Crystalline forms of S1P receptor modulators

Abstract

Described herein are crystalline forms 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, as well as methods for preparing the same.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 358,791, filed on July 6, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] 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 shown to induce many cellular processes, including those leading to platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis and angiogenesis, cytoskeletal rearrangements in many cell types to regulate immune cell trafficking, vascular homeostasis, and cell communication in the central nervous system (CNS) and peripheral organ systems. S1P can bind to members of the endothelial differentiation gene family of plasma membrane-localized G protein-coupled receptors (EDG receptors). To date, five members of this family have been identified as S1P receptors in different cell types: S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P receptor modulators are compounds that signal at one or more S1P receptors as agonists or antagonists. Because S1P mediates a variety of cellular responses, S1P receptor modulators are promising targets for a variety of therapeutic indications. Summary of the invention

[0004] In one aspect, described herein 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 salt or solvate thereof.

[0005] 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 Form 1 having at least one of the following properties:

[0006] (a) with Figure 1 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0007] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5°2-θ, 18.5°2-θ, 21.0°2-θ, 22.1°2-θ, 22.8°2-θ, 26.6°2-θ, 27.8°2-θ and 28.9°2-θ;

[0008] (c) Basically similar to Figure 2 Thermogravimetric analysis (TGA) of those shown in;

[0009] (d) Basically similar to Figure 2 DSC thermogram of the one shown in;

[0010] (e) a DSC thermogram having an endotherm with an onset at about 282°C; or

[0011] (f) combinations thereof.

[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 or a solvate thereof has the same Figure 1 The X-ray powder diffraction (XRPD) patterns shown are substantially the same.

[0013] In some embodiments, it 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, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5°2-θ, 18.5°2-θ, 21.0°2-θ, 22.1°2-θ, 22.8°2-θ, 26.6°2-θ, 27.8°2-θ and 28.9°2-θ.

[0014] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 2 Thermogravimetric analysis (TGA) of those shown in .

[0015] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 2 DSC thermogram of the one shown in .

[0016] In some embodiments 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, wherein the crystalline form has a DSC thermogram with an endotherm starting at about 282°C.

[0017] 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 or a solvate thereof is characterized by having the following properties: (a) Figure 1 (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5°2-θ, 18.5°2-θ, 21.0°2-θ, 22.1°2-θ, 22.8°2-θ, 26.6°2-θ, 27.8°2-θ and 28.9°2-θ; (c) an X-ray powder diffraction (XRPD) pattern substantially similar to Figure 2 Thermogravimetric analysis (TGA) of the samples shown in (d) is substantially similar to Figure 2 and (e) a DSC thermogram having an endotherm onset at about 282°C.

[0018] In some embodiments, it 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, wherein the crystalline form is obtained from THF or EtOAc.

[0019] 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.

[0020] In another embodiment 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, wherein 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 having at least one of the following properties:

[0021] (a) with Figure 3 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0022] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9°2-θ, 17.1°2-θ, 18.1°2-θ, 22.0°2-θ, 24.0°2-θ, 24.8°2-θ, 25.5°2-θ, 26.2°2-θ and 28.2°2-θ;

[0023] (c) Basically similar to Figure 4 Thermogravimetric analysis (TGA) of those shown in;

[0024] (d) Basically similar to Figure 4 DSC thermogram of the one shown in;

[0025] (e) a DSC thermogram having a first endotherm with an onset at about 145°C and a second endotherm with an onset at about 180°C; or

[0026] (f) combinations thereof.

[0027] 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 or a solvate thereof has the same Figure 3 The X-ray powder diffraction (XRPD) patterns shown are substantially the same.

[0028] In some embodiments, it 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, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9°2-θ, 17.1°2-θ, 18.1°2-θ, 22.0°2-θ, 24.0°2-θ, 24.8°2-θ, 25.5°2-θ, 26.2°2-θ and 28.2°2-θ.

[0029] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 4 Thermogravimetric analysis (TGA) of those shown in .

[0030] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 4 DSC thermogram of the one shown in .

[0031] In some embodiments 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, wherein the crystalline form has a DSC thermogram with a first endotherm starting at about 145°C and a second endotherm starting at about 280°C.

[0032] 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 or a solvate thereof is characterized by having the following properties: (a) Figure 3 (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.0°2-θ, 9.5°2-θ, 11.2°2-θ, 14.9°2-θ, 18.6°2-θ, 22.1°2-θ, 24.1°2-θ, 26.2°2-θ and 30.0°2-θ; (c) an X-ray powder diffraction (XRPD) pattern substantially similar to Figure 4Thermogravimetric analysis (TGA) of the samples shown in (d) is substantially similar to Figure 4 (e) DSC thermogram having a first endotherm starting at about 145°C and a second endotherm starting at about 280°C.

[0033] In some embodiments, the invention 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, wherein the crystalline form is obtained from acetic acid.

[0034] 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.

[0035] In another embodiment 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, wherein the crystalline form of the tosylate salt 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 3 having at least one of the following properties:

[0036] (a) with Figure 5 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0037] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9°2-θ, 8.4°2-θ, 17.5°2-θ, 19.8°2-θ, 20.5°2-θ, 24.8°2-θ, 25.6°2-θ and 26.4°2-θ;

[0038] (c) Basically similar to Figure 6 Thermogravimetric analysis (TGA) of those shown in;

[0039] (d) Basically similar to Figure 6 DSC thermogram of the one shown in;

[0040] (e) a DSC thermogram having a first endotherm at about 41°C, a second endotherm onset at about 93°C, and a third endotherm onset at about 156°C; or

[0041] (f) combinations thereof.

[0042] 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 or a solvate thereof has the same Figure 5 The X-ray powder diffraction (XRPD) patterns shown are substantially the same.

[0043] In some embodiments, it 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, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9°2-θ, 8.4°2-θ, 17.5°2-θ, 19.8°2-θ, 20.5°2-θ, 24.8°2-θ, 25.6°2-θ and 26.4°2-θ.

[0044] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 6 Thermogravimetric analysis (TGA) of those shown in .

[0045] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 6 DSC thermogram of the one shown in .

[0046] In some embodiments 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, wherein the crystalline form has a DSC thermogram with a first endotherm at about 41°C, a second endotherm starting at about 93°C, and a third endotherm starting at about 156°C.

[0047] 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 or a solvate thereof is characterized by having the following properties: (a) Figure 5 (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9°2-θ, 8.4°2-θ, 17.5°2-θ, 19.8°2-θ, 20.5°2-θ, 24.8°2-θ, 25.6°2-θ and 26.4°2-θ; (c) an X-ray powder diffraction (XRPD) pattern substantially similar to Figure 6 Thermogravimetric analysis (TGA) of the samples shown in (d) is substantially similar to Figure 6 and (e) a DSC thermogram having a first endotherm at about 41°C, a second endotherm starting at about 93°C, and a third endotherm starting at about 156°C.

[0048] In some embodiments, the invention 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, wherein the crystalline form is obtained from ethyl acetate.

[0049] In another embodiment 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, wherein 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 methanesulfonate is Form 4 having at least one of the following properties:

[0050] (a) with Figure 7 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0051] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8°2-θ, 15.4°2-θ, 17.3°2-θ, 18.2°2-θ, 19.2°2-θ, 20.1°2-θ, 21.6°2-θ, 22.8°2-θ, 23.4°2-θ, 24.8°2-θ, 25.3°2-θ, 26.7°2-θ and 30.9°2-θ;

[0052] (c) Basically similar to Figure 8 Thermogravimetric analysis (TGA) of those shown in;

[0053] (d) Basically similar to Figure 8 DSC thermogram of the one shown in;

[0054] (e) a DSC thermogram having a first endotherm at about 60°C and a second endotherm onset at about 128°C; or

[0055] (f) combinations thereof.

[0056] 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 or a solvate thereof has the same Figure 7 The X-ray powder diffraction (XRPD) patterns shown are substantially the same.

[0057] In some embodiments, it 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, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8°2-θ, 15.4°2-θ, 17.3°2-θ, 18.2°2-θ, 19.2°2-θ, 20.1°2-θ, 21.6°2-θ, 22.8°2-θ, 23.4°2-θ, 24.8°2-θ, 25.3°2-θ, 26.7°2-θ and 30.9°2-θ.

[0058] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 8 Thermogravimetric analysis (TGA) of those shown in .

[0059] In some embodiments, 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, wherein the crystalline form has a substantially similar Figure 8 DSC thermogram of the one shown in .

[0060] In some embodiments 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, wherein the crystalline form has a DSC thermogram with a first endotherm at about 60°C and a second endotherm starting at about 128°C.

[0061] 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 or a solvate thereof is characterized by having the following properties: (a) Figure 7 (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 1 ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8° 2-θ, 15.4° 2-θ, 17.3° 2-θ, 18.2° 2-θ, 19.2° 2-θ, 20.1° 2-θ, 21.6° 2-θ, 22.8° 2-θ, 23.4° 2-θ, 24.8° 2-θ, 25.3° 2-θ, 26.7° 2-θ and 30.9° 2-θ; (c) an X-ray powder diffraction (XRPD) pattern substantially similar to Figure 8 Thermogravimetric analysis (TGA) of the samples shown in (d) is substantially similar to Figure 8 (e) DSC thermogram having a first endotherm at about 60°C and a second endotherm starting at about 128°C.

[0062] In some embodiments, the crystalline form 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 or a solvate thereof, wherein the crystalline form is obtained from ethyl acetate.

[0063] In some embodiments 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 medicine.

[0064] 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 amorphous.

[0065] In another aspect, described 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.

[0066] In another aspect, described 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.

[0067] In another aspect, described herein is a method of treating a disease, disorder, or condition in a mammal that would benefit from sphingosine-1-phosphate (S1P) receptor modulation, the method comprising administering to the individual a therapeutically effective amount 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 crystalline form of a solvate thereof.

[0068] In some embodiments is a method of treating a disease in a mammal selected from the group consisting of multiple sclerosis, ulcerative colitis, and Crohn's disease.

[0069] In some embodiments is a method of treating a disease in an individual in need thereof, 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 described herein or a solvate thereof, 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, a method of treating an immune disorder in an individual in need thereof comprises 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 described herein or a solvate thereof, wherein the therapeutically effective amount is taken with food. In some embodiments, a method of treating an immune disorder in an individual in need thereof comprises 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 described herein or a solvate thereof, wherein the therapeutically effective amount is not taken with food. In some embodiments is a method of treating an immune disorder in a subject in need thereof, comprising administering to the subject 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 described herein or a solvate thereof, 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 subject once daily. In some embodiments is a method of treating an immune disorder in a subject in need thereof, comprising administering to the subject 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 described herein or a solvate thereof, 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 subject twice daily.

[0070] Incorporation by reference

[0071] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the extent applicable and relevant and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 The X-ray powder diffraction (XRPD) pattern of 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 (Compound 1), Form 1 is shown.

