RU2799564C2 - Crystalline forms of magl inhibitor - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to a method of obtaining a crystalline form of monohydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- carboxylate, the process comprising the following steps: i) preparing a saturated solution of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl monohydrochloride )piperazine-1-carboxylate in a solvent selected from acetone, ethanol and tert-butyl methyl ether at a temperature of approximately 60°C; ii) adding a heptane antisolvent to the saturated solution at a temperature of approximately 60°C; iii) cooling to a temperature from about -5°C to about 15°C; iv) collecting the solid substance in the presence of a precipitate and evaporating the solvent to collect the solid substance in the absence of a precipitate; and v) optionally drying. The crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate monohydrochloride obtained by this method is Form 2, characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 14.3° 2-theta, 15.6° 2-theta, 19.0° 2-theta, 19.8° 2-theta and 20.7° 2-theta.

EFFECT: method of obtaining a crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1monohydrochloride-carboxylate with improved stability and solubility as a MAGL inhibitor.

2 cl, 57 dwg, 2 tbl, 19 ex

Description

Link to related applications

[0001] This application claims priority under U.S. Provisional Application No. 62/423,126, filed Nov. 16, 2016, which is incorporated herein by reference in its entirety.

Background of the Invention

[0002] Monoacylglycerol lipase (MAGL) is an enzyme responsible for the hydrolysis of endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate-based lipid, in the nervous system. Serine hydrolase α-β-hydrolase domain 6 (ABHD6) is another lipid mediator.

Brief summary of the present invention

[0003] The MAGL inhibitor described herein is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine -1-carboxylate, including pharmaceutically acceptable solvates (including hydrates), polymorphs of substances and amorphous phases and methods of their use. Pharmaceutically acceptable salts of the MAGL inhibitor 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate are also described. , including pharmaceutically acceptable solvates (including hydrates), polymorphs of substances and amorphous phases and methods of their use. 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, as well as pharmaceutically acceptable salts thereof are used in the manufacture of medicines for the treatment of diseases or conditions that are associated with the activity of MAGL.

[0004] Also described herein are methods for preparing crystalline forms of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate. Additionally, pharmaceutical compositions are described that include crystalline forms and methods of using a MAGL inhibitor in the treatment of diseases or conditions (including diseases or conditions in which irreversible inhibition of MAGL provides a therapeutic benefit to a mammal having a disease or condition).

[0005] According to one embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt thereof, including a solvate thereof.

[0006] According to another embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate is a free base.

[0007] According to another aspect, the present document describes the crystalline form of the free base of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) benzyl)piperazine-1-carboxylate, which has at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 1;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 7.8° 2-theta, 12.0° 2-theta, 18.5° 2-theta, 19.0° 2-theta, 19.6° 2 -theta and 21.2° 2-theta;

(c) thermogravimetric analysis (TGA) is essentially the same as that shown in FIG. 2;

(d) The DSC thermogram is essentially the same as that shown in FIG. 3;

(e) DSC thermogram with endothermicity characterized by onset at approximately 80°C;

(f) the infrared (IR) spectrum is essentially the same as that shown in FIG. 6;

(g) infrared (IR) spectrum with peaks at approximately 1735 cm-1, 1427 cm-1, 1102 cm-1, 982 cm-1 and 888 cm-1;

(h) non-hygroscopic, or

(i) their combinations.

[0008] In some embodiments, the crystalline free base has an X-ray powder diffractometry (XRPD) pattern substantially the same as that shown in FIG. 1. In some embodiments, the crystalline free base is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 7.8° 2-theta, 12.0° 2-theta, 18.5° 2-theta, 19.0° 2- theta, 19.6° 2-theta and 21.2° 2-theta. In some embodiments, the crystalline free base is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 2. In some embodiments, the free crystalline base has a DSC thermogram that is substantially similar to that shown in FIG. 3. In some embodiments, the crystalline free base has an endothermic DSC thermogram characterized by onset at approximately 80°C. In some embodiments, the crystalline free base has an endothermic DSC thermogram characterized by an onset at approximately 80°C and a peak at approximately 83°C. In some embodiments, the crystalline free base has an infrared (IR) spectrum that is substantially similar to the spectrum shown in FIG. 6. In some embodiments, the crystalline free base has weak infrared (IR) peaks at approximately 1735 cm ^-1 , 1427 cm ^-1 , 1102 cm ^-1 , 982 cm ^-1 and 888 cm ^-1 . In some embodiments, the crystalline free base is non-hygroscopic. In some embodiments, the crystalline free base is characterized in that it has properties (a), (b), (c), (d), (e), (f), (g), and (h). In some embodiments, the crystalline free base is derived from acetone, acetone/water, acetonitrile, anisole, dichloromethane, diisopropyl ether, dimethylacetamide, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, isopropyl acetate, methanol, methanol/water, methyl ethyl ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidone, 2-propanol, 2-propanol/water, tert-butyl methyl ketone, tetrahydrofuran, toluene, water, 1-butanol, 2-ethoxyethanol, 2-methyltetrahydrofuran, benzonitrile, chlorobenzene, heptane, hexane, or tert-amyl alcohol. In some embodiments, the crystalline free base is solvated. In some embodiments, the crystalline free base is unsolvated. In some embodiments, the crystalline free base is anhydrous.

[0009] According to another embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate is a salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a salt monohydrochloride, bishydrochloride salt, fumarate salt, besylate salt or mesylate salt or solvate thereof.

[0010] According to another embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate monohydrochloride or its solvate

[0011] According to another embodiment, described herein is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) monohydrochloride crystalline Form 1 )benzyl)piperazine-1-carboxylate, which is characterized by at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 9;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 14.9° 2-theta, 16.9° 2-theta, 18.4° 2-theta and 20.9° 2 -theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 10;

(d) The DSC thermogram is essentially the same as that shown in FIG. eleven;

(e) DSC thermogram with endothermicity characterized by onset at approximately 182°C;

(f) non-hygroscopicity;

or

(g) their combinations.

[0012] In some embodiments, the crystalline monohydrochloride salt, Form 1, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 9. In some embodiments, the crystalline monohydrochloride salt, Form 1, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 14.9° 2-theta, 16.9° 2-theta, 18, 4° 2-theta and 20.9° 2-theta. In some embodiments, the crystalline monohydrochloride salt, Form 1, has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 10. In some embodiments, the crystalline monohydrochloride salt, Form 1, has a DSC thermogram that is substantially similar to that shown in FIG. 11. In some embodiments, the crystalline monohydrochloride salt, Form 1, has an endothermic DSC thermogram characterized by onset at approximately 182°C. In some embodiments, the crystalline monohydrochloride salt, Form 1, has an endothermic DSC thermogram, characterized by an onset at about 182°C and a peak at about 187°C. In some embodiments, the crystalline monohydrochloride salt, Form 1, is non-hygroscopic. In some embodiments, the crystalline monohydrochloride salt, Form 1, is characterized in that it has properties (a), (b), (c), (d), (e), and (f). In some embodiments, the crystalline monohydrochloride salt, Form 1, is derived from acetonitrile, 1,4-dioxane, ethyl acetate, methanol, t-butyl methyl ether, or 2-propanol. In some embodiments, the crystalline monohydrochloride salt, Form 1, is solvated. In some embodiments, the crystalline monohydrochloride salt, Form 1, is unsolvated. In some embodiments, the crystalline monohydrochloride salt, Form 1, is anhydrous.

[0013] According to another embodiment, described herein is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) monohydrochloride crystalline Form 2 )benzyl)piperazine-1-carboxylate, which is characterized by at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 28;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 14.3° 2-theta, 15.6° 2-theta, 19.0° 2-theta, 19.8° 2 -theta and 20.7° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 26;

(d) The DSC thermogram is essentially the same as that shown in FIG. 3;

(e) DSC thermogram with endothermicity characterized by onset at approximately 201°C;

(f) the infrared (IR) spectrum is essentially the same as that shown in FIG. 29;

(g) infrared (IR) spectrum with peaks at approximately 1729 cm ^-1 , 1426 cm ^-1 , 1102 cm ^-1 , 984 cm ^-1 and 907 cm ^-1 ;

(h) non-hygroscopic or

(i) their combinations.

[0014] In some embodiments, the crystalline monohydrochloride salt, Form 2, has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 28. In some embodiments, the crystalline monohydrochloride salt, Form 2, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 14.3° 2-theta, 15.6° 2-theta, 19, 0° 2-theta, 19.8° 2-theta and 20.7° 2-theta. In some embodiments, the crystalline monohydrochloride salt, Form 2, has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 26. In some embodiments, the crystalline monohydrochloride salt, Form 2, has a DSC thermogram that is substantially similar to that shown in FIG. 27. In some embodiments, the crystalline monohydrochloride salt, Form 2, has an endothermic DSC thermogram characterized by onset at approximately 201°C. In some embodiments, the crystalline monohydrochloride salt, Form 2, has an endothermic DSC thermogram characterized by onset at approximately 201°C and peak at approximately 205°C. In some embodiments, the crystalline monohydrochloride salt, Form 2, has an infrared (IR) spectrum that is substantially similar to that shown in FIG. 29. In some embodiments, the crystalline monohydrochloride salt Form 2 has an infrared (IR) spectrum with peaks at approximately 1729 cm ^-1 , 1426 cm ^-1 , 1102 cm ^-1 , 984 cm ^-1 and 907 cm ^-1 . In some embodiments, the crystalline monohydrochloride salt, Form 2, is non-hygroscopic. In some embodiments, the crystalline monohydrochloride salt, Form 2, is characterized in that it has properties (a), (b), (c), (d), (e), (f), (g) and (h). In some embodiments, the crystalline monohydrochloride salt, Form 2, is derived from acetone, acetonitrile, anisole, dichloromethane, diisopropyl ether, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, t-butyl methyl ether, 2-propanol, tetrahydrofuran, toluene, 2 -ethoxyethanol, 2-methyltetrahydrofuran or tert-amyl alcohol. In some embodiments, the crystalline monohydrochloride salt, Form 2, is solvated. In some embodiments, the crystalline monohydrochloride salt, Form 2, is unsolvated. In some embodiments, the crystalline monohydrochloride salt, Form 2, is anhydrous.

[0015] According to another embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate is a bishydrochloride salt of 1,1-1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its solvate.

[0016] According to another embodiment, the present document describes the crystalline form of bishydrochloride 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) benzyl)piperazine-1-carboxylate, which has at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 17;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 12.0° 2-theta, 12.5° 2-theta, 14.3° 2-theta, 18.5° 2 -theta and 22.8° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 18;

(d) The DSC thermogram is essentially the same as that shown in FIG. 19;

(e) a DSC thermogram with endothermicity characterized by onset at approximately 154°C or

(f) their combinations.

[0017] In some embodiments, the crystalline bishydrochloride salt has an X-ray powder diffractometry (XRPD) pattern substantially the same as shown in FIG. 17. In some embodiments, the crystalline bishydrochloride salt is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 12.0° 2-theta, 12.5° 2-theta, 14.3° 2- theta, 18.5° 2-theta and 22.8° 2-theta. In some embodiments, the crystalline bishydrochloride salt is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 18. In some embodiments, the crystalline bishydrochloride salt has a DSC thermogram that is substantially the same as that shown in FIG. 19. In some embodiments, the crystalline bishydrochloride salt has an endothermic DSC thermogram characterized by onset at approximately 154°C. In some embodiments, the crystalline bishydrochloride salt has an endothermic DSC thermogram characterized by onset at about 154°C and peak at about 164°C. In some embodiments, the bishydrochloride crystalline salt is characterized in that it has properties (a), (b), (c), (d), and (e). In some embodiments, the crystalline bishydrochloride salt is prepared from tert-butyl methyl ether and 5 equivalents of HCl. In some embodiments, the crystalline bishydrochloride salt is solvated. In some embodiments, the crystalline bishydrochloride salt is unsolvated. In some embodiments, the crystalline bishydrochloride salt is anhydrous.

[0018] According to another embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate is the fumarate salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its solvate.

[0019] According to another embodiment, described herein is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) fumarate crystalline Form 1 )benzyl)piperazine-1-carboxylate, which is characterized by at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 42;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 13.6° 2-theta, 14.1° 2-theta, 14.3° 2-theta, 20.0° 2-theta and 21.9° 2 -theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 44;

(d) a DSC thermogram essentially similar to that shown in FIG. 45;

(e) DSC thermogram with endothermicity characterized by onset at approximately 126°C;

(f) non-hygroscopic or

(g) their combinations.

[0020] In some embodiments, the crystalline fumarate salt Form 1 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 42. In some embodiments, the crystalline fumarate salt, Form 1, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 13.6° 2-theta, 14.1° 2-theta, 14.3° 2-theta, 20, 0° 2-theta and 21.9° 2-theta. In some embodiments, the crystalline fumarate salt, Form 1, has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 44. In some embodiments, the crystalline fumarate salt Form 1 has a DSC thermogram that is substantially similar to that shown in FIG. 45. In some embodiments, the crystalline fumarate salt Form 1 has an endothermic DSC thermogram characterized by onset at approximately 126°C. In some embodiments, the crystalline fumarate salt, Form 1, has an endothermic DSC thermogram characterized by an onset at approximately 126°C and a peak at approximately 132°C. In some embodiments, the crystalline fumarate salt Form 1 is non-hygroscopic. In some embodiments, the crystalline fumarate salt, Form 1, is characterized in that it has properties (a), (b), (c), (d), (e), and (f). In some embodiments, the crystalline fumarate salt, Form 1, is prepared from 1-butanol, 1-propanol, 2-propanol, acetone/water mixtures, acetonitrile/water mixtures, ethanol, methyl acetate/water, methyl ethyl ketone/water, methanol/acetonitrile, and 2 -methoxyethanol/acetonitrile. In some embodiments, the crystalline fumarate salt Form 1 is solvated. In some embodiments, the crystalline fumarate salt Form 1 is unsolvated. In some embodiments, the crystalline fumarate salt Form 1 is anhydrous.

[0021] According to another embodiment, described herein is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) fumarate crystalline Form 2 )benzyl)piperazine-1-carboxylate, which is characterized by at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 46;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 9.2° 2-theta, 12.1° 2-theta, 15.2° 2-theta, 17.4° 2-theta, 18.2° 2 -theta, 19.1° 2-theta and 19.7° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 48 or

(d) their combinations.

[0022] In some embodiments, the crystalline fumarate salt Form 2 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 46. In some embodiments, the crystalline fumarate salt Form 2 is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 9.2° 2-theta, 12.1° 2-theta, 15.2° 2-theta, 17, 4° 2-theta, 18.2° 2-theta, 19.1° 2-theta and 19.7° 2-theta. In some embodiments, the crystalline fumarate salt, Form 2, has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 48. In some embodiments, the crystalline fumarate salt, Form 2, is characterized in that it has properties (a), (b) and (c). In some embodiments, the crystalline fumarate salt, Form 2, is prepared from acetone/water.

[0023] According to another embodiment, the present document describes crystalline Form 3 of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) fumarate )benzyl)piperazine-1-carboxylate, which is characterized by at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 49;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.7° 2-theta, 9.5° 2-theta, 12.0° 2-theta, 13.9° 2-theta, 14.6° 2 -theta, 17.6° 2-theta, 19.4° 2-theta and 20.3° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 51;

(d) The DSC thermogram is essentially the same as that shown in FIG. 52;

(e) a DSC thermogram with endothermicity characterized by onset at approximately 107°C, or

(f) their combinations.

[0024] In some embodiments, the crystalline fumarate salt, Form 3, has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 49. In some embodiments, the crystalline fumarate salt Form 3 is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.7° 2-theta, 9.5° 2-theta, 12.0° 2-theta, 13, 9° 2-theta, 14.6° 2-theta, 17.6° 2-theta, 19.4° 2-theta and 20.3° 2-theta. In some embodiments, the crystalline fumarate salt, Form 3, has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 51. In some embodiments, the crystalline fumarate salt Form 3 has a DSC thermogram that is substantially similar to that shown in FIG. 52. In some embodiments, the crystalline fumarate salt Form 3 has an endothermic DSC thermogram characterized by onset at a temperature of approximately 107°C. In some embodiments, the crystalline fumarate salt, Form 3, has an endothermic DSC thermogram characterized by onset at approximately 107°C and peak at approximately 115°C. In some embodiments, the crystalline fumarate salt, Form 3, is characterized in that it has properties (a), (b), (c), (d) and (e). In some embodiments, the crystalline fumarate salt, Form 3, is derived from dioxane/water.

[0025] According to another embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate is the mesylate salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its solvate.

[0026] According to another embodiment, the present document describes the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) mesylate benzyl)piperazine-1-carboxylate, which has at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 38;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 12.4° 2-theta, 14.6° 2-theta, 16.5° 2-theta, 17.7° 2 -theta and 19.7° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 40;

(d) The DSC thermogram is essentially the same as that shown in FIG. 41;

(e) DSC thermogram with endothermicity characterized by onset at approximately 179°C; or

(f) their combinations.

[0027] In some embodiments, the crystalline mesylate salt has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 38. In some embodiments, the crystalline mesylate salt is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 12.4° 2-theta, 14.6° 2-theta, 16.5° 2- theta, 17.7° 2-theta and 19.7° 2-theta. In some embodiments, the crystalline mesylate salt is characterized by a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 40. In some embodiments, the crystalline mesylate salt has a DSC thermogram that is substantially the same as that shown in FIG. 41. In some embodiments, the crystalline mesylate salt has an endothermic DSC thermogram characterized by onset at a temperature of approximately 179°C. In some embodiments, the crystalline mesylate salt has an endothermic DSC thermogram characterized by onset at approximately 179°C and peak at approximately 182°C. In some embodiments, the crystalline mesylate salt is characterized in that it has properties (a), (b), (c), (d), and (e). In some embodiments, the crystalline mesylate salt is derived from tert-butyl methyl ether, ethyl acetate, tetrahydrofuran, water/acetone, water/acetonitrile, or water/2-propanol. In some embodiments, the crystalline mesylate salt is solvated. In some embodiments, the crystalline mesylate salt is unsolvated. In some embodiments, the crystalline mesylate salt is anhydrous.

[0028] According to another embodiment, the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate is the besylate salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or its solvate.

[0029] In some embodiments, the crystalline besylate salt, Form 1, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 30. In some embodiments, the crystalline besylate salt, Form 1, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 13.2° 2-theta, 15.2° 2-theta, 18.2° 2-theta, 19, 3° 2-theta and 21.6° 2-theta. In some embodiments, the crystalline besylate salt is derived from acetone, acetonitrile, ethyl acetate, 2-propanol, and THF. In some embodiments, the crystalline besylate salt, Form 1, is solvated. In some embodiments, the crystalline besylate salt, Form 1, is unsolvated. In some embodiments, the crystalline besylate salt, Form 1, is anhydrous.

[0030] In another embodiment, described herein is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) besylate crystalline Form 2 )benzyl)piperazine-1-carboxylate, which is characterized by at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 31;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 15.9° 2-theta, 17.8° 2-theta, 18.8° 2-theta and 19.9° 2 -theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 33; or

(d) their combinations.

[0031] In some embodiments, the crystalline besylate salt, Form 2, has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 31. In some embodiments, the crystalline besylate salt, Form 2, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 15.9° 2-theta, 17.8° 2-theta, 18, 8° 2-theta and 19.9° 2-theta. In some embodiments, the crystalline besylate salt is characterized in that it has properties (a), (b), and (c). In some embodiments, the crystalline besylate salt, Form 2, is derived from tert-butyl methyl ether. In some embodiments, the crystalline besylate salt, Form 2, is solvated. In some embodiments, the crystalline besylate salt, Form 2, is unsolvated. In some embodiments, the crystalline besylate salt, Form 2, is anhydrous.

