Forms and compositions of JAK2 inhibitors

Abstract

This disclosure provides solid-state forms of JAK2 inhibitors, as well as compositions thereof, and methods for their use and preparation. Compounds can form one or more different pharmaceutically acceptable solid-state forms, including amorphous and polymorphic crystalline forms. Individual solid-state forms of bioactive compounds may have different properties. Identifying and selecting appropriate solid-state forms (including appropriate crystalline forms, where applicable) of bioactive compounds is necessary for the development of pharmaceutically acceptable dosage forms for treating various diseases or conditions associated with JAK2.

Description

[Technical Field]

[0001] Related applications This application claims priority under U.S. Patent Application No. 63 / 499,765, filed on 3 May 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a certain role in cellular processes such as immunity, cell division, and cell death. Dysfunction of the JAK-STAT pathway has been shown to be involved in a variety of diseases, including cancer and other proliferative disorders, as well as disorders of the immune system. For example, virtually all BCR-ABL1-negative myeloproliferative neoplasms are associated with mutations that activate JAK2. In particular, JAK2V617F is the most frequent mutation in myeloproliferative neoplasms, occurring in approximately 70% of all patients and up to 95% of patients with polycythemia vera (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even relatively infrequent mutations, such as those in MPL and CALR, have been shown to cause JAK2 activation, thereby initiating and / or promoting disease progression. (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82). Furthermore, JAK2 polymorphisms have been linked to various autoimmune diseases and inflammatory conditions, such as psoriasis and inflammatory bowel disease. (O'Shea, JJ et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115). Increased signaling mediated by JAK2 and other members of the JAK family is also associated with atopic dermatitis. (Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1):33-40). JAK (e.g., JAK2) inhibitors are classified based on their binding mode. All currently approved JAK inhibitors are type I inhibitors, which bind to the ATP binding site in the active conformation of the kinase domain, thereby blocking its catalytic activity (Vainchenker, W. et al.). However, increased phosphorylation of the JAK2 activation loop has been observed with type I inhibitors, which can lead to acquired resistance in certain patients (Meyer SC, Levine, RL Clin. Cancer Res. 2014, 20(8):2051-9). On the other hand, type II inhibitors bind to the ATP binding site of the kinase domain in the inactive conformation, thus avoiding the hyperphosphorylation observed with type I inhibitors (Wu, SC et al. Cancer Cell 2015 Jul 13, 28(1):29-41). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79 [Non-Patent Document 2] Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82 [Non-Patent Document 3] O'Shea, JJ et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115 [Non-Patent Document 4] Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1):33-40 [Non-Patent Document 5] Meyer SC, Levine, RL Clin. Cancer Res. 2014, 20(8):2051-9

Non-Patent Document 6

Summary of the Invention

Means for Solving the Problems

[0004] The compound can form one or more different pharmaceutically acceptable solid forms, including an amorphous form and polymorphic crystalline forms. Individual solid forms of the bioactive compound can have different properties. The development of pharmaceutically acceptable dosage forms for treating various diseases or conditions related to JAK2 requires the identification and selection of appropriate solid forms of the bioactive compound (including appropriate crystalline forms if applicable).

[0005] In the present disclosure, novel solid forms useful as inhibitors of JAK2 are provided. Generally, the provided forms, and their pharmaceutically acceptable compositions, are useful in treating or reducing the severity of various diseases or disorders as described in detail herein.

Brief Description of the Drawings

[0006] [Figure 1] The figure shows an overlay of the XRPD spectra of Lot I of Compound 1, Lot II of Compound 1, Form B of Compound 1, and Form C of Compound 1 from top to bottom.

[0007] [Figure 2] The TGA curve (top) and DSC curve (bottom) of Lot I of Compound 1 are shown.

[0008] [Figure 3A] The figure shows an overlay of the XRPD spectra of Form A of Compound 1, Form B of Compound 1, Form C of Compound 1, Form D of Compound 1, Form E of Compound 1, and Form F of Compound 1 from top to bottom.

[0009] [Figure 3B]Figure showing the overlay of the XRPD spectra of Form G of Compound 1, Form H of Compound 1, a mixture of Form H and Form I of Compound 1, Form J of Compound 1, Form K of Compound 1, and Form L of Compound 1 from top to bottom.

[0010] [Figure 3C] Figure showing the overlay of the XRPD spectra of Form M of Compound 1, Form N of Compound 1, Form O of Compound 1, a mixture of Form P and Form Q of Compound 1, and a mixture of Form S and Form B of Compound 1 from top to bottom.

[0011] [Figure 4] Figure showing the overlay of the XRPD spectra from the interconversion slurry experiment, including the spectrum of Form B of Compound 1 slurried in EtOH:H2O (90:10) at room temperature for 9 days from top to bottom, the spectrum of Form B of Compound 1 slurried in EtOH:H2O (90:10) at 65 °C for 9 days, and the reference spectrum of Form B of Compound 1.

[0012] [Figure 5] The XRPD spectrum of Form B of Compound 1 is shown.

[0013] [Figure 6] The TGA curve (top) and DSC curve (bottom) of Form B of Compound 1 are shown.

[0014] [Figure 7] The DVS plot of Form B of Compound 1 is shown.

[0015] [Figure 8] Figure showing the overlay of the XRPD spectra obtained before (top) and after (bottom) the DVS experiment using Form B of Compound 1.

[0016] [Figure 9] Figure showing the overlay of the XRPD spectra. Top: Form B of Compound 1 slurried in water at room temperature for 5 days, Bottom: Reference spectrum of Form B of Compound 1.

[0017] [Figure 10] The XRPD spectrum of compound 1 in form C is shown.

[0018] [Figure 11] The TGA curve (top) and DSC curve (bottom) for compound 1, form C, are shown.

[0019] [Figure 12] The DVS plot for form C of compound 1 is shown.

[0020] [Figure 13] This figure shows the superimposed XRPD spectra obtained before (top) and after (bottom) a DVS experiment using compound 1, form C.

[0021] [Figure 14] The XRPD spectrum of compound 1 in form D is shown.

[0022] [Figure 15] The TGA curve (top) and DSC curve (bottom) for compound 1, form D, are shown.

[0023] [Figure 16] The XRPD spectrum of compound 1, form E, is shown.

[0024] [Figure 17] The XRPD spectrum of compound 1, form F, is shown.

[0025] [Figure 18] The TGA curve (top) and DSC curve (bottom) for compound 1, form F, are shown.

[0026] [Figure 19] The DVS plot for form F of compound 1 is shown.

[0027] [Figure 20]This figure shows the superimposed XRPD spectra obtained before (top) and after (bottom) a DVS experiment using compound 1, form F.

[0028] [Figure 21] This figure shows the superimposed XRPD spectra obtained before (top, morphology F) and after (bottom, morphology C) slurring of compound 1 (morphology F) in water at ambient temperature for 3 days.

[0029] [Figure 22] The XRPD spectrum of compound 1 in form G is shown.

[0030] [Figure 23] The image shows superimposed XRPD spectra. From top to bottom: Form G of compound 1 and a trace amount of Form P of compound 1 (Sample 3.5.4 in Table 3.5), the reference spectrum of Form G of compound 1, and a mixture of Form P and Form Q of compound 1 (Sample 3.2.3, Table 3.2).

[0031] [Figure 24] The TGA curve (top) and DSC (bottom) curves of compound 1 in form G, obtained from a sample (sample 3.5.4 in Table 3.5) containing compound 1 in form G and a trace amount of compound 1 in form P, are shown.

[0032] [Figure 25] The TGA curve (top) and DSC curve (bottom) for compound 1, form H, are shown.

[0033] [Figure 26] The XRPD spectrum of compound 1 in form J is shown.

[0034] [Figure 27] The XRPD spectrum of compound 1 in form K is shown.

[0035] [Figure 28] The XRPD spectrum of compound 1 in form L is shown.

[0036] [Figure 29] The TGA curve (top) and DSC curve (bottom) for compound 1, form L, are shown.

[0037] [Figure 30] The XRPD spectrum of compound 1 in form M is shown.

[0038] [Figure 31] The XRPD spectrum of compound 1 in form N is shown.

[0039] [Figure 32] The XRPD spectrum of compound 1 in form O is shown.

[0040] [Figure 33] This is a schematic diagram of the results of a screening experiment for a specific polymorph described herein.

[0041] [Figure 34] This is a scanning electron microscope (SEM) image of amorphous compound 1.

[0042] [Figure 35] The XRPD spectra of amorphous compound 1 (top) are shown in comparison to morphology B of compound 1 (bottom).

[0043] [Figure 36] The DSC curve for amorphous compound 1 is shown. [Modes for carrying out the invention]

[0044] compound 1 Compound 1 is a JAK2 inhibitor having the following structure: [ka] Compound 1 is also known by the following chemical name: 3-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-6-yl)oxy)pyridine-2-yl)-1,1-dimethylurea. This disclosure provides various forms of Compound 1, including its solid form, pharmaceutical compositions thereof, and methods for preparing those forms of Compound 1.

[0045] Compound 1 has demonstrated efficacy against JAK2 in in vitro assays (see, for example, Example 22 herein). Therefore, Compound 1 is useful in treating diseases, disorders, or conditions associated with JAK2, as described herein.

[0046] Solid form of compound 1 In some embodiments, the Disclosure provides a solid form of Compound 1. In some embodiments, the Disclosure provides a crystalline solid form of Compound 1. In some embodiments, the Disclosure provides one or more polymorphic solid forms of Compound 1. As used herein, the term “polymorph” means that a compound can exist in one or more different crystalline structures. Each polymorph may differ between one form and another in pharmaceutically relevant physical properties (e.g., solubility, stability, and / or hygroscopicity). A solid form (e.g., a crystalline solid form) confers or can confer properties such as improved water solubility, stability, hygroscopicity (e.g., the provided form may be less hygroscopic than another form, e.g., an anhydrous form), absorbency, bioavailability, and ease of formulation.

[0047] In some embodiments, compound 1 is provided in an amorphous form. In some embodiments, compound 1 is provided in a crystalline form.

[0048] It will be understood that the crystalline solid form of compound 1 can exist in solvent-free (i.e., non-solvated), hydrated, solvated, and / or heterosolvated forms. In some embodiments, the crystalline solid form of compound 1 has neither water nor solvent incorporated into its crystal lattice (i.e., it is "non-solvated" or "anhydrous"). In some embodiments, the crystalline solid form of compound 1 contains water and / or a solvent in its crystal lattice (i.e., it is a hydrate and / or solvate, respectively). It will be recognized that solvates containing only a specific solvent (especially water) are suitable for drug development. Solvates containing other solvents may be useful, in particular, for manufacturing and / or testing, even if they are not permitted for use in approved pharmaceuticals.

[0049] In some embodiments, the disclosure provides compound 1 as a hydrate. In some embodiments, the disclosure provides compound 1 as an anhydride.

[0050] In some embodiments, the disclosure provides compound 1 as a solvate (for example, a solvate of acetic acid, acetone, cyclopentyl methyl ether, dichloromethane, dimethyl sulfoxide, di-n-butyl ether, ethyl acetate, methyl tert-butyl ether, N-methylpyrrolidone, trifluoroethanol, water, or any mixture thereof).

[0051] The structures shown for the form of compound 1 also mean that they include all tautomers of compound 1. Furthermore, the structures shown herein also mean that they include different compounds only in the presence of one or more isotopically enriched atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Except for carbon substitution by carbon-enriched carbon, compounds having the structure of the present disclosure are within the scope of the present disclosure.

[0052] Form A of Compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form A. In some embodiments, form A of compound 1 is a hydrate.

[0053] In some embodiments, morphology A of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20). In some embodiments, morphology A of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20). In some embodiments, morphology A of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20). In some embodiments, morphology A of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20). In some embodiments, morphology A of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20). In some embodiments, morphology A of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20).In some embodiments, morphology A of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20). In some embodiments, morphology A of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20). In some embodiments, form A of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.06 (±0.20).

[0054] In some embodiments, form A of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) that substantially correspond to all of the following: [Table 30]

[0055] In some embodiments, form A of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 3A (top spectrum).

[0056] Form B of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, which is referred to herein as form B. In some embodiments, form A of compound 1 is an anhydride (i.e., non-solvated).

[0057] In some embodiments, form B of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20). In some embodiments, form B of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20). In some embodiments, form B of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20). In some embodiments, form B of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20).In some embodiments, form B of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20). In some embodiments, form B of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20). In some embodiments, form B of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20). In some embodiments, form B of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20).In some embodiments, form B of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.67 (±0.20).

[0058] In some embodiments, form B of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 9.05, 9.09, 10.16, 12.85, 15.10, and 19.35 (±0.20). In some embodiments, form B of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 9.05, 9.09, 10.16, 12.85, 15.10, and 19.35 (±0.20). In some embodiments, form B of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 9.05, 9.09, 10.16, 12.85, 15.10, and 19.35 (±0.20). In some embodiments, form B of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 9.05, 9.09, 10.16, 12.85, 15.10, and 19.35 (±0.20). In some embodiments, form B of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 9.05, 9.09, 10.16, 12.85, 15.10, and 19.35 (±0.20). In some embodiments, form B of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 9.05, 9.09, 10.16, 12.85, 15.10, and 19.35 (±0.20).

[0059] In some embodiments, form B of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 31]

[0060] In some embodiments, morphology B of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 5. In some embodiments, morphology B of compound 1 is characterized by a TGA pattern substantially similar to that shown in Figure 6. In some embodiments, morphology B of compound 1 is characterized by a DSC pattern substantially similar to that shown in Figure 5.

[0061] Form C of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form C. In some embodiments, form C of compound 1 is a hydrate.

[0062] In some embodiments, form C of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20). In some embodiments, form C of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20). In some embodiments, form C of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20). In some embodiments, form C of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20). In some embodiments, form C of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20).In some embodiments, form C of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20). In some embodiments, form C of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20). In some embodiments, form C of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20). In some embodiments, form C of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.51 (±0.20).

[0063] In some embodiments, form C of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 32]

[0064] In some embodiments, morphology C of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 10. In some embodiments, morphology C of compound 1 is characterized by a TGA pattern substantially similar to that shown in Figure 11. In some embodiments, morphology C of compound 1 is characterized by a DSC pattern substantially similar to that shown in Figure 11.

[0065] Form D of Compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form D. In some embodiments, form D of compound 1 is acetone monosolvate.

[0066] In some embodiments, morphology D of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20). In some embodiments, morphology D of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20). In some embodiments, morphology D of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20). In some embodiments, morphology D of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20). In some embodiments, morphology D of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20). In some embodiments, morphology D of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20).In some embodiments, morphology D of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20). In some embodiments, morphology D of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20). In some embodiments, form D of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.32 (±0.20).

[0067] In some embodiments, form D of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 33]

[0068] In some embodiments, morphology D of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 14. In some embodiments, morphology D of compound 1 is characterized by a TGA pattern substantially similar to that shown in Figure 15. In some embodiments, morphology D of compound 1 is characterized by a DSC pattern substantially similar to that shown in Figure 15.