[0073] Figure 2 Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1), Form 1 are shown.

[0074] Figure 3 The X-ray powder diffraction (XRPD) pattern of 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 (Compound 1), Form 2 is shown.

[0075] Figure 4 Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1), Form 2 are shown.

[0076] Figure 5 Shown is the X-ray powder diffraction (XRPD) pattern of 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 (Compound 1) tosylate salt, Form 3.

[0077] Figure 6Shown are thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1) tosylate salt, Form 3.

[0078] Figure 7 Shown is the X-ray powder diffraction (XRPD) pattern of 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 (Compound 1) methanesulfonate, Form 4.

[0079] Figure 8 Shown are thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1) methanesulfonate, Form 4.

[0080] Fig. 9 The X-ray powder diffraction (XRPD) pattern of 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 (Compound 1), Form 5 is shown.

[0081] Fig.10 Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1), Form 5 are shown.

[0082] Fig.11 The X-ray powder diffraction (XRPD) pattern of 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 (Compound 1), Form 6 is shown.

[0083] Fig.12Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1), Form 6 are shown.

[0084] Fig.13 The X-ray powder diffraction (XRPD) pattern of 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 (Compound 1), Form 7 is shown.

[0085] Fig.14 Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1), Form 7 are shown.

[0086] Fig.15 The X-ray powder diffraction (XRPD) pattern of 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 (Compound 1), Form 8 is shown.

[0087] Fig.16 Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of 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 (Compound 1), Form 8 are shown.

[0088] Fig.17 The asymmetric unit in the single crystal structure 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), Form 1 is shown.

[0089] Fig.18 The asymmetric unit in the single crystal structure 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), Form 2 is shown. DETAILED DESCRIPTION

[0090] Sphingosine-1-phosphate receptors regulate fundamental biological processes such as cell proliferation, angiogenesis, migration, cytoskeletal organization, endothelial cell chemotaxis, immune cell trafficking and mitogenesis. Sphingosine-1-phosphate receptors are also involved in immunomodulation and are directly involved in suppressing 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 a variety of tissues, and each subtype shows different cell specificity, although they are found at their highest density on leukocytes.

[0091] In one aspect, at least one S1P receptor modulator as described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from S1P receptor modulation. In some aspects, at least one S1P receptor modulator as described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of an S1P receptor subtype. In some embodiments, at least one S1P receptor modulator as described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of two S1P receptor subtypes. In some embodiments, at least one S1P receptor modulator as described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of one S1P receptor subtype.

[0092] Compound 1

[0093] In one embodiment, it 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:

[0094]

[0095] In some embodiments described herein are pharmaceutically acceptable salts of Compound 1. The term "pharmaceutically acceptable salt" with respect to Compound 1 refers to a salt of Compound 1 that does not cause significant irritation to a mammal to which it is administered and does not substantially abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt comprises:

[0096] - Acid addition salts formed by the reaction of compound 1 with an organic acid, the organic acid comprising aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., and comprising, 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.;

[0097] – Acid addition salts formed by the reaction of compound 1 with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0098] 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 comprises a solvent addition form (solvate). Solvates contain stoichiometric or non-stoichiometric amounts of solvents and are formed during product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, tert-butyl methyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In some embodiments, solvates are formed using, but not limited to, Class 3 solvents. In some embodiments, the solvate is formed using, but not limited to, a Class 2 solvent. The classes 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, or alcoholates are formed when the solvent is an alcohol.

[0099] 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.

[0100] Although not intended to be bound by any particular theory, some solid forms are characterized by physical properties, such as stability, solubility and dissolution rate, suitable for pharmaceutical and therapeutic dosage forms. In addition, although not intended to be bound by any particular theory, some solid forms are characterized by physical properties (such as density, compressibility, hardness, morphology, cracking, viscosity, solubility, water absorption, electrical properties, thermal behavior, solid state reactivity, physical stability and chemical stability), which affect specific processes (such as output, filtering, washing, drying, grinding, mixing, tableting, fluidity, dissolving, preparing and lyophilizing), which makes some solid forms suitable for manufacturing solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, which include solid-state analytical techniques as described herein (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis).

[0101] Crystalline form

[0102] The identification and selection of solid forms of pharmaceutical compounds is complex because changes in solid form may affect various physical and chemical properties that may bring advantages or disadvantages in processing, formulation, stability, bioavailability, storage and handling (e.g., transportation) and other important pharmaceutical properties. Useful pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solids depends on the specific application; sometimes amorphous solids are selected on the basis of, for example, an enhanced dissolution profile, while crystalline solids may be required for properties such as physical or chemical stability.

[0103] Whether crystalline or amorphous, 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 may potentially arise from polymorphism, where a particular pharmaceutical compound exists in multiple three-dimensional arrangements.

[0104] It is noteworthy that it is impossible to predict in advance whether crystalline forms of a compound will exist, let alone how to successfully prepare them (see, e.g., 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, if the instructions are not very precise and / or if other external factors influence the process, the results can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31: 875-879 (at present, it is generally impossible to predict computationally the number of observable polymorphs of even 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 more needs to be learned and done before one can state with any degree of confidence the ability to predict crystal structure, let alone polymorphs).

[0105] The diversity of possible solid forms creates a potential diversity of physical and chemical properties for a given drug compound. The discovery and selection of solid forms is very important in developing an effective, stable, and marketable drug product.

[0106] Crystalline Compound 1, Form 1

[0107] 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 is Form 1, characterized by having at least one of the following properties:

[0108] (a) with Figure 1 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0109] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5°2-θ, 18.5°2-θ, 21.0°2-θ, 22.1°2-θ, 22.8°2-θ, 26.6°2-θ, 27.8°2-θ and 28.9°2-θ;

[0110] (c) Basically similar to Figure 2 Thermogravimetric analysis (TGA) of those shown in;

[0111] (d) Basically similar to Figure 2 DSC thermogram of the one shown in;

[0112] (e) a DSC thermogram having an endotherm with an onset at about 282°C; or

[0113] (f) combinations thereof.

[0114] 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 properties (a) to (e).

[0115] 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 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°2-θ, 18.5°2-θ, 21.0°2-θ, 22.1°2-θ, 22.8°2-θ, 26.6°2-θ, 27.8°2-θ, and 28.9°2-θ. 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 substantially similar Figure 2In 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 substantially similar 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 with an endotherm starting at 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.

[0116] Crystalline Compound 1, Form 2

[0117] 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 Form 2, characterized by having at least one of the following properties:

[0118] (a) with Figure 3 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0119] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9°2-θ, 17.1°2-θ, 18.1°2-θ, 22.0°2-θ, 24.0°2-θ, 24.8°2-θ, 25.5°2-θ, 26.2°2-θ and 28.2°2-θ;

[0120] (c) Basically similar to Figure 4 Thermogravimetric analysis (TGA) of those shown in;

[0121] (d) Basically similar to Figure 4 DSC thermogram of the one shown in;

[0122] (e) a DSC thermogram having a first endotherm with an onset at about 145°C and a second endotherm with an onset at about 280°C; or

[0123] (f) combinations thereof.

[0124] 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) 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 2 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 2 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 2 is characterized by having properties (a) to (e).

[0125] 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 Figure 3In 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°2-θ, 17.1°2-θ, 18.1°2-θ, 22.0°2-θ, 24.0°2-θ, 24.8°2-θ, 25.5°2-θ, 26.2°2-θ, and 28.2°2-θ. 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 substantially similar 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 substantially similar 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 with a first endotherm starting at about 145° C. and a second endotherm starting at 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.

[0126] Crystalline Compound 1 Tosylate Salt, Form 3

[0127] 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 is a p-toluenesulfonate salt and the crystalline form of the (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 toluenesulfonate salt is Form 3 having at least one of the following properties:

[0128] (a) with Figure 5 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0129] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9°2-θ, 8.4°2-θ, 17.5°2-θ, 19.8°2-θ, 20.5°2-θ, 24.8°2-θ, 25.6°2-θ and 26.4°2-θ;

[0130] (c) Basically similar to Figure 6 Thermogravimetric analysis (TGA) of those shown in;

[0131] (d) Basically similar to Figure 6 DSC thermogram of the one shown in;

[0132] (e) a DSC thermogram having a first endotherm at about 41°C, a second endotherm onset at about 93°C, and a third endotherm onset at about 156°C; or

[0133] (f) combinations thereof.

[0134] 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 salt, Form 3 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 tosylate salt, Form 3 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 tosylate salt, Form 3 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 tosylate salt, Form 3 is characterized by having properties (a) to (e).

[0135] 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 tosylate salt, Form 3 has Figure 5 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 tosylate salt, Form 3 has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9°2-θ, 8.4°2-θ, 17.5°2-θ, 19.8°2-θ, 20.5°2-θ, 24.8°2-θ, 25.6°2-θ, and 26.4°2-θ. 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 tosylate salt, Form 3 has a substantially similar Figure 6In 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 tosylate salt, Form 3 has a substantially similar Figure 6 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 tosylate salt, Form 3 has a DSC thermogram with a first endotherm at about 41° C., a second endotherm starting at about 93° C., and a third endotherm starting at about 156° C. 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 tosylate salt, Form 3 is obtained from ethyl acetate. 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 tosylate salt (Form 3) is solvated. 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 tosylate salt (Form 3) is non-solvated.

[0136] Crystalline Compound 1 mesylate salt, Form 4

[0137] 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 is a mesylate 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 salt is Form 4 having at least one of the following properties:

[0138] (a) with Figure 7 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0139] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8°2-θ, 15.4°2-θ, 17.3°2-θ, 18.2°2-θ, 19.2°2-θ, 20.1°2-θ, 21.6°2-θ, 22.8°2-θ, 23.4°2-θ, 24.8°2-θ, 25.3°2-θ, 26.7°2-θ and 30.9°2-θ;

[0140] (c) Basically similar to Figure 8 Thermogravimetric analysis (TGA) of those shown in;

[0141] (d) Basically similar to Figure 8 DSC thermogram of the one shown in;

[0142] (e) a DSC thermogram having a first endotherm at about 60°C and a second endotherm onset at about 128°C; or

[0143] (f) combinations thereof.

[0144] 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 methanesulfonate, Form 4 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 methanesulfonate, Form 4 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 methanesulfonate, Form 4 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 methanesulfonate, Form 4 is characterized by having properties (a) to (e).

[0145] 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 methanesulfonate salt, Form 4 has Figure 7In 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 methanesulfonate, Form 4 has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8°2-θ, 15.4°2-θ, 17.3°2-θ, 18.2°2-θ, 19.2°2-θ, 20.1°2-θ, 21.6°2-θ, 22.8°2-θ, 23.4°2-θ, 24.8°2-θ, 25.3°2-θ, 26.7°2-θ, and 30.9°2-θ. 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 methanesulfonate salt, Form 4 has a substantially similar Figure 8 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 methanesulfonate, Form 4 has a substantially similar Figure 8 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 mesylate, Form 4 has a DSC thermogram having a first endotherm at about 60° C. and a second endotherm starting at about 128° C. 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 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 methanesulfonate (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 methanesulfonate (Form 4) is non-solvated.