[0032] According to a further aspect, pharmaceutical compositions are provided which include 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4 described herein) -(trifluoromethyl)benzyl)piperazine-1-carboxylate and at least one additional ingredient selected from pharmaceutically acceptable carriers, diluents and excipients. In some embodiments, the pharmaceutical composition comprises 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- crystalline free base 1-carboxylate. In some embodiments, the pharmaceutical composition comprises a crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) mono-HCl salt Form 1 benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition comprises a crystalline Form 2 mono-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) benzyl)piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition comprises a crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) bis-HCl salt piperazine-1-carboxylate. In some embodiments, the pharmaceutical composition comprises crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 fumarate -carboxylate. In some embodiments, the pharmaceutical composition comprises crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1 mesylate -carboxylate. In some embodiments, the pharmaceutical composition comprises 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine besylate crystalline Form 1 -1-carboxylate. In some embodiments, the pharmaceutical composition comprises 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine besylate crystalline Form 2 -1-carboxylate. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration to a mammal. In some embodiments, the pharmaceutical composition is an oral solid dosage form. In some embodiments, the pharmaceutical composition contains from about 0.5 mg to about 1000 mg of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4 -(trifluoromethyl)benzyl)piperazine-1-carboxylate.

[0033] In another aspect, provided herein is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate or a pharmaceutically acceptable salt or solvate thereof for use in medicine.

[0034] In another aspect, provided herein is a method for treating pain in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a crystalline form of 1,1,1,3,3,3-hexafluoropropane-2- described herein. yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, a method is provided for treating pain in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein 1,1,1,3,3,3-hexafluoropropan-2-yl-4-( 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain.

[0035] According to another aspect, provided herein is a method for treating epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optic nerve (NMO), Tourette's syndrome, Alzheimer's disease, or abdominal pain associated with irritable bowel syndrome in a patient in need thereof, comprising: administering to a patient in need thereof a therapeutically effective amount of the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) described herein benzyl)piperazine-1-carboxylate. In some embodiments, a method is provided for treating epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optic nerve (NMO), Tourette's syndrome, Alzheimer's disease, or abdominal pain associated with irritable bowel syndrome in a patient in need, comprising administering to the patient in need a therapeutically effective amount of a pharmaceutical composition described herein -carboxylate.

[0036] According to another aspect, provided herein is a method for treating acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, vaso-occlusive sickle cell pain crises, spasticity, or pain associated with multiple sclerosis, functional chest pain, rheumatoid arthritis, osteoarthritis, or functional dyspepsia in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl described herein -4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, a method is provided for treating acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, sickle cell vaso-occlusive pain crises, spasticity or pain associated with multiple sclerosis, functional chest pain, rheumatoid arthritis, osteoarthritis, or functional dyspepsia in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of the pharmaceutical composition described herein 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2 -(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate.

[0037] In another aspect, provided herein is a method for treating dystonia in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of the crystalline form of 1,1,1,3,3,3-hexafluoropropane-2- described herein. yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate. In some embodiments, a method is provided for treating dystonia in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein 1,1,1,3,3,3-hexafluoropropan-2-yl-4-( 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate.

[0038] According to another aspect, provided herein is a pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl )piperazine-1-carboxylate (Compound 1), wherein the pharmaceutically acceptable salt is monohydrochloride, bishydrochloride, fumarate, besylate or mesylate. In some embodiments, a pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a monohydrochloride (Compound 2). In some embodiments, a pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a bishydrochloride (Compound 3). In some embodiments, a pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a fumarate (Compound 6). In some embodiments, a pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a mesylate (Compound 5). In some embodiments, a pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is a besilate (Compound 4).

[0039] In another embodiment, the pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate is crystalline. According to another embodiment, a pharmaceutically acceptable salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate is amorphous.

[0040] Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, as various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. The section headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter of the description. All documents or parts of documents cited in the application, including, without limitation, patents, patent applications, articles, books, manuals and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

Inclusion by reference

[0041] All publications and patent applications referred to in the present description are incorporated herein by reference to the extent that they are applicable and relevant.

Brief description of graphic materials

[0042] FIG. 1 shows X-ray powder diffraction (XRPD) pattern of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine free base. -1-carboxylate.

[0043] FIG. 2 shows thermogram of thermogravimetric analysis (TGA) of crystalline free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine -1-carboxylate.

[0044] FIG. 3 shows a differential scanning calorimetry (DSC) thermogram of the crystalline free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate.

[0045] FIG. 4 shows a gravimetric vapor sorption (GVS) analysis of the crystalline free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate.

[0046] FIG. 5 shows X-ray powder diffraction (XRPD) pattern of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine free base. -1-carboxylate before GVS and after GVS.

[0047] FIG. 6 shows the infrared (IR) spectrum of the crystalline free base 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- 1-carboxylate.

[0048] FIG. 7 shows the NMR spectrum of the crystalline free base of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate .

[0049] FIG. 8 shows HPLC purity of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate crystalline free base .

[0050] FIG. 9 shows the XRPD pattern of a crystalline 1,1,1,3,3,3-he xafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- mono-HCl salt. 1-carboxylate, Form 1.

[0051] FIG. 10 shows a TGA thermogram of a crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 mono-HCl salt -carboxylate, Form 1.

[0052] In FIG. 11 shows a DSC thermogram of a crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 mono-HCl salt -carboxylate, Form 1.

[0053] FIG. 12 shows an X-ray powder diffraction (XRPD) pattern of a crystalline mono-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl )piperazine-1-carboxylate, Form 1, after heating to a temperature of 140°C and cooling.

[0054] FIG. 13 shows gravimetric vapor sorption (GVS) analysis of the crystalline mono-HCl salt 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl) benzyl)piperazine-1-carboxylate, Form 1.

[0055] FIG. 14 shows an X-ray powder diffraction (XRPD) pattern of a crystalline mono-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl )piperazine-1-carboxylate, Form 1, after GVS.

[0056] FIG. 15 shows the NMR spectrum of the crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 mono-HCl salt -carboxylate, Form 1.

[0057] FIG. 16 shows the HPLC purity of the crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 mono-HCl salt -carboxylate, Form 1.

[0058] FIG. 17 shows the XRPD pattern of a crystalline bis-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate.

[0059] FIG. 18 shows a TGA thermogram of a crystalline bis-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate.

[0060] FIG. 19 shows a DSC thermogram of a crystalline bis-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate.

[0061] FIG. 20 shows GVS analysis of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 crystalline salt of bis-HCl -carboxylate.

[0062] In FIG. 21 shows the XRPD pattern of a crystalline bis-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate after GVS.

[0063] FIG. 22 shows the NMR spectrum of the 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 crystalline salt of bis-HCl -carboxylate.

[0064] FIG. 23 shows the HPLC purity of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 crystalline salt of bis-HCl -carboxylate.

[0065] FIG. 24A-D show XRPD analysis of results obtained from solvent solubility screening.

[0066] FIG. 25 shows the XRPD analysis of the results obtained from the primary screening for polymorphs.

[0067] FIG. 26 shows a TGA thermogram of a crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 mono-HCl salt -carboxylate, Form 2.

[0068] FIG. 27 shows a DSC thermogram of a crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 mono-HCl salt -carboxylate, Form 2.

[0069] FIG. 28 shows the XRPD pattern of a crystalline 1,1,1,3,3,3-he xafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin- mono-HCl salt. 1-carboxylate, Form 2.

[0070] FIG. 29 shows the infrared (IR) spectrum of a crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) mono-HCl salt) piperazine-1-carboxylate Form 2.

[0071] FIG. 30 shows XRPD of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate besylate, Forms 1.

[0072] FIG. 31 shows XRPD of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate besylate, Forms 2.

[0073] FIG. 32 shows XRPD of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate besylate, Forms 1 and 2.

[0074] FIG. 33 shows a TGA thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate besylate, Forms 2.

[0075] FIG. 34 and 35 show the XRPD analysis of the results obtained for 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine mesylate -1-carboxylate from a focused screening of salt forms.

[0076] FIG. 36 and 37 show the XRPD analysis of the results obtained for 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate -1-carboxylate from a focused screening of salt forms.

[0077] FIG. 38 shows the XRPD pattern of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate mesylate.

[0078] FIG. 39 shows the NMR spectrum of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate mesylate.

[0079] FIG. 40 shows a TGA thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate mesylate.

[0080] FIG. 41 shows a DSC thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate mesylate.

[0081] FIG. 42 shows XRPD of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 1.

[0082] FIG. 43 shows the NMR spectrum of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 1.

[0083] FIG. 44 shows a TGA thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 1.

[0084] FIG. 45 shows a DSC thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 1.

[0085] FIG. 46 shows XRPD of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 2.

[0086] FIG. 47 shows the NMR spectrum of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 2.

[0087] FIG. 48 shows a TGA thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 2.

[0088] FIG. 49 shows XRPD of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 3.

[0089] FIG. 50 shows the NMR spectrum of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 3.

[0090] FIG. 51 shows a TGA thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 3.

[0091] FIG. 52 shows a DSC thermogram of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 3.

[0092] FIG. 53 shows gravimetric vapor sorption (GVS) analysis of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate. -1-carboxylate, Form 1.

[0093] FIG. 54 shows gravimetric vapor sorption (GVS) analysis of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine fumarate. -1-carboxylate, Form 3.

[0094] FIG. 55 shows XRPD of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Form 1, before GVS and after GVS.

[0095] FIG. 56 shows the NMR spectrum of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 1.

[0096] FIG. 57 shows HPLC purity of crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate, Forms 1.

Detailed description of the present invention

[0097] Monoacylglycerol lipase (MAGL) is the main enzyme responsible for the hydrolysis of endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate-based lipid, in the nervous system. The endocannabinoid system regulates a number of physiological processes, including pain, inflammation, and memory, for example. In addition, disorders such as obesity, chronic pain, anxiety, and depression have been associated with the regulation of endocannabinoid signaling activity.

[0098] For example, MAGL-modulating compounds may be useful for stimulating 2-AG mediated signaling and disorders associated with such signaling, including pain, inflammation, metabolic disorders, and the like.

[0099] However, MAGL-modulating compounds to date generally lack the selectivity required for general use as pharmaceutically acceptable agents in vivo, in particular agents that are selective for fatty acid amide hydrolase (FAAH), the primary hydrolyzing enzyme. N-arachidonoylethanolamide (AEA). A genetic or pharmacological disorder of FAAH can lead to one or more cannabinoid-dependent behavioral effects, such as inflammation, anxiety, depression, or pain relief.

[00100] In addition, MAGL and its free fatty acid products have recently been found to be upregulated in aggressive cancer cells and in primary tumors, where it regulates a fatty acid network that promotes cancer cell migration and tumor growth. Therefore, new selective MAGL inhibitors may be useful in the treatment of cancer.

Compound 1 and its pharmaceutically acceptable salts

[00101] The MAGL inhibitor compound described herein, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl) piperazine-1-carboxylate, is selective for MAGL. Compound 1 is the free base form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate . "Compound 1" or "1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- free base carboxylate" refers to a compound with the following structure:

[00102] A large number of pharmaceutically acceptable salts are derived from Compound 1 and include:

- acid addition salts formed by the reaction of Compound 1 with an organic acid, which includes aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxylalkanoic acids, alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. and includes, for example, acetic 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 acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like;

acid addition salts formed by reacting Compound 1 with an inorganic acid, which includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, and the like.

[00103] The term "pharmaceutically acceptable salts" as applied to Compound 1 refers to a salt of Compound 1 that does not cause significant irritation to the mammal to which it is administered and does not substantially abolish the biological activity and properties of the compound.

[00104] It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition forms (solvates). Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol , methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, but not limited to, class 3 solvent(s). Categories of solvents are defined, for example, at the International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C (R3)" (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of Compound 1 or pharmaceutically acceptable salts thereof are conveniently prepared or formed by the processes described herein. In some embodiments, Compound 1 solvates are anhydrous. In some embodiments, Compound 1, or pharmaceutically acceptable salts thereof, exists in an unsolvated form. In some embodiments, Compound 1, or pharmaceutically acceptable salts thereof, exists in an unsolvated form and is anhydrous.

[00105] In still other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is prepared in various forms, including, but not limited to, amorphous phase, crystalline forms, milled forms, and nanoparticulate forms. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous and anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline and anhydrous.

[00106] Although not intended to be limited by any particular theory, some solid forms have physical properties (eg, stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. Moreover, without being bound by any particular theory, some solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water absorption, electrical properties, thermal properties, solid state reactivity, physical stability and chemical stability) affecting specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tabletting, flow, dissolution, formulation, and lyophilization) that make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using specific analytical chemistry techniques, including solid phase analytical methods (eg, x-ray diffraction, microscopy, spectroscopy, and thermal analysis) as described herein and known in the art.

Amorphous Compound 1

[00107] In some embodiments, Compound 1 is amorphous and anhydrous. In some embodiments, Compound 1 is amorphous. In some embodiments, amorphous Compound 1 is characterized by X-ray powder diffractometry (XRPD) showing no crystallinity.

Crystal forms of MAGL inhibitors

[00108] The identification and selection of the solid form of a pharmaceutical compound is complex given that a change in solid form can affect various physical and chemical properties that can provide advantages or disadvantages in processing, formulation, stability, bioavailability, storage, handling (e.g., delivery), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and route of administration. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired grade of pharmaceutical solid depends on the particular application; amorphous solids are sometimes selected based on, for example, an improved dissolution profile, while crystalline solids may be desirable for properties such as, for example, physical or chemical stability.

[00109] Crystalline or amorphous solid forms of a pharmaceutical compound include single-component and multi-component solids. Single component solids consist primarily of the pharmaceutical compound or active ingredient in the absence of other compounds. Diversity among one-component crystalline materials can potentially arise from the phenomenon of polymorphism, in which many three-dimensional structures exist for a particular pharmaceutical compound.

[00110] Notably, it is not even possible a priori to predict whether crystalline forms of a compound exist, let alone how to successfully obtain them (see, for example, Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem. Commun.: 3635-3645 (with regard to crystal design, if the instructions are not very precise and/or if other external factors influence the process, the result can be unpredictable); Jones et al, 2006, "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement", MRS Bulletin 31:875-879 (currently it is not possible to predict computationally the number of observed 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 59:14-23 (a significant amount still needs to be studied and done before than it will be possible with any degree of certainty to declare the ability to predict the crystal structure, there are far fewer polymorphs)).

[00111] The variety of possible solid forms creates a potential variety of physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms is of great importance for the development of an effective, stable and salable pharmaceutical product.

Crystal Compound 1

[00112] In some embodiments, Compound 1 is crystalline. In some embodiments, crystalline Compound 1 is characterized by having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 1;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 7.8° 2-theta, 12.0° 2-theta, 18.5° 2-theta, 19.0° 2-theta, 19.6° 2 -theta and 21.2° 2-theta;

(c) thermogravimetric analysis (TGA) substantially similar to that shown in FIG. 2;

(d) The DSC thermogram is essentially the same as that shown in FIG. 3;

(e) DSC thermogram with endothermicity characterized by onset at approximately 80°C;

(f) the infrared (IR) spectrum is essentially the same as that shown in FIG. 6;

(g) infrared (IR) spectrum with peaks at approximately 1735 cm ^-1 , 1427 cm ^-1 , 1102 cm ^-1 , 982 cm ^-1 and 888 cm ^-1 ;

(h) non-hygroscopic or

(i) their combinations.

[00113] According to some embodiments, crystalline Compound 1 is characterized in that it has at least two properties selected from (a)-(h). In some embodiments, crystalline Compound 1 is characterized in that it has at least three properties selected from (a)-(h). In some embodiments, crystalline Compound 1 is characterized in that it has at least four properties selected from (a)-(h). In some embodiments, crystalline Compound 1 is characterized in that it has at least five properties selected from (a)-(h). In some embodiments, crystalline Compound 1 is characterized in that it has at least six properties selected from (a)-(h). In some embodiments, crystalline Compound 1 is characterized in that it has at least seven properties selected from (a)-(h). In some embodiments, crystalline Compound 1 is characterized in that it has properties (a)-(h).

[00114] In some embodiments, crystalline Compound 1 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 1. In some embodiments, crystalline Compound 1 is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 7.8° 2-theta, 12.0° 2-theta, 18.5° 2-theta, 19.0° 2- theta, 19.6° 2-theta and 21.2° 2-theta. In some embodiments, crystalline Compound 1 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 2. In some embodiments, free Compound 1 has a DSC thermogram that is substantially similar to that shown in FIG. 3. In some embodiments, crystalline Compound 1 has an endothermic DSC thermogram characterized by onset at approximately 80°C. In some embodiments, crystalline Compound 1 has an endothermic DSC thermogram characterized by an onset at approximately 80°C and a peak at approximately 83°C. In some embodiments, crystalline Compound 1 has an infrared (IR) spectrum that is substantially similar to the spectrum shown in FIG. 6. In some embodiments, crystalline Compound 1 has weak infrared (IR) peaks at approximately 1735 cm ^-1 , 1427 cm ^-1 , 1102 cm ^-1 , 982 cm ^-1 and 888 cm ^-1 . In some embodiments, crystalline Compound 1 is non-hygroscopic. In some embodiments, crystalline Compound 1 is prepared from acetone, acetone/water, acetonitrile, anisole, dichloromethane, diisopropyl ether, dimethylacetamide, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, isopropyl acetate, methanol, methanol/water, methyl ethyl ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidone, 2-propanol, 2-propanol/water, tert-butyl methyl ketone, tetrahydrofuran, toluene, water, 1-butanol, 2-ethoxyethanol, 2-methyltetrahydrofuran, benzonitrile, chlorobenzene, heptane, hexane, or tert-amyl alcohol. In some embodiments, the crystalline free base is solvated. In some embodiments, crystalline Compound 1 is unsolvated. In some embodiments, crystalline Compound 1 is anhydrous.

Compound 2, mono-HCl salt

[00115] Compound 2 is the mono-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine -1-carboxylate. In some embodiments, the mono-HCl salt 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- carboxylate is crystalline Form 1. In some embodiments, the mono-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl )benzyl)piperazine-1-carboxylate is crystalline Form 2.

Compound 2 Form 1

[00116] In some embodiments, Compound 2 is crystalline. In some embodiments, Compound 2 is the crystalline Form 1. The crystalline Form 1 of Compound 2 is characterized by having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 9;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 14.9° 2-theta, 16.9° 2-theta, 18.4° 2-theta and 20.9° 2 -theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 10;

(d) The DSC thermogram is essentially the same as that shown in FIG. eleven;

(e) DSC thermogram with endothermicity characterized by onset at approximately 182°C;

(f) non-hygroscopic or

(g) their combinations.

[00117] According to some embodiments, Compound 2, Form 1, is characterized in that it has at least two properties selected from (a)-(f). In some embodiments, Compound 2, Form 1 is characterized in that it has at least three properties selected from (a)-(f). In some embodiments, Compound 2, Form 1 is characterized in that it has at least four properties selected from (a)-(f). In some embodiments, Compound 2, Form 1 is characterized in that it has at least five properties selected from (a)-(f). In some embodiments, Compound 2, Form 1 is characterized in that it has properties (a)-(f).

[00118] In some embodiments, Compound 2, Form 1 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 9. In some embodiments, Compound 2, Form 1, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 14.9° 2-theta, 16.9° 2-theta, 18.4 ° 2-theta and 20.9° 2-theta. In some embodiments, Compound 2, Form 1 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 10. In some embodiments, Compound 2, Form 1 has a DSC thermogram that is substantially the same as that shown in FIG. 11. In some embodiments, Compound 2, Form 1 has an endothermic DSC thermogram characterized by onset at approximately 182°C. In some embodiments, Compound 2, Form 1 has an endothermic DSC thermogram characterized by an onset at approximately 182°C and a peak at approximately 187°C. In some embodiments, Compound 2 Form 1 is non-hygroscopic. In some embodiments, Compound 2, Form 1 is prepared from acetonitrile, 1,4-dioxane, ethyl acetate, methanol, t-butyl methyl ether, or 2-propanol. In some embodiments, Compound 2, Form 1, is solvated. In some embodiments, Compound 2, Form 1, is unsolvated. In some embodiments, Compound 2 Form 1 is anhydrous.