[0069] Form E of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form E. In some embodiments, form E of compound 1 is DMSO disolvate.

[0070] In some embodiments, form E of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20). In some embodiments, form E of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20). In some embodiments, form E of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20). In some embodiments, form E of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20). In some embodiments, form E of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20).In some embodiments, form E of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20). In some embodiments, form E of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20). In some embodiments, form E of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20). In some embodiments, form E of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.63 (±0.20).

[0071] In some embodiments, form E of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 34]

[0072] In some embodiments, morphology E of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 16.

[0073] Form F of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form F. In some embodiments, form F of compound 1 is an acetate monosolvate.

[0074] In some embodiments, form F of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20). In some embodiments, form F of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20). In some embodiments, form F of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20). In some embodiments, form F of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20). In some embodiments, form F of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20).In some embodiments, form F of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20). In some embodiments, form F of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20). In some embodiments, form F of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.81 (±0.20). In some embodiments, form F of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84 and 28.81 (±0.20).

[0075] In some embodiments, form F of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 35]

[0076] In some embodiments, morphology F of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 17. In some embodiments, morphology F of compound 1 is characterized by a TGA pattern substantially similar to that shown in Figure 18. In some embodiments, morphology F of compound 1 is characterized by a DSC pattern substantially similar to that shown in Figure 18.

[0077] Form G of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form G. In some embodiments, form G of compound 1 is ethyl acetate monosolvate.

[0078] In some embodiments, form G of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20). In some embodiments, form G of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20). In some embodiments, form G of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20). In some embodiments, form G of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20). In some embodiments, form G of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20).In some embodiments, form G of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20). In some embodiments, form G of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20). In some embodiments, form G of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20). In some embodiments, form G of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.02 (±0.20).

[0079] In some embodiments, morphology G of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 36]

[0080] In some embodiments, morphology G of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 22. In some embodiments, morphology G of compound 1 is characterized by a TGA pattern substantially similar to that shown in Figure 24. In some embodiments, morphology G of compound 1 is characterized by a DSC pattern substantially similar to that shown in Figure 24.

[0081] Form H of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form H. In some embodiments, form H of compound 1 is an anhydride (i.e., non-solvated).

[0082] In some embodiments, form H of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20). In some embodiments, form H of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20). In some embodiments, form H of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20). In some embodiments, form H of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20). In some embodiments, form H of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20). In some embodiments, form H of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20). In some embodiments, form H of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20).In some embodiments, form H of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.05 (±0.20).

[0083] In some embodiments, form H of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 37]

[0084] In some embodiments, morphology H of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 3B (second spectrum from the top). In some embodiments, morphology H of compound 1 is characterized by a TGA pattern substantially similar to that shown in Figure 25. In some embodiments, morphology H of compound 1 is characterized by a DSC pattern substantially similar to that shown in Figure 25.

[0085] Form I of Compound 1 In some embodiments, this disclosure provides a solid form of compound 1, which is referred to herein as form I. In some embodiments, form I of compound 1 is an anhydride (i.e., non-solvated).

[0086] In some embodiments, form I of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 3B (third spectrum from the top).

[0087] Form J of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form J. In some embodiments, form J of compound 1 is an MTBE monosolvate.

[0088] In some embodiments, morphology J of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20). In some embodiments, morphology J of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20). In some embodiments, morphology J of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20). In some embodiments, morphology J of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20). In some embodiments, morphology J of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20). In some embodiments, morphology J of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20). In some embodiments, form J of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20).In some embodiments, form J of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.73 (±0.20).

[0089] In some embodiments, form J of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) that substantially correspond to all of the following: [Table 38]

[0090] In some embodiments, morphology J of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 26.

[0091] Form K of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form K. In some embodiments, form K of compound 1 is Bu2O monosolvate.

[0092] In some embodiments, form K of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20). In some embodiments, form K of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20). In some embodiments, form K of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20). In some embodiments, form K of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20). In some embodiments, form K of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20).In some embodiments, form K of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20). In some embodiments, form K of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20). In some embodiments, form K of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20). In some embodiments, form K of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.47 (±0.20).

[0093] In some embodiments, form K of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 39]

[0094] In some embodiments, form K of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 27.

[0095] Form L of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form L. In some embodiments, form L of compound 1 is a DCM monosolvate.

[0096] In some embodiments, form L of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20). In some embodiments, form L of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20). In some embodiments, form L of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20). In some embodiments, form L of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20). In some embodiments, form L of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20). In some embodiments, form L of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20).In some embodiments, form L of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20). In some embodiments, form L of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20). In some embodiments, form L of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.65 (±0.20).

[0097] In some embodiments, form L of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 40]

[0098] In some embodiments, morphology L of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 28. In some embodiments, morphology L of compound 1 is characterized by a TGA pattern substantially similar to that shown in Figure 29. In some embodiments, morphology L of compound 1 is characterized by a DSC pattern substantially similar to that shown in Figure 29.

[0099] Form M of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form M. In some embodiments, form M of compound 1 is a CPME monosolvate.

[0100] In some embodiments, morphology M of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20). In some embodiments, morphology M of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20). In some embodiments, morphology M of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20). In some embodiments, morphology M of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20). In some embodiments, morphology M of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20). In some embodiments, morphology M of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20).In some embodiments, morphology M of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20). In some embodiments, morphology M of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20). In some embodiments, form M of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.63 (±0.20).

[0101] In some embodiments, form M of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 41]

[0102] In some embodiments, form M of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 30.

[0103] Form N of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form N. In some embodiments, form N of compound 1 is an NMP solvate.

[0104] In some embodiments, form N of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20). In some embodiments, form N of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20). In some embodiments, form N of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20). In some embodiments, form N of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20). In some embodiments, form N of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20).In some embodiments, form N of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20). In some embodiments, form N of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20). In some embodiments, form N of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.10 (±0.20). In some embodiments, form N of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86 and 27.10 (±0.20).

[0105] In some embodiments, form N of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 42]

[0106] In some embodiments, morphology N of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 31.

[0107] Form O of compound 1 In some embodiments, this disclosure provides a solid form of compound 1, referred to herein as form O. In some embodiments, form O of compound 1 is a TFE solvate.

[0108] In some embodiments, form O of compound 1 is characterized by one or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20). In some embodiments, form O of compound 1 is characterized by two or more peaks in its XRPD pattern, selected from the peaks 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20). In some embodiments, form O of compound 1 is characterized by three or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20). In some embodiments, form O of compound 1 is characterized by four or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20). In some embodiments, form O of compound 1 is characterized by five or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20).In some embodiments, form O of compound 1 is characterized by six or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20). In some embodiments, form O of compound 1 is characterized by seven or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20). In some embodiments, form O of compound 1 is characterized by eight or more peaks in its XRPD pattern, selected from the peaks at 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20). In some embodiments, form O of compound 1 is characterized by having peaks in its XRPD pattern at 2θ(°) = 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.96 (±0.20).

[0109] In some embodiments, form O of compound 1 is characterized by an XRPD pattern having diffraction at angles (2θ(°)±0.20) corresponding to substantially all of the following: [Table 43]

[0110] In some embodiments, form O of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 32.

[0111] Amorphous compound 1 In some embodiments, the present disclosure provides an amorphous form of compound 1.

[0112] In some embodiments, the amorphous form of compound 1 is characterized by an XRPD pattern substantially similar to that shown in Figure 35.

[0113] In some embodiments, the amorphous form of compound 1 is characterized by a DSC thermogram substantially similar to that shown in Figure 36.

[0114] In some embodiments, the Disclosure provides compositions comprising amorphous compound 1 having a median particle size (D50) of about 25 nm to about 150 nm. In some embodiments, the Disclosure provides compositions comprising amorphous compound 1 having a median particle size (D50) of about 25 nm to about 75 nm. In some embodiments, the Disclosure provides compositions comprising amorphous compound 1 having a median particle size (D50) of about 25 nm to about 50 nm. In some embodiments, the Disclosure provides compositions comprising amorphous compound 1 having a median particle size (D50) of about 25 nm to about 35 nm. In some embodiments, the median particle size (D50) is measured using a scanning electron microscope, for example, as described in Example 21.

[0115] In some embodiments, the amorphous form of compound 1 can be prepared by methods such as freeze-drying, melting, spray-drying, and precipitation from a supercritical fluid. In some embodiments, the amorphous form of compound 1 is prepared as described in Example 21.

[0116] Preparation of the provided solid form In some embodiments, the disclosure provides a method for preparing a crystalline solid form of compound 1.

[0117] In some embodiments, the solid form of compound 1 is prepared by mixing compound 1 (e.g., amorphous compound 1, crystalline compound 1, or a mixture thereof) with a suitable solvent under suitable conditions and then isolating the solid form of compound 1. In some embodiments, the solid form of compound 1 is prepared according to the methods described herein (e.g., slurry, rotational evaporation, fast evaporation, slow evaporation, crush precipitation by direct addition, crush precipitation by back addition, vapor diffusion, and / or heating). In some embodiments, the solid form of compound 1 is prepared according to the methods described in the examples herein.

[0118] In some embodiments, suitable solvents are acetic acid, acetone, chloroform, cyclopentyl methyl ether, dichloromethane, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, di-n-butyl ether, ethanol, ethyl acetate, methanol, methyl ethyl ketone, methyl tert-butyl ether, N-methylpyrrolidone, tert-amyl methyl ether, trifluoroethanol, water, or any mixture thereof. In some embodiments, suitable solvents are dimethylacetamide, dimethylformamide, dimethyl sulfoxide, ethanol, water, or any mixture thereof. In some embodiments, suitable solvents are a mixture of ethanol and water. In some embodiments, suitable solvents are supercritical carbon dioxide.

[0119] In some embodiments, a method for preparing the solid form of compound 1 includes the step of heating a mixture containing compound 1 to a suitable temperature. In some embodiments, a method for preparing the solid form of compound 1 includes the step of stirring a mixture containing compound 1 at ambient temperature. In some embodiments, a method for preparing the solid form of compound 1 includes the step of cooling a mixture containing compound 1 to a suitable temperature.

[0120] In some embodiments, a method for preparing the solid form of compound 1 includes the step of dissolving compound 1 in supercritical carbon dioxide at a high temperature (e.g., about 60°C to about 100°C) and high pressure (e.g., about 300 bar to about 600 bar). In some such embodiments, the method further includes the step of delivering the solution to a recovery container through a nozzle, as described, for example, in Example 21.

[0121] In some embodiments, the solid form of compound 1 precipitates or crystallizes from a mixture (e.g., a solution, suspension, or slurry). In some embodiments, the solid form of compound 1 precipitates or crystallizes from a mixture after cooling, addition of a poor solvent, and / or removal of all or part of the solvent by means of evaporation, distillation, filtration, etc.

[0122] In some embodiments, the method for preparing the solid form of compound 1 includes the step of isolating the solid form. It will be understood that the solid form of compound 1 can be isolated by any suitable means. In some embodiments, compound 1 is separated from the supernatant by filtration. In some embodiments, compound 1 is separated from the supernatant by decantation.

[0123] In some embodiments, the isolated solid form of compound 1 is dried (e.g., in air or under reduced pressure, and possibly at high temperatures).

[0124] In some embodiments, the solid form of compound 1 is prepared by converting one solid form of compound 1 into another solid form of compound 1.

[0125] In some embodiments, a method for preparing a solid form of compound 1 (e.g., form B of compound 1) includes slurring compound 1 in a mixture of ethanol and water (e.g., a 90:10 mixture of ethanol and water). In some embodiments, the method includes slurring compound 1 in a mixture of ethanol and water (e.g., a 90:10 mixture of ethanol and water) for about 10 days. In some embodiments, the method includes slurring compound 1 in a mixture of ethanol and water (e.g., a 90:10 mixture of ethanol and water) at ambient temperature.

[0126] composition In some embodiments, the Disclosure provides compositions comprising one or more solid forms of Compound 1. In some embodiments, the provided compositions comprise Form A of Compound 1, Form B of Compound 1, Form C of Compound 1, Form D of Compound 1, Form E of Compound 1, Form F of Compound 1, Form G of Compound 1, Form H of Compound 1, Form I of Compound 1, Form J of Compound 1, Form K of Compound 1, Form L of Compound 1, Form M of Compound 1, Form N of Compound 1, Form O of Compound 1, Form P of Compound 1, or Form Q of Compound 1, Amorphous Compound 1, or mixtures thereof.

[0127] In some embodiments, the Disclosure provides compositions comprising a solid form of Compound 1 (e.g., a solid form provided herein) that are substantially free of impurities. As used herein, the term “substantially free of impurities” means that the composition does not contain significant amounts of exogenous substances. Such exogenous substances may include different forms of Compound 1, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 1. In some embodiments, at least about 95% by weight of one form of Compound 1 is present. In some embodiments, at least about 96% by weight, about 97% by weight, or about 98% by weight of one form of Compound 1 is present. In some embodiments, at least about 99% by weight of one form of Compound 1 is present.

[0128] Unless otherwise specified, and when used herein in relation to a given value, the terms “about” and “approximately” refer to a value equivalent to the reference value in that context. Generally, a person skilled in the art familiar with the context will understand the magnitude of the relevant variation encompassed by “about” or “approximately” in that context. Unless otherwise specified, in some embodiments, the terms “about” or “approximately” may encompass a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% in either direction (above or below) the given reference value (except when such a number is less than 0% or greater than 100% of the possible values).

[0129] In some embodiments, the Disclosure provides compositions comprising a solid form of Compound 1 present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, with the percentage being based on the total weight of the composition. In some embodiments, the Disclosure provides compositions comprising a solid form of Compound 1, comprising about 3.0 area percent HPLC or less of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, about 1.5 area percent HPLC or less of total organic impurities relative to the total area of ​​the HPLC chromatogram. In some embodiments, compositions comprising a solid form of Compound 1 contain any single impurity of about 1.0 area percent HPLC or less, any single impurity of about 0.6 area percent HPLC or less, and in certain embodiments, any single impurity of about 0.5 area percent HPLC or less, relative to the total area of ​​the HPLC chromatogram.

[0130] In some embodiments, the Disclosure provides compositions comprising amorphous compound 1. In some embodiments, compositions comprising amorphous compound 1 are substantially free of crystalline compound 1. As used herein, the term “substantially free of crystalline compound 1” means that the composition does not contain a significant amount of crystalline compound 1. In some embodiments, at least about 95% by weight of amorphous compound 1 is present. In some embodiments, at least about 96% by weight, about 97% by weight, or about 98% by weight of amorphous compound 1 is present. In some embodiments, at least about 99% by weight of amorphous compound 1 is present.

[0131] In some embodiments, the Disclosure provides compositions comprising amorphous compound 1. In some embodiments, compositions comprising crystalline compound 1 are substantially free of amorphous compound 1. As used herein, the term “substantially free of amorphous compound 1” means that the composition does not contain a significant amount of amorphous compound 1. In some embodiments, at least about 95% by weight of crystalline compound 1 is present. In some embodiments, at least about 96% by weight, about 97% by weight, or about 98% by weight of crystalline compound 1 is present. In some embodiments, at least about 99% by weight of crystalline compound 1 is present.

