Crystalline prolyl hydroxylase domain-containing protein (PHD) inhibitors and their use

Abstract

This specification describes the crystalline form of compound (1), which is a low-molecular-weight prolyl hydroxylase domain-containing protein (PHD) inhibitor, its pharmaceutical composition, and its use in the treatment of diseases or conditions for which treatment with a prolyl hydroxylase domain-containing protein (PHD) inhibitor is beneficial. TIFF2026513705000031.tif32170

Description

[Technical Field]

[0001] [Cross reference] This application claims the interests of International Application PCT / CN2023 / 091755, filed on 28 April 2023, which in whole constitutes part of this specification by reference. [Background technology]

[0002] Hypoxia-inducible factors (HIFs) mediate gene expression in response to changes in cellular oxygen concentration. HIFs are heterodimers containing an oxygen-regulating subunit (HIF-α) and a constitutively expressed subunit (HIF-β). HIF prolyl hydroxylase, also known as prolyl hydroxylase domain-containing protein (PHD), exists in humans as three isoforms (PHD1, PHD2, and PHD3). PHDs function as oxygen sensors that regulate the hypoxia-inducible factor ("HIF") degradation pathway. In short, PHDs are responsible for the hydroxylation of HIFα, a subunit of HIF, which ultimately initiates a pathway leading to proteasome degradation of HIFα. There are three subtypes of PHDs, including PHD1, PHD2, and PHD3. Inhibition of PHDs has been shown as a promising treatment for HIFα-related diseases such as inflammatory bowel disease (IBD).

[0003] PHD inhibitors regulate red blood cell production by inducing erythropoietin ("EPO") synthesis in both the kidneys and liver, stimulating red blood cell production in the bone marrow, and by regulating iron metabolism, an essential component of functional red blood cells. PHD inhibitors can also suppress hepatic hepcidin production, which negatively impacts iron mobilization. It has also been hypothesized that PHD inhibitors may upregulate the expression of several iron metabolism genes, such as DMT1 and DCYTB. Due to the central role that HIF prolyl hydrolase plays in cellular oxygen sensing, PHD inhibitors may be useful, among other things, in the treatment of cardiovascular disorders, metabolic disorders, hematological disorders, pulmonary disorders, renal disorders, hepatic disorders, wound healing disorders, and cancer. [Overview of the project]

[0004] Disclosed herein is tert-butyl 4-(6-(((6-cyanopyridine-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridine-2-yl)piperazine-1-carboxylate: [ka] (Compound 1) or a pharmaceutically acceptable salt thereof in solid form.

[0005] In some embodiments, the solid state is crystalline.

[0006] In some embodiments, the solid form is crystalline compound 1 as a free base.

[0007] In some embodiments, the solid form is the free base C form of crystalline compound 1.

[0008] In some embodiments, the solid form is free base type A of crystalline compound 1, free base type B of crystalline compound 1, free base type C of crystalline compound 1, free base type D of crystalline compound 1, free base type E of crystalline compound 1, free base type F of crystalline compound 1, or free base type 1 of crystalline compound 1.

[0009] Also disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of the crystalline form disclosed herein and pharmaceutically acceptable excipients.

[0010] Also disclosed herein are methods for treating a disease or disorder in a subject, comprising administering to the subject a crystalline form or a pharmaceutical composition disclosed herein, wherein the disease or disorder is inflammatory bowel disease (IBD). In some embodiments, the disease or disorder is ulcerative colitis ("UC") or Crohn's disease ("CD").

[0011] The features of the present invention are set forth in detail in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description which illustrates exemplary embodiments of the principles of the present invention and the accompanying drawings.

Brief Description of the Drawings

[0012] [Figure 1] It is a diagram showing the X-ray powder diffraction (XRPD) pattern of the free base A type of Compound 1. [Figure 2] It is a diagram showing the differential scanning calorimetry (DSC) thermogram of the free base A type of Compound 1. [Figure 3] It is a diagram showing the thermogravimetric analysis (TGA) thermogram of the free base A type of Compound 1. [Figure 4] It is a diagram showing the X-ray powder diffraction (XRPD) pattern of the free base 1 type of Compound 1. [Figure 5] It is a diagram showing the differential scanning calorimetry (DSC) thermogram of the free base 1 type of Compound 1. [Figure 6] It is a diagram showing the thermogravimetric analysis (TGA) thermogram of the free base 1 type of Compound 1. [Figure 7] It is a diagram showing the X-ray powder diffraction (XRPD) pattern of the free base B type of Compound 1. [Figure 8] It is a diagram showing the differential scanning calorimetry (DSC) thermogram of the free base B type of Compound 1. [Figure 9] It is a diagram showing the thermogravimetric analysis (TGA) thermogram of the free base B type of Compound 1. [Figure 10] It is a diagram showing the X-ray powder diffraction (XRPD) pattern of the free base C type of Compound 1. [Figure 11] It is a diagram showing the differential scanning calorimetry (DSC) thermogram of the free base C type of Compound 1. [Figure 12] It is a diagram showing the thermogravimetric analysis (TGA) thermogram of the free base C type of Compound 1. [Figure 13] It is a diagram showing the X-ray powder diffraction (XRPD) pattern of the free base D type of Compound 1. [Figure 14] This figure shows a differential scanning calorimetry (DSC) thermogram of the free base D type of compound 1 at a heating rate of 2°C / min. [Figure 15] This figure shows the thermogravimetric analysis (TGA) thermogram of the free base D type of compound 1. [Figure 16] This figure shows the X-ray powder diffraction (XRPD) pattern of the free base E type of compound 1. [Figure 17] This figure shows a differential scanning calorimetry (DSC) thermogram of the free base E type of compound 1. [Figure 18] This figure shows the thermogravimetric analysis (TGA) thermogram of the free base E type of compound 1. [Figure 19] This figure shows the X-ray powder diffraction (XRPD) pattern of the free base F type of compound 1. [Figure 20] This figure shows a differential scanning calorimetry (DSC) thermogram of the free base F type of compound 1. [Figure 21] This figure shows the thermogravimetric analysis (TGA) thermogram of the free base F form of compound 1. [Figure 22] This figure shows the X-ray powder diffraction (XRPD) pattern of the HCl salt pattern A of compound 1. [Figure 23] This figure shows a differential scanning calorimetry (DSC) thermogram of the HCl salt pattern A of compound 1. [Figure 24] This figure shows the thermogravimetric analysis (TGA) thermogram of the HCl salt pattern A of compound 1. [Figure 25] This figure shows the X-ray powder diffraction (XRPD) pattern of the sulfate pattern A of compound 1. [Figure 26] This figure shows a differential scanning calorimetry (DSC) thermogram of the sulfate pattern A of compound 1. [Figure 27] This figure shows the thermogravimetric analysis (TGA) thermogram of the sulfate pattern A of compound 1. [Figure 28] This figure shows the X-ray powder diffraction (XRPD) pattern of the sulfate pattern B of compound 1. [Figure 29]This figure shows a differential scanning calorimetry (DSC) thermogram of the sulfate pattern B of compound 1. [Figure 30] This figure shows the thermogravimetric analysis (TGA) thermogram of the sulfate pattern B of compound 1. [Figure 31] This figure shows the X-ray powder diffraction (XRPD) pattern of the methanesulfonate pattern A of compound 1. [Figure 32] This figure shows a differential scanning calorimetry (DSC) thermogram of the methanesulfonate pattern A of compound 1. [Figure 33] This figure shows a thermogravimetric analysis (TGA) thermogram of the methanesulfonate pattern A of compound 1. [Figure 34] This figure shows the X-ray powder diffraction (XRPD) pattern of compound 1's benzenesulfonate salt pattern A. [Figure 35] This figure shows a differential scanning calorimetry (DSC) thermogram of the benzenesulfonate pattern A of compound 1. [Figure 36] This figure shows a thermogravimetric analysis (TGA) thermogram of the benzenesulfonate pattern A of compound 1. [Figure 37] This figure shows the X-ray powder diffraction (XRPD) pattern A of naphthalene-1,5-disulfonate of compound 1. [Figure 38] This figure shows a differential scanning calorimetry (DSC) thermogram of pattern A of naphthalene-1,5-disulfonate of compound 1. [Figure 39] This figure shows the thermogravimetric analysis (TGA) thermogram of pattern A of naphthalene-1,5-disulfonate of compound 1. [Figure 40] This figure shows the X-ray powder diffraction (XRPD) pattern B of naphthalene-1,5-disulfonate of compound 1. [Figure 41] This figure shows a differential scanning calorimetry (DSC) thermogram of pattern B of naphthalene-1,5-disulfonate of compound 1. [Figure 42]This figure shows the thermogravimetric analysis (TGA) thermogram of naphthalene-1,5-disulfonate pattern B of compound 1. [Modes for carrying out the invention]

[0013] While small molecule inhibitors are often evaluated based on their activity when first dissolved in solution, solid-state properties such as polymorphism are also important. The polymorphisms of a drug substance (API) can possess a variety of physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can directly affect the processing or manufacturing capacity of the API and the drug. Furthermore, differences in these properties can lead to different pharmacokinetic profiles for each different polymorphism of the drug, and often do. Therefore, polymorphism is often a crucial factor when regulatory authorities assess the "identity" of drugs from various manufacturers.

[0014] compound 1 Compound 1 is tert-butyl 4-(6-(((6-cyanopyridine-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridine-2-yl)piperazine-1-carboxylate: [ka] (Compound 1). In some embodiments, Compound 1 is in the form of a free base. In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, Compound 1 is in the form of an HCl salt. In some embodiments, Compound 1 is in the form of a sulfate. In some embodiments, Compound 1 is in the form of a methanesulfonate. In some embodiments, Compound 1 is in the form of a benzenesulfonate. In some embodiments, Compound 1 is in the form of a naphthalene-1,5-disulfonate.

[0015] Solid form of compound 1 In one embodiment, the following is provided herein: tert-butyl 4-(6-(((6-cyanopyridine-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridine-2-yl)piperazine-1-carboxylate: [ka] (Compound 1) or a pharmaceutically acceptable salt thereof in solid form.

[0016] In some embodiments, the solid state is crystalline.

[0017] In some embodiments, the solid form is crystalline compound 1 as a free base. In some embodiments, the solid form is free base type A of crystalline compound 1. In some embodiments, the solid form is free base type B of crystalline compound 1. In some embodiments, the solid form is free base type C of crystalline compound 1. In some embodiments, the solid form is free base type D of crystalline compound 1. In some embodiments, the solid form is free base type E of crystalline compound 1. In some embodiments, the solid form is free base type F of crystalline compound 1. In some embodiments, the solid form is free base type 1 of crystalline compound 1.

[0018] In some embodiments, the solid form is the HCl salt of compound 1. In some embodiments, the solid form is the HCl salt of crystalline compound 1. In some embodiments, the solid form is the HCl salt type A of crystalline compound 1.

[0019] In some embodiments, the solid form is the sulfate of compound 1. In some embodiments, the solid form is the sulfate of crystalline compound 1. In some embodiments, the solid form is sulfate type A of crystalline compound 1. In some embodiments, the solid form is sulfate type B of crystalline compound 1.

[0020] In some embodiments, the solid form is the methanesulfonate of compound 1. In some embodiments, the solid form is the methanesulfonate of crystalline compound 1. In some embodiments, the solid form is methanesulfonate type A of crystalline compound 1.

[0021] In some embodiments, the solid form is the benzenesulfonate of compound 1. In some embodiments, the solid form is the benzenesulfonate of crystalline compound 1. In some embodiments, the solid form is benzenesulfonate type A of crystalline compound 1.

[0022] In some embodiments, the solid form is naphthalene-1,5-disulfonate of compound 1. In some embodiments, the solid form is naphthalene-1,5-disulfonate of crystalline compound 1. In some embodiments, the solid form is naphthalene-1,5-disulfonate type A of crystalline compound 1. In some embodiments, the solid form is naphthalene-1,5-disulfonate type B of crystalline compound 1.

