Crystal Forms of TYK2 Inhibitors

Abstract

This specification describes crystalline forms of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate and solvates thereof.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 358,790, filed Jul. 6, 2022, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The four JAK family members are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), and have been shown to be important components of cytokine-mediated effects. Unlike JAK1-deficient mice, TYK2-deficient mice are viable, and TYK2 deficiency has been shown to be protective in various autoimmune models.

Summary of the Invention

[0003] In one aspect, a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea, or a pharmaceutically acceptable salt or solvate thereof, is described herein.

[0004] In one embodiment, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is an adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 1, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in Figure 2, (d) A DSC thermogram substantially similar to that described in Figure 2, (e) A DSC thermogram with an exotherm having an onset temperature of about 200 °C, (f) Non-hygroscopic, or (g) One of these combinations is Form 1 having at least one of them.

[0005] In some embodiments, it is the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 1.

[0006] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ.

[0007] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a thermogravimetric analysis (TGA) that is substantially the same as that described in Figure 2.

[0008] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a DSC thermogram that is substantially the same as that described in Figure 2.

[0009] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a DSC thermogram with an exotherm having an onset temperature of about 200 °C.

[0010] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form is non-hygroscopic.

[0011] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate salt, and the crystalline form is characterized by the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 1, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ, (c) a thermogravimetric analysis (TGA) substantially similar to that described in Figure 2, (d) a DSC thermogram substantially similar to that described in Figure 2, (e) a DSC thermogram with an exotherm having an onset temperature of about 200 °C, and (f) being non-hygroscopic.

[0012] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form is obtained from acetone / water.

[0013] In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is non-hygroscopic.

[0014] In another embodiment, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is an adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 3, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in Figure 4, (d) A DSC thermogram substantially similar to that described in Figure 4, (e) A DSC thermogram with an exotherm having an onset temperature of about 194 °C, (f) Non-hygroscopicity, or (g) These combinations is Form 2 having at least one of them.

[0015] In some embodiments, it is the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 3.

[0016] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ.

[0017] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that described in FIG. 4.

[0018] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a DSC thermogram substantially similar to that described in FIG. 4.

[0019] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a DSC thermogram with an exotherm having an onset temperature of about 194 °C.

[0020] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form is non-hygroscopic.

[0021] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, or a solvate thereof, and the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 3, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ, (c) thermogravimetric analysis (TGA) substantially similar to that described in Figure 4, (d) a DSC thermogram substantially similar to that described in Figure 4, (e) a DSC thermogram with an exotherm having an onset temperature of about 194 °C, and (f) being non-hygroscopic.

[0022] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form is obtained from acetone.

[0023] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form is anhydrous.

[0024] In another embodiment, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is the adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 5, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in Figure 6, (d) A DSC thermogram substantially similar to that described in Figure 6, (e) A DSC thermogram with a first exotherm having an onset temperature of about 133°C and a second exotherm having an onset temperature of about 177°C, or (f) A combination of these is Form 3 having at least one of these.

[0025] In some embodiments, it is the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 5.

[0026] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ.

[0027] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that described in FIG. 6.

[0028] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a DSC thermogram substantially similar to that described in FIG. 6.

[0029] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has a DSC thermogram with a first exotherm having an onset temperature of about 133 °C and a second exotherm having an onset temperature of about 177 °C.

[0030] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 5, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ, (c) thermogravimetric analysis (TGA) substantially similar to that described in FIG. 6, (d) a DSC thermogram substantially similar to that described in FIG. 6, and (e) a DSC thermogram with a first exotherm having an onset temperature of about 133° C. and a second exotherm having an onset temperature of about 177° C.

[0031] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and the crystalline form is obtained from methyl t-butyl ether.

[0032] In some embodiments, it is a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate for use in a pharmaceutical.

[0033] In one embodiment, it is 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, and 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate is intangible.

[0034] In another aspect, a pharmaceutical composition is described herein that comprises a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0035] In another aspect, a method is described herein for treating an inflammatory disease or an autoimmune disease in an individual in need of treatment for the inflammatory disease or autoimmune disease, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate, or a solvate thereof, as described herein.

[0036] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference to the extent applicable and relevant, and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Brief Description of the Drawings

[0037]

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Mode for Carrying Out the Invention

[0038] As a member of the JAK family of tyrosine kinases, TYK2 mediates the signaling of inflammatory cytokines and is thus a target for treating various inflammatory and autoimmune diseases. A characteristic structural feature of the JAK family is the pseudokinase (JH2) domain immediately N-terminal to the catalytic domain (JH1). The JH2 domain shares the entire folded structure of a typical catalytic domain, but the individual residues and conformational differences between the JH1 and JH2 domains of TYK2 indicate that the JH2 domain has no catalytic activity. The JH2 domain of the JAK family has been shown to regulate the function of the JH1 domain. The overall body of evidence is consistent with the domain of the TYK2 pseudokinase being autoinhibitory, stabilizing the inactivated state of the kinase domain, and a small molecule ligand interfering with the protein's function in an allosteric manner by stabilizing this autoinhibitory conformation (Moslin et al., Med. Chem. Commun., 2017, 700 - 712).

[0039] The compounds of formula (I') described herein are TYK2 pseudokinase ligands. The compounds of formula (I') described herein, and compositions containing these compounds, are useful for treating inflammatory or autoimmune diseases.

[0040] This specification describes the crystalline forms of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1), a TYK2 pseudokinase ligand. The crystalline forms of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea described herein, and compositions containing these crystalline forms, are useful for the treatment of inflammatory or autoimmune diseases.

[0041] Compound 1 In certain embodiments, it is 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea. "Compound 1" or "1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea" refers to a compound having the following structure:

[0042]

Chemical formula

[0043] A variety of pharmaceutically acceptable salts are formed from Compound 1, and these salts include the following: - An acid addition salt formed by reacting Compound 1 with an organic acid including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., for example, acetic acid, adipic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc., an acid addition salt, - An acid addition salt formed by reacting Compound 1 with an inorganic acid including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. is included.

[0044] The term "pharmaceutically acceptable salt" with respect to Compound 1 refers to a salt of Compound 1 that does not cause significant irritation to the administered mammal and does not substantially impair the biological activity and properties of the compound.

[0045] References to pharmaceutically acceptable salts are to be understood to include solvent addition forms (solvates). Solvates include either a stoichiometric or non-stoichiometric amount of a solvent and are formed during the process of formation or isolation of the product with a pharmaceutically acceptable solvent such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In certain embodiments, the solvate is formed using, but not limited to, Class 3 solvents. The categories of solvents are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). When the solvent is water, a hydrate is formed or when the solvent is an alcohol, an alcoholate is formed. In some embodiments, the solvate of Compound 1, or a pharmaceutically acceptable salt thereof, is conveniently prepared or formed during the processes described herein. In some embodiments, the solvate of Compound 1 is anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, exists in a non-solvated form. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, exists in an unsolvated and anhydrous form.

[0046] In yet another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is prepared in various forms including, but not limited to, an amorphous phase, a crystalline form, a milled form, and a nanoparticle form. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous and anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline and anhydrous.

[0047] While not intending to be bound by any particular theory, certain solid forms are characterized by physical properties suitable for pharmaceutical and therapeutic formulations, such as stability, solubility, and dissolution rate. Further, while not desiring to be bound by any particular theory, certain solid forms are characterized by physical properties (such as density, compressibility, hardness, morphology, friability, adhesiveness, solubility, water absorption, electrical properties, thermal behavior, solid-state responsiveness, physical stability, and chemical stability) that affect certain processes (such as production, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that render a particular solid form suitable for the manufacture of solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, including solid-state analytical techniques (such as X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein or known in the art.

[0048] Crystalline form The identification and selection of solid forms of pharmaceutical compounds are complex because changes in solid form can affect various physical and chemical properties, and among several important pharmaceutical properties, can provide benefits or drawbacks in processing, formulation, stability, bioavailability, storage, and handling (e.g., transportation). Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solids varies depending on the specific application, and amorphous solids may be selected, for example, for improved dissolution profiles, while crystalline solids may be desirable for properties such as physical or chemical stability.

[0049] Regardless of whether they are crystalline or amorphous, the solid forms of pharmaceutical compounds include single-component and multi-component solids. Single-component solids contain no other compounds and consist essentially of the pharmaceutical compound or active ingredient. The diversity among single-component crystalline substances can potentially arise from the phenomenon of polymorphism, where multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

[0050] It should be noted that it is not even possible to predict empirically whether a crystalline form of a compound exists, let alone to predict a method for successfully preparing them (e.g., Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism", Chem. Commun.: 3635 - 3645 (in the case of crystal operations where the instructions are not very precise and / or other external factors affect the process, the results can become unpredictable), Jones et al., 2006, "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement", MRS Bulletin 31: 875 - 879 (currently, it is generally not possible to predict computationally the number of observable polymorphs even for the simplest molecules), Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism", Advanced Drug Delivery Reviews 56: 301 - 319 ("Price"), and Bernstein, 2004, "Crystal Structure Prediction and Polymorphism", Acta Crystallographica A 39: 14 - 23 (much still needs to be learned and done before we can state with any degree of confidence our ability to predict crystal structures, let alone polymorphic forms). See).

[0051] The diversity of possible solid forms imparts potential variability to the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid forms are very important in the development of effective, stable, and marketable pharmaceuticals.

[0052] Crystalline Compound 1, adipate Form 1 In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is the adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate is Form 1. In some embodiments, the adipate of crystalline Compound 1 has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in FIG. 2, (d) A DSC thermogram substantially similar to that described in FIG. 2, (e) A DSC thermogram with an exotherm having an onset temperature of about 200 °C, (f) Non-hygroscopic, or (g) At least one of these combinations Characterized by having at least one of Form 1.

[0053] In some embodiments, the crystalline compound 1, adipate form 1 is characterized by having at least two of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 1 is characterized by having at least three of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 1 is characterized by having at least four of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 1 is characterized by having at least five of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 1 is characterized by having the properties of (a) to (f).

[0054] In some embodiments, the crystalline compound 1, adipate form 1 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 1. In some embodiments, the crystalline compound 1, adipate form 1 has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ. In some embodiments, the crystalline compound 1, adipate form 1 has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in FIG. 2. In some embodiments, the crystalline compound 1, adipate form 1 has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in FIG. 2. In some embodiments, the crystalline compound 1, adipate form 1 has a DSC thermogram with an exotherm having an onset temperature of about 200 °C. In some embodiments, the crystalline compound 1, adipate form 1 is non-hygroscopic. In some embodiments, the crystalline compound 1, adipate form 1 is obtained from acetone / water. In some embodiments, the crystalline compound 1, adipate form 1 is solvated. In some embodiments, the crystalline compound 1, adipate form 1 is not solvated.

[0055] Crystalline compound 1, adipate form 2 In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is the adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate is Form 2. In some embodiments, the crystalline Compound 1 adipate has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 3, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in Figure 4, (d) A DSC thermogram substantially similar to that described in Figure 4, (e) A DSC thermogram with an exotherm having an onset temperature of about 194 °C, (f) Non-hygroscopicity, or (g) At least one of these combinations and is characterized by Form 2 having at least one of these.

[0056] In some embodiments, the crystalline compound 1, adipate form 2 is characterized by having at least two of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 2 is characterized by having at least three of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 2 is characterized by having at least four of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 2 is characterized by having at least five of the properties selected from (a) to (f). In some embodiments, the crystalline compound 1, adipate form 2 is characterized by having the properties of (a) to (f).

