounds 1 Crystalline form type F is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0119]

[0120]

[0121] In some embodiments, compounds 1 Crystalline form type F is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0122]

[0123] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0124]

[0125] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0126]

[0127]

[0128] In some embodiments, compounds 1 The crystalline form type F is characterized by a thermogravimetric analysis (TGA) thermogram with a weight loss of about 6.2% up to 120°C. In some embodiments, the compound 1 Crystalline form type F is characterized by differential scanning heat (DSC) endothermy having a peak temperature of about 100.4°C and an onset temperature of 125.9°C.

[0129] compound 1 Crystalline form type G

[0130] novel compounds 1 Crystalline form type G can be identified by X-ray powder diffraction (XRPD) patterns having one or more characteristic diffractions at angles of 5.36, 14.34, 16.58, and 21.35 (2 theta ± 0.2). Novel compound 1 Crystalline form type G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 5.4, 14.3, 16.6, and 21.4 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 5.36, 14.34, 16.58, and 21.35, corresponding to d-interplanar distances (angstroms ± 0.2) of 16.48, 6.18, 5.35, and 4.16, respectively. In some embodiments, the compound 1 Crystalline form type G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.4, 14.3, 16.6, and 21.4 (2 theta ± 0.2), corresponding to d-interplanar distances (angstrom ± 0.2) of 16.5, 6.2, 5.3, and 4.2, respectively.

[0131] In some embodiments, compounds 1 Crystalline form type G can be identified by an XRPD pattern having one or more characteristic diffractions at angles of 5.4, 14.3, 16.6, 21.3, and 22.3 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type G can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3, corresponding to corresponding d-interplanar distances (angstrom ± 0.2) of c 16.5, 6.2, 5.3, 4.2, and 4.0, respectively.

[0132] In some embodiments, compounds 1 Crystalline form type G can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type G can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type G can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (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, the compound 1Crystalline form type G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2 theta ± 0.2) of 5.4, 12.8, 14.3, 15.0, 16.6, 19.8, 21.3, 22.3, 25.3, and 26.4 (2 theta ± 0.2) corresponding to d-interplanar distances (angstrom ± 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.

[0133] In some embodiments, compounds 1 Crystalline form type G can be identified by an XRPD pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type G can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles (2 theta ± 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, the compound 1 Crystalline form type G can be identified by XRPD having one or more characteristic diffractions at angles (2 theta ± 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-interplanar distances (angstrom ± 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, the compound 1Crystalline form type G can be identified by X-ray powder diffraction (XRPD) patterns having one or more characteristic diffractions at angles (2 theta ± 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 (2 theta ± 0.2) corresponding to d-interplanar distances (angstrom ± 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.

[0134] In some embodiments, compounds 1 Crystalline form type G is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0135]

[0136] In some embodiments, compounds 1 Crystalline form type G is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0137]

[0138]

[0139] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0140]

[0141] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0142]

[0143]

[0144] compound 1 Crystalline form type H

[0145] novel compounds 1 Crystalline form type H may be characterized by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type H can be characterized by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4 (2 theta ± 0.2), and corresponding d-interplanar distances of 15.3, 6.0, 5.4, 4.4, 4.2, and 3.5 (angstrom ± 0.2), respectively.

[0146] In some embodiments, compounds 1 Crystalline form type H is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0147]

[0148]

[0149] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0150]

[0151]

[0152] compound 1 Crystalline Form Type I

[0153] novel compounds 1Crystalline form type I may be characterized by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 5.2, 14.6, 15.5, 20.2, and 21.1 (2 theta ± 0.2). In some embodiments, the compound 1 Crystalline form type I may be characterized by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 5.2, 14.6, 15.5, 20.2, and 21.1 (2 theta ± 0.2) and corresponding d-interplanar distances of 17.1, 6.1, 5.7, 4.4, and 4.2 (angstrom ± 0.2), respectively.

[0154] In some embodiments, compounds 1 Crystalline form type I is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0155]

[0156]

[0157]

[0158] In some embodiments, compounds 1 Crystalline form type I is characterized by an X-ray powder diffraction pattern having one or more characteristic diffractions at the following angles (2 theta ± 0.2) and corresponding d-interplanar distances (angstroms ± 0.2):

[0159]

[0160]

[0161] compound 1 Crystalline form type J

[0162] novel compounds 1 Crystalline form type J can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.5, 5.7, 22.8, 23.1, and 24.5 (2 theta ± 0.2). In some embodiments, the compound1 Crystalline form type J can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles of 4.5, 5.7, 22.8, 23.1, and 24.5 (2 theta ± 0.2) and corresponding d-interplanar distances of 19.5, 15.4, 3.9, 3.8, and 3.6 (angstrom ± 0.2), respectively.

[0163] In some embodiments, compounds 1 Crystalline form type J is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0164]

[0165]

[0166] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0167]

[0168]

[0169] compound 1 Crystalline form type K

[0170] novel compounds 1 Crystalline form type K can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4 (2 theta ± 0.2). In some embodiments, the compound 1Crystalline form type K can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4, corresponding to corresponding d-interplanar distances (angstrom ± 0.2) of 19.2, 5.7, 5.7, 5.5, 3.8, and 3.3, respectively.

[0171] In some embodiments, compounds 1 Crystalline form type K is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0172]

[0173]

[0174] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0175]

[0176]

[0177] compound 1 Crystalline form type L

[0178] novel compounds 1 Crystalline form type L can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1 (2 theta ± 0.2). In some embodiments, the compound 1Crystalline form type L can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1, corresponding to d-interplanar distances (angstrom ± 0.2) of 14.9, 7.5, 5.0, 4.1, 3.7, and 2.5, respectively.

[0179] In some embodiments, compounds 1 Crystalline form type L is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0180]

[0181]

[0182] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0183]

[0184]

[0185] compound 1 Crystalline form type M

[0186] novel compounds 1 Crystalline form type M can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractions at angles of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7 (2 theta ± 0.2). In some embodiments, the compound 1Crystalline form type M can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 theta ± 0.2) of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7, corresponding to d-interplanar distances (angstrom ± 0.2) of 19.5, 15.3, 9.1, 5.7, 4.1, and 3.3, respectively.

[0187] In some embodiments, compounds 1 Crystalline form type M is characterized by X-ray powder diffraction having one or more characteristic diffractions at the following angles (2 theta ± 0.2):

[0188]

[0189]

[0190] In some embodiments, compounds 1 Crystalline form type 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-interplanar distances (ANGS±0.2):

[0191]

[0192]

[0193] compound 1 Pharmaceutical composition including a crystalline form

[0194] In some embodiments, the present disclosure provides a therapeutically effective amount of the compound as discussed above. 1 The present disclosure provides a pharmaceutical composition comprising any crystalline solid form of (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 therapeutically effective amount of the compound as discussed above. 1The present disclosure provides a pharmaceutical composition comprising any crystalline solid form 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, or Type M) and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound as discussed above. 1 The present disclosure provides a pharmaceutical composition comprising any crystalline solid form of (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 compound as discussed above. 1 The present invention provides a pharmaceutical composition comprising any crystalline solid form 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, or Type M) and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration.

[0195] In some embodiments, the present disclosure relates to compounds such as those discussed above. 1 The present disclosure provides a pharmaceutical composition comprising any crystalline solid form (Type A, Type B, Type C, Type D, Type E, Type F, or Type G) and having a moisture content of about 0.5 to 5.0 weight%, preferably about 1.0 to 4.5 weight%, more preferably about 1.5 to 4.0 weight%, even more preferably about 2.0 to 3.5 weight%, and even more preferably about 2.5 to 3.0 weight% with respect to the weight of the pharmaceutical composition. In some embodiments, the present disclosure provides a compound as discussed above. 1The present disclosure provides a pharmaceutical composition comprising any crystalline solid form (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 moisture content of about 0.5 to 5.0 weight%, preferably about 1.0 to 4.5 weight%, more preferably about 1.5 to 4.0 weight%, even more preferably about 2.0 to 3.5 weight%, and even more preferably about 2.5 to 3.0 weight% with respect to the weight of the pharmaceutical composition. In some embodiments, the present disclosure provides a compound as discussed above. 1 The present disclosure provides a pharmaceutical composition comprising any crystalline solid form (Type A, Type B, Type C, Type D, Type E, Type F, or Type G) and having a moisture content selected from the following ranges with respect to the weight of the pharmaceutical composition: about 0.5 to 1.0 wt%, about 1.0 to 1.5 wt%, about 1.5 to 2.0 wt%, about 2.5 to 3.0 wt%, about 3.0 to 3.5 wt%, about 3.5 to 4.0 wt%, about 4.0 to 4.5 wt%, and about 4.5 to 5.0 wt%. In some embodiments, the present disclosure provides a compound as discussed above. 1 The present disclosure provides a pharmaceutical composition comprising any crystalline solid form (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 moisture content selected from the following ranges with respect to the weight of the pharmaceutical composition: about 0.5 to 1.0 wt%, about 1.0 to 1.5 wt%, about 1.5 to 2.0 wt%, about 2.5 to 3.0 wt%, about 3.0 to 3.5 wt%, about 3.5 to 4.0 wt%, about 4.0 to 4.5 wt%, and about 4.5 to 5.0 wt%. In some embodiments, the present disclosure provides a compound as discussed above.1 The present disclosure provides a pharmaceutical composition comprising any crystalline solid form (Type A, Type B, Type C, Type D, Type E, Type F, or Type G) and having a moisture content selected from the following weight percentages with respect to the weight of the pharmaceutical composition: about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, and about 5.0 wt%. In some embodiments, the present disclosure provides a compound as discussed above. 1 The present invention provides a pharmaceutical composition comprising any crystalline solid form (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 moisture content selected from the following weight percentages with respect to the weight of the pharmaceutical composition: about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, and about 5.0 wt%.

[0196] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1 in its crystalline form type A and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound 1 A pharmaceutical composition is provided comprising a crystalline form type A and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition comprises a compound 1 There are substantially no other crystalline forms of it. In some embodiments, the pharmaceutical composition contains an amorphous compound 1 There is practically no such thing.

[0197] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1 in a crystalline form of type B and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound 1 The present invention provides a pharmaceutical composition comprising a crystalline form type B and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition comprises a compound 1 There are substantially no other crystalline forms of it. In some embodiments, the pharmaceutical composition contains an amorphous compound 1 There is practically no such thing.

[0198] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1 in a crystalline form of type C and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound 1 The present invention provides a pharmaceutical composition comprising a crystalline form type C and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition comprises a compound 1 There are substantially no other crystalline forms of it. In some embodiments, the pharmaceutical composition contains an amorphous compound 1 There is practically no such thing.

[0199] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1 in a crystalline form of type D and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound 1 The present invention provides a pharmaceutical composition comprising a crystalline form type D and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition comprises a compound 1There are substantially no other crystalline forms of it. In some embodiments, the pharmaceutical composition contains an amorphous compound 1 There is practically no such thing.

[0200] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1 in its crystalline form type E, and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound 1 The present invention provides a pharmaceutical composition comprising a crystalline form type E and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition comprises a compound 1 There are substantially no other crystalline forms of it. In some embodiments, the pharmaceutical composition contains an amorphous compound 1 There is practically no such thing.

[0201] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1 in a crystalline form of type F and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound 1 The present invention provides a pharmaceutical composition comprising a crystalline form type F and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition comprises a compound 1 There are substantially no other crystalline forms of it. In some embodiments, the pharmaceutical composition contains an amorphous compound 1 There is practically no such thing.

[0202] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1 in a crystalline form of type G and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides a compound 1The present invention provides a pharmaceutical composition comprising a crystalline form type G and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition comprises a compound 1 There are substantially no other crystalline forms of it. In some embodiments, the pharmaceutical composition contains an amorphous compound 1 There is practically no such thing.

[0203] In some embodiments, the present disclosure is a compound 1 The present invention provides a pharmaceutical composition comprising a crystalline form of. In some embodiments, the pharmaceutical composition comprises a compound 1 Crystalline forms and compounds 1 Compound 1 comprises an amorphous form, 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, compound 1 Pharmaceutical compositions containing the crystalline form of amorphous compounds 1 There is practically no such thing.

[0204] In some embodiments, the present disclosure is a compound 1 and its enantiomers ("compounds 2" The present invention provides a pharmaceutical composition comprising ). In some embodiments, the pharmaceutical composition comprises a compound 1 and its enantiomer compounds 2 Includes, but is a compound 1...is having an excess amount of a remanent image isomer 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 a compound 1 and its enantiomer compounds 2 Includes, but is a compound 1 and compounds 2 Compound relative to the total weight of 1 The weight percentage of 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%.

[0205] The pharmaceutical compositions described herein may comprise a pharmaceutically acceptable carrier or one or more excipients. In some embodiments, the pharmaceutical compositions described herein may be provided in a unit-dose form container (e.g., a vial or bag or otherwise). In some embodiments, the pharmaceutical compositions described herein may be provided in an oral administration form. In some embodiments, the oral administration form is a tablet.

[0206] compound 1 Amorphous solid dispersion including

[0207] The present disclosure also covers the following compounds 1 :

[0208]

[0209] The present invention provides an amorphous solid dispersion comprising a polymer. In some embodiments, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene It is selected from the group consisting of glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS) (including any grade thereof (e.g., HPMC AS MG)).

[0210] Various amounts of compounds 1 and polymers can be used in amorphous solid dispersions. In some embodiments, compounds in the amorphous solid dispersion 1The weight ratio of polymer to polymer may 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 compound in the amorphous solid dispersion 1 The weight ratio of polymer to compound is in the range of about 3:1 to about 1:3. In some embodiments, the compound in the amorphous solid dispersion 1 The weight ratio of polymer to compound is in the range of about 2:1 to about 1:3. In some embodiments, the compound in the amorphous solid dispersion 1 The weight ratio of polymer to compound is about 1:3. In some embodiments, the compound in the amorphous solid dispersion 1 The weight ratio of the polymer to the compound is about 1:1. In some embodiments, the compound in the amorphous solid dispersion 1 The weight ratio of polymer 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 compound in the amorphous solid dispersion 1 The weight ratio of the polymer to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, or about 2:1.

[0211] In some embodiments, the amorphous solid dispersion contains a crystalline compound 1 There is none or substantially none. In some embodiments, crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion. In some embodiments, crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion. In some embodiments, there is no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis of the amorphous solid dispersion (Method B).

[0212] In some embodiments, the amorphous solid dispersion is a crystalline compound over time in accelerated stability studies. 1 It is physically stable in that it remains absent or substantially absent. In some embodiments, crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a container as described in Example 20 for 5 months at 2 to 8°C and ambient relative humidity, 5 months at 25°C and 60% relative humidity, 1 month at 2 to 8°C and ambient relative humidity, 1 month at 25°C and 60% relative humidity, or 1 month at 40°C and 75% relative humidity. In some embodiments, there is no melt endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis (Method B) of the amorphous solid dispersion after storage in a container as described in Example 20 for 5 months at 2 to 8°C and ambient relative humidity, 5 months at 25°C and 60% relative humidity, 1 month at 2 to 8°C and ambient relative humidity, 1 month at 25°C and 60% relative humidity, or 1 month at 40°C and 75% relative humidity. In some embodiments, crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a sealed vial at 60°C for 1 week, storage in a sealed vial at 60°C for 2 weeks, storage in an unsealed vial at 25°C and 60% relative humidity for 1 week, storage in an unsealed vial at 25°C and 60% relative humidity for 2 weeks, storage in an unsealed vial at 40°C and 75% relative humidity for 1 week, storage in an unsealed vial at 60°C and 75% relative humidity for 1 week, or storage in an unsealed vial at 60°C and 75% relative humidity for 2 weeks. In some embodiments, there is no melt endothermic and a single glass transition temperature (T G) can be observed by DSC analysis of the amorphous solid dispersion (Method B) after storage in a sealed vial at 60°C for 1 week, storage in a sealed vial at 60°C for 2 weeks, storage in an unsealed vial at 25°C and 60% relative humidity for 1 week, storage in an unsealed vial at 25°C and 60% relative humidity for 2 weeks, storage in an unsealed vial at 40°C and 75% relative humidity for 1 week, storage in an unsealed vial at 40°C and 75% relative humidity for 2 weeks, storage in an unsealed vial at 60°C and 75% relative humidity for 1 week, or storage in an unsealed vial at 60°C and 75% relative humidity for 2 weeks.

[0213] In some embodiments, the amorphous solid dispersion is highly soluble, for example, a compound 1It dissolves rapidly and easily in biological media. In some embodiments, 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 after 30 minutes in the kinetic solubility test described in Example 23. In some embodiments, 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 the kinetic solubility test described in Example 23. 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 test 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 test described in Example 23.

[0214] compound 1 Pharmaceutical composition comprising an amorphous solid dispersion

[0215] The present disclosure concerns a therapeutically effective amount of a compound 1 The present invention further provides a pharmaceutical composition comprising an amorphous solid dispersion comprising and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is for oral administration.

[0216] In some embodiments, the present disclosure is a compound 1The present disclosure provides a pharmaceutical composition comprising an amorphous solid dispersion comprising, wherein the composition has a moisture content of about 0.5 to 5.0 weight%, preferably about 1.0 to 4.5 weight%, more preferably about 1.5 to 4.0 weight%, even more preferably about 2.0 to 3.5 weight%, and even more preferably about 2.5 to 3.0 weight% with respect to the weight of the pharmaceutical composition. In some embodiments, the present disclosure relates to a compound 1 The present disclosure provides a pharmaceutical composition comprising an amorphous solid dispersion comprising, wherein the composition has a moisture content selected from the following ranges with respect to the weight of the pharmaceutical composition: about 0.5 to 1.0 wt%, about 1.0 to 1.5 wt%, about 1.5 to 2.0 wt%, about 2.5 to 3.0 wt%, about 3.0 to 3.5 wt%, about 3.5 to 4.0 wt%, about 4.0 to 4.5 wt%, and about 4.5 to 5.0 wt%. In some embodiments, the present disclosure comprises a compound 1 A pharmaceutical composition is provided that comprises an amorphous solid dispersion and has a moisture content selected from the following weight percentages with respect to the weight of the pharmaceutical composition: about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, and about 5.0 wt%.

[0217] 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 a compound 1 It includes. In some embodiments, the pharmaceutical composition contains about 25 mg of a compound 1 It includes. In some embodiments, the pharmaceutical composition contains about 100 mg of a compound 1 It includes. In some embodiments, the pharmaceutical composition contains about 200 mg of a compound 1 Includes

[0218] The pharmaceutical compositions described herein may comprise a pharmaceutically acceptable carrier or one or more excipients. In some embodiments, the pharmaceutical compositions described herein may be provided in a unit dosage form container (e.g., a vial or bag or otherwise). 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.

