Crystalline Forms of S1P Receptor Modulators

Abstract

(R)-5-(2,5-Dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one in crystalline form, or a salt or solvate thereof, is described herein.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 358,791, filed on Jun. 6, 2022, which is incorporated herein by reference in its entirety.

Background Art

[0002] Sphingosine-1-phosphate (S1P) receptors are a class of G protein-coupled receptors that are targets of the lipid signaling molecule sphingosine-1-phosphate. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that has been demonstrated to induce many cellular processes, including platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis, and angiogenesis, rearrangement of the cytoskeleton in many cell types for the control of immune cell movement, vascular homeostasis, and intercellular communication between the central nervous system (CNS) and peripheral organ systems. S1P can bind to members of the endothelial differentiation gene family (EDG receptors) of plasma membrane-localized G protein-coupled receptors. To date, five members of this family, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5 (EDG-8), have been identified as S1P receptors in different cell types. S1P receptor modulators are compounds that signal as agonists or antagonists at one or more S1P receptors. Because S1P mediates a wide variety of cellular responses, S1P receptor modulators are promising targets for various therapeutic indications.

Summary of the Invention

[0003] In one aspect, a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a salt or solvate thereof, is described herein.

[0004] In some embodiments, the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one 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 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° 2θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 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 having an endotherm with an onset temperature of about 282° C., or (f) A combination thereof and is Form 1 having at least one of them.

[0005] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1.

[0006] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° 2θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 2θ.

[0007] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that described in FIG. 2.

[0008] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a DSC thermogram substantially similar to that described in FIG. 2.

[0009] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a DSC thermogram having an endotherm with an onset temperature of about 282 °C.

[0010] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, 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 FIG. 1, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° 2θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 2θ, (c) Thermogravimetric analysis (TGA) substantially the same as that described in FIG. 2, (d) A DSC thermogram substantially the same as that described in FIG. 2, and (e) A DSC thermogram having an endotherm with an onset temperature of about 282° C. Characterized by having.

[0011] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form is obtained from THF or EtOAc.

[0012] In some embodiments, the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is unsolvated.

[0013] In another embodiment, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is Form 2 and has the following characteristics [[ID=X]] (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that described in FIG. 3, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9° 2θ, 17.1° 2θ, 18.1° 2θ, 22.0° 2θ, 24.0° 2θ, 24.8° 2θ, 25.5° 2θ, 26.2° 2θ, and 28.2° 2θ, (c) Thermogravimetric analysis (TGA) substantially the same as that described in FIG. 4, (d) A DSC thermogram substantially the same as that described in FIG. 4, (e) A DSC thermogram having a first endotherm with an onset temperature of about 145° C. and a second endotherm with an onset temperature of about 180° C., or (f) A combination thereof Among them, it has at least one.

[0014] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 3.

[0015] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9° 2θ, 17.1° 2θ, 18.1° 2θ, 22.0° 2θ, 24.0° 2θ, 24.8° 2θ, 25.5° 2θ, 26.2° 2θ, and 28.2° 2θ.

[0016] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a thermogravimetric analysis (TGA) substantially the same as that described in FIG. 4.

[0017] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a DSC thermogram substantially similar to that described in FIG. 4.

[0018] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a DSC thermogram having a first endotherm with an onset temperature of about 145° C. and a second endotherm with an onset temperature of about 280° C.

[0019] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form is characterized by the following properties: (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 characteristic peaks at 7.0° 2θ, 9.5° 2θ, 11.2° 2θ, 14.9° 2θ, 18.6° 2θ, 22.1° 2θ, 24.1° 2θ, 26.2° 2θ, and 30.0° 2θ; (c) a thermogravimetric analysis (TGA) substantially similar to that described in FIG. 4; (d) a DSC thermogram substantially similar to that described in FIG. 4; (e) a DSC thermogram having a first endotherm with an onset temperature of about 145° C. and a second endotherm with an onset temperature of about 280° C.

[0020] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form is obtained from acetic acid.

[0021] In some embodiments, the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is an acetic acid solvate.

[0022] In another embodiment, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, and the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate has the following characteristics (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 5, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 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 having a first endotherm at about 41° C., a second endotherm having an onset temperature of about 93° C., and a third endotherm having an onset temperature of about 156° C., or (f) A combination thereof and is Form 3 having at least one of them.

[0023] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 5.

[0024] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 2θ.

[0025] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a thermogravimetric analysis (TGA) that is substantially the same as that described in Figure 6.

[0026] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a differential scanning calorimetry (DSC) thermogram that is substantially the same as that described in Figure 6.

[0027] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a DSC thermogram having a first endotherm at about 41 °C, a second endotherm having an onset temperature of about 93 °C, and a third endotherm having an onset temperature of about 156 °C.

[0028] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form is characterized by having: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 5; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 2θ; (c) a thermogravimetric analysis (TGA) substantially similar to that described in Figure 6; (d) a DSC thermogram substantially similar to that described in Figure 6; and (e) a DSC thermogram having a first endotherm at about 41 °C, a second endotherm having an onset temperature of about 93 °C, and a third endotherm having an onset temperature of about 156 °C.

[0029] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form is obtained from ethyl acetate.

[0030] In another embodiment, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, and the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate has the following characteristics (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 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° 2θ, 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ, (c) 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 having a first endotherm at about 60 °C and a second endotherm with an onset temperature of about 128 °C, or (f) A combination thereof and is Form 4 having at least one of them.

[0031] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 7.

[0032] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° 2θ, 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ.

[0033] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that described in FIG. 8.

[0034] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a differential scanning calorimetry (DSC) thermogram substantially similar to that described in FIG. 8.

[0035] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form has a DSC thermogram having a first endotherm at about 60° C. and a second endotherm having an onset temperature of about 128° C.

[0036] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, 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 FIG. 7; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° 2θ, 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ; (c) a thermogravimetric analysis (TGA) substantially similar to that described in FIG. 8; (d) a DSC thermogram substantially similar to that described in FIG. 8; and (e) a DSC thermogram having a first endotherm at about 60° C. and a second endotherm with an onset temperature of about 128° C. Characterized by having.

[0037] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and the crystalline form is obtained from ethyl acetate.

[0038] In some embodiments, there is a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, for use in a pharmaceutical.

[0039] In some embodiments, there is (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, and (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is amorphous.

[0040] In another aspect, disclosed herein is a pharmaceutical composition comprising a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0041] In another aspect, disclosed herein is a pharmaceutical composition comprising a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, formulated for oral, intravenous, intramuscular, or subcutaneous administration.

[0042] In another aspect, described herein is a method of treating a mammalian disease, disorder, or condition that would benefit from modulation of the sphingosine-1-phosphate (S1P) receptor, the method comprising administering to an individual a therapeutically effective amount of a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof.

[0043] In some embodiments, there is a method for treating a mammalian disease selected from multiple sclerosis, ulcerative colitis, and Crohn's disease.

[0044] In some embodiments, there is a method for treating a disease in an individual in need of treatment for the disease, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, as described herein, wherein (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is administered orally. In some embodiments, there is a method for treating an immune disorder in an individual in need of treatment for the immune disorder, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, as described herein, wherein the therapeutically effective amount is ingested with food. In some embodiments, there is a method for treating an immune disorder in an individual in need of treatment for the immune disorder, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, as described herein, wherein the therapeutically effective amount is ingested without food.In some embodiments, there is a method for treating an immune disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, as described herein, wherein (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is administered to the individual once a day. In some embodiments, there is a method for treating an immune disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a solvate thereof, as described herein, wherein (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is administered to the individual twice a day.

[0045] 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 were specifically and individually indicated to be incorporated by reference.

Brief Description of the Drawings

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Figure 18

Mode for Carrying Out the Invention

[0047] Sphingosine-1-phosphate receptors regulate fundamental biological processes such as cell proliferation, angiogenesis, migration, cytoskeletal organization, endothelial cell chemotaxis, immune cell trafficking, and mitogenesis induction. Sphingosine-1-phosphate receptors are also involved in immune-modulation and are directly involved in the suppression of innate immune responses from T cells. Sphingosine-1-phosphate (S1P) receptors are divided into five subtypes, S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. They are expressed in various tissues and are found at the highest density in leukocytes, but each subtype exhibits different cell specificities.

[0048] In one aspect, there is administration to a mammal of at least one S1P receptor modulator described herein in the treatment of a disease, disorder, or condition that would benefit from modulation of an S1P receptor. In some examples, there is administration to a mammal of at least one S1P receptor modulator described herein in the treatment of a disease, disorder, or condition that would benefit from selective modulation of an S1P receptor subtype. In some embodiments, there is administration to a mammal of at least one S1P receptor modulator described herein in the treatment of a disease, disorder, or condition that would benefit from selective modulation of two S1P receptor subtypes. In some embodiments, there is administration to a mammal of at least one S1P receptor modulator described herein in the treatment of a disease, disorder, or condition that would benefit from selective modulation of one S1P receptor subtype.

[0049] Compound 1 In one embodiment, there is (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one. "Compound 1" or "(R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one" refers to a compound having the following structure

[0050]

Chemical formula

[0051] In some embodiments, pharmaceutically acceptable salts of Compound 1 are described herein. In relation to Compound 1, the term "pharmaceutically acceptable salt" refers to a salt of Compound 1 that does not cause significant irritation to the administered mammal and does not substantially inhibit the biological activity and properties of the compound. In some embodiments, as pharmaceutically acceptable salts, - acid addition salts formed by reacting Compound 1 with an organic acid, wherein the organic acid includes aliphatic mono- and dicarboxylic acids, alkanoic acids substituted with phenyl, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., and, 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., acid addition salts - acid addition salts formed by reacting Compound 1 with an inorganic acid, wherein the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc., acid addition salts are included.