[0132] In some embodiments, the Disclosure provides compositions comprising a specific crystalline form of compound 1 and substantially free of other crystalline forms of compound 1. For example, in some embodiments, a composition comprises form B of compound 1 that substantially free of other crystalline forms of compound 1 (e.g., form A, form C, form D, form E, form F, form G, form H, form J, form K, form L, form M, form N, form O, form P and / or form Q). As used herein, the term “substantially free of other crystalline forms of compound 1” means that the composition does not contain a significant amount of other crystalline forms of compound 1. In some embodiments, at least about 95% by weight of a specific crystalline form of compound 1 is present. In some embodiments, at least about 96% by weight, about 97% by weight, or about 98% by weight of a specific crystalline form of compound 1 is present. In some embodiments, at least about 99% by weight of a specific crystalline form of compound 1 is present.

[0133] In some embodiments, the Disclosure provides compositions comprising at least 1 g, 2 g, 5 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g, or 45 g of crystalline compound 1. In some embodiments, the Disclosure provides compositions comprising at least 1 g, 2 g, 5 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g, or 45 g of crystalline compound 1, wherein crystalline compound 1 is substantially a solid form selected from morphology A, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, and combinations thereof. In some embodiments, the Disclosure provides compositions comprising at least 1 g, 2 g, 5 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g, or 45 g of crystalline compound 1, wherein the crystalline compound 1 is substantially form B. In some embodiments, the Disclosure provides compositions comprising at least 1 g of form B of compound 1. In some embodiments, the Disclosure provides compositions comprising at least 5 g of form B of compound 1. In some embodiments, the Disclosure provides compositions comprising at least 10 g of form B of compound 1. In some embodiments, the Disclosure provides compositions comprising at least 20 g of form B of compound 1. In some embodiments, the Disclosure provides compositions comprising at least 40 g of form B of compound 1.

[0134] Pharmaceutical composition In some embodiments, the Disclosure provides pharmaceutical compositions comprising a combination of Compound 1 in any solid form described herein and a pharmaceutically acceptable excipient (e.g., a carrier). In some embodiments, the provided pharmaceutical composition is a solid composition. In some embodiments, the provided pharmaceutical composition is for oral administration.

[0135] As used herein, “pharmaceutically acceptable carrier” refers to a pharmaceutical additive such as a pharmaceutically or physiologically acceptable organic or inorganic carrier substance that is suitable for oral or parenteral administration and does not undesirably react with the active ingredient. Suitable pharmaceutically acceptable carriers include water and one or more excipients, disintegrants, lubricants, anti-adhesion agents, and / or antistatic agents. Such preparations may be sterilized and, if necessary, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or fragrances that do not undesirably react with the compounds and activators of this disclosure.

[0136] The pharmaceutical compositions provided may be in various forms, including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppositories, nasal sprays and / or inhalants, eye drops, intraocular injection forms, depot formulations, and injectable or intravenous solutions. Methods for preparing pharmaceutical compositions are well known in the art.

[0137] In some embodiments, the compounds provided are formulated as unit dosage forms for ease of administration and uniformity of dosage. As used herein, the term “unit dosage form” means a physically distinct unit of an activator (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of the active ingredient. In some embodiments, a unit dosage form contains the entire single dose of the drug. In some embodiments, multiple unit dosage forms are administered to give a total single dose. In some embodiments, administration of multiple unit dosage forms is required or expected to be required to achieve the intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active ingredients, a solid pharmaceutical composition (e.g., a tablet, capsule, etc.) containing a predetermined amount of one or more active ingredients, a sustained-release formulation containing a predetermined amount of one or more active ingredients, or a drug delivery device containing a predetermined amount of one or more active ingredients.

[0138] The compositions provided may be administered in any amount and in any dosage form that is effective in treating or reducing the severity of any of the diseases or disorders described herein.

[0139] use This disclosure provides uses of the solid forms and compositions described herein. In some embodiments, the provided solid forms and compositions are useful in pharmaceuticals (e.g., as therapeutic agents). In some embodiments, the provided solid forms are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0140] In some embodiments, the Disclosure provides a method for administering a provided solid form or composition to a subject requiring it. In some embodiments, the Disclosure provides a method for administering a provided solid form or composition to a subject having or being susceptible to a disease, disorder, or condition related to JAK2.

[0141] In some embodiments, compound 1 and its solid form are useful as JAK2 inhibitors. In some embodiments, compound 1 and its solid form are useful as type II JAK2 inhibitors. In some embodiments, the disclosure provides a method for inhibiting a target JAK2, comprising administering a provided solid form or composition. In some embodiments, the disclosure provides a method for inhibiting JAK2 in a biological sample, comprising contacting the sample with a provided solid form or composition.

[0142] JAKs (e.g., JAK2) have been shown to be involved in a variety of diseases, disorders, and conditions, including myeloproliferative neoplasms (Vainchenker, W. et al., F1000 Research 2018, 7 (F1000 Faculty Rev): 82), atopic dermatitis (Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1), 33-40), and acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (The Lancet. doi: 10.1016 / S0140-6736(20) 30628-0). Accordingly, in some embodiments, this disclosure provides a method for treating a disease, disorder, or condition of a subject requiring treatment of a disease, disorder, or condition related to JAK2, comprising administering a provided solid form or composition to a subject. In some embodiments, the disease, disorder, or condition is related to the overexpression of JAK2.

[0143] In some embodiments, the Disclosure provides a method for treating cancer, comprising administering a provided solid form or composition to a subject requiring treatment. In some embodiments, the Disclosure provides a method for treating proliferative disorders, comprising administering a provided solid form or composition to a subject requiring treatment.

[0144] In some embodiments, the Disclosure provides a method for treating a hematological malignancy, comprising administering a provided solid form or composition to a subject requiring treatment. In some embodiments, the hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia, or acute monocytic leukemia). In some embodiments, the hematological malignancy is lymphoma (e.g., Burkitt lymphoma, Hodgkin lymphoma, or non-Hodgkin lymphoma). In some embodiments, non-Hodgkin lymphoma is B-cell lymphoma. In some embodiments, non-Hodgkin lymphoma is NK / T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, the hematological malignancy is myeloma (e.g., multiple myeloma). In some embodiments, the hematological malignancy is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, the hematological malignancy is myelodysplastic syndrome.

[0145] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (including those associated with COVID-19) or atopic dermatitis), comprising administering a provided solid form or composition to a subject in need.

[0146] In some embodiments, the provided solid form or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” means a situation in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, two or more regimens may be administered simultaneously. In some embodiments, these regimens may be administered sequentially (e.g., all “doses” of the first regimen are administered before any dose of the second regimen is administered). In some embodiments, these agents are administered in overlapping drug regimens. In some embodiments, “administration” of a combination therapy may include the administration of one or more agents or modalities to a subject that is being administered other agents or modalities in the combination. For clarity, combination therapy does not require that individual agents be administered together (or even necessarily simultaneously) in a single composition, however, in some embodiments, two or more agents or their active portions may be administered together in a composite composition.

[0147] For example, in some embodiments, the provided solid form or composition is administered to a subject who is or has previously received one or more additional therapies (e.g., anticancer therapy, and / or therapies to address one or more side effects of such anticancer therapy, or otherwise to provide palliative care). Exemplary additional therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mibeblesiv), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of JAK2 inhibitors with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from patients with cutaneous T-cell lymphoma (Yumeen, S., et al., Blood Adv. 2020, 4(10), 2213-2226). The combination of a JAK2 inhibitor and an LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasm (Jutzi, JS, et al., HemaSphere 2018, 2(3), http: / / dx.doi.org / 10.1097 / HS9.0000000000000054). CXCR2 activity has been shown to modulate signaling pathways, including the JAK-STAT3 pathway, which are involved in tumor growth, angiogenesis, and / or metastasis (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl.4), S616-S628). [Examples]

[0148] Examples The following embodiments are for illustrative purposes only and are not intended to limit the scope of the Disclosure. [Table 44]

[0149] Equipment and methods AX-ray powder analysis (XRPD) PANalytical X'Pert Pro MPD Diffractometer - Transmission Geometry The selected XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident Cu beam generated by an Optix long fine focus light source. Cu Kα X-rays were focused onto the detector through the sample using an elliptically graded multilayer mirror. Prior to analysis, a silicon sample (NIST SRM 640f) was analyzed to confirm the location of the Si 111 peak. A portion of the sample was sandwiched between 3 μm thick films, and analysis was performed in a transmission configuration. A beam stop and short anti-scattering extensions were used to minimize background noise caused by air. Solar slits were used for both the incident and diffracted beams to minimize divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.5.5.

[0150] PANalytical X'Pert Pro MPD Diffractometer - Reflection Type XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident CuKα beam generated using a long fine-focus light source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano configuration. Data was collected and analyzed using Data Collector software v. 2.2b. Prior to analysis, a silicon sample (NIST SRM 640f) was analyzed to confirm that the observed location of the Si 111 peak matched the NIST-certified location. A portion of the sample was filled into a nickel-coated copper well. A scattering prevention slit (SS) was used to minimize background noise caused by air. Solar slits were used for the incident and diffracted beams to minimize spreading from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) placed 240 mm from the sample and Data Collector software V.2.2b. The pattern data acquisition parameters, including the divergence slit (DS) and incident beam scattering prevention slit (SS), are shown above the image in the data section of this report.

[0151] PANalytical's Empyrean diffractometer - transmission type configuration XRPD patterns were collected using a PANalytical Empyrean diffractometer with a Cu-line incident beam generated by a long fine-focus light source. Cu Kα-line X-rays were focused onto the detector through the sample using an elliptically graded multilayer mirror. Prior to analysis, a silicon sample (NIST SRM 640f) was analyzed to confirm that the observed position of the Si 111 peak matched the NIST-certified position. A portion of the sample was sandwiched between 3 μm thick films, and analysis was performed in a transmission configuration. A beam stop, short anti-scattering extension, and anti-scattering knife edge were used to minimize background noise caused by air. Solar slits were used for both the incident and diffracted beams to minimize divergence and asymmetry. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.5.5.

[0152] The figure containing the XRPD pattern was generated using the validated software P PatternMatch v.2.3.6.

[0153] The table below summarizes the specific numerical data collection parameters used in this specification. [Table 1-1] [Table 1-2]

[0154] B. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) DSC / TGA analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy were adjusted using indium, tin, and zinc, as well as phenyl salicylate, aluminum, and gold, and then validated with indium. The balance was validated with calcium oxalate. The sample was placed in an aluminum pan. The sample was sealed, a hole was made in the lid, and it was placed in a TG furnace. The furnace was heated under nitrogen at a flow rate of 50 mL / min. The sample was heated from 25°C to 350°C at a heating rate of 10°C / min.

[0155] C. Dynamic water vapor sorption (DVS) - specific equipment Adsorption / desorption data were collected using a Surface Measurement System DVS Intrinsic instrument. Samples were not dried before analysis. Adsorption and desorption data were collected under nitrogen purge in 10% RH increments over the range of 5% to 95% RH to 5% RH. The equilibrium criterion used for analysis was a change of less than 0.0100% by weight within 5 minutes over a maximum equilibrium time of 3 hours. Data on the initial water content of the samples were not collected. Example 1. Preparation of Compound 1 Synthesis of Compound 1 [ka]

[0156] A mixture of synthetic benzyl alcohol (102.3 g, 946.13 mmol, 1.0 equivalent) and cesium carbonate (768.7 g, 2365.3 mmol, 2.5 equivalents) in DMF (1000 mL) was stirred at room temperature for 2 hours. A DMF solution (500 mL) of 2-chloro-4-nitropyridine (150 g, 946.13 mmol, 1.0 equivalent) was added and stirred for 16 hours. This mixture was then poured into ice water, stirred, and the precipitated solid was collected by filtration and dried under vacuum to obtain compound 1.1. MS(ES): m / z 220.5 [M+H]+.

[0157] A 1500 mL solution of compound 1.2 (150 g, 682.85 mmol, 1.0 equivalent) in THF was degassed by bubbling with an argon stream for 10 minutes. To this solution, 2-dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane (32.55 g, 68.28 mmol, 0.1 equivalent) and tris(dibenzylideneacetone)dipalladium(0) (31.26 g, 34.14 mmol, 0.05 equivalent) were added, and the mixture was degassed for another 10 minutes. A lithium bis(trimethylsilyl)amide solution (1 M in THF, 1365 mL, 1365.7 mmol, 2.0 equivalents) was added, and the reaction mixture was stirred at 60°C for 1 hour. This was concentrated under reduced pressure. The residue was slowly added to ice and 6N hydrochloric acid (1500 mL) and extracted with ethyl acetate. The aqueous layer was separated, neutralized with solid sodium bicarbonate, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.2. MS(ES): m / z 201.2 [M+H] + This was used in the next process without purification.

[0158] Synthesis of Compound 1.3: To a methanol solution (1000 mL) of Compound 1.2 (100 g, 499 mmol, 1.0 equivalent), di-tert-butyl dicarbonate (130.5 g, 598.8 mmol, 1.2 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the precipitated solid was removed by filtration, rinsed with methanol, and dried under vacuum to obtain Compound 1.3. MS(ES): m / z 259.2 [M+H] +

[0159] Synthesis of Compound 1.4: A mixture of Compound 1.3 (106 g, 410.4 mmol, 1.0 equivalent) and 10% palladium-carbon (100 g) was stirred in methanol (1000 mL) under hydrogen (1 atm) for 1 hour. This was filtered through a Celite® pad and rinsed with methanol. The filtrate was concentrated under reduced pressure to obtain Compound 1.4. MS(ES): m / z 169.1 [M+H] +

[0160] Synthesis of Compound 1.5 To a solution of 1.4 (66 g, 392.5 mmol, 1.0 equivalent) in DMF (660 mL) was added Int-1 (64.55 g, 314 mmol, 0.8 equivalent), followed by sodium carbonate (124.8 g, 1177.5 mmol, 3.0 equivalents). The synthesis of Int-1 is described in WO2021 / 226261. The reaction mixture was stirred at 60 °C for 3 hours. This was poured into ice water, and the precipitated solid was collected by filtration and dried under vacuum to obtain 1.5. MS(ES): m / z 354.5 [M+H] +

[0161] Synthesis of Compound 1.6 To a solution of 1.5 (56 g, 158.3 mmol, 1.0 equivalent) dissolved in ethanol (800 mL) and water (300 mL) was added iron powder (44.3 g, 791.5 mmol, 5.0 equivalents), followed by acetic acid (47.49 g, 791.5 mmol, 5.0 equivalents). The reaction mixture was stirred at 90 °C for 2 hours. This was cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (in DCM, 7.0% methanol) to obtain 1.6. MS(ES): m / z 324.5 [M+H] +

[0162] Synthesis of Compound 1.7 To a solution of 1.6 (38 g, 117.38 mmol, 1.0 equivalent) and Int-2 (41.23 g, 176 mmol, 1.5 equivalents) in THF (1300 mL) was added potassium tert-butoxide (1 M in THF, 704 mL, 704.28 mmol, 6.0 equivalents) at 0 °C. The synthesis of Int-2 is described in WO2021 / 226261. The reaction mixture was stirred at room temperature for 1 hour. This was poured into ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (CombiFlash®, in DCM, 12% methanol) to obtain 1.7. MS(ES): m / z: 524.2 [M+H] +

[0163] Synthesis of Compound 1.8: Zinc (0.012 g, 0.190 mmol, 0.2 equivalents) and zinc cyanide (0.056 g, 0.477 mmol, 0.5 equivalents) were added to DMA solution (11 mL) of Compound 1.7 (0.500 g, 0.954 mmol, 1.0 equivalent). The reaction mixture was degassed by bubbling with an argon stream for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol, 0.15 equivalents) and 1,1'-bis(diphenylphosphin)ferrocene (0.158 g, 0.286 mmol, 0.3 equivalents) were added, and the mixture was degassed for 5 minutes. The reaction mixture was stirred in a microwave reactor at 190°C for 2 hours. This was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the substance.