[0219] In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients comprising one or more of a filler, a drying binder, a lubricant, 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 drying binder, and the drying binder comprises crospovidone. In some embodiments, one or more pharmaceutically acceptable excipients comprise a lubricant, and the lubricant 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 sodium croscarmellose. In some embodiments, one or more pharmaceutically acceptable excipients include a lubricant, and the lubricant includes magnesium stearate.

[0220] 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 combined with the intragranular portion. In some embodiments, the pharmaceutical composition further comprises a coating disposed on the tablet core.

[0221] Various amounts of compounds regarding the purification core 1 This compound 1 It can be used in pharmaceutical compositions comprising an amorphous solid dispersion containing. In some embodiments, the compound 1 The amorphous solid dispersion comprising may be about 10 wt%, about 20 wt%, about 30 wt%, about 40 wt%, about 50 wt%, about 60 wt%, about 70 wt%, about 80 wt%, or about 90 wt% of the tablet core. In some embodiments, the compound 1 The amorphous solid dispersion comprising is at least about 30 weight percent of the tablet core. In some embodiments, the compound 1 The amorphous solid dispersion comprising is at least about 50 weight percent of the tablet core. In some embodiments, the compound 1 The amorphous solid dispersion comprising is at least about 60 weight percent of the tablet core. In some embodiments, the compound 1 The amorphous solid dispersion containing is about 50 weight percent of the tablet core. In some embodiments, the compound 1 The amorphous solid dispersion comprising is about 50 to about 70 weight percent of the tablet core. In some embodiments, the compound 1 The amorphous solid dispersion containing is about 60 to about 65 weight percent of the tablet core.

[0222] In some embodiments, the granule portion further comprises one or more of a filler, a drying binder, a lubricant, and a lubricant. In some embodiments, the granule portion further comprises one or more of a filler, a disintegrant, and a lubricant.

[0223] In some embodiments, the tablet core has the following components:

[0224]

[0225] In some embodiments, the tablet core has the following components:

[0226]

[0227] In some embodiments, the tablet core has the following components:

[0228]

[0229] In some embodiments, the tablet core has the following components:

[0230]

[0231] In some embodiments, the oral unit dosage form of Compound 1 may be a tablet containing a total of about 10 to 35 weight percent 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, a tablet having the composition described in the table above comprises about 50% API formed as an amorphous solid dispersion of Compound 1 obtained from the 1:3 SDD process described in the following examples (e.g., about 12.5% ​​of Compound 1 in the tablet). In one embodiment, a tablet having the composition described in the table above comprises about 30% API formed as an amorphous solid dispersion of Compound 1 obtained from the 1:1 SDD process described in the following examples (e.g., about 15% of Compound 1 in the tablet, total about 100 mg of Compound 1 in the tablet). In one embodiment, a tablet having the composition described in the table above comprises about 62% API formed as an amorphous solid dispersion of Compound 1 obtained from a 1:1 SDD process described in the following examples (e.g., about 31% of Compound 1 in the tablet, a total of about 200 mg of Compound 1 in the tablet).

[0232] compound 1 Method for preparing an amorphous solid dispersion

[0233] The present disclosure also covers the following compounds 1 A method for preparing an amorphous solid dispersion comprising:

[0234]

[0235] In some embodiments, the method comprises a compound 1 , a step of mixing a polymer and a solvent to provide a mixture, and spray-drying the mixture to form a compound 1 It includes the step of providing an amorphous solid dispersion comprising

[0236] In some embodiments, the polymer used in the method is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl caprolactam-polyvinyl It is selected from the group consisting of acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS) (including any grade thereof (e.g., HPMC AS MG)).

[0237] Various amounts of compounds 1 and polymers can be used in a method for preparing an amorphous solid dispersion. In some embodiments, compounds used in a method for preparing a crystalline solid dispersion 1 The weight ratio of polymer to polymer may 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 compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer to polymer is in the range of about 3:1 to about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer to polymer is in the range of about 2:1 to about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the compound is about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the compound is about 1:1. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer 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 compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, or about 2:1.

[0238] Various solvents can be used in the method for preparing an amorphous solid dispersion. In some embodiments, the solvents are dichloromethane and methanol.

[0239] The present disclosure also covers compounds 1, a step of mixing a polymer and a solvent to provide a mixture, and spray-drying the mixture to form a compound 1 A product prepared by a method comprising the step of providing an amorphous solid dispersion comprising:

[0240]

[0241] In some embodiments, the polymer used in the method is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl caprolactam-polyvinyl It is selected from the group consisting of acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS) (including any grade thereof (e.g., HPMC AS MG)).

[0242] Various amounts of compounds 1 and polymers can be used in a method for preparing an amorphous solid dispersion. In some embodiments, compounds used in a method for preparing an amorphous solid dispersion1 The weight ratio of polymer to polymer may 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 compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer to polymer is in the range of about 3:1 to about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer to amorphous solid dispersion is in the range of about 2:1 to about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the compound is about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the compound is about 1:1. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer 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 compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, or about 2:1.

[0243] Various solvents can be used in the method for preparing an amorphous solid dispersion. In some embodiments, the solvents are dichloromethane and methanol.

[0244] compound 1 A pharmaceutical composition comprising

[0245] The present disclosure describes the following compound obtained by the following method. 1 Provides a pharmaceutical composition comprising:

[0246] ,

[0247] The above method is a compound in solid form. 1 , a step of mixing a polymer and a solvent to provide a mixture, and spray-drying the mixture to form a compound 1 It includes the step of providing an amorphous solid dispersion comprising

[0248] In some embodiments, the solid form is a compound 1 It is type A of. In some embodiments, the solid form is a compound 1 It is type B. In some embodiments, the solid form is a compound 1 It is type C of. In some embodiments, the solid form is a compound 1 It is type D of. In some embodiments, the solid form is a compound 1 It is type E. In some embodiments, the solid form is a compound 1 It is type F of. In some embodiments, the solid form is a compound 1 It is type G of. In some embodiments, the solid form is a compound 1 Type H. In some embodiments, the solid form is a compound 1 It is Type I. In some embodiments, the solid form is a compound 1 It is type J of. In some embodiments, the solid form is a compound 1 It is of type K. In some embodiments, the solid form is a compound 1 It is type L of. In some embodiments, the solid form is a compound 1 It is type M of. In some embodiments, the solid form is a compound 1 It 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. In some embodiments, the solid form is a compound 1 It is an amorphous form.

[0249] In some embodiments, the pharmaceutical composition obtained by the above method has a moisture content of about 0.5 to 5.0 wt%, preferably about 1.0 to 4.5 wt%, more preferably about 1.5 to 4.0 wt%, even more preferably about 2.0 to 3.5 wt%, and even more preferably about 2.5 to 3.0 wt% with respect to the weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition obtained by the above method has a moisture content selected from the following ranges with respect to the weight of the pharmaceutical composition: about 0.5 to 1.0 wt%, about 1.0 to 1.5 wt%, about 1.5 to 2.0 wt%, about 2.5 to 3.0 wt%, about 3.0 to 3.5 wt%, about 3.5 to 4.0 wt%, about 4.0 to 4.5 wt%, and about 4.5 to 5.0 wt%. In some embodiments, the pharmaceutical composition obtained by the above method has a moisture content selected from the following weight percentages with respect to the weight of the pharmaceutical composition: about 0.5 wt%, about 1.0 wt%, about 1.5 wt%, about 2.0 wt%, about 2.5 wt%, about 3.0 wt%, about 3.5 wt%, about 4.0 wt%, about 4.5 wt%, and about 5.0 wt%.

[0250] In some embodiments, the polymer used in the method is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl caprolactam-polyvinyl It is selected from the group consisting of acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS) (including any grade thereof (e.g., HPMC AS MG)).

[0251] Various amounts of compounds 1 and polymers can be used in a method for preparing an amorphous solid dispersion. In some embodiments, compounds used in a method for preparing an amorphous solid dispersion 1The weight ratio of polymer to polymer may 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 compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer to polymer is in the range of about 3:1 to about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer to amorphous solid dispersion is in the range of about 2:1 to about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the compound is about 1:3. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the compound is about 1:1. In some embodiments, the compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of polymer 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 compound used in the method for preparing an amorphous solid dispersion. 1 The weight ratio of the polymer to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, or about 2:1.

[0252] Various solvents can be used in the method for preparing an amorphous solid dispersion. In some embodiments, the solvents are dichloromethane and methanol.

[0253] compound 1 of Solid oral administration form

[0254] The present disclosure also covers compounds 1The present invention provides solid oral dosage forms, e.g., tablets and capsules. In some embodiments, the solid oral dosage form comprises a stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one, wherein the stabilized amorphous compound does not exhibit crystallinity by PXRD (Method D) after storage for 2 weeks at 60°C / 75% RH (exposed). In some embodiments, the stabilized amorphous compound exhibits no melting endothermic and a single glass transition temperature (T) by DSC (Method B) after storage for 2 weeks at 60°C / 75% RH (exposed). G It represents ).

[0255] 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]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one. In some embodiments, the solid dosage form has a total weight of 700 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg or less. In some embodiments, the solid oral dosage form is a tablet or a capsule.

[0256] In some embodiments, the stabilized amorphous compound in the form of a solid oral dose exists as a spray-dried dispersion using a polymer. In some embodiments, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene It is selected from the group consisting of glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is HPMC AS. In some embodiments, (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one is spray-dried with HPMC AS in a weight ratio of 1:3 to 2:1. In some embodiments, (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one is spray-dried with HPMC AS in a weight ratio of 1:1.

[0257] The present disclosure also relates to a (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one active pharmaceutical ingredient (API) composition comprising 0.05 to 5.0% of (R)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one as determined by HPLC.

[0258] The present disclosure also relates to a tablet comprising about 100 mg or about 200 mg of a stabilized amorphous compound, (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one, as an active pharmaceutical ingredient (API), wherein the stabilized amorphous compound does not exhibit crystallinity by PXRD (Method D) after 2 weeks of storage of the tablet at 60°C / 75% RH (exposed). In some embodiments, the API comprises less than 5.0% of (R)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one by HPLC. In some embodiments, the API comprises less than 0.05% of (R)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-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.

[0259] compound 1 Tablet dosage form

[0260] The present disclosure also covers compounds 1 A tablet dosage form is provided. In some embodiments, the tablet dosage form comprises a tablet core, and the tablet core comprises at least 10 weight percent of a compound 1 in an amorphous form:

[0261]

[0262] Here, crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D). In some embodiments, the tablet core comprises at least 15 wt%, at least 20 wt%, at least 25 wt%, or at least 30 wt% of compound 1 in an amorphous form. In some embodiments, the tablet core comprises about 200 mg of compound 1 per tablet and has a total weight of about 1200 mg, about 1100 mg, about 1000 mg, about 900 mg, about 800 mg, or about 700 mg or less per tablet.

[0263] In some embodiments, the tablet dosage form comprises a tablet core, the tablet core having a total weight of about 1000 mg or less and containing about 200 mg of amorphous form of compound 1 per tablet, wherein crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D). In some embodiments, the tablet core has a total weight of about 800 mg or less per tablet.

[0264] In some embodiments, the purification core is a highly pure enantiomer of a compound 1 Includes. In some embodiments, the tablet core comprises 0.05 to 5.0% of Compound 2 based on the total amount of Compound 1 and Compound 2:

[0265]

[0266] In some embodiments, the tablet core comprises 0.05 to 3.0% of compound 2 based on the total amount of compound 1 and compound 2. In some embodiments, the tablet core comprises 0.05 to 2.0% of compound 2 based on the total amount of compound 1 and compound 2. In some embodiments, the tablet core comprises 0.05 to 1.0% of compound 2 based on the total amount of compound 1 and compound 2.

[0267] In some embodiments, the tablet dosage form is a crystalline compound over time in an accelerated stability study. 1 It is physically stable in that it remains without or substantially without. In some embodiments, crystalline compound 1 (Type A) is not observable by XRPD analysis of the purified core (Method D) after storage in a sealed container as described in Example 29 for 1 month at 25°C and 60% relative humidity, storage in a sealed container as described in Example 29 for 2 months at 25°C and 60% relative humidity, storage in a sealed container as described in Example 29 for 3 months at 25°C and 60% relative humidity, storage in a sealed container as described in Example 29 for 1 month at 40°C and 75% relative humidity, storage in a sealed container as described in Example 29 for 2 months at 40°C and 75% relative humidity, and storage in a sealed container as described in Example 29 for 3 months at 40°C and 75% relative humidity.

[0268] In some embodiments, compound 1 exists as an amorphous solid dispersion comprising compound 1 and a polymer. In some embodiments, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene It is selected from the group consisting of glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof. In some embodiments, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS). In some embodiments, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS) (including any grade thereof (e.g., HPMC AS MG)).

[0269] In some embodiments, the weight ratio of one compound to the polymer is in the range of about 3:1 to about 1:3. In some embodiments, the weight ratio of one compound to the polymer is in the range of about 2:1 to about 1:3. In some embodiments, the weight ratio of one compound to the polymer is about 1:3. In some embodiments, the weight ratio of one compound to the polymer is about 1:1. In some embodiments, the weight ratio of one compound 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 one compound to the polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, or about 2:1.

[0270] In some embodiments, the tablet core in 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 fillers, drying binders, lubricants, lubricants, disintegrants, and film coating agents.

[0271] In some embodiments, the tablet core comprises an intragranular portion comprising compound 1; and an extragranular portion combined 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 drying binder, a lubricant, 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,

[0272] An amorphous solid dispersion of Compound 1 in an amount of 30 to 70 weight percent of the purified core;

[0273] One or more fillers in an amount of 15 to 50 weight percent of the tablet core;

[0274] One or more dry binders in an amount of 2.50-10 weight% of the tablet core;

[0275] One or more lubricants in an amount of 0.50 to 1.50 weight% of the tablet core; and

[0276] It comprises one or more lubricants in an amount of 0.25 to 1 weight percent of the refined core; and

[0277] The part other than the granules,

[0278] One or more fillers in an amount of 5 to 15 weight percent of the tablet core;

[0279] One or more disintegrants in an amount of 1.25 to 5 weight percent of the tablet core; and

[0280] It contains one or more types of lubricants in an amount of 0.25 to 1 weight percent of the refined core.

[0281] In some embodiments, the tablet dosage form is,

[0282] An amorphous solid dispersion of Compound 1 in an amount of 50 to 75 weight percent of the purified core;

[0283] One or more fillers in an amount of 15 to 50 weight percent of the tablet core;

[0284] One or more dry binders in an amount of 2 to 10 weight percent of the tablet core;

[0285] One or more lubricants in an amount of less than 2 weight percent of the tablet core;

[0286] One or more disintegrants in an amount of 2 to 10 weight percent of the tablet core; and

[0287] It contains one or more types of lubricants in an amount of less than 2 weight percent of the refined core.

[0288] In some embodiments, the amorphous solid dispersion comprises compound 1 and a polymer (as described in any of the embodiments presented 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 polyvinylpyrrolidone. In some embodiments, one or more lubricants comprise colloidal silicon dioxide or fuming silica. In some embodiments, one or more lubricants comprise magnesium stearate. In some embodiments, one or more disintegrants comprise sodium croscarmellose.

[0289] Medical uses of solid forms and pharmaceutical compositions

[0290] In some embodiments, the present disclosure relates to a method for treating a disease associated with reduced activity of PKR in a subject requiring such treatment, comprising the step of administering to the subject an effective amount of a compound of Formula I in any of the forms described herein (including any embodiments).

[0291] embodiments

[0292] In some embodiments, the present disclosure relates to one or more of the embodiments listed below:

[0293] 1. Crystalline solid form of Compound 1 below:

[0294]

[0295] 2. In the crystalline solid form of Example 1, the crystalline solid form is type A of (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one ("Compound 1").

[0296] 3. In the crystalline solid form of embodiment 1 or 2, type A of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 4.61, 15.66, 23.19, and 24.76 (2 theta ± 0.2).

[0297] 4. In any one of embodiments 1 to 3, the crystalline solid form of compound 1 type A is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.61, 15.66, 23.19, and 24.76 corresponding to d-interplanar distances (angstrom ± 0.2) of 19.19, 5.66, 3.84, and 3.60.

[0298] 5. In any one of embodiments 1 to 4, the crystalline solid form of compound 1 type A is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.61, 7.22, 15.66, 20.48, 21.35, 21.66, 22.47, 23.19, 24.76, and 26.73.

[0299] 6. In any one of embodiments 1 to 5, the crystalline solid form of compound 1 type A is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0300] 7. In any one of embodiments 1 to 6, the crystalline solid form of compound 1 type A is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0301]

[0302] 8. In any one of embodiments 1 to 7, type A of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0303]

[0304] 9. In any one of embodiments 1 to 8, the crystalline solid form of compound 1 type A is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.9% up to 100°C.

[0305] 10. In any one of embodiments 1 to 9, the crystalline solid form of compound 1 type A is characterized by differential scanning heat (DSC) endothermy having a peak temperature of about 85.9°C and an onset temperature of about 146.0°C.

[0306] 11. In any one of embodiments 1 to 10, the crystalline solid form of compound 1 type A is characterized by dynamic vapor adsorption (DVS) of about 3.4% by weight of moisture absorption up to 40% relative humidity.

[0307] 12. In any one of embodiments 1 to 11, the crystalline solid form of compound 1 type A is characterized by dynamic vapor adsorption (DVS) of about 1.0% by weight of moisture absorption at a relative humidity of 40% to 80%.

[0308] 13. In the crystalline solid form of Embodiment 1, the crystalline solid form is Type B of Compound 1.

[0309] 14. In the crystalline solid form of either embodiment 1 or 13, type B of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13.

[0310] 15. In any one of the crystalline solid forms of embodiments 1 and 13 to 14, type B of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.52, 15.57, 22.89, 23.34, and 25.13, corresponding to d-planar distances (angstrom ± 0.2) of 19.53, 5.69, 3.89, 3.81, and 3.54, respectively.

[0311] 16. In any one of the crystalline solid forms of embodiments 1 and 13 to 15, type B of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.52, 9.86, 15.57, 19.93, 22.19, 22.89, 23.34, 25.13, and 28.30.

[0312] 17. In any one of the crystalline solid forms of embodiments 1 and 13 to 16, type B of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 0.2) of 19.53, 8.97, 5.69, 4.45, 4.00, 3.89, 3.81, 3.54, and 3.15, respectively.

