Solid forms of naphthyridine compounds

Abstract

Disclosed herein are various solid forms of Compound A, including crystalline and amorphous forms of the free base of Compound A, as well as salt forms, co-crystals, and solvates thereof. Methods of making the salt, co-crystal, and solvate forms, and methods of treating diseases and disorders with the salt, co-crystal, and solvate forms are also disclosed. TIFF2025541772000061.tif26170

Description

[Background technology]

[0001] Naphthyridine compounds have been shown to be important in many biological applications. To investigate their effectiveness, large amounts of material are required. Therefore, there is a need for solid forms of naphthyridine compounds, including crystalline forms, amorphous forms, salts, cocrystals, and solvates, as well as processes for isolating them. Summary of the Invention [Means for solving the problem]

[0002] The present disclosure provides solid forms of Compound A, including crystalline forms, amorphous forms, and salts, solvates, and co-crystals thereof, wherein Compound A has the following structure: [ka]

[0003] In some embodiments, the present disclosure provides an amorphous form of the free base of Compound A.

[0004] In some embodiments, the present disclosure provides a crystalline form of Compound A.

[0005] In some embodiments, the present disclosure provides crystalline Compound A in free base form.

[0006] In some embodiments, the present disclosure provides a crystalline form of the free base of Compound A (“Form 1”) characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.5, 9.0, 13.3, 16.2, and 18.8±0.2 degrees 2θ using CuKα radiation.

[0007] In some embodiments, the present disclosure provides a crystalline form of the free base of Compound A (“Form 3”) characterized by an XRPD pattern comprising peaks at 4.3, 12.6, 14.4, 16.2, and 25.6±0.2 degrees 2θ using CuKα radiation.

[0008] In some embodiments, the present disclosure provides a crystalline form of the free base of Compound A (“Form 6”) characterized by an XRPD pattern comprising peaks at 4.5, 8.6, 9.0, 12.9, and 14.9±0.2 degrees 2θ using CuKα radiation.

[0009] In some embodiments, the present disclosure provides a crystalline form of the free base of Compound A (“Form 7”) characterized by an XRPD pattern comprising peaks at 4.3, 8.5, 12.3, 13.1, and 14.8±0.2 degrees 2θ using CuKα radiation.

[0010] In some embodiments, the present disclosure provides a crystalline form of the free base hydrate of Compound A (“Form 8”), characterized by an XRPD pattern comprising peaks at 4.0, 7.7, 8.0, 12.3, and 15.1±0.2 degrees 2θ using CuKα radiation.

[0011] In some embodiments, the present disclosure also provides a crystalline form of an ethanol solvate of Compound A (“Form 2A”), characterized by an XRPD pattern comprising peaks at 5.8, 11.6, 12.7, 18.0, and 25.7±0.2 degrees 2θ using CuKα radiation.

[0012] In some embodiments, the present disclosure also provides a crystalline form of the isopropanol solvate of Compound A (“Form 3A”), characterized by an XRPD pattern comprising peaks at 5.6, 12.8, 16.4, 17.5, and 25.1±0.2 degrees 2θ using CuKα radiation.

[0013] In some embodiments, the present disclosure also provides a crystalline form of the acetone solvate of Compound A (“Form 4A”), characterized by an XRPD pattern comprising peaks at 5.7, 7.7, 11.5, 14.8, and 15.3±0.2 degrees 2θ using CuKα radiation.

[0014] In some embodiments, the present disclosure also provides a crystalline form of a methanol solvate of Compound A (“Form 5A”), characterized by an XRPD pattern comprising peaks at 4.8, 7.7, 12.3, 15.3, and 16.1±0.2 degrees 2θ using CuKα radiation.

[0015] In some embodiments, the present disclosure also provides a crystalline form of the methyltetrahydrofuran solvate of Compound A (“Form 6A”), characterized by an XRPD pattern comprising peaks at 7.6, 11.3, 15.1, 18.3, and 28.0±0.2 degrees 2θ using CuKα radiation.

[0016] In some embodiments, the present disclosure also provides an amorphous form of Compound A free base, characterized by a differential scanning calorimetry scan substantially as shown in FIG.

[0017] In some embodiments, the present disclosure also provides a crystalline form of the toluenesulfonate salt of Compound A (“Form A1”), characterized by an XRPD pattern comprising peaks at 6.0, 19.1, 20.3, 24.1, 24.9, and 28.9±0.2 degrees 2θ using CuKα radiation.

[0018] In some embodiments, the present disclosure also provides a crystalline form of the toluenesulfonate salt of Compound A (“Form A2”), characterized by an XRPD pattern comprising peaks at 12.7, 15.5, 16.2, 18.7, 19.7, and 21.8±0.2 degrees 2θ using CuKα radiation.

[0019] In some embodiments, the present disclosure also provides a crystalline form of the toluenesulfonate salt of Compound A (“Form A3”), characterized by an XRPD pattern comprising peaks at 4.9, 15.2, 18.8, 19.5, and 24.5±0.2 degrees 2θ using CuKα radiation.

[0020] In some embodiments, the present disclosure also provides a crystalline form of the benzenesulfonate salt of Compound A (“Form B1”), characterized by an XRPD pattern comprising peaks at 5.1, 16.1, 17.9, 19.0, and 25.2±0.2 degrees 2θ using CuKα radiation.

[0021] In some embodiments, the present disclosure also provides a crystalline form of the chloride salt of Compound A (“Form C1”), characterized by an XRPD pattern comprising peaks at 6.8, 11.9, 16.6, 20.7, 23.8, 25.3, and 27.6±0.2 degrees 2θ using CuKα radiation.

[0022] In some embodiments, the present disclosure also provides a crystalline form of the chloride salt of Compound A (“Form C2”), characterized by an XRPD pattern comprising peaks at 4.2, 5.6, 12.2, 12.9, and 18.1±0.2 degrees 2θ using CuKα radiation.

[0023] In some embodiments, the present disclosure also provides a crystalline form of the sulfate salt of Compound A (“Form D1”), characterized by an XRPD pattern comprising peaks at 16.0, 16.5, 16.7, 20.0, and 20.4±0.2 degrees 2θ using CuKα radiation.

[0024] In some embodiments, the present disclosure also provides a crystalline form of the malonate salt of Compound A (“Form E1”), characterized by an XRPD pattern comprising peaks at 6.8, 12.6, 16.6, 20.4, and 22.0±0.2 degrees 2θ using CuKα radiation.

[0025] In some embodiments, the present disclosure also provides a crystalline form of naphthalene-2-sulfonate salt of Compound A (“Form F1”), characterized by an XRPD pattern comprising peaks at 4.7, 14.7, 14.9, 17.0, 19.6, and 22.1±0.2 degrees 2θ using CuKα radiation.

[0026] In some embodiments, the present disclosure also provides a crystalline form of naphthalene-2-sulfonate salt of Compound A (“Form F2”), characterized by an XRPD pattern comprising peaks at 5.8, 11.6, 14.0, 17.5, and 19.7±0.2 degrees 2θ using CuKα radiation.

[0027] In some embodiments, the present disclosure also provides a crystalline form of naphthalene-2-sulfonate salt of Compound A (“Form F3”), characterized by an XRPD pattern comprising peaks at 3.8, 7.6, 9.7, 11.5, and 15.3±0.2 degrees 2θ using CuKα radiation.

[0028] In some embodiments, the present disclosure also provides a crystalline form of the methanesulfonate salt of Compound A (“Form G1”), characterized by an XRPD pattern comprising peaks at 5.1, 6.5, 13.6, 13.8, and 19.5±0.2 degrees 2θ using CuKα radiation.

[0029] In some embodiments, the present disclosure also provides a crystalline form of the methanesulfonate salt of Compound A (“Form G2”), characterized by an XRPD pattern comprising peaks at 5.6, 13.1, 13.3, 16.3, and 18.3±0.2 degrees 2θ using CuKα radiation.

[0030] In some embodiments, the present disclosure also provides a crystalline form of the oxalate salt of Compound A (“Form H2”), characterized by an XRPD pattern comprising peaks at 6.9, 8.7, 13.6, 17.4, and 24.6±0.2 degrees 2θ using CuKα radiation.

[0031] In some embodiments, the present disclosure also provides a crystalline form of the tartrate salt of Compound A (“Form I1”), characterized by an XRPD pattern comprising peaks at 3.4, 14.7, 15.6, 18.02, and 24.3±0.2 degrees 2θ using CuKα radiation.

[0032] In some embodiments, the present disclosure also provides a crystalline form of the ethanesulfonate salt of Compound A (“Form J1”), characterized by an XRPD pattern comprising peaks at 5.6, 7.9, 13.6, 15.7, and 17.9±0.2 degrees 2θ using CuKα radiation.

[0033] In some embodiments, the present disclosure also provides a crystalline form of the ethanesulfonate salt of Compound A (“Form J2”), characterized by an XRPD pattern comprising peaks at 4.0, 6.3, 7.7, 15.8, and 20.9±0.2 degrees 2θ using CuKα radiation.

[0034] In some embodiments, the present disclosure also provides a crystalline form of N-cyclohexylsulfamate salt of Compound A (“Form K1”), characterized by an XRPD pattern comprising peaks at 5.8, 14.0, 15.6, 16.7, and 28.1±0.2 degrees 2θ using CuKα radiation.

[0035] In some embodiments, the present disclosure also provides a crystalline form of the maleate salt of Compound A (“Form L1”), characterized by an XRPD pattern comprising peaks at 5.7, 17.0, 17.5, 25.6, and 26.1±0.2 degrees 2θ using CuKα radiation.

[0036] In some embodiments, the present disclosure also provides a crystalline form of the phosphate salt of Compound A (“Form M1”), characterized by an XRPD pattern comprising peaks at 5.4, 16.2, 20.3, and 22.5±0.2 degrees 2θ using CuKα radiation.

[0037] In some embodiments, the present disclosure also provides a crystalline form of the phosphate salt of Compound A (“Form M2”), characterized by an XRPD pattern comprising peaks at 7.1, 14.2, 14.9, 17.9, and 19.6±0.2 degrees 2θ using CuKα radiation.

[0038] In some embodiments, the present disclosure also provides a crystalline form of the phosphate salt of Compound A (“Form M3”), characterized by an XRPD pattern comprising peaks at 7.5, 7.8, 14.8, 15.0, and 15.4±0.2 degrees 2θ using CuKα radiation.

[0039] In some embodiments, the disclosure also provides a crystalline form of salicylic acid co-crystal of Compound A (“Form CC-1A”), characterized by an XRPD pattern comprising peaks at 9.3, 5.9, 9.7, 6.0, and 13.9 24±0.2 degrees 2θ using CuKα radiation.

[0040] In some embodiments, the disclosure also provides a crystalline form of a salicylic acid co-crystal of Compound A (“Form CC-2A”), characterized by an XRPD pattern comprising peaks at 8.2, 9.2, 16.5, 18.5, and 16.0±0.2 degrees 2θ using CuKα radiation.

[0041] In some embodiments, the disclosure also provides a crystalline form of a salicylic acid co-crystal of Compound A (“Form CC-3A”), characterized by an XRPD pattern comprising peaks at 3.6, 12.6, 8.0, 14.4, and 7.2±0.2 degrees 2θ using CuKα radiation.

[0042] In some embodiments, the present disclosure also provides a crystalline form of salicylic acid co-crystal of Compound A (“Form CC-4A”), characterized by an XRPD pattern comprising peaks at 10.3, 16.2, 9.9, 16.3, 19.9±0.2 degrees 2θ using CuKα radiation.

[0043] In some embodiments, the disclosure also provides a crystalline form of salicylic acid co-crystal of Compound A (“Form CC-5A”), characterized by an XRPD pattern comprising peaks at 5.3, 17.8, 10.6, 18.3, and 15.9±0.2 degrees 2θ using CuKα radiation.

[0044] In some embodiments, the present disclosure also provides a crystalline form of formic acid co-crystal of Compound A (“Form CC-1B”), characterized by an XRPD pattern comprising peaks at 8.6, 4.6, 17.8, 17.4, and 23.0±0.2 degrees 2θ using CuKα radiation.

[0045] In some embodiments, the disclosure also provides a crystalline form of a benzoic acid co-crystal of Compound A (“Form CC-1C”), characterized by an XRPD pattern comprising peaks at 11.6, 16.1, 14.2, 3.9, and 19.8±0.2 degrees 2θ using CuKα radiation.

[0046] In some embodiments, the disclosure also provides a crystalline form of the isobutyric acid co-crystal of Compound A (“Form CC-1D”), characterized by an XRPD pattern comprising peaks at 5.6, 6.1, 13.1, 16.0, and 17.1±0.2 degrees 2θ using CuKα radiation.

[0047] In some embodiments, the present disclosure also provides a crystalline form of the isobutyric acid co-crystal of Compound A (“Form CC-2D”), characterized by an XRPD pattern comprising peaks at 5.2, 5.5, 6.3, 10.3, and 12.6±0.2 degrees 2θ using CuKα radiation.

[0048] In some embodiments, the disclosure also provides a crystalline form of a benzoic acid co-crystal of Compound A (“Form CC-1C”), characterized by an XRPD pattern comprising peaks at 11.6, 16.1, 14.2, 3.9, and 19.8±0.2 degrees 2θ using CuKα radiation.

[0049] In some embodiments, the present disclosure also provides a crystalline form of caprylic acid co-crystal of Compound A (“Form CC-1E”), characterized by an XRPD pattern comprising peaks at 4.8, 6.2, 6.5, 18.1, and 21.1±0.2 degrees 2θ using CuKα radiation.

[0050] In some embodiments, the disclosure also provides a crystalline form of a sorbic acid co-crystal of Compound A (“Form CC-1F”), characterized by an XRPD pattern comprising peaks at 8.18, 10.8, 11.4, 18.2, and 21.2±0.2 degrees 2θ using CuKα radiation.

[0051] In some embodiments, the present disclosure also provides a crystalline form of a saccharin co-crystal of Compound A (“Form CC-1G”), characterized by an XRPD pattern comprising peaks at 5.1, 9.8, 10.1, 16.5, and 20.4±0.2 degrees 2θ using CuKα radiation.

[0052] In some embodiments, the present disclosure also provides a crystalline form of succinic acid co-crystal of Compound A (“Form CC-1H”), characterized by an XRPD pattern comprising peaks at 11.3, 11.5, 18.3, 19.0, and 20.6±0.2 degrees 2θ using CuKα radiation.

[0053] In some embodiments, the present disclosure also provides a crystalline form of succinic acid co-crystal of Compound A (“Form CC-2H”), characterized by an XRPD pattern comprising peaks at 4.2, 5.3, 8.3, 9.0, and 9.2±0.2 degrees 2θ using CuKα radiation.

[0054] In some embodiments, the present disclosure also provides a crystalline form of adipic acid co-crystal of Compound A (“Form CC-1I”), characterized by an XRPD pattern comprising peaks at 7.7, 10.5, 18.5, 18.9, and 21.7±0.2 degrees 2θ using CuKα radiation.

[0055] In some embodiments, the present disclosure also provides pharmaceutical compositions comprising the crystalline forms, amorphous forms, salts, co-crystals, and solvates of Compound A disclosed herein and at least one pharmaceutically acceptable excipient.

[0056] In some embodiments, the present disclosure also provides methods of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form, amorphous form, salt, co-crystal, or solvate of Compound A disclosed herein. [Brief explanation of the drawings]

[0057] [Figure 1] 1 shows the XRPD pattern of Form 1 of the crystalline form of the free base of Compound A. [Figure 2] 1 shows a differential scanning calorimetry (DSC) thermograph and thermogravimetric analysis ("TGA") trace of Form 1, a crystalline form of the free base of Compound A, showing an extrapolated onset of 225°C and a weight loss of 0.03% from 35 to 150°C. [Figure 3] 1 shows the hygroscopicity profile (DVS) of Form 1, a crystalline form of the free base of Compound A, which is non-hygroscopic at 25° C. from 0% to 95% relative humidity. [Figure 4] 1 shows the XRPD pattern of Form 3, a crystalline form of the free base of Compound A. [Figure 5]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis ("TGA") trace of Form 3, a crystalline form of the free base of Compound A, which shows exothermic events with onset temperatures of 105°C and 173°C and peak temperatures of 111°C and 173°C, with endothermic events observed with onset and peak temperatures of 226°C and 229°C. Negligible weight loss is observed up to 200°C. [Figure 6] 1 shows the DVS of Form 3, a crystalline form of the free base of Compound A. [Figure 7] 1 shows the XRPD pattern of Form 6, a crystalline form of the free base of Compound A. [Figure 8] 1 shows a DSC thermograph and thermogravimetric analysis (“TGA”) trace of Form 6, a crystalline form of the free base of Compound A. [Figure 9] 1 shows the XRPD pattern of Form 7, a crystalline form of the free base of Compound A. [Figure 10]1 shows a DSC thermograph and thermogravimetric analysis ("TGA") trace of Form 7, a crystalline form of the free base of Compound A, showing an endothermic event with an onset temperature of 61°C and others at higher temperatures, with peak temperatures of 87°C, 221°C, and 223°C. Exothermic events were observed with onset and peak temperatures of 129°C and 141°C. A weight loss of 1.2% was observed at 94°C, with an additional weight loss of 0.3% observed up to 176°C. [Figure 11] 1 shows the XRPD pattern of the hydrate of Form 8, a crystalline form of the free base of Compound A. [Figure 12]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis ("TGA") trace of a hydrate of Form 8, a crystalline form of the free base of Compound A, showing endothermic events with onset temperatures of 57°C and 219°C, and peak temperatures of 79°C and 225°C, respectively. A weight loss of 3.3% by TGA was observed up to 128°C. [Figure 13] 1 shows the XRPD pattern of Form 2A, a crystalline form of the ethanol solvate of Compound A. [Figure 14]

[0033] Figure 2 shows a DSC thermograph and thermogravimetric analysis ("TGA") of Form 2A, a crystalline form of the ethanol solvate of Compound A. The DSC shows a first endotherm with an extrapolated onset at 132°C as a result of desolvation of ethanol, a second endotherm overlapping with an exotherm accompanying subsequent recrystallization, which was followed by an extrapolated melting onset at 224°C and a 2.9% weight loss from 26 to 160°C. [Figure 15] 1 shows the XRPD pattern of Form 3A, a crystalline form of the isopropanol solvate of Compound A. [Figure 16] 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form 3A, a crystalline form of the isopropanol solvate of Compound A. The DSC shows a first endotherm with an extrapolated onset at 123°C as a result of desolvation of isopropyl alcohol (IPA), a second endotherm overlapping with an exotherm accompanying subsequent recrystallization, which was followed by an extrapolated melting onset at 223°C and a 6.6% weight loss from 28 to 150°C. [Figure 17] 1 shows the XRPD pattern of Form 4A, a crystalline form of the acetone solvate of Compound A. [Figure 18]