[0057] In some embodiments, the crystalline compound 1, adipate form 2 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 3. In some embodiments, the crystalline compound 1, adipate form 2 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ. In some embodiments, the crystalline compound 1, adipate form 2 has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 4. In some embodiments, the crystalline compound 1, adipate form 2 has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 4. In some embodiments, the crystalline compound 1, adipate form 2 has a DSC thermogram with an exotherm having an onset temperature of about 194°C. In some embodiments, the crystalline compound 1, adipate form 2 is non-hygroscopic. In some embodiments, the crystalline compound 1, adipate form 2 is obtained from acetone. In some embodiments, the crystalline compound 1, adipate form 2 is solvated. In some embodiments, the crystalline compound 1, adipate form 2 is not solvated.

[0058] Crystalline compound 1, adipate form 3 In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is the adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) adipate is Form 3. In some embodiments, the crystalline Compound 1 adipate has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 5, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in FIG. 6, (d) A DSC thermogram substantially similar to that described in FIG. 6, (e) A DSC thermogram with a first exotherm having an onset temperature of about 133° C. and a second exotherm having an onset temperature of about 177° C., or (f) Combinations thereof Characterized by having at least one of these, which is Form 3.

[0059] In some embodiments, crystalline compound 1, adipate form 3 is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, crystalline compound 1, adipate form 3 is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, crystalline compound 1, adipate form 3 is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, crystalline compound 1, adipate form 3 is characterized by having the properties of (a) to (e).

[0060] In some embodiments, crystalline compound 1, adipate form 3 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 5. In some embodiments, crystalline compound 1, adipate form 3 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ. In some embodiments, crystalline compound 1, adipate form 3 has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in FIG. 6. In some embodiments, crystalline compound 1, adipate form 3 has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in FIG. 6. In some embodiments, crystalline compound 1, adipate form 3 has a DSC thermogram with a first exotherm having an onset temperature of about 133° C. and a second exotherm having an onset temperature of about 177° C. In some embodiments, crystalline compound 1, adipate form 3 is non-hygroscopic. In some embodiments, crystalline compound 1, adipate form 3 is obtained from methyl t-butyl ether. In some embodiments, crystalline compound 1, adipate form 3 is solvated. In some embodiments, crystalline compound 1, adipate form 3 is not solvated.

[0061] Crystalline compound 1, oxalate form 1 In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is an oxalate, and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) oxalate is Form 1. In some embodiments, the crystalline Compound 1 oxalate has the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 7, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.4° 2θ, 8.8° 2θ, 12.9° 2θ, 16.3° 2θ, 17.8° 2θ, 20.0° 2θ, 21.7° 2θ, 23.9° 2θ, 26.4° 2θ, 27.3° 2θ, and 28.4° 2θ, (c) a thermogravimetric analysis (TGA) substantially similar to that described in Figure 8, (d) a DSC thermogram substantially similar to that described in Figure 8, (e) a DSC thermogram with an endotherm having an onset temperature of about 190 °C, followed by an exothermic signal, or (f) a combination of these Characterized by having at least one of Form 1.

[0062] In some embodiments, crystalline Compound 1, oxalate Form 1 is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, oxalate Form 1 is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, oxalate Form 1 is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, oxalate Form 1 is characterized by having the properties of (a) to (e).

[0063] In some embodiments, crystalline Compound 1, oxalate Form 1 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 7. In some embodiments, crystalline Compound 1, oxalate Form 1 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4° 2θ, 8.8° 2θ, 12.9° 2θ, 16.3° 2θ, 17.8° 2θ, 20.0° 2θ, 21.7° 2θ, 23.9° 2θ, 26.4° 2θ, 27.3° 2θ, and 28.4° 2θ. In some embodiments, crystalline Compound 1, oxalate Form 1 has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in FIG. 8. In some embodiments, crystalline Compound 1, oxalate Form 1 has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in FIG. 8. In some embodiments, crystalline Compound 1, oxalate Form 1 has a DSC thermogram with an endotherm having an onset temperature of about 190° C., followed by an exothermic signal. In some embodiments, crystalline Compound 1, oxalate Form 1 is non-hygroscopic. In some embodiments, crystalline Compound 1, oxalate Form 1 is obtained from acetone. In some embodiments, crystalline Compound 1, oxalate Form 1 is solvated. In some embodiments, crystalline Compound 1, oxalate Form 1 is not solvated.

[0064] Crystalline Compound 1, phosphate Form 1 In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is a phosphate, and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) phosphate is Form 1. In some embodiments, the crystalline Compound 1 phosphate has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 9, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.7° 2θ, 14.3° 2θ, 15.8° 2θ, 17.0° 2θ, 17.3° 2θ, 21.1° 2θ, 21.4° 2θ, and 22.3° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in FIG. 10, (d) A DSC thermogram substantially similar to that described in FIG. 10, (e) A DSC thermogram with an exotherm having an onset temperature of about 200 °C, or (f) A combination of these and is characterized by having at least one of them as Form 1.

[0065] In some embodiments, the crystalline Compound 1, phosphate Form 1, is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, the crystalline Compound 1, phosphate Form 1, is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, the crystalline Compound 1, phosphate Form 1, is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, the crystalline Compound 1, phosphate Form 1, is characterized by having the properties of (a) to (e).

[0066] In some embodiments, the crystalline compound 1, phosphate form 1, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 9. In some embodiments, the crystalline compound 1, phosphate form 1, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.7° 2θ, 14.3° 2θ, 15.8° 2θ, 17.0° 2θ, 17.3° 2θ, 21.1° 2θ, 21.4° 2θ, and 22.3° 2θ. In some embodiments, the crystalline compound 1, phosphate form 1, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in FIG. 10. In some embodiments, the crystalline compound 1, phosphate form 1, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in FIG. 10. In some embodiments, the crystalline compound 1, phosphate form 1, has a DSC thermogram with an exotherm having an onset temperature of about 200 °C. In some embodiments, the crystalline compound 1, phosphate form 1, is non-hygroscopic. In some embodiments, the crystalline compound 1, phosphate form 1, is obtained from methanol. In some embodiments, the crystalline compound 1, phosphate form 1, is solvated. In some embodiments, the crystalline compound 1, phosphate form 1, is not solvated.

[0067] Crystalline compound 1, mesylate form 1 In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is methanesulfonate (mesylate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) mesylate is form 1. In some embodiments, crystalline compound 1 mesylate has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 11, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.5° 2θ, 15.5° 2θ, 17.8° 2θ, 18.9° 2θ, 19.3° 2θ, 21.6° 2θ, 22.2° 2θ, 23.2° 2θ, 24.7° 2θ, and 27.8° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in FIG. 12, (d) A DSC thermogram substantially similar to that described in FIG. 12, (e) A DSC thermogram with an exotherm above 195° C., or (f) A combination of these Characterized in that it has at least one of the above.

[0068] In some embodiments, the crystalline Compound 1, mesylate Form 1 is characterized by having at least two of the properties selected from (a)-(e). In some embodiments, the crystalline Compound 1, mesylate Form 1 is characterized by having at least three of the properties selected from (a)-(e). In some embodiments, the crystalline Compound 1, mesylate Form 1 is characterized by having at least four of the properties selected from (a)-(e). In some embodiments, the crystalline Compound 1, mesylate Form 1 is characterized by having the properties of (a)-(e). In some embodiments, the crystalline Compound 1, mesylate Form 1 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 11. In some embodiments, the crystalline Compound 1, mesylate Form 1 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.5° 2θ, 15.5° 2θ, 17.8° 2θ, 18.9° 2θ, 19.3° 2θ, 21.6° 2θ, 22.2° 2θ, 23.2° 2θ, 24.7° 2θ, and 27.8° 2θ. In some embodiments, the crystalline Compound 1, mesylate Form 1 has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 12. In some embodiments, the crystalline Compound 1, mesylate Form 1 has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 12. In some embodiments, the crystalline Compound 1, mesylate Form 1 has a DSC thermogram with an exotherm above about 195°C. In some embodiments, the crystalline Compound 1, mesylate Form 1 is non-hygroscopic. In some embodiments, the crystalline Compound 1, mesylate Form 1 is obtained from ethanol. In some embodiments, the crystalline Compound 1, mesylate Form 1 is solvated. In some embodiments, the crystalline Compound 1, mesylate Form 1 is not solvated.

[0069] Crystalline Compound 1, free base Form A In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is the free base, and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is Form A. In some embodiments, crystalline Compound 1 has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 13, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.5° 2θ, 11.8° 2θ, 12.3° 2θ, 13.3° 2θ, 17.1° 2θ, 19.4° 2θ, 23.7° 2θ, and 26.8° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in FIG. 14, (d) A DSC thermogram substantially similar to that described in FIG. 14, (e) A DSC thermogram with an exotherm having an onset temperature of about 210° C., or (f) Combinations thereof Characterized in that it has at least one of the above. It is Form A.

[0070] In some embodiments, crystalline Compound 1, Form 1 is characterized by having at least two of the properties selected from (a)-(e). In some embodiments, crystalline Compound 1, Form A is characterized by having at least three of the properties selected from (a)-(e). In some embodiments, crystalline Compound 1, Form A is characterized by having at least four of the properties selected from (a)-(e). In some embodiments, crystalline Compound 1, Form A is characterized by having the properties of (a)-(e).

[0071] In some embodiments, the crystalline compound 1, Form A, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 13. In some embodiments, the crystalline compound 1, Form A, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.5° 2θ, 11.8° 2θ, 12.3° 2θ, 13.3° 2θ, 17.1° 2θ, 19.4° 2θ, 23.7° 2θ, and 26.8° 2θ. In some embodiments, the crystalline compound 1, Form A, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in FIG. 14. In some embodiments, the crystalline compound 1, Form A, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in FIG. 14. In some embodiments, the crystalline compound 1, Form A, has a DSC thermogram with an exotherm having an onset temperature of about 210°C. In some embodiments, the crystalline compound 1, Form A, is non-hygroscopic. In some embodiments, the crystalline compound 1, Form A, is obtained from ethyl acetate. In some embodiments, the crystalline compound 1, Form A, is solvated. In some embodiments, the crystalline compound 1, Form A, is not solvated.

[0072] Crystalline compound 1, free base Form B In some embodiments, the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is the free base, and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) is Form B. In some embodiments, the crystalline compound 1 has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 15, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.6° 2θ, 10.1° 2θ, 14.0° 2θ, 16.6° 2θ, 19.7° 2θ, 22.2° 2θ, 24.1° 2θ, and 26.2° 2θ, (c) A thermogravimetric analysis (TGA) substantially similar to that described in FIG. 16, (d) A DSC thermogram substantially similar to that described in FIG. 16, (e) A DSC thermogram with an endothermic peak at about 177° C., followed by an exothermic signal, or (f) Combinations thereof Characterized in that it has at least one of the above, and is Form B.

[0073] In some embodiments, the crystalline Compound 1, Form B is characterized by having at least two of the properties selected from (a)-(e). In some embodiments, the crystalline Compound 1, Form B is characterized by having at least three of the properties selected from (a)-(e). In some embodiments, the crystalline Compound 1, Form B is characterized by having at least four of the properties selected from (a)-(e). In some embodiments, the crystalline Compound 1, Form B is characterized by having the properties of (a)-(e).