Compound 2, Form 2

[00119] In some embodiments, Compound 2 is crystalline. In some embodiments, Compound 2 is crystalline Form 2. Crystalline Form 2 of Compound 2 is characterized by having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 28;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 14.3° 2-theta, 15.6° 2-theta, 19.0° 2-theta, 19.8° 2 -theta and 20.7° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 26;

(d) a DSC thermogram substantially similar to that shown in FIG. 3;

(e) DSC thermogram with endothermicity characterized by onset at approximately 201°C;

(f) the infrared (IR) spectrum is essentially the same as that shown in FIG. 29;

(g) infrared (IR) spectrum with peaks at approximately 1729 cm ^-1 , 1426 cm ^-1 , 1102 cm ^-1 , 984 cm ^-1 and 907 cm ^-1 ;

(h) non-hygroscopic or

(i) their combinations.

[00120] According to some embodiments, Compound 2, Form 2, is characterized in that it has at least two properties selected from (a) - (h). In some embodiments, Compound 2, Form 2 is characterized in that it has at least three properties selected from (a) - (h). In some embodiments, Compound 2, Form 2 is characterized in that it has at least four properties selected from (a) - (h). In some embodiments, Compound 2, Form 2 is characterized in that it has at least five properties selected from (a)-(h). In some embodiments, Compound 2, Form 2 is characterized in that it has at least six properties selected from (a)-(h). In some embodiments, Compound 2, Form 2 is characterized in that it has at least seven properties selected from (a)-(h). In some embodiments, Compound 2, Form 2 is characterized in that it has properties (a)-(h).

[00121] In some embodiments, Compound 2, Form 2 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 28. In some embodiments, Compound 2, Form 2, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 14.3° 2-theta, 15.6° 2-theta, 19.0 ° 2-theta, 19.8° 2-theta and 20.7° 2-theta. In some embodiments, Compound 1, Form 2 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 26. In some embodiments, Compound 2, Form 2 has a DSC thermogram that is substantially the same as that shown in FIG. 27. In some embodiments, Compound 2, Form 2 has an endothermic DSC thermogram characterized by onset at approximately 201°C. In some embodiments, Compound 2, Form 2 has an endothermic DSC thermogram characterized by onset at approximately 201°C and a peak at approximately 205°C. In some embodiments, Compound 2, Form 2 has an infrared (IR) spectrum that is substantially similar to that shown in FIG. 29. In some embodiments, Compound 2, Form 2 has an infrared (IR) spectrum with peaks at approximately 1729 cm ^-1 , 1426 cm ^-1 , 1102 cm ^-1 , 984 cm ^-1 and 907 cm ^-1 . In some embodiments, Compound 2 Form 2 is non-hygroscopic. In some embodiments, Compound 2, Form 2, is prepared from acetone, acetonitrile, anisole, dichloromethane, diisopropyl ether, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, t-butyl methyl ether, 2-propanol, tetrahydrofuran, toluene, 2- ethoxyethanol, 2-methyltetrahydrofuran or tert-amyl alcohol. In some embodiments, Compound 2, Form 2, is solvated. In some embodiments, Compound 2, Form 2, is unsolvated. In some embodiments, Compound 2 Form 2 is anhydrous.

Compound 3, bis-HCl salt

[00122] Compound 3 is the bis-HCl salt of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine -1-carboxylate.

In some embodiments, Compound 3 is crystalline. In some embodiments, Compound 3 is crystalline, having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 17;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 12.0° 2-theta, 12.5° 2-theta, 14.3° 2-theta, 18.5° 2 -theta and 22.8° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 18;

(d) The DSC thermogram is essentially the same as that shown in FIG. 19;

(e) a DSC thermogram with endothermicity characterized by onset at approximately 154°C or

(f) their combinations.

[00123] According to some embodiments, Compound 3 is characterized in that it has at least two properties selected from (a) - (e). In some embodiments, Compound 3 is characterized in that it has at least three properties selected from (a) to (e). In some embodiments, Compound 3 is characterized in that it has at least four properties selected from (a) to (e). In some embodiments, Compound 3 is characterized in that it has properties (a)-(e).

[00124] In some embodiments, Compound 3 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 17. In some embodiments, Compound 3 is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 12.0° 2-theta, 12.5° 2-theta, 14.3° 2-theta , 18.5° 2-theta and 22.8° 2-theta. In some embodiments, Compound 3 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 18. In some embodiments, Compound 3 has a DSC thermogram that is substantially the same as that shown in FIG. 19. In some embodiments, Compound 3 has an endothermic DSC thermogram characterized by onset at a temperature of approximately 154°C. In some embodiments, Compound 3 has an endothermic DSC thermogram characterized by onset at approximately 154°C and a peak at approximately 164°C. In some embodiments, Compound 3 is prepared from tert-butyl methyl ether and 5 equivalents of HCl. In some embodiments, Compound 3 is solvated. In some embodiments, Compound 3 is unsolvated. In some embodiments, Compound 3 is anhydrous.

Compound 4, besylate salt

[00125] Compound 4 is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- besylate carboxylate. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate besylate is crystalline Form 1. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 besylate -carboxylate is a crystalline Form 2.

Compound 4 Form 1

[00126] In some embodiments, Compound 4 is crystalline. In some embodiments, Compound 4 is crystalline Form 1. In some embodiments, Compound 4 has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in FIG. 30. In some embodiments, Compound 4, Form 1, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 13.2° 2-theta, 15.2° 2-theta, 18.2° 2-theta, 19.3 ° 2-theta and 21.6° 2-theta. In some embodiments, Compound 4, Form 1 is prepared from acetone, acetonitrile, ethyl acetate, 2-propanol, and THF. In some embodiments, Compound 4, Form 1, is solvated. In some embodiments, Compound 4, Form 1, is unsolvated. In some embodiments, Compound 4 Form 1 is anhydrous.

Compound 4 Form 2

[00127] In some embodiments, Compound 4 is crystalline. In some embodiments, Compound 4 is the crystalline Form 2. The crystalline Form 2 of Compound 4 is characterized in that it has at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 31;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 15.9° 2-theta, 17.8° 2-theta, 18.8° 2-theta and 19.9° 2 -theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 33; or

(d) their combinations.

[00128] According to some embodiments, Compound 4, Form 2, is characterized in that it has at least two properties selected from (a)-(c). In some embodiments, Compound 4, Form 1 is characterized in that it has properties (a)-(c). 6.4° 2-theta, 15.9° 2-theta, 17.8° 2-theta, 18.8° 2-theta and 19.9° 2-theta.

[00129] In some embodiments, Compound 4, Form 2 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 31. In some embodiments, Compound 4, Form 2, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.4° 2-theta, 15.9° 2-theta, 17.8° 2-theta, 18.8 ° 2-theta and 19.9° 2-theta. In some embodiments, Compound 4, Form 2, is prepared from tert-butyl methyl ether. In some embodiments, Compound 4 Form 2 is solvated. In some embodiments, Compound 4 Form 2 is unsolvated. In some embodiments, Compound 4 Form 2 is anhydrous.

Compound 5, mesylate salt

[00130] Compound 5 is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- mesylate carboxylate. In some embodiments, Compound 5 is crystalline. In some embodiments, Compound 5 is crystalline, having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 38;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 12.4° 2-theta, 14.6° 2-theta, 16.5° 2-theta, 17.7° 2 -theta and 19.7° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 40;

(d) The DSC thermogram is essentially the same as that shown in FIG. 41;

(e) DSC thermogram with endothermicity characterized by onset at approximately 179°C; or

(f) their combinations.

[00131] According to some embodiments, Compound 5 is characterized in that it has at least two properties selected from (a) - (e). In some embodiments, Compound 5 is characterized in that it has at least three properties selected from (a) to (e). In some embodiments, Compound 5 is characterized in that it has at least four properties selected from (a) to (e). In some embodiments, Compound 5 is characterized in that it has properties (a)-(e).

[00132] In some embodiments, Compound 5 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 38. In some embodiments, Compound 5 is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 8.6° 2-theta, 12.4° 2-theta, 14.6° 2-theta, 16.5° 2-theta , 17.7° 2-theta and 19.7° 2-theta. In some embodiments, Compound 5 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 40. In some embodiments, Compound 5 has a DSC thermogram that is substantially the same as that shown in FIG. 41. In some embodiments, Compound 5 has an endothermic DSC thermogram characterized by onset at a temperature of approximately 179°C. In some embodiments, Compound 5 has an endothermic DSC thermogram characterized by onset at approximately 179°C and a peak at approximately 182°C. In some embodiments, Compound 5 is prepared from tert-butyl methyl ether, ethyl acetate, tetrahydrofuran, water/acetone, water/acetonitrile, or water/2-propanol. In some embodiments, Compound 5 is solvated. In some embodiments, Compound 5 is unsolvated. In some embodiments, Compound 5 is anhydrous.

Compound 6, fumarate salt

[00133] Compound 6 is 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1- fumarate carboxylate. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate fumarate is crystalline Form 1. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 fumarate -carboxylate is a crystalline Form 2. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl fumarate )piperazine-1-carboxylate is Form 3 crystalline.

Compound 6 Form 1

[00134] In some embodiments, Compound 6 is crystalline. In some embodiments, Compound 6 is the crystalline Form 1. The crystalline Form 1 of Compound 6 is characterized by having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 42;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 13.6° 2-theta, 14.1° 2-theta, 14.3° 2-theta, 20.0° 2-theta and 21.9° 2 -theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 44;

(d) The DSC thermogram is essentially the same as that shown in FIG. 45;

(e) DSC thermogram with endothermicity characterized by onset at approximately 126°C;

(f) non-hygroscopic or

(g) their combinations.

[00135] According to some embodiments, Compound 6, Form 1, is characterized in that it has at least two properties selected from (a) - (f). In some embodiments, Compound 6 Form 1 is characterized in that it has at least three properties selected from (a)-(f). In some embodiments, Compound 6 Form 1 is characterized in that it has at least four properties selected from (a)-(f). In some embodiments, Compound 6, Form 1 is characterized in that it has at least five properties selected from (a)-(f). In some embodiments, Compound 6 Form 1 is characterized in that it has properties (a)-(f).

[00136] In some embodiments, Compound 6, Form 1 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 42. In some embodiments, Compound 6, Form 1; characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 13.6° 2-theta, 14.1° 2-theta, 14.3° 2-theta, 20.0° 2-theta and 21.9° 2-theta . In some embodiments, Compound 6 Form 1 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 44. In some embodiments, Compound 6, Form 1 has a DSC thermogram that is substantially the same as that shown in FIG. 45. In some embodiments, Compound 6, Form 1 has an endothermic DSC thermogram characterized by onset at approximately 126°C. In some embodiments, Compound 6, Form 1 has an endothermic DSC thermogram characterized by an onset at approximately 126°C and a peak at approximately 132°C. In some embodiments, Compound 6 Form 1 is non-hygroscopic. In some embodiments, Compound 6, Form 1, is prepared from 1-butanol, 1-propanol, 2-propanol, acetone/water mixtures, acetonitrile/water mixtures, ethanol, methyl acetate/water, methyl ethyl ketone/water, methanol/acetonitrile, and 2- methoxyethanol/acetonitrile. In some embodiments, Compound 6 Form 1 is solvated. In some embodiments, Compound 6 Form 1 is unsolvated. In some embodiments, Compound 6 Form 1 is anhydrous.

Compound 6 Form 2

[00137] In some embodiments, Compound 6 is crystalline. In some embodiments, Compound 6 is the crystalline Form 2. The crystalline Form 2 of Compound 6 is characterized by having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 46;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 9.2° 2-theta, 12.1° 2-theta, 15.2° 2-theta, 17.4° 2-theta, 18.2° 2 -theta, 19.1° 2-theta and 19.7° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 48 or

(d) their combinations.

[00138] According to some embodiments, Compound 6, Form 1, is characterized in that it has at least two properties selected from (a)-(c). In some embodiments, Compound 6 Form 2 is characterized in that it has properties (a)-(c).

[00139] In some embodiments, Compound 6, Form 2 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 46. In some embodiments, Compound 6, Form 2, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 9.2° 2-theta, 12.1° 2-theta, 15.2° 2-theta, 17.4 ° 2-theta, 18.2° 2-theta, 19.1° 2-theta and 19.7° 2-theta. In some embodiments, Compound 6 Form 2 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 48. In some embodiments, Compound 6 Form 2 is prepared from acetone/water.

Compound 6 Form 3

[00140] In some embodiments, Compound 6 is crystalline. In some embodiments, Compound 6 is the crystalline Form 3. The crystalline Form 3 of Compound 6 is characterized by having at least one of the following properties:

(a) The X-ray powder diffraction (XRPD) pattern is essentially the same as shown in FIG. 49;

(b) X-ray powder diffractometry (XRPD) with characteristic peaks at 6.7° 2-theta, 9.5° 2-theta, 12.0° 2-theta, 13.9° 2-theta, 14.6° 2 -theta, 17.6° 2-theta, 19.4° 2-theta and 20.3° 2-theta;

(c) The thermogravimetric analysis (TGA) thermogram is essentially the same as that shown in FIG. 51;

(d) The DSC thermogram is essentially the same as that shown in FIG. 52;

(e) a DSC thermogram with endothermicity characterized by onset at approximately 107°C, or

(f) their combinations.

[00141] According to some embodiments, Compound 6, Form 3, is characterized in that it has at least two properties selected from (a) - (e). In some embodiments, Compound 6 Form 3 is characterized in that it has at least three properties selected from (a) to (e). In some embodiments, Compound 6 Form 3 is characterized in that it has at least four properties selected from (a) to (e). In some embodiments, Compound 6 Form 3 is characterized in that it has properties (a)-(e).

[00142] In some embodiments, Compound 6, Form 3 has an X-ray powder diffractometry (XRPD) pattern that is substantially the same as that shown in FIG. 49. In some embodiments, Compound 6, Form 3, is characterized by X-ray powder diffractometry (XRPD) with characteristic peaks at 6.7° 2-theta, 9.5° 2-theta, 12.0° 2-theta, 13.9 ° 2-theta, 14.6° 2-theta, 17.6° 2-theta, 19.4° 2-theta and 20.3° 2-theta. In some embodiments, Compound 6 Form 3 has a thermogravimetric analysis (TGA) thermogram that is substantially the same as that shown in FIG. 51. In some embodiments, Compound 6 Form 3 has a DSC thermogram that is substantially the same as that shown in FIG. 52. In some embodiments, Compound 6, Form 3 has an endothermic DSC thermogram characterized by onset at approximately 107°C. In some embodiments, Compound 6, Form 3 has an endothermic DSC thermogram characterized by an onset at approximately 107°C and a peak at approximately 115°C. In some embodiments, Compound 6, Form 3, is prepared from dioxane/water.

Obtaining crystalline forms

[00143] According to some embodiments, the crystalline forms of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1 -carboxylate receive, as indicated in the examples. It should be noted that the solvents, temperatures, and other reaction conditions presented herein may vary.

[00144] According to certain embodiments, provided herein are methods for preparing a solid form of Compound 1, comprising 1) obtaining a saturated solution of Compound 1 in a solvent at a first temperature (eg, about 60° C.); 2) adding an anti-solvent to the saturated solution at the first temperature; 3) cooling to a second temperature (eg, from about -5° C. to about 15° C.); and 4) collecting the solid in the presence of a precipitate and evaporating the solvent to collect the solid in the absence of a precipitate; and 5) optionally drying. In certain embodiments, provided herein are methods for preparing a solid form of Compound 1 comprising: 1) obtaining a saturated solution of Compound 1 in a solvent at a temperature of about 60°C; 2) adding an anti-solvent to a saturated solution at a temperature of approximately 60°C; 3) cooling to about 5° C.; and 4) collecting the solid if any precipitate is present and evaporating the solvent to collect the solid if no precipitate is present; and 5) optionally, air drying. In certain embodiments, the ratio by volume of solvent to anti-solvent is approximately 1:9. In some embodiments, the methods for preparing the solid form of Compound 1 are anti-solvent recrystallization experiments.

[00145] In another embodiment, crystalline Compound 1 is substantially pure. In some embodiments, a substantially pure crystalline Compound 1 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of substantially pure crystalline Compound 1 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, not less than about 98.5%. less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00146] In some embodiments, provided herein are methods for preparing a solid form of Compound 2, comprising 1) obtaining a saturated solution of Compound 2 in a solvent at a first temperature (eg, about 60° C.); 2) adding an anti-solvent to the saturated solution at the first temperature; 3) cooling to a second temperature (eg, from about -5° C. to about 15° C.); and 4) collecting the solid in the presence of a precipitate and evaporating the solvent to collect the solid in the absence of a precipitate; and 5) optionally drying. In certain embodiments, provided herein are methods for preparing a solid form of Compound 2 comprising: 1) obtaining a saturated solution of Compound 2 in a solvent at a temperature of about 60°C; 2) adding an anti-solvent to a saturated solution at a temperature of approximately 60°C; 3) cooling to a temperature of approximately 5° C.; 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 ratio by volume of solvent to anti-solvent is approximately 1:9. In some embodiments, the methods for preparing the solid form of Compound 2 are anti-solvent recrystallization experiments. In certain embodiments, Compound 2, Form 1 is obtained. In certain embodiments, Compound 2, Form 2 is obtained.

[00147] According to another embodiment, the crystalline Compound 1, Form 1, is substantially pure. In some embodiments, the substantially pure crystalline Compound 2, Form 1 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of the substantially pure crystalline Compound 2, Form 1 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98, 5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00148] In another embodiment, the crystalline Compound 2, Form 2, is substantially pure. In some embodiments, a substantially pure crystalline Compound 2, Form 2, is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of the substantially pure crystalline Compound 2, Form 2 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98, 5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00149] In certain embodiments, provided herein are methods for preparing a solid form of Compound 3 comprising 1) obtaining a saturated solution of Compound 3 in a solvent at a first temperature (eg, about 60° C.); 2) adding an anti-solvent to the saturated solution at the first temperature; 3) cooling to a second temperature (eg, from about -5° C. to about 15° C.); and 4) collecting the solid in the presence of a precipitate and evaporating the solvent to collect the solid in the absence of a precipitate; and 5) optionally drying. In certain embodiments, provided herein are methods for preparing a solid form of Compound 3 comprising: 1) obtaining a saturated solution of Compound 3 in a solvent at a temperature of about 60°C; 2) adding an anti-solvent to a saturated solution at a temperature of approximately 60°C; 3) cooling to a temperature of approximately 5° C.; 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 ratio by volume of solvent to anti-solvent is approximately 1:9. In some embodiments, the methods for preparing the solid form of Compound 3 are anti-solvent recrystallization experiments.

[00150] In another embodiment, crystalline Compound 3 is substantially pure. In some embodiments, the substantially pure crystalline Compound 3 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of substantially pure crystalline Compound 3 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, not less than about 98.5%. less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00151] In certain embodiments, provided herein are methods for preparing a solid form of Compound 4, comprising: 1) obtaining a saturated solution of Compound 4 in a solvent at a first temperature (eg, about 60° C.); 2) adding an anti-solvent to the saturated solution at the first temperature; 3) cooling to a second temperature (eg, from about -5° C. to about 15° C.); and 4) collecting the solid in the presence of a precipitate and evaporating the solvent to collect the solid in the absence of a precipitate; and 5) optionally drying. In certain embodiments, provided herein are methods for preparing a solid form of Compound 4 comprising: 1) obtaining a saturated solution of Compound 4 in a solvent at a temperature of about 60°C; 2) adding an anti-solvent to a saturated solution at a temperature of approximately 60°C; 3) cooling to a temperature of approximately 5° C.; 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 ratio by volume of solvent to anti-solvent is approximately 1:9. In some embodiments, the methods for preparing the solid form of Compound 4 are anti-solvent recrystallization experiments. In certain embodiments, Compound 4, Form 1 is prepared. In certain embodiments, Compound 4, Form 2 is prepared.