[0313] 18. In any one of the crystalline solid forms of Examples 1 and 13 to 17, Type B of Compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0314]

[0315] 19. In any one of the crystalline solid forms of embodiments 1 and 13 to 18, type B of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0316]

[0317]

[0318] 20. In any one of the crystalline solid forms of embodiments 1 and 13 to 19, type B of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.8% up to 100°C.

[0319] 21. In any one of the crystalline solid forms of embodiments 1 and 13 to 20, type B of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% up to 120°C.

[0320] 22. In any one of the crystalline solid forms of embodiments 1 and 13 to 21, type B of compound 1 is characterized by having differential scanning heat (DSC) endothermic having an onset temperature of about 138.2 to 139.2°C.

[0321] 23. In any one of the crystalline solid forms of embodiments 1 and 13 to 22, type B of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 2.9% by weight of moisture absorption up to 60% relative humidity.

[0322] 24. In any one of the crystalline solid forms of embodiments 1 and 13 to 23, type B of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 0.4% by weight of moisture absorption at a relative humidity of 60% to 80%.

[0323] 25. In the crystalline solid form of Example 1, the crystalline solid form is Type C of Compound 1.

[0324] 26. In the crystalline solid form of Example 1 or 25, Type C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 4.55, 18.85, 23.02, and 24.65 (2 theta ± 0.2).

[0325] 27. In any one of the embodiments 1 and 25 to 26, the crystalline solid form of compound 1 type C is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.55, 18.85, 23.02, and 24.65, corresponding to d-planar distances (angstrom ± 0.2) of 19.43, 4.71, 3.86, and 3.61, respectively.

[0326] 28. In any one of the embodiments 1 and 25 to 27, the type C of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.55, 7.34, 9.07, 11.17, 18.34, 18.85, 19.57, 21.66, 23.02, and 24.65.

[0327] 29. In any one of the embodiments 1 and 25 to 28, the type C of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0328] 30. In any one of the crystalline solid forms of Examples 1 and 25 to 29, Type C of Compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0329]

[0330]

[0331] 31. In any one of the crystalline solid forms of Examples 1 and 25 to 30, Type C of Compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0332]

[0333] 32. In any one of the crystalline solid forms of embodiments 1 and 25 to 31, type C of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.0% at a maximum of 100°C.

[0334] 33. In any one of the crystalline solid forms of embodiments 1 and 25 to 32, type C of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% up to 130°C.

[0335] 34. In any one of the crystalline solid forms of embodiments 1 and 25 to 33, type C of compound 1 is characterized by having differential scanning heat (DSC) endothermic having an onset temperature of about 152.2 to 154.2°C.

[0336] 35. In any one of the crystalline solid forms of embodiments 1 and 25 to 34, type C of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 1.8% by weight of moisture absorption up to 60% relative humidity.

[0337] 36. In any one of the crystalline solid forms of embodiments 1 and 25 to 35, type C of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 0.5% by weight of moisture absorption at 60% to 80% relative humidity.

[0338] 37. In the crystalline solid form of Embodiment 1, the crystalline solid form is Type D of Compound 1.

[0339] 38. In the crystalline solid form of embodiment 1 or 37, type D of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 9.72, 13.08, 15.74, 21.90, and 23.59.

[0340] 39. In any one of the embodiments 1 and 37 to 38, the type D of compound 1 is characterized by an XRPD pattern having diffraction at angles of 9.72, 13.08, 15.74, 21.90, and 23.59 (2 theta ± 0.2), and corresponding d-planar distances of 9.10, 6.77, 5.63, 4.06, and 3.77 (angstrom ± 0.2), respectively.

[0341] 40. In any one of the embodiments 1 and 37 to 39, the type D of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0342] 41. In any one of the crystalline solid forms of Embodiments 1 and 37 to 40, Type D of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0343] 42. In the crystalline solid form of any one of Embodiments 1 and 37 to 41, Type D of Compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0344]

[0345] 43. In the crystalline solid form of any one of Embodiments 1 and 37 to 42, Type D of Compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2) and the corresponding d-interplanar distance (angstrom ± 0.2):

[0346]

[0347] 44. In any one of the crystalline solid forms of Examples 1 and 37 to 43, Type D of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 9.6% up to 130°C.

[0348] 45. In any one of the crystalline solid forms of Embodiments 1 and 37 to 44, Type D of Compound 1 is characterized by having a differential scanning heat (DSC) endothermic having an onset temperature of about 91.9°C.

[0349] 46. ​​In the crystalline solid form of Example 1, the crystalline solid form is Type E of Compound 1.

[0350] 47. In the crystalline solid form of embodiment 1 or 46, type E of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72.

[0351] 48. In any one of the crystalline solid forms of embodiment 1 and 46 to 47, type E of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 15.12, 15.75, 17.48, 20.05, 21.93, and 26.72, corresponding to d-planar distances (angstrom ± 0.2) of 5.86, 5.63, 5.07, 4.43, 4.05, and 3.34, respectively.

[0352] 49. In any one of the embodiments 1 and 46 to 48, the type E of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.59, 15.12, 15.75, 17.48, 20.05, 21.93, 23.18, 23.70, and 26.72.

[0353] 50. In the crystalline solid form of any one of embodiments 1 and 46 to 49, type E of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 0.2) of 19.27, 5.86, 5.63, 5.07, 4.43, 4.05, 3.84, 3.75, and 3.34, respectively.

[0354] 51. In any one of the embodiments 1 and 46 to 50, the type E of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0355] 52. In the crystalline solid form of any one of Embodiments 1 and 46 to 51, type E of Compound 1 corresponds to d-interplanar distances (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, 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, 23.7091, 4.67, 4.43, 4.05, 3.84, 3.75, 3.34, and 3.21, respectively. It features an XRPD pattern having diffraction at angles of 26.72 and 27.81 (2 theta ± 0.2).

[0356] 53. In the crystalline solid form of any one of Embodiments 1 and 46 to 52, Type E of Compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0357]

[0358]

[0359] 54. In the crystalline solid form of any one of Embodiments 1 and 46 to 53, Type E of Compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0360]

[0361]

[0362] 55. In the crystalline solid form of Example 1, the crystalline solid form is Type F of Compound 1.

[0363] 56. In the crystalline solid form of Example 1 or 55, Type F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45.

[0364] 57. In any one of the embodiments 1 and 55 to 56, the type F of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.45, 14.66, 16.00, 16.79, 20.01, 21.36, and 22.45, corresponding to d-planar distances (angstrom ± 0.2) of 16.23, 6.04, 5.54, 5.28, 4.44, 4.16, and 3.96, respectively.

[0365] 58. In any one of the crystalline solid forms of Embodiments 1 and 55 to 57, Type F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.45, 14.66, 16.00, 16.79, 18.99, 20.01, 21.36, 22.45, 23.25, and 25.32.

[0366] 59. In any one of the embodiments 1 and 55 to 58, the type F of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0367] 60. In any one of the embodiments 1 and 55 to 59, the type F of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0368] 61. In the crystalline solid form of any one of Embodiments 1 and 55 to 60, Type F of Compound 1 corresponds to d-interplanar distances (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, 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, 20.01, 20.57, 21.36, 22.45, 23.25, 25.32, 20.01, 20.57, 21.36, 22.45, 23.25, 25.32, 20.32, 20.57, 22.45, 23.25, 255.32, 20.57, 20.57, 20.57, 20.57, 20.57, 20.57 It features an XRPD pattern having diffraction at angles of 26.57, 27.25, 27.97, and 30.02 (2 theta ± 0.2).

[0369] 62. In any one of the crystalline solid forms of Embodiments 1 and 55 to 61, Type F of Compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0370]

[0371]

[0372] 63. In any one of the crystalline solid forms of Embodiments 1 and 55 to 62, Type F of Compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0373]

[0374] 64. In any one of the crystalline solid forms of Embodiments 1 and 55 to 63, Type F of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 6.2% up to 120°C.

[0375] 65. In any one of the crystalline solid forms of Embodiments 1 and 55 to 64, Type F of Compound 1 is characterized by differential scanning heat (DSC) endothermic having a peak temperature of about 100.4°C and an onset temperature of 125.9°C.

[0376] 66. In the crystalline solid form of Example 1, the crystalline solid form is Type G of Compound 1.

[0377] 67. In the crystalline solid form of embodiment 1 or 66, type G of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 5.36, 14.34, 16.58, and 21.35 (2 theta ± 0.2).

[0378] 68. In any one of the crystalline solid forms of Embodiments 1 and 66 to 67, Type G of Compound 1 is characterized by XRPD patterns having diffraction at angles (2 theta ± 0.2) of 5.36, 14.34, 16.58, and 21.35, corresponding to d-planar distances (angstrom ± 0.2) of 16.48, 6.18, 5.35, and 4.16, respectively.

[0379] 69. In any one of the embodiments 1 and 66 to 68, the type G of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of f 5.36, 12.83, 14.34, 15.00, 16.58, 19.78, 21.35, 22.35, 25.33, and 26.43.

[0380] 70. In the crystalline solid form of any one of embodiments 1 and 66 to 69, type G of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0381] 71. In any one of the embodiments 1 and 66 to 70, the type G of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0382] 72. In the crystalline solid form of any one of Embodiments 1 and 66 to 71, Type G of Compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0383] 73. In the crystalline solid form of any one of Embodiments 1 and 66 to 72, Type G of Compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0384]

[0385] 74. In any one of the crystalline solid forms of Embodiments 1 and 66 to 73, Type G of Compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0386]

[0387]

[0388] 75. A pharmaceutical composition comprising a therapeutically effective amount of any one of embodiments 1 to 74 in a crystalline solid form, and one or more pharmaceutically acceptable excipients.

[0389] 76. In the pharmaceutical composition of embodiment 75, the pharmaceutical composition is for oral administration.

[0390] 77. In the pharmaceutical composition of embodiment 75 or 76, the pharmaceutical composition has a moisture content of about 0.5 to 5.0 weight%.

[0391] 78. In any one of embodiments 75 to 77, the pharmaceutical composition has a moisture content of about 1.5 to 4.0 weight%.

[0392] 79. In any one of embodiments 75 to 78, the pharmaceutical composition has a moisture content of about 2.5 to 3.0 weight%.

[0393] 80. The following compound 1:

[0394]

[0395] an amorphous solid dispersion comprising a polymer.

[0396] 81. In the amorphous solid dispersion of Example 80, the polymer is selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof.

[0397] 82. In the amorphous solid dispersion of Example 80 or 81, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0398] 83. In any one of the embodiments 80 to 82, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3.

[0399] 84. In any one of the amorphous solid dispersions of embodiments 80 to 83, the weight ratio of compound to polymer is about 1:3.

[0400] 85. A pharmaceutical composition comprising a therapeutically effective amount of any one of embodiments 80 to 84 of an amorphous solid dispersion and one or more pharmaceutically acceptable excipients.

[0401] 86. In the pharmaceutical composition of embodiment 85, the pharmaceutical composition is for oral administration.

[0402] 87. In the pharmaceutical composition of embodiment 85 or 86, the pharmaceutical composition is in the form of a tablet.

[0403] 88. In any one of embodiments 85 to 87, the pharmaceutical composition has a moisture content of about 0.5 to 5.0 weight%.

[0404] 89. In any one of embodiments 85 to 88, the pharmaceutical composition has a moisture content of about 1.5 to 4.0 weight%.

[0405] 90. In any one of embodiments 85 to 89, the pharmaceutical composition has a moisture content of about 2.5 to 3.0 weight%.

[0406] 91. In any one of embodiments 85 to 90, 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.

[0407] 92. In any one of embodiments 85 to 91, the pharmaceutical composition comprises about 25 mg of compound 1.

[0408] 93. In any one of embodiments 85 to 91, the pharmaceutical composition comprises about 100 mg of compound 1.

[0409] 94. In any one of embodiments 85 to 93, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, including one or more of fillers, drying binders, lubricants, lubricants, disintegrants, and film coating agents.

[0410] 95. In any one of embodiments 85 to 94, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, and the filler comprises microcrystalline cellulose.

[0411] 96. In any one of embodiments 85 to 95, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, and the dry binder comprises crospovidone.

[0412] 97. In any one of embodiments 85 to 96, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, wherein the lubricant comprises colloidal silicon dioxide.

[0413] 98. In any one of embodiments 85 to 97, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, wherein the lubricant comprises magnesium stearate.

[0414] 99. In any one of embodiments 85 to 98, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, wherein the disintegrant comprises croscarmellose sodium.

[0415] 100. In any one of embodiments 85 to 99, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, wherein the lubricant comprises magnesium stearate.

[0416] 101. Any one of embodiments 85 to 100 pharmaceutical composition comprises a tablet core, wherein the tablet core comprises the following:

[0417] A portion within the granules comprising an amorphous solid dispersion; and

[0418] The part inside the granules and the part outside the granules mixed together.

[0419] 102. The pharmaceutical composition of embodiment 101 further comprises a coating disposed on a tablet core.

[0420] 103. In the pharmaceutical composition of embodiment 101 or 102, the amorphous solid dispersion is about 50% by weight of the tablet core.

[0421] 104. In any one of embodiments 101 to 103, the pharmaceutical composition further comprises one or more of a filler, a drying binder, a lubricant, and a lubricant.

[0422] 105. In any one of embodiments 101 to 104, the non-granular portion further comprises one or more of a filler, a disintegrant, and a lubricant.

[0423] 106. A method for preparing an amorphous solid dispersion comprising the following compound 1:

[0424]

[0425] Includes the following steps:

[0426] A step of providing a mixture by mixing compound 1, a polymer, and a solvent; and

[0427] A step of spray-drying the mixture to provide an amorphous solid dispersion containing compound 1.

[0428] 107. In the method of Example 106, the polymer is selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof.

[0429] 108. In the method of embodiment 106 or 107, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0430] 109. In any one of the methods of embodiments 106 to 108, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3.

[0431] 110. In any one of the methods of embodiments 106 to 109, the weight ratio of compound to polymer is about 1:3.

[0432] 111. In any one of the methods of embodiments 106 to 110, the solvents are dichloromethane and methanol.

[0433] 112. A product manufactured by a method comprising the following:

[0434] A step of providing a mixture by mixing compound 1, a polymer, and a solvent; and

[0435] Step of spray-drying the mixture to provide an amorphous solid dispersion containing compound 1:

[0436] .

[0437] 113. In the product of Example 112, the polymer is selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof.

[0438] 114. In the product of Example 112 or 113, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0439] 115. In any one of the products of embodiments 112 to 114, the weight ratio of compound 1 to polymer is in the range of about 3:1 to about 1:3.

[0440] 116. In any one of the products of embodiments 112 to 115, the weight ratio of compound to polymer is about 1:3.

[0441] 117. In any one of the products of embodiments 112 to 116, the solvents are dichloromethane and methanol.

[0442] 118. A pharmaceutical composition comprising the following compound 1, obtained by a method comprising the following steps:

[0443]

[0444] A step of providing a mixture by mixing a compound 1 in solid form, a polymer, and a solvent; and

[0445] A step of spray-drying the mixture to provide an amorphous solid dispersion containing compound 1.

[0446] 119. In the pharmaceutical composition of embodiment 118, the solid form is type A of compound 1.

[0447] 120. In the pharmaceutical composition of embodiment 118, the solid form is type B of compound 1.

[0448] 121. In the pharmaceutical composition of embodiment 118, the solid form is type C of compound 1.

[0449] 122. In the pharmaceutical composition of embodiment 118, the solid form is type D of compound 1.

[0450] 123. In the pharmaceutical composition of embodiment 118, the solid form is type E of compound 1.

[0451] 124. In the pharmaceutical composition of embodiment 118, the solid form is type F of compound 1.

[0452] 125. In the pharmaceutical composition of embodiment 118, the solid form is type G of compound 1.

[0453] 126. In the pharmaceutical composition of embodiment 118, the solid form is the amorphous form of compound 1.

[0454] 127. In any one of embodiments 118 to 126, the pharmaceutical composition has a moisture content of about 0.5 to 5.0 weight%.

[0455] 128. In any one of embodiments 118 to 127, the pharmaceutical composition has a moisture content of about 1.5 to 4.0 weight%.

[0456] 129. In any one of embodiments 118 to 128, the pharmaceutical composition has a moisture content of about 2.5 to 3.0 weight%.

[0457] 130. In any one of the pharmaceutical compositions of embodiments 118 to 129, the polymer is selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof.

[0458] 131. In any one of the pharmaceutical compositions of embodiments 118 to 130, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0459] 132. In any one of the pharmaceutical compositions of embodiments 118 to 131, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3.

[0460] 133. In any one of embodiments 118 to 132, the weight ratio of compound to polymer is about 1:3.

[0461] 134. In any one of the pharmaceutical compositions of embodiments 118 to 133, the solvents are dichloromethane and methanol.

[0462] In some embodiments, the present disclosure relates to one or more of the embodiments listed below:

[0463] 1. Crystalline solid form of Compound 1 below:

[0464]

[0465] 2. In the crystalline solid form of Example 1, the crystalline solid form is type A of (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one ("Compound 1").

[0466] 3. In the crystalline solid form of Example 2, Type A of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 4.6, 15.7, 23.2, and 24.8 (2 theta ± 0.2).

[0467] 4. In the crystalline solid form of embodiment 2 or 3, type A of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 15.7, 23.2, and 24.8, corresponding to d-interplanar distances (angstrom ± 0.2) of 19.2, 5.7, 3.8, and 3.6, respectively.

[0468] 5. In any one of embodiments 2 to 4, the crystalline solid form of compound 1 type A is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 7.2, 15.7, 21.3, 23.2 and 24.8.

[0469] 6. In any one of embodiments 2 to 5, the crystalline solid form of compound 1 type A is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 7.2, 15.7, 21.3, 23.2, and 24.8 corresponding to d-planar distances (angstrom ± 0.2) of 19.2, 12.3, 5.7, 4.2, 3.8, and 3.6, respectively.

[0470] 7. In any one of embodiments 2 to 6, the crystalline solid form of compound 1 type A is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 7.2, 15.7, 20.5, 21.3, 21.7, 22.5, 23.2, 24.8 and 26.7.

[0471] 8. In any one of embodiments 2 to 7, the crystalline solid form of compound 1 type A is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0472] 9. In any one of embodiments 2 to 8, the type A of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0473]

[0474] 10. In any one of embodiments 2 to 9, type A of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0475]

[0476] 11. In any one of embodiments 2 to 10, the crystalline solid form of compound 1 type A is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.9% up to 100°C.