[0074] In some embodiments, the crystalline Compound 1, Form B, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 15. In some embodiments, the crystalline Compound 1, Form B, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.6° 2θ, 10.1° 2θ, 14.0° 2θ, 16.6° 2θ, 19.7° 2θ, 22.2° 2θ, 24.1° 2θ, and 26.2° 2θ. In some embodiments, the crystalline Compound 1, Form B, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in FIG. 16. In some embodiments, the crystalline Compound 1, Form B, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in FIG. 16. In some embodiments, the crystalline Compound 1, Form B, has a DSC thermogram with an endothermic peak at about 177° C., followed by an exothermic signal. In some embodiments, the crystalline Compound 1, Form B, is non-hygroscopic. In some embodiments, the crystalline Compound 1, Form B, is obtained from acetic acid. In some embodiments, the crystalline Compound 1, Form B, is solvated. In some embodiments, the crystalline Compound 1, Form B, is an acetic acid solvate. In some embodiments, the crystalline Compound 1, Form B, is unsolvated.

[0075] Preparation of Crystalline Compound 1 In some embodiments, Compound 1 is prepared as described in U.S. Patent Publication No. 2021 / 0139486, which is hereby incorporated by reference in its entirety. In some embodiments, the crystalline form of Compound 1 is prepared as outlined in the Examples. It should be noted that the solvents, temperatures, and other reaction conditions presented herein may vary.

[0076] In certain embodiments, provided herein is a method for preparing a solid form of Compound 1, comprising: 1) obtaining a saturated solution of Compound 1 in a solvent at a first temperature (e.g., 50 °C); 2) adding an antisolvent to the saturated solution at the first temperature; 3) cooling to a second temperature (e.g., -5 °C to room temperature); 4) recovering the solid if precipitation occurs, or evaporating the solvent to recover the solid if no precipitation occurs; and 5) optionally drying. In certain embodiments, provided herein is a method for preparing a solid form of Compound 1, comprising: 1) obtaining a saturated solution of Compound 1 in a solvent at about 50 °C; 2) adding an antisolvent to the saturated solution at about 50 °C; 3) cooling to about room temperature; 4) recovering the solid if precipitation occurs, or evaporating the solvent to recover the solid if no precipitation occurs; and 5) optionally drying. In certain embodiments, the volume ratio of the solvent to the antisolvent is about 1:9. In certain embodiments, the volume ratio of the solvent to the antisolvent is about 1:4. In certain embodiments, the volume ratio of the solvent to the antisolvent is about 1:2. In certain embodiments, the volume ratio of the solvent to the antisolvent is about 1:1. In certain embodiments, the method for preparing the solid form of Compound 1 is an antisolvent recrystallization experiment.

[0077] In another embodiment, crystalline Compound 1, Form 3 is substantially pure. In certain embodiments, substantially pure crystalline Compound 1, Form 3 is substantially free of other solid forms, such as amorphous solids. In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 3 is about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater.

[0078] In another embodiment, crystalline Compound 1, Form 2 is substantially pure. In certain embodiments, substantially pure crystalline Compound 1, Form 2 is substantially free of other solid forms, such as amorphous solids. In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 2 is about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater.

[0079] In another embodiment, crystalline Compound 1, Form 1 is substantially pure. In certain embodiments, substantially pure crystalline Compound 1, Form 1 is substantially free of other solid forms, such as amorphous solids. In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 1 is about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater.

[0080] Suitable solvents Therapeutic agents that are administrable to mammals such as humans must be prepared in accordance with regulatory guidelines. Such government-regulated guidelines are referred to as Good Manufacturing Practice (GMP) for the manufacture and quality control of pharmaceuticals. GMP guidelines outline acceptable levels of contamination of the active therapeutic agent, such as the amount of residual solvent in the final product. In some embodiments, the solvents disclosed herein are suitable for use in GMP facilities and are compatible with industrial safety concerns. Categories of solvents are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents Q3C(R6)", (October 2016).

[0081] Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents that should be limited to use in the manufacture of therapeutic agents. Class 3 solvents are potentially of low toxicity and solvents with low risk to human health. The data on Class 3 solvents indicate that they are of low toxicity in acute or short-term tests and negative in genotoxicity tests.

[0082] Examples of Class 1 solvents to be avoided include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0083] Examples of Class 2 solvents include acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0084] Examples of low-toxicity Class 3 solvents include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0085] Residual solvents in pharmaceutical active ingredients (APIs) originate from the manufacture of APIs. In some cases, the solvents may not be completely removed depending on the actual manufacturing process. Appropriate selection of solvents for API synthesis can improve the yield, and in some cases, determine properties such as crystal form, purity, and solubility. Therefore, solvents are important parameters in the synthesis process.

[0086] In some embodiments, the composition comprising Compound 1 comprises an organic solvent. In some embodiments, the composition comprising Compound 1 comprises a residual amount of an organic solvent. In some embodiments, the composition comprising Compound 1 comprises a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine. In some embodiments, the Class 3 solvent is selected from the group consisting of acetone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0087] In some embodiments, the composition comprising Compound 1 comprises a residual amount of a Class 2 solvent. In some embodiments, the organic solvent is a Class 2 solvent. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, and toluene. In some embodiments, the Class 2 solvent is acetonitrile.

[0088] In some embodiments, the composition comprising Compound 1 comprises a residual amount of a solvent for which sufficient toxicological data has not been found. In some embodiments, the organic solvent is a solvent for which sufficient toxicological data has not been found. In some embodiments, the solvent is selected from the group consisting of 2-butanone and 2-methyltetrahydrofuran.

[0089] Specific terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter. In this application, the use of the singular is intended to include the plural unless specifically stated otherwise. It should be noted that in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Further, the use of the term "including" is not limiting, as with other forms such as "include", "includes", "included", etc. The term "comprising" (and related terms such as "comprise" or "comprises", or "having" or "including") is not intended to exclude, in other particular embodiments, for example, embodiments of any composition of matter, composition, method, or process described herein, from being "consisting of" or "consisting essentially of" the recited characteristics. The term "about", when referring to a numerical value or range of numerical values, means that the recited numerical value or range of numerical values is an approximation within the range of experimental error (or within statistical experimental error), and thus the numerical value or range of numerical values may vary between 1% and 15% of the recited numerical value or range of numerical values.

[0090] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated by reference in their entirety.

[0091] As used herein, the terms "acceptable" or "pharmaceutically acceptable" with respect to a formulation, composition, or ingredient mean that they have no persistent adverse effects on the overall health of the subject being treated, do not impair the biological activity or properties of the compound, and are relatively non-toxic.

[0092] As used herein, "amelioration" of the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to a reduction in severity, a delay in onset, a deceleration of progression, or a shortening of duration, whether permanent or temporary, persistent or transient, that may result from or be associated with the administration of the compound or composition.

[0093] "Bioavailability" refers to the percentage of a compound 1 administered that is delivered to the systemic circulation of the animal or human being tested. The total exposure (AUC (0-∞) ) of a drug when administered intravenously is generally defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which a compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is taken orally, as compared to intravenous injection.

[0094] "Plasma concentration" refers to the concentration of compound 1 in the plasma component of the blood of a subject. It should be understood that the plasma concentration of compound 1 can vary significantly from subject to subject due to variability associated with metabolism and / or potential interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of compound 1 can vary from subject to subject. Similarly, values such as the maximum plasma concentration (C max ) or the time to reach the maximum plasma concentration (T max ), or the total area under the plasma concentration-time curve (AUC (0-∞) ) can vary from subject to subject. Due to this variability, the amount required to constitute a "therapeutically effective amount" of compound 1 can vary from subject to subject.

[0095] As used herein, the term "co - administration" means the administration of a selected therapeutic agent to a single patient and is intended to include treatment regimens where the agent is administered by the same route of administration or different routes of administration, or at the same time or different times.

[0096] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an administered agent or compound that, to some extent, reduces one or more of the symptoms of the disease or disorder being treated. As a result, the signs, symptoms, or causes of the disease may be reduced and / or alleviated, or any other desired change in the biological system may be brought about. For example, in the case of therapeutic use, an "effective amount" is the amount of a composition comprising a compound disclosed herein that provides a clinically significant decrease in disease symptoms without causing undue harmful side effects. The appropriate "effective amount" in any individual case can be determined using techniques such as dose - escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement without causing undue harmful side effects. It should be understood that the "effective amount" or "therapeutically effective amount" can vary from subject to subject due to variations in the metabolism of the compound, the age, weight, general condition of the subject, the disease being treated, the severity of the disease being treated, and the judgment of the prescribing physician. As just one example, a therapeutically effective amount can be determined by dose - escalation clinical trials.

[0097] The terms "enhance" or "enhancing" mean to increase or extend either the potency or the duration of a desired effect. By way of example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or extend the effect of the therapeutic agent during the treatment of a disease, disorder, or illness, either in potency or duration. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of a therapeutic agent in the treatment of a disease, disorder, or illness. When used in a patient, the amount effective for such use will vary depending on the severity and course of the disease, disorder, or illness, previous treatment, the patient's health status and response to the agent, and the judgment of the treating physician.

[0098] The term "preventive-effective amount," as used herein, refers to the amount of a composition applied to a patient that reduces to some extent one or more of the symptoms of a disease, disorder, or illness being treated. In such preventive uses, such amount may vary depending on the patient's health status, weight, etc. By way of example, such a preventive-effective amount can be determined by a dose escalation clinical trial.

[0099] The term "subject," as used herein, refers to an animal that is the subject of treatment, observation, or experiment. By way of example only, the subject may be, but is not limited to, a mammal including a human.

[0100] As used herein, the term "target activity" refers to a biological activity that can be modified by a selective modifying agent. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or processes related to inflammation, and improvement of one or more symptoms related to a disease or illness.

[0101] As used herein, the terms "treat", "treating", or "treatment" include alleviating, reducing, or ameliorating a disease or disorder, preventing additional symptoms, improving or preventing the underlying metabolic cause of the symptoms, inhibiting a disease or disorder, e.g., preventing the onset of a disease or disorder, reducing a disease or disorder, causing regression of a disease or disorder, alleviating a condition caused by a disease or disorder, or arresting the symptoms of a disease or disorder. The terms "treat", "treating", or "treatment" include, but are not limited to, prophylactic treatment and / or therapeutic treatment.

[0102] As used herein, IC 50 refers to the dose, concentration, or amount of a particular test compound that induces a dose-dependent response at 50% of the maximal expression of a particular response that is caused, stimulated, or enhanced by the particular test compound.

[0103] Pharmaceutical composition / formulation The pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that assist in processing the active compound into a pharmaceutically usable preparation. Suitable formulations vary depending on the chosen route of administration. An overview of pharmaceutical compositions described herein can be found, for example, in: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and these documents are hereby incorporated by reference in their entirety.

[0104] As used herein, a pharmaceutical composition refers to a mixture of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates the administration of the compound to a mammal. When practicing the treatment or use methods provided herein, a therapeutically effective amount of Compound 1 is administered in the pharmaceutical composition to a mammal having a disease, disorder, or illness to be treated. Preferably, the mammal is a human. The therapeutically effective amount varies widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used singly or in combination with one or more therapeutic agents as components of a mixture.