[0164] Synthesis of Compound 1: To a THF solution (2 mL) of 1.8 (0.040 g, 0.087 mmol, 1.0 equivalent) and dimethylcarbamate chloride (0.010 g, 0.096 mmol, 1.1 equivalents), potassium tert-butoxide (1 M in THF) (0.52 mL, 0.522 mmol, 6.0 equivalents) was added at 0°C and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CombiFlash®, 2.5% methanol in DCM) to obtain Compound 1.

[0165] Preparation of Lot I Lot I was prepared in the same manner as described above, with the final step carried out as follows: Dimethylcarbamate chloride (10.9 g, 101.9 mmol, 2.5 equivalents) was added to a 1.8 (18.6 g, 40.7 mmol, 1.0 equivalent) tetrahydrofuran solution (380 mL), followed by potassium tert-butoxide (1 M in tetrahydrofuran) (244 mL, 244 mmol, 6 equivalents) at 0°C, and the mixture was stirred at the same temperature for 15 minutes. After the reaction was complete, the reaction mixture was transferred to ice water, and the product was extracted with ethyl acetate (1000 mL x 2). The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure at 45°C to obtain the crude substance. The crude substance was purified by column chromatography using methanol in dichloromethane as the mobile phase. The product was eluted in dichloromethane with 2.5% to 3.0% methanol to obtain 12.3 g of solid material. The obtained solid material was stirred in methanol (100 mL) at room temperature for 30 minutes. After stirring for 30 minutes, the solid was filtered, and the resulting solid (11.01 g) was stirred in ethyl acetate (100 mL) at room temperature for 30 minutes. After stirring for 30 minutes, the solid was filtered and washed with diethyl ether (50 mL) and pentane (50 mL). The solid was dried under reduced pressure at 65 °C for 2 hours to obtain 10.05 g of compound 1 (yield: 46.75%).

[0166] Preparation of Lot II Lot II was prepared in the same manner as described above, with the final step carried out as follows: Dimethylcarbamate chloride (28.2 g, 282.5 mmol, 1.5 equivalents) was added to 1600 mL of 1.8 (80 g, 175.0 mmol, 1.0 equivalent) tetrahydrofuran solution, followed by potassium tert-butoxide (1 M in tetrahydrofuran) (796 mL, 796.0 mmol, 4.55 equivalents) at 0°C, and the mixture was stirred at the same temperature for 15 minutes. After the reaction was complete, the reaction mixture was transferred to ice water, and the product was extracted with ethyl acetate (500 mL x 2). The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure at 45°C to obtain the crude substance. The crude substance was purified by column chromatography using methanol in dichloromethane as the mobile phase. The product was eluted with 2.5-3.0% methanol in dichloromethane to obtain 46.9 g of solid material. The obtained solid was stirred in methanol (100 mL) at room temperature for 30 minutes. After stirring for 30 minutes, the solid was filtered, and the resulting solid (51 g) was stirred in ethyl acetate (100 mL) at room temperature for 30 minutes. After stirring for 30 minutes, the solid was filtered and washed with diethyl ether (50 mL) and pentane (50 mL). The solid was dried under reduced pressure at 65 °C for 2 hours to obtain 46.3 g of compound 1 (yield: 51.93%).

[0167] Example 2. Characterization of Compound 1 (Lots I and II) In the following examples, lots I and II of compound 1 were used as starting materials. The XRPD patterns of lots I and II showed well-resolved peaks characteristic of crystalline materials (Figure 1). The XRPD patterns of lots I and II were unindexable, suggesting that the material was not composed of a single crystal phase but was likely a mixture of multiple crystalline phases. As further described below, the XRPD pattern of lot I was found to be consistent with a mixture of morphology B and morphology C. Further unidentified peaks were also present in the XRPD pattern of lot I. The XRPD pattern of lot II was consistent with morphology B, with several small unidentified peaks.

[0168] The peak positions and integral values ​​in the proton NMR spectrum of Lot I were consistent with the chemical structure of Compound 1. The presence of ethyl acetate (0.03 mol, 0.5%) was confirmed based on the presence of a 1.18 ppm triplet and a 1.99 ppm singlet. Trace amounts of DCM, methanol, and several unidentified impurities were also present in the spectrum.

[0169] The DSC thermogram of Lot I showed a small endothermic phase with a peak maximum at 255.7°C, followed by a large endothermic phase with a peak maximum at 281.5°C and an onset at 275.7°C (Figure 2). The TGA curve showed a 0.45% weight loss between 45°C and 150°C, which is likely related to the release of residual solvent.

[0170] Rough solubility estimate The approximate solubility of Lot I of Compound 1 was estimated by the solvent addition method and visual observation (Table 2.1). Various solvents or solvent mixtures were added to the measured amount of Lot I of Compound 1 while stirring at ambient temperature. The approximate solubility was calculated based on the total amount of solvent used to obtain the solution, determined by visual observation. Actual solubility may be higher due to the volume of solvent used or the slow dissolution rate. If dissolution did not occur as determined by visual evaluation, the value was recorded as "<". If dissolution occurred with the initial amount, the value was recorded as ">".

[0171] Lot I of compound 1 showed the highest solubility (over 59 mg / mL) in acetic acid, moderate solubility (17 mg / mL) in TFE, and limited solubility (1–8 mg / mL) in acetone, chloroform, MEK, and the aprotic solvents DMSO, DMAc, and NMP. Substantially no solubility was observed in most common organic solvents and water. Addition of 10% water to acetone, ethanol, and methanol slightly increased solubility (1–2 mg / mL). Approximate solubility estimates were used to design experimental conditions for polymorphism screening experiments.

[0172] Table 2.1 summarizes the experimental results for estimating solubility. [Table 2-1] [Table 2-2]

[0173] Example 3. Polymorphic screening of compound 1 Slurry experiment Lot I of Compound 1 was used as the starting material in a series of slurry experiments. Generally, a slurry of Lot I of Compound 1 (approximately 50 mg) was prepared by adding Lot I of Compound 1 to a specific solvent or solvent mixture at ambient temperature or high temperature, ensuring that some undissolved solid remained. The resulting suspension was then stirred for an extended period, and the solid was collected and analyzed. The experimental conditions and results are shown in detail in Table 3.1.

[0174] When approximately 15 slurries were prepared at ambient temperature, the majority were mixtures of crystalline phases. Five of the slurries produced solids with indexable XRPD patterns, indicating that these materials are mainly composed of single-crystal phases.

[0175] Form B of compound 1 was the most frequently observed form in slurry experiments, indicating that form B is a stable, anhydrous form at ambient temperature. Form B was also observed as a single phase in organic solvent / water mixtures with water activity up to 0.49 or 49% RH. Other forms isolated during slurry experiments included forms D, E, F, and N, all of which appeared to be solvated. [Table 3-1]

[0176] Additional polymorphic screening An additional polymorph screening was performed. This screening consisted of 10 solution-based experiments using various crystallization methods, including evaporation (rotary, high-speed, and low-speed under ambient conditions), crush precipitation (direct or by reverse poor solvent addition), and vapor diffusion. Illustrative procedures for each method are as follows:

[0177] Rotary evaporation method (RE): A solution of compound 1 (approximately 50 mg) was prepared in a solvent system at ambient temperature. The solution was filtered and evaporated to dryness using a rotary evaporator. The solid was subjected to XRPD analysis.

[0178] Fast evaporation (FE): A solution of compound 1 (approximately 50 mg) was prepared in solvents or solvent systems at different ambient temperatures. The solution was evaporated from an open vial under ambient conditions. The solid was subjected to XRPD analysis.

[0179] Slow evaporation method (SE): A solution of compound 1 (approximately 50 mg) was prepared in solvents or solvent systems at different ambient temperatures. The solution was evaporated under ambient conditions from a vial sealed with perforated aluminum foil. The solid was subjected to XRPD analysis.

[0180] Crush precipitation (CP) or solvent / poor solvent addition-direct addition method: A solution of compound 1 (approximately 50 mg) was prepared in a specific solvent or solvent combination, and the poor solvent was added gradually. The resulting suspension was stirred at ambient temperature, and the solid was isolated. The solid was subjected to XRPD analysis.

[0181] Crush precipitation (CP) method or solvent / poor solvent addition-reverse solvent method: Solutions of compound 1 (approximately 50 mg) were prepared in solvents at different ambient temperatures and filtered into a large volume of poor solvent at ambient temperature. The resulting solid was subjected to XRPD analysis.

[0182] Vapor diffusion method: A solution of compound 1 (approximately 50 mg) was prepared in a solvent system at ambient temperature. The solution was filtered into a new vial. Each vial was placed open in a larger chamber containing the reverse solvent. The chamber was closed to allow vapor diffusion.

[0183] In most experiments, a mixture of crystalline phases was produced. The experimental conditions and results are shown in detail in Table 3.2. [Table 3-2]

[0184] Diffraction experiment In a series of exposure experiments, lot I of compound 1 was exposed to high relative humidity. Typically, about 50 mg of compound 1 was transferred to a vial, and each vial was placed in a chamber containing saturated aqueous solutions of different salts known to produce different relative humidity levels within the chamber. For example, see “Standard Practice for Maintaining Constant Relative Humidity by Means of Aqueous Solutions” ASTM Standard E 104-85 (1996); “Humidity Fixed Points of Binary Saturated Aqueous Solutions” Greenspan, LJ Res. Natl. Bur. Stand., Sect. A 1997, 81A, 89-96; “Saturated Salt Solutions for Maintaining Specified Relative Humidities” Nyqvist, HE Int. J. Pharma. Technol. Prod. Manuf. 1983, 4, 47-48; and “Evaluation of Relative Humidity Values ​​for Saturated Aqueous Salt Solutions Using Osmotic Coefficients Between 50 and 100℃” Moisture Humidity, Proc. Int. Symp. 1985, 577-96.

[0185] Although various forms of mixtures were produced during the exposure experiment, no single-crystal phase of the hydrated material was formed through the experiment. The experimental conditions and results are shown in detail in Table 3.3. [Table 3-3]

[0186] Scale-up experiment To produce large quantities of the specific solid forms described herein, scale-up slurry experiments were performed. Generally, a slurry of compound 1 (approximately 400-600 mg) was prepared by adding compound 1 to a specific solvent or solvent mixture at ambient temperature or high temperature, ensuring that undissolved solids were present. The resulting suspension was then stirred for an extended period, and the solids were collected and analyzed.

[0187] As summarized in Table 3.4, scale-up slurry experiments targeting form B, form C, form D, and form F of compound 1 were carried out without any problems. [Table 3-4]

[0188] Several scale-up vapor diffusion experiments targeting compound 1 (morph G) were successfully conducted. A solution of compound 1 (approximately 400-600 mg) was prepared in a solvent system at ambient temperature. The solution was filtered into a new vial. Each vial was placed open in a larger chamber containing the reverse solvent. The chamber was then closed to allow vapor diffusion.

[0189] In one of the experiments, morphology G containing extremely small amounts of morphology P was produced. The results of the scale-up vapor diffusion experiment are summarized in Table 3.5. [Table 3-5]

[0190] Heating experiment For the purpose of obtaining anhydrous and non-solvated materials, heating experiments were conducted on the solvated and hydrated forms based on the thermal data of each form. Through these heating experiments, mixtures of crystalline materials such as Form B and Form I, or Form H and Form I were obtained. No single crystal phase material was produced by these heating experiments. The results of the heating experiments are summarized in Table 3.6.

Table 3-6

[0191] Solvent-based conversion experiments For the purpose of obtaining anhydrous and non-solvated substances, solvent-based conversion experiments on the solvated form were carried out in a bulky solvent. Generally, a slurry of Compound 1 (approximately 50 mg) was prepared by adding Compound 1 to a specific solvent or solvent mixture at ambient temperature or elevated temperature such that undissolved solid remained. The resulting suspension was then stirred for a long time, and the solid was recovered and analyzed. The experimental conditions are shown in detail in Table 3.7.

[0192] In most of these experiments, mixtures of Form B and Form H and / or Form I, or novel solvated materials such as Form J, Form K, and Form M were obtained. Form H was obtained as a solid showing an XRPD pattern characteristic of a crystalline material, but could not be indexed due to its disorder.

Table 3-7

[0193] Conclusion Overall, when approximately 75 experiments were conducted as part of the polymorph screening activity, 18 new crystal phases were generated (see Figures 3A, 3B, and 3C). Among the XRPD patterns of 12 of them, indexing was possible, indicating that each is mainly composed of a single crystal phase or only a single crystal phase. The discovery of so many new crystal phases supports the fact that Compound 1 has a strong tendency to polymorph, that is, to form anhydrates, hydrates, and solvates characteristic of a complex phase space.

[0194] Figure 33 shows an overview of the various forms of Compound 1 identified in these experiments.

[0195] Example 4. Interconversion Slurry Experiments Interconversion slurry experiments were conducted using Form B of Compound 1, Form H of Compound 1, and Form I of Compound 1 for the purpose of determining the most stable anhydrous form at various temperatures including ambient temperature.

[0196] Mixtures of Form H and Form I with Form B were used in these interconversion slurry experiments. The experimental conditions are shown in detail in Table 4.1. The interconversion slurry experiments were carried out in different solvents and solvent mixtures at ambient temperature and high temperature (65 °C). The slurry at any temperature yielded Form B, but the solid obtained from the high-temperature slurry experiment showed an additional small peak at 2θ = approximately 8.0° (Figure 4). HPLC analysis of the material containing Form B and the small peak at 2θ = approximately 8.0° showed a small amount of decomposition of Compound 1, suggesting that the small peak represents an unidentified decomposition product.

[0197] The results of the interconversion slurry experiments showed that no forms other than Form B occurred from the experiments at ambient temperature and high temperature. Form B is considered to be the most stable anhydrous form under the tested conditions. [Table 4]

[0198] Example 5. Form A of Compound 1 Form A of Compound 1 was prepared by vapor diffusion of a solution of Compound 1 (approximately 50 mg) in MeOH:DCM (1:3, v / v) in the vapor of ethyl acetate. The solid was isolated and analyzed.