[0146] Crystalline Compound 1, Form 5

[0147] 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 is Form 5, characterized by having at least one of the following properties:

[0148] (a) with Fig. 9 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0149] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.4°2-θ, 5.8°2-θ, 11.1°2-θ, 14.1°2-θ, 17.5°2-θ, 18.6°2-θ, 21.3°2-θ, 22.4°2-θ, 23.8°2-θ, 25.6°2-θ and 25.9°2-θ;

[0150] (c) Basically similar to Fig.10 Thermogravimetric analysis (TGA) of those shown in;

[0151] (d) Basically similar to Fig.10 DSC thermogram of the one shown in;

[0152] (e) a DSC thermogram having an endotherm with an onset at about 273°C; or

[0153] (f) combinations thereof.

[0154] 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 properties (a) to (e).

[0155] 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 Fig. 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 having characteristic peaks at 4.4°2-θ, 5.8°2-θ, 11.1°2-θ, 14.1°2-θ, 17.5°2-θ, 18.6°2-θ, 21.3°2-θ, 22.4°2-θ, 23.8°2-θ, 25.6°2-θ, and 25.9°2-θ. 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 substantially similar Fig.10In 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 substantially similar Fig.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 starting at 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.

[0156] Crystalline Compound 1, Form 6

[0157] 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 is Form 6, characterized by having at least one of the following properties:

[0158] (a) with Fig.11 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0159] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.2°2-θ, 9.5°2-θ, 10.9°2-θ, 18.5°2-θ, 19.0°2-θ, 21.9°2-θ, 22.4°2-θ, 23.7°2-θ, 25.6°2-θ and 26.7°2-θ;

[0160] (c) Basically similar to Fig.12 Thermogravimetric analysis (TGA) of those shown in;

[0161] (d) Basically similar to Fig.12 DSC thermogram of the one shown in;

[0162] (e) a DSC thermogram having an endotherm onset at about 278°C; or

[0163] (f) combinations thereof.

[0164] 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 properties (a) to (e).

[0165] 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 Fig.11In 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 having characteristic peaks at 7.2°2-θ, 9.5°2-θ, 10.9°2-θ, 18.5°2-θ, 19.0°2-θ, 21.9°2-θ, 22.4°2-θ, 23.7°2-θ, 25.6°2-θ, and 26.7°2-θ. 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 substantially similar Fig.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 substantially similar Fig.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 starting at 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.

[0166] Crystalline Compound 1, Form 7

[0167] 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 is Form 7, characterized by having at least one of the following properties:

[0168] (a) with Fig.13 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0169] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.0° 2-θ, 11.0° 2-θ, 12.6° 2-θ, 13.5° 2-θ, 14.1° 2-θ, 21.3° 2-θ, 21.7° 2-θ, 22.1° 2-θ, 25.4° 2-θ, 26.7° 2-θ, 27.1° 2-θ and 29.0° 2-θ;

[0170] (c) Basically similar to Fig.14 Thermogravimetric analysis (TGA) of those shown in;

[0171] (d) Basically similar to Fig.14 DSC thermogram of the one shown in;

[0172] (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

[0173] (f) combinations thereof.

[0174] 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 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 7 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 7 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 7 is characterized by having properties (a) to (e).

[0175] 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 Fig.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°2-θ, 11.0°2-θ, 12.6°2-θ, 13.5°2-θ, 14.1°2-θ, 21.3°2-θ, 21.7°2-θ, 22.1°2-θ, 25.4°2-θ, 26.7°2-θ, 27.1°2-θ, and 29.0°2-θ. 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 substantially similar Fig.14In 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 substantially similar Fig.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 with 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 hydrated. 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 unsolvated.

[0176] Crystalline Compound 1, Form 8

[0177] 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 is Form 8, characterized by having at least one of the following properties:

[0178] (a) with Fig.15 An X-ray powder diffraction (XRPD) pattern substantially the same as shown;

[0179] (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.3°2-θ, 11.6°2-θ, 14.6°2-θ, 16.3°2-θ, 18.7°2-θ, 21.7°2-θ, 21.9°2-θ, 22.6°2-θ, 25.1°2-θ, 29.3°2-θ and 37.8°2-θ;

[0180] (c) Basically similar to Fig.16 Thermogravimetric analysis (TGA) of those shown in;

[0181] (d) Basically similar to Fig.16 DSC thermogram of the one shown in;

[0182] (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

[0183] (f) combinations thereof.

[0184] 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 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 8) 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 8) 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 8 is characterized by having properties (a) to (e).

[0185] 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 has Fig.15In 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 has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.3°2-θ, 11.6°2-θ, 14.6°2-θ, 16.3°2-θ, 18.7°2-θ, 21.7°2-θ, 21.9°2-θ, 22.6°2-θ, 25.1°2-θ, 29.3°2-θ, and 37.8°2-θ. 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 has a substantially similar Fig.16 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 has a substantially similar Fig.16In 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, 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.

[0186] Preparation of crystalline compound 1

[0187] In some embodiments, compound 1 is prepared as described in US2019 / 0241556, which is incorporated herein by reference in its entirety. In some embodiments, the crystalline form of compound 1 is prepared as outlined in the examples. It should be noted that the solvents, temperatures, and other reaction conditions presented herein may vary.

[0188] In certain embodiments, provided herein is a method for preparing a solid form of compound 1, comprising 1) obtaining a saturated solution of compound 1 in a solvent at a first temperature (e.g., about 50°C); 2) adding an antisolvent to the saturated solution at a first temperature; 3) cooling to a second temperature (e.g., about -5°C to room temperature); and 4) collecting the solid if there is a precipitate, and evaporating the solvent to collect the solid if there is no precipitate; and 5) optionally drying. In certain embodiments, provided herein is a method for preparing a solid form of compound 1, comprising 1) obtaining a saturated solution of compound 1 in a solvent at about 50°C; 2) adding an antisolvent to a saturated solution at about 50°C; 3) cooling to about room temperature; and 4) collecting the solid if there is a precipitate, and evaporating the solvent to collect the solid if there is no precipitate; and 5) optionally air drying. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:9. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:4. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:2. In certain embodiments, the volume ratio of solvent to antisolvent is about 1:1. In certain embodiments, the method for preparing a solid form of Compound 1 is an anti-solvent recrystallization experiment.

[0189] In another embodiment, the crystalline Compound 1 (Form 1) is substantially pure. In certain embodiments, the substantially pure crystalline Compound 1 (Form 1) is substantially free of other solid forms, such as amorphous solids. In certain embodiments, the purity of the substantially pure crystalline Compound 1 (Form 1) is not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0190] In another embodiment, crystalline Compound 1 (Form 2) is substantially pure. In certain embodiments, substantially pure crystalline Compound 1 (Form 2) is substantially free of other solid forms, such as amorphous solids. In certain embodiments, substantially pure crystalline Compound 1 (Form 2) has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0191] In another embodiment, crystalline Compound 1 (Form 3) is substantially pure. In certain embodiments, substantially pure crystalline Compound 1 (Form 3) is substantially free of other solid forms, such as amorphous solids. In certain embodiments, substantially pure crystalline Compound 1 (Form 3) has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0192] 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, such as amorphous solids. In certain embodiments, substantially pure crystalline Compound 1 (Form 4) has a purity of not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[0193] Suitable solvent

[0194] The therapeutic agent that can be applied to mammals (such as humans) must be prepared according to regulatory guidelines. Such government regulatory guidelines are called Good Manufacturing Practice (GMP). GMP guidelines outline the acceptable contamination levels of active therapeutic agents, such as the amount of residual solvents in the final product. In some embodiments, the solvent disclosed herein is suitable for use in GMP facilities and meets those solvents considered for industrial safety. Solvent categories are defined in, for example, 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).

[0195] Solvents are divided into three categories. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents with limited use during the manufacture of therapeutic agents. Class 3 solvents are solvents with low toxicity potential and pose a low risk to human health. Data for Class 3 solvents show that they are less toxic in acute or short-term studies and are negative in genotoxicity studies.

[0196] Class 1 solvents that should be avoided include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethylene; and 1,1,1-trichloroethane.

[0197] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, isopropylbenzene, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethylene and xylene.

[0198] Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, ethyl butyrate, 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.

[0199] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of the APIs. In some cases, the solvent cannot be completely removed by practical manufacturing techniques. Appropriate selection of solvents for the synthesis of APIs can improve yields, or determine characteristics such as crystal form, purity, and solubility. Therefore, solvents are a key parameter in the synthesis process.

[0200] In some embodiments, the composition comprising compound 1 comprises one or more organic solvents. In some embodiments, the composition comprising compound 1 comprises a residual amount of one or more organic solvents. 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 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 acetone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol and ethanol.

[0201] In some embodiments, the composition comprising compound 1 comprises a residual amount of a Class 2 solvent. In some embodiments, the organic solvent is a Class 2 solvent. In some embodiments, the Class 2 solvent is selected from acetonitrile, chlorobenzene, chloroform, isopropylbenzene, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethylene and xylene. In some embodiments, the Class 2 solvent is selected from acetonitrile, tetrahydrofuran and toluene. In some embodiments, the Class 2 solvent is acetonitrile.

[0202] In some embodiments, the composition comprising Compound 1 comprises a residual amount of a solvent for which adequate toxicological data has not been found. In some embodiments, the organic solvent is a solvent for which adequate toxicological data has not been found. In some embodiments, the solvent is selected from 2-butanone and 2-methyltetrahydrofuran.

[0203] Certain terms

[0204] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit any subject matter claimed. In the present application, unless otherwise expressly stated, the use of the singular includes the plural. It must be noted that, unless the context clearly states otherwise, as used in this specification and the appended claims, the singular forms "one", "a kind of" and "the" include plural referents. In the present application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms (such as "include", "includes" and "included") is not limited. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude the term in other certain embodiments, for example, any embodiment of the composition of matter, composition, method or process, etc. described herein may "consist of" or "consist essentially of" the features. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the number or numerical range.

[0205] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety.

[0206] As used herein, the term "acceptable" or "pharmaceutically acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0207] As used herein, "improvement" of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening in severity, delay in onset, slowing in progression, or shortening in duration, whether permanent or temporary, persistent or transient, attributable to or associated with the administration of the compound or composition.

[0208] "Bioavailability" refers to the percentage of the administered Compound 1 delivered into the systemic circulation of the animal or human being studied. The total exposure to the drug (AUC (0-∞) ) is generally defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which Compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is taken orally compared to intravenous administration.