[0105] In some embodiments, it is a pharmaceutical composition comprising 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea (Compound 1) and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the adipate of Compound 1, the crystalline form of Form 1, and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the adipate of Compound 1, the crystalline form of Form 2, and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the adipate of Compound 1, the crystalline form of Form 3, and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the oxalate of Compound 1, the crystalline form of Form 1, and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the phosphate of Compound 1, the crystalline form of Form 1, and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the mesylate of Compound 1, the crystalline form of Form 1, and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the free base of Compound 1, the crystalline form of Form A, and a pharmaceutically acceptable excipient. In some embodiments, it is a pharmaceutical composition comprising the free base of Compound 1, the crystalline form of Form B, and a pharmaceutically acceptable excipient.

[0106] As used herein, the term "pharmaceutical combination" means a product resulting from mixing or combining more than one active ingredient, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both the active ingredient, e.g., compound 1, and a co-agent are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient, e.g., compound 1, and a co-agent are administered to a patient as separate entities simultaneously, concurrently, or sequentially without a specific time limit, such that administration provides two compounds at effective levels in the patient's body. The term non-fixed combination also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0107] Pharmaceutical compositions containing the compounds described herein may be manufactured in conventional ways, by way of example only, such as by conventional processes of mixing, dissolving, granulating, sugar coating, levigating, emulsifying, encapsulating, entrapping, or compressing.

[0108] Dosage form The pharmaceutical compositions described herein may be formulated for administration to a mammal by any conventional means, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the terms "subject" or "individual" are used to mean an animal, preferably a mammal including a human or non-human. The terms individual, patient, and subject may be used interchangeably.

[0109] Furthermore, the pharmaceutical compositions described herein containing compound 1 may be formulated into any suitable dosage form, including but not limited to solid oral dosage forms, controlled release formulations, fast dissolving formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiple microparticle formulations, and mixed immediate release and controlled release formulations.

[0110] For oral use, pharmaceutical preparations can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and treating the mixture of granules, after adding suitable auxiliaries if necessary to obtain the core of tablets or dragees. Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Disintegrants such as cross-linked sodium croscarmellose, polyvinylpyrrolidone, agar, or salts of alginic acid such as alginic acid or sodium alginate may be added if necessary.

[0111] Pharmaceutical preparations for oral use include push-fit capsules made of gelatin, as well as soft-sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain an active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Furthermore, a stabilizer may be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0112] In some embodiments, the solid dosage forms disclosed herein may be tablets (including suspension tablets, fast-dissolving tablets, bite-disintegrating tablets, rapid-disintegrating tablets, effervescent tablets, or caplets), pills, powders (including sterile packaged powders, dispersible powders, or effervescent powders), capsules (including both soft capsules and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled-release formulations, pulsatile-release dosage forms, multiple microparticle dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to fast-dissolving tablets. Further, the pharmaceutical formulations described herein may be administered as a single capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered in two, three, or four capsules or tablets.

[0113] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of Compound 1 with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as being homogeneous, it means that the particles of Compound 1 are evenly dispersed throughout the composition, such that the composition can be readily subdivided into equivalent and effective unit dosage forms such as tablets, pills, and capsules. The individual unit dosages may further include a film coating that disintegrates upon oral ingestion or contact with a diluent. These formulations can be manufactured by conventional pharmacological techniques.

[0114] Examples of conventional pharmacological techniques include, for example, (1) dry mixing method, (2) direct compression method, (3) milling method, (4) dry or non-aqueous granulation method, (5) wet granulation method, or (6) fusion method, either alone or in combination. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, solution granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0115] The pharmaceutical solid dosage forms described herein may contain one or more pharmaceutically acceptable additives such as Compound 1, and a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegrant, dispersant, surfactant, lubricant, coloring agent, diluent, solubilizer, humectant, plasticizer, stabilizer, transdermal absorption enhancer, wetting agent, defoaming agent, antioxidant, preservative, or a combination of one or more thereof. In yet another aspect, a film coating is provided around the formulation of Compound 1 using standard coating procedures such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000). In certain embodiments, some or all of the particles of Compound 1 are coated. In another embodiment, some or all of the particles of Compound 1 are microencapsulated. In yet another embodiment, the particles of Compound 1 are neither microencapsulated nor coated.

[0116] Examples of carriers suitable for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, etc.

[0117] Examples of fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrate, dextran, starch, pregelatinized starch, hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc.

[0118] In order to release Compound 1 from a solid dosage form matrix as efficiently as possible, especially when the dosage form is compressed with a binder, disintegrants are often used in the formulation. Disintegrants assist in rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Disintegrants suitable for use in the solid dosage forms described herein include natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolates such as Promogel® or Explotab®, celluloses such as wood products, methylcellulose crystals, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked celluloses such as cross-linked carboxymethylcellulose or cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), agar, guar, locust bean, karaya, pectin, or tragacanth gums, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate combined with starch, etc., but are not limited thereto.In some embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methylcellulose crystals, methylcellulose, croscarmellose, sodium croscarmellose, sodium crosslinked carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, or gums. In some embodiments provided herein, the disintegrant is sodium croscarmellose.

[0119] The binder imparts cohesiveness to solid oral dosage form formulations. In capsule formulations filled with powder, the binder aids in plug formation that can be filled into soft shell or hard shell capsules, and in tablet formulations, the binder ensures that the tablets remain intact after compression and ensures uniform blending prior to the compression or filling step. Substances suitable for use as binders in the solid dosage forms described herein include carboxymethyl cellulose, methyl cellulose (e.g., Methocel®), hydroxypropyl methyl cellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropyl methyl cellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrins, amylose, magnesium aluminum silicate, polygalacturonic acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), sugars such as lactose, gum arabic, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, natural or synthetic gums such as sodium alginate, and the like, but are not limited thereto.

[0120] Generally, in gelatin capsule formulations filled with powder, binder levels of 20 - 70% are used. The level of binder used in tablet formulations varies depending on whether it is direct compression, wet granulation, roller compression, or whether other excipients such as fillers that can act as moderate binders themselves are used. Formulators in the art can determine the binder level for a formulation, but a maximum binder usage level of 70% is common in tablet formulations.

[0121] Lubricants or glidants suitable for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, salts of alkali metals and alkaline earth metals such as calcium, magnesium, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax®, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate. In some embodiments provided herein, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments provided herein, the lubricant is magnesium stearate.

[0122] Diluents suitable for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrins, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, powdered cellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0123] The term "water-insoluble diluent" refers to compounds commonly used in pharmaceutical formulations, such as calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, powdered cellulose (having a density of, for example, about 0.45 g / cm 3 and being, for example, Avicel, powdered cellulose), and talc.

[0124] Wetting agents suitable for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (such as Polyquat 10 (registered trademark)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0125] Surfactants suitable for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like. In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0126] Suspending agents suitable for use in the solid dosage forms described herein include polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethyl cellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums, such as tragacanth gum, gum arabic, guar gum, xanthan gum including xanthan, sugars, cellulose-based, such as sodium carboxymethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like, but are not limited thereto.

[0127] Examples of antioxidants suitable for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0128] It should be recognized that there is a significant overlap among the additives used in the solid dosage forms described herein. Accordingly, the additives listed above are merely exemplary and should not be construed as limiting the types of additives that can be included in the solid dosage forms described herein. The amount of such additives can be readily determined by one of ordinary skill in the art according to the particular desired properties.

[0129] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Exemplarily, the plasticizer is typically a high-boiling solid or liquid. Suitable plasticizers can be added at about 0.01 wt% to about 50 wt% (w / w) of the coating composition. Examples of plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0130] Compressed tablets are solid dosage forms prepared by compressing the bulk formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavoring agents. In other embodiments, the compressed tablets contain a film agent that wraps the final compressed tablet. In some embodiments, a film coating can provide a delayed release of the compound from the formulation. In other embodiments, a film coating (e.g., an Opadry® coating, or a sugar coating) aids in patient compliance. Film coatings containing Opadry® typically range from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets contain one or more excipients.

[0131] The capsule formulation can be prepared, for example, by placing the bulk formulation of Compound 1 inside the capsule. In some embodiments, the formulation (non-aqueous suspensions and solutions) is placed in soft gelatin capsules. In some embodiments, the formulation (non-aqueous suspensions and solutions) is placed in hard shell gelatin capsules. In other embodiments, the formulation is placed in standard gelatin capsules or non-gelatin capsules such as capsules containing HPMC. In other embodiments, the formulation is placed in sprinkle capsules, where the capsule formulation may be swallowed whole or the capsule may be opened and the contents sprinkled on food before a meal. In some embodiments, the therapeutic dose is divided into multiple (e.g., 2, 3, or 4) capsule formulations. In some embodiments, the total dose of the formulation is delivered in the form of capsule formulations.

[0132] In various embodiments, the particles of Compound 1 and one or more excipients are dry blended and compressed into a mass such as a tablet, which has sufficient hardness to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0133] In another aspect, the dosage form may include a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulating material. Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, defoaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizing agents, stabilizers, lubricants, wetting agents, and diluents.

[0134] Materials useful for microencapsulation described herein include materials compatible with Compound 1 that sufficiently separate Compound 1 from other incompatible excipients. Materials compatible with Compound 1 are those that delay the release of the compound of Compound 1 in vivo.

[0135] Exemplary microencapsulation materials useful for delaying the release of formulations containing the compounds described herein include hydroxypropylcellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropylcellulose ether (L-HPC), Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, hydroxypropylmethylcellulose ethers (HPMC) such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS), and methylcellulose polymers such as Metolose®, ethylcellulose (EC) and mixtures thereof, e.g., E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA), e.g., Opadry AMB, hydroxyethylcellulose, e.g., Natrosol®, carboxymethylcellulose, and salts of carboxymethylcellulose (CMC) such as Aqualon®-CMC, polyethylene glycol copolymers such as polyvinyl alcohol and Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, processed food starch, acrylic polymers, and mixtures of acrylic polymers with cellulose ethers, e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5. Examples include, but are not limited to, Eudragit® NE30D and Eudragit® NE40D, cellulose acetate phthalate, sepifilms, such as a mixture of HPMC and stearic acid, cyclodextrin, and mixtures of such materials.

[0136] In still other embodiments, plasticizers such as polyethylene glycol, for example, PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulation material useful for delaying the release of the pharmaceutical composition is from the USP or the National Formulary (NF). In still other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is methocel.

[0137] The microencapsulated Compound 1 can be formulated by several methods, specific examples of which include, for example, spray drying process, rotating disk solvent process, hot melt process, spray cooling process, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at liquid-gas interface or solid-gas interface, pressure extrusion, or spray solvent extraction bath. In addition to these, several chemical techniques, such as complex coacervation, dissolution evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, drying in liquid, and desolvation in liquid medium can also be used. Further, other methods such as roller compression, extrusion / spheronization, coacervation, or nanoparticle coating can also be used.

[0138] In one embodiment, the particles of Compound 1 are microencapsulated before being formulated into one of the above forms. In yet another embodiment, some or most of the particles are coated before further formulation by using standard coating procedures, such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000).

[0139] In other embodiments, the solid dosage formulations of Compound 1 are plasticized (coated) with one or more layers. Exemplarily, the plasticizer is generally a high-boiling solid or liquid. Suitable plasticizers can be added at about 0.01 wt% to about 50 wt% (w / w) of the coating composition. Examples of plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearyl alcohol, stearate, and castor oil.

[0140] In other embodiments, powders containing formulations having Compound 1 can be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders can be prepared, for example, by mixing the formulation and any pharmaceutical excipients to form a bulk blend composition. Additional embodiments include suspending agents and / or wetting agents. This bulk blend is uniformly subdivided into units of unit dose packages or multiple dose packages.