[0199] Figure 3A (the top spectrum) shows the XRPD spectrum of Form A of Compound 1. The XRPD data corresponding to Form A of Compound 1 are summarized in Table 5.1. [Table 5]

[0200] Example 6. Form B of Compound 1 Form B was observed in lot I and lot II of compound 1. Furthermore, as detailed in Table 3.1, form B was prepared by slurring compound 1 in DMA, DMF, DMSO:H2O=85:15 (v / v), or EtOH:H2O=90:10 (v / v) for 5 to 11 days.

[0201] Figure 5 shows the XRPD spectrum of compound 1 in form B. The XRPD pattern of form B exhibited high-intensity, well-resolved peaks characteristic of crystalline materials. The XRPD pattern of form B can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is characteristic of anhydrous / non-solvated materials. The XRPD data corresponding to compound 1 in form B is summarized in Table 6.1. [Table 6-1] [Table 6-2]

[0202] The peak positions and integral values ​​in the proton NMR spectrum of compound B, prepared in ethanol:water = 90:10 (v / v), were consistent with the chemical structure of compound 1. Trace amounts of ethanol and ethyl acetate were also detected in the spectrum.

[0203] The DSC thermogram of morphology B, obtained from a slurry in ethanol:water = 90:10 (v / v), showed a large endothermic effect with a peak maximum at 285.2°C and an onset at 278.7°C (Figure 6). The TGA curve showed a small weight loss of approximately 0.04% from 54°C to 150°C, indicating the anhydrous / non-solvate properties of morphology B (Figure 6).

[0204] The DVS experiment was conducted in Form B (Figure 7 and Table 6.2). No weight change was observed during equilibration at 5% RH. Subsequently, the material showed a small weight gain of 0.43% at 5 - 95% RH, but decreased during the desorption process from 95 - 5% RH. The slight weight change during the sorption / desorption process indicated that Form B is non - hygroscopic. The XRPD pattern of the sample after DVS was consistent with Form B (Figure 8), suggesting that Form B did not change during the DVS experiment.

Table 6 - 3

[0205] The stability stress test was performed on Form B by exposing each sample to three conditions: 57.5% RH / RT, 97.3% RH / RT, and 75% RH / 40 °C, and collecting XRPD data at two time points (14 days and 28 days). The experimental conditions are summarized in Table 6.3. The samples analyzed under all conditions and at all time points were consistent with Form B, suggesting that Form B is stable under the stress conditions tested during the test period.

Table 6 - 4

[0206] When the slurrying of Form B was carried out in water at ambient temperature for 5 days, Form B did not change as determined by XRPD analysis (Figure 9).

[0207] Based on the above characteristic evaluation data, Form B was designated as the anhydrous, non - solvated form of Compound 1.

[0208] Example 7. Form C of Compound 1 As described in Table 3.7, Form C of Compound 1 was obtained by slurrying Form F of Compound 1 in water at ambient temperature for 3 days.

[0209] Figure 10 shows the XRPD spectrum of compound 1 in form C. The XRPD pattern of form C exhibited high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form C can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is thought to be able to contain up to 3-4 water molecules per molecule of compound 1. The XRPD data corresponding to compound 1 in form C is summarized in Table 7.1. [Table 7-1] [Table 7-2]

[0210] The peak positions and integral values ​​of the proton NMR spectrum of morphology C were consistent with the chemical structure of compound 1. Trace amounts of acetic acid and other unidentified impurities were observed in the spectrum.

[0211] The DSC thermogram showed a broad endothermic pattern with a peak maximum at 143.7°C, followed by exothermic reactions with a peak maximum at 190.5°C and an initial point at 187.1°C (Figure 11). The DSC thermogram also observed endothermic reactions with a peak maximum at 277.2°C and an initial point at 265.2°C. The TGA curve showed a broad endothermic pattern with a 5.8% weight loss from 54°C to 180°C, corresponding to 1.8 moles of H2O (Figure 11).

[0212] DVS experiments were performed on morphology C (Figure 12 and Table 7.2). No weight change was observed during equilibration at 5% RH. Subsequently, the material showed a rapid weight increase of 1.74% (0.5 mol H2O, total 2.3 mol H2O) at 5–25% RH, followed by a slight and gradual increase to 2.6% (0.8 mol H2O; total 2.6 mol H2O) at 95% RH, but this was lost during the desorption process at 95–5% RH, leaving 1.8 mol of water in the resulting DVS material. The XRPD pattern of the post-DVS sample was consistent with morphology C, with a slight peak shift (Figure 13), suggesting a slight change in the water content of morphology C during the DVS experiment. [Table 7-3]

[0213] Based on the above characterization data, form C was designated as the hydrated form of compound 1.

[0214] Example 8. Form D of Compound 1 Form D of compound 1 was prepared by slurring compound 1 in acetone at ambient temperature for 11 days, as shown in Table 3.1.

[0215] Figure 14 shows the XRPD spectrum of compound 1 in form D. The XRPD pattern of form D showed high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form D can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is thought to be able to contain up to three acetone molecules per molecule of compound 1. The XRPD data corresponding to compound 1 in form D is summarized in Table 8.1. [Table 8-1] [Table 8-2]

[0216] The peak positions and integral values ​​of the proton NMR spectrum of morphology D were consistent with the chemical structure of compound 1. Trace amounts of acetone and other unidentified impurities were detected in the sample.

[0217] The DSC thermogram of morphology D showed a small exothermic reaction at 142.2°C, followed by a small endothermic reaction with a peak value at 257.5°C and an initial point at 252.2°C, and then a large endothermic reaction with a peak value at 274.7°C and an initial point at 268.7°C (Figure 15). The TGA curve showed a weight loss of 10.05% from 53°C to 165°C, which corresponds to 1.015 moles of acetone (Figure 15).

[0218] Based on the above characterization data, form D was identified as the acetone monosolvate of compound 1.

[0219] Example 9. Form E of Compound 1 Form E of compound 1 was prepared by slurring compound 1 in DMSO at ambient temperature for 5 days, as shown in Table 3.1.

[0220] Figure 16 shows the XRPD spectrum of compound 1 in form E. The XRPD pattern of form E exhibited high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form E can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is thought to be able to contain up to two DMSO molecules per molecule of compound 1. The XRPD data corresponding to compound 1 in form E is summarized in Table 9.1. [Table 9]

[0221] The peak positions and integral values ​​of the proton NMR spectrum of morphology E were consistent with the chemical structure of compound 1. The 2.54 ppm singlet indicated the presence of approximately 2.1 moles of DMSO in the material. Trace amounts of unidentified impurities were also observed.

[0222] Based on the above characterization data, form E was designated as the disolvate of compound 1.

[0223] Example 10. Form F of Compound 1 Form F of compound 1 was prepared by slurring compound 1 in acetic acid:water (30:70, v / v) at ambient temperature for 7 days, as shown in Table 3.1.

[0224] Figure 17 shows the XRPD spectrum of compound 1 in form F. The XRPD pattern of form F exhibited high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form F could be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexed solution, this unit cell is thought to be able to contain one molecule of acetic acid per molecule of compound 1. The XRPD data corresponding to compound 1 in form F is summarized in Table 10.1. [Table 10-1] [Table 10-2]

[0225] The peak positions and integral values ​​of the proton NMR spectrum of morphology F matched the chemical structures of compound 1 and acetic acid in a 1:1 molar ratio. Trace amounts of ethanol and several unidentified impurities were also present in the spectrum.

[0226] The DSC thermogram showed a broad endothermic pattern with a peak maximum at 187.5°C and an onset at 176.4°C, followed by another endothermic pattern with a peak maximum at 276.0°C and an onset at 269.3°C (Figure 18). The TGA curve showed no weight loss up to 130°C (Figure 18). The 11.1% weight loss between 130°C and 205°C was accompanied by a broad endothermic pattern and is likely due to the release of acetic acid. The 11.1% weight loss corresponded to 1.09 moles of acetic acid.

[0227] Morphology F was analyzed by DVS experiments (Figure 19 and Table 10.2). A slight weight change was observed during equilibration at 5% RH. A slight weight increase of 0.3% during the absorption process from 5 to 95% RH and a weight loss of 0.5% during the desorption process from 95 to 5% RH indicated a non-hygroscopic material. The XRPD pattern of the sample after DVS was consistent with morphology F (Figure 20), suggesting that morphology F did not change during the DVS experiment. [Table 10-3]

[0228] Form F appeared to be substantially insoluble in water (<1 mg / mL).

[0229] Form F completely transformed into form C by slurring in water at ambient temperature for 3 days (Figure 21), suggesting that form F is likely acetic acid monosolvate rather than monoacetate.

[0230] Based on the above characterization data, form F was designated as the acetic acid monosolvate of compound 1.

[0231] Example 11. Form G of Compound 1 As shown in Table 3.2, form G of compound 1 was obtained from vapor diffusion experiments of a solution of compound 1 in MeOH:DCM (1:3, v / v) exposed to ethyl acetate vapor.

[0232] Figure 22 shows the XRPD spectrum of compound 1 in form G. The XRPD pattern of form G exhibited high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form G can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is thought to be able to contain two siRNA molecules per molecule of compound 1. The XRPD data corresponding to compound 1 in form G is summarized in Table 11.1. [Table 11]

[0233] Proton NMR characterization was performed on samples containing morphology G and trace amounts of morphology P (Figure 23, sample 3.5.4 from Table 3.5). The peak positions and integral values ​​in the proton NMR spectra were consistent with the chemical structure of compound 1. The following solvents were also present: 1.08 molars of  (15.3%), 0.21 molars (1.3%) of MeOH, and 0.19 molars (3.0%) of DCM.

[0234] DSC / TGA characterization was performed on samples containing morphology G and trace amounts of morphology P (Figure 23, sample 3.5.4 from Table 3.5). The DSC thermogram showed a broad endothermic range at 117.2°C, followed by a shoulder at 275.1°C, and a large endothermic peak at 284.5°C (Figure 24). The TGA curve showed a weight loss of 13.2% from 47°C to 180°C. This weight loss is associated with broad endothermic ranges and likely solvent release from the sample due to dimethyl release, but small amounts of MeOH and DCM were also present in the sample, as determined by NMR (Figure 24).

[0235] Based on the above characterization data, form G was designated as the ethyl acetate monosolvate of compound 1.

[0236] Example 12. Form H of Compound 1 As shown in Table 3.7, form G of compound 1 was slurryed in TAME at 50°C for 4 days, followed by slurrying in TAME at ambient temperature for 6 days to obtain form H of compound 1. Form H of compound 1 obtained by this method had a disordered structure. Slurrying form H of compound 1 in EtOH:H2O (90:10, v / v) at ambient temperature for 3 days did not improve the degree of crystallinity.

[0237] Figure 3B (second spectrum from the top) shows the XRPD spectrum of compound 1, form H. The XRPD pattern of form H exhibits high-intensity, broad peaks characteristic of disordered crystalline materials, and its indexing was not possible. Compound 1. The XRPD data corresponding to form H of compound 1 is summarized in Table 12.1. [Table 12]

[0238] The peak positions and integral values ​​of the proton NMR spectrum of compound 1 (form H) were consistent with the chemical structure of compound 1. Trace amounts of ethanol and TAME, as well as several unidentified impurities, were also present in the spectrum.

[0239] The DSC thermogram showed endothermic activity with a peak maximum at 272.2°C and an onset at 264.9°C (Figure 25). The TGA curve showed a small weight loss of 0.3% between 42°C and 160°C, which is likely related to the release of residual solvent (Figure 25).

[0240] Based on the above characterization data, form H was designated as the anhydrous / non-solvated form of compound 1. Form H was confirmed to be a metastable anhydrous form relative to form B at ambient temperatures of ~65°C.

[0241] Example 13. Form I of Compound 1 Form I of compound 1 was obtained as a mixture with form F and / or form H by heating form A, form D, or form G of compound 1 (as described in Table 3.6), or by solvent-based slurrying of form D or form G of compound 1 in a bulky solvent such as Bu2O, CPME, or TAME (Table 3.7).

[0242] Figure 3B (third spectrum from the top) shows the XRPD spectrum of form I of compound 1 as a mixture with form H of compound 1, obtained by heating form D of compound 1 to 195°C.

[0243] Based on the various methods used to prepare form I of compound 1, it was determined that form I of compound 1 is likely to be the anhydrous form of compound 1.

[0244] A mixture of compound 1 in form H and compound 1 in form I was used in an interconversion slurry experiment with form B. It was confirmed that compound 1 in form I is a metastable form relative to form B at ambient temperatures of ~65°C.

[0245] Example 14. Form J of Compound 1 As shown in Table 3.7, form J of compound 1 was obtained by slurring form F of compound 1 in water at ambient temperature for 6 days.

[0246] Figure 26 shows the XRPD spectrum of compound 1 in form J. The XRPD pattern of form J showed high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form J can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is thought to be able to contain up to two MTBE molecules per molecule of compound 1. The XRPD data corresponding to form J of compound 1 is summarized in Table 14.1. [Table 14-1] [Table 14-2]

[0247] The peak positions and integral values ​​of the proton NMR spectrum of morphology J were consistent with the chemical structure of compound 1. The 1.10 ppm and 3.08 ppm singlets in the spectrum indicated approximately 0.74 moles of MTBE present in the material.

[0248] Based on the above characterization data, form J of compound 1 was specified as the MTBE monosolvate of compound 1.

[0249] Example 15. Form K of Compound 1 As shown in Table 3.7, form K of compound 1 was obtained by slurring form D of compound 1 in Bu2O at 35°C for 5 days.

[0250] Figure 27 shows the XRPD spectrum of compound 1 in form K. The XRPD pattern of form K exhibited high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form K can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is thought to be able to contain one molecule of Bu2O per molecule of compound 1. The XRPD data corresponding to form K of compound 1 is summarized in Table 15.1. [Table 15]

[0251] The peak positions and integral values ​​of the proton NMR spectrum of morphology K were consistent with the chemical structure of compound 1. The 0.86 ppm triplet and 1.27–1.48 ppm multiplets in the spectrum indicated approximately 0.8 moles of Bu2O present in the sample.

[0252] Based on the above characterization data, form K of compound 1 was designated as the Bu2O monosolvate of compound 1.

[0253] Example 16. Form L of Compound 1 As shown in Table 3.1, form L of compound 1 was obtained by slurring it in DCM at ambient temperature for several days.

[0254] Figure 28 shows the XRPD spectrum of compound 1 in form L. The XRPD pattern of form L exhibited high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form L could be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexed solution, this unit cell is thought to be able to contain up to 3 DCM molecules per molecule of compound 1. The XRPD data corresponding to compound 1 in form L is summarized in Table 16.1. [Table 16]

[0255] The peak positions and integral values ​​of the proton NMR spectrum of morphology L were consistent with the chemical structure of compound 1. The presence of DCM (0.85 mol, 12.0%) was indicated by a 5.76 ppm singlet. Trace amounts of ethanol and several unidentified impurities were also observed in the spectrum.