[0033] Figure 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form 4A, a crystalline form of the acetone solvate of Compound A. The DSC shows an endothermic event with onset temperatures of 111°C, 143°C, and 226°C, and peak temperatures of 124°C, 151°C, and 227°C. An exothermic event was observed with onset and peak temperatures of 158°C and 162°C. A weight loss of 4.2% by TGA was observed up to 152°C. [Figure 19] 1 shows the XRPD pattern of Form 5A, a crystalline form of the methanol solvate of Compound A. [Figure 20]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form 5A, a crystalline form of the methanol solvate of Compound A. The DSC shows endothermic events with onset temperatures of 50°C and 226°C, and peak temperatures of 70°C and 227°C. Exothermic events were observed with onset and peak temperatures of 117°C and 137°C. A weight loss of 1.7% by TGA was observed up to 200°C. [Figure 21] 1 shows the XRPD pattern of Form A1, a crystalline form of the toluenesulfonate salt of Compound A. [Figure 22] 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form A1, a crystalline form of the toluenesulfonate salt of Compound A, which shows an extrapolated onset of 293°C and a weight loss of 0.15% from 32 to 200°C. [Figure 23] 1 shows the DVS of Form A1, a crystalline form of the toluenesulfonate salt of Compound A, exhibiting a 0.5% weight gain at 25° C. with 90% relative humidity. [Figure 24] 1 shows the XRPD pattern of Form A2, a crystalline form of the toluenesulfonate salt of Compound A. [Figure 25] 1 shows a DSC thermograph and thermogravimetric analysis ("TGA") of Form A2, a crystalline form of the toluenesulfonate salt of Compound A. The DSC shows an exotherm with an extrapolated onset of 242°C due to recrystallization, followed by an extrapolated melting / decomposition of 287°C, and a weight loss of 0.04% between 32 and 150°C. [Figure 26] 1 shows the XRPD pattern of Form A3, a crystalline form of the toluenesulfonate salt of Compound A. [Figure 27]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis ("TGA") of Form A3, a crystalline form of the toluenesulfonate salt of Compound A. The DSC shows an endothermic event with onset and peak temperatures of 281°C and 289°C, respectively. Form A3 showed negligible weight loss by TGA up to 256.4°C. [Figure 28] 1 shows the DVS of Form A3, a crystalline form of the toluenesulfonate salt of Compound A. [Figure 29] 1 shows the XRPD pattern of Form B1, a crystalline form of the benzenesulfonate salt of Compound A. [Figure 30] 1 shows a DSC thermograph of Form B1, a crystalline form of the benzenesulfonate salt of Compound A. The DSC shows an endotherm with an extrapolated onset of 97°C followed by an extrapolated endothermic melting / decomposition point at 254°C. [Figure 31] 1 shows the XRPD pattern of Form C1, a crystalline form of the hydrochloride salt of Compound A. [Figure 32] 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form C1, a crystalline form of the chloride salt of Compound A. The DSC shows a broad endotherm with an extrapolated onset at 34°C and an extrapolated endothermic melting / decomposition point / salt disproportionation point at 166°C, and a weight loss of 12.6% from 30 to 200°C. [Figure 33] 1 shows the XRPD pattern of Form C2, a crystalline form of the chloride salt of Compound A. [Figure 34]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form C2 of the chloride salt of crystalline Compound A. The DSC shows an endothermic melt with onset temperatures of 54°C and 121°C, and peak temperatures of 75°C and 133°C, respectively. Form C2 exhibited an observed weight loss of 8.6% up to 212°C by TGA. [Figure 35] 1 shows the XRPD pattern of Form D1, a crystalline form of the sulfate salt of Compound A. [Figure 36] 1 shows the XRPD pattern of crystalline Compound A malonate salt Form E1. [Figure 37]1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form E1 of the crystalline malonate salt of Compound A. The DSC shows an endothermic melt with onset and peak temperatures of 182° C. and 183° C., respectively. Form E1 shows negligible weight loss by TGA up to 153° C. [Figure 38] 1 shows the XRPD pattern of Form F1 of the crystalline naphthalene-2-sulfonate salt of Compound A. [Figure 39]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form F1 of the crystalline naphthalene-2-sulfonate salt of Compound A. The DSC shows an endothermic melt with onset and peak temperatures of 206°C and 211°C, respectively. Form F1 shows negligible weight loss by TGA up to 212°C. [Figure 40] 1 shows the DVS of Form F1 of the crystalline naphthalene-2-sulfonate salt of Compound A. [Figure 41] 1 shows the XRPD pattern of Form F2 of the crystalline naphthalene-2-sulfonate salt of Compound A. [Figure 42] 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form F2 of the crystalline naphthalene-2-sulfonate salt of Compound A. The DSC shows an endothermic melt with onset and peak temperatures of 273° C. and 280° C. Form F2 shows negligible weight loss by TGA up to 223° C. [Figure 43] 1 shows the DVS of Form F2 of the crystalline naphthalene-2-sulfonate salt of Compound A. [Figure 44] 1 shows the XRPD pattern of Form F3 of the crystalline naphthalene-2-sulfonate salt of Compound A. [Figure 45]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form F3 of the crystalline naphthalene-2-sulfonate salt of Compound A. The DSC shows endothermic events with onset temperatures of 50°C and 147°C, and peak temperatures of 76°C and 212°C, respectively. Form F3 exhibits a 3.6% weight loss by TGA up to 209°C. [Figure 46] 1 shows the XRPD pattern of Form G1 of the methanesulfonate salt of crystalline Compound A. [Figure 47]1 shows the XRPD pattern of Form G2 of the methanesulfonate salt of crystalline Compound A. [Figure 48]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form G2 of the methanesulfonate salt of crystalline Compound A. The DSC shows an endothermic transition with onset and peak temperatures of 271°C and 272°C, respectively. Form G3 shows negligible weight loss by TGA up to 206°C. [Figure 49] 1 shows the DVS of Form G2 of the methanesulfonate salt of crystalline Compound A. [Figure 50] 1 shows the XRPD pattern of crystalline Compound A oxalate salt form H2. [Figure 51] 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form H2 of the oxalate salt of crystalline Compound A. The DSC shows an endothermic event with onset and peak temperatures of 241° C. and 243° C., respectively. Form H2 shows negligible weight loss by TGA up to 196° C. [Figure 52] 1 shows the XRPD pattern of Form I1 of the crystalline Compound A tartrate salt. [Figure 53]

[0023] Figure 1 shows a DSC thermograph and thermogravimetric analysis (TGA) of Form I1 of the crystalline tartrate salt of Compound A. The DSC shows endothermic events with onset temperatures of 79°C and 144°C, and peak temperatures of 105°C and 152°C, respectively. Form I1 shows a 3.0% weight loss by TGA up to 151°C. [Figure 54] 1 shows the XRPD pattern of Form J1 of the crystalline ethanesulfonic acid salt of Compound A. [Figure 55] 1 shows a DSC thermograph and TGA of Form J1 of the ethanesulfonate salt of crystalline Compound A. The DSC shows endothermic events with onset temperatures of 30° C. and 244° C., and peak temperatures of 64° C. and 254° C. Form J1 shows a 6.2% weight loss by TGA up to 250° C. [Figure 56] 1 shows the XRPD pattern of Form J2 of the crystalline ethanesulfonic acid salt of Compound A. [Figure 57]

[0023] Figure 1 shows a DSC thermograph and TGA of Form J2 of the crystalline ethanesulfonate salt of Compound A. The DSC shows endothermic events with onset temperatures of 34.4°C and 238.0°C, and peak temperatures of 63°C and 249°C, respectively. Form J2 shows a 2.5% weight loss by TGA up to 219°C. [Figure 58] 1 shows the XRPD pattern of Form K1 of the crystalline N-cyclohexylsulfamate salt of Compound A. [Figure 59] 1 shows a DSC thermograph and TGA of Form K1 of crystalline N-cyclohexylsulfamate salt of Compound A. The DSC shows an endothermic event with onset and peak temperatures of 201° C. and 211° C., respectively. Form K1 shows a 2.5% weight loss by TGA up to 213° C. [Figure 60] 1 shows the XRPD pattern of crystalline Compound A maleate salt form L1. [Figure 61] 1 shows a DSC thermograph and TGA of Form L1 of the maleate salt of crystalline Compound A. The DSC shows an endothermic event with onset and peak temperatures of 198° C. and 203° C. Form L1 shows a 2.0% weight loss by TGA up to 181° C. [Figure 62] 1 shows the XRPD pattern of crystalline Compound A phosphate salt Form M1. [Figure 63] 1 shows a DSC thermograph and TGA of Form M1 of the phosphate salt of crystalline Compound A. The DSC shows an endothermic event with an onset temperature of 214° C. and a peak temperature of 217° C. Form M1 shows negligible weight loss by TGA up to 188° C. [Figure 64] 1 shows the DVS of crystalline Compound A phosphate salt form M1. [Figure 65] 1 shows the XRPD pattern of crystalline Compound A phosphate salt form M2. [Figure 66]1 shows a DSC thermograph and TGA of Form M2 of the phosphate salt of crystalline Compound A. The DSC shows endothermic events with onset temperatures of 57° C., 88° C., 141° C., and 198° C., and peak temperatures of 74° C., 109° C., 149° C., and 205° C. Form M2 shows a 1.1% weight loss by TGA up to 106° C. [Figure 67] 1 shows the XRPD pattern of crystalline Compound A phosphate salt form M3. [Figure 68] 1 shows a DSC thermograph and TGA of Form M3 of the crystalline phosphate salt of Compound A. The DSC shows endothermic events with peak temperatures of 69°C, 88°C, and 102°C. Additionally, there are endothermic events with onset temperatures of 157°C and 208°C, and peak temperatures of 165°C and 214°C, respectively. There are exothermic events with onset and peak temperatures of 174°C and 181°C, respectively. Form M3 shows a weight loss of 8.1% by TGA. [Figure 69] 1 shows the XRPD pattern of crystalline Compound A salicylic acid co-crystal form CC-1A. [Figure 70] 1 shows a DSC thermograph and TGA of Form CC-1A of the crystalline Compound A salicylic acid co-crystal. The DSC shows endothermic events with onset temperatures of 43° C. and 103° C., and peak temperatures of 75° C., 107° C., and 239° C., respectively. Form CC1-A shows a weight loss of 11.7% by TGA up to 126° C. [Figure 71] 1 shows the XRPD pattern of crystalline Compound A salicylic acid co-crystal form CC-2A. [Figure 72]

[0023] Figure 1 shows a DSC thermograph and TGA of Form CC-2A of the salicylic acid co-crystal of crystalline Compound A. The DSC shows endothermic events with onset temperatures of 107°C and 195°C, and peak temperatures of 119°C and 196°C, respectively. Form CC2-A shows a 13.6% weight loss by TGA up to 133°C. [Figure 73] 1 shows the XRPD pattern of crystalline Compound A salicylic acid co-crystal form CC-3A. [Figure 74]1 shows a DSC thermograph and TGA of crystalline Compound A salicylic acid co-crystal Form CC-3A. The DSC shows an endothermic event with onset and peak temperatures of 182° C. and 185° C., respectively. Form CC-3A shows negligible weight loss by TGA up to 127° C. [Figure 75] 1 shows the DVS of crystalline Compound A salicylic acid co-crystal form CC-3A, with a mass gain of 1.3% up to 80% relative humidity. [Figure 76] 1 shows the XRPD pattern of crystalline Compound A salicylic acid co-crystal form CC-4A. [Figure 77] 1 shows a DSC thermograph and TGA of crystalline Compound A salicylic acid co-crystal Form CC-4A. The DSC shows endothermic events with onset temperatures of 143° C. and 198° C. and peak temperatures of 152° C. and 200° C., respectively. Form CC-4A shows a 5.7% weight loss by TGA up to 171° C. [Figure 78] 1 shows the XRPD pattern of crystalline Compound A salicylic acid co-crystal form CC-5A. [Figure 79] 1 shows a DSC thermograph and TGA of crystalline Compound A salicylic acid co-crystal Form CC-5A. The DSC shows an endothermic event with a peak temperature of 1224° C. Form CC-5A shows a weight loss of 8.3% by TGA up to 134° C. [Figure 80] 1 shows the XRPD pattern of crystalline Compound A formic acid co-crystal form CC-1B. [Figure 81] 1 shows a DSC thermograph and TGA of crystalline Compound A formic acid co-crystal Form CC-1B. The DSC shows endothermic events with peak temperatures at 62° C. and 105° C. Form CC-1B shows a 1.1% weight loss up to 63° C. as observed by TGA. [Figure 82] 1 shows the XRPD pattern of crystalline Compound A benzoic acid co-crystal form CC-1C. [Figure 83]1 shows a DSC thermograph and TGA of crystalline Compound A benzoic acid co-crystal Form CC-1C. The DSC shows an endothermic melt with onset and peak temperatures of 186° C. and 187° C., respectively. Form CC-1C shows negligible weight loss by TGA up to 117° C. [Figure 84] 1 shows the DVS of crystalline Compound A benzoic acid co-crystal form CC-1C, with a mass gain of 0.3% up to 80% relative humidity. [Figure 85] 1 shows the XRPD pattern of crystalline Compound A isobutyric acid co-crystal form CC-1D. [Figure 86]

[0023] Figure 1 shows a DSC thermograph and TGA of crystalline Compound A isobutyric acid co-crystal Form CC-1D. The DSC shows endothermic events with onset temperatures of 155°C and 226°C, and peak temperatures of 176°C and 227°C, respectively. Form CC-1D shows a 16.3% weight loss by TGA up to 180°C. [Figure 87] 1 shows the DVS of crystalline Compound A isobutyric acid co-crystal form CC-1D, with a mass gain of 0.2% up to 80% relative humidity. [Figure 88] 1 shows the XRPD pattern of crystalline Compound A isobutyric acid co-crystal form CC-2D. [Figure 89] 1 shows a DSC thermograph and TGA of crystalline Compound A isobutyric acid co-crystal Form CC-2D. The DSC shows endothermic events with onset temperatures of 163° C. and 228° C. Form CC-2D shows a weight loss of 18.1% by TGA up to 192° C. [Figure 90] 1 shows the DVS of crystalline Compound A isobutyric acid co-crystal form CC-2D, with a mass gain of 0.2% up to 80% relative humidity. [Figure 91] 1 shows the XRPD pattern of crystalline Compound A caprylic acid co-crystal form CC-1E. [Figure 92] 1 shows a DSC thermograph and TGA of crystalline Compound A caprylic acid co-crystal Form CC-1E. The DSC shows an endothermic event with onset and peak temperatures of 131° C. and 136° C., respectively. Concomitant decomposition is observed by TGA accompanying the endothermic event in the DSC. [Figure 93] 1 shows the XRPD pattern of crystalline Compound A sorbic acid co-crystal form CC-1F. [Figure 94]

[0023] Figure 1 shows a DSC thermograph and TGA of crystalline Compound A sorbic acid co-crystal Form CC-1F. The DSC shows endothermic events with onset temperatures of 62°C and 160°C, and peak temperatures of 90°C and 170°C, respectively. Form CC-1F shows a 20.8% weight loss by TGA up to 218°C. [Figure 95] 1 shows the XRPD pattern of crystalline Compound A saccharin co-crystal form CC-1G. [Figure 96] 1 shows a DSC thermograph and TGA of crystalline Compound A saccharin co-crystal Form CC-1G. The DSC shows an endothermic event with onset and peak temperatures of 243° C. and 244° C., respectively. Form CC-1G shows negligible weight loss by TGA up to 182° C. [Figure 97] 1 shows the DVS of crystalline Compound A saccharin co-crystal form CC-1G, with a mass gain of 0.2% up to 80% relative humidity. [Figure 98] 1 shows the XRPD pattern of crystalline Compound A succinic acid co-crystal form CC-1H. [Figure 99]

[0023] Figure 1 shows a DSC thermograph and TGA of crystalline Compound A succinic acid co-crystal Form CC-1H. The DSC shows an endothermic melt with onset temperatures of 59°C and 186°C, and peak temperatures of 82°C and 187°C, respectively. Form CC-1H shows a 2.9% weight loss by TGA up to 102°C. [Figure 100] 1 shows the XRPD pattern of crystalline Compound A succinic acid co-crystal form CC-2H. [Figure 101]

[0023] Figure 1 shows a DSC thermograph and TGA of crystalline Compound A succinic acid co-crystal Form CC-2H. The DSC shows an endothermic transition with onset temperatures of 94°C and 166°C, and peak temperatures of 99°C and 172°C, respectively. Form CC-2H shows a 24.4% weight loss by TGA up to 235°C. [Figure 102]1 shows the XRPD pattern of crystalline Compound A adipic acid co-crystal form CC-1I. [Figure 103]

[0023] Figure 1 shows a DSC thermograph and TGA of crystalline Compound A adipic acid co-crystal Form CC-1I. The DSC shows an endothermic melt with onset temperatures of 91°C and 137°C, and peak temperatures of 91°C and 140°C, respectively. Form CC-1I shows a 2.7% weight loss by TGA up to 78°C. [Figure 104] 1 shows the XRPD pattern of the amorphous form of Compound A free base. [Figure 105] 1 shows a modulated differential scanning calorimetry (mDSC) thermogram of the amorphous form of Compound A free base exhibiting a Tg of 119° C. DETAILED DESCRIPTION OF THE INVENTION

[0058] Disclosed herein is a solid form of Compound A having the following structure: [ka]

[0059] Compound A is a small molecule MTA-cooperative PRMT5 inhibitor being developed for the treatment of MTAP-null cancers with high unmet medical need, such as squamous non-small cell lung cancer (NSCLC) and pancreatic cancer. The disclosed solid forms include crystalline and amorphous forms of the free base of Compound A, as well as crystalline salts, co-crystals, and solvates of Compound A. The disclosed solid forms may have unique physical properties that are advantageous for novel pharmaceutical compositions of Compound A.

[0060] Also disclosed herein are pharmaceutical compositions comprising the disclosed solid forms of Compound A, and methods of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the disclosed solid forms of Compound A.

[0061] International Patent Applications PCT / US22 / 75648 and PCT / US21 / 63540 (each of which is incorporated herein by reference in its entirety) disclose synthetic procedures for synthesizing PRMT5 inhibitors, such as Compound A.

[0062] Applicants have discovered various solid forms of the compounds disclosed herein using high-throughput (HT) screens, including HT salt screens and HT polymorph screens. For example, various crystalline salt and free base polymorphs were identified, including benzenesulfonic acid (BSA) salt, methanesulfonic acid (MSA) salt, toluenesulfonic acid (TSA) salt, maleate salt, ethanesulfonic acid (ESA) salt, ethanedisulfonic acid (EDSA) salt, hydrochloride (HCl) salt, sulfate (HSO) salt, and bromide (HBr) salt. In addition, novel XRPD groups related to the free base were also identified from the HT salt screen.

[0063] As used herein, the term "solid form" refers to a crystalline form, amorphous form, salt, co-crystal, or solvate, including, but not limited to, the specific solid forms disclosed herein. In some cases, the term "crystalline form" is used herein to refer to the various crystalline forms (e.g., free base forms, salts, solvates, and / or co-crystals) disclosed herein.

[0064] As used herein, the term "salt" refers to a zwitterionic compound consisting of a cation and an anion. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that corresponds to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other exemplary pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.Salts of compounds containing carboxylic acid or other acidic functional groups can be prepared by reacting with a suitable base. Such salts include, but are not limited to, alkali metal, alkaline earth metal, aluminum, ammonium, N+(C1-4 alkyl)4 salts, and salts of organic bases, such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water- or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0065] As used herein, the term "co-crystal" refers to a crystalline material at ambient temperature (e.g., 20°C-25°C) that includes two or more compounds, at least two of which are held together by weak interactions, with at least one of the compounds being a co-crystal former and the other being Compound 1. Weak interactions are defined as interactions that are neither ionic nor covalent, and include, for example, hydrogen bonding, van der Waals forces, and π-π interactions. The term "co-crystal" includes solvate forms.

[0066] As used herein, the terms "amorphous form" or "amorphous" refer to a material that lacks long-range order and therefore does not exhibit distinct X-ray diffraction peaks (i.e., Bragg diffraction peaks). The XRPD pattern of an amorphous material is characterized by one or more amorphous halos. As used herein, the term "amorphous halo" refers to an approximately bell-shaped maximum in the X-ray powder pattern of an amorphous material.

[0067] When used herein to refer to DSC data, "substantially" refers to a variation of ±3°C.

[0068] As used herein, the terms "pharmaceutical composition" and "pharmaceutical formulation" are used interchangeably.

[0069] The disclosed solid forms of Compound A were prepared and analyzed as described in the Examples using one or more of the following techniques: X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), nuclear magnetic resonance spectroscopy (NMR) (e.g., 13 C NMR).