[0023] Free base type A of compound 1 Disclosed herein is the free base A of compound 1. In some embodiments, the crystalline form is the free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 1; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 3.8±0.2° 2θ, 5.9±0.2° 2θ, and 16.7±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 2; (d) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak with a peak temperature of approximately 223.5°C; (e) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 3; or, (f) These combinations.

[0024] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 1; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 3.8±0.2° 2θ, 5.9±0.2° 2θ, and 16.7±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 2; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 3; or, (e) combinations of these.

[0025] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 3.8±0.2° 2θ, 5.9±0.2° 2θ, and 16.7±0.2° 2θ; (b) A differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature at approximately 223.5°C; or, (c) These combinations.

[0026] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu Kα radiation.

[0027] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 1, measured using Cu Kα radiation.

[0028] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 3.8±0.2° 2θ, 5.9±0.2° 2θ, and 16.7±0.2° 2θ.

[0029] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ at 7.6±0.2°, 10.5±0.2°, 13.6±0.2°, and 15.6±0.2°.

[0030] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 3.8±0.2° 2θ, 5.9±0.2° 2θ, 7.6±0.2° 2θ, 10.5±0.2° 2θ, 13.6±0.2° 2θ, 15.6±0.2° 2θ, and 16.7±0.2° 2θ.

[0031] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 3.8±0.2°, 5.9±0.2°, 7.6±0.2°, 10.5±0.2°, 13.6±0.2°, 15.6±0.2°, and 16.7±0.2°.

[0032] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 3.8±0.2°, 5.9±0.2°, 7.6±0.2°, 10.5±0.2°, 13.6±0.2°, 15.6±0.2°, and 16.7±0.2°.

[0033] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 3.8±0.2°, 5.9±0.2°, 7.6±0.2°, 10.5±0.2°, 13.6±0.2°, 15.6±0.2°, and 16.7±0.2°.

[0034] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 3.8±0.2°, 5.9±0.2°, 7.6±0.2°, 10.5±0.2°, 13.6±0.2°, 15.6±0.2°, and 16.7±0.2°.

[0035] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 3.8±0.2°, 5.9±0.2°, 7.6±0.2°, 10.5±0.2°, 13.6±0.2°, 15.6±0.2°, and 16.7±0.2°.

[0036] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 2.

[0037] In some embodiments of the free base of compound 1, differential scanning calorimetry (DSC) thermograms show an endothermic peak with a peak temperature of approximately 223.5°C.

[0038] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 3.

[0039] TIFF2026513705000005.tif234170

[0040] Free base type 1 of compound 1 Disclosed herein is the free base 1 form of compound 1. In some embodiments, the crystalline form is the free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 4; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.9±0.2°, 2θ of 15.6±0.2°, and 2θ of 16.8±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 5; (d) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak with a peak temperature of approximately 124.8°C; (e) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 6; or, (f) These combinations.

[0041] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 4; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.9±0.2°, 2θ of 15.6±0.2°, and 2θ of 16.8±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 5; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 6; or, (e) combinations of these.

[0042] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.9±0.2°, 2θ of 15.6±0.2°, and 2θ of 16.8±0.2°; (b) A differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature at approximately 124.8°C; or, (c) These combinations.

[0043] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 4, measured using Cu Kα radiation.

[0044] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 2, measured using Cu Kα radiation.

[0045] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 5.9±0.2°, 2θ of 15.6±0.2°, and 2θ of 16.8±0.2°.

[0046] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 13.6±0.2°, 2θ of 14.3±0.2°, and 2θ of 23.4±0.2°.

[0047] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ at 5.9±0.2°, 13.6±0.2°, 14.3±0.2°, 15.6±0.2°, 16.8±0.2°, and 2θ at 23.4±0.2°.

[0048] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 5.9±0.2°, 2θ at 13.6±0.2°, 2θ at 14.3±0.2°, 2θ at 15.6±0.2°, 2θ at 16.8±0.2°, and 2θ at 23.4±0.2°.

[0049] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 5.9±0.2°, 2θ at 13.6±0.2°, 2θ at 14.3±0.2°, 2θ at 15.6±0.2°, 2θ at 16.8±0.2°, and 2θ at 23.4±0.2°.

[0050] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 5.9±0.2°, 13.6±0.2°, 14.3±0.2°, 15.6±0.2°, 16.8±0.2°, and 2θ at 23.4±0.2°.

[0051] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 5.9±0.2°, 13.6±0.2°, 14.3±0.2°, 15.6±0.2°, 16.8±0.2°, and 2θ at 23.4±0.2°.

[0052] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 5.

[0053] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram shows an endothermic peak with a peak temperature of approximately 124.8°C.

[0054] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 6.

[0055] In some embodiments of the free base of compound 1, the crystalline form is a solvate.

[0056] In some embodiments of the free base of compound 1, the solvate is acetone solvate, methyl ethyl ketone solvate, tetrahydrofuran solvate, acetonitrile solvate, dimethylformamide solvate, dimethylacetamide solvate, 2-methyltetrahydrofuran solvate, or ethyl acetate solvate.

[0057] TIFF2026513705000006.tif200170

[0058] Free base type B of compound 1 Disclosed herein is the free base B form of compound 1. In some embodiments, the crystalline form of the free base of compound 1 is characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 7; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.9±0.2°, 2θ of 13.7±0.2°, and 2θ of 16.7±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 8; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 9; or, (e) combinations of these.

[0059] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 7, measured using Cu Kα radiation.

[0060] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 3, measured using Cu Kα radiation.

[0061] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 5.9±0.2°, 2θ of 13.7±0.2°, and 2θ of 16.7±0.2°.

[0062] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ at 10.5±0.2°, 2θ at 15.6±0.2°, and 2θ at 23.3±0.2°.

[0063] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 14.8±0.2°, 2θ of 20.5±0.2°, and 2θ of 21.1±0.2°.

[0064] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0065] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0066] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0067] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0068] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0069] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0070] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least seven peaks selected from 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0071] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least eight peaks selected from 2θ at 5.9±0.2°, 10.5±0.2°, 13.7±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.3±0.2°.

[0072] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 8.

[0073] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 9.

[0074] TIFF2026513705000007.tif103170

[0075] Free base C type of compound 1 Disclosed herein is the free base C form of compound 1. In some embodiments, the crystalline form is the free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, substantially the same as that shown in Figure 10; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 2θ of 6.2±0.2°, and 2θ of 14.7±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 11; (d) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak with a peak temperature of approximately 231.2°C; (e) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 12; or, (f) These combinations.

[0076] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, substantially the same as that shown in Figure 10; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 2θ of 6.2±0.2°, and 2θ of 14.7±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 11; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 12; or, (e) combinations of these.

[0077] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 2θ of 6.2±0.2°, and 2θ of 14.7±0.2°; (b) A differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature of approximately 231.2°C; or, (c) These combinations.

[0078] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 10, measured using Cu Kα radiation.

[0079] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 4, measured using Cu Kα radiation.

[0080] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 5.2±0.2° 2θ, 6.2±0.2° 2θ, and 14.7±0.2° 2θ.

[0081] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 13.7±0.2°, 2θ of 17.9±0.2°, and 2θ of 24.0±0.2°.

[0082] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 11.5±0.2° and 21.2±0.2°.

[0083] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ at 8.6±0.2°, 2θ at 24.7±0.2°, and 2θ at 28.3±0.2°.

[0084] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0085] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0086] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0087] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0088] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least five peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0089] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0090] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0091] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least eight peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0092] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least nine peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0093] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least 10 peaks selected from 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 28.3±0.2°.

[0094] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 11.

[0095] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram shows an endothermic peak with a peak temperature of approximately 231.2°C.

[0096] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 12.

[0097] In some embodiments of the free base of compound 1, the crystalline form is anhydrous.

[0098] In some embodiments of the free base of compound 1, the crystalline form is stable.

[0099] In some embodiments of the free base of compound 1, the crystalline form is chemically stable.

[0100] In some embodiments of the free base of compound 1, the crystalline form is thermodynamically stable.

[0101] In some embodiments of the free base of compound 1, the crystalline form is more stable than free base A, free base B, free base D, free base E, or free base F of compound 1.

[0102] TIFF2026513705000008.tif132170

[0103] Free base D type of compound 1 Disclosed herein is the free base D form of compound 1. In some embodiments, the crystalline form is the free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 13; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 3.8±0.2°, 2θ of 20.3±0.2°, and 2θ of 21.1±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 14; (d) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak with a peak temperature of approximately 194.3°C; (e) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 15; or, (f) These combinations.

[0104] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 3.8±0.2°, 2θ of 20.3±0.2°, and 2θ of 21.1±0.2°; (b) A differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature at approximately 194.3°C; or, (c) These combinations.

[0105] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 13; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 3.8±0.2°, 2θ of 20.3±0.2°, and 2θ of 21.1±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 14; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 15; or, (e) combinations of these.

[0106] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 13, measured using Cu Kα radiation.

[0107] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 5, measured using Cu Kα radiation.

[0108] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 3.8±0.2°, 20.3±0.2°, and 21.1±0.2°.

[0109] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ at 14.4±0.2°, 16.7±0.2°, and 19.7±0.2°.

[0110] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 7.7±0.2° and 2θ of 15.3±0.2°.

[0111] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 3.8±0.2°, 7.7±0.2°, 14.4±0.2°, 15.3±0.2°, 16.7±0.2°, 19.7±0.2°, 20.3±0.2°, and 21.1±0.2°.

[0112] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least two peaks selected from 2θ at 3.8±0.2°, 7.7±0.2°, 14.4±0.2°, 15.3±0.2°, 16.7±0.2°, 19.7±0.2°, 2θ at 20.3±0.2°, and 2θ at 21.1±0.2°.

[0113] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 3.8±0.2°, 7.7±0.2°, 14.4±0.2°, 15.3±0.2°, 16.7±0.2°, 19.7±0.2°, 2θ at 20.3±0.2°, and 2θ at 21.1±0.2°.

[0114] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least four peaks selected from 2θ at 3.8±0.2°, 7.7±0.2°, 14.4±0.2°, 15.3±0.2°, 16.7±0.2°, 19.7±0.2°, 2θ at 20.3±0.2°, and 2θ at 21.1±0.2°.

[0115] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 3.8±0.2°, 7.7±0.2°, 14.4±0.2°, 15.3±0.2°, 16.7±0.2°, 19.7±0.2°, 2θ at 20.3±0.2°, and 2θ at 21.1±0.2°.

[0116] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 3.8±0.2°, 7.7±0.2°, 14.4±0.2°, 15.3±0.2°, 16.7±0.2°, 19.7±0.2°, 2θ at 20.3±0.2°, and 2θ at 21.1±0.2°.

[0117] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least seven peaks selected from 2θ at 3.8±0.2°, 7.7±0.2°, 14.4±0.2°, 15.3±0.2°, 16.7±0.2°, 19.7±0.2°, 2θ at 20.3±0.2°, and 2θ at 21.1±0.2°.

[0118] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 14.

[0119] In some embodiments of the free base of compound 1, differential scanning calorimetry (DSC) thermograms show an endothermic peak with a peak temperature of approximately 194.3°C.

[0120] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 15.

[0121] In some embodiments of the free base of compound 1, the crystalline form is anhydrous.

[0122] TIFF2026513705000009.tif247170

[0123] Free base type E of compound 1 Disclosed herein is the free base E form of compound 1. In some embodiments, the crystalline form is the free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 16; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 6.3±0.2° 2θ, 12.5±0.2° 2θ, and 17.0±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 17; (d) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak with a peak temperature of approximately 224.2°C; (e) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 18; or, (f) These combinations.