[0052] In some embodiments, (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one includes a solvated form (solvate). The solvate contains either a stoichiometric or non-stoichiometric amount of the solvent and is formed in the process of product formation or separation using pharmaceutically acceptable solvents such as water, ethanol, methanol, tert-butyl methyl 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 some embodiments, the solvate is formed using, but not limited to, Class 3 solvents. In some embodiments, the solvate is formed using, but not limited to, Class 2 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(R6),” (October 2016). Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol.

[0053] In other embodiments, (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one 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 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.

[0054] While not intending to be bound by any particular theory, certain solid forms are characterized by physical properties suitable for pharmaceutical and therapeutic forms, 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 uptake, electrical properties, thermal behavior, solid reactivity, physical stability, and chemical stability) that affect particular processes (such as production, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that render the particular solid form suitable for the manufacture of solid dosage forms. Such properties can be determined using specific analytical chemistry techniques including, but not limited to, the solid state analytical techniques described herein (such as X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0055] Crystalline form The identification and selection of solid forms of pharmaceutical compounds is complex considering that changes in solid form can affect various physical and chemical properties, which can result in benefits or drawbacks in processing, formulation, stability, bioavailability, storage, and handling (e.g., transportation), among other important pharmaceutical properties. Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by the absence of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the specific application; amorphous solids are sometimes selected, for example, based on an enhanced dissolution profile, while crystalline solids may be desirable for properties such as physical or chemical stability.

[0056] Whether crystalline or amorphous, the solid forms of pharmaceutical compounds include single-component and multi-component solids. Single-component solids consist essentially of the pharmaceutical compound or active ingredient in the absence of other compounds. The diversity among single-component crystalline materials can potentially arise from the phenomenon of polymorphism, where multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

[0057] In particular, it is not possible to predict a priori not only how to prepare successfully, but even whether there are crystalline forms of the compound (for reference, see, for example, Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun.: 3635 - 3645 (with respect to crystal engineering, the results can be unpredictable if the instructions are not very precise and / or other external factors affect the process); 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 computationally predict 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,” ACA Transactions 39: 14 - 23 (much still needs to be learned and done before even fewer polymorphs can be declared with any confidence in the ability to predict the crystal structure).

[0058] The various possible solid forms give rise to potential diversity in the physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms are very important in the development of effective, stable, and marketable pharmaceuticals.

[0059] Crystalline Compound 1, Form 1 In some embodiments, (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is crystalline. In some embodiments, (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is crystalline and anhydrous. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one has the following properties (a) an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 1, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° 2θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 2θ, (c) a thermogravimetric analysis (TGA) that is substantially similar to that described in Figure 2, (d) a DSC thermogram that is substantially similar to that described in Figure 2, (e) a DSC thermogram having an endotherm with an onset temperature of about 282 °C, or (f) a combination thereof Characterized by having at least one of them, it is Form 1.

[0060] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1 is characterized by having at least two properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1 is characterized by having at least three properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1 is characterized by having at least four properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1 is characterized by having the properties of (a) to (e).

[0061] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 1. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° 2θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 2θ. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 2. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 2. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, has a DSC thermogram having an endotherm with an onset temperature of about 282 °C. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, is obtained from THF or ethyl acetate.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, is obtained from ethyl acetate. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, is obtained from THF. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 1, is unsolvated.

[0062] Crystalline Compound 1, Form 2 In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one has the following characteristics (a) An X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 3, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9° 2θ, 17.1° 2θ, 18.1° 2θ, 22.0° 2θ, 24.0° 2θ, 24.8° 2θ, 25.5° 2θ, 26.2° 2θ, and 28.2° 2θ, (c) Thermogravimetric analysis (TGA) that is substantially similar to that described in Figure 4, (d) A DSC thermogram that is substantially similar to that described in Figure 4. (e) A DSC thermogram having a first endotherm with an onset temperature of about 145° C. and a second endotherm with an onset temperature of about 280° C., or (f) A combination thereof Characterized by having at least one of them, it is Form 2.

[0063] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2 is characterized by having at least two properties selected from (a)-(e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2 is characterized by having at least three properties selected from (a)-(e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2 is characterized by having at least four properties selected from (a)-(e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2 is characterized by having the properties of (a)-(e). [[ID=IO]]

[0064] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 3. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9° 2θ, 17.1° 2θ, 18.1° 2θ, 22.0° 2θ, 24.0° 2θ, 24.8° 2θ, 25.5° 2θ, 26.2° 2θ, and 28.2° 2θ. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 4. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 4. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, has a DSC thermogram having a first endotherm with an onset temperature of about 145°C and a second endotherm with an onset temperature of about 280°C.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, is obtained from acetic acid. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, is an acetic acid solvate. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 2, is unsolvated.

[0065] Crystalline Compound 1 tosylate, Form 3 In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-�- yl)phenoxy)piperidin-2-one is a p-toluenesulfonate salt, and the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate has the following characteristics (a) an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 5, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 2θ (c) Thermogravimetric analysis (TGA) substantially the same as that described in FIG. 6, (d) A DSC thermogram substantially the same as that described in FIG. 6, (e) A DSC thermogram having a first endotherm at about 41° C., a second endotherm having an onset temperature of about 93° C., and a third endotherm having an onset temperature of about 156° C., or (f) A combination thereof Characterized by having at least one of the above, Form 3.

[0066] In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3 is characterized by having at least two properties selected from (a)-(e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3 is characterized by having at least three properties selected from (a)-(e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3 is characterized by having at least four properties selected from (a)-(e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3 is characterized by having the properties of (a)-(e).

[0067] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 5. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 2θ. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 6. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 6. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, has a DSC thermogram having a first endotherm at about 41 °C, a second endotherm having an onset temperature of about 93 °C, and a third endotherm having an onset temperature of about 156 °C.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, is obtained from ethyl acetate. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate, Form 3, is unsolvated.

[0068] Crystalline Compound 1 mesylate, Form 4 In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is a methanesulfonate salt, and the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate has the following characteristics (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 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° , 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ, (c) a thermogravimetric analysis (TGA) substantially similar to that described in Figure 8, (d) A DSC thermogram substantially the same as that described in FIG. 8, (e) A DSC thermogram having a first endotherm at about 60° C. and a second endotherm having an onset temperature of about 128° C., or (f) A combination thereof is Form 4 having at least one of them.

[0069] In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4 is characterized by having at least two properties selected from (a)-(e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4 is characterized by having at least three properties selected from (a)-(e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4 is characterized by having at least four properties selected from (a)-(e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4 is characterized by having the properties of (a)-(e).

[0070] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 7. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° 2θ, 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 8. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 8. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, has a DSC thermogram with a first endotherm at about 60 °C and a second endotherm with an onset temperature of about 128 °C.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, is obtained from ethyl acetate. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate, Form 4, is unsolvated.

[0071] Crystalline Compound 1, Form 5 In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one has the following properties (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 9, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.4° 2θ, 5.8° 2θ, 11.1° 2θ, 14.1° 2θ, 17.5° 2θ, 18.6° 2θ, 21.3° 2θ, 22.4° 2θ, 23.8° 2θ, 25.6° 2θ, and 25.9° 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 having an endotherm with an onset temperature of about 273° C., or (f) A combination thereof Characterized by having at least one of these, Form 5.

[0072] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5 is characterized by having at least two properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5 is characterized by having at least three properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5 is characterized by having at least four properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5 is characterized by having the properties of (a) to (e).

[0073] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 9. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.4° 2θ, 5.8° 2θ, 11.1° 2θ, 14.1° 2θ, 17.5° 2θ, 18.6° 2θ, 21.3° 2θ, 22.4° 2θ, 23.8° 2θ, 25.6° 2θ, and 25.9° 2θ. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that described in Figure 10. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, has a differential scanning calorimetry (DSC) thermogram that is substantially the same as that described in Figure 10. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, has a DSC thermogram with an endotherm having an onset temperature of about 273 °C.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, is obtained from DMSO / water. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 5, is unsolvated.

[0074] Crystalline Compound 1, Form 6 In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one has the following characteristics (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 11, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.2° 2θ, 9.5° 2θ, 10.9° 2θ, 18.5° 2θ, 19.0° 2θ, 21.9° 2θ, 22.4° 2θ, 23.7° 2θ, 25.6° 2θ, and 26.7° 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 having an endotherm with an onset temperature of about 278 °C, or (f) A combination thereof Characterized by having at least one of these, Form 6.

[0075] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6 is characterized by having at least two properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6 is characterized by having at least three properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6 is characterized by having at least four properties selected from (a) to (e). In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6 is characterized by having the properties of (a) to (e).

[0076] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 11. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.2° 2θ, 9.5° 2θ, 10.9° 2θ, 18.5° 2θ, 19.0° 2θ, 21.9° 2θ, 22.4° 2θ, 23.7° 2θ, 25.6° 2θ, and 26.7° 2θ. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 12. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 12. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, has a DSC thermogram with an endotherm having an onset temperature of about 278 °C.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, is obtained from dichloromethane / methanol / heptane. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 6, is unsolvated.

[0077] Crystalline Compound 1, Form 7 In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one has the following properties, (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 13, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.0° 2θ, 11.0° 2θ, 12.6° 2θ, 13.5° 2θ, 14.1° 2θ, 21.3° 2θ, 21.7° 2θ, 22.1° 2θ, 25.4° 2θ, 26.7° 2θ, 27.1° 2θ, and 29.0° 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 having a first endotherm at about 113° C., an exotherm at about 168° C., and a second endotherm at about 279° C., or (f) Combinations thereof It is Form 7, characterized by having at least one of .

[0078] In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7 is characterized by having at least two properties selected from (a) to (e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7 is characterized by having at least three properties selected from (a) to (e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7 is characterized by having at least four properties selected from (a) to (e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7 is characterized by having the properties of (a) to (e).