[0256] The DSC thermogram showed a broad endothermic pattern with a peak maximum at 90.3°C, followed by exothermic reactions with a peak maximum at 174.8°C and an initial point at 162.8°C (Figure 29). The DSC thermogram also observed endothermic reactions with a peak maximum at 279.7°C and an initial point at 274.5°C. The TGA curve showed a broad endothermic pattern with an 8.5% weight loss from 46°C to 180°C, corresponding to 0.6 moles of DCM (Figure 29).

[0257] Based on the above characterization data, form L of compound 1 was designated as the DCM monosolvate of compound 1.

[0258] Example 17. Form M of Compound 1 As shown in Table 3.7, form M of compound 1 was obtained by slurring form F of compound 1 in CPME at 50°C for 3 days.

[0259] Figure 30 shows the XRPD spectrum of compound 1 in form M. The XRPD pattern of form M showed high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form M can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexed solution, this unit cell is thought to be able to contain one molecule of CPME per molecule of compound 1. The XRPD data corresponding to compound 1 in form M is summarized in Table 17.1. [Table 17]

[0260] The peak positions and integral values ​​of the proton NMR spectrum of morphology M were consistent with the chemical structure of compound 1. The multiplets at 1.43–166 ppm, the singlet at 3.26 ppm, and the multiplets at 3.72–3.78 ppm in the spectrum indicated approximately 0.93 moles of CPME present in the sample.

[0261] Based on the above characterization data, form M of compound 1 was designated as the DCM monosolvate of compound 1.

[0262] Example 18. Form N of Compound 1 As shown in Table 3.1, compound 1 was prepared in form N by slurring compound 1 in NMP at ambient temperature for 5 days.

[0263] Figure 31 shows the XRPD spectrum of compound 1 in form N. The XRPD pattern of form N showed high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form N can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexing solution, this unit cell is thought to be able to contain 2 NMP molecules per molecule of compound 1. The XRPD data corresponding to compound 1 in form N is summarized in Table 18.1. [Table 18-1] [Table 18-2]

[0264] Based on the above characterization data, form N of compound 1 was designated as the NMP solvate of compound 1.

[0265] Example 19. Form O of Compound 1 As shown in Table 3.2, form O of compound 1 was obtained by rapidly evaporating a solution of compound 1 in TFE:H2O(95:5) under ambient conditions.

[0266] Figure 32 shows the XRPD spectrum of compound 1 in form O. The XRPD pattern of form O showed high-intensity, well-separated peaks characteristic of crystalline materials. The XRPD pattern of form O can be indexed, indicating that this material is composed mainly of, or solely of, a single-crystal phase. Based on the volume calculated from the indexed solution, this unit cell is thought to be able to contain two TFE molecules per molecule of compound 1. The XRPD data corresponding to compound 1 in form O is summarized in Table 19.1. [Table 19-1] [Table 19-2]

[0267] Based on the above characterization data, form O of compound 1 was designated as the TFE solvate of compound 1.

[0268] Example 20. Forms P and Q of Compound 1 As shown in Table 3.2, a mixture of form P and form Q of compound 1 was obtained by vapor diffusion experiments of a solution of compound 1 in MeOH:DCM (1:3, v / v) exposed to water-saturated ethyl acetate vapor. Figure 3C (fourth spectrum from the top) shows the XRPD spectrum of the obtained mixture of form P and form Q of compound 1.

[0269] As described above, small amounts of compound 1 in form P were also observed in specific samples of compound 1 in form G (Figure 23, sample 3.5.4 from Table 3.5).

[0270] Example 21. Amorphous compound 1 Amorphous compound 1 was prepared using the CESS® process described in J. Pessi, et al., Controlled Expansion of Supercritical Solution: A Robust Method to Produce Pure Drug Nanoparticles With Narrow Size-Distribution, J. Pharm. Sci., 2016, 105, 2293-97. Briefly, compound 1 was loaded into a constant temperature and pressure vessel and dissolved in supercritical CO2 at a specified temperature and pressure. The solution was then delivered from the solubilization vessel through a nozzle into a recovery vessel under thermodynamic flow control. The temperature of the mixture before the nozzle was controlled during the process. As the pressure and temperature of the supercritical CO2 decreased during expansion at the nozzle, solid CO2 (dry ice flakes) were formed, which captured the nanoparticles of compound 1. Table 21.1 summarizes the parameters used in these experiments. [Table 21]

[0271] Scanning electron microscopy (SEM) Scanning electron microscope (SEM) images of bulk materials and nanoforming materials were acquired using a Zeiss Sigma 300VP field emission SEM to evaluate particle size and particle shape. Briefly, the sample was placed on an SEM stub, partially covered with carbon tape, and then sputtered with Pt (measured with a QCM sensor, Pt density 21.45 g / m²). cm3 (Assuming a typical coating thickness of 5-8 nm). An acceleration voltage of 10-15 kV was used. A representative image with the highest number of visually identifiable individual particles was selected for further particle size distribution analysis. The particles in each image were counted and classified according to the measurable ellipsoidal shape attribute. For nanoformed compound 1, the magnification that enabled this classification was 10,000x to 25,000x. Each histogram is based on more than 60 randomly selected particles that were counted. The statistics evaluated by SEM imaging are as follows: • D50: The median particle size (nm), which in the case of an ellipsoid is the geometric mean of the lengths of the two principal axes (x and y coordinates) that define the ellipsoid. This value is the same as the diameter of circles with the same total area. • Span: This value provides statistics on the width of the particle size distribution. The span is defined as (D90-D10) / D50. D10 is the 10th percentile mark, i.e., 10% of all particles are smaller than this value (conversely, 90% of particles are larger than this value). D90 is defined similarly (i.e., 90% of all particles are smaller than this value). The span value is normalized relative to the D50 value. • Minimum and maximum values: These correspond to the smallest and largest particle size (D, diameter) confirmed by the analysis, respectively.

[0272] The materials obtained from the experiments shown in Table 21.1 were analyzed using SEM. In these experiments, spherical particles were generally obtained. The particles produced at low pressure (Experiments 4 and 7) had relatively large particle sizes with D50s of 68 nm and 139 nm, respectively. At high pressure (Experiments 6 and 9), the obtained particles were smaller, with D50s of 32 nm and 29 nm, respectively. At intermediate pressure (Experiments 5 and 8), the D50s of the obtained particles were 40 nm and 34 nm, respectively. Figure 34 is an SEM image of the material obtained from Experiment 9.

[0273] XRPD XRPD analysis was performed using a Malvern PANalytical Empyrean X-ray diffractometer equipped with a multicore optics system and a solid-state PIXcel3D detector. Powder samples were loaded into a standard back-loading sample holder sealed with Kapton tape. CuKα (1.54 angstroms) rays were generated using a voltage of 45 kV and a current of 40 mA. Measurements were performed from 5 to 40 (2θ(°)) with a step size of 0.007 (2θ(°)) and a scan step time of 59.6 seconds. Diffraction maps were plotted using OriginLab 2021 software.

[0274] XRPD analysis performed on materials obtained from the experiments described in Table 21.1 showed that the samples were amorphous. A representative XRPD spectrum is shown in Figure 35, compared with form B of compound 1.

[0275] DSC DSC measurements were performed using a Discovery DSC 250 instrument under a dry N2(g) purge. The sample (typically 3-5 mg) was placed in a T0 low-mass pan (aluminum) and the pan was closed with an appropriate lid. The routine used consisted of a first cycle (heating to 285°C at a heating rate of 10°C / min and cooling to -40°C at 50°C / min) and a second cycle (heating to 285°C at a heating rate of 3°C / min with a temperature modulation of 0.5°C every 60 seconds). Thermal events are shown from the second cycle onwards. The nanoforming material was measured using the same settings as the heating program of the second cycle.

[0276] The thermal behavior of the nanoforming material was determined using DSC. The DSC thermogram (Figure 36) showed that amorphous nanoparticles exhibited endothermic properties between 10 and 90°C, which is typical of the evaporation of absorbed water. The main thermal phenomenon was a glass transition, the temperature of which was measured from the reversible heat flow signal and recorded at 139.8°C.

[0277] Example 22. Biological characterization of compound 1 JAK2 binding assay In transiently transfected HEK293 cells, JAK2 (JH1 domain catalyzed, Y1007F, Y1008F) kinase was expressed as an N-terminal fusion with the DNA-binding domain of NFκB, and subsequently tagged with DNA for qPCR detection. Streptoavidin-coated magnetic beads were treated with biotinylated small molecule ligands at room temperature for 30 minutes to generate affinity resins for kinase assays. Ligand-bound beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween® 20, 1 mmol / L DTT) to remove unbound ligands and reduce nonspecific phage binding. The binding reaction was constructed by combining the kinase, ligand-bound affinity beads, and test compounds in 1x binding buffer (1x PBS, 0.05% Tween® 20, 0.1% BSA, 1 mmol / L DTT). The test compounds were prepared as 111x stock in 100% DMSO and diluted directly into the assay wells. All reactions were carried out in a 384-well polypropylene plate with a final volume of 0.02 mL. The assay plates were incubated at room temperature for 1 hour with shaking, and the affinity beads were washed with washing buffer (1x PBS, 0.05% Tween® 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween® 20, 0.5 μmol / L non-biotinylated affinity ligand) and incubated at room temperature for 30 minutes with shaking. The kinase concentration in the eluate was measured by qPCR. K of compound 1 dThis assay revealed that the concentration was less than 10 nM.

[0278] JAK Family Selective Assay In the above JAK2 binding assay, the JAK2 binding affinity (K) of the provided compound d ) their binding affinity (K) to one or more other kinases dThe selectivity of the provided compound is evaluated by comparison with other kinases. Binding affinity to other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in E. coli hosts derived from the BL21 strain. E. coli are grown to the logarithmic phase, infected with T7 phage, and incubated with shaking at 32°C until lysed. The lysates are centrifuged and filtered to remove cell debris. The remaining kinase is produced in HEK-293 cells and then tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands at room temperature for 30 minutes to generate affinity resins for kinase assays. Ligand-bound beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween® 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific binding. The binding reaction is constructed by combining the kinase, ligand-bound affinity beads, and test compound in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween® 20, 6 mM DTT). The test compound is prepared as an 111X stock in 100% DMSO. Kd is determined using an 11-point 3x compound dilution series with three DMSO control points. All compounds for Kd measurement are partitioned by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds are then directly diluted in the assay to a final DMSO concentration of 0.9%. All reactions are carried out in a 384-well polypropylene plate. Each final volume is 0.02 ml. The assay plate is incubated at room temperature for 1 hour with shaking, and the affinity beads are washed with washing buffer (1x PBS, 0.05% Tween® 20). Next, the beads are resuspended in elution buffer (1x PBS, 0.05% Tween® 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature for 30 minutes with shaking. The kinase concentration in the eluate is measured by qPCR. Compounds that show better binding affinity to JAK2 compared to one or more other kinases are considered to be JAK2-selective compounds.In some embodiments, the provided compound is considered to be more selective to JAK2 than to one or more kinases among JAK1, JAK3, and Tyk2.

[0279] The results of the JAK2 selectivity assay described above are summarized in the table below. Compounds indicated by "A" are K d / K d The ratio is ≥ 1000, and the compound indicated by "B" is K d / K d Compounds represented by "C" with a ratio <1000 and ≥300 are K d / K d The ratio was <300 and ≥100. [Table 45] [ka]

[0280] SET2-pSTAT5 cell assay This assay measures the inhibition of JAK2-mediated pSTAT5 signaling in constitutively active essential thrombocytopenic cells carrying the V617F mutation. Transfer the cells from the flask to the cell culture medium and count the number of cells. Dilute the cells with the culture medium and add 100 μL of cell suspension (50,000 cells / well) to each well of a 96-well cell culture plate. Add the solution of the test compound to the assay plate. Cover the plate with a lid and incubate in a 5% CO2 incubator at 37°C for 4 hours. After 4 hours, centrifuge the cells and resuspend the cell pellet in 100 μL of cold PBS. Next, centrifuge the cells again at 4°C and 4000 rpm for 5 minutes. Aspirate the PBS and add 25 μL of lysis buffer (containing a cocktail of protease and phosphatase inhibitors) to each cell pellet. Shake the cell lysates at 4°C for 20 minutes to completely lyse the cells. Centrifuge the cell lysates at 4°C and 4000 rpm for 15 minutes, then transfer the supernatant to a new plate and store at -80°C. Analyze the plates using Meso-scale discovery (MSD) as follows: Coat a standard MSD plate with capture antibody in PBS (40 μL / well) and incubate overnight at 4°C with shaking. Wash the MSD plate three times with 150 μL / well of 1x MSD wash buffer (Tris buffered saline containing 0.1% Tween® 20 surfactant, TBST). Next, block the MSD plate with 150 μL of blocking buffer (TBST containing 5% BSA) and shake at room temperature and 600 rpm for 1 hour. Wash the MSD plate three times with 150 μL / well of 1x MSD wash buffer (TBST). Next, add the sample lysates to the MSD plate (25 μL / well) and shake at room temperature and 600 rpm for 1 hour. Wash the MSD plate three times with 150 μL / well of 1x MSD washing buffer (TBST). Next, add the detection antibody (prepared in antibody detection buffer, 1% BSA-containing 1x TBST) to the MSD plate and shake at room temperature at 600 rpm for 1 hour. Wash the MSD plate three times with 150 μL / well of 1x MSD washing buffer (TBST).Next, add the secondary detection antibody (prepared in antibody detection buffer, 1x TBST containing 1% BSA) to the MSD plate and shake at room temperature at 600 rpm for 1 hour. Wash the MSD plate three times with 150 μL / well of 1x MSD washing buffer (TBST). Add 1x MSD reading buffer to the plate (150 μL / well) and dilute with water by 4x. Image the plate using the MSD imaging instrument according to the manufacturer's instructions.