[0141] In yet other embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are typically granules or coarse powders containing a drug in a dry mixture composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the compositions described herein are added to water, the acid and base react to release carbon dioxide gas, thereby causing "effervescence". Examples of effervescent salts include, for example, the following components: sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the release of carbon dioxide can be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, provided the components are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0142] In some embodiments, the solid dosage forms described herein can be formulated as enteric-coated delayed-release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein that utilize enteric coating to affect release in the small intestine of the gastrointestinal tract. Also, enteric-coated dosage forms can be compressed, molded, or extruded (coated or uncoated) tablets / molds that contain granules, powders, pellets, beads, or particles of the active ingredient and / or other composition components, whether coated or uncoated. Enteric-coated oral dosage forms can be capsules (coated or uncoated) that contain pellets, beads, or granules of a solid carrier or composition, whether coated or uncoated.

[0143] As used herein, the term "delayed release" refers to delivery such that release can be achieved at some generally predictable location in the intestinal tract, distal to the location that would have been achieved in the absence of a change in delayed release. In some embodiments, the method for delaying release is a coating. Any coating agent should be applied to a sufficient thickness such that the entire coating does not dissolve in digestive fluid at a pH of less than about 5, but does dissolve at a pH of about 5 or greater. It is contemplated that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and mixtures having compatibility therewith, and some of their properties include, but are not limited to, the following.

[0144] Shellac, also referred to as purified lac, is a purified product obtained from the resinous secretion of insects. This coating agent dissolves in media with a pH above 7.

[0145] Acrylic polymers. The performance of acrylic polymers (primarily solubility in biological fluids) can vary depending on the degree and type of substitution. Examples of suitable acrylic polymers include copolymers of methacrylic acid and ammonium methacrylate. The Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available solubilized in organic solvents, aqueous dispersions, or as dry powders. The Eudragit series RL, NE, and RS are insoluble but permeable in the digestive tract and are primarily used for colonic targeting. The Eudragit series E dissolves in the stomach. The Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine.

[0146] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose, and a reaction mixture of a partial acetate ester of cellulose with phthalic anhydride. Their performance can vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves above pH 6. Aquateric (FMC) is an aqueous-based system, a spray-dried CAP pseudolatex with particles less than 1 μm. Other components in Aquateric can include Pluronic®, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman), methyl cellulose (Pharmacoat, Methocel), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCS), and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Their performance can vary depending on the degree and type of substitution. For example, grades of HPMCP such as HP-50, HP-55, HP-55S, or HP-55F are suitable. Their performance can vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF) which dissolves at pH 5, AS-MG (MF) which dissolves at pH 5.5, and AS-HG (HF) which dissolves at a higher pH. These polymers are provided as granules or fine powders for aqueous dispersions. Polyvinyl acetate phthalate (PVAP). PVAP dissolves above pH 5 and has very low permeability to water vapor and gastric juice.

[0147] In some embodiments, the coating agent may include a plasticizer and, optionally, other coating excipients such as a colorant, talc, and / or magnesium stearate, and usually includes these. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyltriethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglyceride, glycerol, fatty acid ester, propylene glycol, and dibutyl phthalate. In particular, an anionic carboxylic acid acrylic polymer usually contains 10% to 25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. To apply the coating agent, conventional coating techniques such as spray coating or pan coating are used. The thickness of the coating must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired site of local delivery in the intestinal tract.

[0148] Colorants, detackifiers, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG) are added to the coating agent in addition to the plasticizer to solubilize or disperse the coating material and improve the coating performance and the coated product.

[0149] In other embodiments, the formulations described herein that include Compound 1 are delivered using a pulsatile dosage form. The pulsatile dosage form can provide one or more immediate release pulses at a predetermined time point after a controlled delay time or at a specific site. Other types of controlled release systems may be used. Examples of such delivery systems include, for example, polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides, and polycaprolactone, porous matrices, sterols such as cholesterol, cholesterol esters, and fatty acids, or neutral fats such as monoglycerides, diglycerides, and triglycerides, non-polymer-based systems, hydrogel release systems, silastic systems, peptide-based systems, wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990), Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002), U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983 (each of these references and patents is specifically incorporated by reference).

[0150] In some embodiments, a pharmaceutical formulation is provided for oral administration to a subject, the formulation comprising particles of Compound 1 and at least one dispersing or suspending agent. The formulation may be a powder and / or granule for suspension that, when mixed with water, provides a substantially homogeneous suspension.

[0151] Since a given additive is often classified differently by different practitioners in the art, or is commonly used for any of a plurality of different functions, it should be understood that there is overlap among the additives listed above that are used in the aqueous dispersions and suspensions described herein. Accordingly, the additives listed above should be construed as merely exemplary of the types of additives that may be included in the formulations described herein, and not as limiting. The amount of such additives can be readily determined by one of ordinary skill in the art in accordance with the particular properties desired.

[0152] Method In some embodiments, it is a method for treating an inflammatory disease or an autoimmune disease in a patient in need of treatment for the inflammatory disease or autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein. In some embodiments, it is a method for treating an inflammatory disease in a patient in need of treatment for the inflammatory disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein. In some embodiments, it is a method for treating an autoimmune disease in a patient in need of treatment for the autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein. In some embodiments, it is a method for treating an inflammatory disease or an autoimmune disease in a patient in need of treatment for the inflammatory disease or autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis. In some embodiments, it is a method for treating an inflammatory disease or an autoimmune disease in a patient in need of treatment for the inflammatory disease or autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is rheumatoid arthritis. In some embodiments, it is a method for treating an inflammatory disease or an autoimmune disease in a patient in need of treatment for the inflammatory disease or autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is multiple sclerosis. In some embodiments, it is a method for treating an inflammatory disease or an autoimmune disease in a patient in need of treatment for the inflammatory disease or autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is psoriasis. In some embodiments, it is a method for treating an inflammatory disease or an autoimmune disease in a patient in need of treatment for the inflammatory disease or autoimmune disease, comprising the step of administering to the patient a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is lupus.In some embodiments, a method of treating an inflammatory disease or autoimmune disease in a patient in need of treatment of an inflammatory disease or autoimmune disease, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is an intestinal disease. In some embodiments, a method of treating an inflammatory disease or autoimmune disease in a patient in need of treatment of an inflammatory disease or autoimmune disease, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is Crohn's disease. In some embodiments, a method of treating an inflammatory disease or autoimmune disease in a patient in need of treatment of an inflammatory disease or autoimmune disease, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is ulcerative colitis. In some embodiments, a method of treating an inflammatory disease or autoimmune disease in a patient in need of treatment of an inflammatory disease or autoimmune disease, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is ankylosing spondylitis. In some embodiments, a method of treating an inflammatory disease or autoimmune disease in a patient in need of treatment of an inflammatory disease or autoimmune disease, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is vitiligo. In some embodiments, a method of treating an inflammatory disease or autoimmune disease in a patient in need of treatment of an inflammatory disease or autoimmune disease, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness is atopic dermatitis.

[0153] Dosage Methods and Treatment Regimens In some embodiments, crystalline Compound 1 is used in the preparation of a medicament for treating a disease or disorder that would benefit from TYK2 inhibition. Further, in an individual in need of treatment for any of the diseases or disorders described herein, a method of treating any of the diseases or disorders comprises administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising crystalline Compound 1 or a pharmaceutically acceptable solvate thereof.

[0154] In some embodiments, the composition comprising crystalline Compound 1 is administered for prophylactic treatment, therapeutic treatment, or maintenance treatment. In some embodiments, the composition comprising Compound 1 is administered for therapeutic use. In some embodiments, the composition comprising Compound 1 is administered for prophylactic use.

[0155] For therapeutic use, the composition is administered to a patient already suffering from a disease or disorder in an amount sufficient to remove or at least partially arrest the symptoms of the disease or disorder. The amount effective for this use varies depending on the severity and course of the disease or disorder, previous treatment, the health status, weight, and response of the patient to the drug, as well as the judgment of the physician administering the treatment.

[0156] For prophylactic use, the composition comprising the compounds described herein is administered to a patient who is susceptible to or at risk of developing a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also varies depending on the health status, weight, etc. of the patient. When used in a patient, the amount effective for this use varies depending on the severity and course of the disease, disorder, or condition, previous treatment, the health status of the patient, and response to the drug, as well as the judgment of the physician administering the treatment.

[0157] In some embodiments, crystalline Compound 1 is administered daily. In some embodiments, crystalline Compound 1 is administered every other day.

[0158] In some embodiments, crystalline Compound 1 is administered once a day. In some embodiments, crystalline Compound 1 is administered twice a day. In some embodiments, crystalline Compound 1 is administered three times a day. In some embodiments, crystalline Compound 1 is administered four times a day.

[0159] If the patient's disease does not improve, based on the discretion of the physician, the administration of the compound may be carried out chronically, i.e., over a long period including the patient's lifetime, in order to reduce or otherwise control or limit the symptoms of the patient's disorder or disease.

[0160] When the patient's condition improves, a maintenance dose is administered as needed. Thereafter, the dose or dosing frequency, or both, may be reduced to a level at which improvement of the disease, disorder, or disease persists, depending on the symptoms. However, upon any recurrence of symptoms, the patient may require intermittent treatment over a long period.

[0161] The amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the disease or disorder and its severity, the identity (e.g., weight) of the subject or host in need of treatment, etc., but nevertheless can be determined in a manner recognized in the art according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, the subject or host being treated. However, generally, the doses used for the treatment of adults are typically from about 0.002 mg to about 5000 mg per day, and in some embodiments, from about 1 mg to 1500 mg per day. The desired dose may conveniently be presented as a single dose or as divided doses, administered simultaneously (or over a short period) or at appropriate intervals, for example, as two, three, or more sub-doses per day.

[0162] The pharmaceutical compositions described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage forms, the formulation is divided into unit doses containing an appropriate amount of one or more compounds. The unit dosage may be in the form of a package containing a discrete quantity of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. An aqueous suspension composition can be packaged in a non-reclosable container for single dosage. Alternatively, a reclosable container for multiple dosages can be used, in which case it is typical to include a preservative in the composition. By way of example only, a formulation for parenteral injection can be presented in unit dosage forms including, but not limited to, ampoules, or in a multiple-dose container with added preservative.

[0163] A suitable daily dosage for the compounds described herein is from about 0.01 mg / kg to about 20 mg / kg. In certain embodiments, the daily dosage is from about 0.1 mg / kg to about 10 mg / kg. The specified daily dosage in large mammals, including but not limited to humans, ranges from about 0.5 mg to about 1000 mg and is preferably administered in a single dose, or in divided doses including, but not limited to, up to 4 times a day, or in a sustained release form. Unit dosage forms suitable for oral administration contain from about 1 mg to about 500 mg of the active ingredient. In certain embodiments, the unit dosage is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. Because of the large number of variables regarding individual treatment regimens, the foregoing ranges are only suggestive and it is not uncommon to deviate considerably from these recommended values. Such dosages may be varied depending upon numerous variables, including but not limited to the activity of the compound used, the disease or disorder being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disorder being treated, and the judgment of the physician.