[0477] 12. In any one of embodiments 2 to 11, the crystalline solid form of compound 1 type A is characterized by differential scanning heat (DSC) endothermy having a peak temperature of about 85.9°C and an onset temperature of about 146.0°C.

[0478] 13. In any one of embodiments 2 to 12, the crystalline solid form of compound 1 type A is characterized by dynamic vapor adsorption (DVS) of about 3.4% by weight of moisture absorption up to 40% relative humidity.

[0479] 14. In any one of embodiments 2 to 13, the crystalline solid form of compound 1 type A is characterized by dynamic vapor adsorption (DVS) of about 1.0% by weight of moisture absorption at a relative humidity of 40% to 80%.

[0480] 15. In the crystalline solid form of Embodiment 1, the crystalline solid form is Type B of Compound 1.

[0481] 16. In the crystalline solid form of Example 15, Type B of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 4.5, 15.6, 22.9, 23.3, and 25.1 (2 theta ± 0.2).

[0482] 17. In the crystalline solid form of embodiment 15 or 16, type B of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 15.6, 22.9, 23.3, and 25.1, corresponding to d-planar distances (angstrom ± 0.2) of 19.5, 5.7, 3.9, 3.8, and 3.5, respectively.

[0483] 18. In any one of embodiments 15 to 17, type B of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 15.6, 22.2, 22.9, 23.3 and 25.1.

[0484] 19. In any one of embodiments 15 to 18, the type B of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1, corresponding to d-planar distances (angstrom ± 0.2) of 19.5, 5.7, 4.0, 3.9, 3.8, and 3.5, respectively.

[0485] 20. In any one of embodiments 15 to 19, the type B of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 9.9, 15.6, 19.9, 22.2, 22.9, 23.3, 25.1, and 28.3.

[0486] 21. In any one of the embodiments 15 to 20, the type B of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 0.2) of 19.5, 9.0, 5.7, 4.5, 4.0, 3.9, 3.8, 3.5, and 3.2, respectively.

[0487] 22. In any one of embodiments 15 to 21, the type B of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0488]

[0489] 23. In any one of embodiments 15 to 22, type B of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0490]

[0491]

[0492] 24. In any one of embodiments 15 to 23, the type B of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.8% up to 100°C.

[0493] 25. In any one of embodiments 15 to 24, type B of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% up to 120°C.

[0494] 26. In any one of embodiments 15 to 25, the type B of compound 1 is characterized by having differential scanning heat (DSC) endothermic heat having an onset temperature of about 138.2 to 139.2°C.

[0495] 27. In any one of embodiments 15 to 26, the type B of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 2.9% by weight of moisture absorption up to 60% relative humidity.

[0496] 28. In any one of embodiments 15 to 27, the type B of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 0.4% by weight of moisture absorption at a relative humidity of 60% to 80%.

[0497] 29. In the crystalline solid form of Example 1, the crystalline solid form is Type C of Compound 1.

[0498] 30. In the crystalline solid form of Example 29, Type C of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 4.5, 18.9, 23.0, and 24.7 (2 theta ± 0.2).

[0499] 31. In the crystalline solid form of embodiment 29 or 30, type C of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 18.9, 23.0, and 24.7, corresponding to d-interplanar distances (angstrom ± 0.2) of 19.4, 4.7, 3.9, and 3.6, respectively.

[0500] 32. In any one of embodiments 29 to 31, the type C of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7 (2 theta ± 0.2).

[0501] 33. In any one of embodiments 29 to 32, the crystalline solid form of compound 1 type C is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7, corresponding to d-planar distances (angstrom ± 0.2) of 19.4, 12.0, 7.9, 4.7, 3.9, and 3.6, respectively.

[0502] 34. In any one of embodiments 29 to 33, the type C of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 7.3, 9.1, 11.2, 18.3, 18.9, 19.6, 21.7, 23.0, and 24.7.

[0503] 35. In any one of embodiments 9 to 34, the crystalline solid form of compound 1 type C is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0504] 36. In any one of embodiments 29 to 35, the type C of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0505]

[0506] 37. In any one of embodiments 29 to 36, type C of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0507]

[0508]

[0509] 38. In any one of embodiments 29 to 37, the type C of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 1.0% at a maximum of 100°C.

[0510] 39. In any one of embodiments 29 to 38, the type C of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3% up to 130°C.

[0511] 40. In any one of embodiments 29 to 39, the crystalline solid form of compound 1 type C is characterized by having differential scanning heat (DSC) endothermic having an onset temperature of about 152.2 to 154.2°C.

[0512] 41. In any one of embodiments 29 to 40, the type C of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 1.8% by weight of moisture absorption up to 60% relative humidity.

[0513] 42. In any one of embodiments 29 to 41, the type C of compound 1 is characterized by dynamic vapor adsorption (DVS) of about 0.5% by weight of moisture absorption at 60% to 80% relative humidity.

[0514] 43. In the crystalline solid form of Embodiment 1, the crystalline solid form is Type D of Compound 1.

[0515] 44. In the crystalline solid form of Example 43, Type D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 9.7, 13.1, 15.7, 21.9, and 23.6 (2 theta ± 0.2).

[0516] 45. In the crystalline solid form of embodiment 43 or 44, type D of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 9.7, 13.1, 15.7, 21.9, and 23.6, corresponding to d-interplanar distances (angstrom ± 0.2) of 9.1, 6.8, 5.6, 4.1, and 3.8, respectively.

[0517] 46. ​​In any one of embodiments 43 to 45, the type D of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 6.2, 9.7, 13.1, 15.7, 21.9 and 23.6 and not having diffraction at angle 23.3 (2 theta ± 0.2).

[0518] 47. In any one of embodiments 43 to 46, the crystalline solid form of compound 1 type D is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 (2 theta ± 0.2) corresponding to d-interplanar distances (angstrom ± 0.2) of 14.4, 9.1, 6.8, 5.6, 4.1, and 3.8, respectively, and having no diffraction at angle 23.3 (2 theta ± 0.2).

[0519] 48. In any one of embodiments 43 to 47, the type D of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0520] 49. In any one of embodiments 43 to 48, the type D of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0521] 50. In any one of embodiments 43 to 49, the type D of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0522]

[0523] 51. In any one of embodiments 43 to 50, the type D of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0524]

[0525]

[0526] 52. In any one of embodiments 43 to 51, the type D of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 9.6% up to 130°C.

[0527] 53. In any one of embodiments 43 to 52, the type D of compound 1 is characterized by having differential scanning heat (DSC) endothermic heat having an onset temperature of about 91.9°C.

[0528] 54. In the crystalline solid form of Example 1, the crystalline solid form is Type E of Compound 1.

[0529] 55. In the crystalline solid form of Example 54, Type E of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7.

[0530] 56. In the crystalline solid form of embodiment 54 or 55, type E of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7, corresponding to d-planar distances (angstrom ± 0.2) of 5.9, 5.6, 5.1, 4.4, 4.1, and 3.3, respectively.

[0531] 57. In any one of embodiments 54 to 56, the type E of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9 and 26.7.

[0532] 58. In any one of embodiments 54 to 57, the type E of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 19.0, 20.1, 21.9, and 26.7, corresponding to d-planar distances (angstrom ± 0.2) of 5.9, 5.6, 5.1, 4.7, 4.4, 4.1, and 3.3, respectively.

[0533] 59. In any one of embodiments 54 to 56, the type E of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 15.1, 15.8, 17.5, 20.1, 21.9, 23.2, 23.7, and 26.7.

[0534] 60. In any one of embodiments 54 to 56, the type E of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 0.2) of 19.3, 5.9, 5.6, 5.1, 4.4, 4.1, 3.8, 3.8, and 3.3, respectively.

[0535] 61. In any one of embodiments 54 to 60, the type E of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0536] 62. In any one of embodiments 54 to 61, the crystalline solid form of compound 1 type E is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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, 3.3, and 3.2, respectively, corresponding to d-planar distances (angstrom ± 0.2) of 19.3, 9.1, 7.2, 6.7, 5.3, and 3.2.

[0537] 63. In any one of embodiments 54 to 62, the type E of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0538]

[0539]

[0540] 64. In any one of embodiments 54 to 63, type E of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0541]

[0542]

[0543] 65. In the crystalline solid form of Example 1, the crystalline solid form is Type F of Compound 1.

[0544] 66. In the crystalline solid form of Example 65, Type F of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 5.4, 14.7, 16.0, 16.8, and 21.4 (2 theta ± 0.2).

[0545] 67. In the crystalline solid form of embodiment 65 or 66, type F of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.7, 16.0, 16.8, and 21.4, corresponding to d-interplanar distances (angstrom ± 0.2) of 16.2, 6.0, 5.5, 5.3, and 4.2, respectively.

[0546] 68. In any one of embodiments 65 to 67, the type F of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5.

[0547] 69. In any one of embodiments 65 to 68, the type F of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.7, 16.0, 16.8, 20.0, 21.4, and 22.5, corresponding to d-planar distances (angstrom ± 0.2) of 16.2, 6.0, 5.5, 5.3, 4.4, 4.2, and 4.0, respectively.

[0548] 70. In any one of embodiments 65 to 69, the type F of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.7, 16.0, 16.8, 19.0, 20.0, 21.4, 22.5, 23.2 and 25.3.

[0549] 71. In any one of embodiments 65 to 70, the type F of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0550] 72. In any one of embodiments 65 to 71, the type F of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0551] 73. In the crystalline solid form of any one of embodiments 65 to 72, type F of compound 1 corresponds to d-interplanar distances (angstroms ± 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 at angles (2 theta ± 0.2) corresponding to d-interplanar distances (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. It features an XRPD pattern having diffraction.

[0552] 74. In any one of embodiments 65 to 73, the type F of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0553]

[0554]

[0555] 75. In any one of embodiments 65 to 74, the type F of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0556]

[0557]

[0558] 76. In any one of embodiments 65 to 75, the type F of compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 6.2% at 120°C.

[0559] 77. In any one of embodiments 65 to 76, the type F of compound 1 is characterized by differential scanning heat (DSC) endothermic having a peak temperature of about 100.4°C and an onset temperature of 125.9°C.

[0560] 78. In the crystalline solid form of Embodiment 1, the crystalline solid form is type G of Compound 1.

[0561] 79. In the crystalline solid form of Example 78, Type G of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 5.4, 14.3, 16.6, and 21.3 (2 theta ± 0.2).

[0562] 80. In the crystalline solid form of embodiment 78 or 79, type G of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.3, 16.6, and 21.3 corresponding to d-planar distances (angstrom ± 0.2) of 16.5, 6.2, 5.3, and 4.2, respectively.

[0563] 81. In any one of embodiments 78 to 80, the type G of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.3, 16.6, 21.3 and 22.3.

[0564] 82. In any one of embodiments 78 to 81, the type G of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3, corresponding to d-planar distances (angstrom ± 0.2) of 16.5, 6.2, 5.3, 4.2, and 4.0, respectively.

[0565] 83. In any one of embodiments 78 to 82, the type G of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 12.8, 14.3, 15.0, 16.6, 19.8, 21.3, 22.3, 25.3, and 26.4.

[0566] 84. In any one of the embodiments 78 to 83, the type G of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0567] 85. In any one of embodiments 78 to 84, the type G of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 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.

[0568] 86. In any one of embodiments 78 to 85, the type G of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 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-planar distances (angstrom ± 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.

[0569] 87. In any one of embodiments 78 to 86, the type G of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0570]

[0571]

[0572] 88. In any one of embodiments 78 to 87, the type G of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0573]

[0574] 89. In the crystalline solid form of Embodiment 1, the crystalline solid form is Type H of Compound 1.

[0575] 90. In the crystalline solid form of embodiment 89, type H of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4 (2 theta ± 0.2).

[0576] 91. In the crystalline solid form of embodiment 89 or 90, type H of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4, corresponding to d-planar distances (angstrom ± 0.2) of 15.3, 6.0, 5.4, 4.4, 4.2, and 3.5, respectively.

[0577] 92. In any one of embodiments 89 to 91, the type H of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0578]

[0579]

[0580] 93. In any one of embodiments 89 to 92, the type H of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0581]

[0582]

[0583] 94. In the crystalline solid form of Example 1, the crystalline solid form is Type I of Compound 1.

[0584] 95. In the crystalline solid form of Example 94, Type I of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.2, 14.6, 15.5, 20.2 and 21.1.

[0585] 96. In the crystalline solid form of embodiment 94 or 95, type I of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1, corresponding to d-interplanar distances (angstrom ± 0.2) of 17.1, 6.1, 5.7, 4.4, and 4.2, respectively.

[0586] 97. In any one of embodiments 94 to 96, the type I of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0587]

[0588]

[0589]

[0590] 98. In the crystalline solid form of any one of embodiments 94 to 97, type I of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0591]

[0592]

[0593] 99. In the crystalline solid form of Embodiment 1, the crystalline solid form is Type J of Compound 1.

[0594] 100. The crystalline solid form of Example 99 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of type J 4.5, 5.7, 22.8, 23.1 and 24.5 of Compound 1.

[0595] 101. In the crystalline solid form of embodiment 99 or 100, type J of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 5.7, 22.8, 23.1, and 24.5, corresponding to d-planar distances (angstrom ± 0.2) of 19.5, 15.4, 3.9, 3.8, and 3.6, respectively.

[0596] 102. In the crystalline solid form of any one of embodiments 99 to 101, type J of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0597]

[0598]

[0599] 103. In any one of embodiments 99 to 102, the type J of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0600]

[0601]

[0602] 104. In the crystalline solid form of Example 1, the crystalline solid form is Type K of Compound 1.

[0603] 105. In the crystalline solid form of Example 104, Type K of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4.

[0604] 106. In the crystalline solid form of embodiment 104 or 105, type K of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4, corresponding to d-planar distances (angstrom ± 0.2) of 19.2, 5.7, 5.7, 5.5, 3.8, and 3.3, respectively.

[0605] 107. In any one of embodiments 104 to 106, the type K of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0606]

[0607] 108. In any one of embodiments 104 to 107, the type K of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0608]

[0609] 109. In the crystalline solid form of Example 1, the crystalline solid form is type L of Compound 1.

[0610] 110. In the crystalline solid form of Example 109, type L of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1.

[0611] 111. In the crystalline solid form of embodiment 109 or 110, type L of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1, corresponding to d-planar distances (angstrom ± 0.2) of 14.9, 7.5, 5.0, 4.1, 3.7, and 2.5, respectively.

[0612] 112. In any one of embodiments 109 to 111, the type L of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0613]

[0614] 113. In any one of embodiments 109 to 112, the type L of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0615]

[0616] 114. In the crystalline solid form of Embodiment 1, the crystalline solid form is type M of Compound 1.

[0617] 115. In the crystalline solid form of Example 114, Type M of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7 (2 theta ± 0.2).

[0618] 116. In the crystalline solid form of embodiment 114 or 115, type M of compound 1 is characterized by an XRPD pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 5.8, 9.7, 15.6, 21.9, and 26.7, corresponding to d-planar distances (angstrom ± 0.2) of 19.5, 15.3, 9.1, 5.7, 4.1, and 3.3, respectively.

[0619] 117. In any one of embodiments 114 to 116, the type M of compound 1 is characterized by an XRPD pattern having diffraction at the following angle (2 theta ± 0.2):

[0620]

[0621]

[0622] 118. In any one of embodiments 114 to 117, type M of compound 1 is characterized by an XRPD pattern having diffraction at an angle (2 theta ± 0.2) corresponding to the following d-interplanar distance (angstrom ± 0.2):

[0623]

[0624]

[0625] 119. In the crystalline solid form of Embodiment 1, the crystalline solid form is selected from the group consisting of the following:

[0626] 1) Type A of compound 1, wherein Type A of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 7.2, 15.7, 21.4, 23.2, and 24.8;

[0627] 2) Type B of compound 1, wherein Type B of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 15.6, 22.2, 22.9, 23.3, and 25.1;

[0628] 3) Type C of compound 1, wherein Type C of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 7.3, 11.2, 18.9, 23.0, and 24.7;

[0629] 4) Type D of Compound 1, wherein Type D of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 6.2, 9.7, 13.1, 15.7, 21.9, and 23.6 and not having diffraction at angle 23.3 (2 theta ± 0.2);

[0630] 5) Type E of compound 1, wherein Type E of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 15.1, 15.8, 17.5, 20.1, 21.9, and 26.7;

[0631] 6) Type F of compound 1, wherein Type F of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.5, 14.7, 16.0, 16.8, and 21.4;

[0632] 7) Type G of compound 1, wherein Type G of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.4, 14.3, 16.6, 21.3, and 22.3;

[0633] 8) Type H of compound 1, wherein Type H of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.8, 14.7, 16.6, 20.0, 21.3, and 25.4;

[0634] 9) Type I of compound 1, wherein Type I of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.2, 14.6, 15.5, 20.2, and 21.1;

[0635] 10) Type J of compound 1, wherein Type J of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 5.7, 22.8, 23.1, and 24.5;

[0636] 11) Type K of compound 1, wherein Type K of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.6, 15.4, 15.6, 16.1, 23.2, and 27.4;

[0637] 12) Type L of compound 1, wherein Type L of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 5.9, 11.9, 17.8, 21.6, 23.9, and 36.1; and

[0638] 13) Type M of compound 1, wherein Type M of compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 theta ± 0.2) of 4.5, 5.8, 9.7, 15.6, 21.9 and 26.7.

[0639] 120. A pharmaceutical composition comprising a therapeutically effective amount of any one of embodiments 1 to 119 in a crystalline solid form and one or more pharmaceutically acceptable excipients.

[0640] 121. In the pharmaceutical composition of embodiment 120, the pharmaceutical composition is for oral administration.

[0641] 122. In the pharmaceutical composition of embodiment 120 or 121, the pharmaceutical composition has a moisture content of about 0.5 to 5.0 weight%.

[0642] 123. In any one of embodiments 120 to 122, the pharmaceutical composition has a moisture content of about 1.5 to 4.0 weight%.

[0643] 124. In any one of embodiments 120 to 123, the pharmaceutical composition has a moisture content of about 2.5 to 3.0 weight%.

[0644] 125. The following compound 1:

[0645]

[0646] an amorphous solid dispersion comprising a polymer.

[0647] 126. In the amorphous solid dispersion of Example 125, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), It is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof.

[0648] 127. In the amorphous solid dispersion of Example 125 or 126, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0649] 128. In any one of the amorphous solid dispersions of embodiments 125 to 127, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0650] 129. In any one of the embodiments 125 to 128, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[0651] 130. In any one of the amorphous solid dispersions of embodiments 125 to 129, the weight ratio of compound to polymer is about 1:3.