[0070] Free base form Crystalline Compound A Free Base ("Form 1") In some embodiments, the disclosure provides Compound A as a free base, wherein the free base is crystalline (e.g., a crystalline Compound A free base). In some embodiments, the disclosure provides a crystalline form of the free base of Compound A ("Form 1"), characterized by an XRPD pattern comprising peaks at 4.5, 9.0, 13.3, 16.2, and 18.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form 1 is further characterized by peaks in the XRPD pattern at 14.7, 15.7, 16.7, 17.6, 22.5, 26.2, and 26.4±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form 1 has an XRPD pattern substantially as shown in FIG. 1.

[0071] In some embodiments, Form 1 is 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.6, 23.0, 23.2, 23.4, 24.0, 24.2, 24.6, 25.0, 25.4, 26.0, 26.2, 26.6, 27.0, 27.2, 27.4, 28.0, 28.2, 28.4, 29.0, 30.0, 30.2, 30.4, 30.6, 31.0, 31.2, 31.4, 32.0, 32.2, 32.4, 33.0, 33.2, 33.4, 34.0, 34.2, 34.4, 35.0, 35.2, 35.4, 36.0, 36.2, 36.4, 37.0, 37.2, 37.4, 38.0, 38.2, 38.4, 38.6, 39.0, 40.0, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 4 The compound is characterized by an XRPD pattern comprising at least three peaks selected from 2.5, 23.0, 23.8, 24.1, 24.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

[0072] In some embodiments, Form 1 is 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.6, 23.0, 23.2, 23.4, 24.0, 24.2, 24.6, 25.0, 25.4, 26.0, 26.2, 26.6, 27.0, 27.2, 27.4, 28.0, 28.2, 28.4, 29.0, 30.0, 30.2, 30.4, 30.6, 31.0, 31.2, 31.4, 32.0, 32.2, 32.4, 33.0, 33.2, 33.4, 34.0, 34.2, 34.4, 35.0, 35.2, 35.4, 36.0, 36.2, 36.4, 37.0, 37.2, 37.4, 38.0, 38.2, 38.4, 38.6, 39.0, 40.0, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 4 The compound is characterized by an XRPD pattern comprising at least five peaks selected from 2.5, 23.0, 23.8, 24.1, 24.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

[0073] In some embodiments, Form 1 is 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.6, 23.0, 23.2, 23.4, 24.0, 24.2, 24.6, 25.0, 25.4, 26.0, 26.2, 26.6, 27.0, 27.2, 27.4, 28.0, 28.2, 28.4, 29.0, 30.0, 30.2, 30.4, 30.6, 31.0, 31.2, 31.4, 32.0, 32.2, 32.4, 33.0, 33.2, 33.4, 34.0, 34.2, 34.4, 35.0, 35.2, 35.4, 36.0, 36.2, 36.4, 37.0, 37.2, 37.4, 38.0, 38.2, 38.4, 38.6, 39.0, 40.0, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 4 The compound is characterized by an XRPD pattern comprising at least seven peaks selected from 2.5, 23.0, 23.8, 24.1, 24.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

[0074] In some embodiments, Form 1 is 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.6, 23.0, 23.2, 23.4, 24.0, 24.2, 24.6, 25.0, 25.4, 26.0, 26.2, 26.6, 27.0, 27.2, 27.4, 28.0, 28.2, 28.4, 29.0, 30.0, 30.2, 30.4, 30.6, 31.0, 31.2, 31.4, 32.0, 32.2, 32.4, 33.0, 33.2, 33.4, 34.0, 34.2, 34.4, 35.0, 35.2, 35.4, 36.0, 36.2, 36.4, 37.0, 37.2, 37.4, 38.0, 38.2, 38.4, 38.6, 39.0, 40.0, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 40.2, 4 The compound is characterized by an XRPD pattern comprising at least eight peaks selected from 2.5, 23.0, 23.8, 24.1, 24.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

[0075] In some embodiments, Form 1 comprises at least three peaks selected from 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm. 13 Characterized by C solid-state NMR.

[0076] In some embodiments, Form 1 comprises at least five peaks selected from 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm. 13 Characterized by C solid-state NMR.

[0077] In some embodiments, Form 1 comprises at least seven peaks selected from 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm. 13Characterized by C solid-state NMR.

[0078] In some embodiments, Form 1 comprises peaks at -62.0 and -63.9 ppm. 19 Characterized by F solid-state NMR.

[0079] Single crystals of Form 1 of the free base of Compound A were grown by slow evaporation from ethyl acetate and used for single crystal X-ray structure determination. Results confirmed that it was the anhydrous form, crystallizing in the monoclinic chiral C2 space group with two Compound A molecules in the asymmetric unit (Z'=2). The absolute configuration was confirmed, with the chiral carbon in the S configuration in all molecules within the unit cell (Z=8).

[0080] In some embodiments, Form 1 has unit cell dimensions of a=40.410(2) Å; b=7.0626(3) Å; c=14.5109(6) Å; α=90°; β=106.722(3)°; and γ=90°.

[0081] Alternatively or additionally, Form 1 can be characterized using differential scanning calorimetry (DSC). In some embodiments, Form 1 has a DSC substantially as shown in Figure 2. A differential scanning calorimetry (DSC) thermogram of Form 1 was obtained as described in the Examples. The DSC curve exhibits an endothermic transition between 218°C and 235°C. In some embodiments, Form 1 has an extrapolated onset of 225°C ± 3°C. Form 1 exhibits negligible weight loss by TGA up to 226°C.

[0082] Alternatively or additionally, crystalline Compound A free base Form 1 is characterized using thermogravimetric analysis (TGA). In some embodiments, crystalline Compound A free base Form 1 has a dynamic vapor sorption (DVS) substantially as shown in Figure 3.

[0083] Furthermore, Form 1 is stable under compression forces typical of tableting processes. For example, Form 1 shows no morphological changes by DSC and XRPD after compression to 200 MPa. Furthermore, Form 1 exhibits favorable stability. For example, Form 1 is physically and chemically stable as measured by ssNMR in studies of various excipient blends under a variety of conditions, including 40°C / 75% RH, 25°C / 60% RH open, and 40°C / 75% RH closed conditions, with no evidence of Maillard reaction-related degradation identified after two weeks. Furthermore, Form 1 has high solubility in many organic solvents, especially with water as a co-solvent (e.g., acetonitrile (13.2 mg / mL), 1:1 acetonitrile / water (31.1 mg / mL), ethanol 4.8 mg / mL), 1:1 ethanol / water (15.9 mg / mL), acetone (33.0 mg / mL), 1:4 acetone / water (0.2 mg / mL), and isopropanol (9.1 mg / mL)). Solubility studies demonstrate that Form 1 exhibits desirable solubility of greater than 10 μg / mL in aqueous media at pHs between 1 and 8.

[0084] Crystalline Compound A Free Base ("Form 3") In some embodiments, the present disclosure provides a crystalline form of the free base of Compound A ("Form 3") characterized by an XRPD pattern comprising peaks at 4.3, 12.6, 14.4, 16.2, and 25.6±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form 3 is further characterized by peaks in its XRPD pattern at 8.6, 13.9, 15.6, 16.7, and 25.3±0.2 degrees two-theta using CuKα radiation. In yet other embodiments, Form 3 is further characterized by peaks in its XRPD pattern at 18.4, 19.7, 20.3, 26.7, 27.9, and 28.4±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form 3 has an XRPD pattern substantially as shown in FIG. 4.

[0085] Alternatively or additionally, Form 3 may be characterized using DSC. In some embodiments, Form 3 has a DSC substantially as shown in Figure 5. A DSC thermogram of Form 3 was obtained as described in the Examples. The DSC curve shows exothermic events with onset temperatures of 105°C and 173°C, and peak temperatures of 111°C and 173°C. An endothermic event with onset and peak temperatures of 226°C and 229°C was observed.

[0086] Alternatively or additionally, Form 3 is characterized using thermogravimetric analysis (TGA). In some embodiments, Form 3 of the free base of Compound A has a TGA substantially as shown in Figure 5. As shown in Figure 5, Form 3 exhibited negligible weight loss up to 200°C.

[0087] Alternatively or additionally, Form 3 is characterized using DVS. In some embodiments, Form 3 has a DVS isotherm plot as shown in FIG.

[0088] Crystalline Compound A Free Base ("Form 6") In some embodiments, the disclosure provides a crystalline form of the free base of Compound A ("Form 6") characterized by an XRPD pattern comprising peaks at 4.5, 8.6, 9.0, 12.9, and 14.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form 6 is further characterized by peaks in the XRPD pattern at 7.4, 12.3, 13.3, 16.2, 17.8, and 18.8±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form 6 has an XRPD pattern substantially as shown in Figure 7.

[0089] Alternatively or additionally, Form 6 may be characterized using DSC. In some embodiments, Form 6 has a DSC substantially as shown in Figure 8. A differential scanning calorimetry (DSC) thermogram of Form 6 was obtained as described in the Examples. As shown in Figure 8, an endothermic event was observed with onset and peak temperatures of 225°C and 227°C.

[0090] Alternatively or additionally, Form 6 is characterized using thermogravimetric analysis (TGA). In some embodiments, Form 6 of the free base of Compound A has a TGA substantially as shown in Figure 8. As shown in Figure 8, Form 6 exhibited negligible weight loss up to 216°C.

[0091] Crystalline Compound A Free Base ("Form 7") In some embodiments, the present disclosure provides a crystalline form of the free base of Compound A ("Form 7") characterized by an XRPD pattern comprising peaks at 4.3, 8.5, 12.3, 13.1, and 14.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 7 is further characterized by peaks in its XRPD pattern at 15.5, 19.1, and 20.9±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 7 has an XRPD pattern substantially as shown in Figure 9.

[0092] Alternatively or additionally, Form 7 may be characterized using DSC. In some embodiments, Form 7 has a DSC substantially as shown in Figure 10. A differential scanning calorimetry (DSC) thermogram of Form 7 was obtained as described in the Examples.

[0093] Alternatively or additionally, Form 7 is characterized using thermogravimetric analysis (TGA). In some embodiments, Form 7 of the free base of Compound A has a TGA substantially as shown in FIG.

[0094] As shown in Figure 10, Form 7 exhibited an endothermic event with an onset temperature of 61°C and other endothermic events at higher temperatures. The endothermic events had peak temperatures at 87°C, 221°C, and 223°C. Exothermic events were observed with onset and peak temperatures of 129°C and 141°C. Additionally, Form 7 exhibited a 1.2% weight loss by TGA up to 94°C and an additional 0.3% weight loss up to 176°C.

[0095] Amorphous Compound A Free Base In some embodiments, the disclosure provides an amorphous form of the free base of Compound A. In some embodiments, the disclosure provides an amorphous form of the free base of Compound A characterized by mDSC as described in the Examples and substantially as shown in Figure 103. In some embodiments, the amorphous form of the free base of Compound A has a glass transition temperature (Tg) of 115°C to 125°C, for example, a Tg that is 118°C ± 3°C.

[0096] The amorphous form of Compound A free base can be formed under suitable conditions upon cooling a melt of Compound A free base. For example, in some embodiments, Compound A free base Form 1 can be heated at a rate of 20°C / min to a temperature of 300°C and melted on a hot stage microscope, upon which the sample can be removed and rapidly cooled to room temperature.

[0097] crystalline solvate In some embodiments, the present disclosure provides crystalline solvates and hydrates of Compound A. Typically, the solvates and hydrates are formed (e.g., by slurrying or evaporation) from a mixture comprising Compound A and water and / or one or more organic solvents. Non-limiting examples of suitable organic solvents for forming solvates of Compound A include ethanol, isopropanol, methanol, and acetonitrile. For example, the ethanol and isopropanol solvates of Compound A disclosed herein can be obtained by slow evaporation or slurrying a mixture comprising Compound A and ethanol and / or isopropanol.

[0098] Crystalline Compound A Free Base Hydrate ("Form 8") In some embodiments, the disclosure provides a crystalline form of the free base hydrate of Compound A ("Form 8") characterized by an XRPD pattern comprising peaks at 4.0, 7.7, 8.0, 12.3, and 15.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 8 is further characterized by peaks in its XRPD pattern at 6.1, 10.0, 13.7, 17.0, 18.4, and 19.9±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 8 has an XRPD pattern substantially as shown in Figure 11.

[0099] Alternatively or additionally, Form 8 may be characterized using DSC. In some embodiments, Form 8 has a DSC substantially as shown in Figure 12. A differential scanning calorimetry (DSC) thermogram of Form 8 was obtained as described in the Examples.

[0100] Alternatively or additionally, Form 8 may be characterized using thermogravimetric analysis (TGA). In some embodiments, Form 8 of the free base of Compound A has a TGA substantially as shown in FIG.

[0101] As shown in Figure 12, Form 8 exhibits endothermic events with onset temperatures of 57°C and 219°C, and peak temperatures of 79°C and 225°C, respectively. Additionally, Form 8 exhibited a weight loss of 3.3% as determined by TGA up to 128°C.

[0102] Crystalline Ethanol Solvate of Compound A ("Form 2A") In some embodiments, the present disclosure provides a crystalline ethanol solvate of Compound A ("Form 2A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.8, 11.6, 12.7, 18.0, and 25.7±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 2A is further characterized by peaks in its XRPD pattern at 16.5, 22.6, 23.3, and 25.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 2A has an XRPD pattern substantially as shown in Figure 13.

[0103] In some embodiments, the present disclosure provides Form 2A having unit cell dimensions of a=14.0551(3) Å; b=5.4000(10) Å; c=14.9397(3) Å; α=90°; β=95.5093(8)°; and γ=90°.

[0104] Alternatively or additionally, Form 2A may be characterized using DSC. In some embodiments, Form 2A has a DSC substantially as shown in Figure 14. A differential scanning calorimetry (DSC) thermogram of Form 2A was obtained as described in the Examples.

[0105] Alternatively or additionally, Form 2A may be characterized using thermogravimetric analysis (TGA). In some embodiments, Form 2A of the free base of Compound A has a TGA substantially as shown in Figure 14.

[0106] As shown in Figure 14, the DSC curve for Form 2A exhibits a first small endotherm with an extrapolated onset at 132°C as a result of desolvation of ethanol, a second endotherm overlapping with a subsequent recrystallization exotherm, followed by an extrapolated melting onset at 224°C and a melting endothermic transition between 218 and 236°C. In some embodiments, the extrapolated onset is 224°C ± 3°C. The melting onsets of the solvates / hydrates are all close to the melting onset of free base Form 1. The DSC heating process may result in the recrystallization of the solvates / hydrates to free base Form 1.

[0107] Crystalline Compound A isopropanol solvate ("Form 3A") In some embodiments, the present disclosure provides a crystalline isopropanol solvate of Compound A ("Form 3A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 12.8, 16.4, 17.5, and 25.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, the XRPD of Form 3A is further characterized by peaks in the XRPD pattern at 8.2, 11.2, 12.5, 18.6, and 21.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, the XRPD of Form 3A is further characterized by peaks in the XRPD pattern at 6.4, 8.8, 9.2, 13.6, 21.0, 22.4, 22.9, 24.5, and 25.9±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 3A has an XRPD pattern substantially as shown in FIG.

[0108] Alternatively or additionally, Form 3A may be characterized using DSC. In some embodiments, Form 3A has a DSC substantially as shown in Figure 16. A differential scanning calorimetry (DSC) thermogram of Form 3A was obtained as described in the Examples.

[0109] Alternatively or additionally, Form 3A may be characterized using thermogravimetric analysis (TGA). In some embodiments, Form 3A of the free base of Compound A has a TGA substantially as shown in Figure 16.

[0110] In some embodiments, Form 3A exhibits a first minor endotherm with an extrapolated onset at 122.6° C. as a result of desolvation of isopropyl alcohol (IPA), with a second endotherm overlapping with a subsequent recrystallization exotherm, followed by an extrapolated melting onset at 223° C.±3° C. In some embodiments, the DSC of Form 3A has an endothermic onset transition at 223° C.±3° C.

[0111] Crystalline Acetone Solvate of Compound A ("Form 4A") In some embodiments, the present disclosure provides a crystalline acetone solvate of Compound A ("Form 4A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.7, 7.7, 11.5, 14.8, and 15.3±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 4A is further characterized by peaks in its XRPD pattern at 4.3, 7.3, 13.4, 16.2, and 24.0±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 4A is also characterized by peaks in its XRPD pattern at 11.2, 18.5, 19.6, and 20.4±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 4A has an XRPD pattern substantially as shown in FIG. 17.

[0112] Alternatively or additionally, Form 4A may be characterized using DSC. In some embodiments, Form 4A has a DSC substantially as shown in Figure 18. A differential scanning calorimetry (DSC) thermogram of Form 4A was obtained as described in the Examples.

[0113] Alternatively or additionally, Form 4A may be characterized using thermogravimetric analysis (TGA). In some embodiments, Form 4A of the free base of Compound A has a TGA substantially as shown in Figure 18.

[0114] Crystalline methanol solvate of the free base of Compound A ("Form 5A") In some embodiments, the present disclosure provides a crystalline methanol solvate of Compound A ("Form 5A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.8, 7.7, 12.3, 15.3, and 16.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 5A is further characterized by peaks in its XRPD pattern at 8.9, 10.5, 13.1, 13.4, 14.5, 17.6, 21.5, and 25.0±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 5A is also characterized by peaks in its XRPD pattern at 9.7, 14.1, 18.7, 19.6, 22.7, 24.7, 26.0, and 26.6±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 5A has an XRPD pattern substantially as shown in FIG. 19.

[0115] Alternatively or additionally, Form 5A may be characterized using DSC. In some embodiments, Form 5A has a DSC substantially as shown in Figure 20. A differential scanning calorimetry (DSC) thermogram of Form 5A was obtained as described in the Examples.

[0116] Alternatively or additionally, Form 5A may be characterized using thermogravimetric analysis (TGA). In some embodiments, Form 5A of the free base of Compound A has a TGA substantially as shown in Figure 20.

[0117] Crystalline methyltetrahydrofuran solvate of the free base of Compound A ("Form 6A") In some embodiments, the present disclosure provides a crystalline methyltetrahydrofuran solvate of Compound A ("Form 6A") characterized by an XRPD pattern comprising peaks at 7.6, 11.3, 15.1, 18.3, and 28.0±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 6A is further characterized by peaks in its XRPD pattern at 12.4, 15.7, 17.3, 17.7, 18.8, 19.7, 21.3, 22.7, 25.8, 26.1, and 26.5±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form 6A is also characterized by peaks in its XRPD pattern at 13.6, 14.2, 16.5, 16.9, 20.5, 26.9, and 28.4±0.2 degrees 2θ using CuKα radiation.

[0118] In some embodiments, the present disclosure provides a crystalline salt form of Compound A. Compound A has an ionizable functional group with a weakly basic pKa value of 4.27, making it suitable for salt formation. Suitable non-limiting examples of counterions for forming salts with Compound A include benzenesulfonic acid (BSA), toluenesulfonic acid (TSA), sulfuric acid, hydrochloric acid, malonic acid, naphthalene-2-sulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, ethanesulfonic acid, cyclamic acid, maleic acid, or phosphoric acid.

[0119] Crystalline Toluenesulfonate Salt of Compound A ("Form A1") In some embodiments, the crystalline form of the toluenesulfonate salt of Compound A ("Form A1") is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.0, 19.1, 20.3, 24.1, 24.9, and 28.9±0.2 degrees 2θ using CuKα radiation. In some embodiments, XRPD Form A1 is further characterized by peaks at 9.5, 11.9, 14.3, 17.9, 26.2, 33.8, and 35.4±0.2 degrees 2θ using CuKα radiation. Alternatively or additionally, in some embodiments, Form A1 disclosed herein has an XRPD pattern substantially as shown in FIG. 21.