[0281] The results of the SET2-pSTAT5 cell assay described above are shown in the table below. Compounds indicated by "A" are IC 50 The compound with a minimum viscosity of <125nM and indicated by "C" is IC 50 The levels were ≥200 nM and <1 μM. [Table 46]

[0282] hPBMC-GMCSF-STAT5 assay This assay measures the inhibition of JAK2 homodimer-mediated STAT5 signaling in human peripheral blood mononuclear cells. PBMCs are thawed in assay medium containing the following: [Table 47] Next, count the cells. Dilute the cells in culture medium and add 120 μL of cell suspension (500,000 cells / well) to each well of a 96-well cell culture plate. Dilute the test compound 10X in assay medium and add 15 μL of the solution to the assay plate. Cover the plate with a lid and incubate in a 5% CO2 incubator at 37°C for 4 hours. After 4 hours, dilute the GM-CSF stock solution (100 μg / mL) in assay medium to 50 ng / mL and add 15 μL of the solution to the assay plate so that the final concentration in the assay is 5 ng / mL. Cover the plate with a lid and incubate in a 5% CO2 incubator at 37°C for 5 minutes. After 5 minutes, centrifuge the cells and aspirate the culture medium. Next, add 50 μL of lysis buffer (containing a cocktail of protease and phosphatase inhibitors) to each cell pellet and shake the cell lysates at 4°C for 20 minutes. Next, centrifuge the cell lysate at 4°C and 4000 rpm for 5 minutes, transfer the supernatant to a new plate, and store at -80°C until use. Coat the MSD standard plate with PBS containing capture antibody (40 μL / well) and incubate overnight at 4°C with shaking. Next, wash the MSD plate three times with 150 μL / well TBST. Add the sample lysate (50 μL / well) to the MSD plate and shake at room temperature and 600 rpm for 1 hour. Next, wash the MSD plate three times with 150 μL / well TBST. Add the detection antibody (25 μL / well) and shake at room temperature and 600 rpm for 1 hour. The detection antibody is prepared in antibody detection buffer (TBST containing 1% Blocker A). Next, wash the MSD plate three times with 150 μL / well TBST. Add the second detection antibody (25 μL / well) and shake at room temperature and 600 rpm for 1 hour. The second detection antibody is prepared in antibody detection buffer (TBST containing 1% Blocker A). Next, the MSD plate is washed three times with 150 μL / well of TBST. Then, MSD reading buffer (2x) is added (150 μL / well) and diluted 4x with water. The plate is imaged using the MSD imaging instrument according to the manufacturer's instructions.

[0283] hPBMC-IL12-STAT4 assay This assay measures the inhibition of Tyk2 / JAK2-mediated STAT4 signaling in human peripheral blood mononuclear cells. PBMCs are thawed in assay medium containing the following: [Table 48] Next, count the cells. Dilute the cells in culture medium and add 120 μL of cell suspension (200,000 cells / well) to each well of a 96-well cell culture plate. Dilute the test compound 10X in assay medium and add 15 μL of the solution to the assay plate. Cover the plate with a lid and incubate in a 5% CO2 incubator at 37°C for 1 hour. After 1 hour, dilute the IL12 stock solution (50 ng / mL) to 50 ng / mL in assay medium and add 15 μL of the solution to the assay plate so that the final concentration in the assay is 1.7 ng / mL. Cover the plate with a lid and incubate in a 5% CO2 incubator at 37°C for 25 minutes. After 25 minutes, centrifuge the cells and aspirate the culture medium. Next, add 65 μL of lysis buffer (containing a cocktail of protease and phosphatase inhibitors) to each cell pellet and shake the cell lysates at 4°C for 30 minutes. Next, centrifuge the cell lysate at 4°C and 4000 rpm for 5 minutes, transfer the supernatant to a new plate, and store at -80°C until use. Block the MSD standard plate with blocking buffer (wash buffer containing 3% Blocker A) and shake at room temperature and 600 rpm for 1 hour. Next, wash the MSD plate three times with 150 μL / well of wash buffer. Add the sample lysate (25 μL / well) to the MSD plate and shake at room temperature and 600 rpm for 1 hour. Next, wash the MSD plate three times with 150 μL / well of wash buffer. Add the detection antibody (25 μL / well) and shake at room temperature and 600 rpm for 1 hour. The detection antibody is prepared in antibody detection buffer (150 μL of 2% Blocker DM, 30 μL of 10% Blocker DR, 1 mL of Blocker A solution, and 1.82 mL of 1x wash buffer per plate). Next, wash the MSD plate three times with 150 μL / well of TBST. Then, add MSD Reading Buffer (1x) (150 μL / well) and dilute with water by 4x. Image the plate using the MSD imaging instrument according to the manufacturer's instructions.

[0284] hPBMC-IL2-STAT5 assay This assay measures the inhibition of JAK1 / JAK3-mediated STAT5 signaling in human peripheral blood mononuclear cells. PBMCs are thawed in assay medium containing the following: [Table 49] Next, count the cells. Dilute the cells in culture medium and add 120 μL of cell suspension (200,000 cells / well) to each well of a 96-well cell culture plate. Dilute the test compound 10X in assay medium and add 15 μL of the solution to the assay plate. Cover the plate with a lid and incubate in a 5% CO2 incubator at 37°C for 1 hour. After 1 hour, dilute the IL2 stock solution (100 μg / mL) in assay medium to 250 ng / mL and add 15 μL of the solution to the assay plate so that the final concentration in the assay is 25 ng / mL. Cover the plate with a lid and incubate in a 5% CO2 incubator at 37°C for 5 minutes. After 5 minutes, centrifuge the cells and aspirate the culture medium. Next, add 40 μL of lysis buffer (containing a cocktail of protease and phosphatase inhibitors) to each cell pellet and shake the cell lysates at 4°C for 20 minutes. Next, centrifuge the cell lysate at 4°C and 4000 rpm for 5 minutes, transfer the supernatant to a new plate, and store at -80°C until use. Coat the MSD standard plate with PBS containing capture antibody (40 μL / well) and incubate overnight at 4°C with shaking. Next, wash the MSD plate three times with 150 μL / well TBST. Next, block the MSD plate with blocking buffer (150 μL of TBST containing 3% Blocker A) and shake at room temperature and 600 rpm for 1 hour. Next, wash the MSD plate three times with 150 μL / well TBST. Add the sample lysate (40 μL / well) to the MSD plate and shake at room temperature and 600 rpm for 1 hour. Next, wash the MSD plate three times with 150 μL / well TBST. Add the detection antibody (25 μL / well) and shake at room temperature and 600 rpm for 1 hour. The detection antibody is prepared in antibody detection buffer (TBST containing 1% Blocker A). Next, the MSD plate is washed three times with 150 μL / well of TBST. The second detection antibody is added (25 μL / well) and shaken at room temperature at 600 rpm for 1 hour. The second detection antibody is prepared in antibody detection buffer (TBST containing 1% Blocker A). Next, the MSD plate is washed three times with 150 μL / well of TBST. Next, MSD reading buffer (2x) is added (150 μL / well) and diluted 4x with water.Use the MSD imaging equipment according to the manufacturer's instructions to image the plate.

[0285] Kinome profiling assay Kinome profiling is performed as described in Anastassiadis T, et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1039-45. doi:10.1038 / nbt.2017. Generally, the substrate is prepared in a reaction buffer prepared immediately before use (20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij® 35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO). Next, any necessary cofactors are added to the substrate solution. Then, the kinase is supplied to the substrate solution and gently mixed. Next, using Acoustic technology (Echo550; nanoliter range), the test compound is added to the kinase reaction mixture in 100% DMSO and incubated at room temperature for 20 minutes. 33 P-ATP is added to the reaction mixture and incubated at room temperature for 2 hours. Kinase activity is detected by the P981 filter-coupled method.

[0286] Caco2 permeability assay Preparation of Caco-2 cells: Add 50 μL and 25 mL of cell culture medium to each well of the Transwell® insert and reservoir, respectively. Next, incubate the HTS Transwell® plate at 37°C and 5% CO2 for 1 hour, then seed the cells. Dilute the Caco-2 cells with culture medium to 6.86 × 10⁵ cells / mL and dispense 50 μL of cell suspension into the filter wells of a 96-well HTS Transwell® plate. Culture the cells for 14–18 days in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity. Change the cell culture medium every other day, starting within 24 hours of the initial plating.

[0287] Preparation of stock solutions: A 10 mM stock solution of the test compound is prepared in DMSO. A stock solution for the positive control is prepared in DMSO at a concentration of 10 mM. In this assay, digoxin and propranolol are used as control compounds.

[0288] Evaluation of cell monolayer integrity: Remove the culture medium from the reservoir and each Transwell® insert and replace it with warmed fresh culture medium. Measure the transepithelial electrical resistance (TEER) across the monolayer using the Millicell Epithelial Volt-Ohm measurement system (Millipore, USA). Return the plate to the incubator after measurement. The TEER value is calculated according to the following equation: TEER value (ohms) × membrane area (cm²) 2 ) = TEER value (ohms·cm) 2 230 ohms / cm² 2 A TEER value exceeding this indicates a sufficiently qualified Caco-2 monolayer.

[0289] Assay procedure: Remove the Caco-2 plate from the incubator, wash it twice with warmed HBSS (10 mM HEPES, pH 7.4), and then incubate at 37°C for 30 minutes. Dilute the control compound stock solution with DMSO to a 1 mM solution, then dilute with HBSS (10 mM HEPES, pH 7.4) to a 5 μM working solution. Dilute the test compound stock solution with DMSO to a 1 mM solution, then dilute with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to a 5 μM working solution. The final concentration of DMSO in the incubation system is 0.5%. To determine the rate of drug transport from the apical to the basal outward direction, add 75 μL of a 5 μM working solution of the test compound to the Transwell® insert (apical compartment) and fill the receiver plate well (basal outward compartment) with 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). To determine the rate of drug transport from the apical to the basal outward direction, add 75 μL of a 5 μM working solution of the test compound to the Transwell® insert (apical compartment) and fill the receiver plate well (basal outward compartment) with 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). Prepare the 0-hour sample by transferring 50 μL of the 5 μM working solution to the wells of a 96-deep-well plate, followed by the addition of 200 μL of cold methanol containing an appropriate internal standard (IS). Incubate the plate at 37°C for 2 hours. At the end of incubation, 50 μL of the sample from the donor side (apical compartment for Ap→Bl flux, basal outer compartment for Bl→Ap) and the receiver side (basal outer compartment for Ap→Bl flux, apical compartment for Bl→Ap) are transferred to the wells of a new 96-well plate, followed by the addition of 4 times the volume of cold acetonitrile or methanol containing an appropriate internal standard (IS). The sample is vortexed for 5 minutes, then centrifuged at 3,220 g for 40 minutes. A 100 μL aliquot of the supernatant is mixed with an appropriate amount of ultrapure water, and then LC-MS / MS analysis is performed.To determine the leakage of Lucifer Yellow after a 2-hour transport period, a stock solution of Lucifer Yellow is prepared in ultrapure water and diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100 μM. 100 μL of the Lucifer Yellow solution is added to each Transwell® insert (apical compartment), followed by filling the receiver plate wells (basal outer compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plate is incubated at 37°C for 30 minutes. 80 μL of the sample is removed directly from the apical and basal outer wells (using the basal outer access pores) and transferred to the wells of a new 96-well plate. The fluorescence signal of Lucifer Yellow (to monitor monolayer integrity) is measured using a fluorescence plate reader at excitation 485 nM and emission 530 nM.

[0290] The results of the Caco-2 permeability assay described above are shown in the table below. Compounds labeled "B" had ER > 2 and ≤ 5, while compounds labeled "D" had ER > 10 and ≤ 30. [Table 50]

[0291] Cytotoxicity assay Transfer HEK293T cells from the flask to the cell culture medium, then count the cells. Dilute the cells with the culture medium to the desired density and add 40 μL of cell suspension to each well of a 384-well cell culture plate. Cover the plate with a lid and centrifuge at 1,000 RPM for 1 minute at room temperature, then transfer to a 37°C 5% CO2 incubator and leave overnight. Dissolve the test compound in 10 mM DMSO stock solution. Next, transfer 45 μL of the stock solution to a 384 PP plate. Perform a 3-fold 10-point dilution by transferring 15 μL of the compound to 30 μL of DMSO using a TECAN (EVO200) liquid handler. Centrifuge the plate at 1,000 RPM for 1 minute at room temperature and shake in a plate shaker for 2 minutes. Transfer 40 nL of the diluted compound from the compound source plate to the cell plate using a liquid handler Echo550. After 48 hours of compound treatment, CTG detection is performed on the compound-treated plates: Remove the plates from the incubator and equilibrate at room temperature for 15 minutes. Add 30 μL of CellTiter-Glo reagent to each well and perform detection. Next, leave the plates at room temperature for 30 minutes, then read them using EnVision. Inhibitory activity is calculated using the following formula: Inhibition rate (%) = 100 × (LumHC - LumSample) / (LumHC - LumLC), where HC is the reading obtained from cells treated with 0.1% DMSO alone, and LC is the reading from cells treated with 10 μL of staurosporine. IC 50 The value is calculated using XLFit (equation 201).

[0292] Hepatocyte stability assay Prepare 10 mM stock solutions of the test compound and positive control in DMSO. Dilute the stock solution to 100 μM by combining 198 μL of 50% acetonitrile / 50% water with 2 μL of the 10 mM stock solution. Verapamil is used as the positive control in this assay. Thaw the cryopreserved hepatocyte vial in a 37°C water bath with gentle shaking. Pour the contents into a 50 mL conical tube of thawed medium. Centrifuge the vial at 100 g for 10 minutes at room temperature. Aspirate the thawed medium and resuspend the hepatocytes in serum-free incubation medium to approximately 1.5 × 10⁶ cells / mL. Count the cell viability and density using trypan blue exclusion, then dilute the cells in serum-free incubation medium to a working cell density of 0.5 × 10⁶ viable cells / mL. Before adding the negative control to the plate, boil a portion of 0.5 × 10⁶ live cells / mL of hepatocytes for 5 minutes to eliminate enzyme activity so that little or no substrate turnover is observed. Dispense 198 μL of hepatocytes into each well of a 96-well uncoated plate. Incubate the plate for approximately 10 minutes. Add 2 μL of 100 μM test compound and 2 μL of positive control aliquots to each well of the uncoated 96-well plate to initiate the reaction. The final concentration of the test compound is 1 μM. This assay is performed in a double-cycle. Incubate the plates in the incubator until the designed time. Transfer 25 μL of the contents and mix with 6 times the volume (150 μL) of cold acetonitrile containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac), and terminate the reaction at 0, 15, 30, 60, 90, and 120 minutes. Centrifuge the sample at 3,220 g for 25 minutes, and use a 150 μL aliquot of the supernatant for LC-MS / MS analysis.