[0652] 131. In any one of the amorphous solid dispersions of embodiments 125 to 129, the weight ratio of compound to polymer is about 1:1.

[0653] 132. In any one of the embodiments 125 to 129, the weight ratio of compound to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[0654] 133. In any one of the embodiments 125 to 132, the crystalline diffraction peaks are not observable by XRPD analysis of the amorphous solid dispersion (Method D).

[0655] 134. In any one of the amorphous solid dispersions of embodiments 125 to 133, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a container as described in Example 20 for 5 months at 2 to 8°C and ambient relative humidity.

[0656] 135. In any one of the amorphous solid dispersions of embodiments 125 to 134, crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a container as described in Example 20 for 5 months at 25°C and 60% relative humidity.

[0657] 136. In any one of the amorphous solid dispersions of embodiments 125 to 135, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a container as described in Example 20 for 1 month at 2 to 8°C and ambient relative humidity.

[0658] 137. In any one of the amorphous solid dispersions of embodiments 125 to 136, crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a container as described in Example 20 for one month at 25°C and 60% relative humidity.

[0659] 138. In any one of the amorphous solid dispersions of embodiments 125 to 137, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a container as described in Example 20 for one month at 40°C and 75% relative humidity.

[0660] 139. In any one of embodiments 125 to 138, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis of the amorphous solid dispersion (Method B).

[0661] 140. In any one of embodiments 125 to 139, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G) can be observed by DSC analysis (Method B) of the amorphous solid dispersion after storage in a container as described in Example 20 for 5 months at 2 to 8°C and ambient relative humidity.

[0662] 141. In any one of embodiments 125 to 140, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis (Method B) of the amorphous solid dispersion after storage in a container as described in Example 20 for 5 months at 25°C and 60% relative humidity.

[0663] 142. In any one of embodiments 125 to 141, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis (Method B) of the amorphous solid dispersion after storage in a container as described in Example 20 for 1 month at 2 to 8°C and ambient relative humidity.

[0664] 143. In any one of embodiments 125 to 142, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis (Method B) of the amorphous solid dispersion after storage in a container as described in Example 20 for one month at 25°C and 60% relative humidity.

[0665] 144. In any one of embodiments 125 to 143, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis (Method B) of the amorphous solid dispersion after storage in a container as described in Example 20 for one month at 40°C and 75% relative humidity.

[0666] 145. In any one of the embodiments 125 to 144, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion.

[0667] 146. In any one of the embodiments 125 to 145, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a sealed vial at 60°C for one week.

[0668] 147. In any one of the embodiments 125 to 146, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in a sealed vial at 60°C for 2 weeks.

[0669] 148. In any one of the embodiments 125 to 147, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 25°C and 60% relative humidity for one week.

[0670] 149. In any one of the embodiments 125 to 148, the crystalline diffraction peaks are not observable 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.

[0671] 150. In any one of the embodiments 125 to 149, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 40°C and 75% relative humidity for one week.

[0672] 151. In any one of the embodiments 125 to 150, the crystalline diffraction peaks are not observable 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.

[0673] 152. In any one of the embodiments 125 to 151, the crystalline diffraction peaks are not observable by XRPD analysis (Method D) of the amorphous solid dispersion after storage in an unsealed vial at 60°C and 75% relative humidity for one week.

[0674] 153. In any one of the embodiments 125 to 152, the crystalline diffraction peaks are not observable 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.

[0675] 154. In any one of embodiments 125 to 136, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis of the amorphous solid dispersion (Method B).

[0676] 155. In any one of embodiments 125 to 154, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis of the amorphous solid dispersion (Method B) after storage in a sealed vial at 60°C for 1 or 2 weeks.

[0677] 156. In any one of embodiments 125 to 155, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G) can be observed by DSC analysis of the amorphous solid dispersion (Method B) after storage in an unsealed vial for 1 or 2 weeks at 25°C and 60% relative humidity.

[0678] 157. In any one of embodiments 125 to 156, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis of the amorphous solid dispersion (Method B) after storage in an unsealed vial for 1 or 2 weeks at 40°C and 75% relative humidity.

[0679] 158. In any one of embodiments 125 to 157, an amorphous solid dispersion having no melting endothermic and a single glass transition temperature (T G ) can be observed by DSC analysis of the amorphous solid dispersion (Method B) after storage in an unsealed vial for 1 or 2 weeks at 60°C and 75% relative humidity.

[0680] 159. In any one of the amorphous solid dispersions of embodiments 125 to 158, compound 1 has a concentration of at least 300 μg / ml after 30 minutes in the kinetic solubility test described in Example 23.

[0681] 160. In any one of the amorphous solid dispersions of embodiments 125 to 159, compound 1 has a Cmax of at least 600 μg / ml in the kinetic solubility test described in Example 23.

[0682] 161. In any one of the amorphous solid dispersions of embodiments 125 to 160, compound 1 has a concentration of at least 450 μg / ml after 4 hours in the kinetic solubility test described in Example 23.

[0683] 162. In any one of the amorphous solid dispersions of embodiments 125 to 158, compound 1 has a concentration of at least 200 μg / ml after 16 hours in the kinetic solubility test described in Example 23.

[0684] 163. A pharmaceutical composition comprising a therapeutically effective amount of any one of embodiments 125 to 162 of an amorphous solid dispersion and one or more pharmaceutically acceptable excipients.

[0685] 164. In the pharmaceutical composition of embodiment 163, the pharmaceutical composition is for oral administration.

[0686] 165. In the pharmaceutical composition of embodiment 163 or 164, the pharmaceutical composition is in the form of a tablet.

[0687] 166. In any one of embodiments 163 to 165, the pharmaceutical composition has a moisture content of about 0.5 to 5.0 weight%.

[0688] 167. In any one of embodiments 163 to 166, the pharmaceutical composition has a moisture content of about 1.5 to 4.0 weight%.

[0689] 168. In any one of embodiments 163 to 167, the pharmaceutical composition has a moisture content of about 2.5 to 3.0 weight%.

[0690] 169. In any one of embodiments 163 to 168, 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.

[0691] 170. In any one of embodiments 163 to 169, the pharmaceutical composition comprises about 25 mg of compound 1.

[0692] 171. In any one of embodiments 163 to 169, the pharmaceutical composition comprises about 100 mg of compound 1.

[0693] 172. In any one of embodiments 163 to 169, the pharmaceutical composition comprises about 200 mg of compound 1.

[0694] 173. In any one of embodiments 163 to 172, one or more pharmaceutically acceptable excipients include one or more of fillers, drying binders, lubricants, lubricants, disintegrants, and film coating agents.

[0695] 174. In any one of embodiments 163 to 173, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, and the filler comprises microcrystalline cellulose.

[0696] 175. In any one of embodiments 163 to 174, one or more pharmaceutically acceptable excipients comprise a filler, and the filler comprises lactose monohydrate.

[0697] 176. In any one of embodiments 163 to 175, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, and the dry binder comprises crospovidone.

[0698] 177. In any one of embodiments 163 to 176, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, wherein the lubricant comprises colloidal silicon dioxide.

[0699] 178. In any one of embodiments 163 to 177, one or more pharmaceutically acceptable excipients include a lubricant, and the lubricant includes magnesium stearate.

[0700] 179. In any one of embodiments 163 to 178, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, wherein the disintegrant comprises croscarmellose sodium.

[0701] 180. Any one of embodiments 163 to 179 pharmaceutical composition comprises a tablet core, wherein the tablet core comprises the following:

[0702] A portion within the granules comprising an amorphous solid dispersion; and

[0703] The part inside the granules and the part outside the granules mixed together.

[0704] 181. The pharmaceutical composition of embodiment 180 further comprises a coating disposed on a tablet core.

[0705] 182. In the pharmaceutical composition of embodiment 180 or 181, the amorphous solid dispersion is at least about 30 weight percent of the tablet core.

[0706] 183. In any one of embodiments 180 to 182, the amorphous solid dispersion is at least about 50% by weight of the tablet core.

[0707] 184. In any one of embodiments 180 to 183, the amorphous solid dispersion is at least about 60 weight percent of the tablet core.

[0708] 185. In any one of embodiments 180 to 184, the amorphous solid dispersion is about 50% by weight of the tablet core.

[0709] 186. In any one of embodiments 180 to 185, the amorphous solid dispersion is about 50 to about 70 weight percent of the tablet core.

[0710] 187. In any one of embodiments 180 to 186, the amorphous solid dispersion is about 60 to about 65 weight percent of the tablet core.

[0711] 188. In any one of embodiments 180 to 187, the portion within the granule further comprises one or more of a filler, a drying binder, a lubricant, and a lubricant.

[0712] 189. In any one of embodiments 180 to 188, the non-granular portion further comprises one or more of a filler, a disintegrant, and a lubricant.

[0713] 190. A method for preparing an amorphous solid dispersion comprising the following compound 1, comprising the following steps:

[0714]

[0715] A step of providing a mixture by mixing compound 1, a polymer, and a solvent; and

[0716] A step of spray-drying the mixture to provide an amorphous solid dispersion containing compound 1.

[0717] 191. In the method of Example 190, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl It is selected from the group consisting of caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof.

[0718] 192. In the method of embodiment 190 or 191, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0719] 193. In any one of the methods of embodiments 190 to 192, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0720] 194. In any one of the methods of embodiments 190 to 193, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[0721] 195. In any one of the methods of embodiments 190 to 194, the weight ratio of compound to polymer is about 1:3.

[0722] 196. In any one of the methods of embodiments 190 to 194, the weight ratio of compound to polymer is about 1:1.

[0723] 197. In any one of embodiments 190 to 194, the weight ratio of compound to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[0724] 198. In any one of the methods of embodiments 190 to 197, the solvents are dichloromethane and methanol.

[0725] 199. A product prepared by a method comprising the following:

[0726] A step of providing a mixture by mixing compound 1, a polymer, and a solvent; and

[0727] Step of spray-drying the mixture to provide an amorphous solid dispersion containing compound 1:

[0728]

[0729] 200. In the product of Example 199, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl It is selected from the group consisting of caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof.

[0730] 201. In the product of Example 199 or 200, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0731] 202. In any one of the products of embodiments 199 to 201, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0732] 203. In any one of the products of embodiments 199 to 202, the weight ratio of compound 1 to polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[0733] 204. In any one of the products of embodiments 199 to 203, the weight ratio of compound to polymer is about 1:3.

[0734] 205. In any one of the products of embodiments 199 to 203, the weight ratio of compound to polymer is about 1:1.

[0735] 206. In any one of the products of embodiments 199 to 203, the weight ratio of compound to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[0736] 207. In any one of the products of embodiments 199 to 206, the solvents are dichloromethane and methanol.

[0737] 208. A pharmaceutical composition comprising the following compound 1, obtained by a method comprising the following steps:

[0738]

[0739] A step of providing a mixture by mixing a compound 1 in solid form, a polymer, and a solvent; and

[0740] A step of spray-drying the mixture to provide an amorphous solid dispersion containing compound 1.

[0741] 209. In the pharmaceutical composition of embodiment 208, the solid form is type A of compound 1.

[0742] 210. In the pharmaceutical composition of embodiment 208, the solid form is type B of compound 1.

[0743] 211. In the pharmaceutical composition of embodiment 208, the solid form is type C of compound 1.

[0744] 212. In the pharmaceutical composition of embodiment 208, the solid form is type D of compound 1.

[0745] 213. In the pharmaceutical composition of embodiment 208, the solid form is type E of compound 1.

[0746] 214. In the pharmaceutical composition of embodiment 208, the solid form is type F of compound 1.

[0747] 215. In the pharmaceutical composition of embodiment 208, the solid form is type G of compound 1.

[0748] 216. In the pharmaceutical composition of embodiment 208, the solid form is type H of compound 1.

[0749] 217. In the pharmaceutical composition of embodiment 208, the solid form is type I of compound 1.

[0750] 218. In the pharmaceutical composition of embodiment 208, the solid form is type J of compound 1.

[0751] 219. In the pharmaceutical composition of embodiment 208, the solid form is type K of compound 1.

[0752] 220. In the pharmaceutical composition of embodiment 208, the solid form is type L of compound 1.

[0753] 221. In the pharmaceutical composition of embodiment 208, the solid form is type M of compound 1.

[0754] 222. In the pharmaceutical composition of embodiment 208, 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.

[0755] 223. In the pharmaceutical composition of embodiment 208, the solid form is the amorphous form of compound 1.

[0756] 224. In any one of embodiments 208 to 223, the pharmaceutical composition has a moisture content of about 0.5 to 5.0 weight%.

[0757] 225. In any one of embodiments 208 to 224, the pharmaceutical composition has a moisture content of about 1.5 to 4.0 weight%.

[0758] 226. In any one of embodiments 208 to 225, the pharmaceutical composition has a moisture content of about 2.5 to 3.0 weight%.

[0759] 227. In any one of the pharmaceutical compositions of Examples 208 to 226, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® It is selected from the group consisting of HS15), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof.

[0760] 228. In any one of the pharmaceutical compositions of embodiments 208 to 227, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0761] 229. In any one of embodiments 208 to 228, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0762] 230. In any one of the pharmaceutical compositions of embodiments 208 to 229, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[0763] 231. In any one of embodiments 208 to 230, the weight ratio of compound to polymer is about 1:3.

[0764] 232. In any one of embodiments 208 to 230, the weight ratio of compound to polymer is about 1:1.

[0765] 233. In any one of embodiments 208 to 230, the weight ratio of compound to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[0766] 234. In any one of the pharmaceutical compositions of embodiments 208 to 233, the solvents are dichloromethane and methanol.

[0767] 235. A tablet dosage form comprising a tablet core, wherein the tablet core comprises at least 10 weight percent of a compound 1 in an amorphous form:

[0768]

[0769] Here, crystalline compound 1 (Type A) is not observable by XRPD analysis of the purified core (Method D).

[0770] 236. In the tablet dosage form of embodiment 235, the tablet core comprises at least 15 weight% of amorphous form of compound 1.

[0771] 237. In the tablet dosage form of embodiment 235 or 236, the tablet core comprises at least 30 weight% of amorphous form of compound 1.

[0772] 238. In any one of embodiments 235 to 237, the tablet core contains about 200 mg of compound 1 per tablet and has a total weight of about 1200 mg or less per tablet.

[0773] 239. In the tablet dosage form of Example 238, the tablet core has a total weight of about 1100 mg, about 1000 mg, about 900 mg, about 800 mg, or about 700 mg or less per tablet.

[0774] 240. A tablet dosage form comprising a tablet core, wherein the tablet core has a total weight of about 1000 mg or less and comprises about 200 mg of amorphous form of compound 1 per tablet:

[0775]

[0776] Here, crystalline compound 1 (Type A) is not observable by XRPD analysis of the purified core (Method D).

[0777] 241. In the tablet administration form of embodiment 240, the tablet core has a total weight of about 800 mg or less per tablet.

[0778] 242. In any one of embodiments 235 to 241, the tablet core comprises 0.05 to 5.0% of compound 2 based on the total amount of compound 1 and compound 2:

[0779]

[0780] 243. In the tablet dosage form of embodiment 242, the tablet core contains 0.05 to 3.0% of compound 2 based on the total amount of compound 1 and compound 2.

[0781] 244. In the tablet dosage form of embodiment 242 or 243, the tablet core contains 0.05 to 2.0% of compound 2 based on the total amount of compound 1 and compound 2.

[0782] 245. In any one of embodiments 242 to 244, the tablet core contains 0.05 to 1.0% of compound 2 based on the total amount of compound 1 and compound 2.

[0783] 246. In any one of the tablet dosage forms of Examples 235 to 245, crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D) after storage in a sealed container as described in Example 29 for 1 month at 25°C and 60% relative humidity.

[0784] 247. In any one of the tablet dosage forms of embodiments 235 to 246, crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D) after storage in a sealed container as described in Example 29 for 2 months at 25°C and 60% relative humidity.

[0785] 248. In any one of the tablet dosage forms of Examples 235 to 247, crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D) after storage in a sealed container as described in Example 29 for 3 months at 25°C and 60% relative humidity.

[0786] 249. In any one of the tablet dosage forms of Examples 235 to 248, crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D) after storage in a sealed container as described in Example 29 for one month at 40°C and 75% relative humidity.

[0787] 250. In any one of the tablet dosage forms of embodiments 235 to 249, crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D) after storage in a sealed container as described in Example 29 for 2 months at 40°C and 75% relative humidity.

[0788] 251. In any one of the tablet dosage forms of embodiments 235 to 250, crystalline compound 1 (Type A) is not observable by XRPD analysis of the tablet core (Method D) after storage in a sealed container as described in Example 29 for 3 months at 40°C and 75% relative humidity.

[0789] 252. In any one of embodiments 235 to 251, compound 1 exists as an amorphous solid dispersion comprising compound 1 and a polymer.

[0790] 253. In the tablet dosage form of Example 252, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl It is selected from the group consisting of caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof.

[0791] 254. In the tablet dosage form of Example 252 or 253, the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0792] 255. In any one of the tablet dosage forms of embodiments 252 to 254, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0793] 256. In any one of the tablet dosage forms of embodiments 252 to 255, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[0794] 257. In any one of the tablet dosage forms of embodiments 252 to 256, the weight ratio of compound to polymer is about 1:3.

[0795] 258. In any one of the tablet dosage forms of embodiments 252 to 256, the weight ratio of compound to polymer is about 1:1.

[0796] 259. In any one of the tablet dosage forms of embodiments 252 to 256, the weight ratio of compound to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[0797] 260. Any one of the tablet dosage forms of embodiments 235 to 259 further comprises one or more pharmaceutically acceptable excipients.

[0798] 261. In the tablet dosage form of Example 260, one or more pharmaceutically acceptable excipients include one or more of fillers, drying binders, lubricants, lubricants, disintegrants, and film coating agents.

[0799] 262. In any one of embodiments 235 to 261, the tablet core comprises the following:

[0800] A granular portion containing compound 1; and

[0801] The part inside the granules and the part outside the granules mixed together.

[0802] 263. In the tablet dosage form of Example 262, the granule portion comprises an amorphous solid dispersion comprising compound 1 and a polymer, and one or more of a filler, a drying binder, a lubricant, and a lubricant, and the granule portion comprises one or more of a filler, a disintegrant, and a lubricant.