[0120] Alternatively or additionally, Form A1 may be characterized using DSC and / or TGA. In some embodiments, Form A1 has a DSC substantially as shown in Figure 22. As shown in Figure 22, Form A1 has an endothermic transition at 290°C to 300°C as measured by DSC. In some embodiments, the extrapolated onset is 293°C ± 3°C due to endothermic melting and / or decomposition.

[0121] In some embodiments, Form A1 has a TGA curve substantially as shown in FIG.

[0122] In some embodiments, Form A1 has a DVS substantially as shown in FIG.

[0123] Crystalline Compound A Toluenesulfonate Salt ("Form A2") In some embodiments, the disclosure provides a crystalline toluenesulfonate salt of Compound A ("Form A2") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.7, 15.5, 16.2, 18.7, 19.7, and 21.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form A2 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.2, 23.2, 24.1, 24.6, 26.3, and 27.2±0.2 degrees 2θ using CuKα radiation. Alternatively or additionally, in some embodiments, the XRPD pattern of Form A2 is as shown in Figure 24.

[0124] Alternatively or additionally, Form A2 may be characterized using DSC and / or TGA. In some embodiments, Form A2 has a DSC substantially as shown in Figure 25. As shown in Figure 25, Form A2 exhibits an exotherm with an extrapolated onset at 241.9°C due to recrystallization, followed by an extrapolated melting / decomposition at 287°C. Form A2 has an endothermic transition between 270°C and 300°C due to endothermic melting or decomposition, as measured by DSC. In some embodiments, the extrapolated onset is 287°C ± 3°C.

[0125] In some embodiments, Form A2 has a TGA curve substantially as shown in FIG.

[0126] Crystalline Compound A Toluenesulfonate ("Form A3") In some embodiments, the present disclosure provides a crystalline toluenesulfonate salt of Compound A ("Form A3") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.9, 15.2, 18, 8, 19.5, and 24.5±0.2 degrees 2θ using CuKα radiation. Alternatively or additionally, in some embodiments, the XRPD pattern of Form A3 is as shown in Figure 26.

[0127] Alternatively or additionally, Form A3 may be characterized using DSC, TGA, and / or DVS. In some embodiments, Form A3 has a DSC substantially as shown in Figure 27. In some embodiments, Form A3 has a TGA as shown in Figure 27.

[0128] Furthermore, Form A3 may be characterized using a DVS. In some embodiments, the present disclosure provides Form A3 having a DVS as shown in FIG.

[0129] Crystalline benzenesulfonate salt of Compound A ("Form B1") In some embodiments, the present disclosure provides a crystalline form of the benzenesulfonate salt of Compound A ("Form B1") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.1, 16.1, 17.9, 19.0, and 25.2±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form B1 is further characterized by peaks in its XRPD pattern at 20.2, 20.6, 23.2, 26.0, 27.0, and 30.4±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form B1 has an XRPD pattern substantially as shown in Figure 29.

[0130] In some embodiments, the DSC of Form B1 shows an endotherm with an extrapolated onset of 97° C. followed by an extrapolated endothermic melting / decomposition point at 254° C. Form B1 has an endothermic transition at 240° C. to 260° C. as measured by DSC. In some embodiments, the extrapolated onset is 254° C.±3° C. due to the endothermic melting and / or decomposition. In some embodiments, Form B1 has a DSC substantially as shown in FIG. 30.

[0131] Crystalline Compound A Chloride ("Form C1") In some embodiments, the crystalline form of the chloride salt of Compound A ("Form C1") is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.8, 11.9, 16.6, 20.7, 23.8, 25.3, and 27.6±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline Form C1 of the chloride salt of Compound A has an XRPD pattern substantially as shown in Figure 31.

[0132] In some embodiments, Form C1 has a DSC substantially as shown in Figure 32. As shown in Figure 32, the DSC of Form C1 shows a first broad endotherm with an extrapolated onset at 34°C and a first endothermic transition between 30°C and 110°C, and an extrapolated endothermic melting / decomposition point / salt disproportionation at 166.4°C. In some embodiments, the extrapolated onset is 34°C ± 3°C. In some embodiments, Form C1 is further characterized by a second endothermic transition between 160°C and 170°C, as measured by DSC. In some embodiments, the second extrapolated onset is 166°C ± 3°C, due to endothermic melting and / or decomposition.

[0133] Form C1 of the crystalline chloride salt of Compound A may be characterized by TGA. In some embodiments, Form C1 of the present disclosure has a TGA substantially as shown in FIG.

[0134] Crystalline Compound A Chloride ("Form C2") In some embodiments, a crystalline form of the chloride salt of Compound A ("Form C2") is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 5.6, 12.2, 12.9, and 18.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form C2 is further characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.8, 7.1, 9.4, 13.4, 14.0, 16.5, and 17.7±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form C2 is also characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.8, 8.7, 10.9, 11.8, 14.9, 15.4, and 19.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, the present disclosure provides a crystalline form of the chloride salt of Compound A (“Form C2”) having an XRPD pattern substantially as shown in FIG.

[0135] Alternatively or additionally, Form C2 may be characterized using DSC, TGA, and / or DVS.

[0136] In some embodiments, the disclosure provides Form C2 having a DSC substantially as shown in Figure 34. As shown in Figure 34, the DSC of Form C2 shows a first broad endotherm with an extrapolated onset at 34°C and a first endothermic transition between 30°C and 110°C, and an extrapolated endothermic melting / decomposition point / salt disproportionation at 166°C. In some embodiments, the extrapolated onset is 34°C ± 3°C. In some embodiments, Form C2 is further characterized by a second endothermic transition between 160°C and 170°C, as measured by DSC. In some embodiments, the second extrapolated onset is 166°C ± 3°C, due to endothermic melting and / or decomposition.

[0137] In some embodiments, Form C2 of the present disclosure has a TGA substantially as shown in FIG.

[0138] Crystalline Compound A Sulfate ("Form D1") In some embodiments, the disclosure provides a crystalline sulfonate salt of Compound A ("Form D1") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 16.0, 16.5, 16.7, 20.0, and 20.4±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form D1 is further characterized by peaks in its XRPD pattern at 8.4, 12.1, 13.8, 14.2, 23.6, 24.6, and 25.2±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides a salt of Form D1 having an XRPD substantially as shown in FIG. 35.

[0139] Crystalline Malonate of Compound A ("Form E1") In some embodiments, the disclosure provides crystalline Compound A malonate salt ("Form E1") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.8, 12.6, 16.6, 20.4, and 22.0±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form E1 is further characterized by peaks in its XRPD pattern at 5.4, 8.3, 17.2, 19.4, 21.0, 22.9, and 26.2±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Compound A malonate salt Form E1 having an XRPD substantially as shown in FIG. 36.

[0140] In some embodiments, Form E1 is characterized by DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form E1 having a DSC substantially as shown in FIG.

[0141] In some embodiments, the present disclosure provides Form E1 having a TGA substantially as shown in FIG.

[0142] Crystalline naphthalene-2-sulfonate salt of Compound A ("Form F1") In some embodiments, the disclosure provides crystalline naphthalene-2-sulfonate salt of Compound A ("Form F1") characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising peaks at 4.7, 14.7, 14.9, 17.0, 19.6, and 22.1±0.2 degrees 2θ. In some embodiments, the disclosure provides Form F1 of crystalline naphthalene-2-sulfonate salt of Compound A having an XRPD substantially as shown in FIG.

[0143] In some embodiments, Form F1 is characterized by DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form F1 having a DSC substantially as shown in FIG.

[0144] In some embodiments, the present disclosure provides Form F1 having a TGA substantially as shown in FIG.

[0145] In some embodiments, the present disclosure provides Form F1 having a DVS substantially as shown in FIG.

[0146] Crystalline naphthalene-2-sulfonate salt of Compound A ("Form F2") In some embodiments, the present disclosure provides crystalline naphthalene-2-sulfonate salt of Compound A ("Form F2") characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising peaks at 5.8, 11.6, 14.0, 17.5, and 19.7±0.2 degrees 2θ. In some embodiments, the present disclosure provides Form F2 of crystalline naphthalene-2-sulfonate salt of Compound A having an XRPD substantially as shown in FIG.

[0147] In some embodiments, form F2 is characterized by DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form F2 having a DSC substantially as shown in FIG.

[0148] In some embodiments, the present disclosure provides form F2 having a TGA substantially as shown in FIG.

[0149] In some embodiments, the present disclosure provides Form F2 having a DVS substantially as shown in FIG.

[0150] Crystalline naphthalene-2-sulfonate salt of Compound A ("Form F3") In some embodiments, the disclosure provides crystalline naphthalene-2-sulfonate salt of Compound A ("Form F3") characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising peaks at 3.8, 7.6, 9.7, 11.5, and 15.3±0.2 degrees 2θ. In some embodiments, the disclosure provides crystalline Form F3 of naphthalene-2-sulfonate salt of Compound A having an XRPD substantially as shown in Figure 44.

[0151] In some embodiments, Form F3 is characterized by DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form F3 having a DSC substantially as shown in FIG.

[0152] In some embodiments, the present disclosure provides form F3 having a TGA substantially as shown in FIG.

[0153] Crystalline methanesulfonate salt of Compound A ("Form G1") In some embodiments, the disclosure provides crystalline Compound A methanesulfonate salt ("Form G1") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.1, 6.5, 13.6, 13.8, and 19.5±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form G1 is further characterized by XRPD pattern peaks at 6.9, 9.3, 18.5, 20.8, and 21.5±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Compound A methanesulfonate salt Form G1 having an XRPD substantially as shown in FIG. 46.

[0154] Crystalline methanesulfonate salt of Compound A ("Form G2") In some embodiments, the disclosure provides a crystalline methanesulfonate salt of Compound A ("Form G2") characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising peaks at 5.6, 13.1, 13.3, 16.3, and 18.3±0.2 degrees 2θ. In some embodiments, Form G2 is further characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising peaks at 12.5, 19.8, 21.5, and 9.4±0.2 degrees 2θ. In some embodiments, the disclosure provides Form G2 of a crystalline methanesulfonate salt of Compound A having an XRPD substantially as shown in FIG. 47.

[0155] Form G2 may be characterized by DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides crystalline Form G2 of the methanesulfonate salt of Compound A having a DSC substantially as shown in Figure 48.

[0156] In some embodiments, the present disclosure provides crystalline Form G2 of the methanesulfonate salt of Compound A, having a TGA substantially as shown in FIG.

[0157] In some embodiments, the present disclosure provides Form G2 of a crystalline methanesulfonate salt of Compound A, having a DVS profile substantially as shown in FIG.

[0158] Crystalline Compound A Oxalate Salt ("Form H2") In some embodiments, the present disclosure provides a crystalline oxalate salt of Compound A ("Form H2") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.9, 8.7, 13.6, 17.4, and 24.6±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form H2 is further characterized by peaks in its XRPD pattern at 11.0, 19.6, 20.8, 21.0, 22.0, 25.3, and 27.3±0.2 degrees two-theta using CuKα radiation. In some embodiments, the present disclosure provides Form H2, a crystalline form of the oxalate salt of Compound A, having an XRPD substantially as shown in Figure 50.

[0159] Form H2 may be characterized by DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form H2 of a crystalline oxalate salt of Compound A having a DSC substantially as shown in Figure 51.

[0160] In some embodiments, the present disclosure provides crystalline Form H2 of the oxalate salt of Compound A, having a TGA substantially as shown in FIG.

[0161] Crystalline Compound A Tartrate Salt ("Form I1") In some embodiments, the present disclosure provides crystalline Compound A tartrate salt ("Form I1") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.4, 14.7, 15.6, 18.0, and 24.3±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form I1 is further characterized by peaks in its XRPD pattern at 14.3, 15.1, 18.7, 19.4, and 19.7±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form I1 is also characterized by peaks in its XRPD pattern at 13.3, 13.5, 20.6, 21.1, 23.1, 23.5, 24.9, 26.7, and 27.2±0.2 degrees two-theta using CuKα radiation. In some embodiments, the present disclosure provides Form I1 of crystalline Compound A tartrate salt having an XRPD substantially as shown in FIG. 52.

[0162] Form I1 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides crystalline Form I1 of the tartrate salt of Compound A having a DSC substantially as shown in Figure 53.

[0163] In some embodiments, the present disclosure provides crystalline Compound A tartrate salt Form I1 having a TGA substantially as shown in FIG.

[0164] Crystalline Ethanesulfonic Acid Salt of Compound A ("Form J1") In some embodiments, the disclosure provides a crystalline ethanesulfonate salt of Compound A ("Form J1") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 7.9, 13.6, 15.7, and 17.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form J1 is further characterized by peaks in its XRPD pattern at 6.6, 11.1, 13.1, 16.8, 18.7, and 20.4±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides Form J1, a crystalline form of the ethanesulfonate salt of Compound A having an XRPD substantially as shown in FIG. 54.

[0165] Form J1 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form J1 of a crystalline ethanesulfonate salt of Compound A having a DSC substantially as shown in Figure 55.

[0166] In some embodiments, the present disclosure provides crystalline Form J1 of the ethanesulfonate salt of Compound A, having a TGA substantially as shown in FIG.

[0167] Crystalline Ethanesulfonic Acid Salt of Compound A ("Form J2") In some embodiments, the disclosure provides a crystalline ethanesulfonate salt of Compound A ("Form J2") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.0, 6.3, 7.7, 15.8, and 20.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form J2 is further characterized by peaks in its XRPD pattern at 7.9, 16.8, 18.4, 18.6, 19.5, and 20.0±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form J2 is also characterized by peaks in its XRPD pattern at 6.9, 17.6, 21.6, 23.3, 23.8, 24.1, 24.7, and 26.1±0.2 degrees two-theta using CuKα radiation. In some embodiments, the present disclosure provides Form J2, a crystalline form of the ethanesulfonic acid salt of Compound A, having an XRPD substantially as shown in FIG.

[0168] Form J2 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form J2 of a crystalline ethanesulfonate salt of Compound A having a DSC substantially as shown in Figure 57.

[0169] In some embodiments, the present disclosure provides crystalline Form J2 of the ethanesulfonate salt of Compound A, having a TGA substantially as shown in FIG.

[0170] Crystalline N-cyclohexylsulfamate salt of Compound A ("Form K1") In some embodiments, the disclosure provides crystalline N-cyclohexylsulfamate of Compound A ("Form K1") characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising peaks at 5.8, 14.0, 15.6, 16.7, and 28.1±0.2 degrees 2θ. In some embodiments, the disclosure provides Form K1 of crystalline N-cyclohexylsulfamate of Compound A having an XRPD substantially as shown in Figure 58.

[0171] Form K1 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form K1 having a DSC substantially as shown in FIG.

[0172] In some embodiments, the present disclosure provides Form K1 having a TGA substantially as shown in FIG.

[0173] Crystalline Compound A Maleate Salt ("Form L1") In some embodiments, the present disclosure provides crystalline Compound A maleate salt ("Form L1") characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising peaks at 5.7, 17.0, 17.5, 25.6, and 26.1±0.2 degrees 2θ. In some embodiments, the present disclosure provides crystalline Compound A maleate salt Form L1 having an XRPD substantially as shown in Figure 60.

[0174] Form L1 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form L1 of a crystalline maleate salt of Compound A having a DSC substantially as shown in Figure 61.

[0175] In some embodiments, the present disclosure provides crystalline Form L1 of the maleate salt of Compound A, having a TGA substantially as shown in FIG.

[0176] Crystalline Compound A Phosphate Salt ("Form M1") In some embodiments, the disclosure provides a crystalline Form M1 of a phosphate salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.4, 16.2, 20.3, and 22.5±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form M1 is further characterized by peaks in an XRPD pattern at 10.8, 12.3, 21.8, and 32.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Form M1 of a phosphate salt of Compound A having an XRPD substantially as shown in Figure 62.

[0177] Form M1 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form M1 having a DSC substantially as shown in FIG.

[0178] In some embodiments, the present disclosure provides Form M1 having a TGA substantially as shown in FIG.

[0179] In some embodiments, the present disclosure provides a form M1 having a DVS substantially as shown in FIG.

[0180] Crystalline Compound A Phosphate Salt ("Form M2") In some embodiments, the disclosure provides a crystalline Compound A phosphate salt ("Form M2") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.1, 14.2, 14.9, 17.8, and 19.6±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form M2 is further characterized by peaks in its XRPD pattern at 8.9, 10.6, 10.9, 13.4, 16.4, 16.8, and 21.4±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form M2 is also characterized by peaks in its XRPD pattern at 3.6, 7.4, 21.0, 21.8, 23.0, 25.0, 25.4, 26.3, and 26.9±0.2 degrees 2θ using CuKα radiation. In some embodiments, the present disclosure provides crystalline Form M2 of the phosphate salt of Compound A, having an XRPD substantially as shown in FIG.

[0181] Form M2 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form M2 having a DSC substantially as shown in FIG.

[0182] In some embodiments, the present disclosure provides form M2 having a TGA substantially as shown in FIG.

[0183] Crystalline Compound A Phosphate Salt ("Form M3") In some embodiments, the disclosure provides a crystalline Form M3 of a phosphate salt of Compound A characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.5, 7.8, 14.8, 15.0, and 15.4±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form M3 is further characterized by peaks in its XRPD pattern at 9.0, 9.8, 11.6, 11.7, 18.3, 22.2, and 25.2±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form M3 is also characterized by peaks in its XRPD pattern at 3.9, 16.2, 27.2, and 27.2±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides a crystalline Form M3 of a phosphate salt of Compound A having an XRPD substantially as shown in FIG. 67.

[0184] Form M3 may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form M3 having a DSC substantially as shown in FIG.

[0185] In some embodiments, the present disclosure provides form M3 having a TGA substantially as shown in FIG.

[0186] Cocrystals In some embodiments, the present disclosure provides a crystalline co-crystal comprising Compound A and a coformer. Non-limiting examples of molecules suitable as coformers include, for example, salicylic acid, formic acid, benzoic acid, isobutyric acid, caprylic acid, sorbic acid, succinic acid, and adipic acid.

[0187] Crystalline Compound A Salicylic Acid Co-Crystal ("Form CC-1A") In some embodiments, the disclosure provides a crystalline salicylic acid co-crystal of Compound A ("Form CC-1A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.3, 5.9, 9.7, 6.0, and 13.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1A is further characterized by peaks in its XRPD pattern at 13.1, 8.3, and 18.6±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Form CC-1A of the salicylic acid co-crystal of Compound A having an XRPD substantially as shown in Figure 69.

[0188] Form CC-1A may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-1A having a DSC substantially as shown in Figure 70.

[0189] In some embodiments, the present disclosure provides form CC-1A having a TGA substantially as shown in FIG.

[0190] Crystalline Compound A Salicylic Acid Co-Crystal ("Form CC-2A") In some embodiments, the disclosure provides a crystalline salicylic acid co-crystal of Compound A ("Form CC-2A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.2, 9.2, 16.5, 18.5, and 16.0±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-2A is further characterized by peaks in its XRPD pattern at 17.2, 11.1, 3.2, 11.8, 24.6, and 25.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Form CC-2A of the salicylic acid co-crystal of Compound A having an XRPD substantially as shown in Figure 71.

[0191] Form CC-2A may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-2A having a DSC substantially as shown in FIG.

[0192] In some embodiments, the present disclosure provides form CC-2A having a TGA substantially as shown in FIG.

[0193] Crystalline Compound A Salicylic Acid Co-Crystal ("Form CC-3A") In some embodiments, the disclosure provides a crystalline salicylic acid co-crystal of Compound A ("Form CC-3A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.6, 12.6, 8.0, 14.4, and 7.2±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-3A is further characterized by peaks in its XRPD pattern at 15.7, 11.2, 13.0, 21.5, 10.8, and 16.1±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Form CC-3A of the salicylic acid co-crystal of Compound A having an XRPD substantially as shown in Figure 73.