[0079] In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 13. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.0° 2θ, 11.0° 2θ, 12.6° 2θ, 13.5° 2θ, 14.1° 2θ, 21.3° 2θ, 21.7° 2θ, 22.1° 2θ, 25.4° 2θ, 26.7° 2θ, 27.1° 2θ, and 29.0° 2θ. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 14. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 14. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, has a DSC thermogram having a first endotherm at about 113 °C, an exotherm at about 168 °C, and a second endotherm at about 279 °C.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, is obtained from methanol / water. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 7, is a hydrate. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-�- yl)phenoxy)piperidin-2-one, Form 7, is unsolvated.

[0080] Crystalline Compound 1, Form 8 In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one has the following properties (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 15, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.3° 2θ, 11.6° 2θ, 14.6° 2θ, 16.3° 2θ, 18.7° 2θ, 21.7° 2θ, 21.9° 2θ, 22.6° 2θ, 25.1° 2θ, 29.3° 2θ, and 37.8° 2θ, (c) Thermogravimetric analysis (TGA) substantially similar to that described in Figure 16, (d) A DSC thermogram substantially similar to that described in Figure 16. (e) A DSC thermogram having a first endotherm at about 89 °C, a second endotherm at about 119 °C, and a third endotherm at about 284 °C, or (f) a combination thereof Characterized by having at least one of them, it is Form 8.

[0081] In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8 is characterized by having at least two properties selected from (a) to (e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8 is characterized by having at least three properties selected from (a) to (e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8 is characterized by having at least four properties selected from (a) to (e). In some embodiments, for crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8 is characterized by having the properties of (a) to (e).

[0082] In some embodiments, the crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 15. In some embodiments, the crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.3° 2θ, 11.6° 2θ, 14.6° 2θ, 16.3° 2θ, 18.7° 2θ, 21.7° 2θ, 21.9° 2θ, 22.6° 2θ, 25.1° 2θ, 29.3° 2θ, and 37.8° 2θ. In some embodiments, the crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, has a thermogravimetric analysis (TGA) thermogram that is substantially similar to that described in Figure 16. In some embodiments, the crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, has a differential scanning calorimetry (DSC) thermogram that is substantially similar to that described in Figure 16. In some embodiments, the crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, has a DSC thermogram with a first endotherm at about 89 °C, a second endotherm at about 119 °C, and a third endotherm at about 284 °C.In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, is obtained from DMSO / water. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, is solvated. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, is a DMSO solvate. In some embodiments, crystalline (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, Form 8, is unsolvated.

[0083] [[ID=Z]] Preparation of Crystalline Compound 1 In some embodiments, Compound 1 is prepared as described in US2019 / 0241556, which is hereby incorporated by reference in its entirety. In some embodiments, the crystalline forms of Compound 1 are prepared as outlined in the Examples. It should be noted that the solvents, temperatures, and other reaction conditions presented herein may vary.

[0084] In certain embodiments, a method for making a solid form of Compound 1 is provided herein, the method comprising: 1) obtaining a saturated solution of Compound 1 in a solvent at a first temperature (e.g., about 50 °C); 2) adding an antisolvent into the saturated solution at the first temperature; 3) cooling to a second temperature (e.g., about -5 °C to room temperature); 4) collecting the solid if there is precipitation, or evaporating the solvent to collect the solid if there is no precipitation; and 5) optionally drying. In certain embodiments, a method for making a solid form of Compound 1 is provided herein, the method comprising: 1) obtaining a saturated solution of Compound 1 in a solvent at about 50 °C; 2) adding an antisolvent into the saturated solution at about 50 °C; 3) cooling to about room temperature; 4) collecting the solid if there is precipitation, or evaporating the solvent to collect the solid if there is no precipitation; and 5) optionally air 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 making a solid form of Compound 1 is an antisolvent recrystallization experiment.

[0085] 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 (e.g., amorphous solids). In certain embodiments, the purity of substantially pure crystalline Compound 1 (Form 1) is about ≥95%, about ≥96%, about ≥97%, about ≥98%, about ≥98.5%, about ≥99%, about ≥99.5%, or about ≥99.8%.

[0086] 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 (e.g., amorphous solid forms). In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 2 is about ≥95%, about ≥96%, about ≥97%, about ≥98%, about ≥98.5%, about ≥99%, about ≥99.5%, or about ≥99.8%.

[0087] 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 (e.g., amorphous solid forms). 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 about 99.8% or greater.

[0088] In another embodiment, crystalline Compound 1, Form 4 is substantially pure. In certain embodiments, substantially pure crystalline Compound 1, Form 4 is substantially free of other solid forms (e.g., amorphous solid forms). In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 4 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 about 99.8% or greater.

[0089] Suitable solvents Therapeutic agents administrable to mammals such as humans must be prepared in accordance with regulatory guidelines. Such government regulatory guidelines are referred to as the "Good Manufacturing Practice (GMP) Rules for the Manufacture and Quality Control of Pharmaceuticals and Quasi-Drugs". The GMP guidelines outline acceptable levels of contamination of the active therapeutic agent, for example, 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 consistent with industrial safety concerns. 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(R6)" (October 2016).

[0090] Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents with restricted use in the manufacture of therapeutic agents. Class 3 solvents are potentially of low toxicity and have a low risk to human health. The data on Class 3 solvents indicate that they are of low toxicity in acute or short-term studies and are also negative in genotoxicity tests.

[0091] Class 1 solvents to be avoided are benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0092] Examples of Class 2 solvents are 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-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0093] Examples of Class 3 solvents with low toxicity 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.

[0094] Residual solvents in pharmaceutical active ingredients (APIs) arise from the manufacture of APIs. In some cases, the solvents cannot be completely removed by the actual manufacturing techniques. Appropriate selection of solvents for API synthesis may enhance the yield, or may determine properties such as crystal form, purity, and solubility. Therefore, solvents are critical parameters in the synthesis process.

[0095] 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, 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.

[0096] 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 solvate of a Class 2 solvent. In some embodiments, Class 2 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-methylpyrrolidine, 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.

[0097] 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.

[0098] 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 this subject matter belongs. It is understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. As used in the 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 in the same manner as the other forms such as "include", "includes", "included", etc. The term "comprising" (and related terms such as "comprise", "comprises", "having", "including", etc.) is not intended to exclude, in other embodiments, for example, embodiments of any composition, mixture, method, or process described herein from consisting of or consisting essentially of the recited features. The term "about" when referring to a number or a range of numbers means that the recited number or range of numbers is an approximation within the scope of experimental variability (or within statistical experimental error), and thus the number or range of numbers may vary between 1% and 15% of the recited number or range of numbers.

[0099] The section headings used herein are for organizational purposes only and are not to be construed as limiting the described inventive subject matter. 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.

[0100] The terms "acceptable" or "pharmaceutically acceptable" as used herein with respect to a formulation, composition, or ingredient mean that they have no persistent deleterious effect on the general health of the subject being treated, or that they do not inhibit the biological activity or properties of the compound and are relatively non-toxic.

[0101] As used herein, "amelioration" of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any reduction in severity, delay in onset, blunting of progression, or shortening of duration, whether permanent or temporary, fixed or transient, that results from or is associated with administration of the compound or composition.

[0102] "Bioavailability" refers to the percentage of a compound 1 administered that is delivered to the systemic circulation of the animal or human being studied. The complete exposure (AUC (0~∞) ) of a drug when administered intravenously is generally defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which compound 1 is absorbed into the systemic circulation when the pharmaceutical composition is taken orally, compared to intravenous injection.

[0103] "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 be different for each 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 be different for each subject. Due to this variability, the amount required to constitute a "therapeutically effective amount" of compound 1 can be different for each subject.

[0104] As used herein, terms such as "co-administration" are meant to encompass the administration of a selected therapeutic agent to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes or at the same or different times.

[0105] "Effective amount" or "therapeutically effective amount," as used herein, refers to an amount of an administered agent or compound sufficient to reduce to some extent one or more of the symptoms of a disease or disorder being treated. The result can be that the signs, symptoms, or causes of a disease are reduced and / or alleviated, or that any other desired change in a biological system can be brought about. For example, an "effective amount" for therapeutic use is the amount of a composition (including a compound disclosed herein) necessary to clinically sufficiently reduce the symptoms of a disease without causing undue adverse 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, an amount effective for prophylaxis. An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacological effect or improvement in treatment without causing undue adverse side effects. It should be noted that the "effective amount" or "therapeutically effective amount" can vary from subject to subject depending on variations in the metabolism of Compound 1, 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. By way of example only, a therapeutically effective amount can be determined by a stepwise dose escalation clinical trial.

[0106] The term "enhance or enhancing" means an increase or extension in either efficacy or duration. 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 terms of efficacy or duration. An "enhancing-effective amount", as used herein, refers to an appropriate amount that enhances 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 depends on the severity and course of the disease, disorder, or illness, previous treatment, the patient's health state and response to the medicament, and the judgment of the physician treating the patient.

[0107] The term "prophylactically 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 prophylactic applications, such amount may depend on the patient's condition, weight, etc. By way of example, such prophylactically effective amount may be determined by a stepwise dose-increasing clinical trial.

[0108] The term "subject", as used herein, refers to an animal that is the subject of treatment, observation, or experiment. By way of one example only, the subject can be a mammal including, but not limited to, a human, but is not limited to a human.

[0109] As used herein, the term "target activity" refers to a biological activity that can be modified by a selective modifying substance. Some 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 associated with a disease or illness.

[0110] As used herein, the terms "treating," "treatment," or "treat" include alleviating, reducing, or ameliorating a disease or disorder or symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disease or disorder, e.g., preventing the occurrence 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 stopping the symptoms of a disease or disorder. The terms "treating," "treatment," or "treat" include, but are not limited to, prophylactic and / or therapeutic treatment.

[0111] 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.