[0124] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 16; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 6.3±0.2° 2θ, 12.5±0.2° 2θ, and 17.0±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 17; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 18; or, (e) combinations of these.

[0125] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 6.3±0.2° 2θ, 12.5±0.2° 2θ, and 17.0±0.2° 2θ; (b) A differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature at approximately 224.2°C; or, (c) These combinations.

[0126] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 16, measured using Cu Kα radiation.

[0127] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 6, measured using Cu Kα radiation.

[0128] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 6.3±0.2° 2θ, 12.5±0.2° 2θ, and 17.0±0.2° 2θ.

[0129] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ at 10.9±0.2°, 2θ at 15.8±0.2°, and 2θ at 20.9±0.2°.

[0130] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 14.3±0.2° and 2θ of 26.0±0.2°.

[0131] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 6.3±0.2°, 10.9±0.2°, 12.5±0.2°, 14.3±0.2°, 15.8±0.2°, 17.0±0.2°, 20.9±0.2°, and 26.0±0.2°.

[0132] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 6.3±0.2°, 10.9±0.2°, 12.5±0.2°, 14.3±0.2°, 15.8±0.2°, 17.0±0.2°, 2θ at 20.9±0.2°, and 2θ at 26.0±0.2°.

[0133] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 6.3±0.2°, 10.9±0.2°, 12.5±0.2°, 14.3±0.2°, 15.8±0.2°, 17.0±0.2°, 2θ at 20.9±0.2°, and 2θ at 26.0±0.2°.

[0134] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 6.3±0.2°, 10.9±0.2°, 12.5±0.2°, 14.3±0.2°, 15.8±0.2°, 17.0±0.2°, 2θ at 20.9±0.2°, and 2θ at 26.0±0.2°.

[0135] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 6.3±0.2°, 10.9±0.2°, 12.5±0.2°, 14.3±0.2°, 15.8±0.2°, 17.0±0.2°, 2θ at 20.9±0.2°, and 2θ at 26.0±0.2°.

[0136] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 6.3±0.2°, 10.9±0.2°, 12.5±0.2°, 14.3±0.2°, 15.8±0.2°, 17.0±0.2°, 2θ at 20.9±0.2°, and 2θ at 26.0±0.2°.

[0137] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 6.3±0.2°, 10.9±0.2°, 12.5±0.2°, 14.3±0.2°, 15.8±0.2°, 17.0±0.2°, 2θ at 20.9±0.2°, and 2θ at 26.0±0.2°.

[0138] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 17.

[0139] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram shows an endothermic peak with a peak temperature of approximately 224.2°C.

[0140] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 18.

[0141] In some embodiments of the free base of compound 1, the crystalline form is anhydrous.

[0142] TIFF2026513705000010.tif156170

[0143] Free base F form of compound 1 Disclosed herein is the free base F form of compound 1. In some embodiments, the crystalline form is the free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 19; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 6.0±0.2° 2θ, 15.3±0.2° 2θ, and 21.0±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 20; (d) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak with a peak temperature of approximately 228.4°C; (e) A differential scanning calorimetry (DSC) thermogram showing an exothermic peak with a peak temperature of approximately 106.4°C; (f) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 21; or, (g) These combinations.

[0144] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 19; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 6.0±0.2° 2θ, 15.3±0.2° 2θ, and 21.0±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 20; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 21; or, (e) combinations of these.

[0145] In some embodiments, the crystalline form is a free base of compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 6.0±0.2° 2θ, 15.3±0.2° 2θ, and 21.0±0.2° 2θ; (b) Differential scanning calorimetry (DSC) thermogram showing an endothermic peak with a peak temperature of approximately 228.4°C; (c) A differential scanning calorimetry (DSC) thermogram having an exothermic peak with a peak temperature of approximately 106.4°C; or, (d) These combinations.

[0146] In some embodiments of the free base of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 19, measured using Cu Kα radiation.

[0147] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 7, measured using Cu Kα radiation.

[0148] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 6.0±0.2° 2θ, 15.3±0.2° 2θ, and 21.0±0.2° 2θ.

[0149] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ at 10.5±0.2°, 2θ at 17.9±0.2°, and 2θ at 19.9±0.2°.

[0150] In some embodiments of the free base of compound 1, the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ at 11.9±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0151] In some embodiments of the free base of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 21.0±0.2°, 25.2±0.2°, and 25.9±0.2°.

[0152] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 2θ at 21.0±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0153] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 2θ at 21.0±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0154] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 2θ at 21.0±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0155] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 2θ at 21.0±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0156] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 2θ at 21.0±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0157] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 2θ at 21.0±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0158] In some embodiments of the free base of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least eight peaks selected from 2θ at 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 15.3±0.2°, 17.9±0.2°, 19.9±0.2°, 2θ at 21.0±0.2°, 2θ at 25.2±0.2°, and 2θ at 25.9±0.2°.

[0159] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 20.

[0160] In some embodiments of the free base of compound 1, the differential scanning calorimetry (DSC) thermogram shows an endothermic peak with a peak temperature of approximately 228.4°C.

[0161] In some embodiments of the free base of compound 1, differential scanning calorimetry (DSC) thermograms show an exothermic peak with a peak temperature of approximately 106.4°C.

[0162] In some embodiments of the free base of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 21.

[0163] In some embodiments of the free base of compound 1, the crystalline form is anhydrous.

[0164] TIFF2026513705000011.tif152170

[0165] HCl salt type A of compound 1 Disclosed herein is the HCl salt of compound 1, type A. In some embodiments, the crystalline form is the HCl salt of compound 1, characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 22; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 4.1±0.2° 2θ, 10.3±0.2° 2θ, and 16.6±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 23; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 24; or, (e) combinations of these.

[0166] In some embodiments of the HCl salt of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 22, measured using Cu Kα radiation.

[0167] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 8, measured using Cu Kα radiation.

[0168] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.1±0.2° 2θ, 10.3±0.2° 2θ, and 16.6±0.2° 2θ.

[0169] In some embodiments of the HCl salt of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ at 6.6±0.2°, 2θ at 13.8±0.2°, and 2θ at 20.8±0.2°.

[0170] In some embodiments of the HCl salt of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 26.0 ± 0.2° and 2θ of 26.4 ± 0.2°.

[0171] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 26.0±0.2°, and 26.4±0.2°.

[0172] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least two peaks selected from 2θ at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 2θ at 26.0±0.2°, and 2θ at 26.4±0.2°.

[0173] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 2θ at 26.0±0.2°, and 2θ at 26.4±0.2°.

[0174] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 2θ at 26.0±0.2°, and 2θ at 26.4±0.2°.

[0175] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 2θ at 26.0±0.2°, and 2θ at 26.4±0.2°.

[0176] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 2θ at 26.0±0.2°, and 2θ at 26.4±0.2°.

[0177] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 2θ at 26.0±0.2°, and 2θ at 26.4±0.2°.

[0178] In some embodiments of the HCl salt of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least eight peaks selected from 2θ at 4.1±0.2°, 6.6±0.2°, 10.3±0.2°, 13.8±0.2°, 16.6±0.2°, 20.8±0.2°, 2θ at 26.0±0.2°, and 2θ at 26.4±0.2°.

[0179] In some embodiments of the HCl salt of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 23.

[0180] In some embodiments of the HCl salt of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 24.

[0181] In some embodiments of the HCl salt of compound 1, the crystalline form is anhydrous.

[0182] TIFF2026513705000012.tif65170

[0183] Sulfate type A of compound 1 Disclosed herein is the sulfate A form of compound 1. In some embodiments, the crystalline form of the sulfate of compound 1 is characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, substantially the same as that shown in Figure 25; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 4.9±0.2° 2θ, 17.2±0.2° 2θ, and 21.5±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 26; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 27; or, (e) combinations of these.

[0184] In some embodiments of the sulfate of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 25, measured using Cu Kα radiation.

[0185] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 9, measured using Cu Kα radiation.

[0186] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.9±0.2° 2θ, 17.2±0.2° 2θ, and 21.5±0.2° 2θ.

[0187] In some embodiments of the sulfate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 14.2±0.2°, 2θ of 17.8±0.2°, and 2θ of 25.1±0.2°.

[0188] In some embodiments of the sulfate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ at 10.2±0.2°, 2θ at 16.6±0.2°, and 2θ at 28.1±0.2°.

[0189] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 21.5±0.2°, 25.1±0.2°, and 28.1±0.2°.

[0190] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 2θ at 21.5±0.2°, 2θ at 25.1±0.2°, and 2θ at 28.1±0.2°.

[0191] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 2θ at 21.5±0.2°, 2θ at 25.1±0.2°, and 2θ at 28.1±0.2°.

[0192] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 2θ at 21.5±0.2°, 2θ at 25.1±0.2°, and 2θ at 28.1±0.2°.

[0193] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 2θ at 21.5±0.2°, 2θ at 25.1±0.2°, and 2θ at 28.1±0.2°.

[0194] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 2θ at 21.5±0.2°, 2θ at 25.1±0.2°, and 2θ at 28.1±0.2°.

[0195] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 21.5±0.2°, 2θ at 25.1±0.2°, and 2θ at 28.1±0.2°.

[0196] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least eight peaks selected from 2θ at 4.9±0.2°, 10.2±0.2°, 14.2±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 2θ at 21.5±0.2°, 2θ at 25.1±0.2°, and 2θ at 28.1±0.2°.

[0197] In some embodiments of the sulfate of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 26.

[0198] In some embodiments of the sulfate of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 27.

[0199] In some embodiments of the sulfate of compound 1, the crystalline form is anhydrous.

[0200] TIFF2026513705000013.tif160170

[0201] Sulfate type B of compound 1 Disclosed herein is the sulfate B form of compound 1. In some embodiments, the crystalline form of the sulfate of compound 1 is characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, substantially the same as that shown in Figure 28; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.5±0.2°, 2θ of 17.6±0.2°, and 2θ of 20.3±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 29; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 30; or, (e) combinations of these.

[0202] In some embodiments of the sulfate of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 28, measured using Cu Kα radiation.

[0203] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 10, measured using Cu Kα radiation.

[0204] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 5.5±0.2°, 2θ of 17.6±0.2°, and 2θ of 20.3±0.2°.

[0205] In some embodiments of the sulfate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 16.5±0.2°, 2θ of 18.3±0.2°, and 2θ of 24.9±0.2°.

[0206] In some embodiments of the sulfate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 19.6±0.2°, 2θ of 21.0±0.2°, and 2θ of 22.1±0.2°.

[0207] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ at 5.5±0.2°, 16.5±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.3±0.2°, 21.0±0.2°, 22.1±0.2°, and 24.9±0.2°.

[0208] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 5.5±0.2°, 16.5±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.3±0.2°, 21.0±0.2°, 22.1±0.2°, and 24.9±0.2°, and 28.1±0.2°.

[0209] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 5.5±0.2°, 16.5±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.3±0.2°, 21.0±0.2°, 22.1±0.2°, and 24.9±0.2°, and 28.1±0.2°.

[0210] In some embodiments of the sulfate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 5.5±0.2°, 16.5±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.3±0.2°, 21.0±0.2°, 22.1±0.2°, and 24.9±0.2°, and 28.1±0.2°.

[0211] In some embodiments of the sulfate of Compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern having at least 5 peaks selected from 2θ of 5.5±0.2°, 2θ of 16.5±0.2°, 2θ of 17.6±0.2°, 2θ of 18.3±0.2°, 2θ of 19.6±0.2°, 2θ of 20.3±0.2°, 2θ of 21.0±0.2°, 2θ of 22.1±0.2°, 2θ of 24.9±0.2°, and 2θ of 28.1±0.2°, measured using Cu Kα radiation.