[0293] Table 6 shows the results of the hepatocyte stability assay described above, using human or rat hepatocytes. (Human heps CL) int In this case: The compound indicated by "A" is CL int The compound indicated by "C" is ≤6 mL / min / kg.int The flow rate was >12 mL / min / kg and <20 mL / min / kg in rats (heps CL). int In this case: The compound indicated by "B" is CL int Compounds that are ≥17 mL / min / kg and <35 mL / min / kg and are denoted by "C" are CL int The values ​​were ≥35 mL / min / kg and <45 mL / min / kg. [Table 51]

[0294] Dynamic solubility assay Prepare a stock solution of the test compound at a concentration of 10 mM in DMSO, and a stock solution of the control compound at a concentration of 30 mM in DMSO. Diclofenac is used as the positive control in this assay. Place 30 μL of the stock solution of each compound into a 96-well rack, and then add 970 μL of PBS at pH 4.0 and pH 7.4 to each vial of the capless solubility sample plate. This study is performed in a double row. Add one stirring bar to each vial, and then seal the vials using a molded PTDE / SIL 96-well plate cover. Transfer the solubility sample plate to a Thermomixer Comfort plate shaker and incubate at room temperature for 2 hours while shaking at 1100 rpm. After 2 hours of incubation, remove the stirring bar using a large magnet and transfer all samples from the solubility sample plate to a filter plate. Filter all samples using a vacuum manifold. Dilute the filtered samples with methanol. The sample is analyzed by LC-MS / MS, and LC is used in combination with identification and quantification of mass spectral peaks to quantify the solubility relative to a standard of known concentration in DMSO. The solubility value of the test compound is calculated as follows, where INJ VOL is the injection volume, DF is the dilution factor, and STD is the standard:

number

[0295] The results of the dynamic solubility assay described above are shown in Table 7. Compounds labeled "B" had solubility ≥ 9 μM and < 100 μM, while compounds labeled "C" had solubility ≥ 100 μM and < 200 μM. [Table 52]

[0296] Plasma protein binding assay Working solutions for the test compound and control compound are prepared at a concentration of 200 μM in DMSO, and then the working solutions are spiked into the plasma. The final concentration of the compound is 1 μM. The final concentration of DMSO is 0.5%. In this assay, ketoconazole is used as a positive control. Dialysis membranes are immersed in ultrapure water for 60 minutes to separate the strips, then immersed in 20% ethanol for 20 minutes, and finally immersed in dialysis buffer for 20 minutes. The dialysis setup is configured according to the manufacturer's instructions. Each cell contains 150 μL of plasma sample and is dialyzed against an equal volume of dialysis buffer (PBS). This assay is performed in a double-row system. The dialysis plate is sealed and incubated in a 37°C incubator with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 μL of sample is transferred from both the buffer chamber and the plasma chamber to the wells of a 96-well plate. 50 μL of plasma is added to each buffer sample, and the recovered plasma samples are supplemented with an equal volume of PBS. Add 400 μL of acetonitrile precipitation buffer containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine, and 2 μM ketoprofen) to precipitate the protein and release the compounds. Vortex the sample for 2 minutes and centrifuge at 3,220 g for 30 minutes. Dilute a 50 μL aliquot of the supernatant with 150 μL of acetonitrile containing internal standards and ultrapure H2O = 1:1, and use this mixture for LC-MS / MS analysis.

[0297] Although several embodiments of the present invention have been described, it is clear that the basic examples here may be modified to provide other embodiments utilizing the compounds and methods of the present invention. Therefore, it will be understood that the scope of the present invention is defined not by the specific embodiments presented as examples, but by the appended claims.

Claims

1. The crystalline solid form of compound 1: 【Chemistry 4】

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

3. The solid form according to claim 1 or 2, characterized by three or more peaks in its X-ray powder diffraction (XRPD) pattern, selected from peaks at angles (2θ(°) ± 0.2) of 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.

06.

4. A solid form according to any one of claims 1 to 3, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 8.53, 14.31, 15.58, 17.37, 17.72, 18.80, 20.68, 21.90, 23.34, 23.66, and 24.

06.

5. A solid form according to any one of claims 1 to 4, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 61 。

6. A solid form according to any one of claims 1 to 5, characterized by an XRPD pattern substantially similar to that shown in Figure 3A (top spectrum).

7. The solid form according to claim 1, which is a hydrate.

8. A solid morphology according to claim 1 or 7, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.

67.

9. A solid form according to any one of claims 1, 7, or 8, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 9.05, 9.09, 10.16, 12.85, 14.42, 15.10, 16.39, 17.08, 17.66, 19.35, 19.85, 20.35, 21.89, 22.83, 23.71, 24.20, 25.09, 27.10, 27.57, 28.59, and 28.

67.

10. The solid form according to claim 8, characterized by three or more peaks in its X-ray powder diffraction (XRPD) pattern, selected from peaks at angles of 9.05, 9.09, 10.16, 12.85, 15.10, and 19.35 (2θ(°) ± 0.2).

11. The solid form according to claim 9, characterized by peaks in its X-ray powder diffraction (XRPD) pattern selected from peaks at angles (2θ(°) ± 0.2) of 9.05, 9.09, 10.16, 12.85, 15.10, and 19.

35.

12. A solid form according to any one of claims 1 or 7-11, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 62 。

13. A solid form according to any one of claims 1 or 7 to 12, characterized by an XRPD pattern substantially similar to that shown in Figure 6.

14. The solid morphology according to claim 1 or 2, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.

51.

15. A solid form according to any one of claims 1, 2, or 14, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.92, 10.36, 11.44, 12.02, 12.57, 13.10, 16.71, 17.86, 18.54, 18.82, 23.40, 24.19, 24.85, 27.23, and 28.

51.

16. A solid form according to any one of claims 1, 2, 14, or 15, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 63 。

17. A solid form according to any one of claims 1, 2, or 14-16, characterized by an XRPD pattern substantially similar to that shown in Figure 10.

18. The solid form according to claim 1, which is an acetone solvate.

19. The solid form according to claim 1 or 18, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.

32.

20. A solid form according to any one of claims 1, 18, or 19, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.27, 11.87, 14.58, 16.57, 17.24, 18.01, 20.03, 20.77, 21.52, 23.85, and 24.

32.

21. A solid form according to any one of claims 1 or 18-20, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 64 。

22. A solid form according to claim 1 or any one of claims 18 to 21, characterized by an XRPD pattern substantially similar to that shown in Figure 14.

23. The solid form according to claim 1, which is a dimethyl sulfoxide solvate.

24. The solid morphology according to claim 1 or 23, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.

63.

25. A solid form according to any one of claims 1, 23, or 24, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.26, 11.89, 12.56, 14.56, 16.51, 17.15, 17.94, 17.98, 18.77, 19.68, 19.99, 20.75, 21.65, 22.14, 23.76, 24.42, 27.04, and 27.

63.

26. A solid form according to any one of claims 1 or 23-25, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 65 。

27. A solid form according to claim 1 or any one of claims 23 to 26, characterized by an XRPD pattern substantially similar to that shown in Figure 16.

28. The solid form according to claim 1, which is an acetate solvate.

29. The solid form according to claim 1 or 28, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.

81.

30. A solid form according to any one of claims 1, 28, or 29, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 6.93, 8.50, 11.21, 13.60, 15.81, 16.44, 17.35, 17.54, 21.32, 22.69, 22.83, 23.23, 24.60, 25.20, 25.84, and 28.

81.

31. A solid form according to any one of claims 1 or 28-30, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 66 。

32. A solid form according to claim 1 or any one of claims 28 to 31, characterized by an XRPD pattern substantially similar to that shown in Figure 17.

33. The solid form according to claim 1, which is ethyl acetate solvate.

34. The solid morphology according to claim 1 or 33, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.

02.

35. A solid form according to any one of claims 1, 33, or 34, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.30, 8.16, 8.57, 11.86, 12.80, 14.64, 16.11, 16.85, 17.48, 17.70, 20.43, 21.97, 22.18, 22.30, 23.85, 24.72, and 27.

02.

36. A solid form according to any one of claims 1 or 33 to 35, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 67 。

37. A solid form according to claim 1 or any one of claims 33 to 36, characterized by an XRPD pattern substantially similar to that shown in Figure 22.

38. The solid form according to claim 1 or 7, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.

05.

39. A solid form according to any one of claims 1, 7, or 38, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 8.74, 9.63, 14.60, 16.53, 18.78, 19.35, 23.50, 24.02, and 26.

05.

40. A solid form according to any one of claims 1, 7, 38, or 39, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 68 。

41. A solid form according to any one of claims 1, 7, or 38-40, characterized by an XRPD pattern substantially similar to that shown in Figure 3B (second spectrum from the top).

42. The solid form according to claim 1 or 7, characterized by an XRPD pattern substantially similar to that shown in Figure 3B (third spectrum from the top).

43. The solid form according to claim 1, which is a methyl tert-butyl ether solvate.

44. The solid form according to claim 1 or 43, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.

73.

45. A solid form according to any one of claims 1, 43, or 44, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.00, 11.79, 14.06, 16.19, 16.52, 20.28, 21.58, 22.65, and 26.

73.

46. A solid form according to claim 1 or any one of claims 43 to 45, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 69-1 Table 69-2 。

47. A solid form according to claim 1 or any one of claims 43 to 46, characterized by an XRPD pattern substantially similar to that shown in Figure 26.

48. The solid form according to claim 1, which is a di-n-butyl ether solvate.

49. The solid form according to claim 1 or 48, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.

47.

50. A solid form according to any one of claims 1, 48, or 49, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.21, 8.35, 11.77, 12.50, 14.47, 16.17, 16.67, 17.80, 18.13, 19.51, 21.37, 22.15, 23.70, 24.08, and 24.

47.

51. A solid form according to claim 1 or any one of claims 48-50, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 70 。

52. A solid form according to claim 1 or any one of claims 48 to 51, characterized by an XRPD pattern substantially similar to that shown in Figure 27.

53. The solid form according to claim 1, which is a dichloromethane solvate.

54. The solid morphology according to claim 1 or 53, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.

65.

55. A solid form according to any one of claims 1, 53, or 54, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.30, 11.88, 14.62, 16.45, 17.10, 17.96, 19.92, 20.75, 21.28, 21.92, 23.96, 24.47, 24.75, and 27.

65.

56. A solid form according to claim 1 or any one of claims 53 to 55, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 71 。

57. A solid form according to claim 1 or any one of claims 53 to 56, characterized by an XRPD pattern substantially similar to that shown in Figure 28.

58. The solid form according to claim 1, which is a cyclopentyl methyl ether solvate.

59. The solid form according to claim 1 or 58, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.

63.

60. A solid form according to any one of claims 1, 58, or 59, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.13, 11.89, 14.29, 16.21, 16.67, 17.63, 19.89, 20.35, 22.07, 23.36, 24.22, and 24.

63.

61. A solid form according to claim 1 or any one of claims 58 to 60, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 72 。

62. A solid form according to claim 1 or any one of claims 58 to 61, characterized by an XRPD pattern substantially similar to that shown in Figure 30.

63. The solid form according to claim 1, which is N-methylpyrrolidone solvate.

64. The solid form according to claim 1 or 58, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.

10.

65. A solid form according to any one of claims 1, 63, or 64, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.09, 11.57, 14.22, 16.31, 16.52, 17.56, 19.33, 20.24, 21.56, 23.25, 23.51, 24.01, 24.08, 25.99, 26.86, and 27.

10.

66. A solid form according to claim 1 or any one of claims 63 to 65, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 73-1 Table 73-2 。

67. A solid form according to claim 1 or any one of claims 63 to 66, characterized by an XRPD pattern substantially similar to that shown in Figure 31.

68. The solid form according to claim 1, which is 2,2,2-trifluoroethanol solvate.

69. The solid form according to claim 1 or 68, characterized by three or more peaks in its XRPD pattern, selected from peaks at angles (2θ(°) ± 0.2) of 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.

96.

70. A solid form according to any one of claims 1, 68, or 69, characterized by peaks in its XRPD pattern selected from peaks at angles (2θ(°) ± 0.2) of 7.44, 8.18, 8.34, 10.38, 11.70, 13.99, 16.49, 17.57, 17.87, 18.46, 19.91, 20.12, 20.85, 21.24, 21.47, 22.05, 22.83, 24.01, 26.01, and 28.

96.

71. A solid form according to claim 1 or any one of claims 68 to 70, characterized by peaks in its XRPD pattern, including peaks at substantially all of the following angles (2θ(°) ± 0.2): Table 74-1 Table 74-2 。

72. A solid form according to claim 1 or any one of claims 68 to 71, characterized by an XRPD pattern substantially similar to that shown in Figure 32.

73. The solid form according to any one of claims 3-6, 8-17, 19-22, 24-27, 29-32, 34-42, 44-47, 49-52, 54-57, 59-62, 64-67, or 69-72, wherein the XRPD pattern is collected using Cu Kα lines having a wavelength of 1.54059 angstroms, and optionally the XRPD pattern is collected according to the parameters in Table 13.

74. A crystalline solid form of compound 1 that can be obtained by the process described herein.

75. A step of slurring compound 1 in a mixture of ethanol and water, A crystalline solid form of compound 1, comprising the step of isolating the crystalline solid of compound 1.

76. Amorphous form of compound 1 【Transformation 5】

77. The solid form according to claim 76, characterized by an XRPD pattern substantially similar to that shown in Figure 35 (top spectrum).

78. An amorphous form of compound 1 that can be obtained by the process described herein.

79. The amorphous form of compound 1, prepared by a process including the following steps: A process of dissolving compound 1 in supercritical carbon dioxide at high temperature and pressure, An amorphous form of compound 1 prepared by a process comprising the step of sending the aforementioned solution into a collection container through a nozzle.

80. A composition comprising a solid form according to any one of claims 1 to 75, which substantially does not contain the amorphous form of compound 1.

81. A composition comprising a solid form according to any one of claims 76 to 79, which substantially does not contain the crystalline form of compound 1.

82. A composition comprising a solid form according to any one of claims 1 to 79, which is substantially free of impurities.

83. A composition comprising the solid form according to any one of claims 1 to 75, substantially free from other crystalline solid forms of compound 1.

84. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 79 and a pharmaceutically acceptable carrier or additive.

85. A pharmaceutical composition prepared by a method comprising the steps of: obtaining a solid form according to any one of claims 1 to 79; and formulating the solid form together with one or more suitable carriers and / or additives to obtain the pharmaceutical composition.

86. The pharmaceutical composition according to claim 84 or 85, which is a solid.

87. A method for preparing a pharmaceutical composition according to any one of claims 84 to 86, comprising the steps of: obtaining a solid form according to any one of claims 1 to 79; and formulating the solid form together with one or more suitable carriers and / or additives to obtain the pharmaceutical composition.

88. A process for preparing a solid form according to any one of claims 1 to 79, comprising the steps of stirring compound 1 in a suitable solvent and removing the solvent to obtain the solid form.

89. The process according to claim 88, wherein the suitable solvent is selected from the group consisting of acetic acid, acetone, chloroform, cyclopentyl methyl ether, dichloromethane, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, di-n-butyl ether, ethanol, ethyl acetate, methanol, methyl ethyl ketone, methyl tert-butyl ether, N-methylpyrrolidone, tert-amyl methyl ether, trifluoroethanol, water, or any mixture thereof.

90. A method for inhibiting a target JAK2, comprising administering a solid form according to any one of claims 1 to 79, or a composition according to any one of claims 80 to 86.

91. A method for treating a disease, disorder, or condition related to JAK2, comprising administering to a subject in need of treatment for the disease, disorder, or condition a compound according to any one of claims 1 to 79 or a composition according to any one of claims 80 to 86.

92. A method for treating cancer, comprising administering a compound according to any one of claims 1 to 79 or a composition according to any one of claims 80 to 86 to a subject in need of treatment for cancer.

93. A method for treating a hematological malignancy, comprising administering to a subject requiring treatment for cancer a compound according to any one of claims 1 to 79 or a composition according to any one of claims 80 to 86.

94. The method according to claim 93, wherein the hematological malignancy is leukemia or lymphoma.

95. A method for treating a myeloproliferative neoplasm, comprising administering to a subject in need of treatment for the myeloproliferative neoplasm a compound according to any one of claims 1 to 79 or a composition according to any one of claims 80 to 86.

96. The method according to claim 95, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.

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