[0112] Pharmaceutical composition / formulation The pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that assist in processing the active compound into a pharmaceutically usable preparation. Suitable formulations depend on the chosen route of administration. Summaries of pharmaceutical compositions described herein are 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, Pennsylvania 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) (Lippincott Williams & Wilkins 1999), all of which are hereby incorporated by reference in their entirety.

[0113] As used herein, a pharmaceutical composition refers to a mixture of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) with a carrier, stabilizer, diluent, dispersant, anti-precipitant, thickening agent, and / or other chemical components such as excipients. The pharmaceutical composition facilitates the administration of the compound to a mammal. In practicing the treatment methods or uses provided herein, a therapeutically effective amount of the compound is administered as a pharmaceutical composition to a mammal having a disease, disorder, or illness to be treated. Preferably, the mammal is a human. The therapeutically effective amount can vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound being used, and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of a mixture.

[0114] In some embodiments, there is a pharmaceutical composition comprising (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (Compound 1) and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 1, and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 2, and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1 tosylate, Form 3, and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1 mesylate, Form 4, and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 5, and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 6, and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 7, and a pharmaceutically acceptable excipient. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 8, and a pharmaceutically acceptable excipient.

[0115] As used herein, the term "pharmaceutical combination" means a product resulting from the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both the active ingredient, e.g., Compound 1, and the adjuvant are administered to a patient simultaneously in a single entity or dosage. The term "non-fixed combination" means that the active ingredient, e.g., Compound 1, and the adjuvant are administered to a patient as separate entities simultaneously, in parallel, or sequentially without the intervention of a specific time limit, and such administration provides an effective level of the two compounds in the patient's body. The latter term also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0116] Pharmaceutical compositions containing the compounds described herein can be manufactured by conventional techniques such as, by way of example only, conventional processes of mixing, dissolving, granulating, dragee manufacture, gelling, emulsifying, encapsulating, entrapping, or compressing.

[0117] Dosage form The pharmaceutical compositions described herein can be formulated for administration to a mammal via 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 can be used interchangeably.

[0118] Furthermore, the pharmaceutical compositions described herein containing Compound 1 can 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, extended release formulations, pulsatile release formulations, multiple microparticle formulations, and mixed immediate release and controlled release formulations.

[0119] An oral pharmaceutical preparation 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 appropriate auxiliaries if necessary, to obtain tablets or dragee cores. 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, methyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose; or others including polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethyl cellulose, polyvinyl pyrrolidone, agar, or salts of alginic acid such as alginic acid or sodium alginate may be added.

[0120] Examples of orally administrable formulations include gelatin push-fit capsules and soft, sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-fit capsules can contain the active ingredient in combination 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. Additionally, a stabilizer may be added. All formulations for oral administration must be in an amount suitable for such administration.

[0121] In some embodiments, the solid dosage forms disclosed herein are tablets (including suspension tablets, fast-dissolving tablets, chewable disintegrating tablets, immediate disintegrating tablets, effervescent tablets, or caplets), pills, powders (including aseptically packaged powders, dispensable powders, or effervescent powders), capsules (both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersants, solid solutions, bioerodible dosage forms, controlled release formulations, pulsed release dosage forms, multiple microparticle dosage forms, pellet dosage forms, granule dosage forms, or in the form of 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. Additionally, the pharmaceutical formulations described herein may be administered as a single capsule or as a dosage form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered in 2, 3, or 4 capsules or tablets.

[0122] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, capsules, are prepared by mixing the particles of Compound 1 with one or more pharmaceutical excipients to form a bulk mixture composition. When referring to these bulk blend compositions as homogeneous, it means that the particles of Compound 1 are evenly dispersed throughout the composition such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsule dosage forms. The individual unit dosages may further include a film coating that disintegrates upon oral ingestion or upon contact with a diluent. Such formulations can be manufactured by conventional pharmacological techniques.

[0123] Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation method, or (6) fusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0124] The pharmaceutical solid dosage forms described herein may include Compound 1 and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filler, suspending agent, flavoring additive, sweetener, disintegrant, dispersant, surfactant, lubricant, coloring agent, diluent, solvent, humectant, plasticizer, stabilizer, transdermal absorption enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or a combination of one or more thereof. In another aspect, a film coating is applied around the formulation of Compound 1 using standard coating procedures such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, 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.

[0125] 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, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0126] 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, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0127] To release compound 1 as efficiently as possible from a solid dosage form matrix, particularly 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. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, wood products, methylcellulose crystals, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or celluloses such as crosslinked cellulose (sodium carboxymethylcellulose crosslinked (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose), crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate combined with starch, and the like.In some embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methylcellulose crystals, methylcellulose, croscarmellose, croscarmellose sodium, sodium carboxymethylcellulose cross-linked, carboxymethylcellulose cross-linked, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments provided herein, the disintegrant is croscarmellose sodium.

[0128] Binders impart adhesiveness to the formulation of solid oral dosage forms. In the formulation of powder-filled capsules, the binder aids in the formation of plugs that can be filled into soft-shell or hard-shell capsules. And in the formulation of tablets, the binder ensures that the tablets remain intact after compression and ensures mixing uniformity before the compression or filling process. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrins, amylose, magnesium aluminum silicate, poly saccharide acids, 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, acacia, tragacanth, ghatti gum, mucilage of isapol husk, natural or synthetic rubbers, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and the like.

[0129] Generally, a binder level of 20 to 70% is used in gelatin capsule formulations filled with powders. The level of binder used in tablet formulations varies depending on either direct compression, wet granulation, roller compression, or the use of other excipients such as fillers that can act as moderate binders themselves. Formulators in the art can determine the binder level for a formulation, but binder usage levels up to 70% are common in tablet formulations.

[0130] 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, Carbowax®, polyethylene glycols or methoxypolyethylene glycols such as PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium, 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.

[0131] 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, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microfine cellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0132] The term "water-insoluble diluent" represents compounds such as calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose (e.g., having a density of about 0.45 g / cm 3 such as Avicel, powdered cellulose), and talc, which are typically used in the formulation of pharmaceuticals.

[0133] 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 (e.g., Polyquat 10 (registered trademark)), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0134] 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, and copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0135] Suspending agents suitable for use in the solid dosage forms described herein include, for example, polyvinylpyrrolidone such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol which may have a molecular weight of from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth gum and acacia gum, xanthan gums including xanthan gum, saccharides, such as celluloses including sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0136] Examples of antioxidants suitable for use in solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0137] It should be understood that there is significant overlap among the additives used in the solid dosage forms described herein. Thus, the above-listed additives should be received merely as exemplary and, without limitation, as being of the types of additives that may be included in the solid dosage forms described herein. The amounts of such additives can be readily determined by one of ordinary skill in the art according to the particular properties desired.

[0138] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Exemplarily, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers can be added in an amount of from about 0.01% to about 50% by weight (w / w) of the coating composition. 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.

[0139] Compressed tablets are solid dosage forms prepared by compression of the bulk mixture of the above-described formulations. 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 surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of the compound from the formulation. In other embodiments, the film coating (e.g., Opadry® coating, or 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.

[0140] The capsule can be prepared, for example, by placing a bulk formulation of Compound 1 inside the capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in hard shell gelatin capsules. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules, such as capsules containing HPMC. In other embodiments, the formulations are placed in sprinkle capsules, where the capsules can be swallowed whole or the contents can be sprinkled on food by opening the capsule before a meal. In some embodiments, the therapeutic dose is divided into a plurality of (e.g., 2, 3, or 4) capsules. In some embodiments, the total dose of the formulation is delivered in capsule form.

[0141] In various embodiments, the particles of Compound 1 and one or more excipients are dry mixed and compressed into a mass, such as a tablet, and the mass has a hardness sufficient 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.

[0142] In another aspect, the dosage form can include a microencapsulated formulation. In some embodiments, one or more other compatible materials are present within the microencapsulating material. Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, defoamers, antioxidants, flavorants, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0143] The materials useful for microencapsulation described herein include materials compatible with Compound 1 that sufficiently separate Compound 1 from other incompatible excipients. The materials compatible with Compound 1 are those that delay the release of the compound of Compound 1 in vivo.

[0144] Typical microencapsulation materials useful for delaying the release of formulations containing the compounds described herein include, but are not limited to, 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), methylcellulose (such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose ethers (HPMC) such as Aqoat (HF-LS, HF-LG, HF-MS) and Metolose®, E461, Ethocel®, Aqualon®-EC, Surelease®, Opadry AMB, etc. of polyvinyl alcohol (PVA), hydroxyethylcellulose such as Natrosol®, carboxymethylcellulose and salts of carboxymethylcellulose (CMC) such as Aqualon®-CMC, polyvinyl alcohol, and polyethylene glycol copolymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers, and mixtures of acrylic polymers with cellulose ethers, 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 Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms (such as a mixture of HPMC and stearic acid), cyclodextrin, and mixtures of these materials.

[0145] In other embodiments, plasticizers such as polyethylene glycol (e.g., 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 materials useful for delaying the release of pharmaceutical compositions are from the USP or the National Formulary (NF). In other embodiments, the microencapsulation material is Klucel. In other embodiments, the microencapsulation material is methocel.

[0146] The microencapsulated compound 1 described herein may be formulated by several methods including, for example, spray drying processes, rotary disk solvent processes, thermal solvent processes, spray chilling methods, fluidized beds, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at liquid - gas or solid - gas interfaces, pressure extrusion, or spray solvent extraction baths. In addition to these, various chemical techniques such as complex coacervation, dissolution evaporation, polymer - polymer incompatibility, interfacial polymerization in liquid media, in - situ polymerization, drying in liquid method, and desolvation in liquid media may also be used. Further, other methods such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating may also be used.

[0147] In one embodiment, the particles of Compound 1 are microencapsulated before being formulated into one of the above forms. In another embodiment, some or most of the particles are coated before being further formulated by using standard coating procedures (such as those described in Remington’s Pharmaceutical Sciences, 20th Edition (2000)).