[0212] In some embodiments of the sulfate of Compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern having at least 6 peaks selected from 2θ of 5.5±0.2°, 2θ of 16.5±0.2°, 2θ of 17.6±0.2°, 2θ of 18.3±0.2°, 2θ of 19.6±0.2°, 2θ of 20.3±0.2°, 2θ of 21.0±0.2°, 2θ of 22.1±0.2°, and 2θ of 24.9±0.2°, measured using Cu Kα radiation.

[0213] In some embodiments of the sulfate of Compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern having at least 7 peaks selected from 2θ of 5.5±0.2°, 2θ of 16.5±0.2°, 2θ of 17.6±0.2°, 2θ of 18.3±0.2°, 2θ of 19.6±0.2°, 2θ of 20.3±0.2°, 2θ of 21.0±0.2°, 2θ of 22.1±0.2°, and 2θ of 24.9±0.2°, measured using Cu Kα radiation.

[0214] In some embodiments of the sulfate of Compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern having at least 8 peaks selected from 2θ of 5.5±0.2°, 2θ of 16.5±0.2°, 2θ of 17.6±0.2°, 2θ of 18.3±0.2°, 2θ of 19.6±0.2°, 2θ of 20.3±0.2°, 2θ of 21.0±0.2°, 2θ of 22.1±0.2°, and 2θ of 24.9±0.2°, measured using Cu Kα radiation.

[0215] In some embodiments of the sulfate of Compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 29.

[0216] In some embodiments of the sulfate of Compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 30.

[0217] In some embodiments of the sulfate of Compound 1, the crystalline form is an anhydrate.

[0218] TIFF2026513705000014.tif132170 [[ID=!16]]

[0219] Compound 1 Methanesulfonate A Type Disclosed herein is Compound 1 Methanesulfonate A Type. In some embodiments, the crystalline form is a methanesulfonate of Compound 1 characterized by having at least one of the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 31, measured using Cu Kα radiation; (b) An X-ray powder diffraction (XRPD) pattern having peaks at 2θ of 5.2 ± 0.2°, 2θ of 17.8 ± 0.2°, and 2θ of 20.5 ± 0.2°, measured using Cu Kα radiation; (c) A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 32; (d) A thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 33; or, (e) Combinations thereof.

[0220] In some embodiments of the methanesulfonate of Compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 31, measured using Cu Kα radiation.

[0221] In some embodiments of the methanesulfonate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 11, measured using Cu Kα radiation.

[0222] In some embodiments of the methanesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 2θ of 17.8±0.2°, and 2θ of 20.5±0.2°.

[0223] In some embodiments of the methanesulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 14.1±0.2°, 2θ of 18.8±0.2°, and 2θ of 26.0±0.2°.

[0224] In some embodiments of the methanesulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 15.2 ± 0.2° and 25.0 ± 0.2°.

[0225] In some embodiments of the methanesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 14.1±0.2°, 15.2±0.2°, 17.8±0.2°, 18.8±0.2°, 20.5±0.2°, 25.0±0.2°, and 26.0±0.2°.

[0226] In some embodiments of the methanesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 5.2±0.2°, 14.1±0.2°, 15.2±0.2°, 17.8±0.2°, 18.8±0.2°, 2θ at 20.5±0.2°, 2θ at 25.0±0.2°, and 2θ at 26.0±0.2°.

[0227] In some embodiments of the methanesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 5.2±0.2°, 14.1±0.2°, 15.2±0.2°, 17.8±0.2°, 18.8±0.2°, 2θ at 20.5±0.2°, 2θ at 25.0±0.2°, and 2θ at 26.0±0.2°.

[0228] In some embodiments of the methanesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 5.2±0.2°, 14.1±0.2°, 15.2±0.2°, 17.8±0.2°, 18.8±0.2°, 2θ at 20.5±0.2°, 2θ at 25.0±0.2°, and 2θ at 26.0±0.2°.

[0229] In some embodiments of the methanesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 5.2±0.2°, 14.1±0.2°, 15.2±0.2°, 17.8±0.2°, 18.8±0.2°, 2θ at 20.5±0.2°, 2θ at 25.0±0.2°, and 2θ at 26.0±0.2°.

[0230] In some embodiments of the methanesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 5.2±0.2°, 14.1±0.2°, 15.2±0.2°, 17.8±0.2°, 18.8±0.2°, 2θ at 20.5±0.2°, 2θ at 25.0±0.2°, and 2θ at 26.0±0.2°.

[0231] In some embodiments of the methanesulfonate of Compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern having at least seven peaks selected from 2θ of 5.2 ± 0.2°, 2θ of 14.1 ± 0.2°, 2θ of 15.2 ± 0.2°, 2θ of 17.8 ± 0.2°, 2θ of 18.8 ± 0.2°, 2θ of 20.5 ± 0.2°, 2θ of 25.0 ± 0.2°, and 2θ of 26.0 ± 0.2°, measured using Cu Kα radiation.

[0232] In some embodiments of the methanesulfonate of Compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern having at least eight peaks selected from 2θ of 5.2 ± 0.2°, 2θ of 14.1 ± 0.2°, 2θ of 15.2 ± 0.2°, 2θ of 17.8 ± 0.2°, 2θ of 18.8 ± 0.2°, 2θ of 20.5 ± 0.2°, 2θ of 25.0 ± 0.2°, and 2θ of 26.0 ± 0.2°, measured using Cu Kα radiation.

[0233] In some embodiments of the methanesulfonate of Compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 32.

[0234] In some embodiments of the methanesulfonate of Compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 33.

[0235] In some embodiments of the methanesulfonate of Compound 1, the crystalline form is an anhydrate.

[0236] TIFF2026513705000015.tif118170

[0237] Compound 1 benzene sulfonate A type Disclosed herein is Compound 1 benzene sulfonate A type. In some embodiments, the crystalline form is a benzene sulfonate of Compound 1 characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 34; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 4.4±0.2° 2θ, 17.0±0.2° 2θ, and 20.4±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 35; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 36; or, (e) combinations of these.

[0238] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 34, measured using Cu Kα radiation.

[0239] In some embodiments of the benzenesulfonate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 12, measured using Cu Kα radiation.

[0240] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.4±0.2° 2θ, 17.0±0.2° 2θ, and 20.4±0.2° 2θ.

[0241] In some embodiments of the benzenesulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 14.4±0.2° and 2θ of 19.3±0.2°.

[0242] In some embodiments of the benzenesulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ at 8.9±0.2°, 13.2±0.2°, 15.6±0.2°, and 23.7±0.2°.

[0243] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.4±0.2° 2θ, 8.9±0.2° 2θ, 13.2±0.2° 2θ, 14.4±0.2° 2θ, 15.6±0.2° 2θ, 17.0±0.2° 2θ, 19.3±0.2° 2θ, 20.4±0.2° 2θ, and 23.7±0.2° 2θ.

[0244] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 4.4±0.2°, 8.9±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, 2θ at 20.4±0.2°, and 2θ at 23.7±0.2°.

[0245] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 4.4±0.2°, 8.9±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, 2θ at 20.4±0.2°, and 2θ at 23.7±0.2°.

[0246] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 4.4±0.2°, 8.9±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, 2θ at 20.4±0.2°, and 2θ at 23.7±0.2°.

[0247] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 4.4±0.2°, 8.9±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, 2θ at 20.4±0.2°, and 2θ at 23.7±0.2°.

[0248] In some embodiments of the benzenesulfonate of compound 1, the crystalline form has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 4.4±0.2°, 8.9±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, 2θ at 20.4±0.2°, and 2θ at 23.7±0.2°.

[0249] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 4.4±0.2°, 8.9±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, 2θ at 20.4±0.2°, and 2θ at 23.7±0.2°.

[0250] In some embodiments of the benzenesulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least eight peaks selected from 2θ at 4.4±0.2°, 8.9±0.2°, 13.2±0.2°, 14.4±0.2°, 15.6±0.2°, 17.0±0.2°, 19.3±0.2°, 2θ at 20.4±0.2°, and 2θ at 23.7±0.2°.

[0251] In some embodiments of the benzenesulfonate of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 35.

[0252] In some embodiments of the benzenesulfonate of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 36.

[0253] In some embodiments of the benzenesulfonate of compound 1, the crystalline form is anhydrous.

[0254] TIFF2026513705000016.tif139170

[0255] Naphthalene-1,5-disulfonate type A of Compound 1 Disclosed herein is naphthalene-1,5-disulfonate type A of compound 1. In some embodiments, the crystalline form of naphthalene-1,5-disulfonate of compound 1 is characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, substantially the same as those shown in Figure 37; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 4.3±0.2° 2θ, 14.8±0.2° 2θ, and 19.2±0.2° 2θ; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 38; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 39; or, (e) combinations of these.

[0256] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 37, measured using Cu Kα radiation.

[0257] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 13, measured using Cu Kα radiation.

[0258] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.3±0.2° 2θ, 14.8±0.2° 2θ, and 19.2±0.2° 2θ.

[0259] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ at 12.0±0.2°, 2θ at 17.2±0.2°, and 2θ at 25.6±0.2°.

[0260] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ of 13.9±0.2°, 2θ of 20.4±0.2°, and 2θ of 25.8±0.2°.

[0261] In several embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0262] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0263] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0264] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having at least four peaks selected from 2θ at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0265] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0266] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0267] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0268] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least eight peaks selected from 2θ at 4.3±0.2°, 12.0±0.2°, 13.9±0.2°, 14.8±0.2°, 17.2±0.2°, 19.2±0.2°, 20.4±0.2°, 25.6±0.2°, and 25.8±0.2°.

[0269] In some embodiments of naphthalene-1,5-disulfonate of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 38.

[0270] In some embodiments of naphthalene-1,5-disulfonate of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 39.

[0271] In some embodiments of naphthalene-1,5-disulfonate of compound 1, the crystalline form is a hydrate.

[0272] TIFF2026513705000017.tif171170

[0273] Naphthalene-1,5-disulfonate type B of Compound 1 Disclosed herein is naphthalene-1,5-disulfonate type B of compound 1. In some embodiments, the crystalline form of naphthalene-1,5-disulfonate of compound 1 is characterized by having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, substantially the same as that shown in Figure 40; (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 2θ of 16.1±0.2°, and 2θ of 19.3±0.2°; (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 41; (d) A thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 42; or, (e) combinations of these.

[0274] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 40, measured using Cu Kα radiation.

[0275] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern with peaks found in Table 14, as measured using Cu Kα radiation.

[0276] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 2θ of 16.1±0.2°, and 2θ of 19.3±0.2°.

[0277] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 2θ at 12.7±0.2°, 2θ at 18.7±0.2°, and 2θ at 19.9±0.2°.

[0278] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the X-ray powder diffraction (XRPD) patterns, measured using Cu Kα radiation, further include peaks at 22.7±0.2° 2θ, 24.6±0.2° 2θ, and 25.2±0.2° 2θ.

[0279] In several embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, with peaks at 2θ of 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 24.6±0.2°, and 25.2±0.2°.

[0280] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least two peaks selected from 2θ at 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 24.6±0.2°, and 25.2±0.2°.

[0281] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least three peaks selected from 2θ at 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 2θ at 24.6±0.2°, and 2θ at 25.2±0.2°.

[0282] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least four peaks selected from 2θ at 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 2θ at 24.6±0.2°, and 2θ at 25.2±0.2°.

[0283] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least five peaks selected from 2θ at 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 2θ at 24.6±0.2°, and 2θ at 25.2±0.2°.

[0284] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least six peaks selected from 2θ at 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 2θ at 24.6±0.2°, and 2θ at 25.2±0.2°.

[0285] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least seven peaks selected from 2θ at 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 2θ at 24.6±0.2°, and 2θ at 25.2±0.2°.

[0286] In some embodiments of the naphthalene-1,5-disulfonate of compound 1, the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, which has at least eight peaks selected from 2θ at 5.2±0.2°, 12.7±0.2°, 16.1±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.7±0.2°, 24.6±0.2°, and 25.2±0.2°.