[0194] Form CC-3A may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-3A having a DSC substantially as shown in Figure 74.

[0195] In some embodiments, the present disclosure provides form CC-3A having a TGA substantially as shown in FIG.

[0196] In some embodiments, the present disclosure provides Form CC-3A having a DVS profile substantially as shown in FIG.

[0197] Crystalline Compound A Salicylic Acid Co-Crystal ("Form CC-4A") In some embodiments, the disclosure provides a crystalline Compound A salicylic acid co-crystal ("Form CC-4A") characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 10.3, 16.2, 9.9, 16.3, and 19.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-4A is further characterized by peaks in its XRPD pattern at 26.3, 27.0, 25.3, 18.0, 12.8, and 9.7±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-4A is also characterized by peaks in its XRPD pattern at 28.5, 28.1, 24.8, 24.4, 23.4, and 22.3±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-4A is also characterized by peaks in an XRPD pattern at 17.8, 16.2, 15.7, 15.67, 15.4, 13.6, and 13.4±0.2 degrees 2θ using CuKα radiation. In some embodiments, the disclosure provides crystalline Form CC-4A of a salicylic acid co-crystal of Compound A having an XRPD substantially as shown in Figure 76.

[0198] Form CC-4A may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-4A having a DSC substantially as shown in Figure 77.

[0199] In some embodiments, the present disclosure provides form CC-4A having a TGA substantially as shown in FIG.

[0200] Crystalline Compound A Salicylic Acid Co-Crystal ("Form CC-5A") In some embodiments, the disclosure provides a crystalline Compound A salicylic acid co-crystal ("Form CC-5A") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.3, 17.8, 10.6, 18.3, and 15.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-5A is further characterized by peaks in its XRPD pattern at 25.7, 15.5, 19.1, 28.7, 9.2, 12.2, 11.0, and 12.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-5A is also characterized by peaks in its XRPD pattern at 21.3, 19.8, 20.7, 24.3, 13.2, 26.6, 27.2, and 11.3±0.2 degrees two-theta using CuKα radiation. In some embodiments, the present disclosure provides crystalline form CC-5A of a salicylic acid co-crystal of Compound A, having an XRPD substantially as shown in FIG. 78.

[0201] Form CC-5A may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-5A having a DSC substantially as shown in Figure 79.

[0202] In some embodiments, the present disclosure provides form CC-5A having a TGA substantially as shown in FIG.

[0203] Crystalline Compound A Formic Acid Co-Crystal ("Form CC-1B") In some embodiments, the disclosure provides a crystalline formic acid co-crystal of Compound A ("Form CC-1B") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.6, 4.6, 17.8, 17.4, and 23.0±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1B is further characterized by peaks in its XRPD pattern at 11.3, 14.8, 15.7, 16.5, 18.4, 19.3, 20.7, 24.9, and 26.8±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Form CC-1B of the formic acid co-crystal of Compound A having an XRPD substantially as shown in Figure 80.

[0204] Form CC-1B may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form CC-1B having a DSC substantially as shown in FIG.

[0205] In some embodiments, the present disclosure provides form CC-1B having a TGA substantially as shown in FIG.

[0206] Crystalline Compound A Benzoic Acid Co-Crystal ("Form CC-1C") In some embodiments, the disclosure provides a crystalline benzoic acid co-crystal of Compound A ("Form CC-1C") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.6, 16.1, 14.2, 3.9, and 19.8±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1C is further characterized by peaks in its XRPD pattern at 10.4, 10.6, 12.4, 14.5, 17.3, 18.3, and 19.4±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1C is also characterized by peaks in its XRPD pattern at 7.7, 8.8, 17.7, 21.7, 23.2, 26.3, and 26.69±0.2 degrees two-theta using CuKα radiation. In some embodiments, the present disclosure provides a crystalline Compound A benzoic acid co-crystal of Form CC-1C having an XRPD substantially as shown in FIG.

[0207] Form CC-1C may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form CC-1C having a DSC substantially as shown in FIG.

[0208] In some embodiments, the present disclosure provides form CC-1C having a TGA substantially as shown in FIG.

[0209] In some embodiments, the present disclosure provides Form CC-1C having a DVS profile substantially as shown in FIG.

[0210] Crystalline Compound A Isobutyric Acid Cocrystal ("Form CC-1D") In some embodiments, the disclosure provides crystalline Compound A isobutyric acid co-crystal ("Form CC-1D") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 6.1, 13.1, 16.0, and 17.1±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1D is further characterized by peaks in its XRPD pattern at 6.5, 8.0, 8.6, 10.7, 11.1, 12.2, and 19.6±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Compound A isobutyric acid co-crystal Form CC-1D having an XRPD substantially as shown in Figure 85.

[0211] Form CC-1D may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-1D having a DSC substantially as shown in FIG.

[0212] In some embodiments, the present disclosure provides form CC-1D having a TGA substantially as shown in FIG.

[0213] In some embodiments, the present disclosure provides a form CC-1D having a DVS profile substantially as shown in FIG.

[0214] Crystalline Compound A Isobutyric Acid Cocrystal ("Form CC-2D") In some embodiments, the disclosure provides crystalline Compound A isobutyric acid co-crystal ("Form CC-2D") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.2, 5.5, 6.3, 10.3, and 12.6±0.2 degrees 2θ using CuKα radiation. In some embodiments, Form CC-2D is further characterized by peaks in its XRPD pattern at 6.8, 12.1, 13.0, and 14.3±0.2 degrees 2θ using CuKα radiation. In some embodiments, the disclosure provides crystalline Compound A isobutyric acid co-crystal Form CC-2D having an XRPD substantially as shown in Figure 88.

[0215] Form CC-2D may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-2D having a DSC substantially as shown in FIG.

[0216] In some embodiments, the present disclosure provides form CC-2D having a TGA substantially as shown in FIG.

[0217] In some embodiments, the present disclosure provides a configuration CC-2D having a DVS profile substantially as shown in FIG.

[0218] Crystalline Compound A Caprylic Acid Co-Crystal ("Form CC-1E") In some embodiments, the disclosure provides crystalline Compound A caprylic acid co-crystal ("Form CC-1E") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.8, 6.2, 6.5, 18.1, and 21.1±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1E is further characterized by peaks in its XRPD pattern at 15.6, 20.6, 21.4, 22.4, and 24.9±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Compound A caprylic acid co-crystal Form CC-1E having an XRPD substantially as shown in Figure 91.

[0219] Form CC-1E may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form CC-1E having a DSC substantially as shown in FIG.

[0220] In some embodiments, the present disclosure provides form CC-1E having a TGA substantially as shown in FIG.

[0221] Crystalline Compound A Co-Crystal with Sorbic Acid ("Form CC-1F") In some embodiments, the disclosure provides crystalline Compound A sorbic acid co-crystal ("Form CC-1F") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.2, 10.8, 11.4, 18.2, and 21±0.2 degrees two-theta using CuKa radiation. In some embodiments, Form CC-1F is further characterized by peaks in its XRPD pattern at 5.4, 7.1, 8.9, 12.7, 13.4, 14.8, 17.7, 21.6, and 24.6±0.2 degrees two-theta using CuKa radiation. In some embodiments, the disclosure provides crystalline Compound A sorbic acid co-crystal Form CC-1F having an XRPD substantially as shown in Figure 93.

[0222] Form CC-1F may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form CC-1F having a DSC substantially as shown in Figure 94.

[0223] In some embodiments, the present disclosure provides form CC-1F having a TGA substantially as shown in FIG.

[0224] Crystalline Compound A Saccharin Cocrystal ("Form CC-1G") In some embodiments, the present disclosure provides a crystalline Compound A saccharin co-crystal ("Form CC-1G") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.1, 9.8, 10.1, 16.5, and 20.4. In some embodiments, the present disclosure provides a crystalline Compound A saccharin co-crystal Form CC-1G having an XRPD substantially as shown in Figure 95.

[0225] Form CC-1G may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form CC-1G having a DSC substantially as shown in FIG.

[0226] In some embodiments, the present disclosure provides form CC-1G having a TGA substantially as shown in FIG.

[0227] In some embodiments, the present disclosure provides Form CC-1G having a DVS substantially as shown in FIG.

[0228] Crystalline Compound A succinic acid co-crystal ("Form CC-1H") In some embodiments, the disclosure provides crystalline Compound A succinic acid co-crystal ("Form CC-1H") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.3, 11.5, 18.3, 19.0, and 20.6±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1H is further characterized by peaks in its XRPD pattern at 13.7, 24.2, 25.2, and 28.3±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Compound A succinic acid co-crystal Form CC-1H having an XRPD substantially as shown in Figure 98.

[0229] Form CC-1H may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form CC-1H having a DSC substantially as shown in FIG.

[0230] In some embodiments, the present disclosure provides form CC-1H having a TGA substantially as shown in FIG.

[0231] Crystalline Compound A succinic acid co-crystal ("Form CC-2H") In some embodiments, the present disclosure provides a crystalline Compound A succinic acid co-crystal ("Form CC-2H") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.2, 5.3, 8.3, 9.0, and 9.2±0.2 degrees 2θ using CuKα radiation. In some embodiments, the present disclosure provides a crystalline Compound A succinic acid co-crystal Form CC-2H having an XRPD substantially as shown in Figure 100.

[0232] Form CC-2H may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides form CC-2H having a DSC substantially as shown in Figure 101.

[0233] In some embodiments, the present disclosure provides form CC-2H having a TGA substantially as shown in FIG.

[0234] Crystalline Compound A co-crystal with adipic acid ("Form CC-1I") In some embodiments, the disclosure provides crystalline Compound A adipic acid co-crystal ("Form CC-1I") characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.7, 10.5, 18.5, 18.9, and 21.7±0.2 degrees two-theta using CuKα radiation. In some embodiments, Form CC-1I is further characterized by peaks in its XRPD pattern at 5.3, 12.1, 20.7, 24.2, and 25.7±0.2 degrees two-theta using CuKα radiation. In some embodiments, the disclosure provides crystalline Compound A adipic acid co-crystal Form CC-1I having an XRPD substantially as shown in Figure 102.

[0235] Form CC-1I may be characterized using DSC, TGA, and / or DVS. In some embodiments, the present disclosure provides Form CC-1I having a DSC substantially as shown in Figure 103.

[0236] In some embodiments, the present disclosure provides form CC-1I having a TGA substantially as shown in FIG.

[0237] Pharmaceutical Composition Further provided herein are pharmaceutical compositions of the solid forms of Compound A and methods of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the disclosed solid forms of Compound A.

[0238] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a crystalline or amorphous form disclosed herein, or a co-crystal or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising Form 1.

[0239] In some examples, the crystalline or amorphous form disclosed herein, or a pharmaceutically acceptable salt thereof, is present in a pharmaceutical composition in an amount effective to treat a PRMT5-dependent cancer. In some aspects, the pharmaceutical composition is formulated for oral delivery or administration, while in other embodiments, the pharmaceutical composition is formulated for intravenous delivery or administration. In some embodiments, the pharmaceutical composition is formulated for once-daily (i.e., QD) oral administration, and in some such formulations are tablets with an effective amount of active ingredient ranging from 1 mg to 2000 mg (e.g., 1, 25, 50, 100, 200, 400, 500, 750, 800, 1000, 1200, 1500, or 2000 mg).

[0240] How to Treat a Subject Further provided herein is a method of treating a subject suffering from cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline or amorphous form of Compound A disclosed herein, or a pharmaceutically acceptable salt thereof, optionally as a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of treating a subject suffering from cancer, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline Form 1.

[0241] In some embodiments, the cancer is ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer.

[0242] MTAP-null cancer refers to cancer lacking expression of the enzyme methylthioadenosine phosphorylase (MTAP). The MTAP gene, located at chromosomal locus 9p21, is frequently co-deleted with the CDKN2A and CDKN2B genes. Selective MTAP deficiency refers to a defect without co-deletion of the CDKN2 gene, resulting from either selective deletion of the MTAP locus or methylation of the MTAP promoter. MTAP-null cancer contains MTAP deficiency in at least 1% of diseased cells. The terms "MTAP-null," "MTAP-deficient," and "MTAP-negative" are used interchangeably.

[0243] "MTAP deficiency-associated," or "MTAP-deficient," or "MTAP-deficient" disease (e.g., a proliferative disease, e.g., cancer), or "MTAP deficiency-associated" disease (e.g., a proliferative disease, e.g., cancer), or "characterized by MTAP deficiency" (e.g., a proliferative disease, e.g., cancer), etc., refer to a condition (e.g., a proliferative disease, e.g., cancer) in which a significant number of cells are deficient in MTAP. For example, in an MTAP deficiency-associated disease, one or more diseased cells may have significantly reduced post-translational modification, production, expression, levels, stability, and / or activity of MTAP. Examples of MTAP-deficiency-associated diseases include, but are not limited to, glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct sarcoma, brain cancer, stomach cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, and colorectal cancer or sarcoma. In patients with MTAP-deficiency-associated diseases, MTAP may be defective in some diseased cells (e.g., cancer cells) but not in others. Similarly, some diseased cells may accumulate MTA, while others may not. Thus, the present disclosure encompasses treatment methods involving diseases of these or any other tissues, in which the proliferation of MTAP-deficient and / or MTA-accumulating cells can be inhibited by administering a PRMT5 inhibitor. Some cancer cells deficient in MTAP are also deficient in CDKN2A, and these cells exhibit reduced post-translational modification, production, expression, level, stability, and / or activity of the CDKN2A gene or its product. The MTAP and CDKN2A genes are located in close proximity on chromosome 9p21, with MTAP located approximately 100 kb telomeric to CDKN2A. Many cancer cell types have CDKN2A / MTAP deficiency (deficiency of both genes). Thus, in some embodiments, MTAP-deficient cells are also deficient in CDKN2A.

[0244] In some embodiments, the cancer is selected from acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder (CMD), chronic myeloproliferative disorder (CRD ... Reproductive disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney Cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of occult primary, midline duct cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer , pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood anomaly cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some cases, the cancer is pancreatic cancer, esophageal cancer, melanoma, lung cancer, mixed Müllerian carcinoma, ovarian cancer, or gallbladder cancer.

[0245] In some embodiments, the cancer is glioblastoma, malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, bile duct sarcoma, brain cancer, stomach cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, and colorectal cancer or sarcoma.

[0246] In some embodiments, the MTAP-null cancer is lung cancer, biliary tract cancer, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, gallbladder cancer, or mesothelioma.

[0247] In some embodiments, the MTAP-null cancer is lung cancer. In some embodiments, the lung cancer is non-squamous cell lung cancer (NSCLC).

[0248] In some embodiments, the MTAP-null cancer is a solid tumor. Exemplary MTAP-null solid tumors include MTAP-null brain cancer (including, but not limited to, MTAP-null glioblastoma, MTAP-null oligodendroglioma, MTAP-null glioblastoma multiforme, MTAP-null astrocytoma, MTAP-null medulloblastoma, MTAP-null ependymoma, and MTAP-null meningioma), MTAP-null head and neck cancer (including, but not limited to, MTAP-null salivary gland (parotid) tumor, MTAP-null head and neck squamous cell carcinoma, and MTAP-null thyroid carcinoma), MTAP-null breast cancer (including, but not limited to, invasive ductal carcinoma, mixed mucinous carcinoma, and MTAP-null thyroid carcinoma), and MTAP-null thyroid cancer. liquid breast cancer and lobular carcinoma), MTAP-null mesothelioma, MTAP-null gastrointestinal cancer (including but not limited to MTAP-null esophageal cancer (including but not limited to adenocarcinoma and squamous cell carcinoma), MTAP-null gastroesophageal junction cancer, MTAP-null gastric cancer (including but not limited to adenocarcinoma and signet ring cell carcinoma), MTAP-null small intestine cancer, MTAP-null colon cancer, MTAP-null rectal cancer, and MTAP-null gastrointestinal stromal tumor), MTAP-null neuroendocrine tumor, MTAP-null liver Biliary tract cancer (including, but not limited to, MTAP-null biliary tract cancer (including cholangiocarcinoma, gallbladder cancer, and ampullary cancer) and MTAP-null hepatocellular carcinoma), MTAP-null pancreatic cancer (including pancreatic adenocarcinoma), MTAP-null kidney cancer (including, but not limited to, MTAP-null renal cell carcinoma), MTAP-null adrenocortical carcinoma, MTAP-null bladder cancer (including, but not limited to, MTAP-null urothelial carcinoma), MTAP-null adrenocortical carcinoma, MTAP-null endometrial cancer, MTAP-null uterine cancer, MTAP-null testicular cancer, MTAP-null germ cell tumors, or MTAP-null prostate cancer, MTAP-null sarcoma or MTAP-null bone cancer (including, but not limited to, MTAP-null osteosarcoma, MTAP-null chondrosarcoma, MTAP-null soft tissue sarcoma, MTAP-null Ewing's sarcoma, MTAP-null liposarcoma, MTAP-null leiomyosarcoma, and MTAP-null myxofibrosarcoma), MTAP-null skin tumors (MTAP-null cutaneous squamous cell carcinoma and MTAP-null melanoma), MTAP-null nerve sheath tumor, and MTAP-null carcinoma of unknown primary (CUP).

[0249] In some embodiments, the MTAP-null cancer is a hematological tumor. Exemplary hematological tumors include, but are not limited to, MTAP-null leukemia (including, but not limited to, MTAP-null acute lymphocytic leukemia, MTAP-null acute myeloid leukemia), MTAP-null lymphoma (including, but not limited to, MTAP-null mantle cell lymphoma, MTAP-null follicular lymphoma, MTAP-null diffuse large B-cell lymphoma), and MTAP-null fungal lymphoma.

[0250] In some embodiments, the cancer is not a primary brain tumor or lymphoma.

[0251] In some embodiments, the subject does not have or has never had interstitial lung disease or pneumonia.