[0148] 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 in an amount of about 0.01 wt% to about 50 wt% (w / w) of the coating composition. 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.

[0149] 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 formulated, for example, by mixing the formulation with an optional pharmaceutical excipient to form a bulk mixture composition. Additional embodiments also include suspending agents and / or wetting agents. This bulk mixture is uniformly subdivided into units of unit-dose packaging or multi-dose packaging.

[0150] In other embodiments, effervescent powders are also prepared according to the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are granular or coarse powders containing a drug in a dry mixture, usually 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 liberate 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 combination of acid and base that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the components are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0151] 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. Enteric-coated dosage forms can be compressed, molded, or extruded tablets / molds (coated or uncoated) containing granules, powders, pellets, beads, or microparticles (coated or uncoated themselves) of the active ingredient and / or other composition components. Enteric-coated oral dosage forms can be capsules (coated or uncoated) containing pellets, beads, or granules of a solid carrier, and / or compositions (coated or uncoated themselves).

[0152] As used herein, the term "delayed release" refers to delivery such that release can be achieved at some generally predictable locations in the gastrointestinal tract distal to that which would be achieved in the absence of a change in delayed release. In some embodiments, the means for delaying release is a coating. Any coating should be applied to a sufficient thickness such that the entire coating is insoluble in gastrointestinal fluid at a pH below about 5, but soluble at a pH regarding 5 or above. It is contemplated that any anionic polymer exhibiting pH-dependent solubility characteristics 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 their compatible mixtures, and some of their properties include, but are not limited to:

[0153] Shellac (a purified product obtained from the resinous secretion of insects, also called purified lac. This coating dissolves in solvents with pH > 7);

[0154] Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include copolymers of methacrylic acid and ammonium methacrylate salts. The Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available as solubilized in organic solvents, aqueous dispersions, or dry powders. The Eudragit series RL, NE, and RS are insoluble but permeable in the gastrointestinal 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.

[0155] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose and a reaction mixture of a partial acetate ester of cellulose and phthalic anhydride. Their performance can vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH > 6. Aquateric (FMC) is an aqueous system and is a spray-dried pseudo-latex of particles < 1 μm. Other components in Aquateric may include Pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include the following: 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)). Performance can vary based on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, or HP-55F are suitable. Performance can vary based 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, polyvinyl acetate phthalate (PVAP), are provided as granules or as fine powders for aqueous dispersions. PVAP dissolves at pH > 5 and is much less permeable to water vapor and gastric juice.

[0156] In some embodiments, the coating may contain, and typically does contain, a plasticizer, as well as other possible coating excipients such as colorants, talc, and / or magnesium stearate. 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 esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers will typically contain 10 - 25 wt% plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as spraying or pan coating are utilized to apply the coating. 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.

[0157] In addition to plasticizers, colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnauba wax or PEG) can be added to the coating to solubilize or disperse the coating material and to improve coating performance and the coated product.

[0158] In other embodiments, the formulations described herein that include Compound 1 are delivered using a pulsatile dosage form. A pulsatile dosage form can provide one or more immediate release pulses at a predetermined time 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; non-polymeric systems that are lipids including sterols such as porous matrices, cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. 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, which are specifically incorporated by reference.

[0159] In some embodiments, a pharmaceutical formulation is provided that includes particles of Compound 1 and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension and, when mixed with water, provides a substantially uniform suspension.

[0160] It should be understood that a given additive is often classified differently by different practitioners in the art, or is commonly used for any of several different functions, such that there is overlap among the additives listed as being used in the aqueous dispersions or suspensions described herein. Thus, the additives listed above should be construed as merely illustrative of the types of additives that may be included in the formulations described herein, and are not limiting. The amount of such additives can be readily determined by one of ordinary skill in the art according to the particular properties desired.

[0161] Method In another aspect, there is a method of treating a disease, disorder, or illness in a mammal that would benefit from modulation of an S1P receptor, the method comprising administering to the mammal a therapeutically effective amount of the crystalline form of Compound 1 described herein.

[0162] In another embodiment, there is a method of treating a disease, disorder, or illness in a mammal that would benefit from modulation of an S1P receptor, the method comprising administering to the mammal a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness in the mammal is selected from multiple sclerosis, ulcerative colitis, and Crohn's disease. In another embodiment, there is a method of treating a disease, disorder, or illness in a mammal that would benefit from modulation of an S1P receptor, the method comprising administering to the mammal a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness in the mammal is multiple sclerosis. In another embodiment, there is a method of treating a disease, disorder, or illness in a mammal that would benefit from modulation of an S1P receptor, the method comprising administering to the mammal a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness in the mammal is ulcerative colitis. In another embodiment, there is a method of treating a disease, disorder, or illness in a mammal that would benefit from modulation of an S1P receptor, the method comprising administering to the mammal a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness in the mammal is Crohn's disease.

[0163] In a further embodiment, there is provided a method of treating a mammalian disease, disorder, or illness that would benefit from modulation of the S1P receptor, the method comprising administering to the mammal a therapeutically effective amount of the crystalline form of Compound 1 described herein, wherein the disease, disorder, or illness in the mammal is rejection of a transplanted organ or tissue, graft-versus-host disease caused by transplantation, rheumatoid arthritis, multiple sclerosis, an autoimmune syndrome including myasthenia gravis, hay fever, type I diabetes, prevention of psoriasis, Crohn's disease, ulcerative colitis, acute respiratory distress syndrome, adult respiratory distress syndrome, influenza, rheumatic fever, and post-infectious autoimmune diseases including post-infectious glomerulonephritis, and metastasis of cancer.

[0164] Dosage Methods and Treatment Regimens In some embodiments, crystalline Compound 1 is used in the preparation of a medicament for the treatment of a disease or illness that would benefit from modulation of the S1P receptor. Additionally, a method of treating any of the diseases or illnesses described herein in an individual in need thereof comprises administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of crystalline Compound 1 or a pharmaceutically acceptable solvate thereof.

[0165] In some embodiments, the composition comprising crystalline Compound 1 is administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the composition containing Compound 1 is administered for therapeutic use. In some embodiments, the composition containing Compound 1 is administered for prophylactic use.

[0166] For therapeutic use, the composition is administered to a patient suffering from the disease or illness in an amount sufficient to treat or at least partially arrest the symptoms of the disease or illness. The amount effective for this use depends on the severity and course of the disease or illness, previous treatment, the health state, weight, and response of the patient to the drug, as well as the judgment of the treating physician.

[0167] For prophylactic use, a composition containing the compounds described herein is administered to a patient who is susceptible to, or at risk of, a particular disease, disorder, or illness. Such amounts are defined as "prophylactically effective amounts or prophylactic dosages." In this use, the exact amount varies depending on the patient's condition, weight, etc. When used in a patient, the amount effective for this use depends on the severity and course of the disease, disorder, or illness, previous treatment, the patient's health status, and response to the drug, as well as the judgment of the physician administering the treatment.

[0168] In some embodiments, crystalline Compound 1 is administered daily. In some embodiments, crystalline Compound 1 is administered every other day.

[0169] In some embodiments, Compound 1 is administered once a day. In some embodiments, Compound 1 is administered twice a day. In some embodiments, Compound 1 is administered three times a day. In some embodiments, Compound 1 is administered four times a day.

[0170] If the patient's condition does not improve, based on the judgment of the physician, the compound is administered long-term, i.e., over a long period including the lifetime of the patient, to relieve or otherwise control or suppress the symptoms of the patient's disease or illness.

[0171] If the patient's condition improves, a maintenance dosage is administered if necessary. Subsequently, the dosage or dosing frequency, or both, can be reduced to a level that sustains improvement of the disease, disorder, or illness, depending on the symptoms. However, the patient may require intermittent treatment over a long period for any recurrence of symptoms.

[0172] The amount of a given agent corresponding to such amounts will vary depending on factors such as the particular compound, disease or disorder, and its severity, and the characteristics (e.g., weight) of the subject or host in need of treatment, 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, and the subject or host being treated. However, generally, dosages utilized for the treatment of adult humans typically range from about 0.02 to about 5000 mg per day, and in some embodiments from about 1 to about 1500 mg per day. The desired dosage may conveniently be presented as a single dose or as divided doses, administered simultaneously (or over a short period of time) or at appropriate intervals, for example, as sub-doses two, three, or more times per day.

[0173] The pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit dosages containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing discrete quantities 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 single-dose, non-resealable container. Alternatively, a resealable container for multiple administrations can be used, in which case it is typical to include a preservative in the composition. As but one example, a formulation for parenteral injection can be provided in unit dosage form (including, but not limited to, ampoules) or in multiple-dose containers, together with an added preservative.

[0174] Suitable daily dosages for the compounds described herein are from about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dosage is from about 0.1 mg / kg to about 10 mg / kg. The daily dosages indicated for larger mammals, not limited to humans, are in the range of about 0.5 mg to 1000 mg, and are conveniently 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 to about 500 mg of the active ingredient. In one embodiment, 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 great variability in the variables regarding individual treatment regimens, the foregoing ranges are merely suggestive and it is not uncommon for there to be some deviation from these recommended values. Such dosages may be varied depending upon many 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.

[0175] The toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD 50 (50% lethal dose for the population) and ED 50 (therapeutically effective dose at 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD 50 and ED 50 . Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages to be used in humans. The dosages of such compounds preferably lie within a range of circulating concentrations that includes the ED 50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form used and the route of administration utilized.

[0176] Kit / Manufactured Product Kits and products for use in the therapeutic methods of use described herein are also described herein. Such kits include a carrier, package, or container partitioned to contain one or more containers, such as vials, tubes, etc., each container comprising one of the separate elements for using the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the containers are formed from a variety of materials such as glass or plastic.