[0287] In some embodiments of naphthalene-1,5-disulfonate of compound 1, the differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in Figure 41.

[0288] In some embodiments of naphthalene-1,5-disulfonate of compound 1, the thermogravimetric analysis (TGA) thermogram is substantially the same as that shown in Figure 42.

[0289] In some embodiments of naphthalene-1,5-disulfonate of compound 1, the crystalline form is a hydrate.

[0290] TIFF2026513705000018.tif127170

[0291] Treatment method Disclosed herein are methods for treating a disease or disorder in a subject, comprising administering the crystalline form disclosed herein to the subject, wherein the disease or disorder is inflammatory bowel disease (IBD). In some embodiments, the disease or disorder is ulcerative colitis ("UC") or Crohn's disease ("CD"). In some embodiments, the disease or disorder is ulcerative colitis ("UC"). In some embodiments, the disease or disorder is Crohn's disease ("CD").

[0292] Inflammatory bowel disease (IBD) IBD is a broad term used to describe chronic inflammatory disorders of the gastrointestinal tract. Types of IBD include ulcerative colitis ("UC") and Crohn's disease ("CD"). The symptoms of IBD vary and depend on the severity and location of the inflammation. According to GlobalData, in 2019, 1.7 million UC patients were diagnosed in eight major markets (the United States, the five EU countries, Japan, and Canada), and market sales for that year reached $6.8 billion (furthermore, there were 1.3 million diagnosed UC patients in the eight major markets (the United States, the five EU countries, Japan, and Canada), and market sales reached $7.4 billion).

[0293] Inflammatory bowel disease (PHD) is characterized by repeated inflammation and wounding of the mucosa, as well as loss of intestinal epithelial barrier function, which allows bacteria or bacterial products to migrate from the intestinal lumen to the serosal membrane and then into the bloodstream, leading to systemic bacteremia and endotoxemia. PHD inhibition has been shown to reduce disease severity in a mouse model of colitis at several levels of clinical scoring. The proposed mechanism for the therapeutic activity of PHD inhibitors is through the stabilization of HIF-1α, which drives the enhancement and healing of the epithelial barrier.

[0294] While current treatments with anti-inflammatory or immunosuppressant agents are effective, the majority of IBD patients do not respond adequately to currently available therapies and do not achieve long-term remission. PHD inhibitors may offer a new treatment option for IBD and may enhance efficacy when combined with available anti-inflammatory drugs.

[0295] dosage In certain embodiments, compositions containing the crystalline forms described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially block at least one symptom of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, the patient's medical history, their health status, weight, and response to the drug, as well as the judgment of the physician administering the treatment. The therapeutically effective dose may be determined arbitrarily by methods including, but not limited to, dose escalation and / or dose-range exploration clinical trials.

[0296] For prophylactic use, compositions containing the crystalline forms described herein are administered to patients who are susceptible to, or otherwise at risk of, a particular disease, disorder, or condition. Such amounts are defined as “a prophylactically effective amount or dose.” In this use, the exact amount is also determined by the patient’s health, weight, etc. When used in a patient, the effective amount for this use is determined by the severity and course of the disease, disorder, or condition, the patient’s treatment history, the patient’s health and response to the drug, and the judgment of the physician administering the treatment. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing the compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission, in order to prevent recurrence of symptoms of the disease or condition.

[0297] Further embodiments exist in which, in any of the embodiments described herein, an effective amount of the crystalline form described herein, or a pharmaceutically acceptable salt thereof, is administered (a) systemically to a mammal, and / or (b) orally to a mammal, and / or (c) intravenously to a mammal, and / or (d) by injection to a mammal, and / or (e) topically to a mammal, and / or (f) non-systemically or topically to a mammal.

[0298] definition Unless otherwise specified, the following terms used in this application have the definitions set forth below. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limited. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein.

[0299] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not have any permanent adverse effects on the general health of the subject being treated.

[0300] As used herein, terms such as “administer,” “administering,” and “administration” refer to methods that may be used to deliver a compound or composition to a desired site of action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art will be familiar with the administration techniques that can be used with respect to the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0301] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to the amount of an active substance or compound administered that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. This could result in a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desirable change in the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compounds disclosed herein required to produce a clinically significant reduction in disease symptoms. The appropriate “effective” dose in each individual case may be determined, at will, using techniques such as dose-escalation studies.

[0302] As used herein, the terms “enhance” or “enhancing” mean increasing or extending either the potency or duration of a desired effect. Therefore, with respect to enhancing the effect of a therapeutic agent, “enhancing” refers to the ability to increase or extend the effect of another therapeutic agent on a system in either potency or duration. As used herein, “enhancing-effective amount” means an amount sufficient to enhance the effect of another therapeutic agent on a desired system.

[0303] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, all members of the class Mammalia, namely humans, non-human primates such as chimpanzees, and other apes and monkey species, farm animals such as cattle, horses, sheep, goats, and pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0304] As used herein, the terms “treat,” “treating,” and “treatment” include reducing, alleviating, or improving at least one symptom of a disease or condition; preventing additional symptoms; stopping a disease or condition, for example, by inhibiting its progression; alleviating a disease or condition; causing regression of a disease or condition; alleviating a condition caused by a disease or condition; or preventing and / or curatively stopping the symptoms of a disease or condition.

[0305] The term "approximately" means within a specified range of statistically meaningful values, such as a concentration range, time frame, molecular weight, particle size, temperature, or pH. Such a range may be within one order of magnitude of the indicated value or range, typically within 10%, more typically within 5%, and even more typically within 3%. Sometimes such a range may be within the range of typical experimental error of the standard method used to measure and / or determine a given value or range. The acceptable variation encompassed by the term "approximately" will depend on the particular system under study and will be readily apparent to those skilled in the art. Wherever a range is enumerated in this application, all integers within that range are also contemplated as embodiments of this disclosure. Wherever words such as "approximately" are used, or whether they are used, in the context of this disclosure, this means within 10% of a given value or range, appropriately within 5%, and particularly within 1%.

[0306] When multiple diffraction patterns are available, particle statistics (PS) and / or selective orientation (PO) can be evaluated. Consistency of relative intensities between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, observed XRPD patterns can be compared to XRPD patterns calculated based on a single crystal structure, if available. PS / PO can also be evaluated using two-dimensional scattering patterns with an area detector. If the effects of both PS and PO are deemed negligible, the XRPD pattern represents the average powder intensity for the sample, and prominent peaks can be identified as "representative peaks." Generally, the more data collected to determine representative peaks, the greater the confidence in classifying those peaks.

[0307] Characteristic peaks, as long as they exist, are a subset of representative peaks and are used to distinguish one crystalline polymorph from another (polymorphs are crystalline forms with the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if present, are within ±0.2° of 2θ for a given crystalline polymorph of a compound compared to all other known crystalline polymorphs of that compound. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0308] As used herein, the term “selective orientation” refers to an extreme case of non-random distribution of crystallites in solid form. In XRPD, an ideal sample is homogeneous, and crystallites are randomly distributed within the bulk solid. In a truly random sample, each possible reflection from a given set of planes will have an equal number of crystallites contributing to it. However, this is not the case when the solid form is selectively oriented. Therefore, comparing the intensities of randomly oriented diffraction patterns with those of selectively oriented diffraction patterns can appear quite different. Quantitative analysis that depends on the intensity ratio is greatly distorted by selective orientation. Careful sample preparation is crucial to reduce the incidence of selective orientation.

[0309] The term “substantially identical” as used herein to refer to figures is intended to mean that the figures are considered to correspond to the type and kind of characteristic data obtained by a person skilled in the art, taking into account acceptable deviations in the art. Such deviations may be caused by factors relating to variations in sample size, sample preparation, specific equipment used, operating conditions, and other experimental conditions known in the art. For example, a person skilled in the art will understand that the endothermic onset temperature and peak temperature measured by differential scanning calorimetry (DSC) may vary considerably from experiment to experiment. For example, a person skilled in the art can easily identify whether two X-ray diffraction patterns or two DSC thermograms are substantially identical. In some embodiments, two X-ray diffraction patterns are considered substantially identical if their characteristic peaks do not vary by more than ±0.2° of 2θ.

[0310] As used herein, salts of compound 1 (e.g., HCl salts, sulfates, methanesulfonates, benzenesulfonates, and naphthalene-1,5-disulfonates) include compounds in which the corresponding acid is in an ionized, non-ionized, associated, or non-associative form. In some embodiments, the corresponding acid is in an ionized and / or associated form. In some embodiments, the corresponding acid is in a non-ionized and / or non-associative form. Salts of compound 1 also include monoacids, diacids, and the like of salts. [Examples]

[0311] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0312] Example 1: PHD2 Enzyme Assay Procedure Preparation of DMSO stock of the compound: Compound 1 was reconstituted into a 20 mM stock using DMSO.

[0313] Compound storage: Compound 1 in DMSO was stored at room temperature in a desiccator for short-term storage (maximum 3 months).

[0314] Preparation of work stock: The reference roxadustat (FG-4592) was serially diluted 3-fold in DMSO from 400 μM to 10 doses. The compound was serially diluted 3-fold in DMSO from 400 μM to 10 doses. A 200-fold positive control (400 μM, FG-4592) and a 200-fold vehicle control (100% DMSO) were prepared. The compound plate was centrifuged at 1000 rpm for 1 minute.

[0315] Compound screening: a) Using Echo655, 40 nl of compound dilution was transferred to each well of the assay plate; b) The assay plate was sealed, and the compound plate was centrifuged at 1000 rpm for 1 minute. c) Prepare a 2x PHD2 enzyme working solution and add 4 μL to each well of the assay plate. d) Seal the assay plate and centrifuge the compound plate at 1000 rpm for 1 minute. Incubate the plate at room temperature for 30 minutes. e) Prepare a 2x PHD2 substrate working solution and add 4 μl to each well of the assay plate. f) A 4x stop solution was prepared and 4 μL was added to each well of the assay plate. g) A 4-fold detection solution was prepared using AlphaScreen streptavidin donor beads, AlphaScreen protein A acceptor beads, and hydroxy-HIF-1α(Pro564)(D43B5)XP® rabbit mAb. h) Add 4 μL of 4x detection solution to each well of the assay plate. Repeat step d. i) The Alphascreen signal was read using the Envision HTS plate reader.

[0316] Data Analysis The ALPHASCREEN signal (ALPcmpd) is calculated for each well. The inhibition rate (%) is calculated as follows: Inhibition rate (%)=[1-(ALP 化合物 -ALP 陽性 ) / (ALP ビヒクル -ALP 陽性 )] × 100 ALP 陽性 : Average ALP of positive controls across the entire plate. ALP vehicle: Average ALP of the negative control across the entire plate. I C 50 Calculate the effect and plot the effect-dose curve of the compound. Using Graphpad 8.0, IC was calculated by fitting the logarithm of the inhibition rate (%) and compound concentration to a nonlinear regression (variable dose-response gradient). 50 I calculated it. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope)) X: Logarithm of inhibitor concentration; Y: Inhibition rate (%).

[0317] Example 2: EPO Elisa assay The compound powder was dissolved in 100% DMSO. The compound stock solution was stored in a nitrogen cabinet.