[0252] Embodiment 1. Crystalline form of Compound A. [ka] 2. The crystalline form of embodiment 1, wherein Compound A is in free base form. 3. The crystalline form of embodiment 1 or 2 ("Form 1"), as the free base of Compound A, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.5, 9.0, 13.3, 16.2, and 18.8±0.2 degrees 2θ using CuKα radiation. 4. Using CuKα irradiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 27.8, 27.9, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 29.0, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 3. The crystalline form of embodiment 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from 4.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ. 5. Using CuKα irradiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2 3. The crystalline form of embodiment 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks selected from 4.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ. 6. Using CuKα irradiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2 3. The crystalline form of embodiment 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks selected from 4.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ. 7. Using CuKα irradiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2 3. The crystalline form of embodiment 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks selected from 4.6, 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ. 8. The crystalline form of any one of embodiments 1-7, characterized by a differential scanning calorimetry (DSC) thermograph comprising an endotherm with an onset at 225°C ± 3°C. Contains at least three peaks selected from 9, 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm 13 9. The crystalline form of any one of embodiments 1-8, characterized by C solid state NMR. At least five peaks selected from 10, 39, 2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm 13 9. The crystalline form of any one of embodiments 1-8, characterized by C solid state NMR. At least seven peaks selected from 11, 39, 2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm 13 9. The crystalline form of any one of embodiments 1-8, characterized by C solid state NMR. 12. Includes peaks at -62.0 and -63.9 ppm. 19 12. The crystalline form of any one of embodiments 1-11, characterized by F solid state NMR. 13. A crystalline form of the free base of Compound A ("Form 3"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.3, 12.6, 14.4, 16.2, and 25.6±0.2 degrees 2θ using CuKα radiation. 14. The crystalline form of embodiment 13, further characterized by peaks in an XRPD pattern at 8.6, 13.9, 15.6, 16.7, and 25.3±0.2 degrees 2θ using CuKα radiation. 15. The crystalline form of embodiment 13 or 14, further characterized by peaks in an XRPD pattern at 18.4, 19.7, 20.3, 26.7, 27.9, and 28.4±0.2 degrees 2θ using CuKα radiation. 16. A crystalline form of the free base of Compound A ("Form 6"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.5, 8.6, 9.0, 12.9, and 14.9±0.2 degrees 2θ using CuKα radiation. 17. The crystalline form of embodiment 16, further characterized by peaks in an XRPD pattern at 7.4, 12.3, 13.3, 16.2, 17.8, and 18.8±0.2 degrees 2θ using CuKα radiation. 18. A crystalline form of the free base of Compound A ("Form 7"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.3, 8.5, 12.3, 13.1, and 14.8±0.2 degrees 2θ using CuKα radiation. 19. The crystalline form of embodiment 18, further characterized by peaks in an XRPD pattern at 15.5, 19.1, and 20.9±0.2 degrees 2θ using CuKα radiation. 20. A crystalline form of the free base hydrate of Compound A ("Form 8"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.0, 7.7, 8.0, 12.3, and 15.1±0.2 degrees 2θ using CuKα radiation. 21. The crystalline form of embodiment 20, further characterized by peaks in an XRPD pattern at 6.1, 10.0, 13.7, 17.0, 18.4, and 19.9±0.2 degrees 2θ using CuKα radiation. 22. A crystalline form of the ethanol solvate of Compound A ("Form 2A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.8, 11.6, 12.7, 18.0, and 25.7±0.2 degrees 2θ using CuKα radiation. 23. The crystalline form of embodiment 22, further characterized by peaks in an XRPD pattern at 16.5, 22.6, 23.3, and 25.8±0.2 degrees 2θ using CuKα radiation. 24. A crystalline form of the isopropanol solvate of Compound A ("Form 3A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.6, 12.8, 16.4, 17.5, and 25.1±0.2 degrees 2θ using CuKα radiation. 25. The crystalline form of embodiment 24, further characterized by peaks in an XRPD pattern at 8.2, 11.2, 12.5, 18.6, and 21.8±0.2 degrees 2θ using CuKα radiation. 26. The crystalline form of embodiment 24 or 25, further characterized by peaks in an XRPD pattern at 6.4, 8.8, 9.2, 13.6, 21.0, 22.4, 22.9, 24.5, and 25.9±0.2 degrees 2θ using CuKα radiation. 27. A crystalline form of the acetone solvate of Compound A ("Form 4A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.7, 7.7, 11.5, 14.8, and 15.3±0.2 degrees 2θ using CuKα radiation. 28. The crystalline form of embodiment 27, further characterized by peaks in an XRPD pattern at 4.3, 7.3, 13.4, 16.2, and 24.0±0.2 degrees 2θ using CuKα radiation. 29. The crystalline form of embodiment 27 or 28, further characterized by peaks in an XRPD pattern at 11.2, 18.5, 19.6, and 20.4±0.2 degrees 2θ using CuKα radiation. 30. A crystalline form of the methanol solvate of Compound A ("Form 5A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.8, 7.7, 12.3, 15.3, and 16.1±0.2 degrees 2θ using CuKα radiation. 31. The crystalline form of embodiment 30, further characterized by peaks in an XRPD pattern at 8.9, 10.5, 13.1, 13.4, 14.5, 17.6, 21.5, and 25.0±0.2 degrees 2θ using CuKα radiation. 32. The crystalline form of embodiment 30 or 31, further characterized by peaks in an XRPD pattern at 9.7, 14.1, 18.7, 19.6, 22.7, 24.7, 26.0, and 26.6±0.2 degrees 2θ using CuKα radiation. 33. A crystalline form of the methyltetrahydrofuran solvate of Compound A ("Form 6A"), characterized by an XRPD pattern containing peaks at 7.6, 11.3, 15.1, 18.3, and 28.0±0.2 degrees 2θ using CuKα radiation. 34. The crystalline form of embodiment 33, further characterized by peaks in an XRPD pattern at 12.4, 15.7, 17.3, 17.7, 18.8, 19.7, 21.3, 22.7, 25.8, 26.1, and 26.5±0.2 degrees 2θ using CuKα radiation. 35. The crystalline form of embodiment 33 or 34, further characterized by peaks in an XRPD pattern at 13.6, 14.2, 16.5, 16.9, 20.5, 26.9, and 28.4±0.2 degrees 2θ using CuKα radiation. 36. A crystalline form of the toluenesulfonate salt of Compound A ("Form A1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.0, 19.0, 20.3, 24.1, 24.9, and 28.9±0.2°2θ using CuKα radiation. 37. The crystalline form of embodiment 36, further characterized by peaks in an XRPD pattern at 9.5, 11.9, 14.3, 17.9, 26.2, 33.8, and 35.4±0.2 degrees 2θ using CuKα radiation. 38. A crystalline form of the toluenesulfonate salt of Compound A ("Form A2"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 12.7, 15.5, 16.2, 18.7, 19.7, and 21.8±0.2°2θ using CuKα radiation. 39. The crystalline form of embodiment 38, further characterized by peaks in an XRPD pattern at 10.2, 23.2, 24.1, 24.6, 26.3, and 27.2±0.2 degrees 2θ using CuKα radiation. 40. A crystalline form of the toluenesulfonate salt of Compound A ("Form A3"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.9, 15.2, 18.8, 19.5, and 24.5±0.2°2θ using CuKα radiation. 41. A crystalline form of the benzenesulfonate salt of Compound A ("Form B1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.1, 16.1, 17.9, 19.0, and 25.2±0.2 degrees 2θ using CuKα radiation. 42. The crystalline form of embodiment 41, further characterized by peaks in an XRPD pattern at 20.2, 20.6, 23.2, 26.0, 27.0, and 30.4±0.2 degrees 2θ using CuKα radiation. 43. A crystalline form of the chloride salt of Compound A ("Form C1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.8, 11.9, 16.6, 20.7, 23.8, 25.3, and 27.6±0.2°2θ using CuKα radiation. 44. A crystalline form of the chloride salt of Compound A ("Form C2"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.2, 5.6, 12.2, 12.9, and 18.1±0.2°2θ using CuKα radiation. 45. The crystalline form of embodiment 44, further characterized by peaks in an XRPD pattern at 6.8, 7.1, 9.4, 13.4, 14.0, 16.5, and 17.7±0.2 degrees 2θ using CuKα radiation. 46. ​​The crystalline form of embodiment 44 or 45, further characterized by peaks in an XRPD pattern at 7.8, 8.7, 10.9, 11.8, 14.9, 15.4, and 19.1±0.2 degrees 2θ using CuKα radiation. 47. A crystalline form of the sulfate salt of Compound A ("Form D1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 16.0, 16.5, 16.7, 20.0, and 20.4±0.2°2θ using CuKα radiation. 48. The crystalline form of embodiment 47, further characterized by peaks in an XRPD pattern at 8.4, 12.1, 13.8, 14.2, 23.6, 24.6, and 25.2±0.2 degrees 2θ using CuKα radiation. 49. A crystalline form of the malonate salt of Compound A ("Form E1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.8, 12.6, 16.6, 20.4, and 22.0±0.2°2θ using CuKα radiation. 50. The crystalline form of embodiment 49, further characterized by peaks in an XRPD pattern at 5.4, 8.3, 17.2, 19.4, 21.0, 22.9, and 26.2±0.2 degrees 2θ using CuKα radiation. 51. A crystalline form of the naphthalene-2-sulfonate salt of Compound A ("Form F1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.7, 14.7, 14.9, 17.0, 19.6, and 22.1±0.2°2θ using CuKα radiation. 52. A crystalline form of the naphthalene-2-sulfonate salt of Compound A ("Form F2"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.8, 11.6, 14.0, 17.5, and 19.7±0.2°2θ using CuKα radiation. 53. A crystalline form of the naphthalene-2-sulfonate salt of Compound A ("Form F3"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 3.8, 7.6, 9.7, 11.5, and 15.3±0.2°2θ using CuKα radiation. 54. A crystalline form of the methanesulfonate salt of Compound A ("Form G1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.1, 6.5, 13.6, 13.8, and 19.5±0.2°2θ using CuKα radiation. 55. The crystalline form of embodiment 54, further characterized by peaks in an XRPD pattern at 6.9, 9.3, 18.5, 20.8, and 21.5±0.2 degrees 2θ using CuKα radiation. 56. A crystalline form of the methanesulfonate salt of Compound A ("Form G2"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.6, 13.1, 13.3, 16.3, and 18.3±0.2°2θ using CuKα radiation. 57. The crystalline form of embodiment 56, further characterized by peaks in an XRPD pattern at 12.5, 19.8, 21.5, and 9.4±0.2 degrees 2θ using CuKα radiation. 58. A crystalline form of the oxalate salt of Compound A ("Form H2"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 6.9, 8.7, 13.6, 17.4, and 24.6±0.2°2θ using CuKα radiation. 59. The crystalline form of embodiment 58, further characterized by peaks in an XRPD pattern at 11.0, 19.6, 20.8, 21.0, 22.0, 25.3, and 27.3±0.2 degrees 2θ using CuKα radiation. 60. A crystalline form of the tartrate salt of Compound A ("Form I1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 3.4, 14.7, 15.6, 18.0, and 24.3±0.2°2θ using CuKα radiation. 61. The crystalline form of embodiment 60, further characterized by peaks in an XRPD pattern at 14.3, 15.1, 18.7, 19.4, and 19.7±0.2 degrees 2θ using CuKα radiation. 62. The crystalline form of embodiment 60 or 61, further characterized by peaks in an XRPD pattern at 13.3, 13.5, 20.6, 21.1, 23.1, 23.5, 24.9, 26.7, and 27.2±0.2 degrees 2θ using CuKα radiation. 63. A crystalline form of the ethanesulfonate salt of Compound A ("Form J1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.6, 7.9, 13.6, 15.7, and 17.9±0.2°2θ using CuKα radiation. 64. The crystalline form of embodiment 63, further characterized by peaks in an XRPD pattern at 6.6, 11.1, 13.1, 16.8, 18.7, and 20.4±0.2 degrees 2θ using CuKα radiation. 65. A crystalline form of the ethanesulfonate salt of Compound A ("Form J2"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.0, 6.3, 7.7, 15.8, and 20.9±0.2°2θ using CuKα radiation. 66. The crystalline form of embodiment 65, further characterized by peaks in an XRPD pattern at 7.9, 16.8, 18.4, 18.6, 19.5, and 20.0±0.2 degrees 2θ using CuKα radiation. 67. The crystalline form of embodiment 65 or 66, further characterized by peaks in an XRPD pattern at 6.9, 17.6, 21.6, 23.3, 23.8, 24.1, 24.7, and 26.1±0.2 degrees 2θ using CuKα radiation. 68. A crystalline form of the cyclamate salt of Compound A ("Form K1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.8, 14.0, 15.6, 16.7, and 28.1±0.2 degrees 2θ using CuKα radiation. 69. A crystalline form of the maleate salt of Compound A ("Form L1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.7, 17.0, 17.5, 25.6, and 26.1±0.2 degrees 2θ using CuKα radiation. 70. A crystalline form of the phosphate salt of Compound A ("Form M1"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.4, 16.2, 20.3, and 22.5±0.2°2θ using CuKα radiation. 71. The crystalline form of embodiment 70, further characterized by peaks in an XRPD pattern at 10.8, 12.3, 21.8, and 32.9±0.2 degrees 2θ using CuKα radiation. 72. A crystalline form of the phosphate salt of Compound A ("Form M2"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 7.1, 14.2, 14.9, 17.8, and 19.6±0.2°2θ using CuKα radiation. 73. The crystalline form of embodiment 72, further characterized by peaks in an XRPD pattern at 8.9, 10.6, 10.9, 13.4, 16.4, 16.8, and 21.4±0.2 degrees 2θ using CuKα radiation. 74. The crystalline form of embodiment 72 or 73, further characterized by peaks in an XRPD pattern at 3.6, 7.4, 21.0, 21.8, 23.0, 25.0, 25.4, 26.3, and 26.9±0.2 degrees 2θ using CuKα radiation. 75. A crystalline form of the phosphate salt of Compound A ("Form M3"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 7.5, 7.8, 14.8, 15.0, and 15.4±0.2°2θ using CuKα radiation. 76. The crystalline form of embodiment 75, further characterized by peaks in an XRPD pattern at 9.0, 9.8, 11.6, 11.7, 18.3, 22.2, and 25.2±0.2 degrees 2θ using CuKα radiation. 77. The crystalline form of embodiment 75 or 76, further characterized by peaks in an XRPD pattern at 3.9, 16.2, 27.2, and 27.2±0.2 degrees 2θ using CuKα radiation. 78. A crystalline form of the salicylic acid co-crystal of Compound A ("Form CC-1A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 9.3, 5.9, 9.7, 6.0, and 13.9, 24.0 ± 0.2° 2θ using CuKα radiation. 79. The crystalline form of embodiment 78, further characterized by peaks in an XRPD pattern at 13.1, 8.3, and 18.6±0.2 degrees 2θ using CuKα radiation. 80. A crystalline form of the salicylic acid co-crystal of Compound A ("Form CC-2A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.2, 9.2, 16.5, 18.5, and 16.0±0.2 degrees 2θ using CuKα radiation. 81. The crystalline form of embodiment 80, further characterized by peaks in an XRPD pattern at 17.2, 11.1, 3.2, 11.8, 24.6, and 25.9±0.2 degrees 2θ using CuKα radiation. 82. A crystalline form of the salicylic acid co-crystal of Compound A ("Form CC-3A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 3.6, 12.6, 8.0, 14.4, and 7.2±0.2°2θ using CuKα radiation. 83. The crystalline form of embodiment 82, further characterized by peaks in an XRPD pattern at 15.7, 11.2, 13.0, 21.5, 10.8, and 16.1±0.2 degrees 2θ using CuKα radiation. 84. A crystalline form of the salicylic acid co-crystal of Compound A ("Form CC-4A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 10.3, 16.2, 9.9, 16.3, and 19.9 ± 0.2 degrees 2θ using CuKα radiation. 85. The crystalline form of embodiment 84, further characterized by peaks in an XRPD pattern at 26.3, 27.0, 25.3, 18.0, 12.8, and 9.7±0.2 degrees 2θ using CuKα radiation. 86. The crystalline form of embodiment 84 or 85, further characterized by peaks in an XRPD pattern at 28.5, 28.0, 24.8, 24.4, 23.4, and 22.3±0.2 degrees 2θ using CuKα radiation. 87. The crystalline form of any one of embodiments 84-86, further characterized by α = 17.8, 16.2, 15.7, 15.6, 15.4, 13.6, and 13.4 ± 0.2 degrees 2θ using CuKα radiation. 88. A crystalline form of the salicylic acid co-crystal of Compound A ("Form CC-5A"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.3, 17.8, 10.6, 18.3, and 15.9±0.2°2θ using CuKα radiation. 89. The crystalline form of embodiment 88, further characterized by peaks in an XRPD pattern at 25.7, 15.5, 19.1, 28.7, 9.2, 12.2, 11.0, and 12.9±0.2 degrees 2θ using CuKα radiation. 90. The crystalline form of embodiment 88 or 89, further characterized by peaks in an XRPD pattern at 21.3, 19.8, 20.7, 24.3, 13.2, 26.6, 27.2, and 11.3±0.2 degrees 2θ using CuKα radiation. 91. A crystalline form of the formic acid co-crystal of Compound A ("Form CC-1B"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.6, 4.6, 17.8, 17.4, and 23.0±0.2°2θ using CuKα radiation. 92. The crystalline form of embodiment 91, further characterized by peaks in an XRPD pattern at 11.3, 14.8, 15.7, 16.5, 18.4, 19.3, 20.7, 24.9, and 26.8±0.2 degrees 2θ using CuKα radiation. 93. A crystalline form of the benzoic acid co-crystal of Compound A ("Form CC-1C"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 11.6, 16.1, 14.2, 3.9, and 19.8±0.2°2θ using CuKα radiation. 94. The crystalline form of embodiment 93, further characterized by peaks in an XRPD pattern at 10.4, 10.6, 12.4, 14.5, 17.3, 18.3, and 19.4±0.2 degrees 2θ using CuKα radiation. 95. The crystalline form of embodiment 93 or 94, further characterized by peaks in an XRPD pattern at 7.7, 8.8, 17.7, 21.7, 23.2, 26.3, and 26.7±0.2 degrees 2θ using CuKα radiation. 96. A crystalline form of the isobutyric acid co-crystal of Compound A ("Form CC-1D"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.6, 6.1, 13.1, 16.0, and 17.1±0.2°2θ using CuKα radiation. 97. The crystalline form of embodiment 96, further characterized by peaks in an XRPD pattern at 6.5, 8.0, 8.6, 10.7, 11.1, 12.2, and 19.6±0.2 degrees 2θ using CuKα radiation. 98. A crystalline form of the isobutyric acid co-crystal of Compound A ("Form CC-2D"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.2, 5.5, 6.3, 10.3, and 12.6±0.2°2θ using CuKα radiation. 99. The crystalline form of embodiment 98, further characterized by peaks in an XRPD pattern at 6.8, 12.1, 13.0, and 14.3±0.2 degrees 2θ using CuKα radiation. 100. A crystalline form of the caprylic acid co-crystal of Compound A ("Form CC-1E"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.8, 6.2, 6.5, 18.1, and 21.1±0.2°2θ using CuKα radiation. 101. The crystalline form of embodiment 100, further characterized by peaks in an XRPD pattern at 15.6, 20.6, 21.4, 22.4, and 24.9±0.2 degrees 2θ using CuKα radiation. 102. A crystalline form of a sorbic acid co-crystal of Compound A ("Form CC-1F"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 8.2, 10.8, 11.4, 18.2, and 21.2±0.2 degrees 2θ using CuKα radiation. 103. The crystalline form of embodiment 102, further characterized by peaks in an XRPD pattern at 5.4, 7.1, 8.9, 12.7, 13.4, 14.8, 17.7, 21.6, and 24.6±0.2 degrees 2θ using CuKα radiation. 104. A crystalline form of a saccharin co-crystal of Compound A ("Form CC-1G"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.1, 9.8, 10.1, 16.5, and 20.4±0.2°2θ using CuKα radiation. 105. A crystalline form of succinic acid co-crystal of Compound A ("Form CC-1H"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 11.3, 11.5, 18.3, 19.0, and 20.6±0.2°2θ using CuKα radiation. 106. The crystalline form of embodiment 105, further characterized by peaks in an XRPD pattern at 13.7, 24.2, 25.2, and 28.3±0.2 degrees 2θ using CuKα radiation. 107. A crystalline form of succinic acid co-crystal of Compound A ("Form CC-2H"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 4.2, 5.3, 8.3, 9.0, and 9.2±0.2 degrees 2θ using CuKα radiation. 108. A crystalline form of the adipic acid co-crystal of Compound A ("Form CC-1I"), characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 7.7, 10.5, 18.5, 18.9, and 21.7±0.2°2θ using CuKα radiation. 109. The crystalline form of embodiment 108, further characterized by peaks in an XRPD pattern at 5.3, 12.1, 20.7, 24.2, and 25.7±0.2 degrees 2θ using CuKα radiation. 110. Amorphous form of the free base of Compound A. [ka] 111. The amorphous form of embodiment 110, having a glass transition temperature (Tg) of 119°C ± 3°C. 112. A pharmaceutical composition comprising the crystalline or amorphous form according to any one of embodiments 1 to 111, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 113. The pharmaceutical composition of embodiment 112, wherein the composition is formulated for oral delivery. 114. The pharmaceutical composition according to embodiment 112 or 113, wherein the composition is formulated for once-daily administration. 115. The pharmaceutical composition according to any one of embodiments 112-114, wherein the composition is an oral tablet. 116. The pharmaceutical composition according to any one of embodiments 112-115, comprising 1 to 4000 mg of the crystalline or amorphous form. 117. The pharmaceutical composition according to embodiment 116, comprising 1 to 2000 mg of the compound or crystalline form. 118. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline or amorphous form of any one of embodiments 1-108, or a pharmaceutically acceptable salt thereof. 119. The method of embodiment 118, wherein the cancer is selected from ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer. 120. The method of embodiment 119, wherein the cancer is non-small cell lung cancer. 121. The method of embodiment 119, wherein the cancer is pancreatic cancer. 122. The method of any one of embodiments 118-121, wherein the cancer is an MTAP-null cancer. 123. The method of embodiment 122, wherein the MTAP-null cancer is selected from lung cancer, biliary tract cancer, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, gallbladder cancer, and mesothelioma. 124. The method of embodiment 123, wherein the MTAP-null cancer is lung cancer. 125. The method of embodiment 124, wherein the lung cancer is non-squamous cell lung cancer (NSCLC). 126. The method of any one of embodiments 118 to 123, wherein the cancer is not a primary brain tumor or lymphoma. 127. The method of any one of embodiments 118-126, wherein the subject does not suffer from and has never suffered from interstitial lung disease or pneumonia. 128. The method of any one of embodiments 118-127, wherein the crystalline form is crystalline form 1.