[0177] The articles of manufacture provided herein include a packaging material. Packaging materials used in the packaging of pharmaceutical products include, for example, U.S. Patent No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment.

[0178] In some embodiments, the compounds or compositions described herein are provided in a packaging or dispensing 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 another component or additive. In some embodiments, the packaging includes one or more containers filled with one or more of the components of the pharmaceutical composition. In some embodiments, the packaging includes a metal or plastic foil such as a blister pack. In some embodiments, the packaging or dispensing device is accompanied by instructions for administration, such as instructions for the administration of the compound or composition for treating a tumor disease. In some embodiments, the packaging or dispenser is accompanied by a notice attached to the container in a form specified by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and the notice reflects the approval of the government agency regarding the form of the drug for human or animal administration. In some embodiments, such a notice is, for example, a label approved by the U.S. Food and Drug Administration regarding a prescription drug or an approved product insert. In some embodiments, a composition containing a compound described herein formulated with a suitable pharmaceutical carrier is prepared, placed in a suitable container, and labeled for the treatment of the indicated disease.

[0179] For example, the container contains crystalline Compound 1 disclosed herein. Such a kit optionally includes a descriptive or labeling for identification or instructions regarding use in the methods described herein.

[0180] The kit typically includes a label listing the contents and / or instructions for use and an accompanying document with the instructions for use. Typically, a set of instructions will also be included.

[0181] In one embodiment, the label is on or associated with the container. In one embodiment, when the characters, numbers or other indicia forming the label are affixed to, molded or engraved on the container itself, the label is on the container. The label is associated with the container, for example, when it is present in a receptacle or carrier device that holds the container as an accompanying document. In one embodiment, the label is used to indicate that the contents are to be used for a particular therapeutic use. The label may be used, for example, to indicate instructions for using the contents in the methods described herein.

[0182] In certain embodiments, the pharmaceutical composition is provided in a pack or dispenser device comprising one or more unit dosage forms comprising the compounds provided herein. In embodiments, the pack comprises, for example, a metal or plastic foil such as a blister pack. In further embodiments, the pack or dispenser device is accompanied by instructions for administration. In another embodiment, the pack or dispenser is accompanied by a notice attached to the container in a form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceuticals, the notice reflecting the approval of the government agency for the form of the drug for human or animal administration. In embodiments, such notice is, for example, a label approved by the US Food and Drug Administration for prescription drugs or inserts for approved products. In one embodiment also, a composition comprising a compound provided herein formulated in a pharmaceutically acceptable carrier is prepared, placed in a suitable container and labeled for the treatment of the indicated disease.

Examples

[0183] List of Abbreviations As used throughout the specification of the present invention, the following abbreviations are understood to have the following meanings unless otherwise defined. ACN or MeCN Acetonitrile Bn Benzyl BOC or Boc tert-Butyl carbamate 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 dimethyl sulfoxide eq or equive equivalent Et ethyl Et2O diethyl ether EtOH ethanol EtOAc ethyl acetate HPLC high performance liquid chromatography Me methyl MeOH methanol MS mass spectrometry GC gas chromatography h hour KF Karl Fischer min minute MsOH methanesulfonic acid NMR nuclear magnetic resonance RP-HPLC reverse phase high performance liquid chromatography RT or rt room temperature TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography V volume

[0184] I. Synthesis of Polymorphs Example 1: Compound 1, Form 1: 20 mg of Compound 1 and 0.3 mL of solvent (THF or EtOAc) were stirred at room temperature for 3 days, and the resulting solid was separated and dried at 50 °C for 2 hours to obtain Compound 1, Form 1.

[0185] Example 2: Compound 1, Form 2: 200 mg of Compound 1 and 2 mL of acetic acid in a vial were stirred at room temperature for 2 hours. The solid was separated and dried at room temperature overnight to obtain Compound 1, Form 2.

[0186] Scale-up synthesis of Compound 1, Form 2: 1) Under N2, at 25 ± 5 °C, the reactor was charged with DMAc (6V). 2) Under N2, at 25 ± 5 °C, the reactor was charged with Compound 1 (1.0 equivalent). 3) Under N2, at 25 ± 5 °C, DMAc (1V) was charged to rinse the reactor. 4) The temperature was adjusted to 110 ± 5 °C and stirred for at least 24 hours. 5) The temperature was adjusted to 25 ± 5 °C. 6) The reactor was charged with H2O (7V) for at least 5 hours and stirred at 30 ± 10 °C for at least 4 hours. 7) Filtered, and the wet cake was washed twice with H2O (2V). 8) The cake was dried at 60 ± 5 °C for at least 20 hours. 9) Under N2, at 25 ± 5 °C, the reactor was charged with AcOH (8V). 10) Under N2, at 25 ± 5 °C, the reactor was charged with the dry cake. 11) Under N2, at 25 ± 5 °C, AcOH (2V) was charged to rinse the reactor. 12) The temperature was adjusted to 95 ± 5 °C. 13) Stirred at 95 ± 5 °C for 1 hour. 14) The temperature was adjusted to 55 ± 5 °C. 15) Filtered with activated carbon (50 wt%). 16) The activated carbon was washed twice with AcOH (2V). 17) The filtrate was concentrated to 5 - 6V at 60 °C or below. 18) At 55 ± 5 °C, the reactor was charged with n-heptane (18V) in at least 6 hours and stirred for at least 1 hour. 19) The temperature was adjusted to 25 ± 5 °C and stirred for at least 12 hours. 20) Filtered, and the wet cake was washed twice with heptane (5.0V). 21) The cake was dried and purged with nitrogen for 1 hour or less. 22) Samples were taken for XRPD and Polymorph 2 was confirmed.

[0187] Example 3: Tosylate of Compound 1, Polymorph 3: 20 mg of Compound 1 and 0.3 mL of EtOAc were added into a vial, and then p-toluenesulfonic acid was added at a molar filling ratio of 1:1 (acid / base). The mixture was stirred at room temperature for 3 days, and the resulting solid was separated and dried at 50 °C for 2 hours to obtain the tosylate of Compound 1, Polymorph 3.

[0188] Example 4: Mesylate of Compound 1, Polymorph 4: 20 mg of Compound 1 and 0.3 mL of EtOAc were added into a vial, and then methanesulfonic acid was added at a molar filling ratio of 1:1 (acid / base). The mixture was stirred at room temperature for 3 days, and the resulting solid was separated and dried at 50 °C for 2 hours to obtain Compound 1, Polymorph 4.

[0189] Example 5: Compound 1, Polymorph 5: 120 mg of Compound 1 was dissolved in DMSO (4 mL) at 50 °C, and then 4 mL of the solution was filtered at room temperature. 8 mL of water (anti-solvent) was added to the filtrate over 2 hours. The precipitated solid was collected and dried at 50 °C for 4 hours to obtain Compound 1, Polymorph 5.

[0190] Example 6: Compound 1, Polymorph 6: MTBE (2 mL) was added to 100 mg of Compound 1, and the suspension was slurried at room temperature for 5 hours. The solid was separated to obtain Compound 1, Polymorph 6.

[0191] Example 7: Compound 1, Polymorph 7: 2 mL of MeOH / water (v / v, 9 / 1) was added to 100 mg of Compound 1. The suspension was stirred at room temperature for 5 hours. The solid was separated to obtain Compound 1, Polymorph 7.

[0192] Example 8: Compound 1, Polymorph 8: 120 mg of Compound 1 was dissolved in DMSO (4 mL) at room temperature for 1 hour, and the resulting solid was separated and dried to obtain Compound 1, Form 8.

[0193] II. Characterization of Polymorphs Example 9: X-ray Powder Diffraction (XRPD) X-ray powder diffraction studies were carried out using a Malvern Panalytical Empyrean with the following instrument parameters. Scan: 3° (2θ) to 40° (2θ) Increment: 0.0167° (2θ) Scan rate: 17.8 seconds / step Voltage: 45 KV Current: 40 mA Rotation: On Sample holder: Zero-background sample holder

[0194] XRPD analysis of Form 1 of Compound 1 (Figure 1) showed that Form 1 is crystalline with characteristic peaks at 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° 2θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 2θ.

[0195] XRPD analysis of Form 2 of Compound 1 (Figure 3) showed that Form 2 is crystalline with characteristic peaks at 6.9° 2θ, 17.1° 2θ, 18.1° 2θ, 22.0° 2θ, 24.0° 2θ, 24.8° 2θ, 25.5° 2θ, 26.2° 2θ, and 28.2° 2θ.

[0196] XRPD analysis of Form 3 of Compound 1 (Figure 5) showed that Form 3 is crystalline with characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 2θ.

[0197] The XRPD analysis of Form 4 of Compound 1 (Figure 7) showed that Form 4 is crystalline with characteristic peaks at 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° 2θ, 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ.

[0198] The XRPD analysis of Form 5 of Compound 1 (Figure 9) showed that Form 5 is crystalline with characteristic peaks at 4.4° 2θ, 5.8° 2θ, 11.1° 2θ, 14.1° 2θ, 17.5° 2θ, 18.6° 2θ, 21.3° 2θ, 22.4° 2θ, 23.8° 2θ, 25.6° 2θ, and 25.9° 2θ.

[0199] The XRPD analysis of Form 6 of Compound 1 (Figure ll) showed that Form 6 is crystalline with characteristic peaks at 7.2° 2θ, 9.5° 2θ, 10.9° 2θ, 18.5° 2θ, 19.0° 2θ, 21.9° 2θ, 22.4° 2θ, 23.7° 2θ, 25.6° 2θ, and 26.7° 2θ.

[0200] The XRPD analysis of Form 7 of Compound 1 (Figure 13) showed that Form 7 is crystalline with characteristic peaks at 10.0° 2θ, 11.0° 2θ, 12.6° 2θ, 13.5° 2θ, 14.1° 2θ, 21.3° 2θ, 21.7° 2θ, 22.1° 2θ, 25.4° 2θ, 26.7° 2θ, 27.1° 2θ, and 29.0° 2θ.