[0318] Experimental method Cell seeding: 100 μl of cell suspension containing 20,000 Hep3B cells was added to each well. Preparation of compound concentration gradient: Compound 1 in 8 doses, single or double, with a maximum dose of 100 μM, 3-fold dilution. Prepare a solution 200-fold of the final concentration in a 96-well plate, dilute the compound 200 / 3-fold with cell culture medium, and then pipette 50 μL into the wells. Add 50 μL of culture medium containing DMSO to the smallest control well so that the final concentration contains 5‰ DMSO, add 50 μL of the highest concentration of the reference compound to the largest control well, and incubate at 37°C for 24 hours. The reaction plate was washed twice with 400 μL of 1-fold washing buffer per well. 100 μL of the diluted standard (including the standard blank control) was added to the appropriate wells. 50 μL of the sample and 50 μL of the sample diluent were added to the sample wells. 50 μL of 1-fold biotin-labeled antibody was added to all wells and incubated at room temperature for 1 hour. The reaction plate was washed six times with 400 μL of 1-fold washing buffer per well. 100 μL of 1-fold streptavidin-HRP was added to each well. Incubate at room temperature for 15 minutes. The reaction plate was washed six times with 400 μL of 1-fold washing buffer per well. 100 μL of the TMB substrate solution was added to each well. Incubate at room temperature for 10 minutes. 100 μL of the stop solution was added to each well. OD450 was read with EnSight.

[0319] Data analysis GraphPad Prism 5 was used. Activity (%) = (Compound signal - Minimum signal) / (Maximum signal - Minimum signal) × 100.

[0320] The maximum signal was obtained from the maximum control well.

[0321] The minimum signal was obtained from the minimum control well.

[0322] The logarithmic value of the concentration was taken as the X-axis, and the inhibition rate (%) was taken as the Y-axis. The dose-response curve was fitted using the log(inhibitor) vs. response - variable slope of the analysis software GraphPad Prism 5, and the EC 50 value of each compound was obtained.

[0323] The data of Example 1 and Example 2 are shown below.

[0324] TIFF2026513705000019.tif44170

[0325] Example 3: Preparation of free base A of compound 1 [ka] To a solution of methyl 2-(bromomethyl)-6-chloronicotinate (5 g, 18.9 mmol) and methyl 2-(p-tolylsulfonylamino)acetate (4.6 g, 18.9 mmol) in DMF (50 mL), K2CO3 (5.02 g, 47.4 mmol) and NaI (0.28 g, 1.86 mmol) were added. The mixture was stirred at 50°C for 12 hours under an N2 atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with H2O (80 mL x 3). The organic layer was washed with brine (80 mL x 3), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography to obtain methyl 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)nicotinate (6 g, crude) as a yellow solid.

[0326] 6-chloro-2-(((N-(2-methoxy-2-oxoethyl)-4-methylphenyl)sulfonamide)methyl)nicotinate methyl (6 g, 14 mmol) was dissolved in DMSO (60 mL) and K2CO3 (11.6 g, 84.3 mmol) was added. The mixture was stirred at 50°C for 4 hours under an N2 atmosphere. The mixture was diluted with H2O (60 mL), and the aqueous layer was adjusted to pH 6 with 1 M HCl. The precipitated solid was filtered and dried to obtain 2-chloro-5-hydroxy-1,7-naphthyridine-6-carboxylate methyl (1.5 g, yield 45%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.72 (d, J = 0.9 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H).

[0327] To a solution of methyl 2-chloro-5-hydroxy-1,7-naphthyridine-6-carboxylate (1 g, 4.19 mmol) in MeOH (30 mL), 5-(aminomethyl)pyridine-2-carbonitrile (0.84 g, 6.29 mmol) and TEA (2.91 mL, 20.95 mmol) were added, and the reaction mixture was stirred overnight at 75°C. The reaction mixture was filtered through a standard funnel, the filter cake was washed with 10 mL of MeOH, and vacuum-dried to obtain 2-chloro-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (1.1 g, 3.24 mmol, yield 77%) as a yellow solid.

[0328] To a DMSO (15 mL) solution of 2-chloro-N-((6-cyanopyridine-3-yl)methyl)-5-hydroxy-1,7-naphthyridine-6-carboxamide (1.1 g, 3.24 mmol), TEA (1.35 mL, 9.71 mmol) and piperazine-1-carboxylate tert-butyl (904 mg, 4.86 mmol) were added, and the reaction mixture was stirred under N2 at 100°C for 2 hours. The reaction mixture was cooled and poured into water (H2O) (200 mL). The mixture was extracted with Âr (50 mL x 3). The combined organic layers were washed with saturated NaCl solution (30 mL x 3) and concentrated under vacuum. The residue was tritulated with CH3CN (20 mL) and CH2Cl2 (5 mL), filtered, and compound 1 (500 mg, 1.02 mmol, yield 32%) was obtained as a white solid. LCMS:RT=1.838min;MS m / z(ESI)[M+H] + = 490.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.77 (t, J = 6.3 Hz, 1H), 8.76 (s, 1H), 8.44 (s, 1H), 8.29 (d, J = 9.4 Hz, 1H), 8.00 (s, 2H), 7.48 (d, J = 9.5 Hz, 1H), 4.63 (d, J = 6.3 Hz, 2H), 3.82 - 3.79 (m, 4H), 3.50 - 3.48 (m, 4H), 1.46 (s, 9H).

[0329] Approximately 50 mg of the obtained solid (compound 1) was equilibrated in 0.4 mL to 0.5 mL of a solvent mixture (1v:1v) of methanol / ethanol / isopropanol / ethyl acetate / dimethyl sulfoxide and water at 25°C for 2 weeks, or in a solvent mixture (1v:1v) of dimethyl sulfoxide and water at 50°C for 1 week. The solid precipitate was collected and subjected to XRPD, DSC, TGA, and 1 The sample was subjected to 1H-NMR.

[0330] Figure 1 shows the XRPD pattern of free base A of compound 1. Table 1 shows the major peaks in the XRPD pattern and their associated intensities. Type A is a mixture of free bases B and D of compound 1.

[0331] Characterization method: DSC analysis: TA Discovery 2500, 30°C to 250°C or before decomposition, heating rate 10°C / min.

[0332] TGA analysis: Discovery 5500, if 300°C or weight is less than 80% (w / w), discontinue the next segment, heating rate 10°C / min.

[0333] XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu / Kα1 radiation. Tube voltage was 40kV. Tube current was 40mA. Scan range was 3° to 40°²θ. Step size was 0.02°, and scan speed was 0.12 sec / step.

[0334] The DSC and TGA results shown in Figures 2 and 3 indicate that the free base A of compound 1 has an endothermic event initiation at around 223.5°C.

[0335] Example 4: Alternative preparation of free base A of compound 1 Approximately 50 mg of the obtained compound 1 solid was equilibrated in 0.4 mL to 0.5 mL of a solvent mixture (1v:1v) of ethyl acetate / 2-methyltetrahydrofuran / ethanol / isopropanol / dimethyl sulfoxide and water for 10 cycles under a temperature cycle between 50°C and 5°C at a cooling / heating rate of 0.1°C / min. The temperature cycle was started at 50°C. The solid precipitate was collected and subjected to XRPD, DSC, and TGA. The XRPD pattern of the solid was the same as that in Table 1, confirming that it was the free base A type of compound 1.

[0336] Example 5: Preparation of free base type 1 of compound 1 Approximately 50 mg of free base A of compound 1 was equilibrated in 0.4 mL to 0.5 mL of a solvent mixture of acetone / methyl ethyl ketone / tetrahydrofuran / acetonitrile / dimethylformamide and isopropyl acetate (1v:1v) / dimethylacetamide and water (95v:5v) at 25°C for 2 weeks, or in a solvent mixture of methyl ethyl ketone / tetrahydrofuran / acetonitrile / dimethylacetamide and water (95v:5v) at 50°C for 1 week. The solid precipitate was collected and subjected to XRPD, DSC, and TGA.

[0337] The XRPD pattern of the free base 1 type of compound 1 is shown in Figure 4. The major peaks of the XRPD pattern and their associated intensities are shown in Table 2. The free base 1 type of compound 1 prepared by this method is compound 1 acetone solvate, methyl ethyl ketone solvate, tetrahydrofuran solvate, acetonitrile solvate, dimethylformamide solvate, or dimethylacetamide solvate.

[0338] Characterization method: XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu / Kα1 radiation. Tube voltage was 40kV. Tube current was 40mA. Scan range was 3° to 40°²θ. Step size was 0.02°, and scan speed was 0.12 sec / step.

[0339] DSC analysis: TA Discovery 2500, 30°C to 250°C or before decomposition, heating rate 10°C / min.

[0340] TGA analysis: Discovery 5500, if 300°C or weight is less than 80% (w / w), discontinue the next segment, heating rate 10°C / min.

[0341] The DSC and TGA results shown in Figures 5 and 6 indicate that the free base type 1 of compound 1 has an endothermic event initiation at around 124.8°C and a melting initiation temperature at around 231.7°C.

[0342] Information on residual solvents in type 1

[0343] TIFF2026513705000021.tif79170

[0344] Example 6: Alternative preparation of free base type 1 of compound 1 Approximately 50 mg of free base A of compound 1 was equilibrated in 0.4 mL to 0.5 mL of a solvent mixture of acetone / methyl ethyl ketone / tetrahydrofuran / acetonitrile / dimethylformamide and isopropyl acetate (1v:1v) / dimethylacetamide and water (95v:5v) for 10 cycles under a temperature cycle between 50°C and 5°C at a cooling / heating rate of 0.1°C / min. The temperature cycle was started at 50°C. The solid precipitate was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 2, confirming that it was free base I of compound 1. Free base I of compound 1 prepared by this method is compound 1 in the form of acetone solvate, methyl ethyl ketone solvate, tetrahydrofuran solvate, acetonitrile solvate, dimethylformamide solvate, or dimethylacetamide solvate.

[0345] Example 7: Alternative preparation of free base type 1 of compound 1 Approximately 20-30 mg of free base A of compound 1 was dissolved in 1.5-6 mL of acetone / methyl ethyl ketone / tetrahydrofuran / 2-methyltetrahydrofuran and filtered. The filtrate was slowly evaporated under ambient conditions (approximately 20°C-25°C, 20%-30% RH). After precipitation, the solid was recovered by filtration and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 2, confirming that it was free base I of compound 1. Free base I of compound 1 prepared by this method is compound 1 in acetone solvate, methyl ethyl ketone solvate, tetrahydrofuran solvate, or 2-methyltetrahydrofuran solvate.

[0346] Example 8: Alternative preparation of free base type 1 of compound 1 Approximately 30 mg of free base A of compound 1 was dissolved in the minimum volume of acetone / methyl ethyl ketone / tetrahydrofuran / 2-methyltetrahydrofuran at 50°C and filtered. The filtrate was cooled to 5°C at 0.1°C / min and stirred until sufficient precipitate was obtained. Samples that did not precipitate at 5°C were further cooled to -20°C for precipitation. The solid was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 2, confirming that it was free base I of compound 1. Free base I of compound 1 prepared by this method is compound 1 in acetone solvate, methyl ethyl ketone solvate, tetrahydrofuran solvate, or 2-methyltetrahydrofuran solvate.

[0347] Example 9: Alternative preparation of free base type 1 of compound 1 Approximately 30 mg of free base A of compound 1 was dissolved in the minimum volume of acetone / methyl ethyl ketone / ethyl acetate / tetrahydrofuran / 2-methyltetrahydrofuran at 50°C and filtered. The filtrate was cooled and stirred in an ice bath at 0°C. The precipitate was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 2, confirming that it was free base I of compound 1. Free base I of compound 1 prepared by this method is compound 1 in acetone solvate, methyl ethyl ketone solvate, ethyl acetate solvate, tetrahydrofuran solvate, or 2-methyltetrahydrofuran solvate.

[0348] Example 10: Alternative preparation of free base type 1 of compound 1 Approximately 25-40 mg of free base A of compound 1 was dissolved in the minimum volume of 2-methyltetrahydrofuran at ambient temperature (20°C-25°C). After filtration, acetonitrile was slowly added to the filtrate in 1-4 times the volume. The precipitate was collected and subjected to XRPD analysis. The XRPD pattern of the solid was the same as that shown in Table 2, confirming that it was free base 1 of compound 1.