[00152] In another embodiment, the crystalline Compound 4, Form 1, is substantially pure. In certain embodiments, the substantially pure crystalline Compound 4, Form 1 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of the substantially pure crystalline Compound 4, Form 1 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98, 5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00153] In another embodiment, the crystalline Compound 4, Form 2, is substantially pure. In some embodiments, the substantially pure crystalline Compound 4, Form 2 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of the substantially pure crystalline Compound 4, Form 2 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98, 5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00154] In some embodiments, provided herein are methods for preparing a solid form of Compound 5, comprising 1) obtaining a saturated solution of Compound 5 in a solvent at a first temperature (eg, about 60° C.); 2) adding an anti-solvent to the saturated solution at the first temperature; 3) cooling to a second temperature (eg, from about -5° C. to about 15° C.); and 4) collecting the solid in the presence of a precipitate and evaporating the solvent to collect the solid in the absence of a precipitate; and 5) optionally drying. In certain embodiments, provided herein are methods for preparing a solid form of Compound 5 comprising: 1) obtaining a saturated solution of Compound 5 in a solvent at a temperature of approximately 60°C; 2) adding an anti-solvent to a saturated solution at a temperature of approximately 60°C; 3) cooling to a temperature of approximately 5° C.; 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 ratio by volume of solvent to anti-solvent is approximately 1:9. In some embodiments, the methods for preparing the solid form of Compound 5 are anti-solvent recrystallization experiments.

[00155] In another embodiment, crystalline Compound 5 is substantially pure. In some embodiments, substantially pure crystalline Compound 5 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of substantially pure crystalline Compound 5 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, not less than about 98.5%. less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00156] According to certain embodiments, provided herein are methods for preparing a solid form of Compound 6, comprising 1) obtaining a saturated solution of Compound 6 in a solvent at a first temperature (eg, about 60° C.); 2) adding an anti-solvent to the saturated solution at the first temperature; 3) cooling to a second temperature (eg, from about -5° C. to about 15° C.); and 4) collecting the solid in the presence of a precipitate and evaporating the solvent to collect the solid in the absence of a precipitate; and 5) optionally, drying. In certain embodiments, provided herein are methods for preparing a solid form of Compound 6 comprising: 1) obtaining a saturated solution of Compound 6 in a solvent at a temperature of about 60°C; 2) adding an anti-solvent to a saturated solution at a temperature of approximately 60°C; 3) cooling to a temperature of approximately 5° C.; 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 ratio by volume of solvent to anti-solvent is approximately 1:9. In some embodiments, the methods for preparing the solid form of Compound 6 are anti-solvent recrystallization experiments. In certain embodiments, Compound 6, Form 1 is obtained. In certain embodiments, Compound 6, Form 2 is obtained. In certain embodiments, Compound 6, Form 3 is obtained.

[00157] According to another embodiment, the crystalline Compound 6, Form 1, is essentially pure. In some embodiments, the substantially pure crystalline Compound 6 Form 1 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of the substantially pure crystalline Compound 6, Form 1 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98, 5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00158] According to another embodiment, the crystalline Compound 6, Form 2, is substantially pure. In some embodiments, the substantially pure crystalline Compound 6 Form 2 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of the substantially pure crystalline Compound 6, Form 2 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5 %, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

[00159] In another embodiment, the crystalline Compound 6, Form 3, is substantially pure. In some embodiments, the substantially pure crystalline Compound 6, Form 3 is substantially free of other solid forms, such as an amorphous solid. In some embodiments, the purity of the substantially pure crystalline Compound 6, Form 3 is at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98, 5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

Suitable solvents

[00160] Therapeutic agents that are administered to mammals, such as humans, must be prepared in accordance with regulatory guidelines. Such government-regulated guidelines are called Good Manufacturing Practices (GMP). GMP guidelines define acceptable levels of contamination of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. Preferred solvents are those suitable for use in GMP facilities and comply with industrial safety requirements. Categories of solvents are defined, for example, at the International Conference on Harmonization of Specifications for Registration of Medicinal Products for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C (R3)" (November 2005).

[00161] Solvents are divided into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents whose use should be limited in the manufacture of a therapeutic agent. Class 3 solvents are solvents with low toxic potential and less risk to human health. Data for class 3 solvents show that they are less toxic in acute or short term studies and negative in genotoxicity studies.

[00162] Class 1 solvents to be avoided include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene and 1,1,1-trichloroethane.

[00163] Examples of class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2 -ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene and xylene.

[00164] Class 3 solvents that have low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, t-butyl methyl ether (MTBE), cumene, dimethylsulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydrofuran.

[00165] Residual solvents in active pharmaceutical ingredients (APIs) come from API manufacturing. In some cases, solvents are not completely removed by practical manufacturing techniques. Appropriate choice of solvent for API synthesis can increase yield or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthesis process.

[00166] In some embodiments, compositions containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 contain an organic solvent(s). In some embodiments, compositions containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 contain a residual amount of organic solvent(s). In some embodiments, compositions containing Compound 1, Compound 1, Compound 3, Compound 4, Compound 5, or Compound 6 contain a residual Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is 3 is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl formate ethyl ester, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, t-butyl methyl ether, heptane, isopropanol, and ethanol.

Certain terminology

[00167] Unless otherwise defined, all technical and scientific terms used in this document are characterized by the same meaning, which is usually understood by a person skilled in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are illustrative and explanatory only and do not limit any claimed subject matter. In this application, the use of the singular includes the plural, unless specifically stated otherwise. It should be noted that the singular forms used in the description and the appended claims include references to the plural, unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or", unless otherwise indicated. In addition, the use of the term "including", as well as other forms such as "includes", "include" and "included", is not limiting.

[00168] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter of the description. All documents or parts of documents cited in the application, including but not limited to patents, patent applications, articles, books, manuals and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

[00169] The term "acceptable" or "pharmaceutically acceptable" in relation to the composition, composition or ingredient used herein means the absence of persistent adverse effects on the general health of the subject being treated or that they do not cancel the biological activity or properties of the compound and are relatively non-toxic.

[00170] As used herein, the term "improvement" of the symptoms of a particular disease, disorder, or condition by administering a particular compound or pharmaceutical composition refers to any reduction in severity, delay in onset, slow progression, or reduction in duration, whether permanent or temporary, long-term or short-term, which can be attributed to or associated with the introduction of the compound or composition.

[00171] "Bioavailability" refers to the percentage of a dosed Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 that is delivered to the general circulation of the test animal or human. The total exposure (AUC _(0-∞) ) of an intravenous drug is generally defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[00172] "Plasma concentration" refers to the concentration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 in the plasma component of a subject's blood. It is understood that the plasma concentration of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 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, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 may vary from subject to subject. Likewise, values such as maximum plasma concentration (C _max ) or time to reach maximum plasma concentration (T _max ), or total area under the plasma concentration versus time curve (AUC _(0-∞) ) may vary from subject to subject. . Because of this variability, the amount required to form a "therapeutically effective amount" of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 may vary from subject to subject.

[00173] As used herein, the terms "co-administration" or the like. are intended to cover the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration, or at the same or different times.

[00174] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of an agent or compound administered that will relieve one or more symptoms of the disease or condition being treated to some extent. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as described herein necessary to provide a clinically meaningful reduction in disease symptoms without undue side effects. An appropriate "effective amount" in any individual case may be determined using methods such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic benefit without undue side effects. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject due to changes in the metabolism of Compound 1, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the attending physician. By way of example only, therapeutically effective amounts can be determined by routine experimentation, including but not limited to dose escalation clinical trials.

[00175] The terms "enhance" or "enhancement" means an increase or prolongation of the action or duration of a desired effect. By way of example, "enhancement" of the effect of therapeutic agents refers to the ability to increase or prolong, in terms of efficacy or duration, the effect of therapeutic agents in the treatment of a disease, disorder or condition. As used herein, the term "effectively enhancing amount" refers to an amount sufficient to enhance the effect of a therapeutic agent in the treatment of a disease, disorder, or condition. When administered to a patient, amounts effective for that administration will depend upon the severity and course of the disease, disorder or condition prior to therapy, the patient's medical condition and drug response, and the judgment of the attending physician.

[00176] As used herein, the term "identical" refers to two or more sequences or subsequences that are the same. In addition, as used herein, the term "substantially identical" refers to two or more sequences that are characterized by the percentage of consecutive units that are the same when compared and aligned for best fit over a comparison window or designated area, as measured using comparison algorithms or by manual alignment and visual control. By way of example only, two or more sequences may be "substantially identical" if the consecutive units are approximately 60% identical, approximately 65% identical, approximately 70% identical, approximately 75% identical, approximately 80% identical, approximately 85% identical, approximately 90% identical, or approximately 95% identical in the specified area. Such percentages to describe the "percent identity" of two or more sequences. Sequence identity may exist in a region that is at least about 75-100 consecutive units long, in a region that is about 50 consecutive units long, or, if not specified, the entire sequence. This definition also applies to the complement of the sequence under study. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are the same, while two or more polypeptide sequences are "substantially identical" when the amino acid residues are about 60% identical, about 65% identical. , approximately 70% identical, approximately 75% identical, approximately 80% identical, approximately 85% identical, approximately 90% identical, or approximately 95% identical in the specified region. An identity may exist in a region that is at least about 75-100 amino acids long, in a region that is about 50 amino acids long, or, where not indicated, throughout the sequence of a polypeptide sequence. Furthermore, by way of example only, two or more polynucleotide sequences are identical when the nucleic acid residues are the same, while two or more polynucleotide sequences are "substantially identical" when the nucleic acid residues are approximately 60% identical, approximately 65% identical, approximately 70% identical, approximately 75% identical, approximately 80% identical, approximately 85% identical, approximately 90% identical, or approximately 95% identical in the specified area. An identity may exist in a region that is at least about 75-100 nucleic acids in length, in a region that is about 50 nucleic acids in length, or, where not indicated, in the entire sequence of a polynucleotide sequence.

[00177] As used herein, the terms "inhibits", "inhibition", or "inhibitor" of a kinase refers to the inhibition of enzymatic activity.

[00178] As used herein, the term "isolated" refers to separating and removing a component of interest from components of no interest. The isolated materials may be in a dry or semi-dry state, or in solution, including, but not limited to, an aqueous solution. The isolated component may be in a homogeneous state, or the isolated component may be part of a pharmaceutical composition that contains additional pharmaceutically acceptable carriers and/or excipients. By way of example only, nucleic acids or proteins are "isolated" when such nucleic acids or proteins are free of at least some of the cellular components to which they are naturally associated, or when the nucleic acid or protein is concentrated to a level in excess of concentration its production in vivo or in vitro. Further, by way of example, a gene is isolated upon separation from open reading frames that flank the gene and encode a protein other than the gene of interest.

[00179] As used herein, the term "modulate" means interacting with a target, directly or indirectly, to change the activity of the target, including, by way of example only, to increase the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to prolong target activity.

[00180] As used herein, the term "modulator" refers to a compound that alters the activity of a molecule. For example, the modulator may cause an increase or decrease in the amount of a certain activity of the molecule compared to the amount of activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor that reduces the amount of one or more activities of the molecule. In certain embodiments, the inhibitor completely prevents one or more activities of the molecule. In certain embodiments, the modulator is an activator that increases the amount of at least one activity of the molecule. In some embodiments, the presence of the modulator results in activity that does not occur in the absence of the modulator.

[00181] As used herein, the term "prophylactically effective amount" refers to the amount of a composition administered to a patient that will, to some extent, alleviate one or more symptoms of the disease, condition, or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's health, weight, and the like. It is believed that those skilled in the art can determine such prophylactically effective amounts through routine experimentation, including, but not limited to, dose escalation clinical trials.

[00182] As used herein, the term "subject" refers to an animal that is the object of treatment, observation, or experiment. By way of example only, the subject may be, without limitation, a mammal, including but not limited to a human.

[00183] As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Some illustrative target activities include, without limitation, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

[00184] As used herein, the terms "treat" or "treatment" are intended to alleviate, alleviate, or lessen the symptoms of a disease or condition, prevent additional symptoms, improve or prevent the underlying metabolic causes of the symptoms, inhibit the disease or condition, e.g., stop the progression of the disease or condition , amelioration of a disease or condition, causing regression of a disease or condition, amelioration of a condition caused by a disease or condition, or cessation of symptoms of a disease or condition. The terms "treat" or "treatment" include, without limitation, prophylactic and/or therapeutic treatment.

[00185] As used herein, the term "IC ₅₀ " refers to the amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response, such as MAGL inhibition, in an assay that measures that response.

[00186] As used herein, EC ₅₀ refers to the dose, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% maximum expression of the particular response that is induced, provoked, or enhanced by the particular test compound.

Pharmaceutical compositions/formulations

[00187] Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate processing of the active compounds into formulations that can be used pharmaceutically. The correct composition depends on the chosen route of administration. Any of the well known techniques, carriers and excipients may be used as appropriate and understood in the present art. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980 and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference in their entirety.

[00188] As used herein, a pharmaceutical composition refers to a mixture of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and /or excipients. The pharmaceutical composition facilitates administration of the compound to a mammal. In carrying out the methods of treatment or use provided herein, a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered in a pharmaceutical composition to a mammal with the disease, disorder, or condition being treated. Preferably the mammal is a human. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of mixtures.

[00189] As used herein, the term "pharmaceutical combination" means a product that results from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, for example, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6, and a concomitant agent, are both administered to the patient simultaneously in the form of a single object or dose. The term "non-fixed combination" means that the active ingredients, for example. Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, and the concomitant agent are administered to the patient as separate entities simultaneously or sequentially without any specific time intervals, such administration providing effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[00190] In some embodiments, crystalline Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is incorporated into pharmaceutical compositions to form solid oral dosage forms. In other embodiments, crystalline Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is used to prepare pharmaceutical compositions other than oral solid dosage forms. The pharmaceutical formulations described herein may be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical formulations described herein include, without limitation, aqueous liquid dispersions, self-emulsifiable dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, quick melt formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00191] Pharmaceutical compositions comprising a compound described herein can be made in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, drageeing, triturating, emulsifying, encapsulating, trapping, or compression.

Dosage forms

[00192] The pharmaceutical compositions described herein may be formulated for administration to a mammal by any conventional route, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term "subject" is used to refer to an animal, preferably a mammal, including human or non-human. The terms patient and subject may be used interchangeably.

[00193] In addition, the pharmaceutical compositions described herein, which include Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, may be formulated into any suitable dosage form, including but not limited to , oral solid dosage forms, controlled release formulations, quick melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed formulations with immediate release and controlled release.

[00194] Pharmaceutical preparations for oral administration can be prepared by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable excipients, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, excipients such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations 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: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.

[00195] Pharmaceutical preparations that can be used orally include hard capsules made from gelatin, as well as soft, sealed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Hard capsules may contain the active ingredients in admixture with an excipient such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[00196] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet (including a suspendable tablet, a rapidly dissolving tablet, a bite-disintegrating tablet, a rapidly disintegrating tablet, an effervescent tablet, or a capsule-shaped tablet), a pill, a powder (including including sterile-packaged powder, doseable powder or effervescent powder), capsule (including both soft and hard capsules, e.g. , biodegradable dosage form, controlled release dosage forms, pulsed release dosage forms, multiparticulate dosage forms, pellets, granules or aerosol. In other embodiments, the pharmaceutical composition is in the form of a powder. According to still other embodiments, the pharmaceutical composition is in the form of a tablet, including, without limitation, an instant tablet. In addition, the pharmaceutical compositions described herein may be administered as a single capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical composition is administered as two, three, or four capsules or tablets.

[00197] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 with one or more pharmaceutical excipients to form bulk mixture compositions. When these bulk mixture compositions are referred to as homogeneous, it means that the particles of Compound 1, Compound 1, Compound 3, Compound 4, Compound 5, or Compound 6 are evenly distributed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such like tablets, pills and capsules. Individual dosage units may also include film coats which disintegrate upon oral ingestion or upon contact with a diluent. These formulations can be prepared by conventional pharmacological methods.

[00198] Conventional pharmacological techniques include, for example, one or a combination of methods: (1) dry blending, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, or (6 ) merge. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, panning, melt granulation, granulation, fluid bed spray drying or coating (eg, Wurster coating), tangential coating, top spraying, tableting, extruding, and the like.

[00199] The pharmaceutical solid dosage forms described herein may include Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, excipient, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, defoamer, antioxidant, preservative, or one or more combinations thereof . In another aspect, using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coat is applied around a formulation of Compound 1, Compound 2, Compound 3, Compound 5, or Compound 6. In one embodiment, some or all particles of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 are characterized by the presence of a coating. In another embodiment, some or all of the Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 particles are microencapsulated. In another embodiment, Compound 1, Compound 1, Compound 3, Compound 4, Compound 5, or Compound 6 particles are not microencapsulated or coated.

[00200] Suitable carriers for use in the solid dosage forms described herein include, without limitation, gum, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, chloride sodium, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[00201] Suitable excipients for use in the solid dosage forms described herein include, without limitation, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches , 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.

[00202] In order to release Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with a binder. Disintegrants help break down the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, without limitation, natural starch such as corn starch or potato starch, pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as ^Promogel® or Explotab® ^, wood pulp, methylcrystalline cellulose such as ^Avicel® , ^Avicel® PH101, ^Avicel® PH102, Avicel® PH105, ^Elcema® P100, ^Emcocel® , ^{Vivacel® ,} Ming ^Tia® and Solka- ^Floc® , methylcellulose, croscarmellose or a crosslinked cellulose such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose, a crosslinked starch such as sodium starch glycolate, a crosslinked polymer such as crospovidone, a crosslinked polyvinylpyrrolidone, an alginate such as alginic acid, or an alginic acid salt such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural a sponge, a surfactant, a resin such as a cation exchanger, citrus cellulose, sodium lauryl sulfate, sodium lauryl sulfate combined with starch, and the like. In some embodiments, the disintegrant provided herein is selected from the group consisting of natural starch, pregelatinized starch, sodium stearate, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, crosslinked carboxymethylcellulose sodium, crosslinked carboxymethylcellulose, crosslinked croscarmellose, such a crosslinked starch, such as sodium starch glycolate, a crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay or gum. In some embodiments, the disintegrant provided herein is croscarmellose sodium.

[00203] Binders provide cohesiveness to solid oral dosage forms: for powdered capsule formulations, they promote the formation of plugs that can be filled into soft or hard capsule shells, and for tablet formulations, they maintain the integrity of the tablet after compression and help ensure uniformity of mixing up to the stage compression or filling. Suitable materials for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (eg Klucel ^® ), ethyl cellulose (eg Ethocel ^® ) and microcrystalline cellulose (eg Avicel ^® ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, copolymer gelatin/vinylvinylpyrol, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugar such as sucrose (eg Dipac ^® ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (eg Xylitab ^® ), lactose, natural or synthetic gum such as gum, tragacanth, ghatti gum, isapol husk gum, starch, polyvinylpyrrolidone (e.g. ^Povidone® CL, ^Kollidon® CL, ^{Polyplazdon®} XL-10 and ^Povidone® K-12), arabogolactan from larch, Veegum ^® , polyethylene glycol, waxes, sodium alginate, etc.

[00204] As a rule, the content of the binder in powdered compositions of gelatin capsules is 20-70%. Binder applications in tablet formulations include direct compression, wet granulation, rolling, or other excipients, such as excipients, which by themselves can act as a mild binder. Those skilled in the art can determine the level of binder for formulations, but binder usage levels of up to 70% in tablet formulations are common.

[00205] Suitable lubricants or glidants for use in the solid dosage forms described herein include, without limitation, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxy polyethylene glycol such as Carbowax™, PEG-4000, PEG-5000, PEG-6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, etc. In some embodiments, the lubricant provided herein is selected from the group consisting of stearic acid, calcium hydroxide, talc, cornstarch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant provided herein is magnesium stearate.

[00206] Suitable diluents for use in the solid dosage forms described herein include, without limitation, sugars (including lactose, sucrose and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol , xylitol and sorbitol), cyclodextrins, and the like. In some embodiments, the diluent provided herein is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. . In some embodiments, the diluent provided herein is microcrystalline cellulose.

[00207] The term "water-insoluble diluent" refers to compounds commonly used in pharmaceutical formulations such as calcium phosphate, calcium sulfate, starches, modified starches, and microcrystalline cellulose and microcellulose (for example, having a density of approximately 0.45 g/ cm ³ eg Avicel, powdered cellulose) and talc.

[00208] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolaminooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat ^10® ), oleic at sodium, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E, TPGS, etc.

[00209] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, for example, Pluronic® ⁽ BASF), etc. In some embodiments, the surfactant provided herein is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, ethylene oxide-propylene oxide copolymers. In some embodiments, the surfactant provided herein is sodium lauryl sulfate.