[0209] "Plasma concentration" refers to the concentration of Compound 1 in the plasma component of a subject's blood. It is understood that the plasma concentration of Compound 1 may vary significantly between subjects due to variability in metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of Compound 1 may vary from subject to subject. Similarly, values ​​such as maximum plasma concentration (C 最大 ) or the time to reach maximum plasma concentration (T 最大 ) or the total area under the plasma concentration-time curve (AUC (0-∞) ) may vary from subject to subject. Due to this variability, the amount required to constitute a "therapeutically effective amount" of Compound 1 may vary from subject to subject.

[0210] As used herein, the terms "administered in combination" and the like are intended to encompass administration of selected therapeutic agents to a single patient, and are intended to encompass treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0211] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the administered agent or compound that will alleviate one or more symptoms of the disease or condition being treated to a certain extent. The result can be a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired biological system changes. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein that is required to provide a clinically significant reduction in disease symptoms without excessive 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, a preventive effective amount. The "effective amount" of a compound disclosed herein is an amount that effectively achieves the desired pharmacological effect or therapeutic improvement without excessive adverse side effects. It should be understood that the "effective amount" or "therapeutically effective amount" may vary from subject to subject due to the metabolism of Compound 1, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount can be determined by a dose escalation clinical trial.

[0212] The term "enhance" or "enhancing" refers to increasing or prolonging the potency or duration of a desired effect. For example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong the effect of a therapeutic agent in potency or duration during the treatment of a disease, disorder, or condition. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of a therapeutic agent in treating a disease, disorder, or condition. When used in a patient, an amount effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0213] As used herein, the term "prophylactically effective amount" refers to the amount of the composition applied to a patient that will alleviate to some extent one or more symptoms of the disease, disorder or condition being treated. In such prophylactic applications, such amount may depend on the patient's health status, weight, etc. For example, such a prophylactically effective amount can be determined by a dose escalation clinical trial.

[0214] The term "subject" as used herein refers to an animal that is the subject of treatment, observation or experiment. By way of example only, a subject may be, but is not limited to, a mammal, including, but not limited to, a human.

[0215] As used herein, the term "target activity" refers to a biological activity that can be regulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or condition.

[0216] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting a disease or condition, such as arresting the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by a disease or condition, or stopping symptoms of a disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatments.

[0217] As used herein, IC 50 Refers to the dose, concentration or amount of a specific test compound that elicits a dose-dependent response at 50% of the maximal expression of a specific response induced, stimulated or enhanced by the specific test compound.

[0218] Pharmaceutical compositions / preparations

[0219] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that aid in processing the active compound into pharmaceutically usable products. Appropriate formulations depend on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in the following literature: Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entirety.

[0220] 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) and other chemical components (such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients). Pharmaceutical compositions facilitate administration of the compound to a mammal. In practicing the treatment or use methods provided herein, a therapeutically effective amount of Compound 1 is administered in the form of a pharmaceutical composition to a mammal suffering from a disease, disorder or condition to be treated. Preferably, the mammal is a human. The therapeutically effective amount can vary greatly depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0221] In some embodiments, a pharmaceutical composition is provided, 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, a pharmaceutical composition is provided, comprising a crystalline form of Compound 1 and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided, comprising a crystalline form of Compound 1 (Form 1) and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided, comprising a crystalline form of Compound 1 (Form 2) and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided, comprising a crystalline form of Compound 1 tosylate (Form 3) and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a crystalline form of a mesylate salt of Compound 1 (Form 4) and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a crystalline form of Compound 1 (Form 5) and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a crystalline form of Compound 1 (Form 6) and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a crystalline form of Compound 1 (Form 7) and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprising a crystalline form of Compound 1 (Form 8) and a pharmaceutically acceptable excipient.

[0222] The term "drug combination" as used herein refers to a product produced by mixing or combining more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to an active ingredient (e.g., Compound 1) and an adjuvant being administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to an active ingredient (e.g., Compound 1) and an adjuvant being administered to a patient simultaneously, concurrently or continuously as separate entities, without specific intermediate time limits, wherein such administration provides effective levels of the two compounds in the patient's body. The latter is also applicable to cocktail therapy, such as the administration of three or more active ingredients.

[0223] Pharmaceutical compositions comprising the compounds described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating or compression processes.

[0224] Dosage form

[0225] The pharmaceutical compositions described herein can be formulated for administration to mammals by any conventional means, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous or intramuscular), oral, intranasal, rectal or transdermal administration routes. The term "subject" or "individual" as used herein refers to an animal, preferably a mammal, including humans or non-humans. The terms individual, patient and subject can be used interchangeably.

[0226] In addition, the pharmaceutical compositions comprising Compound 1 described herein can be formulated into any suitable dosage form, including but not limited to solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and mixed immediate release and controlled release formulations.

[0227] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable excipients (if necessary) to obtain tablets or dragees. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose products such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, can be added.

[0228] Pharmaceutical preparations that can be used orally include push-in capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-in capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. The dosage of all formulations for oral administration should be suitable for such administration.

[0229] In some embodiments, the solid dosage forms disclosed herein can be in the form of tablets (including suspension tablets, fast-melt tablets, bite-disintegrating tablets, rapidly disintegrating tablets, effervescent tablets or caplets), pills, powders (including sterile packaged powders, dispensable powders or effervescent powders), capsules (including soft capsules or hard capsules, such as capsules made of animal-derived gelatin or plant-derived HPMC or "sprinkle capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulsed release dosage forms, multi-particulate dosage forms, pills, granules or aerosols. In other embodiments, the pharmaceutical preparation is in powder form. In other embodiments, the pharmaceutical preparation is in tablet form, including but not limited to fast-melt tablets. In addition, the pharmaceutical preparations described herein can be administered in a single capsule or in multiple capsule dosage forms. In some embodiments, the pharmaceutical preparation is administered in two, three or four capsules or tablets.

[0230] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of compound 1 with one or more pharmaceutical excipients to form a bulk mixed composition. When these bulk mixed compositions are referred to as homogeneous, it means that the particles of compound 1 are evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. A single unit dose may also include a film coating that disintegrates when taken orally or in contact with a diluent. These preparations can be manufactured by conventional pharmacological techniques.

[0231] Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, 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.

[0232] The pharmaceutical solid dosage forms described herein may include compound 1 and one or more pharmaceutically acceptable additives, such as compatible carriers, adhesives, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. In other aspects, a film coating is provided around the formulation of compound 1 using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th edition (2000). In one embodiment, some or all of the particles of compound 1 are coated. In another embodiment, some or some of the particles of compound 1 are microencapsulated. In yet another embodiment, the particles of compound 1 are not microencapsulated and are not coated.

[0233] Suitable carriers for the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0234] Fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium phosphate dibasic, calcium sulfate, microcrystalline cellulose, cellulose powder, glucose, dextrates, 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.

[0235] In order to release Compound 1 from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. When water is absorbed into the dosage form, the disintegrant helps the dosage form matrix to rupture by swelling or capillary action. Disintegrants suitable for 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 or sodium starch glycolate, such as or Cellulose, such as wood products, methyl crystalline cellulose, e.g. PH101, PH102, PH105, P 100, Ming and Solka- Methylcellulose, cross-linked carboxymethylcellulose, or a cross-linked cellulose such as cross-linked carboxymethylcellulose sodium (Ac-Di- ), cross-linked carboxymethyl cellulose or cross-linked cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as cross-linked povidone, cross-linked polyvinyl pyrrolidone, alginates such as alginic acid or alginates such as sodium alginate, clays such as HV (magnesium aluminum silicate), gums (such as agar, guar gum, locust bean gum, Karaya gum, pectin or tragacanth), sodium starch glycolate, bentonite, natural sponge, surfactant, resin (such as cation exchange resin), citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate and starch combination, etc. In some embodiments provided herein, the disintegrant is selected from natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch (such as sodium starch glycolate), cross-linked polymer (such as cross-linked povidone), cross-linked polyvinyl pyrrolidone, sodium alginate, clay or gum. In some embodiments provided herein, the disintegrant is cross-linked carboxymethyl cellulose sodium.

[0236] Binders impart cohesiveness to solid oral dosage form formulations: for powder-filled capsule formulations, they help form plugs that can be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blending uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., ), hydroxypropyl methylcellulose (e.g. Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. ), ethyl cellulose (e.g. ) and microcrystalline cellulose (e.g. ), microcrystalline glucose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinyl pyrrolidone / vinyl acetate copolymer, cross-linked polyvidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars (such as sucrose (e.g. )), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., ), lactose, natural or synthetic gums (such as gum arabic, tragacanth, gum ghatti, mucilage of isapol husks), starch, polyvinyl pyrrolidone (e.g., CL, CL, XL-10 and K-12), larch arabinogalactan, Polyethylene glycol, wax, sodium alginate, etc.

[0237] Typically, the binder level used in powder-filled gelatin capsule formulations is 20-70%. The level of binder used in tablet formulations varies due to direct compression, wet granulation, roller compaction, or the use of other excipients (such as fillers, which themselves can act as a medium binder). The formulator in the art can determine the binder level of the formulation, but it is common to use binder levels as high as 70% in tablet formulations.

[0238] 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, alkali metal and alkaline earth metal salts (such as calcium, magnesium), stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol (such as Carbowax TM , PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate, etc. In some embodiments provided herein, the lubricant is selected from 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.

[0239] Diluents suitable for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and glucose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like. In some embodiments provided herein, the diluent is selected from lactose, sucrose, glucose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0240] The term "water-insoluble diluent" refers to compounds commonly used in drug formulation, such as calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose (e.g., having a viscosity of about 0.45 g / cm 3 density, such as Avicel, powdered cellulose) and talc.

[0241] Suitable wetting agents 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 ), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS, etc.

[0242] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g. (BASF) etc. In some embodiments provided herein, the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glycerol monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0243] Suspending agents suitable for the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyethylene glycol, such as polyethylene glycol having a molecular weight of about 300 to about 6000, or about 3350 to about 4000 or about 7000 to about 5400, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, Methylcellulose, hydroxypropyl methylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum arabic, guar gum, xanthan gum, including xanthan gum, sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0244] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0245] It should be recognized that there is considerable overlap between the additives used in the solid dosage forms described herein. Therefore, the additives listed above should only be used as examples of the types of additives that can be included in the solid dosage forms described herein, rather than as limitations. The amount of such additives can be easily determined by those skilled in the art based on the specific properties desired.

[0246] In other embodiments, one or more layers of the pharmaceutical preparation are plasticized. Exemplarily, plasticizers are generally high boiling solids or liquids. Appropriate plasticizers of about 0.01% to about 50% weight (w / w) of the coating composition can be added. Plasticizers include but are not limited to diethyl phthalate, citrate, polyethylene glycol, glycerine, acetylated glyceride, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearyl alcohol, stearate and castor oil.