[0349] Example 11: Alternative preparation of free base type 1 of compound 1 Approximately 25-40 mg of free base A of compound 1 was dissolved in the minimum volume of tetrahydrofuran at ambient temperature (20°C-25°C) and filtered. Isopropyl acetate was slowly added to the filtrate in approximately 1-4 times the volume and cooled to 5°C. After equilibration at 5°C for 3 days, the precipitate was collected and subjected to XRPD analysis. The XRPD pattern of the solid was the same as that shown in Table 2, confirming that it was free base 1 of compound 1.

[0350] Example 12: Preparation of the free base B form of compound 1 Free base B of compound 1 was obtained by heating the methyl ethyl ketone solvate, tetrahydrofuran solvate, acetone solvate, or acetonitrile solvate of compound 1 at 150°C. The XRPD pattern of free base B of compound 1 is shown in Figure 7. The main peaks of the XRPD pattern and their associated intensities are shown in Table 3. The DSC and TGA results shown in Figures 8 and 9 indicate that free base B of compound 1 has an endothermic event initiation around 232.9°C. No solvent residue was found in free base B of compound 1. Therefore, free base B of compound 1 is a polymorph of compound 1.

[0351] Characterization method: XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu / Kα1 radiation. Tube voltage was 40kV. Tube current was 40mA. Scan range was 3° to 40°²θ. Step size was 0.02°, and scan speed was 0.12 sec / step.

[0352] DSC analysis: TA Discovery 2500, 30°C to 250°C or before decomposition, heating rate 10°C / min.

[0353] TGA analysis: Discovery 5500, if 300°C or weight is less than 80% (w / w), discontinue the next segment, heating rate 10°C / min.

[0354] Example 13: Preparation of the free base C form of Compound 1 Approximately 25-40 mg of the free base A of compound 1 was dissolved in a minimum volume (0.5 mL) of acetone at ambient temperature (20°C-25°C), filtered, and then 1-4 times the volume of water was slowly added to the filtrate. The precipitate was collected and subjected to XRPD, DSC, TGA, 1 The samples were subjected to 1HNMR and DVS testing.

[0355] Figure 10 shows the XRPD pattern of the free base C type of compound 1. Table 4 shows the major peaks in the XRPD pattern and their associated intensities.

[0356] Characterization method: DSC analysis: TA Discovery 2500, 30°C to 250°C or before decomposition, heating rate 10°C / min.

[0357] TGA analysis: Discovery 5500, if 300°C or weight is less than 80% (w / w), discontinue the next segment, heating rate 10°C / min.

[0358] DVS analysis: ProUmind fast DVS. The relative humidity cycle was 40% → 95% → 0% → 95% → 40%, the stage step was 10%, and the equilibrium time was 240 minutes. The total gas flow rate was 4000 sccm. Water was used as the solvent. The oven temperature was 25°C.

[0359] XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu / Kα1 radiation. Tube voltage was 40kV. Tube current was 40mA. Scan range was 3° to 40°²θ. Step size was 0.02°, and scan speed was 0.12 sec / step.

[0360] The DSC results shown in Figure 11 indicate that the free base C form of compound 1 has an endothermic event initiation at around 231.2°C. Figure 12 shows approximately 0.2% water absorption at 25°C and 80% relative humidity. No solvent residue was found in the free base C form of compound 1. The free base C form of compound 1 is an anhydrous polymorph of compound 1.

[0361] Example 14: Alternative preparation of the free base C type of Compound 1 Approximately 50 mg of free base A of compound 1 was equilibrated in 0.4 mL to 0.5 mL of methanol under a temperature cycle between 50°C and 5°C at a cooling / heating rate of 0.1°C / min for 10 cycles. The temperature cycle was started at 50°C. The solid precipitate was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 4, confirming that it was free base C of compound 1.

[0362] Example 15: Alternative preparation of the free base C type of Compound 1 Approximately 50 mg of free base A of compound 1 was equilibrated at 50°C for 1 week in 0.4 mL to 0.5 mL of a solvent mixture (1v:1v) of methanol / dimethylformamide and isopropyl acetate. The solid precipitate was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 4, confirming that it was free base C of compound 1.

[0363] Example 16: Alternative preparation of the free base C type of compound 1 Approximately 1 g of a mixture of free base B, free base D, and free base I of compound 1 was triturated in 30 mL of ethanol at 50°C for 7 days. The solid was isolated and vacuum-dried at 50°C for 4 hours. The XRPD test results of the solid were the same as those in Table 4, confirming that it was free base C of compound 1.

[0364] Example 17: Preparation of the free base D form of Compound 1 Approximately 50 mg of the free base A of compound 1 was equilibrated in 0.4 mL to 0.5 mL of ethanol / isopropanol / ethyl acetate / 2-methyltetrahydrofuran at 50°C for 1 week. The solid precipitate was collected and subjected to XRPD, DSC, and TGA.

[0365] Figure 13 shows the XRPD pattern of the free base D form of compound 1. Table 5 shows the major peaks in the XRPD pattern and their associated intensities. The free base D form of compound 1 is the anhydride of compound 1.

[0366] Characterization method: XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu / Kα1 radiation. Tube voltage was 40kV. Tube current was 40mA. Scan range was 3° to 40°²θ. Step size was 0.02°, and scan speed was 0.12 sec / step.

[0367] DSC analysis: TA Discovery 2500, 30°C to 250°C or before decomposition, heating rate 10°C / min.

[0368] TGA analysis: Discovery 5500, if 300°C or weight is less than 80% (w / w), discontinue the next segment, heating rate 10°C / min.

[0369] The DSC and TGA results shown in Figures 14 and 15 indicate that the free base D form of compound 1 has an endothermic event initiation at around 194.3°C.

[0370] Example 18: Alternative preparation of the free base D form of Compound 1 Approximately 20-30 mg of the free base A of compound 1 was dissolved in 1.5-6 mL of ethanol, filtered, and the filtrate was slowly evaporated under ambient conditions (approximately 20°C-25°C, 20%-30% RH). After precipitation, the solid was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 5, confirming that it was the free base D of compound 1.

[0371] Example 19: Alternative preparation of free base D type of compound 1 Approximately 25-40 mg of the free base A of compound 1 was dissolved in the minimum volume of tetrahydrofuran at ambient temperature (20°C-25°C). After filtration, methyl tert-butyl ether was slowly added to the filtrate in 1-4 times the volume. The precipitate was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 5, confirming that it was the free base D of compound 1.

[0372] Example 20: Alternative preparation of free base D type of compound 1 Approximately 25-40 mg of the free base A of compound 1 was dissolved in the minimum volume of 2-methyltetrahydrofuran at ambient temperature (20°C-25°C). After filtration, heptane was slowly added to the filtrate in 1-5 times the volume. The precipitate was collected and subjected to XRPD testing. The XRPD pattern of the solid was the same as that shown in Table 5, confirming that it was the free base D of compound 1.

[0373] Example 21: Preparation of the free base E form of Compound 1 Approximately 20-30 mg of free base A of compound 1 was dissolved in dichloromethane, filtered, and the filtrate was slowly evaporated under ambient conditions (approximately 20°C-25°C, 20%-30% RH). After precipitation, the solid was collected and subjected to XRPD, DSC, and TGA tests. The XRPD pattern of free base E of compound 1 is shown in Figure 16. The main peaks in the XRPD pattern and their associated intensities are shown in Table 6. Free base E of compound 1 is the anhydrous form of compound 1.

[0374] Characterization method: XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu / Kα1 radiation. Tube voltage was 40kV. Tube current was 40mA. Scan range was 3° to 40°²θ. Step size was 0.02°, and scan speed was 0.12 sec / step.

[0375] DSC analysis: TA Discovery 2500, 30°C to 250°C or before decomposition, heating rate 10°C / min.

[0376] TGA analysis: Discovery 5500, if 300°C or weight is less than 80% (w / w), discontinue the next segment, heating rate 10°C / min.

[0377] The DSC and TGA results shown in Figures 17 and 18 indicate that the free base E form of compound 1 has an endothermic event initiation at around 224.2°C.

[0378] Example 22: Preparation of the free base F form of compound 1 Approximately 50 mg of a mixture of free bases B, D, and I of compound 1 was added to 4 mL of dichloromethane at 25°C, stirred, and then filtered. The filtrate was slowly evaporated at room temperature for 2 to 7 days. The precipitated solid was collected and subjected to XRPD, DSC, and TGA tests.

[0379] Figure 19 shows the XRPD pattern of the free base F form of compound 1. Table 7 shows the major peaks in the XRPD pattern and their associated intensities. The free base F form of compound 1 is the anhydride of compound 1.

[0380] Characterization method: XRPD: Bruker D8 Advance X-ray powder diffractometer, Cu / Kα1 radiation. Tube voltage was 30kV. Tube current was 10mA. Scan range was 3° to 40°²θ. Step size was 0.02°, and scan speed was 0.2 seconds / step.

[0381] DSC analysis: Discovery DSC 250, 25°C to 250°C or before decomposition, heating rate 10°C / min.

[0382] TGA analysis: Discovery 550, if 300°C or less than 80% (w / w) by weight, discontinue the next segment, heating rate 10°C / min.

[0383] The DSC and TGA results shown in Figures 20 and 21 indicate that the free base F form of compound 1 exhibits an exothermic event at 106.4°C and an endothermic event at approximately 228.4°C.

[0384] Example 23: Preparation of HCl salt type A of compound 1 Approximately 50 mg of free base A of compound 1 and 1 or 2 equivalents of HCl were added to 1 mL of methyl ethyl ketone or tetrahydrofuran. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C for 48 hours. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14000 rpm. After vacuum drying at 50°C for about 2 hours, the solid was subjected to XRPD, DSC, TGA, 1 The compounds were characterized by 1H-NMR, IC, and KF. The HCl salt A of compound 1 is an anhydride. The main peaks of the XRPD pattern and their associated intensities are shown in Table 8.

[0385] The XRPD pattern of compound 1's HCl salt type A is shown in Figure 22. The DSC and TGA results are shown in Figures 23 and 24.

[0386] Example 24: Alternative preparation of HCl salt type A of compound 1 Approximately 400 mg of free base A of compound 1 was weighed into a 20 mL glass vial. 3.3 mL of THF was added to the vial while stirring at 50°C for approximately 2 minutes.

[0387] 1.0 equivalent of 1.2N HCl aqueous solution (0.73 mL, 0.1 mL of 12N HCl diluted with 0.9 mL of THF) was slowly added to the suspension.

[0388] 5 mg to 10 mg of HCl salt type A seed crystals were added to the suspension. To improve fluidity, 2 mL of THF was added to the suspension.

[0389] After stirring at 50°C for approximately 2 hours, the suspension was allowed to cool naturally to 25°C, and stirring was continued at 25°C.

[0390] The solid was recovered by centrifugal filtration and then vacuum-dried at 50°C for approximately 2 hours.

[0391] Approximately 375 mg of HCl salt type A was obtained as an off-white solid with a yield of 77.4%.

[0392] Solids are subjected to XRPD, DSC, TGA, HPLC, 1 The samples were characterized by 1H-NMR and IC.

[0393] DSC is T onset It shows a melting peak at 182.5°C. Decomposition occurs during melting. TGA shows a weight loss of approximately 1.7% at approximately 160°C and approximately 12.5% ​​from approximately 160°C to 206°C. HPLC shows a chemical purity of 97.5%. IC shows that the compound (I):HCl ratio is 1:1.06. 1 1H-NMR shows a THF residue of 1.3 wt%.

[0394] Example 25: Preparation of sulfate type A of compound 1 Approximately 50 mg of free base A of compound 1 and 1 equivalent of H2SO4 were added to 1 mL of methyl ethyl ketone or tetrahydrofuran. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C for 48 hours. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14000 rpm. After vacuum drying at 50°C for about 2 hours, the solid was subjected to XRPD, DSC, TGA, 1 The compounds were characterized by 1H-NMR, IC, and KF. The sulfate A form of compound 1 is an anhydride. The main peaks in the XRPD pattern and their associated intensities are shown in Table 9.