[0253] Other embodiments It should be understood that the foregoing description, while read in conjunction with the present disclosure and its detailed description, is intended to be illustrative and not limiting of the scope of the present disclosure, as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. [Example]

[0254] The following examples are provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0255] Materials and Methods Unless otherwise stated, commercially available reagents are used as received without further purification.

[0256] The crystalline forms disclosed herein may be characterized using conventional means, including physical constants, diffraction data, and spectral data.

[0257] X-ray Powder Diffraction—Method 1: X-ray powder diffraction (XRPD) data were obtained on a PANalytical X'Pert PRO X-ray diffraction system equipped with a RTMS detector. Samples were scanned at ambient temperature in continuous mode from 5 to 45° or 3 to 40° (2θ) with a step size of 0.0334° or 0.0167°, respectively, using CuKα radiation (1.541874 Å) at 45 kV and 40 mA, with a time per step of 50 seconds. Some X-ray powder diffraction (XRPD) data were also obtained on a Burker D8 Advance equipped with a Twin twin optical detector and an Eiger detector. Samples were scanned at ambient temperature in continuous mode from 3 to 40° (2θ) with a step size of 0.02°, using Cu radiation (K1 = 1.5406 Å) at 40 kV and 40 mA, with a time per step of 0.2 seconds (scan time of 7 minutes).

[0258] X-ray Powder Diffraction - Method 2: In some cases, XRPD was performed using a PANalytical Aeris Powder XRPD on a Si zero background holder. 2θ positions were calibrated against a PANalytical Si reference standard disc. The parameters used are listed in the table below.

[0259] [Table 1]

[0260] X-ray Powder Diffraction - Method 3: Powder X-ray diffractograms were collected using a Bruker D8 Advance diffractometer equipped with twin-twin optics in reflection mode and an Eiger X-ray detector. Samples were scanned at ambient temperature in continuous mode from 3 to 45°2θ with a step size of 0.02°2θ at 40 kV and 40 mA using CuKα radiation (1.54 Å). The incident beam path was equipped with a 0.2 mm nickel filter and an air anti-scatter slit. Samples were prepared on a low-background sample holder and mounted on a rotation stage with a rotation time of 10 revolutions per minute. Data were collected using DIFFRAC.MEASUREMENT CENTER (v.7.5) and processed in DIFFRAC.EVA (v.5.2).

[0261] Single-crystal structure: High-quality single crystals were mounted in a MiteGEN loop using mineral oil. Data were collected at 100 K on a Bruker-AXS X8 Kappa diffractometer connected to a Bruker Photon 2 CPAD detector using CuKα radiation (λ = 1.54178 Å) from an IμS microsource. All non-hydrogen atoms were anisotropically refined. All carbon-bonded hydrogen atoms were placed in geometrically calculated positions and refined using a riding model, constraining their Uiso to 1.2 times the Ueq of the atom to which they are bonded. Data reduction was performed using the program SAINT, and equivalent-based semi-empirical absorption corrections were performed using the program SADABS.

[0262] Differential Scanning Calorimetry (DSC) - Method 1: DSC analysis was performed on a TA Instruments Discovery Series calorimeter using a nickel reference standard under dry nitrogen at 50 mL / min on a crimped aluminum T zero The heating was carried out in a pan at 10°C / min from 30°C to 300°C, and the sample size was approximately 2-4 mg.

[0263] Thermogravimetric Analysis (TGA) - Method 1: TGA was performed on a TA Instruments Discovery Series analyzer using an indium reference standard in a platinum pan under dry nitrogen at 25 mL / min, from ambient temperature to 300°C at 10°C / min. Sample size was approximately 5 mg. The detailed parameters used are listed in the table below.

[0264] [Table 2]

[0265] Differential Scanning Calorimetry - Method 2: Differential scanning calorimetry (DSC) analysis was performed on a TA Instruments Q2000, Q1000, and / or Discovery Series calorimeter using a sample size of approximately 1-5 mg and a pressure-sensitive T under a 50 mL / min flow of dry nitrogen. zero The heating was carried out in an aluminum dish from -5 to 30°C to 250 to 350°C at 10°C / min.

[0266] Alternatively, DSC was performed using a TA Instruments Q2000 Differential Scanning Calorimeter. Temperature calibration was performed using NIST-traceable indium metal. Samples were placed in aluminum Tzero pans, covered with lids, crimped, and the weights accurately recorded. A weighing aluminum pan configured as the sample pan was placed on the reference side of the cell. Data collection parameters and pan configuration for each thermogram are displayed in images in the data section of this report.

[0267] An exemplary procedure for the amorphous form of Compound A free base form 4mDSC was performed using the following steps / settings: 1) equilibrate at 0.00°C; 2) turn on data storage; 3) modulate + / - 0.50°C every 60 seconds; 4) ramp to 26.00°C at 2.00°C / min; 5) mark the end of cycle 1; and 6) end of method.

[0268] Thermogravimetric Analysis - Method 2: Thermogravimetric analysis (TGA) was performed on a TA instruments Q5000, Q500, and / or Discovery Series analyzer using a sample size of approximately 1-5 mg in a platinum pan under 25 mL / min of dry nitrogen at 10°C / min from ambient to 250-400°C.

[0269] DVS - Method 1: DVS was measured by SMS (Surface Measurement Systems) DVS Resolution. Relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2 and KCl. The actual parameters of the DVS are shown in the table below.

[0270] [Table 3]

[0271] DVS-Method 2: Moisture sorption data were collected using a DVS vapor sorption analyzer. Sample sizes of approximately 10-20 mg were used in glass or metal pans. Moisture sorption was evaluated from 40-90 to 0-90-40% RH in 5% RH increments, or from 40-0 to 95 to 0-95% RH in 10% RH increments. Data were collected for adsorption and desorption cycles. Equilibrium criteria were set at 0.002% weight change per minute with a maximum equilibration time of 180 minutes.

[0272] NMR: 13 C solid-state NMR spectra were acquired at 298 K and 11.7 T on a wide-bore Bruker Avance III spectrometer equipped with a 4 mm H / F / X magic-angle spinning probe. 19 Using Teflon (PTFE) with the F resonance set at -123.2 ppm, 13 Chemical shifts were externally referenced using adamantane, which set the C CH resonance to 38.48 ppm. Approximately 100 mg of sample was packed into a 4 mm zirconia rotor, and a magic angle spinning frequency of 14 kHz was used. NMR data were processed using Topspin 3.6.4 or 3.5 software.

[0273] As an example, the following parameters were used for Form 1: 1 H- 13 For cross polarization (CP), 64 kHz 1 H excitation pulse, followed by an amplitude ramp from 70 to 100% 1 H pulse and constant amplitude 13 A C pulse was used with a contact time of 3 ms; during acquisition, 1 H heteronuclear decoupling was achieved using SPINAL-64. 2048 transients of the spectrum were acquired using a recycle delay of 28 seconds. 19 In the F experiment, 45 kHz 19 F excitation pulses are used, and during acquisition, 1 H heteronuclear decoupling was achieved in SPINAL-64, and 256 transients of the spectrum were acquired using a recycle delay of 4.03 s.

[0274] Example 1: Crystalline Compound A Form 1 A crystalline form of the free base of Compound A (Form 1) was prepared by first slurrying Compound A in water at 37° C. By way of example, Form 1 can be prepared by slurry conversion of Form 8. Alternatively, Form 1 can be prepared by slurry conversion of the free base amorphous form.

[0275] The following procedures illustrate various processes for preparing Form 1. Form 1 can be prepared by a) slurry inversion at 55° C. for 8 hours in heptane, cyclohexane, 2-methyltetrahydrofuran, 1,2-dichloroethane / heptane (1:1), acetonitrile / heptane (1:1), water, isopropyl alcohol / water (1:4), ethanol / water (1:1), ethanol / water (1:4), acetonitrile / water (1:4), dimethylformamide / water (1:1), dimethylformamide / water (1:4) at 55° C.; b) slow evaporation at room temperature from toluene, acetone, dioxane, dimethoxyethane, isopropyl acetate, or ethyl acetate; c) acetone / water 40 / 60, acetone / water 20 / 4 ... / 80, acetonitrile / water 20 / 80, acetonitrile / water 10 / 90, ethanol / water 40 / 60, ethanol / water 50 / 50, ethanol / water 70 / 30, ethanol / water 80 / 20, ethanol / water 90 / 10, isopropyl alcohol / water 10 / 90, isopropyl alcohol / water 30 / 70, isopropyl alcohol / water 40 / 60, isopropyl alcohol / water 60 / 40, isopropyl alcohol / water 80 / 10, isopropyl alcohol / water 90 / 10, by slurry inversion at room temperature for 5 days; and / or d) addition of an anti-solvent to acetone or DMSO.

[0276] The resulting solid was identified as crystalline Form 1 by XRPD, as shown in Table 1 and Figure 1. Additionally, DSC and DVS are shown in Figures 2 and 3, respectively. As shown in Figure 2, DSC shows an extrapolated onset of melting at 225°C, and a weight loss of 0.03% between 35 and 150°C, as well as thermal decomposition above 250°C. As shown in Figure 3, DVS indicates that Form 1 is non-hygroscopic at 25°C and 0-95% relative humidity, with no observable change in morphology.

[0277] [Table 4]

[0278] Additionally, single crystals of free base Form 1 were grown in ethyl acetate by slow evaporation at room temperature and used for single crystal X-ray structure determination.

[0279] [Table 5]

[0280] 13 C ssNMR data. 13 C NMR isotropic peaks: 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm. 19 F ssNMR data: -62.0 and -63.9 ppm at 25°C.

[0281] Crystalline Compound A Form 3 was prepared using any one of the following conditions: a) adding a solution of Compound A in 2-methyltetrahydrofuran to heptane such that the volume ratio of 2-methyltetrahydrofuran to heptane was 1:2 at room temperature; b) adding a solution of Compound A in tetrahydrofuran to methyl t-butyl ether such that the volume ratio of tetrahydrofuran to methyl t-butyl ether was 1:2 at 5°C; c) slow evaporation from methanol / methyl t-butyl ether (1:2); d) slow evaporation from dichloromethane at room temperature; e) dichloromethane. Form 3 was formed by adding a solution of Compound A in dichloromethane to pentane at a volume ratio of 1:2 at room temperature; f) by slurry inversion in dichloromethane at 5°C; and g) by liquid vapor diffusion from a dioxane solution and an anti-solvent of methyl t-butyl ether at 5°C; h) by slow evaporation from methyl ethyl ketone / toluene (1:2); i) by liquid vapor diffusion from a solution of 2-methyltetrahydrofuran and an anti-solvent of pentane at room temperature; and j) by slow evaporation from methyl t-butyl ether at room temperature. Form 3 was also formed by slow evaporation from dichloromethane at room temperature.

[0282] Example 2: Crystalline Compound A Free Base Form 3 Crystalline Compound A free base Form 3 was prepared using any one of the following conditions: a) adding heptane as an antisolvent to a solution of Compound A in 2-methyltetrahydrofuran / heptane (1:2) at room temperature; b) adding methyl t-butyl ether as an antisolvent to a solution of Compound A in tetrahydrofuran / methyl t-butyl ether (1:2) at 5° C.; c) evaporation from methanol / methyl t-butyl ether (1:2); d) evaporation from dichloromethane at room temperature; e) adding pentane as an antisolvent to a solution of Compound A in dichloromethane / pentane (1:2) at room temperature; f) formation by slurry inversion in dichloromethane at 5° C.; and g) formation by liquid vapor diffusion from a dioxane solution and an antisolvent of methyl t-butyl ether at 5° C. Form 3 was also formed by slow evaporation from dichloromethane at room temperature.

[0283] The resulting solid was identified as crystalline Form 3 by XRPD, as shown in Table 3 and FIG.

[0284] [Table 6]

[0285] Example 3: Crystalline Compound A Free Base Form 6 Crystalline Compound A free base Form 6 was prepared by slurrying Compound A in ethanol at room temperature. The resulting solid was identified as crystalline Form 6 by XRPD, as shown in Table 4 and Figure 7.

[0286] [Table 7]

[0287] Example 4: Crystalline Compound A Free Base Form 7 Crystalline Compound A free base Form 7 was prepared using the following conditions: a) slow evaporation from acetonitrile and pentane (1:2); b) slow evaporation from ethyl acetate and toluene (1:2); and c) slow evaporation from acetonitrile. The resulting solid was identified as crystalline Form 7 by XRPD, as shown in Table 5 and Figure 9.

[0288] [Table 8]

[0289] Example 5: Crystalline Compound A Free Base Form Octahydrate Crystalline Compound A free base form octahydrate was prepared by slow evaporation from acetonitrile and water. The resulting solid was identified as crystalline form octahydrate by XRPD, as shown in Table 6 and Figure 11.

[0290] [Table 9]

[0291] Example 6: Crystalline Compound A Ethanol Solvate (Form 2A) Crystalline Compound A monoethanol solvate (Form 2A) was prepared by first slurrying Compound A in ethanol at room temperature. The resulting solid was identified as crystalline by XRPD, as shown in Table 7 and Figure 13.

[0292] [Table 10]

[0293] Single crystals of Form 2A were grown in ethanol at room temperature and used for single crystal X-ray structure determination.

[0294] [Table 11]

[0295] Example 3: Crystalline Compound A Isopropanol Solvate (Form 3A) The crystalline isopropanol solvate of Compound A (Form 3A) was prepared by first slurrying Compound A in isopropanol at room temperature. The resulting solid was identified as crystalline Form 3A by XRPD, as shown in Table 9 and Figure 15.

[0296] [Table 12]

[0297] Example 4: Crystalline acetone solvate of Compound A (Form 4A) Crystalline acetone solvate Form 4A of Compound A was prepared by slurry conversion of Compound A in acetone at 5° C. and room temperature. The resulting solid was identified as crystalline Form 4A by XRPD, as shown in Table 10 and Figure 17.

[0298] [Table 13]

[0299] Example 5: Crystalline Methanol Solvate of Compound A (Form 5A) Crystalline methanol solvate Form 5A of Compound A was prepared by slurry conversion of Compound A in methanol at 5° C. and room temperature. Form 5A was also prepared by slow evaporation of Compound A from methanol at room temperature. The resulting solid was identified as crystalline Form 5A by XRPD, as shown in Table 11 and Figure 19.

[0300] [Table 14]

[0301] Example 6: Amorphous Compound A Free Base (Form 4AA) Amorphous Compound A free base (Form 4AA) was formed upon cooling of the melt at 300° C. The resulting solid was characterized using XRPD (Figure 104) and DSC (Figure 105).

[0302] The amorphous form of Compound A free base can be formed under suitable conditions upon cooling a melt of Compound A free base. For example, in some embodiments, Compound A free base Form 1 can be heated at a rate of 20°C / min to a temperature of 300°C and melted on a hot stage microscope, whereupon the sample can be removed and rapidly cooled to room temperature.

[0303] DSC was performed in a sealed crimp pan heated at 2°C / min with modulation of ±0.5°C every 60 seconds and showed a glass transition (Tg) at approximately 1189°C.

[0304] Example 7: Crystalline Toluenesulfonate Salt of Compound A (Form A1) Crystalline toluenesulfonate salt of Compound A (Form A1) was prepared by slurrying one equivalent of toluenesulfonic acid with Compound A in a 50 / 50 toluene / methanol solvent mixture under ambient conditions. The resulting solid was identified as crystalline by XRPD, as shown in Table 12 and Figure 21.

[0305] [Table 15]

[0306] Example 8: Crystalline Toluenesulfonate Salt of Compound A (Form A2) Crystalline toluenesulfonate salt of Compound A (Form A2) was prepared by slurrying a 1:1 molar ratio of Compound A and the counterion toluenesulfonic acid in 2-methyltetrahydrofuran, acetone, or ethyl acetate at ambient conditions. The resulting solid was identified as crystalline by XRPD, as shown in Table 13 and Figure 24.

[0307] [Table 16]

[0308] [Table 17]

[0309] Example 9: Crystalline Toluenesulfonate Salt of Compound A (Form A3) Crystalline toluenesulfonate salt of Compound A (Form A3) was prepared by reactive crystallization at room temperature using p-toluenesulfonic acid in acetone / heptane (1:1) with a 1:1 molar ratio of Compound A and counterion. It was also formed by reactive crystallization at room temperature using p-toluenesulfonic acid in methyl isobutyl ketone and dioxane with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form A3 by XRPD, as shown in Table 14 and Figure 26.

[0310] [Table 18]

[0311] Example 10: Crystalline benzenesulfonate salt of Compound A (Form B1) Crystalline benzenesulfonate salt of Compound A (Form B1) was prepared by cooling a 1:1 molar ratio of Compound A and the counterion benzenesulfonic acid in a 50:50 toluene:methanol solvent mixture. It was also formed by reactive crystallization at room temperature with a 1:1 molar ratio of Compound A and the counterion in ethanol, methyl isobutyl ketone, dioxane, acetone / heptane (1:1), or dichloromethane. It was also formed by slow evaporation in acetonitrile / water (1:1) at room temperature. The resulting solid was identified as crystalline Form B1 by XRPD, as shown in Table 15 and Figure 29.

[0312] [Table 19]

[0313] Example 11: Crystalline Chloride Salt of Compound A (Form C1) Crystalline chloride salt of Compound A (Form C1) was prepared by slurrying a 1:1 molar ratio of Compound A and counterion HCl in isopropanol at ambient conditions. The resulting solid was identified as crystalline Form C1 by XRPD, as shown in Table 16 and Figure 31.

[0314] [Table 20]

[0315] Example 12: Crystalline Chloride Salt of Compound A (Form C2) Crystalline chloride salt of Compound A (Form C2) was prepared by reactive crystallization at room temperature using HCl in methyl isobutyl ketone with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form C1 by XRPD, as shown in Table 17 and Figure 33.

[0316] [Table 21]

[0317] Example 13: Crystalline Compound A Sulfate Salt (Form D1) Crystalline sulfate salt of Compound A (Form D1) was prepared by slurrying a 1:1 molar ratio of Compound A and counterion sulfate in isopropanol at ambient conditions. The resulting solid was identified as crystalline Form D1 by XRPD, as shown in Table 18 and Figure 35.

[0318] [Table 22]

[0319] Example 14: Crystalline Malonate Salt of Compound A (Form E1) Crystalline malonate salt of Compound A (Form E1) was prepared by reactive crystallization at room temperature using malonic acid in methyl isobutyl ketone with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form E1 by XRPD, as shown in Table 19 and Figure 36.