[0164] The toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. This pharmaceutical procedure involves LD 50(Lethal dose for 50% of the population) and ED 50 (Dose at which 50% of the population shows a therapeutic effect), including but not limited to. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, and LD 50 and ED 50 can be expressed as the ratio of. Data obtained from cell culture assays and animal tests can be used to formulate various doses for use in humans. The dosage of such compounds preferably lies within the circulating concentration that includes the minimally toxic ED 50 . The dosage may vary within this range depending on the dosage form used and the route of administration utilized.

[0165] Kit / Product For use in the treatment methods described herein, kits and products are also described herein. Such kits include a carrier, wrapper, or container partitioned to contain one or more containers such as vials, tubes, etc., each of the containers containing one of the distinct elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In certain embodiments, the containers are formed from various materials such as glass or plastic.

[0166] The products provided herein include a packaging material. Examples of packaging materials used for the packaging of pharmaceuticals include, for example, U.S. Patent No. 5,323,907. Examples of packaging materials for pharmaceuticals include blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment, but are not limited thereto.

[0167] In some embodiments, the compounds or compositions described herein are presented in a package or dispenser device that may include one or more unit dosage forms containing the active ingredient. The compounds or compositions described herein may be packaged alone or together with another compound or other ingredient or additive. In some embodiments, the package includes one or more containers filled with one or more of the components of the pharmaceutical composition. In some embodiments, the package includes a metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser device is accompanied by instructions for administration, such as instructions for the administration of the compound or composition for treating a neoplastic disease. In some embodiments, the package or dispenser is accompanied by a notice affixed to the container in a form determined by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and this notice reflects the approval of the government agency for the form of the agent for administration to humans or animals. In some embodiments, such a notice is, for example, a label approved by the U.S. Food and Drug Administration for a prescription drug or approved product insert. In some embodiments, a composition comprising a compound described herein formulated in a pharmaceutically compatible carrier is prepared, placed in a suitable container, and labeled for the treatment of the indicated disease.

[0168] For example, the container optionally contains crystalline Compound 1 in the composition or in combination with another agent disclosed herein. Such a kit optionally includes a descriptive label or tag for identification or instructions for use in the methods described herein.

[0169] Kits typically include a label listing the contents and / or instructions for use and a product insert with instructions for use. Typically, a set of instructions is also included.

[0170] In certain embodiments, the label is on or associated with the container. In certain embodiments, if the letters, numbers, or other symbols forming the label are affixed, molded, or engraved on the container itself, the label is on the container, and the label is associated with the container if it is present, for example, as an accompanying document, in a receptacle or carrier that also holds the container. In certain embodiments, the label is used to indicate that the contents are to be used for a particular therapeutic purpose. The label also indicates, for example, the method of use of the contents, such as by the methods described herein.

[0171] In certain specific embodiments, the pharmaceutical composition is presented in a pack or dispenser device comprising one or more unit dosage forms containing the compounds provided herein. The pack includes, for example, a metal or plastic foil such as a blister pack. In certain embodiments, the pack or dispenser device is accompanied by instructions for administration. In certain embodiments, the pack or dispenser is also accompanied by a notice attached to a container in a form determined by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and this notice reflects the approval of the government agency regarding the form of the agent for administration to humans or animals. Such a notice is, for example, a label approved by the US Food and Drug Administration for prescription drugs or approved accompanying documents. In certain embodiments, a composition comprising a compound provided herein, formulated in a pharmaceutically compatible carrier, is prepared, placed in a suitable container, and labeled for the treatment of the indicated disease.

Examples

[0172] List of Abbreviations Throughout the description of the present invention, the following abbreviations are to be understood to have the following meanings unless otherwise indicated. ACN or MeCN Acetonitrile Bn Benzyl BOC or Boc tert-Butylcarbamate t-Bu tert-Butyl Cy Cyclohexyl DCE Dichloroethane (ClCH2CH2Cl) DCM Dichloromethane (CH2Cl2) DIPEA or DIEA Diisopropylethylamine DMAP 4-(N,N-Dimethylamino)pyridine DMF Dimethylformamide DMA N,N-Dimethylacetamide DMSO Dimethylsulfoxide eq or equiv Equivalent Et Ethyl Et2O Diethyl ether EtOH Ethanol EtOAc Ethyl acetate HPLC High Performance Liquid Chromatography IPA Isopropanol Me Methyl MeOH Methanol MS Mass Spectrometry GC Gas Chromatography h Hour KF Karl Fischer min Minute MsOH Methanesulfonic acid NMP N-Methylpyrrolidine NMR Nuclear Magnetic Resonance RP-HPLC Reverse Phase High Performance Liquid Chromatography rt Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography V Volume

[0173] I. Synthesis of the Free Base Polymorphs of Compound 1

[0174] [Chemical formula] Example 1A: Synthesis of the Free Base of Compound 1, Form A A solution of intermediate A (84 g, 0.152 mol, 1.0 equiv) in DCM (1000 mL), prepared as described in US Patent Publication No. 2021 / 0139486, was added with triethylsilane (26.5 g, 0.228 mol, 1.5 equiv). After stirring for 10 minutes, TFA (200 mL) was added to the mixture, and the reaction solution was stirred at room temperature for 0.5 hour. TfOH (45 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated NaHCO3 (250 mL). The solid was collected by filtration and dried under vacuum. The solid was triturated with EtOH (250 mL) and collected by filtration. The solid was triturated with EtOAc (2 x 250 mL). The solid was collected by filtration and dried under vacuum to obtain the free base of Compound 1, Form A (39.6 g, 60%) as a yellow solid. LCMS: m / z calculated for [M+H] + = 432.2, 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.17 (dd, J = 11.8, 3.2 Hz, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.55 (q, J = 4.4 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 6.35 (dd, J = 9.6, 3.0 Hz, 1H), 5.94 (s, 1H), 4.71 (ddd, J = 65.2, 8.4, 5.8 Hz, 1H), 4.31 (q, J = 4.8 Hz, 4H), 2.88 (d, J = 4.7 Hz, 3H), 2.63 (m, 1H), 1.03 (m, 1H), 0.88 - 0.73 (m, 1H).

[0175] Example 1B: Synthesis of the free base of Compound 1, Form B The free base of Compound 1, Form A (4 g) was added to acetic acid (40 mL), and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed with cold acetic acid (15 mL). The solid was dried under high vacuum at 45 °C for 6 hours to obtain the free base of Compound 1, Form B.

[0176] II. Characterization of Polymorphs Example 2: X-ray Powder Diffraction (XRPD) The XRPD pattern was identified by an X-ray diffractometer (PANalytical Empyrean). The system was equipped with a PIXcel1D detector. The sample was scanned from 3 to 40° 2θ with a step size of 0.013° 2θ. The tube voltage and tube current were 45 kV and 40 mA, respectively.

[0177] Alternatively, the XRPD pattern was collected using a Bruker D8 Advance diffractometer. The X-ray source was a Cu tube operated at 40 kV and 40 mA. The axial soller was 4.1° and the divergence slit was 0.6 mm. The powder sample was prepared on a zero-background Si holder using manual optical pressure to keep the sample surface flat. Each sample was analyzed from 3 to 45° 2θ with an effective step size of 0.02° 2θ and an exposure time of 0.2 s.

[0178] XRPD analysis of adipate of Compound 1, Form 1 (Figure 1) showed that adipate of Compound 1, Form 1 is crystalline with characteristic peaks at 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ.

[0179] XRPD analysis of adipate of Compound 1, Form 2 (Figure 3) showed that adipate of Compound 1, Form 2 is crystalline with characteristic peaks at 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ.

[0180] XRPD analysis of adipate of Compound 1, Form 1 (Figure 5) showed that adipate of Compound 1, Form 1 is crystalline with characteristic peaks at 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ.

[0181] The XRPD analysis (Figure 7) of the oxalate of Compound 1, Form 1, showed that the oxalate of Compound 1, Form 1, is crystalline with characteristic peaks at 5.4° 2θ, 8.8° 2θ, 12.9° 2θ, 16.3° 2θ, 17.8° 2θ, 20.0° 2θ, 21.7° 2θ, 23.9° 2θ, 26.4° 2θ, 27.3° 2θ, and 28.4° 2θ.

[0182] The XRPD analysis (Figure 9) of the phosphate of Compound 1, Form 1, showed that the phosphate of Compound 1, Form 1, is crystalline with characteristic peaks at 8.7° 2θ, 14.3° 2θ, 15.8° 2θ, 17.0° 2θ, 17.3° 2θ, 21.1° 2θ, 21.4° 2θ, and 22.3° 2θ.

[0183] The XRPD analysis (Figure 11) of the mesylate of Compound 1, Form 1, showed that the mesylate of Compound 1, Form 1, is crystalline with characteristic peaks at 7.5° 2θ, 15.5° 2θ, 17.8° 2θ, 18.9° 2θ, 19.3° 2θ, 21.6° 2θ, 22.2° 2θ, 23.2° 2θ, 24.7° 2θ, and 27.8° 2θ.

[0184] The XRPD analysis (Figure 13) of the free base of Compound 1, Form A, showed that the free base of Compound 1, Form A, is crystalline with characteristic peaks at 8.5° 2θ, 11.8° 2θ, 12.3° 2θ, 13.3° 2θ, 17.1° 2θ, 19.4° 2θ, 23.7° 2θ, and 26.8° 2θ.

[0185] The XRPD analysis (Figure 15) of the free base of Compound 1, Form B, showed that the free base of Compound 1, Form B, is crystalline with characteristic peaks at 6.6° 2θ, 10.1° 2θ, 14.0° 2θ, 16.6° 2θ, 19.7° 2θ, 22.2° 2θ, 24.1° 2θ, and 26.2° 2θ.

[0186] Example 3: Polarized Light Microscopy (PLM) Optical microscopy was performed using a polarizing microscope ECLIPSE LV100POL (Nikon, JPN) or a Motic BA310Met (Motic, CN) optical microscope equipped with a polarizer under a 50x objective lens.

[0187] For the adipate of Compound 1, PLM analysis of Form 1 showed plate-like crystals with a particle size of 10 - 100 μm.

[0188] For the adipate of Compound 1, PLM analysis of Form 2 showed lumps and irregularly shaped crystals with a particle size of less than 10 μm.

[0189] For the adipate of Compound 1, PLM analysis of Form 3 showed lumps and irregularly shaped crystals with a particle size of less than 20 μm.

[0190] For the oxalate of Compound 1, PLM analysis of Form 1 showed irregularly shaped crystals with high crystallinity and a particle size of less than 10 μm.

[0191] For the phosphate of Compound 1, PLM analysis of Form 1 showed irregularly shaped crystals with high crystallinity and a particle size of less than 10 μm.

[0192] For the mesylate of Compound 1, PLM analysis of Form 1 showed microcrystalline prisms.

[0193] For Compound 1, PLM analysis of Form A showed microcrystalline clusters.

[0194] For Compound 1, PLM analysis of Form B showed microcrystalline prisms.

[0195] Example 4: Thermogravimetric analysis (TGA) TGA was performed using a Discovery TGA 55 (TA Instruments, USA). The sample was placed in a pre-weighed aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated from room temperature (RT) to the final temperature at a rate of 10 °C / min.

[0196] For the adipate of Compound 1, the TGA of Form 1 (Figure 2) showed no weight loss before 150 °C.

[0197] For the adipate of Compound 1, the TGA of Form 2 (Figure 4) showed no weight loss before decomposition onset at about 150 °C.

[0198] For the adipate of Compound 1, the TGA of Form 3 (Figure 6) showed a weight loss of about 0.2% before 100 °C.