[00210] Suitable suspending agents for use in the solid dosage forms described herein include, without limitation, polyvinylpyrrolidone, e.g. 300 to about 6000 or about 3350 to about 4000 or about 7000 to about 5400, vinylpyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, resins such as, for example , gum tragacanth and acacia gum, guar gum, xanthans, including xanthan gum, sugars, cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolau rat, polyethoxylated sorbitan monolaurate, povidone, and the like.

[00211] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[00212] It should be appreciated that there is significant overlap between the additives used in the solid dosage forms described herein. Thus, the additives listed above should be considered merely illustrative, and not limiting, of the types of additives that may be included in the solid dosage forms described herein. The amount of such additives can be readily determined by one of skill in the art according to the specific desired properties.

[00213] According to other embodiments, one or more layers of the pharmaceutical composition are plasticized. By way of illustration, a plasticizer is typically a solid or liquid with a high boiling point. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, without limitation, diethyl phthalate, citrate esters, polyethylene glycol, glycerin, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00214] Compressed tablets are solid dosage forms obtained by compressing a bulk mixture of the formulations described above. In various embodiments, compressed tablets that are intended to dissolve in the mouth will include one or more flavors. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coat may provide delayed release of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 from a formulation. In other embodiments, the film coat aids patient compliance (eg, ^Opadry® coatings or sugar coating). Film shells, including Opadry ^® , typically comprise from about 1% to about 3% by weight of the tablet. In other embodiments, the compressed tablets include one or more excipients.

[00215] A capsule can be prepared, for example, by placing a volumetric mixture of the composition of Compound 1, Compound 2, Compound 3, Compound 5, or Compound 6 within a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a hard shell gelatin capsule. In other embodiments, the compositions are filled into standard gelatin capsules or non-gelatin capsules, such as capsules containing HPMC. In other embodiments, the formulation is placed in an openable capsule, wherein the capsule may be swallowed whole, or the capsule may be opened and the contents sprinkled on food before meals. In some embodiments, the therapeutic dose is divided into multiple (eg, two, three, or four) capsules. In some embodiments, the entire dose of the composition is delivered in the form of capsules.

[00216] In various embodiments, particles of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 and one or more excipients are dry blended and compressed into a mass, such as a tablet, having sufficient hardness to form a pharmaceutical a 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 composition into the gastrointestinal fluid.

[00217] According to another aspect, dosage forms may include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Illustrative materials include, without limitation, pH modifiers, erosion enhancers, defoamers, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents. agents and diluents.

[00218] Materials useful for the microencapsulation described herein include those compatible with Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 that sufficiently release Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 from other incompatible excipients. Materials compatible with Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 are materials that delay the release of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 compounds in vivo.

[00219] Exemplary microencapsulation materials useful for slow release formulations, including compounds described herein, include, but are not limited to, hydroxypropyl cellulose (HPC) ethers such as Klucel® or Nisso HPC, low substituted hydroxypropyl cellulose ethers ( L-HPC), hydroxypropyl methylcellulose (HPMC) ethers such as Seppifilm-LC, ^Pharmacoat® , Metolose SR, ^Methocel® -E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methylcellulose polymers such as Methocel® ^- A, hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose ^® , ethyl cellulose (EC) and mixtures thereof such as E461, Ethocel ^® , Aqualon ^® -EC, Surelease ^® , polyvinyl alcohol (PVA), such such as Opadry AMB, hydroxyethylcelluloses such as ^Natrosol® , carboxymethylcelluloses and carboxymethylcellulose (CMC) salts such as ^Aqualon® -CMC copolymers, polyvinyl alcohol and polyethylene glycol such as Kollicoat ^IR® , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as ^Eudragit® EPO, ^Eudragit® L30D-55, ^Eudragit® FS 30D ^Eudragit® L100-55, ^Eudragit® L100, ^Eudragit® S100, ^Eudragit® RD100, ^Eudragit® E100, ^Eudragit® L12.5, ^Eudragit® S12.5, ^Eudragit® NE30D and ^Eudragit® NE 40D, cellulose acetate phthalate, sepifilm, such as mixtures of HPMC and stearic acid, cyclodextrins and mixtures of these materials.

[00220] According to other embodiments, plasticizers such as polyethylene glycols, for example, PEG-300, PEG-400, PEG-600, PEG-1450, PEG-3350 and PEG-800, stearic acid, propylene glycol, oleic acid and triacetin are included in the composition of the material for microencapsulation. In other embodiments, the microencapsulation material useful for delayed release of pharmaceutical compositions is USP or National Formulary (NF). In still other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

[00221] Microencapsulated Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 can be formulated by methods known to those skilled in the art. Such known processes include, for example, spray drying processes, spinning disc dissolution processes, melt deposition processes, spray cooling processes, fluidized bed, electrostatic precipitation, centrifugal extrusion, rotary slurry separation, liquid-gas or solid-gas polymerization. , pressure extrusion or solvent extraction spray bath. In addition, several chemical methods can also be used, for example, complex coacervation, solvent evaporation, polymer-polymer incompatibility, liquid media interfacial polymerization, in situ polymerization, liquid drying, and liquid media desolvation. In addition, other methods such as rolling, extrusion/spheronization, coacervation or nanoparticle deposition can also be used.

[00222] In one embodiment, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 particles are microencapsulated prior to being formulated into one of the above forms. In yet another embodiment, some or most of the particles are coated prior to further formulation using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[00223] According to other embodiments, the solid dosage formulations of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 are plasticized (coated) with one or more layers. By way of illustration, a plasticizer is typically a solid or liquid with a high boiling point. Suitable plasticizers may be added in an amount of from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, without limitation, diethyl phthalate, citrate esters, polyethylene glycol, glycerin, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00224] In other embodiments, a powder containing formulations with Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 may be formulated to include one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk mixture composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk mixture is evenly subdivided into single dose packaging or multi-dose packaging units.

[00225] In still other embodiments, effervescent powders are also prepared according to the present disclosure. Effervescent salts have been used to disperse drugs in oral water. Effervescent salts are granules or coarse powders containing the drug in a dry mixture, usually consisting of sodium bicarbonate, citric acid and/or tartaric acid. When the salts of the compositions described herein are added to water, the acids 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 results in the release of carbon dioxide may be used in place of the combination of sodium bicarbonate, citric and tartaric acids, provided the ingredients are pharmaceutically acceptable and have a pH of about 6.0 or greater.

[00226] In some embodiments, the solid dosage forms described herein may be formulated as delayed-release oral dosage forms coated with an enteric coating, i. in the form of an oral dosage form of the pharmaceutical composition described herein, which uses an enteric coating to influence the release in the small intestine of the gastrointestinal tract. The enteric-coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other components of the composition, which are themselves coated or uncovered. The enteric-coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, pellets or granules of a solid carrier or compositions, which are themselves coated or uncoated.

[00227] As used herein, the term "delayed release" refers to delivery such that release can occur at some generally predictable location in the intestinal tract, more distal than what would be achieved if there were no no delayed release changes. In some embodiments, the delayed release method is a coating. Any coatings should be applied to a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but does dissolve at a pH of about 5 and above. It is expected that any anionic polymer exhibiting a pH dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic polymers. In other embodiments, the polymers and their compatible mixtures and some of their properties include, without limitation:

[00228] Shellac, also referred to as refined lacquer, is a refined product obtained from the resinous secretion of an insect. This coating dissolves in an environment with a pH>7;

[00229] Acrylic polymers. The characteristics of acrylic polymers (primarily their solubility in biological fluids) may vary depending 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) are available as solubilized in organic solvent, aqueous dispersion or dry powders. Eudragit RL, NE and RS series are insoluble in the gastrointestinal tract but are permeable and are used primarily for targeting in the colon. Eudragit E series dissolve in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine;

[00230] Cellulose derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial cellulose acetate esters with phthalic anhydride. Performance may vary depending 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 ATS polymer pseudo-sol with <1 µm particles. 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 methyl cellulose succinate (HPMCS); and hydroxypropyl methyl cellulose acetate succinate (for example, AQOAT (Shin Etsu)). Characteristics may vary depending on the degree and type of substitution. For example, HPMCPs such as HP-50, HP-55, HP-55S, HP-55F are suitable. Characteristics may vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, without limitation, 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 offered as granules or fine powders for aqueous dispersions; polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH >5 and is much less permeable to water vapor and gastric fluids.

[00231] In some embodiments, the coating may, and typically does, contain a plasticizer and possibly other coating auxiliaries such as colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerin, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers typically contain 10-25 wt. % plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. For coating, conventional coating methods such as spraying or panning are used. The thickness of the coating should be sufficient to ensure that the oral dosage form remains intact until the desired local delivery site in the intestinal tract is reached.

[00232] Colorants, detackifiers, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG) can be added to coatings in addition to plasticizers to dissolve or disperse the coating material, and to improve coating and product performance. coated.

[00233] In other embodiments, formulations described herein that include Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 are delivered using a pulsatile release dosage form. A pulsatile release dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled delay time or at predetermined locations. Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic and polyglycolic acid, polyanhydrides, and polycaprolactone; porous matrices, systems based on non-polymers that are lipids, including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, ^2nd Ed., pp. 751-753 (2002); US Pat. Nos. 4,327,725; 4,624,848; 4,968,509; 5,461,140; 5,456,923;

[00234] In some embodiments, pharmaceutical compositions are provided that include particles of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, at least one dispersant or suspending agent for oral administration to a subject. The compositions may be in the form of powder and/or granules for suspension and upon mixing with water a substantially homogeneous suspension is obtained.

[00235] It should be appreciated that there is overlap between the additives listed above used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by various specialists in the present field of technology or, as a rule, is applied to any from several different functions. Thus, the additives listed above should be considered merely illustrative, and not limiting, of the types of additives that may be included in the formulations described herein. The amount of such additives can be readily determined by one of skill in the art according to the specific desired properties.

Dosing and treatment regimens

[00236] In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 0.5 mg/day to about 1000 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 1 mg/day to about 500 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 2 mg/day to about 400 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 5 mg/day to about 300 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 10 mg/day to about 160 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 5 mg/day to about 100 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 1 mg/day to about 50 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 2 mg/day to about 50 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 2 mg/day to about 30 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 1 mg/day to about 20 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 2 mg/day to about 20 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 1 mg/day to about 10 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is from about 2 mg/day to about 10 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 500 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 450 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 400 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 350 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 300 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 275 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 250 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 225 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 200 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 190 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 180 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 170 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 160 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 150 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 140 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 130 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 120 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 110 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 100 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 95 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 90 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 85 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 80 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 75 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 70 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 65 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 60 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 55 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 50 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 45 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 40 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 35 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 30 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 25 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 20 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 15 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 10 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 5 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 2 mg/day. In some embodiments, the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 administered to a mammal is approximately 1 mg/day. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered orally. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered once a day, twice a day, or three times a day. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered daily. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered once a day. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered every other day. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is maintenance therapy. .

[00237] Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 may be used in the preparation of medicaments to inhibit MAGL or to treat diseases or conditions that would benefit, at least in part, from inhibition of MAGL , including in the treatment of inflammation or neuropathic pain. In addition, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering pharmaceutical compositions containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, or a pharmaceutically acceptable solvate thereof, in a therapeutically effective amounts for the specified subject.

[00238] Compositions containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 are administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, compositions containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 are administered for therapeutic applications. In some embodiments, compositions containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 are administered for prophylactic applications.

[00239] In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered daily. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered every other day.

[00240] In some embodiments, Compound 1, Compound 3, Compound 4, Compound 5, or Compound 6 is administered once a day. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered twice a day. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered three times a day. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 are administered four times a day.

[00241] In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered prior to disease progression, unacceptable toxicity, or individual choice. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered daily until disease progression, unacceptable toxicity, or individual choice. In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered every other day until disease progression, unacceptable toxicity, or individual choice.

[00242] In the case where the patient's condition does improve, at the discretion of the physician, the administration of the compounds can be continuous; alternatively, the dose of drug administered may be temporarily reduced or temporarily suspended for a specified period of time (i.e., a "drug holiday"). The duration of a medicinal holiday can vary from 2 days to 1 year, including by way of example only: 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. Dose reductions during drug holidays can range from 10% to 100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[00243] After improvement of the patient's condition, if necessary, a maintenance dose is administered. Subsequently, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which an improved disease, disorder, or condition is maintained. Patients, however, may require intermittent therapy on a long-term basis for any recurrence of symptoms.

[00244] The amount of a given agent that will correspond to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the individuality (for example, weight) of the subject or host in need of treatment, but nevertheless can be determined by the usual in a manner known in the present technical field, in accordance with the specific circumstances associated with this case, including, for example, the specific input agent, the route of administration and the subject or host being treated. In general, however, doses used to treat an adult are typically in the range of 0.02-5000 mg per day, or about 1-1500 mg per day. The desired dose may conveniently be presented as a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, such as two, three, four or more sub-doses per day.

[00245] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. A single dose may be in the form of a pack containing individual amounts of the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions may be packaged in disposable non-reclosable containers. Alternatively, reusable reclosable containers can be used, in which case a preservative is typically included in the composition. The above ranges are merely suggestive as the number of variables in relation to an individual treatment regimen is large and significant deviations from these recommended values are not uncommon. Such dosages may be varied depending on a number of variables, not limited to the potency of the compound used, the disease or condition being treated, the route of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the attending physician.

[00246] The toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, without limitation, determination of LD ₅₀ (dose lethal to 50% of the population) and ED ₅₀ (therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is a therapeutic index, and it can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds showing high therapeutic performance are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a dosage range for human use. The dosage of such compounds is preferably in the range of circulating concentrations that include the ED ₅₀ with minimal toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration used.

Ways

[00247] In some embodiments, provided herein are methods for modulating MAGL activity. Contemplated methods, for example, involve exposing said enzyme to a compound described herein. The ability of the compounds described herein to modulate or inhibit MAGL is assessed using procedures known in the art and/or described herein. According to another aspect of the present disclosure, methods are provided for treating a disease associated with MAGL expression or activity in a patient.

[00248] Also disclosed herein are methods of treating and/or preventing a disorder such as one or more of acute or chronic pain and neuropathy in a patient in need thereof. The disclosed methods involve administering a pharmaceutically effective amount of a compound described herein.

Neuropathic pain and inflammation

[00249] MAGL inhibitors are effective in several rodent pain models, including neuropathic pain models. MAGL inhibitors also reduce disease and inflammation in many preclinical models. In an experimental model of autoimmune encephalomyelitis in mice with multiple sclerosis, MAGL inhibition reduced disease severity, prevented demyelination, and reduced inflammation. In some embodiments, a method for treating pain in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In another embodiment, a method for treating neuropathic pain is provided. pain in a patient in need, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. According to another embodiment, a method for treating inflammatory pain in a patient in need thereof is provided, comprising administering to a patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 herein.

Acute pain, inflammatory pain, cancer pain, and pain caused by peripheral neuropathy

[00250] MAGL inhibitors have been shown to be effective in several rodent models of pain, including models of acute pain, inflammatory pain, cancer pain, and pain caused by chemotherapy-induced peripheral neuropathy.

[00251] In some embodiments, disclosed herein is a method for treating acute pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, disclosed herein is a method for treating inflammatory pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, in disclosed herein is a method of treating cancer pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, a method is disclosed herein. treating pain caused by peripheral neuropathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

central pain

[00252] Central pain is neuropathic pain caused by a lesion or dysfunction of the central nervous system, such as after stroke, multiple sclerosis, optic neuromyelitis, idiopathic inflammatory transverse myelitis, spinal cord injury, brachioradiation pain syndrome, and central craniofacial syndrome . Exocannabinoids have shown activity in central pain associated with multiple sclerosis. For example, a three-way, 4-week, randomized, double-blind, placebo-controlled, parallel-group study with MS and central pain using an oromucosal spray, THC/CBD containing the CB1 agonist delta-9-tetrahydrocannabinol and cannabidiol (another cannabis-derived alcohol), found that the active agent was superior to placebo in reducing mean pain intensity (NRS-11) and sleep disturbance. The same THC/CBD drug was studied in a larger cohort of MS patients with central neuropathic pain using a two-stage design; in the second phase of this study, time to treatment failure (primary endpoint) statistically favored THC/CBD, as did improvements in NRS-11 pain and sleep quality. Several other independent studies of exocannabinoids for central pain have shown activity.

[00253] In some embodiments, the MAGL inhibitors described herein are effective in treating central pain. In some embodiments, disclosed herein is a method for treating central pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, disclosed herein is a method of treating pain following a stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, herein disclosed is a method of treating pain associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, herein disclosed is a method of treating neuromyelitis of the optic nerve in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, a method is disclosed herein. treatment of idiopathic inflammatory transverse myelitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, a method for treating pain is disclosed herein. associated with spinal cord injury in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, a method is disclosed herein. treatment of upper limb pain syndrome in a patient in need, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, disclosed herein is a method of treating central craniofacial pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

fibromyalgia

[00254] Fibromyalgia (FM) is a common chronic idiopathic condition characterized by diffuse body pain and the presence of pressure-induced allodynia. Several third party studies of exocannabinoids in FM have shown activity. For example, pain measurements (eg, NRS-11, Pain VAS) and the Fibromyalgia Effect Questionnaire (FIQ), which measures limitations in several daily activities affected by FM, have demonstrated drug activity in FM clinical trials. In an 8-week study with 40 patients, compared with placebo, the exocannabinoid improved pain measured per 10 cm VAS and improved FIQ anxiety area and overall FIQ score.

[00255] In some embodiments, the MAGL inhibitors described herein are effective in treating FM. In some embodiments, disclosed herein is a method of treating fibromyalgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Migraine

[00256] Migraine is a common episodic headache and facial pain disorder. Migraine attacks can be treated with NSAIDs, acetaminophen, various triptans (such as sumatriptan), and antiemetics, but for some migraine sufferers, pain does not respond to existing treatment options. Third-party evidence suggests that endocannabinoid pathways may play a role in migraine. In patients with chronic migraine and probable pain-induced headache, CSF samples showed higher levels of endocannabinoid palmitoylethanolamide and lower levels of anandamide compared to healthy controls. In addition, patients with a primary diagnosis of migraine found a reduction in the frequency of migraines after initiation of marijuana therapy.

[00257] In some embodiments, the MAGL inhibitors described herein are effective in treating migraine. In some embodiments, disclosed herein is a method of treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Vaso-occlusive painful crisis in sickle cell disease

[00258] Vasocclusive painful crisis is believed to be the result of altered erythrocyte (RBC) rheology with microcapillary occlusion and ischemic pain in patients with sickle cell anemia (SCD), an inherited condition caused by mutations in the beta hemoglobin gene in adults. Third-party data demonstrate pain-related behavior and neurochemical changes in mice expressing sickle-shaped human hemoglobin that are markedly improved when mice are treated with a cannabinoid receptor agonist.

[00259] In some embodiments, the MAGL inhibitors described herein are effective in treating vaso-occlusive pain crisis in SCD. In some embodiments, disclosed herein is a method of treating a vaso-occlusive sickle cell pain crisis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Symptomatic treatment of multiple sclerosis

[00260] Almost all patients with multiple sclerosis (MS) of all subtypes are characterized by one or more symptoms of spasticity, pain, sleep disturbance, bladder dysfunction, and fatigue. Disease-modifying therapy does not improve symptoms. Spasticity affects over 80% of MS patients; 34% are characterized by moderate, severe or complete spasticity. Severe spasticity is associated with cost and level of care and is independently associated with quality of life in MS. Third-party data support the use of exocannabinoids for the treatment of spasticity and pain in MS.

[00261] In some embodiments, the MAGL inhibitors described herein are effective in treating MS-associated spasticity, pain, sleep disturbance, or bladder dysfunction. In some embodiments, disclosed herein is a method of treating MS-associated spasticity, pain, sleep disturbance, or bladder dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 3, as described herein. 4, Connection 5 or Connection 6.

functional chest pain

[00262] Functional chest pain, sometimes referred to as non-GERD, non-cardiac chest pain, is a functional gastrointestinal disorder in which upper GI discomfort is felt in the chest. In addition to consuming medical resources to rule out other treatable conditions, functional chest pain is stressful for patients. It can be treated with tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors, but not all patients respond. In patients with functional chest pain, a syndrome attributed to GI hypersensitivity, third-party data showed that an exocannabinoid improved chest pain symptoms and increased the sensory threshold for esophageal balloon distension in a placebo-controlled 4-week study.