[0803] 264. In any one of the tablet administration forms of embodiments 235 to 263, the portion within the granule is,

[0804] An amorphous solid dispersion of Compound 1 in an amount of 30 to 70 weight percent of the purified core;

[0805] One or more fillers in an amount of 15 to 50 weight percent of the tablet core;

[0806] One or more dry binders in an amount of 2.50 to 10 weight percent of the tablet core;

[0807] One or more lubricants in an amount of 0.50 to 1.50 weight% of the tablet core; and

[0808] It comprises one or more lubricants in an amount of 0.25 to 1 weight percent of the refined core; and

[0809] The part other than the granules,

[0810] One or more fillers in an amount of 5 to 15 weight percent of the tablet core;

[0811] One or more disintegrants in an amount of 1.25 to 5 weight percent of the tablet core; and

[0812] It comprises one or more lubricants in an amount of 0.25 to 1 weight percent of the refined core; or

[0813] The tablet dosage form is,

[0814] An amorphous solid dispersion of Compound 1 in an amount of 50 to 75 weight percent of the purified core;

[0815] One or more fillers in an amount of 15 to 50 weight percent of the tablet core;

[0816] One or more dry binders in an amount of 2 to 10 weight percent of the tablet core;

[0817] One or more lubricants in an amount of less than 2 weight percent of the tablet core;

[0818] One or more disintegrants in an amount of 2 to 10 weight percent of the tablet core; and

[0819] It contains one or more types of lubricants in an amount of less than 2 weight percent of the refined core.

[0820] 265. In the tablet dosage form of Example 264, the amorphous solid dispersion comprises compound 1 and a polymer.

[0821] 266. In the tablet dosage form of Example 265, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), polyvinyl It is selected from the group consisting of caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof.

[0822] 267. In the tablet dosage form of Example 265 or 266, the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

[0823] 268. In any one of the tablet dosage forms of embodiments 265 to 267, the weight ratio of compound to polymer is in the range of about 3:1 to about 1:3 or about 2:1 to about 1:3.

[0824] 269. In any one of the tablet dosage forms of embodiments 265 to 268, the weight ratio of compound to polymer is about 1:3.

[0825] 270. In any one of the tablet dosage forms of embodiments 265 to 269, the weight ratio of compound to polymer is about 1:1.

[0826] 271. In any one of the tablet dosage forms of embodiments 265 to 270, the weight ratio of compound to polymer is about 1:3, about 2:3, about 1:1, about 1.5:1, about 2:1, or about 3:1.

[0827] 272. In any one of the tablet dosage forms of embodiments 264 to 271, one or more fillers comprise microcrystalline cellulose or lactose monohydrate.

[0828] 273. In any one of the tablet dosage forms of embodiments 264 to 272, one or more drying binders comprise crospovidone or cross-linked polyvinylpyrrolidone.

[0829] 274. In any one of the tablet dosage forms of embodiments 264 to 273, one or more lubricants comprise colloidal silicon dioxide or fuming silica.

[0830] 275. In any one of the tablet dosage forms of embodiments 264 to 274, one or more lubricants include magnesium stearate.

[0831] 276. In any one of the tablet administration forms of embodiments 264 to 275, one or more disintegrants comprise croscarmellose sodium.

[0832] 277. A solid oral administration form comprising (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one, which is a stabilized amorphous compound, wherein the stabilized amorphous compound does not exhibit crystallinity by PXRD (Method D) after storage for 2 weeks at 60°C / 75% RH (exposed).

[0833] 278. In the solid oral administration form of Example 277, the stabilized amorphous compound has no melting endothermic and a single glass transition temperature (T) by DSC (Method B) after storage at 60°C / 75% RH (exposed) for 2 weeks. G It represents ).

[0834] 279. In the solid oral administration form of embodiment 277 or 278, the solid oral administration form contains a total of 200 mg of (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one.

[0835] 280. In any one of embodiments 277 to 279, the solid oral administration form has a total weight of less than 800 mg.

[0836] 281. In any one of embodiments 277 to 280, the solid oral administration form is a tablet or a capsule.

[0837] 282. In any one of embodiments 277 to 281, the stabilized amorphous compound exists as a spray-dried dispersion using a polymer.

[0838] 283. In the solid oral administration form of Example 282, the polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, or polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxyethylcellulose (HEC), poly(methacrylic acid-co-methyl methacrylate) (e.g., Eudragit® L100-55), macrogol 15 hydroxystearate (e.g., Solutol® HS15), It is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers (e.g., Soluplus®), polyethylene glycol (PEG), and combinations thereof.

[0839] 284. In the solid oral administration form of Example 283, the polymer is HPMC AS.

[0840] 285. In the solid oral administration form of Example 284, (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one is spray-dried with HPMC AS in a weight ratio of 1:3 to 2:1.

[0841] 286. In the solid oral administration form of Example 284, (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one is spray-dried with HPMC AS in a weight ratio of 1:1.

[0842] 287. A composition of (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one active pharmaceutical ingredient (API) composition comprising 0.05 to 5.0% of (R)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one as determined by HPLC.

[0843] 288. A tablet comprising 200 mg of the stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one as an active pharmaceutical ingredient (API), wherein the stabilized amorphous compound does not exhibit crystallinity by PXRD (Method D) after 2 weeks of storage of the tablet at 60°C / 75% RH (exposed).

[0844] 289. In the purification of Example 288, the API comprises less than 5.0% (R)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one by HPLC.

[0845] 290. In the purification of Example 288 or 289, the API comprises less than 0.05% (R)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one by HPLC.

[0846] 291. A tablet of any one of embodiments 288 to 290 having a total weight of less than 800 mg.

[0847] Examples

[0848] The teachings provided herein include descriptions provided in the embodiments, which are not intended to limit the scope of any claims. The following non-limiting examples are provided to further illustrate the teachings provided herein. Those skilled in the art will understand that many modifications may be made to the specific embodiments provided herein in light of this application, and that such or similar results may still be obtained without departing from the spirit and scope of the teachings provided herein.

[0849] abbreviation

[0850]

[0851]

[0852] Device and method

[0853] Unless otherwise indicated, the following apparatus and method were used in the work examples described herein.

[0854] X-ray powder diffraction (XRPD or PXRD)

[0855] Method A. XRPD analysis was performed using Panalytical X'Pert3 Powder XRPD on a Si zero-background holder. The 2θ position was calibrated against Panalytical 640 Si powder standards. Details of the XRPD methods used are listed in Table 1.

[0856]

[0857] Method B. XRPD analysis was performed on a Rigaku X-ray powder diffraction analyzer MiniFlex 600 with the parameters listed in Table 2.

[0858]

[0859] Method C. XRPD analysis was performed in reflection mode using a Panalytical X'Pert3 powder diffractometer. The details of the XRPD method used in the experiment are as follows:

[0860]

[0861] Method D. XRPD analysis was performed with the following parameters:

[0862]

[0863] Thermal analysis (TGA and DSC)

[0864] 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.

[0865]

[0866] Method B. DSC analysis was performed according to the following procedure: DSC controlled to 1.00°C was performed for 60 seconds at a ramp rate of 2°C / min up to 250°C. An ambient temperature range of 20° to 25°C was used.

[0867] Dynamic vapor deposition

[0868] Dynamic vapor deposition (DVS) was measured using the Surface Measurement System (SMS) DVS Intrinsic. The parameters for DVS analysis are listed in Table 4.

[0869]

[0870] High Pressure Liquid Chromatography (HPLC)

[0871] Method A. The HPLC parameters and gradients presented in Tables 5 and 6, respectively, were used for sample analysis.

[0872]

[0873]

[0874] Super-performance liquid chromatography

[0875] The UPLC parameters and linear method gradients disclosed in Tables 7 and 8, respectively, were used for sample analysis.

[0876]

[0877]

[0878] moisture content

[0879] Moisture content is USP <921> , was determined by method 1c.

[0880] dissolution

[0881] Unless otherwise indicated, the dissolution of tablets is USP <711> It is performed by USP Device 2 (Paddle). The determination of the calibration is achieved by quantification against an external reference standard using the reverse-phase gradient UPLC method. The UPLC method uses an Acquity UPLC BEH Shield column utilizing two mobile phases consisting of both acetonitrile, water, and phosphate buffer.

[0882] Example 1 - (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one( 1 Synthesis of )

[0883] PKR-activating compound 1 can be obtained by the method described herein and the reaction scheme shown in FIGS. 1 and 2. Compound 1 It has a molecular weight of 457.50 Da.

[0884] Step 1. 2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl chloride ( 3 )

[0885] In a 100 ml round-bottom flask purged and maintained under an inert atmosphere of nitrogen, in hexane n - In a solution of BuLi (2.5M, 2 mL, 5.0 mmol, 0.54 equiv) and hexane n A solution of -Bu2Mg (1.0M, 4.8mL, 4.8 mmol, 0.53 equiv) was added. The resulting solution was stirred at room temperature (20℃) for 10 minutes. Subsequently, 7-bromo-2 in tetrahydrofuran (16mL) was stirred at -10℃ for 10 minutes. H ,3 H-[1,4]Dioxyno[2,3- b A solution of pyridine (2 g, 9.26 mmol, 1.00 equiv) was added dropwise. The resulting mixture was stirred at -10°C for 1 hour. The reaction mixture was slowly added to a solution of sulfuryl chloride (16 ml) at -10°C. The resulting mixture was stirred at -10°C for 0.5 hours. Subsequently, the reaction was stopped by carefully adding 30 ml of saturated ammonium chloride solution at 0°C. The resulting mixture was extracted with 3 × 50 ml of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with ethyl acetate / petroleum ether (1:3). This yielded 1.3 g (60%) of 2 H ,3 H -[1,4]Dioxyno[2,3- b ]Pyridine-7-sulfonyl chloride was provided as a white solid. LCMS m / z : Calculated value for C7H6ClNO4S: 235.64; Measured value: 236 [M+H] + .

[0886] Step 2. tert-butyl 5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate( 4 )

[0887] 2 in a 100-ml round-bottom flask H ,3 H -[1,4]Dioxyno[2,3- b ]pyridine-7-sulfonyl chloride (1.3g, 5.52 mmol, 1.00 equiv), tert -Butyl 1 H ,2 H ,3 H ,4 H ,5 H ,6 H -pyrrolo[3,4- c]pyrrole-2-carboxylate (1.16 g, 5.52 mmol), dichloromethane (40 mL), and triethylamine (1.39 g, 13.74 mmol, 2.49 equiv) were added. This solution was stirred at 20°C for 2 hours and then diluted with 40 mL of water. The resulting mixture was extracted with 3 × 30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with dichloromethane / methanol (10:1). This yielded 1.2 g (53%) tert -butyl 5-[2 H ,3 H -[1,4]Dioxyno[2,3- b ]pyridine-7-sulfonyl]-1 H ,2 H ,3 H ,4 H ,5 H ,6 H -pyrrolo[3,4- c ]Pyrrol-2-carboxylate was provided as a yellow solid. LCMS m / z : C 18 H 23 Calculated value for N3O6S: 409.46; Measured value: 410 [M+H] + .

[0888] Step 3. 2-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole ( 5 )

[0889] In a 100-ml round-bottom flask tert -butyl 5-[2H,3H-[1,4]dioxyno[2,3- b ]pyridine-7-sulfonyl]-1 H ,2 H ,3 H ,4 H ,5 H ,6 H -pyrrolo[3,4- c]pyrrole-2-carboxylate (1.2 g, 2.93 mmol, 1.00 equiv), dichloromethane (30 mL), and trifluoroacetic acid (6 mL) were added. This solution was stirred at 20°C for 1 hour. The resulting mixture was concentrated under vacuum. The residue was dissolved in 10 mL of methanol, and the pH was adjusted to 8 using sodium bicarbonate (2 mol / L). The resulting solution was extracted with 3 × 10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluted with dichloromethane / methanol (10:1). This resulted in 650 mg (72%) of 2-[2 H ,3 H -[1,4]Dioxyno[2,3- b ]pyridine-7-sulfonyl]-1 H ,2 H ,3 H ,4 H ,5 H ,6 H -pyrrolo[3,4- c ]Pyrrol was provided as a yellow solid. LCMS m / z : C 13 H 15 Calculated value for N3O4S: 309.34; Measured value: 310 [M+H] + .

[0890] Step 4. (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one( 1 ) and (R)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrolo-2-yl)-3-hydroxy-2-phenylpropan-1-one( 2 )

[0891] 2-[2 in a 100 ml round-bottom flask H ,3 H -[1,4]Dioxyno[2,3-b]pyridine-7-sulfonyl]-1 H ,2 H ,3 H ,4 H ,5 H ,6 Hpyrrolo[3,4-c]pyrrole (150 mg, 0.48 mmol, 1.00 equiv), 3-hydroxy-2-phenylpropanoic 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) were added. The resulting solution was stirred overnight at 20°C. The reaction mixture was diluted with 20 mL of water and then extracted with 3 × 20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative TLC eluted with dichloromethane / methanol (20:1) and further purified by preparative HPLC (column: XBridge C18 OBD Prep column, 100 Å, 5 µm, 19 mm × 250 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; gradient: 15% B to 45% B over 8 minutes; flow rate: 20 mL / min; UV detector: 254 nm). The two enantiomers were separated by preparative chiral HPLC (column: Daicel CHIRALPAK® IF, 2.0 cm × 25 cm, 5 µm; mobile phase A: DCM, phase B: MeOH (maintained at 60% MeOH over 15 minutes); flow rate: 16 mL / min; detector: UV 254 and 220 nm). This is peak 1( 2 , Rt: 8.47 min) 9.0 mg (4%) of (R)-1-(5-[2 H ,3 H -[1,4]Dioxyno[2,3-b]pyridine-7-sulfonyl]-1 H ,2 H ,3 H ,4 H ,5 H ,6 H -pyrrolo[3,4-c]pyrrole-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-[2 H ,3 H-[1,4]Dioxyno[2,3-b]pyridine-7-sulfonyl]-1 H ,2 H ,3 H ,4 H ,5 H ,6 H -Pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one was obtained as a yellow solid.

[0892] ( 1 ): 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 8.13 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.31-7.20 (m, 5H), 4.75 (t, J = 5.2 Hz, 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 to 3.77 (m, 1H), 3.44-3.41 (m, 1H). LC-MS (ESI) m / z: C 22 H 23 Calculated value for N3O6S: 457.13; Measured value: 458.0 [M+H] + .

[0893] ( 2 ): 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 8.13 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.31-7.18 (m, 5H), 4.75 (t, J= 5.2 Hz, 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 to 3.78 (m, 1H), 3.44-3.43 (m, 1H). LC-MS (ESI) m / z: C 22 H 23 Calculated value for N3O6S: 457.13; Measured value: 458.0 [M+H] + .

[0894] Step 5. (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one( 1 )

[0895] Alternatively, compounds 1 It can be synthesized using the procedure described in this specification as step 5.

[0896] 3-hydroxy-2-phenylpropanoic acid (1 g) was separated by preparative-SFC under the following conditions: Instrument name: SHIMADZU LC-20AD, LC parameters: Pump mode: binary gradient, Starting concentration of pump B: 100.0%, Total flow rate: 170 mL / min, Phase A, Phase B: MeOH (0.1% HAC), Column name: CHIRALPAK AD-H, Length: 100 mm, Inner diameter: 4.6 mm, Particle size: 5 µm, Column temperature: 20°C, PDA model: SPD-M20A, Wavelength: 190 nm to 500 nm. This is Peak 1: (Rt = 5.76 min) of 380 mg ( S )-3-hydroxy-2-phenylpropanoic acid as a white solid, and peak 2: (Rt = 6.87 min) 370 mg ( R )-3-hydroxy-2-phenylpropanoic acid was provided as a white solid. 1 H NMR (300 MHz, DMSO-d6): δ ppm 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 - Enantiomers: = -110(C 0.02, water); [Reference: -79 ] R - Enantiomers : = +125(C 0.02, water).

[0897] 7-((3,4,5,6-tetrahydropyrrolo[3,4- in DMF (2.5 ml) c ]Pyrrol-2(1 H )-yl)sulfonyl)-2,3-dihydro-[1,4]dioxyno[2,3- b A solution of ]pyridine (130.9 mg, 0.423 mmol) was cooled in an ice bath, and then ( S The sample was treated with )-3-hydroxy-2-phenylpropanoic 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. This solution was diluted with EtOAc (20 mL), washed sequentially with water (20 mL) and brine (2 × 20 mL), dried (MgSO4), filtered, treated with silica gel, and evaporated under reduced pressure. The material was chromatographed using Biotage MPLC (10 g silica gel column, 0 to 5% MeOH in DCM) to yield 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) (2 S )-1-(5-[2 H ,3 H -[1,4]Dioxyno[2,3- b ]pyridine-7-sulfonyl]-1 H ,2 H ,3 H ,4 H ,5 H ,6 H -pyrrolo[3,4- c ]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one (106.5 mg, 0.233 mmol, 55% yield) was provided as a white solid.

[0898] Example 2 - Compound 1 Manufacturing and characterization of Type A

[0899] Preparation of Type A of Compound 1

[0900] 7-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)sulfonyl)-2,3-dihydro-[1,4]dioxyno[2,3-b]pyridine (33.24 g, 96 mmol), (S)-3-hydroxy-2-phenylpropanoic acid (19.08 g, 115 mmol), and DMF (361 mL) were injected into a 1 L round-bottom flask equipped with a temperature probe and an N2 inlet, under overhead stirring. The mixture was cooled to 0°C, HATU (43.7 g, 115 mmol) was added, and a mild exothermic reaction of approximately 5°C was observed. DIEA (70.2 mL, 402 mmol) was added dropwise over 20 minutes, and the vessel was maintained at around 0°C. This reaction mixture was sampled after 2 hours, followed by 3 hours. After 3 hours, an additional 50 ml of DMF was added to the reaction mixture to dilute it.

[0901] After 3.5 hours at 0°C, 37 volumes of DCM were added to the reaction mixture, the solution was transferred to a 4 L separatory funnel, and washed with water (2060 ml). Subsequently, the organic layer was washed with 3 × 2060 ml of brine (26% W / W NaCl) and dried overnight with MgSO4. The solution was concentrated over a rotary evaporator to yield a waxy white solid (>80 g).

[0902] The solid was triturated with 500 ml of 5:4 EtOAc / hexane, filtered, washed with 100 ml of 1:1 EtOAc / hexane, and dried in a vacuum oven at ambient temperature to yield 50.3 g of white solid.

[0903] The obtained material was ground in a mortar and pestle, poured into a 3 L round-bottom flask under 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 through a Buchner funnel. The filtrate was returned to the round-bottom flask, stirred overnight, and slowly cooled to room temperature.