[0247] Compressed tablets are solid dosage forms prepared by compressing a bulk mixture of the above formulations. In various embodiments, compressed tablets designed to dissolve in the mouth will contain one or more flavoring agents. In other embodiments, compressed tablets will contain a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of Compound 1 from the formulation. In other embodiments, the film coating helps patient compliance (e.g., coated or sugar coated). Contains The film coating, including , typically comprises about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets contain one or more excipients.

[0248] For example, a capsule can be prepared by placing a bulk mixture of the compound 1 preparation into a capsule. In some embodiments, the preparation (non-aqueous suspension and solution) is placed in a soft gelatin capsule. In some embodiments, the preparation (non-aqueous suspension and solution) is placed in a hard shell gelatin capsule. In other embodiments, the preparation is placed in a standard gelatin capsule or a non-gelatin capsule, such as a capsule comprising HPMC. In other embodiments, the preparation is placed in a spray capsule, wherein the capsule can be swallowed whole, or the capsule can be opened and the contents can be sprinkled on the food before eating. In some embodiments, the therapeutic dose is divided into multiple (e.g., two, three or four) capsules. In some embodiments, the entire dose of the preparation is delivered in capsule form.

[0249] In various embodiments, particles of Compound 1 and one or more excipients are dry blended and compressed into a mass, such as a tablet, having 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.

[0250] In another aspect, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Exemplary materials include, but are not limited to, pH regulators, corrosion accelerators, defoamers, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0251] Materials used for microencapsulation as described herein include materials that are compatible with Compound 1 and that are sufficient to isolate Compound 1 from other incompatible excipients. Materials that are compatible with Compound 1 are those that delay the release of Compound 1 in vivo.

[0252] Exemplary microencapsulation materials for delayed release of formulations comprising the compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as or Nisso HPC, low-substituted hydroxypropyl cellulose ether (L-HPC), hydroxypropyl methyl cellulose ether (HPMC), such as Seppifilm-LC, Metolose SR, -E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methylcellulose polymers such as -A, Hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Ethyl cellulose (EC) and its mixtures, such as E461, -EC, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethyl cellulose such as Carboxymethyl cellulose and carboxymethyl cellulose (CMC) salts such as - CMC, polyvinyl alcohol and polyethylene glycol copolymers such as Kollicoat Monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic acid polymers, and mixtures of acrylic acid polymers and cellulose ethers such as EPO, L30D-55, FS 30D, L100-55, L100, S100, RD100, E100, L12.5, S12.5, NE30D and NE 40D, cellulose acetate phthalate, sepifilm such as a mixture of HPMC and stearic acid, cyclodextrin, and mixtures of these materials.

[0253] In other embodiments, plasticizers such as polyethylene glycol, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulation material used to delay the release of the pharmaceutical composition is from USP or National Formulary (NF). In other embodiments, the microencapsulation material is Klucel. In other embodiments, the microencapsulation material is methylcellulose.

[0254] Microencapsulated compound 1 can be formulated by a variety of methods, illustrative examples of which include, for example, spray drying, spinning disk solvent method, hot melt method, spray cooling method, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, liquid-gas or solid-gas interfacial polymerization, pressure extrusion or spray solvent extraction bath. In addition, a variety of chemical techniques can also be used, for example, complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in-situ polymerization, drying in liquid and desolvation in liquid medium. In addition, other methods such as rolling, extrusion / spheronization, coacervation or nanoparticle coating can also be used.

[0255] In one embodiment, the particles of Compound 1 are microencapsulated prior to formulation into one of the above forms. In yet another embodiment, some or most of the particles are coated prior to further formulation by using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0256] In other embodiments, the solid dosage formulation of Compound 1 is plasticized (coated) one or more layers. Exemplarily, the plasticizer is generally a high boiling solid or liquid. Appropriate plasticizers of about 0.01% to about 50% weight (w / w) of the coating composition may be added. Plasticizers include but are not limited to diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearyl alcohol, stearate and castor oil.

[0257] In other embodiments, powders of formulations comprising Compound 1 can be formulated to include one or more pharmaceutical excipients and flavoring agents. For example, such powders can be prepared by mixing formulations and optional pharmaceutical excipients to form a bulk mixed composition. Other embodiments also include suspending agents and / or wetting agents. The bulk mixture is uniformly subdivided into unit dose packages or multi-dose packaging units.

[0258] 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 particles or coarse powders of medicaments in dry mixtures, usually composed of sodium bicarbonate, citric acid and / or tartaric acid. When the salt of the composition described herein is added to water, the acid and base react to release carbon dioxide gas, thereby causing "effervescence". Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any acid-base combination that causes carbon dioxide release can be used to replace the combination of sodium bicarbonate and citric acid and tartaric acid, as long as these ingredients are suitable for pharmaceutical use and cause pH to be about 6.0 or higher.

[0259] In some embodiments, solid dosage forms as described herein can be formulated into enteric coated delayed release oral dosage forms, that is, formulated into an oral dosage form of a pharmaceutical composition as described herein, which utilizes enteric coating to affect the release in the small intestine of the gastrointestinal tract. Enteric coated dosage forms can be compressed or molded or extruded tablets / molds (coated or uncoated), which contain particles, powders, pills, beads or particles of active ingredients and / or other composition components (which themselves are coated or uncoated). Enteric coated oral dosage forms can also be capsules (coated or uncoated), which contain pills, beads or particles of solid carriers or compositions (which themselves are coated or uncoated).

[0260] The term "delayed release" as used herein refers to delivery such that release can be completed at some generally predictable location in the intestinal tract, which is further away than the location where it would be completed if there were no delayed release change. In some embodiments, the method of delayed release is coating. Any coating should be applied to a sufficient thickness so that the entire coating will not dissolve in the gastrointestinal fluid when the pH is below about 5, but dissolves at a pH of about 5 and above. It is expected that any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymer described herein is an anionic carboxylic acid polymer. In other embodiments, polymers and compatible mixtures thereof and some of their characteristics include, but are not limited to:

[0261] Shellac, also known as purified shellac, is a refined product obtained from the resinous secretions of insects. This coating dissolves in a medium with a pH>7;

[0262] Acrylic polymers. The properties 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 methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) can be used soluble in organic solvents, aqueous dispersions or dry powders. Eudragit series RL, NE and RS are insoluble in the gastrointestinal tract, but are permeable and are primarily used for colon targeting. Eudragit series E is soluble in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach, but soluble in the intestine;

[0263] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose; and reaction mixtures of cellulose acetate esters with phthalic anhydride. Performance may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a water-based system and is a spray-dried CAP psuedolatex with particles <1 μm. Other components in Aquateric may include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Performance may vary based on the degree and type of substitution. For example, HPMCP (such as HP-50, HP-55, HP-55S or HP-55F grades) are suitable. Performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose 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 higher pH). These polymers are provided in granular or fine powder form for aqueous dispersion; polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH>5 and is much less permeable to water vapor and gastric fluid.

[0264] In some embodiments, the coating may contain and usually does contain a plasticizer and possibly other coating excipients, such as a colorant, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex2), triacetin (triacetin), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. Specifically, anionic carboxylic acid acrylic polymers usually contain 10-25% by weight of plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. The coating is applied using conventional coating techniques (such as spray or pan coating). The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired local delivery site in the intestinal tract is reached.

[0265] In addition to plasticizers, colorants, anti-adherents, surfactants, defoamers, lubricants (such as carnauba wax or PEG) may be added to the coating to dissolve or disperse the coating material and improve coating properties and coated products.

[0266] In other embodiments, a pulsatile dosage form is used to deliver the formulations described herein comprising Compound 1. Pulsatile dosage forms are capable of providing one or more immediate release pulses at a predetermined time point or at a specific site after a controlled lag time. Other types of controlled release systems may be used. Examples of such delivery systems include, for example, polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides and polycaprolactone; porous matrices, non-polymer-based systems, which are lipids, including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as monoglycerides, diglycerides and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional adhesives, and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2nd Edition, Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Edition, pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is specifically incorporated by reference.

[0267] In some embodiments, a pharmaceutical formulation is provided (which comprises particles of Compound 1 and at least one dispersing agent or suspending agent) for oral administration to a subject. The formulation can be a powder and / or granules for suspension, and upon mixing with water, a substantially uniform suspension is obtained.

[0268] It should be understood that there is overlap between the above-mentioned additives used in the aqueous dispersions or suspensions described herein, as a given additive is often classified differently by different practitioners in the art, or is often used for any of a variety of different functions. Therefore, the above-mentioned additives should only be used as examples of the types of additives that can be included in the formulations described herein, and not as limitations. The amount of such additives can be readily determined by those skilled in the art based on the specific properties desired.

[0269] method

[0270] In another aspect is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound 1 described herein.

[0271] In another embodiment is a method of treating a disease, disorder, or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound 1 as described herein; wherein the disease, disorder, or condition of the mammal is selected from multiple sclerosis, ulcerative colitis, and Crohn's disease. In another embodiment is a method of treating a disease, disorder, or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound 1 as described herein; wherein the disease, disorder, or condition of the mammal is multiple sclerosis. In another embodiment is a method of treating a disease, disorder, or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound 1 as described herein; wherein the disease, disorder, or condition of the mammal is ulcerative colitis. In another embodiment is a method of treating a disease, disorder, or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound 1 as described herein; wherein the disease, disorder, or condition of the mammal is Crohn's disease.

[0272] In a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, the method comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound 1 as described herein; wherein the disease, disorder or condition in the mammal is rejection of a transplanted organ or tissue; graft-versus-host disease caused by transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergy; type I diabetes; prevention of psoriasis; Crohn's disease; ulcerative colitis, acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and cancer metastasis.

[0273] Dosage and treatment regimen

[0274] In some embodiments, crystalline Compound 1 is used in the preparation of a medicament for treating a disease or condition that would benefit from S1P receptor modulation. In addition, a method for treating any disease or condition described herein in an individual in need of such treatment comprises administering to the individual a pharmaceutical composition containing crystalline Compound 1 or a pharmaceutically acceptable solvate thereof in a therapeutically effective amount.

[0275] In some embodiments, compositions containing crystalline Compound 1 are administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, compositions containing Compound 1 are administered for therapeutic applications. In some embodiments, compositions containing Compound 1 are administered for prophylactic applications.

[0276] In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatment, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0277] In preventive applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount will also depend on the patient's health, weight, etc. When used in a patient, an amount effective for this use will depend on the severity and course of the disease, disorder or condition, previous treatment, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0278] In some embodiments, crystalline Compound 1 is administered daily. In some embodiments, crystalline Compound 1 is administered every other day.

[0279] In some embodiments, crystalline Compound 1 is administered once a day. In some embodiments, crystalline Compound 1 is administered twice a day. In some embodiments, crystalline Compound 1 is administered three times a day. In some embodiments, crystalline Compound 1 is administered four times a day.