[00263] In some embodiments, the MAGL inhibitors described herein are effective in treating functional chest pain. In some embodiments, disclosed herein is a method of treating functional chest pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Rheumatoid arthritis and osteoarthritis

[00264] Third party data have found that CB1 and CB2 receptors are present in the synovium of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The endocannabinoids anandamide and 2-AG have been identified in the synovial fluid of patients with RA and OA, but not in normal volunteers. In addition, a small study of RA patients with nabiximols (THC/CBD or oromucosal spray) showed improvement in pain on movement and at rest, improvement in sleep, and improvement in standard RA disease activity score in 28 joints.

[00265] In some embodiments, the MAGL inhibitors described herein are effective in treating pain and inflammation in RA and OA. In some embodiments, disclosed herein is a method of treating rheumatoid arthritis or osteoarthritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In embodiments, disclosed herein is a method of treating rheumatoid arthritis pain or osteoarthritis pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Alzheimer's disease

[00266] Alzheimer's disease (AD) is the most common cause of dementia, affecting ~5.3 million people in the US. Anxiety and aggression are risk factors for the institutionalization of patients with dementia. Third-party data showed that the exocannabinoid improved anorexia and decreased arousal in AD patients and reduced nocturnal arousal. These data suggest that a MAGL inhibitor would be effective in AD patients suffering from dementia and agitation.

[00267] In some embodiments, the MAGL inhibitors described herein are effective in the treatment of Alzheimer's disease. In some embodiments, disclosed herein is a method of treating agitation or aggression associated with Alzheimer's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, as described herein, or Connections 6.

functional dyspepsia

[00268] Functional dyspepsia (FD) is one of the most common gastrointestinal disorders encountered in clinical practice. Several pathophysiological mechanisms have been proposed to underlie the onset of symptoms in FD, including visceral hypersensitivity due to central or peripheral sensitization, mild inflammatory conditions, altered gastrointestinal hormone secretion, genetic predisposition, and abnormal gastric emptying or gastric accommodation. Third-party data support the hypothesis that endocannabinoid system function is altered in FD patients.

[00269] In some embodiments, the MAGL inhibitors described herein are effective in treating functional dyspepsia. In some embodiments, disclosed herein is a method of treating functional dyspepsia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

inflammatory bowel disease

[00270] Inflammatory bowel disease (IBD) includes chronic inflammation of all or part of the digestive tract. IBD mainly includes ulcerative colitis and Crohn's disease. Both conditions typically include severe diarrhea, pain, fatigue, and weight loss. IBD can be debilitating and sometimes leads to life-threatening complications. Third-party data showed that MAGL inhibition was protective in a mouse model of IBD.

[00271] In some embodiments, the MAGL inhibitors described herein are effective in treating inflammatory bowel disease. In some embodiments, disclosed herein is a method of treating inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Bruised skeletal mouse

[00272] A skeletal muscle contusion indicates a direct, blunt, compressive force on a muscle. Contusions are one of the most common sports injuries. The severity of bruises varies from simple skin bruises to muscle and bone bruises to internal bruises. Outside data, MAGL inhibition has shown anti-inflammatory effects in a rat skeletal muscle contusion model.

[00273] In some embodiments, the MAGL inhibitors described herein are effective in treating skeletal muscle contusion. In some embodiments, disclosed herein is a method of treating skeletal muscle contusion in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

[00274] According to another embodiment, a method of treating a disease or disorder in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein, wherein the disease or the disorder is selected from the group consisting of epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optic nerve (NMO), Tourette's syndrome, Alzheimer's disease and abdominal pain associated with irritable bowel syndrome. In another embodiment, a method for treating epilepsy/seizure disorder in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. a method of treating multiple sclerosis in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In another embodiment, a method for treating neuromyelitis optic nerve (NMO) is provided. ) in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. in this patient, a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. herein Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6. According to another embodiment, a method for treating abdominal pain associated with irritable bowel syndrome in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

[00275] According to another embodiment, a method is provided for the treatment of acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, fibromyalgia, migraine, sickle cell vaso-occlusive painful crises, functional chest pain, rheumatoid arthritis, osteoarthritis, functional dyspepsia or spasticity or multiple sclerosis-associated pain, sleep disturbance, or bladder dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Tourette syndrome and chronic motor tic disorders

[00276] Tourette syndrome (TS) is a neurodevelopmental condition characterized by chronic motor and vocal tics with onset before age 18. Tics are fast, repetitive, aimless movements or vocalizations. Persistent motor or vocal tic disorder are two recognized syndromes characterized by isolated motor or vocal tics, respectively. In other aspects, the conditions of the permanent motor or voice disorder are similar to those of TS.

[00277] TS is generally considered a disease of childhood with onset at about 5 years of age. Tics tend to increase until mid-teens and then decrease in late adolescence and early adulthood. An objective re-examination of the persistence of tics into adulthood showed that 90% of adults diagnosed with children with TS still had tics.

[00278] TS is highly heritable with variable expression. Men are more commonly affected than women, with a male to female ratio of three to four to one. TS often occurs in association with attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The impact of TS is significant: reduced quality of life is often associated with unemployment, underachievement, increased tic severity, and the presence of comorbidities such as OCD, ADHD, anxiety, and depression.

[00279] Third-party quantitative imaging studies in TS have shown caudate volume reduction and sensorimotor cortical thinning in children and adults. These observations suggest that motor cortical areas and dysfunction of the basal ganglia are causally related to TS. This hypothesis is supported by the involvement of the basal ganglia in the selection or suppression of motor behaviors, including routine behaviors or habits. The caudate is strongly innervated by dopaminergic projections from the substantia nigra, which may be related to the clinical utility of dopaminergic antagonists in reducing tic severity in TS. The involvement of the endocannabinoid (eCB) system in suppressing basal ganglia dopaminergic transmission offers a rationale for manipulating this receptor system for therapeutic purposes in TS. Several third-party studies have reported improvements in tic symptoms with cannabis or THC.

[00280] In some embodiments, the MAGL inhibitors described herein are effective in the treatment of Tourette's syndrome, chronic motor tic disorder, and chronic vocal tic disorder. In some embodiments, disclosed herein is a method of treating Tourette's syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin- 1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating Tourette's syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, the implementation disclosed herein is a method for treating chronic motor tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1- yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating chronic motor tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In embodiments, disclosed herein is a method for treating chronic vocal tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidine- 1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating a chronic vocal tic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Attention Deficit Hyperactivity Disorder (ADHD)

[00281] ADHD is a chronic mental health condition with inattention, hyperactivity, and impulsive behavior that occur in a variety of settings and affect function in academic, social, or professional activities. Symptoms begin in childhood and may persist into adulthood. An estimated 8 to 11% of US school-age children have ADHD, and 4% of US adults have adult ADHD. Diagnosis can be made according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, version 5. Target symptoms can be monitored using rating scales specific to ADHD.

[00282] Adults with ADHD often report improvement in symptoms with cannabis use, and some report a preference for cannabis over their ADHD stimulant drugs. A third-party study of ADHD patients resistant to multiple pharmacological treatments describes an improvement in ADHD symptoms with cannabis smoking, especially improvements in concentration, impulsivity, and sleep. Another third-party study noted improvements in attention associated with driving after oral THC. In addition, patients with Tourette syndrome are often characterized by the presence of ADHD as a comorbidity.

[00283] In some embodiments, the MAGL inhibitors described herein are effective in treating attention deficit hyperactivity disorder. In some embodiments, disclosed herein is a method for treating attention deficit hyperactivity disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-( 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method for treating attention deficit hyperactivity disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Obsessive Compulsive Disorder (OCD)

[00284] Obsessive-compulsive disorder (OCD) is a chronic mental health condition characterized by repetitive intrusive thoughts, images, or urges (obsessions) that tend to cause anxiety or distress, and repetitive mental or behavioral activities (compulsive disorders) that the person feels compelled to carry out. OCD typically begins in adolescence, persists throughout a person's life, and results in significant functional impairment due to the severe and chronic nature of the disease. The lifetime risk of getting sick is estimated at 2% in the US. Diagnosis can be made according to criteria in the Diagnostic and Statistical Manual of Mental Disorders, version 5. Target symptoms can be monitored using OCD-specific rating scales. Ample evidence indicates that cortico-striato-thalamo-cortical circuits are associated with the pathophysiology of OCD. Patients with OCD often have diagnoses of an anxiety disorder. For the treatment of OCD, treatment aimed at treating anxiety is often considered.

[00285] In a rodent model of anxiety disorder repetitive behavior, both THC and MAGL inhibitor were identified to reduce repetitive behavior, but MAGL inhibitor alone did not show a reduction in motor behavior. The effects were mediated by the CB1 receptor. In addition, third-party case reports of adults with refractive-obsessive-compulsive disorder describe the benefit of oral THC. A controlled study of oral THC in adults with Tourette syndrome, often accompanied by concomitant OCD, found improvements in obsessive-compulsive behavior.

[00286] In some embodiments, the MAGL inhibitors described herein are effective in treating obsessive-compulsive disorder. In some embodiments, disclosed herein is a method of treating obsessive-compulsive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-( pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating obsessive-compulsive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Trichotillomania

[00287] Trichotillomania is characterized by repetitive hair pulling resulting in hair loss and functional impairment. This hair-pulling disorder is quite common and is associated with social disorders. An overlap with Tourette syndrome has been suggested, as both diagnostic groups are characterized by motor impulses that are difficult to suppress. In a third-party study, oral THC reduced the symptoms of trichotillomania in an open-label clinical study, indicating involvement of the endocannabinoid pathway.

[00288] In some embodiments, the MAGL inhibitors described herein are effective in treating trichotillomania. In some embodiments, disclosed herein is a method for treating trichotillomania in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1 -yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating trichotillomania in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Trigeminal neuralgia and glossopharyngeal neuralgia

[00289] A rare form of chronic neuropathic pain is trigeminal neuralgia or glossopharyngeal neuralgia. Trigeminal neuralgia (TN) or tic douloureux is characterized by recurrent, brief episodes of unilateral pain in the distribution of one or more divisions of the fifth cranial (trigeminal) nerve or the ninth or tenth cranial (glossopharyngeal) nerve. Many cases are caused by vascular compression of the nerve, resulting in symptoms. Other causes may be infection (such as shingles), a post-traumatic condition, or may be caused by a tumor. Demyelination lesions, such as those found in multiple sclerosis, can also cause trigeminal neuralgia by establishing the generation of ectopic nerve impulses in the brainstem.

[00290] TG is considered one of the most painful human ailments. Third-party evidence suggests that refractory trigeminal neuralgia is sensitive to cannabis-based medicine.

[00291] In some embodiments, the MAGL inhibitors described herein are effective in treating trigeminal neuralgia or glossopharyngeal neuralgia. In some embodiments, disclosed herein is a method of treating trigeminal neuralgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidine -1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating trigeminal neuralgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, disclosed herein is a method for treating glossopharyngeal neuralgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl )-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating glossophyringeal neuralgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Traumatic brain injury (TBI)

[00292] Traumatic brain injury (TBI) is the leading cause of death in North America in people under 45 years of age. Survivors may live with significant disabilities, resulting in severe socioeconomic burdens.

[00293] The pathophysiology of brain injury associated with TBI is divided into two separate concepts of primary brain injury and secondary brain injury. Acute brain injury after TBI occurs as a result of primary injury, which is the result of an external mechanical force leading to contusion, rupture, and coagulopathy.

[00294] Secondary brain injury immediately follows primary injury, which is mediated by a complex cascade of molecular, cellular, and immune responses leading to neuroinflammation, excitotoxicity, oxidative stress, impaired calcium homeostasis, mitochondrial dysfunction, neuronal injury, and neuronal death. Repeated attacks of mild TBI occur in military personnel and at sporting events and can lead to chronic traumatic encephalopathy or "dementia". Chronic traumatic encephalopathy (CTE) is clinically characterized by memory impairment, emotional lability, personality changes and may eventually progress to dementia. Pathologically, these changes are characterized by atrophy, deposition of abnormal proteins consisting of beta-amyloid, phosphorylated tau protein, and the transactivating response of DNA binding protein 43 (TDP-43). Similar pathological changes can be seen years after a single episode of TBI. Interrupting the process of secondary brain injury has been at the center of neuroprotective treatment to prevent the consequences of TBI.

[00295] In responses to secondary injury, the inflammatory response associated with other processes likely plays a key role in the onset of neuropathology after TBI. Inflammation has been recognized as one of the important features of TBI. Pro-inflammatory markers such as cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor alpha (TNFα), and chemokines released from activated astroglial cells and infiltrated leukocytes in the brain and cerebrospinal fluid are significantly elevated after TBI and may correlate with the result. Histological changes found in the chronic condition demonstrate neurofibrillary tangles and tau aggregates. Chronic traumatic encephalopathy is now considered a "tauopathy" with histological similarities to those seen in other degenerative diseases with tau aggregates. Appropriate and timely intervention during this critical period after primary injury after TBI can significantly reduce secondary brain damage and ultimately prevent STE from occurring.

[00296] Third-party data showed that MAGL inhibition reduced widespread neuroinflammation in several animal models of AD. The effect of the MAGL inhibitor was tested in a working mouse model of repeated mild blunt head injury. This model showed deterioration in the animals' neurological function, including tests of special learning and memory. In other third-party data, the MAGL inhibitor also improved cognitive function and reduced neuroinflammation, neurodegeneration, accumulation of phospho-tau protein and TDP-43 aggregates in various areas of the brain.

[00297] In some embodiments, the MAGL inhibitors described herein are effective in treating traumatic brain injury. In some embodiments, disclosed herein is a method for treating traumatic brain injury in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-( pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating a traumatic brain injury in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Alzheimer's disease

[00298] Alzheimer's disease (AD) is often classified as a secondary tauopathy along with chronic traumatic encephalopathy caused by traumatic brain injury. The pathological hallmark of neurofibrillary tangles in AD consists of a hyperphosphorylated tau protein that inhibits microtubule function. Mutant tau protein extracts in mice lead to the spread of tau pathology to other areas of the brain. There are several approaches to control tau hyperphosphorylation in AD clinical trials. These include passive and active immunization against phospho-tau, tau-kinase inhibitors, inhibition of O-N-acetylglucosamination and small molecules that can disaggregate tau filaments and tangles.

[00299] Third-party data showed MAGL inhibition to reduce microglial activation, neurodegeneration, and behavioral abnormalities in these mice. Similar benefits of MAGL inhibition were observed in a separate genetic mouse model of AD (PS1/APP+).

[00300] In some embodiments, the MAGL inhibitors described herein are effective in treating Alzheimer's associated cognitive decline. In some embodiments, disclosed herein is a method of treating Alzheimer's associated cognitive decline in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-( 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating Alzheimer's disease-related cognitive decline in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. .

Primary tauopathies

[00301] Primary taupathies include progressive supranuclear palsy (PSP), corticobasal degeneration, and frontotemporal dementia (FTD). Secondary tauopathies include chronic traumatic encephalopathy and Alzheimer's disease.

[00302] Frontotemporal dementia (FTD) is a clinically and neuropathologically diverse disorder characterized by disturbances in personality behavior and language. In patients younger than 65 years of age, the same common cause of dementia as Alzheimer's disease. Degeneration of the frontal and temporal lobes occurs and correlates relatively well with the clinical syndrome but not with the pathological subtype. FTD is a generic term that includes a clinical spectrum that includes a behavioral variant of FTD (bvFTD), affecting 50% of cases, and three forms of primary progressive aphasia, differing in type of language impairment.

[00303] Frontotemporal lobar degeneration (FTLD) is a pathological diagnosis associated with a clinical spectrum. Neuronal atrophy and loss, myelin loss, and gliosis are seen in the frontal and temporal lobes. The hallmark pathological feature in FTLD is the presence of abnormal intraneuronal and glial protein inclusions consisting of hyperphosphorylated tau protein aggregates or a DNA-binding protein transactivation response, TDP-43, or FUS proteinopathy.

[00304] Progressive supranuclear palsy (PSP) is a rare neurodegenerative motor syndrome characterized by some features of parkinsonism (bradykinesia, rigidity, and postural instability). PSP consists of motor and cognitive changes. Motor aspects include dysphagia, rigidity, axial dystonia, characteristic gait, and falls. One of the unique motor features is supranuclear ophthalmoplegia (weakness in vertical conjugated eye movements), which manifests itself as a characteristic facial appearance with constant surprise. Cognitive changes similar to those of bvFTD occur in PSP. Pathological features are neuronal loss and gliosis in the basal ganglia, cerebellum, brainstem, and, to a lesser extent, the cerebral cortex. In third-party studies, patients with PSP show marked atrophy of the midbrain. Numerous neurochemical abnormalities have been described, including a decrease in acetylcholine neurons and a decrease in dopaminergic neurons protruding into the striatum. GABAergic neurons decrease. Ultrastructural changes show aggregation of phosphorylated tau protein in neurons (spherical neurofibrillary tangles, which are single straight filaments), oligodendrocytes (helical bodies), and astrocytes (fascicular astrocytes). These changes appear to damage neurons expressing multiple neurotransmitters. Tau protein is found at lower levels in CSF. The progression of the disease is rapid: patients become dependent after 3–4 years, and death occurs 6–12 years after onset.

[00305] In some embodiments, the MAGL inhibitors described herein are effective in treating primary tauopathies. In some embodiments, the MAGL inhibitors described herein are effective in the treatment of progressive supranuclear palsy, corticobasal degeneration, or frontotemporal dementia. In some embodiments, disclosed herein is a method of treating progressive supranuclear palsy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidine -1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating progressive supranuclear palsy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, disclosed herein is a method for treating corticobasal degeneration in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl )-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating corticobasal degeneration in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, disclosed herein is a method for treating frontotemporal dementia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1- yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating frontotemporal dementia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Stroke

[00306] A stroke causes neuronal death when the blood supply to part of the brain is blocked. Ischemic stroke is more common than hemorrhagic stroke, and atherosclerosis is the most common cause of localized disease in the arteries that supply the brain. Like traumatic brain injury, the pathophysiology of stroke is conceptually divided into two areas: a primary area strongly dependent on interrupted blood supply, and a secondary area of the brain at risk due to developmental factors driven by dying neurons, activated glial and astrocytic cells, and inflammatory cell influx. .

[00307] Third-party data showed that MAGL inhibitor pre-exposure protected hypoxic ischemic brain injury in neonatal rats. Another model of neuroprotection is the study of the effect of toxic damage to retinal ganglion cells in the eye. Retinal ganglion cells are neurons that are very sensitive to ischemia. MAGL inhibitors increase levels of the endocannabinoid 2-AG, which acts as a CB1 and CB2 receptor agonist. CB1 receptor agonists prevent the death of retinal ganglion cells. The physiological role of cannabinoids is to serve as a feedback mechanism for excess neurotransmission, limiting excitatory neurotoxicity in the brain.

[00308] In some embodiments, the MAGL inhibitors described herein are effective in improving functional outcome after stroke. In some embodiments, disclosed herein is a method of improving functional outcome after a stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-( pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of improving functional outcome after a stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

amyotrophic lateral sclerosis

[00309] Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a rapidly progressive neurodegenerative disease characterized by selective loss of motor neurons in the brain and spinal cord, leading to complete paralysis and death, usually within 3- 5 years from the date of diagnosis. While most cases of ALS are sporadic, an increasing number of familial forms of the disease are being detected (~10% of the total number of cases), including those caused by mutations in the genes encoding superoxide dismutase-1 (SOD-1), TAR-DNA- binding protein-43 (TDP-43) or FUS protein (fused in sarcoma), as well as the expansion of a hexanucleotide repeat in the non-coding region of the C90RF72 gene. There is still a lack of effective treatment of symptoms and/or disease progression. In a mouse model (G93A) of SOD-1 ALS, treatment with exocannabinoids Δ9-THC, cannabinol, WIN55,212-2, or AM1241, as well as an increase in endogenous cannabinoids by genetic ablation of the endocannabinoid degrading enzyme FAAH, is characterized by a significant delay in disease progression. Third-party studies of ALS patients who self-medicate with cannabis have shown improvement in symptoms associated with ALS, including pain, cramps, spasticity, and excessive salivation. The randomized clinical trial also showed the potential for disease modification in ALS using endpoints of death or time to tracheostomy.