[0904] The obtained slurry was cooled to 10°C, stirred for 1 hour, and filtered. The round-bottom flask and filter cake were washed with 100 ml of ethanol. The filter cake was dried on a funnel for 1 hour and then in a vacuum oven at ambient temperature overnight to obtain 38.43 g of the compound 1 It was provided as a white solid, and this was designated as Type A of Compound 1.

[0905] Characterization of Type A of Compound 1

[0906] Type A was characterized by XRPD (Method A), TGA (Method A), DSC (Method A), and DVS analysis.

[0907] The XRPD pattern for Type A is depicted in Fig. 3, and the corresponding data is summarized in the table below:

[0908]

[0909] The above XRPD data for Type A may also be rounded to the first decimal place as summarized in the table below:

[0910]

[0911] The TGA and DSC curves for Type A are shown in Fig. 4. As shown in Fig. 4, Type A exhibited a 1.9% weight loss up to 100°C by TGA and two endothermic reactions at 85.9°C (peak temperature) and 146.0°C (start temperature) by DSC.

[0912] According to the DSC cycling as shown in Fig. 5, Type A was heated to 120°C, cooled to 25°C, and then heated up to a maximum of 300°C. In the second heating cycle, there was no endothermic reaction below 100°C. XRPD analysis after DSC cycling showed no morphological change compared to Type A (Fig. 3).

[0913] The DVS results showed 3.4% moisture absorption up to 40% RH (ambient conditions) and 1.0% moisture absorption from 40% RH to 80% RH at room temperature, indicating that Type A is hygroscopic (Fig. 6). As determined by XRPD analysis, no morphological change was observed for Type A before and after the DVS test at room temperature.

[0914] Based on the above analysis data, Type A is considered to be a channel hydrate.

[0915] Example 3 - Compound 1 Polymorph screening

[0916] Polymorph screening experiments were performed using a series of crystallization and solid-state transition methods.

[0917] Solid vapor diffusion

[0918] Solid vapor diffusion experiments were performed using 13 different solvents. Approximately 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 volatile solvent. The 20-mL vial was sealed with a cap and kept at room temperature for 7 days to allow solvent vapors to interact with the sample. The solid was characterized by XRPD analysis (Method A), and the results summarized in Table 9 indicated that Type A or a mixture of Type A and Type D was obtained.

[0919]

[0920] Slurry conversion at 4℃, RT, or 50℃

[0921] Slurry experiments were performed at room temperature in different solvent systems. Approximately 15 mg of compound 1 (Type A) was suspended in 0.3 mL of solvent in a 2 mL glass vial. After magnetically stirring the suspension at 4 °C, RT, or 50 °C for 7 days, the remaining solid was isolated for XRPD analysis (Method A). The results summarized in Table 10 indicated that types A, B, C, and D, or mixtures thereof, were obtained.

[0922]

[0923] Liquid vapor diffusion

[0924] Approximately 15 mg of compound 1 (Type A) was dissolved in a suitable solvent to obtain a clear solution in a 4-mL vial. Subsequently, this solution was placed in a 20-mL vial with 3 mL of anti-solvent. The 20-mL vial was sealed with a cap and kept at room temperature to allow sufficient time for organic vapors to interact with the solution. After 7 days, the solid was isolated for XRPD analysis (Method A). The results summarized in Table 11 indicated that Types A and B were produced.

[0925]

[0926] Another series of liquid vapor diffusion experiments was performed under the conditions presented in Table 12. Compounds 1 (Type A) was weighed into a 3 mL glass vial with the addition of the corresponding solvent or solvent mixture. 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 (Type A) was added as a seed crystal. Subsequently, the shell vial was sealed with a polyethylene plug having a single pinhole and placed into a 20 mL glass vial containing 3 mL of antisolvent at room temperature for liquid-vapor diffusion. The solid form obtained from the experiment was characterized by XRPD analysis (Method C).

[0927]

[0928] Slow evaporation

[0929] Slow evaporation experiments were performed under four conditions. Briefly, about 15 mg of the compound 1 (Type A) was mixed with 1.0 to 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 (0.2 µm pore size), and the filtrate was used in a subsequent step. The visually clear solution was Parafilm ® Evaporation was performed at room temperature using vials sealed with (3 to 5 pinholes). The solid was isolated for XRPD analysis (Method A), and the results summarized in Table 13 indicated that only Type A was obtained.

[0930]

[0931] Another series of slow evaporation experiments was performed under the conditions presented in Table 14. Compound 1 (Type A) was weighed into a 3 mL glass vial with the addition of the corresponding solvent or solvent mixture. After vortexing and sonicating, the suspension was filtered, and the filtrate was transferred to a clean 4 mL shell vial. A small amount of Compound 1 (Type A) was added as a seed crystal. Subsequently, the shell vial was sealed with a polyethylene plug having a single pinhole and placed in a fume hood at room temperature for slow evaporation. The solid form obtained from the experiment was characterized by XRPD analysis (Method C).

[0932]

[0933] Antisolvent addition

[0934] A total of 8 antisolvent addition experiments were performed. Approximately 15 mg of the compound 1(Type A) was dissolved in 0.2 to 4.0 ml of solvent to obtain a clear solution. After magnetically stirring this solution, 0.2 ml of half-solvent was added stepwise until a precipitate formed or the total amount of half-solvent reached 15.0 ml. The obtained precipitate was isolated for XRPD analysis (Method A). The results in Table 15 indicated the formation of Type A and amorphous materials.

[0935]

[0936] Reverse antisolvent addition

[0937] A total of two reverse antisolvent addition experiments were performed. Approximately 15 mg of Compound 1 (Type A) was dissolved in 0.2 mL of solvent to obtain a clear solution. This solution was added to 2 mL of antisolvent. The resulting precipitate was isolated for XRPD analysis (Method A). The results summarized in Table 16 indicated the formation of Type A or a mixture of Type A and amorphous material.

[0938]

[0939] Slow cooling

[0940] Slow cooling experiments were performed under the conditions presented in Table 17. Compound 1 (Type A) was weighed into a 3 mL glass vial with the addition of the corresponding solvent or solvent mixture. After accelerating dissolution by vortexing and ultrasonic shaking, the suspension was placed in a biochemical incubator and equilibrated at 50°C for 30 minutes. Subsequently, the hot suspension was filtered through 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 for slow cooling from 50°C to 5°C at a rate of 0.01°C / min. The solid form obtained from the experiment was characterized by XRPD analysis (Method C).

[0941]

[0942] Example 4 - Preparation and Characterization of Type B of Compound 1

[0943] Preparation of Type B of Compound 1

[0944] Type B was prepared on a 100 mg scale from a slurry of Type A in methanol at 50°C through a method similar to the slurry conversion method described in Example 3.

[0945] Characterization of Type B of Compound 1

[0946] Type B was characterized by XRPD (Method A), TGA (Method A), DSC (Method A), and DVS analysis.

[0947] The XRPD pattern for Type B is illustrated in Fig. 7, and the corresponding data is summarized in the table below:

[0948]

[0949] The above XRPD data for Type B may also be rounded to the first decimal place as summarized in the table below:

[0950]

[0951] The TGA and DSC curves for Type B are shown in Fig. 8. As shown in Fig. 8, Type B exhibited a 1.8% weight loss up to 100°C and endothermic reaction at 138.2°C (start temperature), possibly due to melting.

[0952] As shown in Fig. 9, by DSC cycling (RT-120℃-RT-250℃), only one melt endotherm was observed at 139.2℃ (starting temperature), and in the second heating cycle, there was no broad endotherm below 120℃.

[0953] As shown in Fig. 10, Type B showed a weight loss of 1.7% up to 120°C by an immediate TGA test after heating to 120°C and exposure to ambient conditions for 1 minute. The normal TGA curve of Type B showed a weight loss of 2.3% up to 120°C without preheating treatment.

[0954] After heating to 120°C by DSC cycling and cooling to room temperature, no morphological change was observed by XRPD analysis.

[0955] According to the DVS analysis (Fig. 11), Type B showed 2.9% moisture absorption up to 60% RH (ambient conditions) and 0.4% moisture absorption from 60% RH to 80% RH at room temperature, indicating that Type B is hygroscopic. As determined by XRPD analysis, no change in form was observed for Type B before and after the DVS test at room temperature.

[0956] Based on the above analysis data, Type B is considered to be a channel hydrate.

[0957] Example 5 - Preparation and Characterization of Type C of Compound 1

[0958] Preparation of Type C of Compound 1

[0959] Type C was prepared on a 100 mg scale from a slurry of Type A in 1,4-dioxane at room temperature through a method similar to the method for slurry conversion described in Example 3.

[0960] Characterization of Type C of Compound 1

[0961] Type C was characterized by XRPD (Method A), TGA (Method A), DSC (Method A), and DVS analysis.

[0962] The XRPD pattern for Type C is shown in Fig. 12, and the corresponding data is summarized in the table below:

[0963]

[0964] The above XRPD data for Type C may also be rounded to the first decimal place as summarized in the table below:

[0965]

[0966] TGA and DSC curves for Type C are shown in Fig. 13. As shown in Fig. 13, Type C exhibited a 1.0% weight loss up to 100°C and endothermic reaction at 152.2°C (start temperature), possibly due to melting.

[0967] Using DSC cycling (RT-120℃-RT-250℃), only melt endothermic was observed at 154.2℃ (starting temperature), and in the second heating cycle, there was no broad endothermic below 120℃ (Fig. 14).

[0968] As shown in Fig. 15, Type C exhibited a weight loss of 0.7% up to 130°C by an immediate TGA test after heating to 120°C and exposing to ambient conditions for 1 minute. The normal TGA curve of Type C showed a weight loss of 2.3% up to 130°C without preheating treatment.

[0969] After heating to 120°C by DSC cycling and cooling to room temperature, no morphological change was observed by XRPD analysis.

[0970] According to DVS analysis (Fig. 16), Type C showed 1.8% moisture absorption up to 60% RH (ambient conditions) and 0.5% moisture absorption from 60% RH to 80% RH at room temperature, indicating that Type C is hygroscopic. As determined by XRPD analysis, no morphological change was observed for Type C before and after the DVS test at room temperature.

[0971] Based on the above analysis data, Type B is considered to be a channel hydrate.

[0972] Example 6 - Preparation and Characterization of Type D of Compound 1

[0973] Preparation of Type D of Compound 1

[0974] Type D was prepared from a slurry of Type A in tetrahydrofuran (THF) at 4°C through a method similar to the method for slurry conversion described in Example 3.

[0975] Characterization of Type D of Compound 1

[0976] Type D is XRPD (Method A), TGA (Method A), DSC (Method A) and 1 It was characterized by H NMR analysis.

[0977] The XRPD pattern for Type D is shown in FIG. 17, and the corresponding data is summarized in the table below:

[0978]

[0979] The above XRPD data for Type D may also be rounded to the first decimal place as summarized in the table below:

[0980]

[0981] The TGA and DSC curves for Type D are shown in Fig. 18. As shown in Fig. 18, Type D exhibited a 9.6% weight loss up to 130°C by TGA and endothermic reaction at 91.9°C (starting temperature) by DSC.

[0982] Type A and Type D 1 The 1H NMR spectrum is shown in Fig. 19. Type D is 1 As indicated by the H NMR spectrum (600 MHz, DMSO-d6), it appears to be a THF solvate, which detected the presence of THF protons at approximately 1.76 and approximately 3.60 ppm.

[0983] Example 7 - Preparation and Characterization of Type E of Compound 1

[0984] Characterization of Type E of Compound 1

[0985] Type E was characterized by XRPD (Method A) analysis.

[0986] The XRPD pattern for Type E is illustrated in FIG. 20, and the corresponding data is summarized in the table below:

[0987]

[0988] The above XRPD data for Type E may also be rounded to the first decimal place as summarized in the table below:

[0989]

[0990] Example 8 - Preparation and Characterization of Type F of Compound 1

[0991] Preparation of Type F of Compound 1

[0992] Type F of compound 1 was produced by liquid vapor diffusion in 1,4-dioxane / heptane at room temperature.

[0993] Characterization of Type F of Compound 1

[0994] Type F was characterized by XRPD (Method A), TGA, and DSC analysis (Method A).

[0995] The XRPD pattern for type F is shown in FIG. 21, and the corresponding data is summarized in the table below:

[0996]

[0997] The above XRPD data for Type F may also be rounded to the first decimal place as summarized in the table below:

[0998]

[0999] The TGA and DSC curves for Type F are shown in Fig. 22. As shown in Fig. 22, Type F exhibited a 6.2% weight loss up to 120°C by TGA and two endothermic reactions at 100.4°C and 125.9°C (starting temperature) by DSC.

[1000] Example 9 - Preparation and Characterization of Type G of Compound 1

[1001] Preparation of Type G of Compound 1

[1002] Type G was prepared from a slurry of Type A in methyl ethyl ketone at room temperature.

[1003] Characterization of Type G of Compound 1

[1004] Type G was characterized by XRPD (Method A) analysis.

[1005] The XRPD pattern for type G is shown in FIG. 23, and the corresponding data is summarized in the table below:

[1006]

[1007] The above XRPD data for Type G may also be rounded to the first decimal place as summarized in the table below:

[1008]

[1009] Example 10 - Preparation and Characterization of Type H of Compound 1

[1010] Preparation of Type H of Compound 1

[1011] Type H was prepared by liquid vapor diffusion as described in Example 3.

[1012] Characterization of Type H of Compound 1

[1013] Type H was characterized by XRPD (Method C) analysis.

[1014] The XRPD pattern for type H is shown in FIG. 24, and the corresponding data is summarized in the table below:

[1015]

[1016]

[1017] Example 11 - Preparation and Characterization of Type I Compound 1

[1018] Preparation of Type I Compound 1

[1019] Type I was prepared by liquid vapor diffusion as described in Example 3.

[1020] Characterization of Type I Compound 1

[1021] Type I was characterized by XRPD (Method C) analysis.

[1022] The XRPD pattern for Type I is illustrated in FIG. 25, and the corresponding data is summarized in the table below:

[1023]

[1024]

[1025] Example 12 - Preparation and Characterization of Type J of Compound 1

[1026] Preparation of Type J of Compound 1

[1027] Type J was prepared by liquid vapor diffusion as described in Example 3.

[1028] Characterization of Type J of Compound 1

[1029] Type J was characterized by XRPD (Method C) analysis.

[1030] The XRPD pattern for type J is shown in Fig. 26, and the corresponding data is summarized in the table below:

[1031]

[1032]

[1033] Example 13 - Preparation and Characterization of Type K of Compound 1

[1034] Preparation of Type K of Compound 1

[1035] Type K was manufactured by slow cooling as described in Example 3.

[1036] Characterization of Type K of Compound 1

[1037] Type K was characterized by XRPD (Method C) analysis.

[1038] The XRPD pattern for type K is shown in FIG. 27, and the corresponding data are summarized in the table below:

[1039]

[1040]

[1041] Example 14 - Preparation and Characterization of Type L of Compound 1

[1042] Preparation of Type L of Compound 1

[1043] Type L was manufactured by slow cooling as described in Example 3.

[1044] Characterization of Type L of Compound 1

[1045] Type L was characterized by XRPD (Method C) analysis.

[1046] The XRPD pattern for type L is shown in FIG. 28, and the corresponding data is summarized in the table below:

[1047]

[1048]

[1049] Single-crystal X-ray analysis revealed that type L is a THF / water co-solvent of compound 1, and compound 1, THF, and water exist in a 1:1:1 ratio.

[1050] Example 15 - Preparation and Characterization of Type M of Compound 1

[1051] Preparation of Type M of Compound 1

[1052] Type M was prepared by liquid vapor diffusion as described in Example 3.

[1053] Characterization of Type M of Compound 1

[1054] Type M was characterized by XRPD (Method C) analysis.

[1055] The XRPD pattern for type M is shown in FIG. 29, and the corresponding data is summarized in the table below:

[1056]

[1057] Example 16 - Preparation and Characterization of Spray-Dry Dispersion of Compound 1

[1058] A spray-dried dispersion (SDD) of Compound 1 was prepared. The SDD consisted of Compound 1 and a polymer (hydroxypropylmethylcellulose AS-MG) in a weight ratio of 1:3. Compound 1 and the polymer were dissolved in organic solvents (dichloromethane and methanol) and spray-dried to obtain an amorphous drug material. The SDD comprising Compound 1 and HPMC AS (1:3) is referred to herein as SDD 0.

[1059] A spray solution was prepared according to Table 18 at a solid content of 7.8% in 80:20 DCM:methanol (1:3 Compound 1:HPMC AS-MG). An API correction factor of 0.966 was used to prepare the spray solution. The spray solution was prepared by adding DCM and methanol to a 36 L stainless steel mixing vessel. HPMC AS-MG was added to the solvent system while mixing with a downward mixer in a medium vortex. Subsequently, Compound 1 was added to this solution. The solution had a clear yellow / brown appearance, but white fibrous particles were observed in the solution.

[1060]

[1061] The Mobile Minor spray-drying apparatus was set up according to Table 19 and preheated for approximately 1 hour prior to spraying. A wash solution (80:20 DCM:methanol) was sprayed prior to the active solution to equilibrate the nozzle. The active solution of Compound 1 was sprayed according to the settings in Table 19. The spray-dried dispersion was dried overnight (approximately 20 hours) in a Shel vacuum oven at 50°C and under a nitrogen purge of 15 scfh at a vacuum of -25 in Hg. The obtained spray-dried dispersion was confirmed to be dry by GC analysis. This procedure produced approximately 2.1 kg of spray-dried dispersion.

[1062]

[1063] SDD was characterized by XRPD (Method B) and DSC analysis (at an atmosphere of 200°C, 2°C / min ramp), as illustrated in FIGS. 30 and 31, respectively. SDD exhibited an amorphous diffraction pattern, a lack of crystalline melting, and a single T at 100°C. G It was determined to be homogeneous and amorphous as indicated by.

[1064] Example 17 - Bioavailability of Spray-Dry Dispersion (SDD) of Compound 1 in Rats and Mice

[1065] Systemic exposure to Compound 1 in rats and mice was evaluated by administering an SDD (SDD 0, which can be prepared as described in Example 16) composed of Compound 1 dispersed in an aqueous vehicle (0.5% hydroxypropylmethylcellulose in water) and HPMC AS-MG (1:3). The SDD formulation administered to rats at 500 mg / kg ("500 mpk SDD") resulted in an AUC 40 times greater than the maximum exposure obtained with the standard formulation ("300 mpk suspension" composed of Compound 1 (Type A) in 10% propylene glycol, 10% Cremophore, and 80% water), as shown in Table 20 and Figure 32. last It was shown. In addition, exposure to a 500 mpk nano-suspension composed of nanoparticles of compound 1 (type A) was evaluated as shown in Fig. 32. Strong exposure was also observed in mice with the SDD formulation.