[0280] In cases where the patient's condition does not improve, at the physician's discretion, administration of the compound may be given chronically, i.e., for an extended period of time, including throughout the patient's life, in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0281] Once the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dose or frequency of administration, or both, may be reduced, depending on the symptoms, to a level that maintains the improved disease, disorder or condition. However, the patient may require long-term intermittent treatment upon any recurrence of symptoms.

[0282] The amount of a given medicament corresponding to this amount will vary according to factors such as the specific compound, the disease or condition and its severity, the characteristics of the subject or host to be treated (e.g., body weight), but can still be determined in a manner recognized in the art according to the specific circumstances of the case, including, for example, the specific medicament administered, the route of administration, the condition treated, and the subject or host treated. However, in general, the dosage for adult treatment will generally be in the range of about 0.02 to about 5000 mg per day, in some embodiments, in the range of about 1 to about 1500 mg per day. The desired dosage can be conveniently presented in a single dose or divided doses, which are administered simultaneously (or over a short period of time) or at appropriate intervals, such as two, three, four or more sub-doses per day.

[0283] The pharmaceutical compositions described herein can be unit dosage forms suitable for single administration of precise doses. In unit dosage forms, the preparation is divided into unit doses containing an appropriate amount of one or more compounds. The unit dose can be a packaged form containing discrete amounts of preparations. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, a multi-dose reclosable container can be used, in which case a preservative is typically included in the composition. By way of example only, preparations for parenteral injection can be presented in unit dosage forms including, but not limited to, ampoules, or in multi-dose containers with preservatives added.

[0284] The daily dose suitable for the compounds described herein is about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dose is about 0.1 mg / kg to about 10 mg / kg. The indicated daily dose for larger mammals (including but not limited to humans) is in the range of about 0.5 mg to about 1000 mg, conveniently administered in a single dose or divided dose, including but not limited to up to four times a day or in an extended release form. Unit dosage forms suitable for oral administration include about 1 to about 500 mg of active ingredient. In one embodiment, the unit dose 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. The above ranges are only suggestive, because the number of variables associated with individual treatment regimens is large, and it is not uncommon to have large deviations from these recommended values. Such dosage may vary according to a variety of variables including but not limited to the activity of the compound employed, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0285] The toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to determining the LD 50 (a dose lethal to 50% of the population) and ED 50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as LD 50 and ED 50 The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably within the range containing the ED 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0286] Kits / Products

[0287] For use in therapeutic methods of use as described herein, kits and articles are also described herein. Such kits include carriers, packages or containers that are separated to receive one or more containers, such as vials, tubes, etc., each container containing one of the individual elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is formed of a variety of materials such as glass or plastic.

[0288] The articles provided herein include packaging materials. Packaging materials for packaging pharmaceutical products include, for example, U.S. Pat. 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 intended administration and treatment mode.

[0289] In some embodiments, the compound or composition described herein is presented in a package or dispenser device, which may include one or more unit dosage forms containing active ingredients. The compound or composition described herein is packaged alone or with another compound or another ingredient or additive. In some embodiments, the package comprises one or more containers, wherein the ingredients of one or more pharmaceutical compositions are contained. In some embodiments, the package comprises a metal or plastic foil, such as a blister package. In some embodiments, the package or dispenser device is accompanied by instructions for use, such as instructions for use of the compound or composition for the treatment of tumor diseases. In some embodiments, the package or dispenser is accompanied by a notice associated with the container, the form of which is specified by a government agency that manages drug manufacturing, use or sales, and the notice reflects the agency's approval of the drug form for human or veterinary administration. In some embodiments, such a notice is, for example, a prescription drug label approved by the U.S. Food and Drug Administration or an approved product insert. In some embodiments, a composition comprising a compound described herein formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for treatment of the indicated condition.

[0290] For example, the container comprises crystalline Compound 1 disclosed herein. Such kits optionally comprise an identifying description or label or instructions relating to its use in the methods described herein.

[0291] The kit will typically contain a label listing the contents and / or instructions for use, and a package insert with instructions for use. A set of instructions will also typically be included.

[0292] In one embodiment, the label is located on or associated with the container. In one embodiment, the label is located on the container when the letters, numbers or other characters forming the label are attached, molded or etched into the container itself; when the label is present in a reservoir or carrier that also holds the container, for example as a package insert, the label is associated with the container. In one embodiment, the label is used to indicate the contents to be used for a specific therapeutic application. The label also indicates instructions such as use of the contents in the methods described herein.

[0293] In certain embodiments, the pharmaceutical composition is presented in a package or dispenser device, which contains one or more unit dosage forms containing a compound provided herein. For example, the package contains metal or plastic foil, such as a blister package. In one embodiment, the package or dispenser device is accompanied by instructions for use. In one embodiment, the package or dispenser is also accompanied by a notice associated with the container, the form of which is specified by a government agency that manages drug manufacturing, use or sales, and the notice reflects the agency's approval of the drug form for human or veterinary administration. For example, this notice is a prescription drug label approved by the U.S. Food and Drug Administration or an approved product insert. In one embodiment, a composition containing a compound provided herein formulated in a compatible pharmaceutical carrier is also prepared, placed in an appropriate container, and labeled for treatment of the indicated condition.

[0294] Example

[0295] List of abbreviations

[0296] As used throughout the specification of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0297] ACN or MeCN Acetonitrile

[0298] Bn Benzyl

[0299] BOC or Boc tert-butyl carbamate

[0300] t-Bu tert-butyl

[0301] Cy Cyclohexyl

[0302] DCE Dichloroethane (ClCH2CH2C1)

[0303] DCM Dichloromethane (CH2Cl2)

[0304] DIPEA or DIEA diisopropylethylamine

[0305] DMAP 4-(N,N-dimethylamino)pyridine

[0306] DMF Dimethylformamide

[0307] DMA N,N-Dimethylacetamide

[0308] DMSO Dimethyl sulfoxide

[0309] eq or equiv equivalent

[0310] Et Ethyl

[0311] Et2O Ether

[0312] EtOH

[0313] EtOAc Ethyl acetate

[0314] HPLC High Performance Liquid Chromatography

[0315] Me Methyl

[0316] MeOH Methanol

[0317] MS mass spectrometry

[0318] GC Gas chromatography

[0319] h hour

[0320] KF Karl Fischer

[0321] min

[0322] MsOH Methanesulfonic acid

[0323] NMR Nuclear Magnetic Resonance

[0324] RP-HPLC Reverse Phase High Performance Liquid Chromatography

[0325] RT or rt Room temperature

[0326] TFA Trifluoroacetic acid

[0327] THF Tetrahydrofuran

[0328] TLC Thin layer chromatography

[0329] V Volume

[0330] I. Synthesis of Polymorphs

[0331] Example 1: Compound 1, Form 1:

[0332] 20 mg of Compound 1 and 0.3 mL of solvent (THF or EtOAc) were stirred at RT for three days, and the resulting solid was isolated and dried at 50 °C for 2 hours to provide Compound 1, Form 1.

[0333] Example 2: Compound 1, Form 2:

[0334] 200 mg of Compound 1 and 2 mL of acetic acid were stirred in a vial at RT for 2 hours. The solid was isolated and dried at RT overnight to provide Compound 1, Form 2.

[0335] Scaled-up synthesis of compound 1, form 2:

[0336] 1) Add DMAc (6 V) into a reactor at 25 ± 5 °C under N2.

[0337] 2) Compound 1 (1.0 eq.) was added into a reactor at 25±5°C under N2.

[0338] 3) Add DMAc (1 V) under N2 to flush the reactor at 25±5°C.

[0339] 4) Adjust the temperature to 110±5°C and stir for at least 24 hours.

[0340] 5) Adjust the temperature to 25±5℃.

[0341] 6) Add H2O (7V) into the reactor at 30±10°C for at least 5 hours and stir for at least 4 hours.

[0342] 7) Filter and wash the wet cake twice with H2O (2V).

[0343] 8) Dry the cake at 60±5°C for at least 20 hours.

[0344] 9) Add AcOH (8 V) into the reactor at 25±5°C under N2.

[0345] 10) Add the dried cake into the reactor at 25±5°C under N2.

[0346] 11) Add AcOH (2 V) under N2 to flush the reactor at 25±5°C.

[0347] 12) Adjust the temperature to 95±5℃.

[0348] 13) Stir at 95±5°C for 1 hour.

[0349] 14) Adjust the temperature to 55±5°C.

[0350] 15) Filter with activated carbon (50 wt%).

[0351] 16) Wash the activated carbon twice with AcOH (2V).

[0352] 17) Concentrate the filtrate to 5-6V at no more than 60°C.

[0353] 18) Add n-heptane (18V) to the reactor at 55±5°C for at least 6 hours and stir for at least 1 hour.

[0354] 19) Adjust the temperature to 25±5°C and stir for at least 12 hours.

[0355] 20) Filter and wash the wet cake twice with heptane (5.0 V).

[0356] 21) Dry the cake and purge with nitrogen for no more than 1 hour.

[0357] 22) Samples were taken for XRPD and confirmed to be Form 2.

[0358] Example 3: Compound 1 Tosylate Salt, Form 3:

[0359] 20 mg of Compound 1 and 0.3 mL of EtOAc were added to a vial, followed by p-toluenesulfonic acid at a molar charge ratio of 1:1 (acid / base). The mixture was stirred at RT for three days, and the resulting solid was isolated and dried at 50° C. for 2 hours to provide Compound 1 tosylate salt, Form 3.

[0360] Example 4: Compound 1 Methanesulfonate, Form 4:

[0361] 20 mg of Compound 1 and 0.3 mL of EtOAc were added to a vial, followed by the addition of methanesulfonic acid at a molar charge ratio of 1:1 (acid / base). The mixture was stirred at RT for three days, and the resulting solid was isolated and dried at 50° C. for 2 hours to provide Compound 1, Form 4.

[0362] Example 5: Compound 1, Form 5:

[0363] 120 mg of Compound 1 was dissolved in DMSO (4 mL) at 50°C, and 4 mL of the solution was then filtered at RT. 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 provide Compound 1, Form 5.

[0364] Example 6: Compound 1, Form 6:

[0365] 100 mg of Compound 1 was added to MTBE (2 mL) and the suspension was slurried at rt for 5 h. The solid was isolated to provide Compound 1, Form 6.

[0366] Example 7: Compound 1, Form 7:

[0367] 100 mg of Compound 1 was added to 2 mL of MeOH / water (v / v, 9 / 1). The suspension was slurried at RT for 5 hours. The solid was isolated to provide Compound 1, Form 7.

[0368] Example 8: Compound 1, Form 8:

[0369] 120 mg of Compound 1 was dissolved in DMSO (4 mL) at room temperature for 1 hour, and the resulting solid was isolated and dried to provide Compound 1, Form 8.