[00310] In some embodiments, the MAGL inhibitors described herein are effective in treating amyotrophic lateral sclerosis (ALS) or ALS-related symptoms. In some embodiments, disclosed herein is a method for treating amyotrophic lateral sclerosis (ALS) or ALS-related symptoms in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl -4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method for treating amyotrophic lateral sclerosis (ALS) or ALS-related symptoms in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 3, Compound 4, Compound 5 or Connections 6.

Huntington's disease

[00311] Huntington's disease (HD) is a genetic fatal progressive neurodegenerative disorder characterized by cognitive, psychiatric and motor impairments. HD is caused by a polymorphic extension of the CAG trinucleotide repeats in the huntingtin gene and is inherited in an autosomal dominant fashion. Approximately 30,000 people in the United States have the condition and another 200,000 are at risk of inheriting it. Medications to relieve symptoms in HD are currently available but limited, and no treatment can prevent disease-related worsening. Third-party data have shown that exogenous cannabinoids such as cannabidiol and pharmacological CB1/CB2 agonists confer neuroprotection in various animal models of HD (e.g., R6/2 mice, quinolinate lesion mice, 3-nitropropionate or malonate lesion rats).

[00312] In some embodiments, the MAGL inhibitors described herein are effective in the treatment of Huntington's disease. In some embodiments, disclosed herein is a method of treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin- 1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Glaucoma

[00313] Glaucoma is a group of optic neuropathies characterized by selective loss of retinal ganglion cells (RGCs) and progressive damage to the optic nerve leading to permanent visual field loss and blindness. Elevated intraocular pressure (IOP) is a major risk factor for optic nerve damage in glaucoma. All currently approved glaucoma treatments work by modulating IOP without directly preventing RGC loss. Third-party data have demonstrated the IOP-reducing effects of systemic and local cannabinoid receptor agonists in humans, non-human primates, and rodents. An increase in the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) after MAGL inhibition also showed a similar decrease in IOP in mice.

[00314] In some embodiments, the MAGL inhibitors described herein are effective in the treatment of glaucoma. In some embodiments, disclosed herein is a method of treating glaucoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1 -yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating glaucoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Atopic dermatitis

[00315] Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin disease associated with dysfunction of the body's immune system. AD affects up to 20% of children, but can spread into adulthood, affecting up to 3% of adults. In AD, the skin becomes very itchy. Excessive scratching leads to redness, swelling, cracking, weeping clear fluid and crusting of the skin. A functional endocannabinoid signaling system is present in the skin and mediates numerous aspects of skin biology. Third-party studies show that CB1 and CB2 receptors are activated in atopic dermatitis and that the endocannabinoid system has a protective effect in skin allergy models. In addition, it has been demonstrated that MAGL inhibitors can reduce MAGL activity and increase 2-AG levels in rodent skin.

[00316] In some embodiments, the MAGL inhibitors described herein are effective in treating atopic dermatitis. In some embodiments, disclosed herein is a method of treating atopic dermatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin- 1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating atopic dermatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Itching

[00317] Itching, or scabies, is an unpleasant sensation that causes a desire to itch. Itching is a common and unpleasant symptom of many skin conditions (eg, atopic dermatitis), but is also associated with many systemic (eg, liver and kidney disease), neurogenic (eg, herpetic neuralgia, surgery, stroke), and pharmacological (opioid-induced pruritus) reasons. Despite multiple causes, itching is mediated by a common sensory pathway in the nervous system that is thought to be regulated by the endocannabinoid system. In third-party human studies, topical application of a potent mixed CB1 and CB2 agonist reduced histamine-induced pruritus. In addition, CB1 antagonists have been shown to promote scratching in rodents, while agonists have been shown to reduce itching in rodent models.

[00318] In some embodiments, the MAGL inhibitors described herein are effective in treating pruritus. In some embodiments, disclosed herein is a method for treating pruritus in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1 -yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating pruritus in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Parkinson's disease

[00319] Parkinson's disease (PD) is a progressive neurodegenerative disease that affects the basal ganglia. The characteristic motor symptoms of PD include tremor, rigidity, bradykinesia, and muscle rigidity. The motor symptoms of PD are predominantly due to changes in the substantia nigra, including the death of dopaminergic neurons. Current treatment for PD, such as dopamine replacement therapy, serves to relieve symptoms, but no disease-modifying therapy is available. Exogenous cannabinoids have been found to have beneficial effects on PD symptoms. For example, in a third-party, open-label, observational study, cannabis smoking was found to result in significant improvement in tremor, rigidity, and bradykinesia in patients with PD-related severe pain and tremor that were not adequately controlled by current anti-PD drugs. A significant improvement in pain and sleep has also been observed after cannabis use. Preclinically, exogenous cannabinoids and MAGL inhibitors induce disease-modifying protective effects in parkinsonian rodent models.

[00320] In some embodiments, the MAGL inhibitors described herein are effective in the treatment of Parkinson's disease. In some embodiments, disclosed herein is a method of treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin- 1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Autism

[00321] Autism Spectrum Disorder (ASD) is a group of common neurodevelopmental disorders characterized by repetitive behaviors and impairments in social interaction and communication. Autism affects approximately 22 million people worldwide and approximately 1.5% of children in the United States. Symptoms vary widely from person to person, but begin in early childhood and affect daily activities. Autism has a strong genetic link and numerous genes are associated with this disorder, including more than 30 mutations in the neuroligin 1-4 genes, which are postsynaptic cell adhesion molecules that control synaptic properties. In third-party data on mice carrying autism-associated mutations in neuroligin-3, tonic transmission of endocannabinoids is significantly reduced, resulting in excessive inhibitory synaptic activity.

[00322] In some embodiments, the MAGL inhibitors described herein are effective in treating autism. In some embodiments, disclosed herein is a method of treating autism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1 -yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating autism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

Opioid-sparing effect on pain

[00323] The clinical use of opioid analgesics for the treatment of pain is associated with serious clinical disadvantages, including constipation, respiratory depression, pruritus, resistance, abuse, and dependence. The abuse of prescription opioids is considered a public health crisis. It is estimated that approximately 2.1 million people in the United States suffer from substance use disorders associated with prescription pain medications. One strategy to reduce the negative side effects of opioids is to reduce the dose of the opioid needed for adequate pain control in combination with another antinociceptive.

[00324] MAGL inhibitors are effective as monotherapy in multiple pain models, including acute, neuropathic, inflammatory, and oncological pain models. MAGL inhibition has also been shown to induce opioid-sparing effects in preclinical pain models. In a chronic stenosing injury (CCI) mouse model of neuropathic pain, combined treatment with a MAGL inhibitor and opioid morphine resulted in a synergistic improvement in efficacy compared to treatment with either compound alone. The combination of MAGL inhibition and morphine did not result in an opioid-like decrease in gastric motility, did not cause a cannabimimetic effect in a drug discrimination assay, and did not undergo resistance after repeated dosing.

[00325] In a formalin model of acute pain in rats, inhibition of MAGL synergistically enhanced the activity of opioid morphine. In this study, doses of MAGL inhibitor and morphine that were ineffective as monotherapy produced significant antinociceptive effects when combined, suggesting that MAGL inhibitors provide adequate pain relief in patients with a substantially reduced opioid drug load. Since the side effects of opioid drugs are dose-dependent, in some embodiments, this opioid-sparing effect reduces the acute side effects associated with opioid analgesics, such as constipation, dizziness, constipation, sedation, and dry mouth, and reduces the potential for adverse effects of long-term use. opioids, including addiction, withdrawal, and overdose death.

[00326] In some embodiments, the MAGL inhibitors described herein synergistically enhance the activity of an opioid analgesic. In some embodiments, the MAGL inhibitors described herein reduce the acute side effects associated with an opioid analgesic. In some embodiments, disclosed herein is a method for synergistically enhancing the activity of an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2 -(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of synergistically enhancing the activity of an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein. In some embodiments, disclosed herein is a method for reducing acute side effects associated with an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl- 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method for reducing acute side effects associated with an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 as described herein. or Compound 6.

Dystonia

[00327] Dystonias are a heterogeneous group of movement disorders conceptually re-characterized in the late 1980s by presumed involvement of the basal ganglia, and clinically characterized by sustained or intermittent muscle contractions causing abnormal, repetitive movements, postures, or both. Dystonic movements are typically characterized by repetition, twisting, and may be trembling. Dystonia is often initiated or exacerbated by voluntary action and is associated with the activation of excess inflow to the muscles.

[00328] Dystonias can be classified based on clinical characteristics (age at onset, body location, temporal structure, coexistence of other movement disorders and other neurological manifestations) and etiological characteristics (other nervous system pathology and mode of inheritance). Primary dystonias occur in children, are often systemic and may be accompanied by other clinical features such as spasticity or encephalopathy, and may have a genetic basis. Primary dystonias in adults tend to be isolated, activity-related, and more common than in children, and are idiopathic and non-progressive. Examples of primary isolated dystonia are blepharospasm, cervical dystonia (torticollis), and graphospasm. There is an unmet need in dystonia for oral drugs that improve function.

[00329] In some embodiments, the MAGL inhibitors described herein are effective in treating dystonia. In some embodiments, disclosed herein is a method of treating dystonia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1 -yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of treating dystonia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

[00330] According to another embodiment, a method for treating Down's syndrome in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin- 1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. According to another embodiment, a method of treating Down syndrome in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

[00331] According to another embodiment, there is provided a method for reducing eye intraocular pressure (IOP) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-( 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for reducing intraocular ocular pressure (IOP) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 5, Compound 5, or Compound 6 described herein. In another embodiment, embodiment, a method for treating glaucoma in a patient in need thereof is presented, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin)-1-yl)-4 -(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. According to another embodiment, a method of treating glaucoma in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

[00332] According to another embodiment, a method is provided for treating complex regional pain syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-( pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, a method is provided for treating complex regional pain syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 described herein.

[00333] In certain embodiments, a disclosed compound used in one or more of the above methods is one of the generic, subgeneric, or specific compounds described herein, such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6.

[00334] The disclosed compounds are administered to patients (animals and humans) in need of such treatment at dosages that will provide optimal pharmaceutical efficacy. It is understood that the dose required for use in any particular application will vary from patient to patient, not only depending on the particular compound or composition chosen, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, the concomitant medication or special diet followed by the patient, and other factors, with the appropriate dosage ultimately left to the discretion of the attending physician. For the treatment of the above clinical conditions and diseases, the subject compound disclosed herein is administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage form formulations containing conventional non-toxic pharmaceutically acceptable carriers, auxiliaries and excipients. Parenteral administration includes subcutaneous injections, intravenous or intramuscular injections or infusion methods.

Combination Therapy

[00335] This document also contemplates combination therapies, for example, for the co-administration of a disclosed compound and an additional active agent, as part of a particular treatment regimen designed to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effect of the combination includes, without limitation, pharmacokinetic or pharmacodynamic interaction resulting from the combination of therapeutic agents. The introduction of these therapeutic agents in combination, as a rule, is carried out over a certain period of time (usually weeks, months or years, depending on the chosen combination). Combination therapy is intended for the sequential administration of several therapeutic agents, that is, when each therapeutic agent is administered at different times, as well as for the administration of these therapeutic agents or at least two therapeutic agents in an essentially simultaneous manner.

[00336] Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition (eg, tablets or capsules with a fixed ratio of each therapeutic agent) or in multiple separate formulations (eg, capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is by any suitable route, including, without limitation, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. Therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered intravenously.

[00337] Combination therapy also involves the administration of therapeutic agents, as described above, in additional combination with other biologically active ingredients and non-drug therapy. If the combination therapy further provides for non-drug treatment, the non-drug treatment is administered at any appropriate time as long as the beneficial effect of the combination of therapeutic agents and the non-drug treatment is achieved. For example, in appropriate cases, a beneficial effect is still achieved when non-drug treatment is temporarily discontinued from the administration of therapeutic agents, perhaps for several days or even weeks.

[00338] The components of the combination are administered to the patient simultaneously or sequentially. It is clear that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered either simultaneously or sequentially.

[00339] For example, for the intended treatment of pain, the disclosed compound is co-administered with another pain therapeutic agent such as an opioid, cannabinoid receptor modulator (CB1 or CB2), COX-2 inhibitor. acetaminophen and/or non-steroidal anti-inflammatory drug. Additional therapeutic agents, for example for the treatment of pain, which are co-administered include morphine, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol.

[00340] Other contemplated co-administration therapeutics include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprosin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam , lornoxicam, celecoxib, parecoxib, rimonabant and/or etoricoxib.

[00341] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a tricyclic antidepressant such as imipramine, amitriptyline or desipramine. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with a serotonin-norepinephrine reuptake inhibitor such as duloxetine, milnacipran, venlafaxine, or clomipramine. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with an alpha-2-delta inhibitor such as gabapentin or pregabalin. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with an antiepileptic drug such as topiramate, lamotrigine, levetiracetam, valproate, clonazepam, oxcarbazine, or carbamazepine.

[00342] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with an opioid such as morphine, codeine, oxycodone, oxymorphone, tramadol, tapentadol, methadone, or fentanyl .

[00343] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with acetaminophen. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is administered together with a non-steroidal anti-inflammatory drug such as ibuprofen, naproxen, celecoxib or diclofenac. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with a disease-modifying antirheumatic drug such as tofacitinib, leflunomide, or methotrexate.

[00344] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with exocannabinoids such as oral delta-9-THC and nabiximols (Sativex).

[00345] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a muscle relaxant such as baclofen and tizanidine. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with diazepam.

[00346] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a prokinetic agent such as metoclopramide, domperidone or itopride. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a 5-HT4 agonist such as tegaserod or mosapride. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with buspirone.

[00347] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with an antipsychotic such as pimozide, olanzapine, risperidone or quetiapine.

[00348] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a cholinesterase inhibitor such as donepezil, rivastigmine or galantamine. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with an NMDA antagonist such as memantine.

[00349] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with dopamine replacement therapy such as levodopa or carbidopa-levodopa. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a catechol-O-methyltransferase (COMT) inhibitor such as tolcapone or entacapone. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a dopamine agonist such as bromocriptine, pramipexole or ropinirole. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a monamine oxidase (MAO) B inhibitor such as selegiline or rasagiline. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with an anticholinergic agent such as benztropine, trihexyphenidyl or procyclidine.

[00350] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a dopamine antagonist such as haloperidol, pimozide or fluphenazine. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or pharmaceutically a suitable salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with a VMAT2 inhibitor that depletes dopamine, such as tetrabenazine. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable a salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with an alpha-adrenergic agonist such as clonidine or guanfacine.

[00351] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is co-administered with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, paroxetine, citalopram, or escitalopram.

[00352] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a stimulant such as methylphenidate, dextroamphetamine or lisdexamfetamine. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable a salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with an antidepressant such as bupropion or atomoxetine.

[00353] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a serotonin 1b/1d agonist. In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate, or a pharmaceutically acceptable a salt or solvate such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a triptan such as sumatriptan or zolmitriptan.

[00354] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with a glutamate inhibitor such as riluzole.

[00355] In some embodiments, 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof such as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 or Compound 6 is co-administered with an H1 antihistamine such as diphenhydramine, hydroxyzine, cetirizine, loratadine or desloratadine.

Kits/Products

[00356] Also described herein are kits and articles for use in the therapeutic methods described herein. Such kits include a carrier, package or container that is divided into parts to receive one or more containers, such as vials, test tubes, etc., each of which contains one or more separate elements to be used in the described in this document method. Suitable containers include, for example, bottles, vials, syringes and test tubes. According to one embodiment, the containers are made from various materials such as glass or plastic.

[00357] Presented in this document, the products contain packaging materials. Packaging materials for use in packaging pharmaceutical products include, for example, US Pat. No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, vials, tubes, pouches, containers, and any packaging material suitable for the formulation chosen and the intended mode of administration and exposure.

[00358] In some embodiments, the compounds or compositions described herein are presented in a package or dispenser that may contain one or more unit dosage forms containing the active ingredient. A compound or composition described herein is packaged alone or packaged with another compound or other ingredient or additive. In some embodiments, the package contains one or more containers filled with one or more pharmaceutical composition ingredients. In some embodiments, the package contains a metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser is accompanied by instructions for administration, such as instructions for administering compounds or compositions to treat a neoplasm. In some embodiments, the package or dispenser is accompanied by a notice associated with the container in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the human or veterinary drug form. In some embodiments, such notification is, for example, a US Food and Drug Administration-approved label for prescription drugs or an approved package insert. In some embodiments, compositions are prepared comprising a compound described herein formulated in a compatible pharmaceutical carrier, placed in an appropriate container, and labeled for treatment of the indicated condition.

[00359] For example, the container(s) contains Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, optionally in composition or in combination with another agent described herein. Such kits optionally include an identifying description or label, or instructions relating to its use in the methods described herein.

[00360] The kit typically includes labels with a list of contents and/or instructions for use, as well as inserts with instructions for use. An instruction set will usually also be included.

[00361] According to one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container when the letters, numbers, or other symbols forming the label are affixed, molded, or etched into the container itself; the label is associated with the container when it is inside a receptacle or holder that also holds the container, such as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a particular therapeutic application. The label also provides guidance on how to use the contents, such as in the methods described herein.

[00362] In certain embodiments, the pharmaceutical compositions are presented in a package or dispenser that contains one or more unit dosage forms containing a compound as provided herein. The package, for example, contains a metal or plastic foil, such as a blister pack. In one embodiment, the package or dispenser is accompanied by instructions for administration. In one embodiment, the package or dispenser is also accompanied by a notice associated with the container in the form prescribed by the government agency that regulates the manufacture, use, or sale of pharmaceutical drugs, which notice reflects the agency's approval of the human or veterinary drug form. Such notice, for example, is a US Food and Drug Administration-approved label for a prescription drug or an approved product. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for the treatment of said condition.

EXAMPLES

List of abbreviations

[00363] As used above and throughout the description of the present invention, the following abbreviations, unless otherwise indicated, should be understood as characterized by the following meanings:

ACN or MeCN - acetonitrile

Bn - benzyl

BOC or Boc - tert-butyl carbamate

t-Bu - tert-butyl

Su - cyclohexyl

DCE - dichloroethane (ClCH ₂ CH ₂ Cl)

DCM - dichloromethane (CH ₂ Cl ₂ )

DIPEA or DIEA - diisopropylethylamine

DMAP - 4-(N,N-dimethylamine)pyridine

DMF - dimethylformamide

DMA - N,N-dimethylacetamide

DMSO - dimethyl sulfoxide

Eq. - equivalent(s)

Et - ethyl

Et ₂ O - diethyl ether

EtOH - ethanol

EtOAc - ethyl acetate

HPLC - high performance liquid chromatography

Me - methyl

MeOH - methanol

MS - mass spectroscopy

NMR - nuclear magnetic resonance

RP-HPLC - Reversed Phase High Performance Liquid Chromatography

TFA - trifluoroacetic acid

THF - tetrahydrofuran

TLC - thin layer chromatography

I. Chemical synthesis

[00364] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven dried glassware have been used for moisture and/or oxygen sensitive synthetic transformations. The output was not optimized. Response times are approximate and have not been optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted.

Example 1 Preparation of Compound 1 (Form 1) [[free base]]

[00365] Compound 1 preparation is disclosed in WO 2013/103973, the contents of which are incorporated by reference in their entirety.

Example 2 Preparation of Compound 2 (Form 1) [[mono-HCl]]

[00366] To Compound 1 (20.0 g) in 9 v/w. tert-butyl methyl ether was added conc. HCl (1.06 eq.) at 35°C. The suspension was cooled to room temperature and the solid was collected by filtration and washed with t-butyl methyl ether. The solid was dried to give Compound 2 (19.3 g, 90%).

Example 3 Preparation of Compound 3 (Form 1) [[bis-HCl]]

[00367] Compound 3 was prepared in a manner similar to that described for Compound 2 in Example 2, except that 5 equivalents of HCl were used in the procedure.