[0199] For the oxalate of Compound 1, the TGA of Form 1 (Figure 8) showed no weight loss before 150 °C.

[0200] For the phosphate of Compound 1, the TGA of Form 1 (Figure 10) showed no weight loss before 150 °C.

[0201] For the mesylate of Compound 1, the TGA of Form 1 (Figure 12) showed a weight loss of about 0.5% before 100 °C.

[0202] For Compound 1, Form A, the TGA (Figure 14) showed a weight loss of about 1.7% before 100 °C.

[0203] For Compound 1, Form B, the TGA (Figure 16) showed a weight loss of about 10.6% before 150 °C.

[0204] Example 5: Differential Scanning Calorimetry (DSC) DSC was performed using a Discovery DSC 250 (TA Instruments, USA). The sample was placed in an aluminum pinhole-sealed pan and its weight was accurately recorded. Then, the sample was heated from 25 °C to the final temperature at a rate of 10 °C / min.

[0205] For the adipate of Compound 1, the DSC analysis of Form 1 (Figure 2) showed a single exothermic peak with an onset at 200 °C.

[0206] The adipate of Compound 1, DSC analysis of Form 2 (Figure 4) showed a single exothermic peak with an onset at 194 °C.

[0207] The adipate of Compound 1, DSC analysis of Form 3 (Figure 6) showed a first exotherm with an onset temperature of about 133 °C and a second exotherm with an onset temperature of about 177 °C.

[0208] The oxalate of Compound 1, DSC of Form 1 (Figure 8) showed an endotherm with an onset temperature of about 190 °C, followed by an exothermic signal.

[0209] The phosphate of Compound 1, DSC of Form 1 (Figure 10) showed a single exothermic peak with an onset temperature of 200 °C.

[0210] The mesylate of Compound 1, DSC of Form 1 (Figure 12) showed an exotherm at a temperature higher than 195 °C.

[0211] Compound 1, DSC of Form A (Figure 14) showed a single exothermic peak with an onset temperature of 210 °C.

[0212] Compound 1, DSC of Form B (Figure 16) showed an endothermic peak at about 177 °C, followed by an exothermic signal.

[0213] Example 6: Dynamic Vapor Sorption Analysis (DVS) DVS data were collected using a Vsorp Dynamic Moisture Sorption Analyzer (ProUmid GmbH & Co. KG, Germany). The sample was placed in a degassed sample chamber and automatically weighed. Sample temperature: 25 °C Cycle: Complete cycle Adsorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 Desorption: 80, 70, 60, 50, 40, 30, 20, 10, 0 The sample after the DVS experiment was characterized by XRPD.

[0214] Alternatively, the DVS analysis was performed using a Surface Measurement System DVS Intrinsic analyzer. The instrument was calibrated with a standard weight. Samples of approximately 15 - 20 mg were loaded into the analysis pans. The samples were analyzed at 25 °C with 10% relative humidity (RH) steps of 50% - 95% RH (adsorption cycle), 95% - 0% RH (desorption cycle), and 0% - 50% RH (adsorption cycle). The transition from one step to the next occurred either after meeting an equilibrium criterion of a 0.002% weight change (dm / dt) or after 10 hours if the equilibrium criterion was not met. The samples after the DVS test were examined by XRPD.

[0215] For the adipate of Compound 1, Form 1, the DVS analysis showed less than 0.2% water uptake at 80% RH and 25 °C. The analysis by XRPD after DVS showed no change. The material was non - hygroscopic.

[0216] For the oxalate of Compound 1, Form 1, the DVS analysis showed 0.37% water uptake at 80% RH and 25 °C. The analysis by XRPD after DVS showed no change. The material was slightly hygroscopic.

[0217] For the phosphate of Compound 1, Form 1, the DVS analysis showed 1.20% water uptake at 80% RH and 25 °C. The analysis by XRPD after DVS showed no change. The material was slightly hygroscopic.

[0218] For the mesylate of Compound 1, Form 1, the DVS analysis showed 2.65% water uptake at 95% RH and 25 °C. The analysis by XRPD after DVS showed no change.

[0219] For Compound 1, Form A, the DVS analysis showed 5.08% water uptake at 95% RH and 25 °C. The analysis by XRPD after DVS showed no change.

[0220] For Compound 1, Form B, the DVS analysis showed 0.68% water uptake at 95% RH and 25 °C. The analysis by XRPD after DVS showed no change.

[0221] III. Polymorphic Screen Example 7: Evaporation Method A transparent solution of 20 mg of Compound 1 was dissolved in a selected solvent and left standing in a fume hood without a lid to evaporate the solvent at 25°C. The XRPD characteristics of the obtained solid sample were evaluated directly. The results are shown in Table 1.

[0222]

Table 1

[0223] Example 8: Rapid Precipitation A 20 mg sample of Compound 1 was dissolved in a selected solvent (acetone, DMF, DMSO, 2-methoxyethanol (2-ME), NMP, THF, acetic acid, formic acid). An antisolvent (MeOH, EtOH, EtOAc, IPA, butyl formate, heptane, diethyl ether, water, acetonitrile, toluene, chloroform) was added at 25°C until a precipitate formed. If crystals did not form, the solution was cooled to 0°C in a freezer for crystallization. If solids did not form, the solution was further transferred to a -15°C freezer. The obtained precipitate was centrifuged and dried in vacuo for XRPD characterization. The results are shown in Table 2.

[0224]

Table 2-1

[0225]

Table 2-2

[0226] Example 9: Slurry Method at 25°C A 20 mg sample of Compound 1 was stirred in a suspension of a selected single solvent or binary solvent mixture at 25°C for 7 days (5 days for acetic acid slurry). The results are shown in Table 3.

[0227]

Table 3

[0228] Example 10: Slurry method at 50 °C A 20 mg sample of Compound 1 was stirred in a suspension of a selected single solvent or binary solvent mixture at 50 °C for 1 day. The results are shown in Table 4.

[0229]

Table 4

[0230] Example 11: Vapor diffusion method A 20 mg sample of Compound 1 was dissolved in a suitable solvent. A vial containing the freshly prepared clear solution was placed in a specific antisolvent atmosphere and allowed to vapor diffuse at room temperature. The results are shown in Table 5.

[0231]

Table 5

[0232] III. Crystalline salt forms Example 12: Preliminary salt screening An appropriate amount of Compound 1, the free base, was suspended in different solvents at room temperature, and then a solid acid or acid solution (about 1 - 2 equivalents) was added to form a salt. The suspension was stirred at room temperature for 3 days. If no precipitation occurred, the reaction solution was concentrated or some antisolvent was added. The solid was recovered by filtration and analyzed by XRPD.

[0233] Example 13A: Synthesis of adipate of Compound 1, Form 1 Adipic acid (7.4 g, 2.0 eq) was suspended in acetone (200 mL) and water (10 mL). The suspension was stirred at room temperature for 15 minutes to form a clear solution. To this solution, compound 1, free base (10.8 g, 1.0 eq) was added portionwise. The mixture was stirred at room temperature for 24 hours. The solid was collected by filtration and washed with acetone (2 x 10 mL). The solid was dried under high vacuum at 45 °C for 24 hours to obtain adipate of compound 1, Form 1 (11.45 g).

[0234] Example 13Ab: First separate synthesis of adipate of compound 1, Form 1 (acetone / water 19 / 1) To a solution of adipic acid (2.0 eq) in acetone:water (19V:1V) at 25 °C, compound 1, free base (0.25 eq) and seed crystal (1%) were added. The suspension was stirred at 25 °C for 2 hours. Then, compound 1, free base (0.25 eq) was added to the suspension. The suspension was stirred at 25 °C for 1 hour. Then, compound 1, free base (0.25 eq) was added to the suspension. The suspension was stirred at 25 °C for 1 hour. Then, compound 1, free base (0.25 eq) was added to the suspension. The suspension was stirred at 25 °C for 6 hours. The solid was collected by filtration and dried under vacuum at 50 °C for 3 - 5 hours to obtain adipate of compound 1, Form 1.

[0235] Example 13Ac: Second separate synthesis of adipate of compound 1, Form 1 (DMSO / EtOAc / EtOH) To a solution of compound 1, free base (1.0 eq) in DMSO (2V) at 50 °C, adipic acid (2.0 eq) was added. The solution was cooled to room temperature and seed crystal (1%) was added. The suspension was stirred at room temperature for 2 hours. Then EtOAc:EtOH (1:5, 12V) was added to the suspension and then added to the suspension at a rate of 1V / h. The suspension was stirred at room temperature for 4 hours. The solid was collected by filtration and washed with EtOAc (2 x 2V). The solid was dried under vacuum at 40 °C for 3 hours to obtain adipate of compound 1, Form 1.

[0236] Example 13Ad: Third separate synthesis of adipate of compound 1, Form 1 (DMSO / EtOH / water) To a solution of Compound 1, free base (1.0 eq) in DMSO (3V) at 25 °C, adipic acid (2.0 eq), EtOH (1V), and seed crystals (1%) were added. The suspension was stirred at 25 °C for 2 hours. Then, EtOH (1V) was added to the suspension at a rate of 1V / hour, followed by water (6V) at a rate of 2V / hour. The solid was collected by filtration and washed with water (2×2V). The solid was dried under vacuum at 50 °C for 3 hours to obtain the adipate of Compound 1, Form 1.

[0237] Example 13B: Synthesis of the adipate of Compound 1, Form 3 Adipic acid (8.5 g, 2.0 eq) was suspended in acetone (400 mL). The suspension was stirred at room temperature for 15 minutes to form a clear solution. To this solution, Compound 1, free base (12.5 g, 1.0 eq) was added portionwise. Additional acetone was added (100 mL). The mixture was stirred at room temperature for 3 days. The solid was collected by filtration and rinsed with acetone (2×50 mL). The solid was dried under high vacuum at 45 °C for 24 hours to obtain the adipate of Compound 1, Form 3 (28.8 g).

[0238] Example 13C: Synthesis of the adipate of Compound 1, Form 2 The adipate of Compound 1, Form 3 (28.8 g) was suspended in TBME (290 mL) and stirred at room temperature for 5 hours. The solid was collected by filtration and rinsed with TBME (2×50 mL). The solid was dried under high vacuum at 45 °C for 2 hours to obtain the adipate of Compound 1, Form 2 (28.1 g).

[0239] Example 13D: Synthesis of the oxalate of Compound 1, Form 1 Approximately 250 mg of Compound 1, free base and solid oxalic acid (1.1 eq) were suspended in 3.0 mL of acetone. The suspension was continuously stirred at room temperature for 14 hours. The solid was collected by filtration and dried in vacuo at 40 °C for 14 hours to obtain the oxalate of Compound 1, Form 1.

[0240] Example 13E: Synthesis of the phosphate of Compound 1, Form 1 About 250 mg of Compound 1, free base, and concentrated phosphoric acid (1.1 equivalents) were suspended in 3.0 mL of MeOH. The suspension was continuously stirred at room temperature for 14 hours. The solid was collected by filtration and dried in vacuo at 40 °C for 14 hours to obtain the phosphate of Compound 1, Form 1.

[0241] Example 13F: Synthesis of the mesylate of Compound 1, Form 1 To a slurry of Compound 1, free base (297 mg) in EtOH (12 mL) was added a 1.37 M methanesulfonic acid solution in EtOH (1 mL). After stirring at room temperature for 4 hours, the solid product was collected by centrifugation and dried in vacuo at room temperature to obtain the mesylate of Compound 1, Form 1.