[0370] II. Characterization of Polymorphs

[0371] Example 9: X-ray powder diffraction (XRPD)

[0372] X-ray powder diffraction studies were performed using a Malvern Panalytical Empyrean with the following instrument parameters:

[0373] Scan: 3°(2θ) to 40°(2θ)

[0374] Increment: 0.0167°(2θ)

[0375] Scanning speed: 17.8 seconds / step

[0376] Voltage: 45KV

[0377] Current: 40mA

[0378] Rotation: On

[0379] Sample holding: Zero background sample holder

[0380] XRPD analysis of Form 1 of Compound 1 ( Figure 1 ) showed that Form 1 was crystalline, with characteristic peaks at 16.5°2-θ, 18.5°2-θ, 21.0°2-θ, 22.1°2-θ, 22.8°2-θ, 26.6°2-θ, 27.8°2-θ, and 28.9°2-θ.

[0381] XRPD analysis of Form 2 of Compound 1 ( Figure 3 ) showed that Form 2 was crystalline, with characteristic peaks at 6.9°2-θ, 17.1°2-θ, 18.1°2-θ, 22.0°2-θ, 24.0°2-θ, 24.8°2-θ, 25.5°2-θ, 26.2°2-θ, and 28.2°2-θ.

[0382] XRPD analysis of Form 3 of Compound 1 ( Figure 5 ) showed that Form 3 was crystalline, with characteristic peaks at 4.9°2-θ, 8.4°2-θ, 17.5°2-θ, 19.8°2-θ, 20.5°2-θ, 24.8°2-θ, 25.6°2-θ, and 26.4°2-θ.

[0383] XRPD analysis of Form 4 of Compound 1 ( Figure 7 ) showed that Form 4 was crystalline, with characteristic peaks at 10.8°2-θ, 15.4°2-θ, 17.3°2-θ, 18.2°2-θ, 19.2°2-θ, 20.1°2-θ, 21.6°2-θ, 22.8°2-θ, 23.4°2-θ, 24.8°2-θ, 25.3°2-θ, 26.7°2-θ, and 30.9°2-θ.

[0384] XRPD analysis of Form 5 of Compound 1 ( Fig. 9) showed that Form 5 was crystalline, with characteristic peaks at 4.4°2-θ, 5.8°2-θ, 11.1°2-θ, 14.1°2-θ, 17.5°2-θ, 18.6°2-θ, 21.3°2-θ, 22.4°2-θ, 23.8°2-θ, 25.6°2-θ, and 25.9°2-θ.

[0385] XRPD analysis of Form 6 of Compound 1 ( Fig.11 ) showed that Form 6 was crystalline, with characteristic peaks at 7.2°2-θ, 9.5°2-θ, 10.9°2-θ, 18.5°2-θ, 19.0°2-θ, 21.9°2-θ, 22.4°2-θ, 23.7°2-θ, 25.6°2-θ, and 26.7°2-θ.

[0386] XRPD analysis of Form 7 of Compound 1 ( Fig.13 ) showed that Form 7 was crystalline, with characteristic peaks at 10.0°2-θ, 11.0°2-θ, 12.6°2-θ, 13.5°2-θ, 14.1°2-θ, 21.3°2-θ, 21.7°2-θ, 22.1°2-θ, 25.4°2-θ, 26.7°2-θ, 27.1°2-θ, and 29.0°2-θ.

[0387] XRPD analysis of Form 8 of Compound 1 ( Fig.15 ) showed that Form 8 was crystalline, with characteristic peaks at 7.3°2-θ, 11.6°2-θ, 14.6°2-θ, 16.3°2-θ, 18.7°2-θ, 21.7°2-θ, 21.9°2-θ, 22.6°2-θ, 25.1°2-θ, 29.3°2-θ, and 37.8°2-θ.

[0388] Example 10: Thermogravimetric analysis

[0389] Thermogravimetric analysis of solids was performed using TA Instruments' TA Q500 / Q5000. The sample was placed in an open aluminum pan and the sample weight was automatically weighed. The sample was heated to the final temperature at a heating rate of 10°C / min.

[0390] TGA of Form 1 of Compound 1 ( Figure 2 ) showed a weight loss of 1.3% before 150°C, consistent with the anhydrate.

[0391] TGA of Form 2 of Compound 1 ( Figure 4 ) showed a 9.0% weight loss before 150°C, consistent with a monoacetic acid solvate.

[0392] TGA of Form 3 of Compound 1 ( Figure 6) showed a weight loss of 2.4% before 150°C, consistent with the anhydrate.

[0393] TGA of Form 4 of Compound 1 ( Figure 8 ) showed a weight loss of 4.3% before 130°C.

[0394] TGA of Form 5 of Compound 1 ( Fig.10 ) showed a weight loss of 0.6% up to 150 °C, consistent with the anhydrate.

[0395] TGA of Form 6 of Compound 1 ( Fig.12 ) showed a weight loss of 1.8% up to 200 °C, consistent with an anhydrate.

[0396] TGA of Form 7 of Compound 1 ( Fig.14 ) showed a weight loss of 8.7% up to 100 °C, consistent with a hydrate.

[0397] TGA of Form 8 of Compound 1 ( Fig.16 ) showed a weight loss of 10.6% up to 150°C.

[0398] Example 11: Differential Scanning Calorimetry (DSC)

[0399] DSC studies were performed 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 at a heating rate of 10°C / min from 25°C to the final temperature using a nitrogen purge of 50 mL / min.

[0400] DSC analysis of Form 1 of Compound 1 ( Figure 2 ) shows that a sharp melting endotherm begins to appear at 282°C.

[0401] DSC analysis of Form 2 of Compound 1 ( Figure 4 ) shows a first endotherm starting at about 145 °C and a second endotherm starting at about 280 °C.

[0402] DSC analysis of Form 3 of Compound 1 ( Figure 6 ) shows a first endotherm at about 41 °C, a second endotherm starting at about 93 °C, and a third endotherm starting at about 156 °C.

[0403] DSC analysis of Form 4 of Compound 1 ( Figure 8 ) shows a first endotherm at about 60 °C and a second endotherm starting at about 128 °C.

[0404] DSC analysis of Form 5 of Compound 1 ( Fig.10 ) shows an endotherm starting at about 273°C.

[0405] DSC analysis of Form 6 of Compound 1 ( Fig.12 ) shows an endotherm starting at about 278°C.

[0406] DSC analysis of Form 7 of Compound 1 ( Fig.14 ) shows a first endotherm at about 113 °C, an exotherm at about 168 °C, and a second endotherm at about 279 °C.

[0407] DSC analysis of Form 8 of Compound 1 ( Fig.16 ) shows a first endotherm at about 89°C, a second endotherm at about 119°C, and a third endotherm at about 284°C.

[0408] Example 12: Dynamic Vapor Sorption (DVS)

[0409] DVS studies were performed using DVS Intrinsic (SMS, UK). 10 to 20 mg of compound were transferred into the DVS and the weight change at 25°C for different atmospheric humidities was recorded using the following parameters:

[0410] Dry at 25°C until dm / dt < ±0.002% / min

[0411] Minimum time: 10min, maximum time: 180min

[0412] Balance: 60 minutes

[0413] Cycle: 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 0

[0414] Characterization of samples by XRPD after DVS experiments

[0415] DVS analysis of Form 1 of Compound 1 showed 0.3% moisture uptake between 0-80% RH. Analysis by XRPD after DVS showed no change. The material is slightly hygroscopic.

[0416] III. Polymorph Screening

[0417] Example 13: Slurry method at 25°C

[0418] About 15 mg of Compound 1 amorphous free base was suspended in 0.5 mL of solvent in a HPLC glass vial. After magnetic stirring the suspension at RT for 6 days, the remaining solid was isolated for XRPD analysis. The results are shown in Table 1.

[0419] Table 1

[0420]

[0421] Example 14: Slurry method at 50°C

[0422] Slurry conversion experiments were performed at 50°C in different solvent systems. About 15 mg of amorphous free base of Compound 1 was suspended in 0.3 mL of solvent in a HPLC glass vial. After stirring the suspension at 50°C for about 6 days, the remaining solid was separated for XRPD analysis. The results are shown in Table 2.

[0423] Table 2

[0424] Solvent 1 Solvent 2 XRPD results IPA - Form 6 MIBK - Form 6 IPA - Form 6 1,4-Dioxane - Form 6 ACN - Form 1 Chloroform - Form 6 Anisole - Form 1 water - Form 5

[0425] Example 15: Solid Vapor Diffusion

[0426] Solid vapor diffusion experiments were performed using 13 different solvents. About 15 mg of compound 1 free base was weighed into a 3 mL vial and placed into a 20 mL vial containing 2 mL of a volatile solvent. The 20 mL vial was sealed with a lid and stored at RT for 7 days to allow the solvent vapor to interact with the sample. Solids were tested by XRPD, and the results are shown in Table 3.

[0427] Table 3

[0428] Solvents XRPD results water Form 5 MeOH Forms 1 and 6 IPA Form 5 acetone Form 6 EtOAc Form 6 MTBE Form 6 THF Form 6 1,4-Dioxane Form 6 ACN Form 1 Toluene Form 1 DCM Form 6 DMF Form 1 Acetic acid Form 2

[0429] Example 16: Liquid Vapor Diffusion

[0430] Nine liquid vapor diffusion experiments were performed. About 15 mg of compound 1 free base was dissolved in an appropriate solvent to obtain a clear solution in a 3 mL vial. The solution was then placed in a 20 mL vial containing 3 mL of a volatile solvent. The 20 mL vial was sealed with a lid and stored at RT to allow enough time for the organic vapor to interact with the solution. The precipitate was separated for XRPD analysis. The solid was tested by XRPD, and the results are shown in Table 4.

[0431] Table 4

[0432] Solvents Antisolvent XRPD results Benzyl alcohol acetone Form 1 Benzyl alcohol IPA Form 1 Benzyl alcohol ACN Form 1 DMF MIBK Form 1 DMF IPA Form 1 DMF Toluene Form 1 THF / MeOH(3:1) Toluene Form 1 THF / MeOH(3:1) MIBK Form 1 THF / MeOH(3:1) Heptane Form 5

[0433] Example 17: Slow Evaporation

[0434] Slow evaporation experiments were performed under six conditions. Briefly, 10-17 mg of compound 1 free base was dissolved in 2.5 mL of 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 following steps. The visually clear solution was covered and evaporated at RT. The results are shown in Table 5.

[0435] Table 5

[0436] Solvents XRPD results THF Form 1 1,4-Dioxane Form 1 Chloroform Form 6 Acetic acid No crystallization THF / MeOH(3:1) Form 1 DCM / MeOH (3:1) Form 1

[0437] Example 18: Slow Cooling

[0438] Slow cooling experiments were carried out in seven solvent systems. About 20 mg of compound 1 free base was suspended in 0.5-1.0 mL of solvent in a 3 mL glass vial at RT. The suspension was then heated to 50 ° C, balanced for about five hours, and filtered using a nylon membrane (pore size of 0.45 μm). The filtrate was slowly cooled to 5 ° C at a rate of 0.1 ° C / min. No solid was obtained in any system, and the solution was then transferred to -20 ° C. If no precipitation was observed, the solution was evaporated at RT. The results are shown in Table 6.