[1066]

[1067] Example 18 - Bioavailability of spray-dried dispersion of Compound 1 in monkeys

[1068] Several formulations of Compound 1, including SDD prepared with Compound 1 and HPMC AS-MG (1:3) (SDD 0, which can be prepared as described in Example 16), were evaluated in monkeys. The compositions of the tested formulations are listed in Table 21.

[1069]

[1070] The formulations were evaluated for pharmacokinetic parameters in monkeys and are shown in Fig. 33. This profile indicates that the SDD formulation (Formulation 4) provided a significant increase in total exposure compared to the encapsulated formulations (Formulations 1, 2, and 3). The increase in bioavailability by the SDD formulation was approximately 50 to 62%, which is several times higher compared to the other formulations at a dose equivalent to 100 mg.

[1071] Example 19 - Time-dependent solubility of Type A of Compound 1 and spray-dried dispersion of Compound 1 in biological media

[1072] The solubility of Compound 1 Type A was evaluated in an aqueous medium. The aqueous solubility samples of Compound 1 Type 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 under the same procedure used for the t = 24-hour samples. The sample pH was measured only after 24-hour equilibration.

[1073] After 24-hour 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 the method diluent and analyzed by HPLC (Method A). If no solid was present after overnight equilibration, solubility was reported as "≥" relative to the determined value. The reported concentrations are based on single-point calibration in the nominal method and are reported in free form. The results are shown in Table 22 and Figure 34.

[1074]

[1075] The solubility of the 1:3 compound 1:HPMC-AS-MG spray-dry dispersion (SDD 0, which can be prepared as described in Example 16) varied over 24 hours but was evaluated in an aqueous medium at each time point. Individual saturated samples were prepared for each expected time point by adding approximately 10 mg of SDD material to 1.5 mL of solvent. Samples were placed in a thermal shaker at 600 RPM at 37°C and withdrawn at t = 2 min, 5 min, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours. The mixture was centrifuged through a 0.22 μm nylon filter at 15,000 rpm for approximately 5 minutes. All centrifuged samples were diluted with the method diluent and analyzed by HPLC (Method A). Sample pH was measured only at 24 hours. The results are shown in Table 23 and Figure 35.

[1076]

[1077] The solubility of SDD was significant, particularly at the initial time point. After 4 hours, the solubility of SDD was 72.4 µg / mL in FaSSIF and 558.5 µg / mL in FeSSIF. The 4-hour solubility of SDD was 273.5 µg / mL in SGF. Solubility decreased after 24-hour equilibration in all tested aqueous media.

[1078] Example 20 - Evaluation of the stability of a spray-dried dispersion of Compound 1

[1079] Stability studies were performed on two distinct lots of the 1:3 Compound 1:HPMC-AS-MG spray-dry dispersion (SDD 0, which can be prepared as described in Example 16) under the conditions outlined in Table 24. The results of the stability studies for each lot and storage condition are reported in the table identified in Table 24. Lot 1 at 5 months and Lot 2 at 1 month remained consistent with time T=0.

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086] Example 21 - Preparation and Characterization of Spray-Dry Dispersion of Compound 1

[1087] Spray solutions with various ratios of compound 1 to polymer (hydroxypropylmethylcellulose AS-MG) were prepared with an 8% solid content in 80:20 DCM:MeOH (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 dispersion (SDD) was dried at -25 in at 50°C. The vacuum oven was purged for 19 hours using Hg in nitrogen. The SDD was evaluated by XRPD analysis (Method D; Fig. 36) and DSC analysis (Method B; Fig. 37). The SDD appeared amorphous by PXRD analysis, and no crystalline diffraction peaks were observed. A single well-defined T G This was revealed by DSC for all dispersions. No melting endothermic was observed, further verifying the amorphous properties of all spray-dried dispersions. Residual solvent analysis of spray-dried dispersions dried for 19 hours showed varying levels of dichloromethane. The observed trend is that the level of dichloromethane increases with increasing compound-to-polymer ratio.

[1088]

[1089]

[1090] Example 22 - Preparation and Characterization of Spray-Dried Dispersion of Compound 1

[1091] Spray solutions with various ratios of compound 1 to polymer (hydroxypropylmethylcellulose AS-MG) were prepared with a 12% solid content in 80:20 DCM:MeOH (Table 32). The spray solutions were sprayed using a GEA Mobile Minor spray dryer, SDD was collected, and dried under N2 purging at 50°C and -25 in Hg.

[1092]

[1093] Example 23 - Kinetic Solubility of Compound 1 SDD

[1094] Concentrations were quantified under equilibrium solubility experiments involving SDD 0 (which can be prepared as described in Example 16) and SDD 1 to 4 (which can be prepared as described in Example 21) using a μDISS Profiler™ instrument from Pion, Inc. The instrument consists of six photodiode array (PDA) spectrophotometers, each equipped with its own dedicated fiber optic dip probe, and positioned in the center of a glass vial holding 10 ml of medium. Concentration measurements are performed directly in the analytical medium, and the results are plotted in "real time".

[1095] A probe with a 2-mm path length tip was selected for the quantification of Compound 1 in SDD. The developed calibration curve was used to quantify Compound 1 in the samples during kinetic solubility experiments at each time point. A 2-mm path length tip was selected to detect the concentration of Compound 1 in both SGF and FaSSIF media.

[1096] Standard calibration curves were generated in each calibration medium using a series of additional protocols. A stock solution of Compound 1 was prepared in DMSO at approximately 20 mg / mL. Calculated aliquots of the stock were added to respective buffers to prepare several standard solutions spanning specific concentration ranges. The concentrations of the standard solutions ranged from approximately 50 to approximately 300 µg / mL for each channel in the SGF and FaSSIF media, respectively. Concentrations were calculated using the area under the second derivative curve. The wavelength range was selected for the compound in a manner that avoids sensitivity issues. The linearity of the standard curve in the selected wavelength region is r 2 It was characterized by ≥0.999.

[1097] Standard curves were calculated for each medium using the area under the second derivative curve in the range of 285 to 300 nm (SGF) and 305 to 320 nm (FaSSIF). The concentration of compound 1 was determined in a solubility test using the corresponding standard curves.

[1098] The required amount of SDD material equivalent to 20 mg of Compound 1 was weighed into a 20 mL glass vial. Subsequently, the vial was transferred to the instrument for analysis. A clean stirring bar was added to the vial containing the sample. To achieve an upper limit of approximately 1.25 mg / mL, 16 mL of SGF buffer was transferred to the vial before starting the experiment. Stirring was maintained at 220 RPM and a medium temperature of 37°C. Kinetic solubility data were collected in the SGF medium for 30 minutes. The data indicated that all SDDs exhibited very similar release profiles at different loads, which were achieved for the same concentration of Compound 1 (approximately 300 µg / mL).

[1099] The medium was switched to FaSSIF 6.5 at 30-minute intervals. The final volume in the vial was increased from 20 ml to 16 ml (1.00 mg / ml). Subsequently, the obtained samples were analyzed using a μDiss Profiler in FaSSIF for approximately 18 hours.

[1100] The SDD 0 formulation with a 25% drug load reached a higher solubility of approximately 700 µg / ml but did not remain in a supersaturated state for a long time. At 4 hours, the solubility of SDD 0 was slightly lower than that of SDD 1 with a 40% API load, but the equilibrium solubility after approximately 16 hours was higher than that of all other SDD systems. SDD 3 and SDD 4 did not reach concentrations as high as SDD 0 (spring effect). However, both SDD 3 and SDD 4 remained in a supersaturated state for a longer period compared to all other SDD systems tested. However, after 16 hours, the equilibrium solubility for SDD 3 and SDD 4 was lower than that of SDD 0. SDD 2 and SDD 3 show significant solubility enhancement and prolonged supersaturation. The kinetic solubility profiles are shown in Fig. 38.

[1101] The results are summarized in Table 33. All solubility results reported in this table are the average of n=2 replicates.

[1102]

[1103] Example 24 - Stability of spray-dried dispersion of Compound 1

[1104] Spray-dried dispersions of Compound 1 (SDD 0, which can be prepared as described in Example 16, and SDD 1 to 4, which can be prepared as described in Example 21)) were set up for short-term stability studies in two different storage configurations under various storage conditions. Samples were set as "sealed" and "exposed." Sealed samples were placed in crimp-sealed vials and stored under a single storage condition; 60°C. Exposed samples were placed in vials lightly covered with perforated foil to allow exposure to wet conditions. Exposed samples were stored at 40°C / 75%RH and 60°C / 75%RH. Samples were withdrawn after T = 1 and 2 for PXRD analysis (Method D).

[1105] PXRD diffraction patterns taken after 2 weeks for SDDs 0 to 4 are provided in FIGS. 39 to 43, respectively, and the results are summarized in Table 34. SDDs 0, 1, 2, and 3 exhibited amorphous characteristics by PXRD under all tested conditions over 2 weeks. SDD 4 showed crystallinity by PXRD after 2 weeks of storage at 60°C / 75% RH (exposed). SDD 4 also showed two glass transition temperatures by DSC (Method B) after 2 weeks of storage at 60°C / 75% RH (exposed), which suggests phase separation.

[1106]

[1107]

[1108] Example 25 - Stability of spray-dried dispersion of Compound 1

[1109] Spray-dried dispersions of Compound 1 (SDD 5 and 6 (Example 22)) were stored in two different storage configurations under various storage conditions. The samples were set as "sealed" and "exposed." Sealed samples were stored in amber crimped sealed vials under the following conditions: 2 to 8°C, 25°C / 60%RH, 40°C / 75%RH, and 60°C. Exposed samples were stored in amber crimped vials covered with foil perforated to allow exposure to moisture under the following conditions: 25°C / 75%RH, 40°C / 75%RH, and 60°C / 75%RH.

[1110] Samples were analyzed by PXRD (Method D) and / or DSC (Method B) at T = 0, 1, and 2 weeks. The results are summarized in Table 35. No crystalline diffraction peaks were observed by PXRD in any of the samples. Additionally, there was no melting endotherm and a single T G It was revealed by DSC in all samples.

[1111]

[1112]

[1113] The kinetic dissolution of SDD 5 and SDD 6 samples was determined at T = 0 and T = 1 week (40°C / 75% RH exposure; and sealed 40°C / 75% RH) using the procedure described in Example 23. The results are summarized in Table 36.

[1114]

[1115] Example 26 - Composition and preparation of the tablet dosage form of Compound 1

[1116] Composition in tablet dosage form

[1117] A tablet dosage form of Compound 1 containing an SDD composed of Compound 1 and HPMC AS-MG (1:3) was prepared by pressing the compound into a tablet and film-coating it with a compendial excipient. The tablets were presented in dosage strengths of 25 mg (white-coated round tablet) and 100 mg (white-coated oval tablet). The composition of each dosage strength is summarized in Table 37.

[1118]

[1119] Manufacture in tablet dosage form

[1120] The process for manufacturing the tablet formulation of Compound 1 consists of four steps: 1) spray-dry dispersion, 2) granulation within granules, roller pressing / grinding / combining, 3) granulation outside granules / combining, and 4) tablet compression and coating. The initial step of spray-dry dispersion is performed by producing an organic solution containing the Compound 1 drug substance and hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate MG) (HPMCAS-MG). This solution is spray-dried to produce an SDD composed of Compound 1 and HPMCAS-MG (1:3) using a method similar to that of Example 16. The SDD is combined with the granule excipients and then roller pressed / grinded and combined. Subsequently, the resulting granules are mixed with the outside components to produce a final common granule formulation. The final formulation is press-processed into tablets equivalent to 25 mg or 100 mg of activity and then coated.

[1121] Example 27 - Evaluation of Solubility in Tablet Dosage Form

[1122] The 100 mg tablet described in Example 26 was tested for dissolution. The dissolution test parameters are provided in Table 38, and the results are summarized in Table 39.

[1123]

[1124]

[1125] Example 28 - Release test of tablet dosage form

[1126] Dissolution tests were performed on 25 mg and 100 mg tablets with the composition specified in Example 26 according to the dissolution parameters listed in Table 40. Dissolution was determined by UPLC analysis. The results of the dissolution tests are reported in Table 41 and Figure 52.

[1127]

[1128]

[1129] Example 29 - Evaluation of stability of tablet administration form

[1130] Stability studies were performed on two separate lots of 25 mg and 100 mg tablets with the composition specified in Example 26 under the conditions outlined in Table 42. The results of the stability studies for each lot and storage conditions are reported in the table identified in Table 42.

[1131] For XRPD analysis (Method D), tablets were prepared by crushing the tablets with a mortar and pestle, transferring 5 to 10 mg of material to a sample pan, slightly overfilling it, and ensuring that the powder spreads evenly to cover the bottom of the plate. Weighing paper was placed over the powder and gently pressed to ensure the powder surface was even. The XRPD pattern of the tablet was superimposed with the XRPD pattern of the reference standard (Compound 1, Type A). The tablet was considered to be free of diffraction peaks present in the reference standard only if there was no peak at approximately 15 degrees 2-theta. A small, irregular peak at approximately 3 degrees 2-theta is acceptable.

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141] The results of the tablet batches from Lot 1 at the 3-month mark and Lot 2 at the 1-month mark were maintained consistently with time T=0.

[1142] Example 30 - Composition and preparation of a tablet dosage form of Compound 1

[1143] Tablets containing a spray-dried dispersion (SDD) of compound 1 and a complemential excipient are prepared in 100 mg and 200 mg dosage strengths. The composition of the tablets is presented in Tables 51 and 52.

[1144] Tablets are first prepared by spray-drying an SDD (an organic solution of Compound 1 and HPMC-AS (1:1 w / w) (Table 51) or an organic solution of Compound 1 and HPMC-AS (1.5:1 w / w) (Table 52), followed by roller pressing / grinding with excipients inside the granules and mixing with excipients outside the granules. The final mixture is press-processed into tablets and then film-coated.

[1145]

[1146]

[1147] Example 31 - Evaluation of Stability of Tablet Dosage Form

[1148] Tablets with the compositions presented in Tables 51 and 52 were prepared for XRPD analysis (Method D) by crushing the tablets with a mortar and pestle, transferring 5 to 10 mg of the material to a sample pan, slightly overfilling it, and ensuring that the powder spreads evenly to cover the bottom of the plate. Weighing paper was placed over the powder and gently pressed to smooth the powder surface. The XRPD pattern of the tablets was superimposed with the XRPD pattern of the reference standard (Compound 1, Type A). The XRPD pattern of the tablets was considered to be free of diffraction peaks present in the reference standard only if there was no peak at approximately 15 degrees 2-theta. A small, irregular peak at approximately 3 degrees 2-theta is acceptable. The tablets were determined to be free of crystalline Type A because the diffraction peaks present in the reference standard were absent from the XRPD pattern.

[1149] Example 32 - Compound 2 Determination of the maximum capacity

[1150] A predetermined amount of compound 2 Compounds containing 1 Good Laboratory Practice (GLP) toxicology testing of the test products was performed in rats and cynomolgus monkeys. The no-observed-adverse-effect level (NOAEL) was determined for each species using standard toxicology techniques, and the obtained dose levels for humans were calculated using the FDA human equivalent dose approach based on dose per body surface area. Based on these experiments and calculations, the maximum recommended starting dose (MRSD) for the initial human clinical trial was determined based on the results from the GLP toxicology tests. Compounds of less than 5.0% (as determined by area percentage HPLC). 2 Compounds containing 1 The API composition is sufficiently a compound 2 It is within the safe human equivalent dose determined for.

Claims

Claim 1 Compound 1 below: An amorphous solid dispersion comprising a compound and a polymer, wherein the polymer is selected from the group consisting of hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof, and the weight ratio of the compound to the polymer is in the range of 2:1 to 1:

3. Claim 2 The amorphous solid dispersion according to claim 1, characterized in that the polymer is hydroxypropylmethyl cellulose (HPMC) or hydroxypropylmethyl cellulose acetate succinate (HPMC AS). Claim 3 The amorphous solid dispersion according to claim 1, characterized in that the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS). Claim 4 An amorphous solid dispersion characterized in that, in claim 3, the weight ratio of one compound to a polymer is in the range of 1:

1. Claim 5 The amorphous solid dispersion according to claim 1, characterized in that the crystalline diffraction peak is not observable by XPRD analysis (Method D) of the amorphous solid dispersion. Claim 6 A tablet oral formulation comprising a therapeutically effective amount of the amorphous solid dispersion of claim 3 and one or more pharmaceutically acceptable excipients. Claim 7 A tablet oral formulation according to claim 6, characterized by containing 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 300 mg of compound 1. Claim 8 A tablet oral formulation characterized by comprising 200 mg of compound 1 in claim 6. Claim 9 As a solid oral formulation, it comprises the stabilized amorphous compound (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridine-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one, wherein the stabilized amorphous compound does not exhibit crystallinity by PXRD (Method D) after storage for 2 weeks at 60°C / 75% RH (exposed), and the stabilized amorphous compound comprises hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylcellulose (HPC), ethylcellulose, cellulose acetate phthalate, A solid oral formulation existing as a spray-dried dispersion using a polymer selected from the group consisting of polyvinylpyrrolidone (PVP) and combinations thereof, wherein the weight ratio of (S)-1-(5-[2H,3H-[1,4]dioxyno[2,3-b]pyridin-7-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-yl)-3-hydroxy-2-phenylpropan-1-one to the polymer is 1:3 to 2:1, or 1:

1. Claim 10 A solid oral formulation according to claim 9, characterized in that the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMC AS). Claim 11 A tablet formulation comprising an amorphous solid dispersion of Compound 1 and HPMC AS, wherein the weight ratio of Compound 1 to HPMC AS is 1:1, and comprising 200 mg of Compound 1 and the following components: Claim 12 A method for preparing an amorphous solid dispersion of claim 1, comprising the step of mixing a solvent with a polymer selected from the group consisting of compound 1, hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone (PVP), and combinations thereof to provide a mixture, wherein the weight ratio of compound 1 to the polymer is in the range of 2:1 to 1:3; and the step of spray-drying the mixture to provide an amorphous solid dispersion comprising compound 1. Claim 13 A method according to claim 12, characterized in that the weight ratio of compound to polymer is 1:1 and the polymer is HPMC AS. Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete

Images