[0320] [Table 23]

[0321] Example 15: Crystalline naphthalene-2-sulfonate salt of Compound A (Form F1) Crystalline naphthalene-2-sulfonate salt of Compound A (Form F1) was prepared by reactive crystallization at room temperature using naphthalene-2-sulfonic acid in acetone / heptane (1:1) with a 1:1 molar ratio of Compound A and a counterion. Form F1 was also prepared by reactive crystallization at room temperature using a 1:1 molar ratio of Compound A and a counterion in dioxane and methyl isobutyl ketone. The resulting solid was identified as crystalline Form F1 by XRPD, as shown in Table 20 and Figure 40.

[0322] [Table 24]

[0323] Example 16: Crystalline naphthalene-2-sulfonate salt of Compound A (Form F2) Form F2 of the naphthalene-2-sulfonate salt of crystalline Compound A was formed by reactive crystallization at room temperature using naphthalene-2-sulfonic acid in ethanol with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form F2 using XRPD, as shown in Table 21 and Figure 43.

[0324] [Table 25]

[0325] Example 17: Crystalline Compound A naphthalene-2-sulfonate salt (Form F3) Form F3 of the crystalline naphthalene-2-sulfonate salt of Compound A was formed by reactive crystallization at room temperature using naphthalene-2-sulfonic acid in dichloromethane with a 1:1 molar ratio of Compound A and counterion. Form F3 was also formed by reactive crystallization at 5° C. using naphthalene-2-sulfonic acid in acetonitrile / water (1:1) with a 1:1 molar ratio of Compound A:counterion. The resulting solid was identified as crystalline Form F3 using XRPD, as shown in Table 22 and Figure 44.

[0326] [Table 26]

[0327] Example 18: Crystalline methanesulfonate salt of Compound A (Form G1) Form G1 of the crystalline methanesulfonate salt of Compound A was prepared by reactive crystallization at room temperature using methanesulfonic acid in methyl isobutyl ketone and a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form G1 using XRPD, as shown in Table 23 and Figure 46.

[0328] [Table 27]

[0329] Example 19: Crystalline Methanesulfonate Salt of Compound A (Form G2) Form G2 of the crystalline methanesulfonate salt of Compound A was prepared by reactive crystallization at room temperature using methanesulfonic acid in ethanol with a 1:1 molar ratio of Compound A and a counterion. Form G2 was also formed by reactive crystallization at room temperature using a 1:1 molar ratio of Compound A and a counterion in dichloromethane. The resulting solid was identified as crystalline Form G2 using XRPD, as shown in Table 24 and Figure 47.

[0330] [Table 28]

[0331] Example 20: Crystalline Compound A Oxalate Salt (Form H2) Form H2 of the oxalate salt of crystalline Compound A was prepared by reactive crystallization at room temperature using oxalic acid in dichloromethane with a 1:1 molar ratio of Compound A and a counterion. Form H2 was also formed by reactive crystallization at 5° C. using a 1:1 molar ratio of Compound A and a counterion in acetonitrile / water (1:1). The resulting solid was identified as crystalline form H2 using XRPD, as shown in Table 25 and Figure 50.

[0332] [Table 29]

[0333] Example 21: Crystalline Compound A Tartrate Salt (Form I1) Crystalline Compound A tartrate salt Form I1 was prepared by reactive crystallization at room temperature using tartaric acid in dioxane with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form I1 using XRPD, as shown in Table 26 and Figure 52.

[0334] [Table 30]

[0335] Example 22: Crystalline Ethanesulfonic Acid Salt of Compound A (Form J1) Form J1 of the ethanesulfonate salt of crystalline Compound A was prepared by reactive crystallization at room temperature using ethanesulfonic acid in ethanol with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form J1 using XRPD, as shown in Table 27 and Figure 54.

[0336] [Table 31]

[0337] Example 23: Crystalline Ethanesulfonic Acid Salt of Compound A (Form J2) Form J2 of the crystalline ethanesulfonate salt of Compound A was prepared by reactive crystallization at room temperature using ethanesulfonic acid in 1:1 acetone / heptane with a 1:1 molar ratio of Compound A and a counterion. Form J1 was also formed by reactive crystallization at room temperature with ethanesulfonic acid in methyl isobutyl ketone with a 1:1 molar ratio of Compound A and a counterion. The resulting solid was identified as crystalline Form J1 using XRPD, as shown in Table 28 and Figure 56.

[0338] [Table 32]

[0339] Example 24: Crystalline N-cyclohexylsulfamate salt of Compound A (Form K1) Form K1 of the crystalline N-cyclohexylsulfamate salt of Compound A was prepared by reactive crystallization at room temperature using cyclamic acid in dioxane in a 1:1 molar ratio of Compound A and counterion. Form K1 was also formed by reactive crystallization at room temperature using cyclamic acid in ethanol, dichloromethane, and acetone / heptane (1:1) with a 1:1 molar ratio of Compound A and counterion. Form K1 was also formed by reactive crystallization at 5°C using cyclamic acid in acetonitrile / water (1:1) with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form K1 using XRPD, as shown in Table 29 and Figure 58.

[0340] [Table 33]

[0341] Example 25: Crystalline Compound A Maleate Salt (Form L1) Form L1 of the crystalline maleate salt of Compound A was prepared by reactive crystallization at room temperature using maleic acid in ethanol and a 1:1 molar ratio of Compound A to counterion. Form L1 was also formed by reactive crystallization at room temperature using maleic acid in methyl isobutyl ketone, dichloromethane, dioxane, and acetone / heptane (1:1) and a 1:1 molar ratio of API to counterion. Form L1 was also observed by reactive crystallization at 5°C using maleic acid in acetonitrile / water (1:1) and a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form L1 using XRPD, as shown in Table 30 and Figure 60.

[0342] [Table 34]

[0343] Example 26: Crystalline Phosphate Salt of Compound A (Form M1) Form M1 of the phosphate salt of crystalline Compound A was prepared by reactive crystallization at room temperature using phosphoric acid in ethanol with a 1:1 molar ratio of Compound A and counterion. The resulting solid was identified as crystalline Form M1 using XRPD, as shown in Table 30 and Figure 62.

[0344] [Table 35]

[0345] Example 27: Crystalline Compound A Phosphate Salt (Form M2) Crystalline Form M2 of the phosphate salt of Compound A was prepared by reactive crystallization at room temperature using phosphoric acid in dichloromethane and a 1:1 molar ratio of Compound A to counterion. The resulting solid was identified as crystalline Form M2 using XRPD, as shown in Table 31 and Figure 65.

[0346] [Table 36]

[0347] Example 28: Crystalline Compound A Phosphate Salt (Form M3) Form M3 of the crystalline phosphate salt of Compound A was prepared by reactive crystallization using phosphoric acid in dioxane with a 1:1 molar ratio of Compound A and counterion at 5° C. The resulting solid was identified as crystalline form M3 using XRPD, as shown in Table 32 and Figure 67.

[0348] [Table 37]

[0349] Example 29: Crystalline Compound A Salicylic Acid Co-Crystal (Form CC-1A) Crystalline Compound A salicylic acid co-crystal Form CC-1A was prepared by reactive crystallization using salicylic acid in ethanol at room temperature with a 1:1 molar ratio of Compound A and salicylic acid coformer. The resulting solid was identified as crystalline Form CC-1A using XRPD, as shown in Table 33 and Figure 69.

[0350] [Table 38]

[0351] Example 30: Crystalline Compound A Salicylic Acid Co-Crystal (Form CC-2A) Crystalline Compound A salicylic acid co-crystal Form CC-2A was prepared by reactive crystallization of salicylic acid in methyl isobutyl ketone at room temperature using a 1:1 molar ratio of Compound A and salicylic acid coformer. The resulting solid was identified as crystalline Form CC-2A using XRPD, as shown in Table 34 and Figure 71.

[0352] [Table 39]

[0353] Example 31: Crystalline Compound A Salicylic Acid Co-Crystal (Form CC-3A) Crystalline Compound A salicylic acid co-crystal Form CC-3A was prepared by reactive crystallization using salicylic acid and a 1:1 molar ratio of Compound A and salicylic acid coformer in dichloromethane at room temperature. The resulting solid was identified as crystalline Form CC-3A using XRPD, as shown in Table 35 and Figure 73.

[0354] [Table 40]

[0355] Example 32: Crystalline Compound A Salicylic Acid Co-Crystal (Form CC-4A) Crystalline Compound A salicylic acid co-crystal Form CC-4A was prepared by reactive crystallization using salicylic acid in acetonitrile / water (1:1) or acetone / heptane (1:1) at room temperature with a 1:1 molar ratio of Compound A and salicylic acid coformer. The resulting solid was identified as crystalline Form CC-4A using XRPD, as shown in Table 36 and Figure 76.

[0356] [Table 41]

[0357] Example 33: Crystalline Compound A Salicylic Acid Co-Crystal (Form CC-5A) Crystalline Compound A salicylic acid co-crystal Form CC-5A was prepared by slow evaporation of salicylic acid with a 1:1 molar ratio of Compound A and coformer in dioxane at 25° C. The resulting solid was identified as crystalline Form CC-5A using XRPD, as shown in Table 37 and Figure 78.

[0358] [Table 42]

[0359] Example 34: Crystalline Compound A Formic Acid Co-Crystal (Form CC-1B) Crystalline Compound A formic acid co-crystal Form CC-1B was prepared by slow evaporation of formic acid and a 1:1 molar ratio of Compound A and formic acid coformer in dichloromethane at 25° C. The resulting solid was identified as crystalline Form CC-1B using XRPD, as shown in Table 38 and Figure 80.

[0360] [Table 43]

[0361] Example 35: Crystalline Compound A Benzoic Acid Co-Crystal (Form CC-1C) Crystalline Compound A benzoic acid co-crystal Form CC-1C was prepared by reactive crystallization at room temperature using benzoic acid in methyl isobutyl ketone with a 1:1 molar ratio of Compound A and benzoic acid coformer. Form CC-1C was also formed by reactive crystallization using benzoic acid in dichloromethane or acetonitrile / water (1:1) with a 1:1 molar ratio of Compound A and coformer at 5° C. The resulting solid was identified as crystalline Form CC-1C using XRPD, as shown in Table 39 and Figure 82.

[0362] [Table 44]

[0363] Example 36: Crystalline Compound A Isobutyric Acid Co-Crystal (Form CC-1D) Crystalline Compound A isobutyric acid co-crystal Form CC-1D was prepared by reactive crystallization of a 1:1 molar ratio of isobutyric acid coformer and Compound A with isobutyric acid in acetone / heptane (1:1) or methyl isobutyl ketone at room temperature. Form CC-1D was also formed by slow evaporation at room temperature from acetonitrile / water (1:1) and a 1:1 molar ratio of coformer and Compound A. The resulting solid was identified as crystalline Form CC-1D using XRPD, as shown in Table 40 and Figure 85.

[0364] [Table 45]

[0365] Example 37: Crystalline Compound A Isobutyric Acid Co-Crystal (Form CC-2D) Crystalline Compound A isobutyric acid co-crystal Form CC-2D was prepared by slow evaporation at room temperature with isobutyric acid from dichloromethane in a 1:1 molar ratio of Compound A and isobutyric acid coformer. The resulting solid was identified as crystalline Form CC-2D using XRPD, as shown in Table 41 and Figure 88.

[0366] [Table 46]

[0367] Example 38: Crystalline Compound A Caprylic Acid Co-Crystal ("Form CC-1E") Crystalline caprylic acid co-crystal of Compound A was prepared by slow evaporation at room temperature using caprylic acid in acetonitrile / water (1:1) and a 1:1 ratio of caprylic acid coformer to Compound A. The resulting solid was identified as crystalline form CC-1E using XRPD, as shown in Table 42 and Figure 91.

[0368] [Table 47]

[0369] Example 39: Crystalline Compound A Sorbic Acid Co-Crystal (Form CC-1F) Crystalline Compound A sorbic acid co-crystal form CC-1F was prepared by reactive crystallization using sorbic acid in acetonitrile / water (1:1) at 5° C. and a 1:1 ratio of Compound A to sorbic acid coformer. The resulting solid was identified as crystalline form CC-1F using XRPD, as shown in Table 43 and Figure 93.

[0370] [Table 48]

[0371] Example 40: Crystalline Compound A Saccharin Cocrystal (Form CC-1G) Crystalline Compound A saccharin co-crystal Form CC-1G was prepared by reactive crystallization at room temperature using saccharin in acetone / heptane (1:1) with a 1:1 ratio of Compound A and saccharin coformer. Form CC-1G was also formed by reactive crystallization at room temperature using saccharin in ethanol, methyl isobutyl ketone, dichloromethane, or acetonitrile / water (1:1) with a 1:1 molar ratio of Compound A and saccharin coformer. Form CC-1G was also formed by slow evaporation at room temperature using saccharin from dioxane containing a 1:1 molar ratio of Compound A and coformer. The resulting solid was identified as crystalline Form CC-1G using XRPD, as shown in Table 44 and Figure 95.

[0372] [Table 49]

[0373] Example 41: Crystalline Compound A Succinic Acid Co-Crystal (Form CC-1H) Crystalline Compound A succinic acid co-crystal Form CC-1H was prepared by reactive crystallization at room temperature using succinic acid in dichloromethane in a 1:1 ratio. Form CC-1H was also formed by reactive crystallization at room temperature using succinic acid in ethanol, acetonitrile / water (1:1), or acetone / heptane (1:1). The resulting solid was identified as crystalline Form CC-1H using XRPD, as shown in Table 45 and Figure 98.

[0374] [Table 50]

[0375] Example 42: Crystalline Compound A Succinic Acid Co-Crystal (Form CC-2H) Crystalline succinic acid co-crystal Form CC-2H of Compound A was prepared by reactive crystallization at room temperature using a 1:1 molar ratio of Compound A and succinic acid in methyl isobutyl ketone in the succinic acid coformer. The resulting solid was identified as crystalline Form CC-2H using XRPD, as shown in Table 46 and Figure 100.

[0376] [Table 51]

[0377] Example 43: Crystalline Compound A Co-Crystal with Adipic Acid (Form CC-1I) Crystalline Compound A adipic acid co-crystal Form CC-1I was prepared by reactive crystallization at room temperature using adipic acid in acetone / heptane (1:1) and a 1:1 ratio of Compound A and adipic acid coformer. Form CC-1I was also formed by reactive crystallization at room temperature in methyl isobutyl ketone or dichloromethane. Form CC-1I was also formed by slow evaporation at room temperature from acetonitrile / water (1:1) and a 1:1 molar ratio of Compound A and adipic acid coformer. The resulting solid was identified as crystalline Form CC-1I using XRPD, as shown in Table 47 and Figure 102.

[0378] [Table 52]

[0379] Example 44: Crystalline methyltetrahydrofuran solvate of Compound A (Form 6A) Crystalline methyltetrahydrofuran solvate Form 6A of Compound A was prepared using the following procedure: Compound A (3.2 g) was added to methyltetrahydrofuran (40 mL) at 20° C. and allowed to equilibrate for 24 hours. Heptane (40 mL) was then added over 2 hours, and the slurry was allowed to equilibrate for 24 hours. The wet cake was analyzed by XRPD as shown in Table 48.

[0380] [Table 53]

[0381] The foregoing description is set forth for clarity of understanding only, and no unnecessary limitations should be construed therefrom, since modifications within the scope of the invention may be apparent to those skilled in the art.

[0382] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0383] The use of the terms "a," "an," "the," and similar referents in the context of this disclosure (particularly in the context of the claims) should be construed to encompass both the singular and the plural, unless otherwise indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. Any examples provided herein, or the use of exemplary language (e.g., "e.g., "etc."), are intended to better explain the disclosure herein and are not a limitation on the scope of the disclosure herein, unless otherwise indicated. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure herein.

Claims

1. Crystalline forms of Compound A. 【Chemistry 1】

2. 2. The crystalline form of claim 1, wherein Compound A is in free base form.

3. 3. The crystalline form of claim 1 or 2 as the free base of Compound A ("Form 1"), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.5, 9.0, 13.3, 16.2, and 18.8±0.2 degrees 2θ using CuKα radiation.

4. Using CuKα radiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 24.9, 24.9, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8 ...1, 24.

3. The crystalline form of claim 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from: 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

5. Using CuKα radiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 24.9, 24.9, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8 ...1, 24.

3. The crystalline form of claim 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks selected from: 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

6. Using CuKα radiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 24.9, 24.9, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8 ...1, 24.

3. The crystalline form of claim 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven peaks selected from: 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

7. Using CuKα radiation, 4.5, 6.7, 9.0, 12.2, 12.5, 12.8, 13.3, 13.7, 14.3, 14.7, 15.7, 16.2, 16.7, 17.4, 17.6, 18.0, 18.4, 18.8, 19.6, 20.0, 20.3, 20.8, 21.2, 21.6, 22.2, 22.5, 23.0, 23.8, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 24.9, 24.9, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8 ...1, 24.

3. The crystalline form of claim 1 or 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight peaks selected from: 25.1, 26.2, 26.4, 26.8, 27.8, 28.4, 28.8, 29.7, 30.5, 30.9, 32.7, 34.4, 35.1, 35.6, 36.4, 37.8, and 39.4±0.2 degrees 2θ.

8. 8. The crystalline form of any one of claims 1 to 7, characterized by a differential scanning calorimetry (DSC) thermograph containing an endotherm with an onset at 225°C ± 3°C.

9. At least three peaks selected from 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm. １３ 9. The crystalline form of any one of claims 1 to 8, characterized by C solid state NMR.

10. At least five peaks selected from 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm. １３ 9. The crystalline form of any one of claims 1 to 8, characterized by C solid state NMR.

11. At least seven peaks selected from 39.2, 43.8, 51.6, 58.1, 65.9, 71.8, 73.6, 114.7, 120.8, 125.1, 126.1, 128.2, 130.8, 142.2, 143.3, 145.3, 148.5, 149.2, 156.9, and 169.6 ppm. １３ 9. The crystalline form of any one of claims 1 to 8, characterized by C solid state NMR.

12. Contains peaks at -62.0 and -63.9 ppm １９ 12. The crystalline form of any one of claims 1 to 11, characterized by F solid state NMR.

13. Amorphous form of the free base of Compound A. 【Chemistry 2】

14. 14. The amorphous form of claim 13, having a glass transition temperature (Tg) of 119°C ± 3°C.

15. A pharmaceutical composition comprising the crystalline or amorphous form of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

16. 16. The pharmaceutical composition of claim 15, formulated for oral delivery.

17. 17. The pharmaceutical composition of claim 15 or 16, formulated for once-daily administration.

18. The pharmaceutical composition according to any one of claims 15 to 17, which is an oral tablet.

19. 19. The pharmaceutical composition of any one of claims 15 to 18, comprising 1 to 4000 mg of said crystalline or amorphous form.

20. 20. The pharmaceutical composition of claim 19, comprising 1 to 2000 mg of the compound or crystalline form.

21. 15. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline or amorphous form of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

22. 22. The method of claim 21, wherein the cancer is ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.

23. 23. The method of claim 22, wherein the cancer is non-small cell lung cancer.

24. 23. The method of claim 22, wherein the cancer is pancreatic cancer.

25. The method of any one of claims 21 to 24, wherein the cancer is an MTAP-null cancer.

26. 26. The method of claim 25, wherein the MTAP-null cancer is selected from lung cancer, biliary tract cancer, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, gallbladder cancer, and mesothelioma.

27. 27. The method of claim 26, wherein the MTAP-null cancer is lung cancer.

28. 28. The method of claim 27, wherein the lung cancer is non-squamous cell lung cancer (NSCLC).

29. The method of any one of claims 21 to 28, wherein the cancer is not a primary brain tumor or lymphoma.

30. 30. The method of any one of claims 21 to 29, wherein the subject does not suffer from, and has never suffered from, interstitial lung disease or pneumonia.

31. 31. The method of any one of claims 21 to 30, wherein the crystalline form is crystalline form 1.

Images