[0439] Table 6

[0440] Solvents XRPD results THF Forms 1 and 6 1,4-Dioxane Form 6 Chloroform Forms 1 and 6 Benzyl alcohol / MTBE (1:9) No crystallization THF / MeOH(1:1) Form 1 DCM / MeOH (1:1) Form 1 DMF / Toluene (1:9) Form 5

[0441] Example 19: Antisolvent Addition

[0442] A total of 19 antisolvent addition experiments were performed. About 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 then 0.2 mL of antisolvent was added until precipitation occurred or the total amount of antisolvent reached 15.0 mL. The resulting precipitate was separated for XRPD analysis, and the results are shown in Table 7.

[0443] Table 7

[0444]

[0445]

[0446] Example 20: Stability Study

[0447] The physicochemical stability of Form 1 was evaluated by storing the samples at 80°C for one day, 25°C / 60% RH and 40°C / 75% RH for one week and one month. The stability samples were characterized by XRPD and HPLC, and there was no significant change in HPLC purity under all test conditions, indicating good chemical stability. In addition, no form change was observed in Form 1 after storage, as demonstrated by the XRPD pattern.

[0448] Form 2 stability was also evaluated by slurry in acetone and methanol / water at RT. Solids were isolated at 1 hour, 3 hours, 5 hours, and 29 hours. XRPD analysis showed that Form 1 formed within one hour in both solvents.

[0449] Example 21: Thermodynamic Stability Relationships of Anhydrates (Forms 1, 5, and 6)

[0450] 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 monomorphically related to form 5 and is thermodynamically more stable.

[0451] As a result, Form 6 and Form 1 were slurried in acetone and THF systems at 5°C, RT and 50°C. After stirring at the desired temperature for five days, the solid was separated and analyzed by XRPD. As shown in Table 8, only Form 1 was obtained, indicating that Form 1 is a thermodynamically stable form in the range of 5 to 50°C.

[0452] Table 8

[0453]

[0454]

[0455] Example 22: Critical Water Activity Study between Form 1 and Form 7

[0456] The critical water activity between anhydrous Form 1 and hydrated Form 7 was investigated by slurry with various water activities in MeOH / H2O system at room temperature. After stirring overnight, the solid was isolated and analyzed by XRPD. As shown in Table 9, at RT, Form 7 converted to Form 1 at all water activities, indicating that Form 1 was more stable under the selected conditions.

[0457] Table 9

[0458] <![CDATA[MeOH / H2O(v:v);A w ]]> XRPD results 1000:0；0.0 Form 1 937:63；0.2 Form 1 893:107；0.3 Form 1 844:156；0.4 Form 1 775:225；0.5 Form 1 687:313；0.6 Form 1 573:427；0.7 Form 1 418:582；0.8 Form 1 219:781；0.9 Form 1 0:1000；1.0 Form 1

[0459] Example 23: Solubility Evaluation of Form 1 and Form 2

[0460] 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 dissolved by stirring at room temperature or 50°C. If a clear solution was obtained, a certain amount of HPMC-AS was then added to the solution at room temperature. Experimental details and results are listed in Table 10. Form 2 was dissolved in DCM / MeOH at a concentration of 13 mg / mL, while form 1 was dissolved at a lower concentration (10 mg / mL). Therefore, form 2 shows better solubility than form 1 in this vehicle and is therefore the preferred crystalline form of the preparation in this vehicle.

[0461] Table 10

[0462]

[0463]

[0464] IV. Single crystal X-ray diffraction data

[0465] Example 24: Single Crystal X-ray Diffraction, Compound 1, Form 1

[0466] Select a suitable single crystal from the plate-like crystals and analyze it by single crystal X-ray diffractometer. The crystal system of the single crystal is monoclinic, and the space group is P21, and the unit cell parameters are: α=90°, β=100.2303(8)°, γ=90°, The molecular weight is 546.71 g·mol-1, Z = 2, so the density is calculated to be 1.666 g·cm-3. Table 11 lists further crystallographic data and refinement parameters.

[0467] The asymmetric unit of the single crystal structure consists of only one molecule of compound 1, e.g. Fig.17 As shown, this indicates that the crystal is an anhydrate of compound 1. 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)}. XRPD analysis of the single crystal structure shows that it is form 1.

[0468] Table 11

[0469]

[0470] Example 25: Single Crystal X-ray Diffraction, Compound 1, Form 2

[0471] Compound 1, Form 2 crystallizes as monoclinic in the P21 space group with a molecular formula of C 21 H 13 Cl3F3N5O3·C2H4O2. 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. Fig.18 As shown, the chiral carbon shows an "R" (C17, C38) configuration within the asymmetric unit. No proton transfer occurs between compound 1 and acetic acid, so it is a solvate of acetic acid. Table 12 lists further crystallographic data and refinement parameters. XRPD analysis of the single crystal structure shows that it is form 2.

[0472] Table 12

[0473]

[0474] V. Biological Data

[0475] Example 26: GTPγS binding assay

[0476] S1P1 membranes were prepared from CHO-K1 Gαqi5 cells expressing full-length human S1P1. Scintillation proximity assay (SPA) was performed by 35 S and different concentrations of compounds were incubated for 60 min. Wheat germ agglutinin-coated SPA beads were added and incubated for 60 min, followed by centrifugation and scintillation counting. The EC of compound 1 was found to be 50 Data are <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 claim 1, wherein 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 1 having at least one of the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG1 ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5°2-θ, 18.5°2-θ, 21.0°2-θ, 22.1°2-θ, 22.8°2-θ, 26.6°2-θ, 27.8°2-θ and 28.9°2-θ; (c) a thermogravimetric analysis (TGA) substantially similar to that shown in FIG2 ; (d) a DSC thermogram substantially similar to that shown in FIG2 ; (e) a DSC thermogram having an endotherm onset at about 282°C; or (f) combinations thereof.

3. The crystalline form of claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1 .

4. The crystalline form of claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 16.5° 2-θ, 18.5° 2-θ, 21.0° 2-θ, 22.1° 2-θ, 22.8° 2-θ, 26.6° 2-θ, 27.8° 2-θ, and 28.9° 2-θ.

5. The crystalline form of claim 2, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG.

2.

6. The crystalline form of claim 2, wherein the crystalline form has a DSC thermogram substantially similar to that shown in FIG.

2.

7. The crystalline form of claim 2, wherein the crystalline form has a DSC thermogram with an endotherm onset at about 282°C.

8. The crystalline form of claim 2, wherein the crystalline form is characterized by having properties (a), (b), (c), (d), and (e).

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

10. The crystalline form according to any one of claims 2 to 9, wherein the crystalline form is non-solvated.

11. The crystalline form of claim 1, wherein 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 having at least one of the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG3 ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.9°2-θ, 17.1°2-θ, 18.1°2-θ, 22.0°2-θ, 24.0°2-θ, 24.8°2-θ, 25.5°2-θ, 26.2°2-θ and 28.2°2-θ; (c) a thermogravimetric analysis (TGA) substantially similar to that shown in FIG4 ; (d) a DSC thermogram substantially similar to that shown in FIG4 ; (e) a DSC thermogram having a first endotherm with an onset at about 145°C and a second endotherm with an onset at about 280°C; or (f) combinations thereof.

12. The crystalline form of claim 11, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 3.

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

14. The crystalline form of claim 11, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG.

4.

15. The crystalline form of claim 11, wherein the crystalline form has a DSC thermogram substantially similar to that shown in Figure 4.

16. The crystalline form of claim 11, wherein the crystalline form has a DSC thermogram with a first endotherm onset at about 145°C and a second endotherm onset at about 280°C.

17. The crystalline form of claim 11, wherein the crystalline form is characterized by having properties (a), (b), (c), (d), and (e).

18. The crystalline form according to any one of claims 11-17, wherein the crystalline form is obtained from acetic acid.

19. The crystalline form of claim 1, 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 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 salt is Form 3 having at least one of the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG5 ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.9°2-θ, 8.4°2-θ, 17.5°2-θ, 19.8°2-θ, 20.5°2-θ, 24.8°2-θ, 25.6°2-θ and 26.4°2-θ; (c) thermogravimetric analysis (TGA) substantially similar to that shown in FIG6 ; (d) a DSC thermogram substantially similar to that shown in FIG6 ; (e) a DSC thermogram having a first endotherm at about 41°C, a second endotherm onset at about 93°C, and a third endotherm onset at about 156°C; or (f) combinations thereof.

20. The crystalline form of claim 19, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 5.

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

22. The crystalline form of claim 19, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG6.

23. The crystalline form of claim 19, wherein the crystalline form has a DSC thermogram substantially similar to that shown in Figure 6.

24. The crystalline form of claim 19, wherein the crystalline form has a DSC thermogram with a first endotherm at about 41°C, a second endotherm onset at about 93°C, and a third endotherm onset at about 156°C.

25. The crystalline form of claim 19, 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 19-25, wherein the crystalline form is obtained from ethyl acetate.

27. The crystalline form of claim 1, 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 a mesylate salt and the crystalline form of the mesylate salt 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 4 having at least one of the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG7 ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.8°2-θ, 15.4°2-θ, 17.3°2-θ, 18.2°2-θ, 19.2°2-θ, 20.1°2-θ, 21.6°2-θ, 22.8°2-θ, 23.4°2-θ, 24.8°2-θ, 25.3°2-θ, 26.7°2-θ and 30.9°2-θ; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. 8 ; (d) a DSC thermogram substantially similar to that shown in FIG8 ; (e) a DSC thermogram having a first endotherm at about 60°C and a second endotherm onset at about 128°C; or (f) combinations thereof.

28. The crystalline form of claim 27, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 7.

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

30. The crystalline form of claim 27, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG8.

31. The crystalline form of claim 27, wherein the crystalline form has a DSC thermogram substantially similar to that shown in Figure 8.

32. The crystalline form of claim 27, wherein the crystalline form has a DSC thermogram with a first endotherm at about 60°C and a second endotherm onset at about 128°C.

33. The crystalline form of claim 27, 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 27-33, wherein the crystalline form is obtained from ethyl acetate.

35. A crystalline form according to any one of claims 1 to 34 for use in medicine.

36. A pharmaceutical composition comprising the crystalline form according to any one of claims 1-34 and a pharmaceutically acceptable excipient.

37. A method of treating a disease, disorder or condition in a mammal which would benefit from sphingosine-1 -phosphate (S1P) receptor modulation, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1-34.

38. The method of claim 37, wherein the disease, disorder or condition of the mammal is selected from the group consisting of multiple sclerosis, ulcerative colitis and Crohn's disease.

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