[0201] The XRPD analysis of Form 8 of Compound 1 (Figure 15) showed that Form 8 is crystalline with characteristic peaks at 7.3° 2θ, 11.6° 2θ, 14.6° 2θ, 16.3° 2θ, 18.7° 2θ, 21.7° 2θ, 21.9° 2θ, 22.6° 2θ, 25.1° 2θ, 29.3° 2θ, and 37.8° 2θ.

[0202] Example 10: Thermogravimetric Analysis Thermogravimetric analysis of the solid was carried out using a TA Q500 / Q5000 from TA Instruments. The sample was placed in an aluminum open pan and its amount was automatically weighed. The sample was heated to the final temperature at a heating rate of 10 °C / min.

[0203] The TGA of Form 1 of Compound 1 (Figure 2) showed a 1.3% weight loss before 150 °C, consistent with the anhydrate.

[0204] The TGA of Form 2 of Compound 1 (Figure 4) showed a 9.0% weight loss before 150 °C, consistent with the monoacetate solvate.

[0205] The TGA of Form 3 of Compound 1 (Figure 6) showed a 2.4% weight loss before 150 °C, consistent with the anhydrate.

[0206] The TGA of Form 4 of Compound 1 (Figure 8) showed a 4.3% weight loss before 130 °C.

[0207] The TGA of Form 5 of Compound 1 (Figure 10) showed a 0.6% weight loss up to 150 °C, consistent with the anhydrate.

[0208] The TGA of Form 6 of Compound 1 (Figure 12) showed a 1.8% weight loss up to 200 °C, consistent with the anhydrate.

[0209] The TGA of Form 7 of Compound 1 (Figure 14) showed an 8.7% weight loss up to 100 °C, consistent with the hydrate.

[0210] The TGA of Form 8 of Compound 1 (Figure 16) showed a 10.6% weight loss up to 150 °C.

[0211] Example 11: Differential Scanning Calorimetry (DSC) DSC studies were carried out using a TA Q200 / Q2000 from TA Instruments. The sample was weighed in a pinhole aluminum pan and the exact amount was recorded. The sample was heated from 25 °C to the final temperature at a heating rate of 10 °C / min with a nitrogen purge of 50 mL / min.

[0212] The DSC analysis of Form 1 of Compound 1 (Figure 2) showed a sharp endothermic melting with an onset temperature of 282 °C.

[0213] The DSC analysis of Form 2 of Compound 1 (Figure 4) showed a first endotherm with an onset temperature of about 145 °C and a second endotherm with an onset temperature of about 280 °C.

[0214] The DSC analysis of Form 3 of Compound 1 (Figure 6) showed a first endotherm at about 41 °C, a second endotherm with an onset temperature of about 93 °C, and a third endotherm with an onset temperature of about 156 °C.

[0215] The DSC analysis of Form 4 of Compound 1 (Figure 8) showed a first endotherm at about 60 °C and a second endotherm with an onset temperature of about 128 °C.

[0216] The DSC analysis of Form 5 of Compound 1 (Figure 10) showed an endotherm with an onset temperature of about 273 °C.

[0217] The DSC analysis of Form 6 of Compound 1 (Figure 12) showed an endotherm with an onset temperature of about 278 °C.

[0218] The DSC analysis of Form 7 of Compound 1 (Figure 14) showed a first endotherm at about 113 °C, an exotherm at about 168 °C, and a second endotherm at about 279 °C.

[0219] The DSC analysis of Form 8 of Compound 1 (Figure 16) showed a first endotherm at about 89 °C, a second endotherm at about 119 °C, and a third endotherm at about 284 °C.

[0220] Example 12: Dynamic Vapor Sorption (DVS) DVS studies were carried out using DVS Intrinsic (SMS, UK). 10 - 20 mg of the compound was transferred into the DVS, and weight changes were recorded for an atmosphere humidity varying at 25 °C using the following parameters. Drying at 25 °C until dm / dt < 0.002% / min Minimum time: 10 minutes, maximum time: 180 minutes Equilibrium: 60 minutes Cycle: 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 0 After the DVS experiment, the samples are characterized by XRPD.

[0221] The DVS analysis of Form 1 of Compound 1 showed a moisture uptake of 0.3% at RH between 0 and 80%. The post-DVS analysis by XRPD showed no change. The substance was slightly hygroscopic.

[0222] III. Polymorph Screening Example 13: Slurry method at 25 °C Approximately 15 mg of the amorphous free base of Compound 1 was suspended in 0.5 mL of solvent in an HPLC glass vial. After suspension, it was magnetically stirred at room temperature for 6 days, and the remaining solid was separated for XRPD analysis. The results are shown in Table 1.

[0223] [Table 1]

[0224] Example 14: Slurry method at 50 °C The slurry conversion experiments were carried out at 50 °C in different solvent systems. Approximately 15 mg of the amorphous free base of Compound 1 was suspended in 0.3 mL of solvent in an HPLC glass vial. After suspension, it was stirred at 50 °C for about 6 days, and the remaining solid was separated for XRPD analysis. The results are shown in Table 2.

[0225] [Table 2]

[0226] Example 15: Solid Vapor Diffusion Solid vapor diffusion experiments were conducted using 13 different solvents. Approximately 15 mg of the free base of Compound 1 was weighed into a 3-mL vial and placed into a 20-mL vial together with 2 mL of a volatile solvent. The 20-mL vial was capped and maintained at room temperature for 7 days to allow the solvent vapor to interact with the sample. The solid was tested by XRPD and the results are shown in Table 3.

[0227]

Table 3

[0228] Example 16: Liquid Vapor Diffusion Nine liquid vapor diffusion experiments were carried out. Approximately 15 mg of the free base of Compound 1 was dissolved in an appropriate solvent to obtain a clear solution in a 3-mL vial. This solution was then placed into a 20-mL vial together with 3 mL of a volatile solvent. The 20-mL vial was capped and maintained at room temperature for a sufficient time to allow the organic vapor to interact with the solution. The precipitate deposit was separated for XRPD analysis. The solid was tested by XRPD and the results are shown in Table 4.

[0229]

Table 4

[0230] Example 17: Slow Evaporation Slow evaporation experiments were conducted under six conditions. Briefly, 10 - 17 mg of the free base of Compound 1 was dissolved in 2.5 mL of a solvent in a 3-mL glass vial. If dissolution was not achieved, the suspension was filtered using a nylon membrane (pore size 0.45 μm) and the filtrate was used in the subsequent steps. A visually clear solution was covered with Parafilm® having 3 - 4 pinholes and evaporated at room temperature. The results are shown in Table 5.

[0231]

Table 5

[0232] Example 18: Slow Cooling Slow cooling experiments were carried out in seven solvent systems. Approximately 20 mg of Compound 1 free base was suspended in 0.5 - 1.0 mL of solvent in a 3 - mL glass vial at room temperature. Subsequently, the suspension was heated to 50 °C, maintained at equilibrium for about 5 hours, and filtered using a nylon membrane (pore size 0.45 μm). The filtrate was slowly cooled to 5 °C at a rate of 0.1 °C / min. No solids were obtained in any of the systems, and then the solution was transferred to - 20 °C. If no precipitation was observed, the solution was evaporated at room temperature. The results are shown in Table 6.

[0233]

Table 6

[0234] Example 19: Addition of Anti - solvent A total of 19 anti - solvent addition experiments were conducted. Approximately 15 mg of Compound 1 free base was dissolved in 0.5 - 2.0 mL of solvent to obtain a clear solution. The solution was magnetically stirred, and subsequently, 0.2 mL of anti - solvent was added until precipitation appeared or the total amount of anti - solvent reached 15.0 mL. The obtained precipitate deposits were separated for XRPD analysis, and the results are shown in Table 7.

[0235]

Table 7

[0236] Example 20: Stability Study The physicochemical stability of Form 1 was evaluated by storing the samples at 80 °C for 1 day, at 25 °C / 60% RH for 1 week, and at 40 °C / 75% RH for 1 month. The stability samples were characterized by XRPD and HPLC. Substantial changes in HPLC purity were not observed under all the tested conditions, indicating good chemical stability. Furthermore, no morphological changes were observed for Form 1 after storage, as evidenced by the XRPD pattern.

[0237] The stability of Form 2 was also evaluated at room temperature in slurries in acetone and methanol / water. Solids were isolated at 1 hour, 3 hours, 5 hours, and 29 hours. XRPD analysis showed the formation of Form 1 within 1 hour in both solvents.

[0238] Example 21: Relationship of the Thermodynamic Stability of the Anhydrate (Forms 1, 5, and 6) Starting from Form 5, an exothermic signal was observed during heating, and Form 6 was formed at high temperature. According to the Burger-Ramberger rule, Form 6 is monotropically related to Form 5 and is thermodynamically more stable.

[0239] As a result, slurry competition between Form 6 and Form 1 in acetone and THF systems was carried out at 5 °C, room temperature, and 50 °C. After stirring for 5 days at the desired temperature, the solids were separated and analyzed by XRPD. As shown in Table 8, only Form 1 was obtained, indicating that Form 1 is the thermodynamically stable form at 5 - 50 °C.

[0240]

Table 8

[0241] Example 22: Critical Water Activity Study between Form 1 and Form 7 The critical water activity between the anhydrous Form 1 and the hydrated Form 7 was investigated at room temperature via slurries in MeOH / H2O systems with various water activities. After stirring overnight, the solids were isolated and analyzed by XRPD. As shown in Table 9, Form 7 was converted to Form 1 under all water activities at RT, indicating that Form 1 is more stable under the selected conditions.