[0242] Example 14: Competitive slurry experiments of the adipate of Compound 1, Forms 1, 2, and 3 A mixed sample of the adipate of Compound 1, Form 1 and the adipate of Compound 1, Form 2 was suspended in a solvent (40 mg, 0.5 mL) and stirred at 50 °C or 25 °C for 2 hours. The resulting solid was collected by filtration and analyzed by XRPD. As shown in Table 6, all mixed samples were converted to Form I after slurrying in the solvent at 50 °C or 25 °C for 2 hours.

[0243]

Table 6

[0244] A mixed sample of the adipate of Compound 1, Form 2 and the adipate of Compound 1, Form 2 was suspended in a solvent (40 mg, 0.5 mL) and stirred at 50 °C for 1 hour. The resulting solid was collected by filtration and analyzed by XRPD. As shown in Table 7, all mixed samples were converted to Form I after slurrying in the solvent at 50 °C or 25 °C for 2 hours.

[0245]

Table 7

[0246] According to the competitive slurry experiment, adipate of Compound 1, Form 1 is the most stable form among the three adipate forms of Compound 1.

[0247] Example 15: Stability Test of Adipate of Compound 1, Form 1 Approximately 10 mg of adipate of Compound 1, Form 1 obtained from acetone / water (19 / 1) (Example 13Ab), DMSO / EtOAc / EtOH (Example 13Ac), and DMSO / EtOH / water (Example 13Ad) was placed at 60 °C / with lid and 40 °C / 75% RH (without lid) for 7 days. For each condition, samples were prepared in duplicates. On the 7th day, the samples were analyzed by HPLC and XRPD to confirm the purity and crystal form, respectively. The results are summarized in Table 8.

[0248] Adipate of Compound 1, Form 1 was physically and chemically stable for 1 week at 60 °C (with lid) and 40 °C / 75% RH (without lid). The crystal form and HPLC purity of Form I as adipate remained unchanged for 7 days under the two test conditions.

[0249]

Table 8

[0250] IV. Biological Data Example 16: Co-stimulation Assay in Lysed Whole Blood, JAK2:GM-CSF-stimulated STAT5 Phosphorylation and JAK1 / TYK2-stimulated STAT1 Phosphorylation Assay Human blood lysis using abeam's RBC lysis buffer Dilute the RBC lysis buffer 1-fold in distilled water. Add 2 mL of blood to 38 mL of 1-fold RBC lysis buffer. Incubate in the dark at room temperature for 15 minutes. Spin at 300 g for 5 minutes to collect the pellet. Redissolve if necessary. Resuspend the pellet in 5 mL of cRPMI.

[0251] Compound and Cytokine Treatment Aliquots of 80 μL of lysed human blood are aliquoted into the wells of a 96 - deep well plate. 10 μL of compound 1 at different concentrations (10 - fold concentrated) is added to all wells except the controls (unstained and unstimulated), and this is mixed using a 100 - μL multichannel pipette. 10 μL of RPMI medium is added to the controls. For the dilution and dilution range of compound 1, refer to the separate sheet. Incubate at 37 °C for 1 hour on a water bath or in a CO₂ incubator. 10 μL (10 - fold concentrated) of cytokine mixture (GM - CSF and IFNα) (final concentration 10 ng / mL of GM - CSF and 100 ng / mL of IFNα) is added to each well except the unstimulated and unstained controls, and further incubated at 37 °C for 20 minutes on a water bath.

[0252] RBC Lysis and Fixation Add 900 μL of pre - warmed 1 - fold fixation / lysis solution (separate sheet), mix this appropriately using a 1000 - μL multichannel pipette, and further incubate at 37 °C for 10 minutes (including addition time) on a water bath. Centrifuge at 800 × g for 5 minutes at 40 °C, remove 900 μL of the supernatant, and add 900 μL of 1 - fold PBS. Centrifuge at 800 × g for 5 minutes at 40 °C and remove 900 μL of the supernatant. Wash once more with 900 μL of PBS (optional), and resuspend the pellet in 100 μL of PBS.

[0253] Permeabilization Disrupt the pellet by gently tapping, resuspend it in 1000 μL of BD Phosflow Perm Buffer III, and incubate the plate on ice for 30 minutes. Centrifuge the plate at 800 × g for 5 minutes at 40 °C. Wash twice more with 1000 μL of BD Pharmingen Stain Buffer.

[0254] Antibody Treatment Break the pellets by gently tapping. Resuspend the pellets in 100 uL of staining buffer, add 5 uL of pSTAT5_AF488 Ab and 5 μL of pSTATI_PE to all wells except the unstained control, mix appropriately using a 200 μL multichannel pipette, and incubate overnight at 40 °C. Add 900 μL of wash buffer and centrifuge at 1800 rpm for 3 minutes at 40 °C. Wash once more with 1000 μL of BD Pharmingen Stain Buffer. Finally, resuspend the pellets in 300 uL of BD Pharmingen Stain Buffer. Transfer the cells to a 96-well V-bottom plate and acquire the cells in Beckman Coulter CytExpert. Acquisition of cells in the flow cytometer: Maintain the threshold at 250, and the cell concentration should not exceed 100 - 500 cells / μL. Acquire at least 5,000 - 10,000 cells. Compound 1 IFN-a / Jak1Tyk2 IC50 < 1 μm.

[0255] Separate Sheet Preparation of Reagents RPMI1640 Complete Medium: RPMI1640 Medium + 10% FBS.

[0256] Dilution of Cytokines: 1) 100 ug / mL GM-CSF stock. Prepare a 1 ug / mL intermediate dilution by adding 2 uL of the stock to 198 uL of cRPMI. Further dilute to 100 ng / mL by adding 100 uL of the intermediate stock to 900 uL of cRPMI. 2) 200 ug / mL IFNα stock. Dilute the IFNα stock 1:200 by adding 5 uL of the stock to 1000 uL of the above 100 ng / mL GM-CSF working stock to obtain a working stock containing 1000 ng / mL IFNα and 100 ng / mL GM-CSF (10-fold). Store this on ice until use.

[0257] Preparation of Lysis / Fixation Buffer: Dilute the 5x lysis / fixation buffer to 1x using MQ water and store at 37 °C until use.

[0258] BD Phosflow perm bufferIII: Store on ice / in the refrigerator.

[0259]

Table 9

[0260] Example 17: Pharmacokinetics of the crystalline forms of Compound 1 after oral administration in male cynomolgus monkeys After male cynomolgus monkeys were force-fed with Compound 1 (adipate of Compound 1, Form 1, oxalate of Compound 1, Form 1, and free base of Compound 1, Form A), single-dose PK parameters in plasma were measured. After dosing, the dosing tube was washed with 5 mL of vehicle. Plasma samples were collected at the following time points: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after dosing. The concentration of Compound 1 was measured in plasma. As shown in Table 9, the adipate of Compound 1, Form 1, showed a faster Tmax and a higher AUC compared to the free base of Compound 1, Form A. Similarly, as shown in Table 10, the adipate of Compound 1, Form 1, showed a faster Tmax, a higher AUC, and a higher oral bioavailability (%F) compared to the oxalate of Compound 1, Form 1.

[0261]

Table 10

[0262]

Table 11

Claims

1. A crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea, or a pharmaceutically acceptable salt or solvate thereof.

2. The crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is an adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 1, (b) An X-ray powder diffraction (XRPD) pattern having peaks characteristic of 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in Figure 2, (d) A DSC thermogram substantially similar to that described in Figure 2, (e) A DSC thermogram with an exotherm having an onset temperature of about 200 °C, (f) Non-hygroscopic, or (g) These combinations A form 1 having at least one of the above, the crystalline form according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. The crystalline form according to Claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 1.

4. The crystalline form according to Claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks of 7.0° 2θ, 9.3° 2θ, 14.0° 2θ, 21.1° 2θ, 24.9° 2θ, and 25.6° 2θ.

5. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 2, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that described in FIG.

2.

6. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 2, wherein the crystalline form has a DSC thermogram substantially similar to that described in FIG.

2.

7. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 2, wherein the crystalline form has a DSC thermogram with an exotherm having an onset temperature of about 200 °C.

8. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 2, wherein the crystalline form is non-hygroscopic.

9. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 2, characterized in that the crystalline form has the characteristics of (a), (b), (c), (d), (e), and (f).

10. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 2 to 9, wherein the crystalline form is obtained from acetone / water.

11. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 2 to 10, wherein the crystalline form is not solvated.

12. The crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is an adipate (adipate), and the crystalline form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 3, (b) An X-ray powder diffraction (XRPD) pattern having peaks characteristic of 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ, (c) A thermogravimetric analysis (TGA) substantially similar to that described in FIG.

4. (d) A DSC thermogram substantially the same as that described in FIG. 4, (e) A DSC thermogram with an exotherm having an onset temperature of about 194 °C (f) Non-hygroscopic, or (g) A combination of these The crystalline form according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is Form 2 having at least one of the above.

13. The crystalline form according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG.

3.

14. The crystalline form according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0° 2θ, 9.3° 2θ, 13.3° 2θ, 13.8° 2θ, 18.3° 2θ, 18.8° 2θ, 20.6° 2θ, 21.2° 2θ, and 25.6° 2θ.

15. The crystalline form according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially the same as that described in FIG.

4.

16. The crystalline form according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form has a DSC thermogram substantially the same as that described in FIG.

4.

17. The crystalline form according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form has a DSC thermogram with an exotherm having an onset temperature of about 194 °C.

18. The crystalline form according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, characterized in that the crystalline form has the characteristics of (a), (b), (c), (d), (e), and (f).

19. The crystalline form according to any one of claims 12 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein the crystalline form is obtained from acetone.

20. The crystal form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea is an adipate (adipate), and the crystal form of 1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-3-((1R,2S)-2-fluorocyclopropyl)urea adipate has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 5, (b) An X-ray powder diffraction (XRPD) pattern having peaks characteristic of 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in Figure 6, (d) A DSC thermogram substantially similar to that described in Figure 6, (e) A DSC thermogram with a first exotherm having an onset temperature of about 133 °C and a second exotherm having an onset temperature of about 177 °C, or (f) Combinations thereof The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 1, which is Form 3 having at least one of these.

21. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 20, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 5.

22. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 20, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having peaks characteristic of 5.9° 2θ, 6.9° 2θ, 8.9° 2θ, 9.2° 2θ, 11.7° 2θ, 13.8° 2θ, 17.9° 2θ, 20.9° 2θ, 21.9° 2θ, 24.8° 2θ, and 25.8° 2θ.

23. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 20, wherein the crystalline form has thermogravimetric analysis (TGA) substantially similar to that described in Figure 6.

24. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 20, wherein the crystalline form has a DSC thermogram substantially the same as that described in FIG.

6.

25. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 20, wherein the crystalline form has a DSC thermogram with a first exotherm having an onset temperature of about 133 °C and a second exotherm having an onset temperature of about 177 °C.

26. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to claim 20, wherein the crystalline form has the characteristics of (a), (b), (c), (d), and (e).

27. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 20 to 26, wherein the crystalline form is obtained from methyl t-butyl ether.

28. The crystalline form or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 27 for use in a pharmaceutical.

29. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 27 and a pharmaceutically acceptable excipient.

30. A method of treating an inflammatory disease or an autoimmune disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the crystalline form according to any one of claims 1 to 27.

31. The method according to claim 30, wherein the inflammatory disease or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

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