[0395] The XRPD pattern of sulfate type A of compound 1 is shown in Figure 25. The DSC and TGA results are shown in Figures 26 and 27.

[0396] Example 26: Preparation of sulfate type B of compound 1 Approximately 50 mg of free base A of compound 1 and 1 equivalent of H2SO4 were added to 1 mL of methyl ethyl ketone. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C for 48 hours. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14000 rpm. After vacuum drying at 50°C for about 2 hours, the solid was triturated in methyl ethyl ketone for 5 days. The solid was recovered and subjected to XRPD, DSC, TGA, 1 The product was subjected to 1H-NMR, IC, and KF testing. Sulfate type B is an anhydrous form.

[0397] Table 10 shows the main peaks in the XRPD pattern and their associated intensities.

[0398] The XRPD pattern of sulfate type B of compound 1 is shown in Figure 28. The DSC and TGA results are shown in Figures 29 and 30.

[0399] Example 27: Alternative preparation of sulfate type B of compound 1 Approximately 400 mg of free base A of compound 1 was weighed into a 20 mL glass vial. 1 mL of MEK was added to the vial while stirring at 50°C for approximately 2 minutes.

[0400] 1.0 equivalent of sulfuric acid (0.47 mL, 0.1 mL of concentrated sulfuric acid diluted with 0.9 mL of MEK) was slowly added to the suspension.

[0401] 5 mg to 10 mg of type B sulfate seed crystals were added to the suspension. To improve fluidity, 3 mL of MEK was added to the suspension.

[0402] After stirring at 50°C for approximately 2 hours, the suspension was allowed to cool naturally to 25°C, and stirring was continued at 25°C.

[0403] The solid was recovered by centrifugal filtration and then vacuum-dried at 50°C for approximately 2 hours.

[0404] Solids are subjected to XRPD, DSC, TGA, HPLC, 1 The samples were characterized by 1H-NMR and IC.

[0405] DSC is T onset It shows a melting peak at 163.3°C. Decomposition occurs during melting. TGA shows a weight loss of approximately 1.2% at approximately 150°C. HPLC shows a chemical purity of 87.9%. IC shows that the compound (I):sulfuric acid ratio is 1:1.23. 1 1H-NMR shows 0.9 wt% MEK residue.

[0406] Example 28: Preparation of methanesulfonate type A of compound 1 Approximately 50 mg of free base A of compound 1 and 1 equivalent of methanesulfonic acid were added to 1 mL of methyl ethyl ketone or tetrahydrofuran. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C for 48 hours. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14000 rpm. After vacuum drying at 50°C for about 2 hours, the solid was subjected to XRPD, DSC, TGA, 1 The compounds were characterized by 1H-NMR, IC, and KF. The main peaks in the XRPD patterns and their associated intensities are shown in Table 11. Methanesulfonate type A is anhydrous.

[0407] The XRPD pattern of methanesulfonate type A is shown in Figure 31. The results of DSC and TGA are shown in Figures 32 and 33.

[0408] Example 29: Alternative preparation of methanesulfonate type A Approximately 400 mg of free base A of compound 1 was weighed into a 20 mL glass vial. 3 mL of THF was added to the vial while stirring at 50°C for approximately 2 minutes.

[0409] 1.0 equivalent of methanesulfonic acid (0.56 mL, 0.1 mL of methanesulfonic acid diluted with 0.9 mL of THF) was slowly added to the suspension.

[0410] 5 mg to 10 mg of MSA salt type A seed crystals were added to the suspension. Then, 3 mL of THF was added to the suspension to improve fluidity.

[0411] After stirring at 50°C for approximately 2 hours, the suspension was allowed to cool naturally to 25°C, and stirring was continued at 25°C.

[0412] The solid was recovered by centrifugal filtration and then vacuum-dried at 50°C for approximately 2 hours.

[0413] Approximately 461 mg of MSA salt type A was obtained as a white solid in a yield of 95.4%.

[0414] Solids are subjected to XRPD, DSC, TGA, HPLC, and 1 The characteristics were determined by 1H-NMR. DSC was T onset It shows a melting peak at 154.2°C. Decomposition occurs during melting. TGA shows a weight loss of approximately 1.7% at approximately 140°C and approximately 16.7% from approximately 140°C to 184°C. HPLC shows a chemical purity of 97.1%. 1 ¹H-NMR showed a compound (I):methanesulfonic acid ratio of 1:1.04, indicating a 2.0 wt% THF residue.

[0415] Example 30: Preparation of benzenesulfonate type A of compound 1 Approximately 50 mg of free base A of compound 1 and 1 equivalent of benzenesulfonic acid were added to 1 mL of methyl ethyl ketone or tetrahydrofuran. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C for 48 hours. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14000 rpm. After vacuum drying at 50°C for about 2 hours, the solid was subjected to XRPD, DSC, TGA, 1 The compounds were characterized by 1H-NMR, IC, and KF. The main peaks in the XRPD patterns and their associated intensities are shown in Table 12. The benzenesulfonate type A is anhydrous.

[0416] The XRPD pattern of compound 1, benzenesulfonate type A, is shown in Figure 34. The DSC and TGA results are shown in Figures 35 and 36.

[0417] Example 31: Preparation of naphthalene-1,5-disulfonate type A of compound 1 Approximately 50 mg of free base A of compound 1 and 1 equivalent of naphthalene-1,5-disulfonic acid were added to 1 mL of methyl ethyl ketone. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C for 48 hours. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14000 rpm. After vacuum drying at 50°C for about 2 hours, the solid was subjected to XRPD, DSC, TGA, 1 Characterization was performed by 1H-NMR, IC, and KF. The main peaks of the XRPD pattern and their associated intensities are shown in Table 13. Naphthalene-1,5-disulfonate type A is a hydrate.

[0418] The XRPD pattern of naphthalene-1,5-disulfonate type A of compound 1 is shown in Figure 37. The DSC and TGA results are shown in Figures 38 and 39.

[0419] Example 32: Preparation of naphthalene-1,5-disulfonate type B of compound 1 Approximately 50 mg of free base A of compound 1 and 1 equivalent of naphthalene-1,5-disulfonic acid were added to 1 mL of tetrahydrofuran. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C for 48 hours. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14000 rpm. After vacuum drying at 50°C for about 2 hours, the solid was subjected to XRPD, DSC, TGA, 1 The compounds were characterized by 1H-NMR, IC, and KF. The major XRPD peaks and their associated intensities are shown in Table 14 as XRPD patterns. Naphthalene-1,5-disulfonate type B is a hydrate.

[0420] The XRPD pattern of naphthalene-1,5-disulfonate type B of compound 1 is shown in Figure 40. The DSC and TGA results are shown in Figures 41 and 42.

[0421] Example 33: Characterization of salt form

[0422] TIFF2026513705000022.tif77170

[0423] TIFF2026513705000023.tif135170

[0424] Example 34: Competitive Equilibrium Experiment To determine the relative stability of the anhydrous substance, competitive equilibrium experiments were conducted in different solvent systems.

[0425] The relative thermodynamic stability of types C and F was first determined by using them in a competitive slurry experiment. Approximately 5 mg of type F and 5 mg of type C were added to 0.5 mL of a saturated solution of type C in a selected solvent (the saturated solution was prepared from type C and the corresponding solvent). The resulting suspensions were stirred for one week at 5°C, 25°C, and 50°C, respectively. The solid portion (wet cake) was isolated by filtration and investigated by XRPD.

[0426] Pure type D could not be obtained, and only a physical mixture of type A and type D could be prepared. Based on previous studies, type C was more stable than type F. Therefore, a mixture of type A and type D was used in a competitive slurry experiment with type C. Approximately 5 mg of type D + A and 5 mg of type C were added to 0.5 mL of a saturated solution of type C in a selected solvent. The resulting suspensions were stirred for 3 days at 25°C and 50°C, respectively. The solid portion (wet cake) was isolated by filtration and investigated by XRPD.

[0427] The results showed that the C-type is the most thermodynamically stable form of the free base.

[0428] TIFF2026513705000024.tif60170

[0429] TIFF2026513705000025.tif42170

[0430] TIFF2026513705000026.tif213170

[0431] TIFF2026513705000027.tif238170TIFF2026513705000028.tif249170TIFF2026513705000029.tif132170

Claims

1. tert-butyl 4-(6-(((6-cyanopyridine-3-yl)methyl)carbamoyl)-5-hydroxy-1,7-naphthyridine-2-yl)piperazine-1-carboxylate: 【Chemistry 1】 (Compound 1) or a pharmaceutically acceptable salt thereof in solid form.

2. The solid form according to claim 1, wherein the solid form is a crystalline form.

3. The solid form according to claim 1 or 2, wherein the solid form is a crystalline compound 1 as a free base.

4. The solid form according to claim 1 or 2, wherein the solid form is the free base C form of the crystalline compound 1.

5. The solid form according to claim 1 or 2, wherein the solid form is free base type A of crystalline compound 1, free base type B of crystalline compound 1, free base type C of crystalline compound 1, free base type D of crystalline compound 1, free base type E of crystalline compound 1, free base type F of crystalline compound 1, or free base type 1 of crystalline compound 1.

6. The crystalline form is, (a) X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, which is substantially the same as that shown in Figure 10. (b) X-ray powder diffraction (XRPD) patterns measured using Cu Kα radiation, with peaks at 5.2 ± 0.2° 2θ, 6.2 ± 0.2° 2θ, and 14.7 ± 0.2° 2θ. (c) A differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 11, (d) Differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature of approximately 231.2°C. (e) A thermogravimetric analysis (TGA) thermogram substantially the same as that shown in Figure 12, or (f) These combinations, The crystalline form according to claim 2, which is a free base of compound 1 characterized by having at least one of the properties of the above.

7. The crystalline morphology according to claim 6, wherein the crystalline morphology has an X-ray powder diffraction (XRPD) pattern having the peaks found in Table 4, measured using Cu Kα radiation.

8. The crystalline morphology according to claim 6 or 7, wherein the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having peaks at 2θ of 5.2 ± 0.2°, 2θ of 6.2 ± 0.2°, and 2θ of 14.7 ± 0.2°.

9. The crystalline morphology according to any one of claims 6 to 8, wherein the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 13.7 ± 0.2°, 2θ of 17.9 ± 0.2°, and 2θ of 24.0 ± 0.2°.

10. The crystalline morphology according to any one of claims 6 to 9, wherein the X-ray powder diffraction (XRPD) pattern, measured using Cu Kα radiation, further includes peaks at 2θ of 11.5 ± 0.2° and 2θ of 21.2 ± 0.2°.

11. The crystalline morphology according to any one of claims 6 to 10, wherein the X-ray powder diffraction (XRPD) pattern further includes peaks at 2θ of 8.6 ± 0.2°, 2θ of 24.7 ± 0.2°, and 2θ of 28.3 ± 0.2°, as measured using Cu Kα radiation.

12. The crystalline morphology according to any one of claims 6 to 8, wherein the crystalline morphology has an X-ray powder diffraction (XRPD) pattern measured using Cu Kα radiation, having peaks at 2θ at 5.2±0.2°, 6.2±0.2°, 8.6±0.2°, 11.5±0.2°, 13.7±0.2°, 14.7±0.2°, 17.9±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, and 2θ at 28.3±0.2°.

13. The crystalline form according to any one of claims 6 to 12, wherein the crystalline form is anhydrous.

14. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form described in any one of claims 2 to 13 and a pharmaceutically acceptable additive.

15. A method for treating a disease or disorder in a subject, comprising administering to the subject a crystalline form described in any one of claims 2 to 13 or a pharmaceutical composition described in claim 14, wherein the disease or disorder is inflammatory bowel disease (IBD).

16. The method according to claim 15, wherein the disease or disorder is ulcerative colitis ("UC") or Crohn's disease ("CD").

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