[0242]

Table 9

[0243] Example 23: Solubility Evaluation of Forms 1 and 2 The solubility of Form 1 and Form 2 was evaluated in the same vehicle. Form 1 or Form 2 was added to DCM / MeOH and stirred at room temperature or 50 °C until dissolved. Then, once a clear solution was obtained, a certain amount of HPMC-AS was added to the solution at room temperature. The details and results of the experiment are shown in Table 10. Form 2 dissolved in DCM / MeOH at a concentration of 13 mg / mL, while Form 1 dissolved at a lower concentration of 10 mg / mL. Therefore, in this vehicle, Form 2 showed better solubility than Form 1 and is thus the preferred crystalline form for the formulation in this vehicle.

[0244]

Table 10

[0245] IV. Single Crystal X-ray Diffraction Data Example 24: Single Crystal X-ray Diffraction, Compound 1, Form 1 An appropriate single crystal was selected from tabular crystals and analyzed with a single crystal X-ray diffractometer. The crystal system of the single crystal is monoclinic, the space group is P21, and the lattice parameters are as follows: a = 10.70843(9) Å, b = 6.96040(5) Å, c = 14.85483(12) Å, α = 90°, β = 100.2303(8)°, γ = 90°, V = 1089.602(15) Å3. The formula weight is 546.71 g·mol-l, Z = 2, and the density calculated as a result is 1.666 gcm -3 is. Further crystallographic data and refinement parameters are listed in Table 11.

[0246] The asymmetric unit of the single crystal structure consists of only one molecule of Compound 1, as shown in Figure 17, which indicates that the crystal is the anhydrate of Compound 1. The single crystal structure determination confirmed the stereochemistry of Compound 1, which is consistent with the assigned chemical structure. The absolute configuration assignment (R / S) of the chiral atom in Compound 1 is {C4(R)}. The XRPD analysis of the single crystal structure showed that it is Form 1.

[0247]

Table 11

[0248] Example 25: Single crystal X-ray diffraction, Compound 1, Form 2 Compound 1, Form 2 has the formula C 21 H 13 Cl3F3N5O3·C2H4O2 and crystallizes as a monoclinic crystal in the P21 space group. There are two molecules of Compound 1 and two molecules of acetic acid in each asymmetric unit, and the unit cell contains two asymmetric units. As shown in Figure 18, the chiral carbons exhibit an "R" (C17, C38) configuration within the asymmetric unit. Proton transfer does not occur between Compound 1 and acetic acid, and thus it is a solvate of acetic acid. Further crystallographic data and refinement parameters are listed in Table 12. XRPD analysis of the single crystal structure indicated Form 2.

[0249]

Table 12

[0250] V. Biological data Example 26: GTPγS binding assay The S1P1 membrane was prepared from CHO-K1 Gαqi5 cells expressing full-length human S1P1. Membrane GTPγ 35 S and various concentrations of the compound were incubated for 60 minutes to perform a scintillation proximity assay (SPA). Wheatgerm agglutinin-coated SPA beads were added and after incubation for 60 minutes, centrifugation and scintillation counting were performed. The EC 50 data for Compound 1 was found to be <1 μM.

Claims

1. A crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one, or a salt or solvate thereof.

2. The crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one 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 characteristic peaks at 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° 2θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 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 having an endotherm with an onset temperature of about 282 °C, or (f) A combination thereof The crystalline form according to claim 1, or a salt or solvate thereof, which is Form 1 having at least one of them.

3. The crystalline form according to claim 2, or a 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 salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5° 2θ, 18.5° 2θ, 21.0° 2θ, 22.1° θ, 22.8° 2θ, 26.6° 2θ, 27.8° 2θ, and 28.9° 2θ.

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

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

7. The crystalline form according to claim 2, or a salt or solvate thereof, wherein the crystalline form has a DSC thermogram having an endotherm with an onset temperature of about 282 °C.

8. The crystalline form according to claim 2, or a salt or solvate thereof, characterized in that the crystalline form has properties (a), (b), (c), (d), and (e).

9. The crystalline form according to any one of claims 2 to 8, or a salt or solvate thereof, wherein the crystalline form is obtained from dichloromethane / water.

10. The crystalline form according to any one of claims 2 to 9, or a salt or solvate thereof, wherein the crystalline form is not solvated.

11. The crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one has the following properties (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 6.9° 2θ, 17.1° 2θ, 18.1° 2θ, 22.0° 2θ, 24.0° 2θ, 24.8° 2θ, 25.5° 2θ, 26.2° 2θ, and 28.2° 2θ, (c) a thermogravimetric analysis (TGA) substantially similar to that shown in Figure 4, (d) a DSC thermogram substantially similar to that shown in Figure 4, (e) a DSC thermogram having a first endotherm with an onset temperature of about 145 °C and a second endotherm with an onset temperature of about 180 °C, or (f) a combination thereof and is Form 2 having at least one of them, the crystalline form according to claim 1, or a salt or solvate thereof.

12. The crystalline form according to claim 11, or a salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 3.

13. The crystalline form according to claim 11, or a salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9° 2θ, 17.1° 2θ, 18.1° 2θ, 22.0° 2θ, 24.0° 2θ, 24.8° 2θ, 25.5° 2θ, 26.2° 2θ, and 28.2° 2θ.

14. The crystalline form according to claim 11, or a salt or solvate thereof, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in Figure 4.

15. The crystalline form according to claim 11, or a salt or solvate thereof, wherein the crystalline form has a DSC thermogram substantially the same as that described in FIG.

4.

16. The crystalline form according to claim 11, or a salt or solvate thereof, wherein the crystalline form has a DSC thermogram having a first endotherm with an onset temperature of about 145° C. and a second endotherm with an onset temperature of about 280° C.

17. The crystalline form according to claim 11, or a salt or solvate thereof, wherein the crystalline form has characteristics (a), (b), (c), (d), and (e).

18. The crystalline form according to any one of claims 11 to 17, or a salt or solvate thereof, wherein the crystalline form is obtained from acetic acid.

19. (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is paratoluenesulfonate, and the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one tosylate has the following characteristics (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 5, (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 2θ, (c) a thermogravimetric analysis (TGA) substantially the same as that described in FIG. 6, (d) a DSC thermogram substantially the same as that described in FIG. 6, (e) a DSC thermogram having a first endotherm at about 41° C., a second endotherm with an onset temperature of about 93° C., and a third endotherm with an onset temperature of about 156° C., or (f) a combination thereof Form 3 having at least one of them, the crystalline form according to claim 1, or a salt or solvate thereof.

20. The crystalline form according to claim 19, or a salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

5.

21. The crystalline form according to claim 19, or a salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9° 2θ, 8.4° 2θ, 17.5° 2θ, 19.8° 2θ, 20.5° 2θ, 24.8° 2θ, 25.6° 2θ, and 26.4° 2θ.

22. The crystalline form according to claim 19, or a salt or solvate thereof, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that described in FIG.

6.

23. The crystalline form according to claim 19, or a salt or solvate thereof, wherein the crystalline form has a DSC thermogram substantially similar to that described in FIG.

6.

24. The crystalline form according to claim 19, or a salt or solvate thereof, wherein the crystalline form has a DSC thermogram having a first endotherm at about 41° C., a second endotherm having an onset temperature of about 93° C., and a third endotherm having an onset temperature of about 156° C.

25. The crystalline form according to claim 19, or a salt or solvate thereof, wherein the crystalline form is characterized by having properties (a), (b), (c), (d), and (e).

26. The crystalline form according to any one of claims 19 to 25, or a salt or solvate thereof, wherein the crystalline form is obtained from ethyl acetate.

27. (R)-5-(2,5-Dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one is a methanesulfonate, and the crystalline form of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one mesylate has the following properties (a) An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 7, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° 2θ, 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ, (c) A thermogravimetric analysis (TGA) substantially similar to that described in FIG. 8, (d) a DSC thermogram substantially the same as that described in FIG. 8, (e) a DSC thermogram having a first endotherm at about 60° C. and a second endotherm having an onset temperature of about 128° C., (f) a combination thereof The crystalline form according to claim 1, or a salt or solvate thereof, which is Form 4 having at least one of them.

28. The crystalline form according to claim 27, or a salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG.

7.

29. The crystalline form according to claim 27, or a salt or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8° 2θ, 15.4° 2θ, 17.3° 2θ, 18.2° 2θ, 19.2° 2θ, 20.1° 2θ, 21.6° 2θ, 22.8° 2θ, 23.4° 2θ, 24.8° 2θ, 25.3° 2θ, 26.7° 2θ, and 30.9° 2θ.

30. The crystalline form according to claim 27, or a salt or solvate thereof, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially the same as that described in FIG.

8.

31. The crystalline form according to claim 27, or a salt or solvate thereof, wherein the crystalline form has a DSC thermogram substantially the same as that described in FIG.

8.

32. The crystalline form according to claim 27, or a salt or solvate thereof, wherein the crystalline form has a DSC thermogram having a first endotherm at about 60° C. and a second endotherm having an onset temperature of about 128° C.

33. The crystalline form according to claim 27, or a salt or solvate thereof, wherein the crystalline form is characterized by having properties (a), (b), (c), (d), and (e).

34. The crystalline form according to any one of claims 27 to 33, or a salt or solvate thereof, wherein the crystalline form is obtained from ethyl acetate.

35. The crystalline form according to any one of claims 1 to 34, or a salt or solvate thereof, for use in a medicament.

36. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 34, or a salt or solvate thereof, and a pharmaceutically acceptable excipient.

37. A method for treating a disease, disorder, or illness in a mammal that would benefit from modulation of a sphingosine-1-phosphate (S1P) receptor, the method comprising administering to an individual a therapeutically effective amount of the crystalline form according to any one of claims 1 to 34. [

38. ] The method according to claim 37, wherein the disease, disorder, or illness is selected from multiple sclerosis, ulcerative colitis, and Crohn's disease.

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