II. Connection characteristics

Example 1: X-ray Powder Diffraction (XRPD)

[00368] XRPD analysis was performed on a PANalytical X'pert pro x-ray diffractometer, scanning samples between 3 and 35° 2θ. The material was gently pressed into a multiwell plate with Kapton or Mylar polymer film to support the sample. The multiwell plate was then loaded into a PANalytical diffractometer operating in transmit mode and analyzed using the following experimental conditions:

[00369]

Raw Data Source - XRD Dimension (*.XRDML)

Scan axis - Gonio

Start position [°2θ] - 3.0066

End position [°2θ] - 34.9866

Step size [°2θ] - 0.0130

Scan step time [s] - 18.8700

Scan Type - Continuous

PSD Mode - Scan

PSD length [°2θ] - 3.35

Offset [°2θ] - 0.0000

Type of divergence slot - Fixed

Spread gap size [°] - 1.0000

Measurement temperature [°C] - 25.00

Anode material - Cu

- 1,54060K-alpha1

- 1.54060

- 1,54443K-alpha2

- 1.54443

- 1,39225K-beta

- 1.39225

Ratio K-A2/K-A1 - 0.50000

Generator settings - 40 mA, 40 kV

Goniometer radius [mm] - 240.00

Focus distribution-slit flow, [mm] - 91.00

Incident beam monochromator - No

Spin - No

[00370] XRPD analysis (FIG. 1) of Compound 1 Form 1 showed that the free base is crystalline.

[00371] XRPD analysis (FIG. 9) of Compound 2 Form 1 showed that this monohydrochloride form is crystalline.

[00372] XRPD analysis (FIG. 28) of Compound 2 Form 2 showed that this monohydrochloride form is crystalline.

[00373] XRPD analysis (FIG. 17) of Form 1 of Compound 3 showed that this form of the bishydrochloride is crystalline.

[00374] XRPD analysis (FIG. 30) of Form 1 of Compound 4 showed that this form of besylate is crystalline.

[00375] XRPD analysis (FIG. 31) of Form 2 of Compound 4 showed that this form of besylate is crystalline.

[00376] XRPD analysis (FIG. 38) of Form 1 of Compound 5 showed that this form of mesylate is crystalline.

[00377] XRPD analysis (FIG. 42) of Compound 6 Form 1 showed that this form of fumarate is crystalline.

[00378] XRPD analysis (FIG. 46) of Compound 6 Form 2 showed that this form of fumarate is crystalline.

[00379] XRPD analysis (FIG. 49) of Compound 6 Form 3 showed that this form of fumarate is crystalline.

Example 2 Polarizing Optical Microscopy (PLM)

[00380] The presence of crystallinity (birefringence) was determined using an Olympus BX50 polarizing microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded using a 20x objective unless otherwise noted.

[00381] PLM analysis of Form 1 of Compound 1 showed birefringence of particles of lamellar morphology.

[00382] PLM analysis of Compound 2 Form 1 showed birefringence of particles of acicular/planar elongated morphology.

[00383] PLM analysis of Compound 2 Form 2 showed birefringence of platelet morphology particles.

[00384] PLM analysis of Compound 3 Form 1 showed birefringence of rod shaped particles.

[00385] PLM analysis of Form 1 of Compound 6 showed birefringence of particles of lamellar morphology.

[00386] PLM analysis of Compound 6 Form 2 showed birefringence of platelet morphology particles.

[00387] PLM analysis of Compound 6 Form 3 showed birefringence of platelet morphology particles.

Example 3 Thermogravimetric Analysis (TGA)

[00388] Approximately 5 mg of material was weighed into an open aluminum crucible and loaded into a simultaneous thermogravimetric/differential thermal analyzer (TG/DTA) and kept at room temperature. The sample was then heated at a rate of 10° C./min from 25° C. to 300° C. or from 20° C. to 300° C., during which the sample mass change was recorded along with any differential thermal events (DTA). Nitrogen was used as purge gas at a flow rate of 100 or 300 ml/min.

[00389] TGA (FIG. 2) Compound 1 Form 1 showed very little weight loss from 0.1% to about 140° C. before decomposition. One endothermicity was shown by DTA with an initial temperature of approximately 81.4°C.

[00390] TG/DTA (FIG. 10) Compound 2 Form 1 showed a slight weight loss of 0.3%, likely due to loss of residual solvent (water), followed by an 8.3% loss before degradation. By means of DTA, a broad endothermicity was shown with an onset at approximately 159.4°C. The onset was consistent with the DSC data obtained in Example 4.

[00391] The TGA (FIG. 18) of Compound 3 Form 1 showed a loss of 1.2% (probably residual solvent/water) followed by a loss of 8.2% associated with the first endothermic effect. By DTA, broad endothermicity is shown, with an onset at approximately 89.3°C, and a subsequent endothermic process, with an onset at approximately 171.9°C. 3.2% will be required for monohydrate and 6.0% for loss of HCl.

[00392] TG/DTA (FIG. 44) Form 1 Compound 6 showed strong endothermicity with onset at 128.1°C and peak at 133.4°C.

[00393] TG/DTA (FIG. 48) Compound 6 Form 2 showed a broad thermal event starting at approximately 75° C. corresponding to a weight loss of 8.1%.

[00394] TG/DTA (FIG. 51) Compound 6 Form 3 showed a broad thermal event starting at 106° C. corresponding to a weight loss of 6.5%. The thermal event is observed at a temperature of approximately 200°C, which corresponds to the sublimation of the solid, leading to a complete loss of mass.

Example 4 Differential Scanning Calorimetry (DSC)

[00395] Approximately 5 mg of material was weighed into an aluminum DSC crucible and sealed with a sealed aluminum lid. The sample container was then loaded into a Seiko DSC6200 (equipped with a cooler), cooled and kept at 25°C. Once a stable heat flux response was obtained, the sample and reference were heated to 160°C or 175°C or 200°C or 205°C or 215°C or 220°C at a scan rate of 10°C/min. , and the resulting heat flux response was monitored.

[00396] For Compound 1, the sample was analyzed for 1.5 cycles. Nitrogen was used as purge gas at a flow rate of 50 ml/min. DSC analysis (FIG. 3) of Compound 1 Form 1 showed a sharp endothermicity with an initial temperature of 80.3°C.

[00397] DSC analysis (FIG. 11) of Compound 2 Form 1 showed a sharp endothermicity with an initial temperature of 181.6°C followed by a peak at 192.6°C. This occurred at a higher temperature than DTA and could be related to different preparations: DSC analysis was performed in a closed cup with a pinhole (leaky), while TG/DTA was performed in an open cup environment.

[00398] The material from Compound 2 (Form 1) was also heated to 140° C. and allowed to cool. The material was analyzed by XRPD (FIG. 12) to determine any shape change that might correspond to a solid phase transition. The material, as shown, remained unchanged.

[00399] DSC analysis (FIG. 19) of Compound 3 Form 1 showed endothermicity with onset at 154.3°C. The data obtained show values of 168.23°C and 170.69°C. Higher events in the DSC analysis may reflect different preparations: the DSC analysis was performed in a pinhole closed cup (leaky), while the TGA was performed in an open cup.

[00400] DSC analysis (FIG. 45) of Compound 6 Form 1 showed endothermicity with onset at 126.4°C. DSC analysis was performed in a closed cup with a pinhole (leaky), while TGA was performed in an open cup.

[00401] DSC analysis (FIG. 52) of Compound 6 Form 3 showed endothermicity with onset at 106.9°C. DSC analysis was performed in a closed cup with a pinhole (leaky), while TGA was performed in an open cup.

Example 5 Gravimetric Vapor Sorption (GVS)

[00402] Approximately 10 mg of the sample was placed in a sorption balance mesh crucible and loaded into an IGASorp moisture sorption analyzer from Hiden Analytical. The sample was profiled with 40-90% relative humidity (RH) in 10% increments, maintaining the sample at each stage until a stable mass was reached (98% completion of the step). After completion of the sorption cycle, the sample was dried using the same procedure to 0% relative humidity and finally returned to the starting point of 40% relative humidity. The change in mass during the sorption/desorption cycles was plotted, making it possible to determine the hygroscopic nature of the sample.

[00403] GVS analysis (FIG. 4) of Compound 1 Form 1 showed that the free base is very non-hygroscopic with an absorbance of <0.07% wt at 90% relative humidity. Analysis by XRPD after GVS (FIG. 5) showed that the material remained unchanged, indicating a high resistance of this form to extreme humidity.

[00404] GVS analysis (FIG. 13) of Compound 2 Form 1 showed that the material is very non-hygroscopic with <0.1% absorbance at 90% relative humidity. Analysis by XRPD after GVS (FIG. 14) showed that the material remained unchanged, indicating a high resistance of this form to extreme humidity.

[00405] GVS analysis (FIG. 20) of Compound 3 Form 1 showed the material to be slightly hygroscopic with an absorption of 1.4% at 90% relative humidity. A large step between 0-10% relative humidity indicates that the material may have been hydrated. Analysis by XRPD after GVS (FIG. 21) showed that the material remained unchanged.

[00406] GVS analysis (FIG. 53) of Compound 6 Form 1 showed the material to be non-hygroscopic with an absorbance of 0.11% at 90% relative humidity. Analysis by XRPD after GVS (FIG. 55) showed that the material remained unchanged.

[00407] GVS analysis (FIG. 54) of Compound 6 Form 3 showed that the material is non-hygroscopic with an absorbance of 0.08% at 90% relative humidity. Analysis by XRPD after GVS showed little change, indicating that the crystal form may have changed during the GVS experiment. When Form 3 was exposed to high humidity for 1 week, it converted to Form 1 of Compound 6.

Example 6: Dynamic Vapor Sorption (DVS)

[00408] Approximately 10 mg of sample was placed in a mesh sorption balance crucible and loaded into a dynamic balance of a DVS-1 vapor sorption analyzer using Surface Measurement Systems. The sample was subjected to a ramp profile with 40-90% relative humidity (RH) in 10% increments, maintaining the sample at each stage until a stable mass was reached (99.5% completion of the step). After completion of the sorption cycle, the sample was dried using the same procedure to 0% relative humidity and then a second sorption cycle again to 40% relative humidity. The mass changes during the sorption/desorption cycles were plotted, allowing the hygroscopic nature of the sample to be determined. An XRPD analysis of any remaining solid was then performed.

Example 7 Coulometric Karl Fischer (KF) Titration

[00409] Approximately 10-15 mg of solid material was accurately weighed into the vial. The solid was then manually introduced into the titration cell of a Mettler Toledo C30 compact titrator. The vial was weighed after the addition of the solid and the weight of the added solid was injected into the instrument. The titration was started when the sample was completely dissolved in the cell. The water content was automatically calculated by the instrument as a percentage and the data was printed out.

[00410] The Form 1 KF analysis of Compound 2, which was performed for comparison with Form 3, calculated 1.4% water. For monohydrate, 3.1% will be required. Up to about 0.5% may be due to the introduction of the sample into the cell. This calculated value is higher than expected from the TG/DTA and GVS analysis, although there is no assumption about the bound water lattice.

[00411] KF analysis of Compound 3 Form 1 calculated 3.2% water. For monohydrate, 3.1% is required.

Example 8 Infrared Spectroscopy (IR)

[00412] Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer plate and spectra were acquired using the following parameters:

[00413]

[00414] IR analysis of Compound 1 is shown in FIG. 6.

Example 9: ¹ H-Nuclear Magnetic Resonance ( ¹ H-NMR)

[00415] ¹ H-NMR experiments were performed on a Bruker AVA500 (frequency: 500 MHz). Experiments were performed in deuterated DMSO and each sample was prepared at a concentration of approximately 10 mM.

[00416] The ¹ H-NMR spectrum of Compound 1 is shown in FIG. 7. Purity shown in example 10. IR analysis shown in example 8. Additional characterization with XRPD, PLM, TG/DTA, DSC and GVS in examples 1-5 shows that this sample is Compound 1 Form 1.

[00417] The ¹ H-NMR spectrum of Compound 2 is shown in FIG. 15. Purity is shown in Example 10. Additional characterization with XRPD, PLM, TG/DTA, DSC, GVS, KF and IC in Examples 1-5, 7 and 11 shows that this sample is Compound 2 Form 1.

[00418] The ¹ H-NMR spectrum of Compound 3 is shown in FIG. 22. Purity is shown in Example 10. Additional characterization with XRPD, PLM, TG/DTA, DSC, GVS, KF and IC in Examples 1-5, 7 and 11 shows that this sample is Compound 3 Form 1.

[00419] The ¹ H-NMR spectrum of Compound 6 is shown in FIG. 56. Purity is shown in Example 10. Additional characterization with XRPD, PLM, TG/DTA, DSC and GVS in Examples 1-5 shows that this sample is Compound 6 Form 1.

Example 10 Ultraviolet High Performance Liquid Chromatography (HPLC-UV) Detection.

[00420] HPLC-UV was performed using the following parameters:

[00421]

gradient program

[00422] HPLC purity of Compound 1 was measured as >99.9% (see FIG. 8).

[00423] HPLC purity of Compound 2 was measured as >99.9% (see FIG. 16).

[00424] HPLC purity of Compound 3 was measured as >99.8% (see FIG. 23).

[00425] HPLC purity of Compound 6 was measured as >99.9% (see FIG. 57)

Example 11: Ion Chromatography (IC)

[00426] Ion chromatography was performed using the following parameters:

[00427]

[00428] By analyzing the IC of Compound 2 (sample preparation using water: 2-propanol (20% solvent)) a 5.9% w/w was calculated. HCl, which corresponds to 0.86 mol. HCl: free base. By re-analysis (sample preparation using water:methanol (50% solvent)) was calculated 6.4% wt./wt. HCl, corresponding to 0.95 mol HCl: free base. Preparation with methanol led to improved consistent results (2 shots for each sample).

[00429] Through the initial analysis of the IC of Compound 3 (sample preparation using water: 2-propanol (20% solvent)) was calculated 11.2% wt./wt. HCl, which corresponds to 1.95 mol. HCl: free base. Through an initial analysis of sample preparation using water:methanol (50% solvent), 11.1% w/w was calculated. HCl, which corresponds to 1.94 mol. HCl: free base.

Example 12 Solvent Solubility Screen for Compound 1

[00430] Approximately 100 mg of the free base was dissolved in 1.1 ml of dichloromethane and concentrated in vacuo to give a clear gum that turned to a white static solid on standing. The sample was analyzed by XRPD to confirm crystallinity. PLM analysis was also performed, as the preferred orientation was observed using XRPD.

[00431] Approximately 100 mg of the free base was dissolved in 1 ml of acetone and concentrated in vacuo to give a clear resin that turned to a white solid when scratched with a spatula. The sample was analyzed by XRPD to confirm crystallinity. PLM analysis was also performed, as the preferred orientation was observed using XRPD.

[00432] Approximately 200 mg of the free base was ground in a ball mill at 50 Hz for 6 hours and the resulting solid was found to be static.

[00433] Approximately 100 mg of the free base was dissolved in 1 ml of acetone and 1 ml of DCM. Both solutions were filtered through a syringe to remove any "crystal centers" and allowed to evaporate at ambient temperature in new vials.

[00434] It was found that Compound 1, which was concentrated in vacuo from both DCM and acetone, remained in Form 1. In addition, it was found that both evaporation experiments from DCM and acetone and experiments with 6- hourly grinding returns the Form 1 crystalline material.

[00435] Since attempts to prepare an amorphous Compound 1 were unsuccessful, Form 1 crystalline material was used in solvent solubility screening.

[00436] Approximately 10 mg of crystalline Compound 1 was placed in 32 vials and 5 aliquots by volume of the respective solvent systems were added to the respective vial. Between each addition, the mixture was checked for dissolution and, if dissolution was not apparent, the mixture was heated to a temperature of approximately 40° C. and checked again. This procedure was continued until dissolution was observed or until 100 volumes of solvent were added. After adding 100 volumes, an additional 100 volumes were added to the samples that did not dissolve to make a total of 200 volumes. If 200 volumes were added without dissolution, the solubility was calculated to be below this point (<5 mg/mL). The results are shown in table 1.

[00437] Crystalline Compound 1 was found to be completely soluble (≥5 mg/mL) in 29 of 32 solvent systems. Specifically, high solubility (>196 mg/mL) was observed in 19 of 32 solvent systems tested, moderate solubility (>39 mg/mL) in 10 of 32 solvent systems tested, and poor solubility (<5 mg/mL) in 3 of 32 investigated solvent systems. A sample of acetone:water (50%) was found to precipitate after approximately 30 minutes. A sample of 2-propanol was found to precipitate after approximately 2 days.

[00438] XRPD analysis was performed on all samples; soluble samples were allowed to evaporate. These XRPD analyzes showed the observation of Compound 1 Form 1 in all samples. Samples of dimethylformamide, ethanol, methanol, 1-butanol, 2-ethoxyethanol, and heptane that exhibited the preferred orientation were further analyzed by PLM.

Example 13 Primary Screening for Compound 1 Polymorphs

[00439] The following experiments were performed in 24 solvents (acetone, 50:50 acetone/water, acetonitrile, anisole, diisopropyl ether, dimethylformamide, dimethyl sulfoxide, ethanol, ethyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, N-methyl-2-pyrrolidone, 2- propanol, t-butyl methyl ether, tetrahydrofuran, toluene, 1-butanol, 2-ethoxyethanol, benzonitrile, chlorobenzene, heptane, hexane and t-amyl alcohol).

[00440] A. Thermal Cycling Resistance Experiments

[00441] The results obtained from the solubility approximation experiments were used to prepare suspensions for thermal cycling. The slurries were thermally cycled at 40° C. in cycles of 4 hours for 48 hours (the slurries were held at 40° C. for 4 hours followed by 4 hours at ambient temperature, cooling/heating rates after holding for periods 4 hours were approximately 1°C/min). After thermal cycling, most of the samples were stored in a freezer to obtain solids.

[00442] B. Fast cooling resistance experiments

[00443] Rapid cooling stability experiments were performed by placing filtered saturated solutions of the material in each of 24 selected solvent systems in environments with a temperature of 2°C and -18°C. Any solid material was then removed and allowed to dry at ambient conditions prior to analysis.

[00444] C. Re-preparation for quenching with methanol (-18°C)

[00445] A quench sample with methanol at -18°C was re-prepared to determine if the additional peaks that were observed in the original sample were reproducible.

[00446] A suspension of Compound 1 was prepared in 200 μl of methanol, filtered with a syringe and stored in a freezer. A solid formed within approximately 2 hours and was analyzed by XRPD.

[00447] D. Antisolvent Addition Experiments

[00448] Anti-solvent addition experiments were performed at ambient temperature (approximately 22° C.) by adding the selected anti-solvent to filtered saturated material solutions. The anti-solvent was added to each of the 24 selected solvent systems to give 50:50 solvent:anti-solvent mixtures and stored in a refrigerator to accelerate precipitation. Deionized water was used as an anti-solvent for all samples. Another aliquot of anti-solvent was added to samples that did not precipitate.

[00449] E. Evaporation Experiments

[00450] Evaporation experiments were performed by allowing the solvents from the filtered saturated solutions in each of the 24 solvent systems to evaporate under ambient conditions in open vials. Any resulting solid material was then recovered and analyzed after the sample had evaporated to dryness.

[00451] Samples from these experiments were analyzed by the XPRD method. Thermal cycling results were consistent with the solubility patterns in Example 9. Form 1 was obtained in all experiments that had sufficient solids for analysis, assuming a monomorphic system.

[00452] Samples that showed the preferred orientation were analyzed by PLM and showed plate-like morphology as observed for Compound 1 starting material (see Example 2).

Example 14 Solvent Solubility Screen for Compound 2

[00453] Approximately 100 mg of the HCl salt (Form 1, Compound 2) was ball milled at 50 Hz and analyzed by XRPD after 15 and 30 minutes to check how easily an amorphous material could be obtained. After 15 minutes of grinding, the HCl salt (100 mg) was poorly crystalline; however, after 30 minutes of grinding, the HCl salt was found to be amorphous.

[00454] Approximately 500 mg of the HCl salt (Form 1, Compound 2) was ball milled at 50 Hz and analyzed by XRPD every 30 minutes to 3.5 hours. After 3 hours of grinding, the HCl salt (500 mg) showed minimal crystallinity; however, after 3.5 hours, the HCl salt was found to be amorphous.

[00455] Approximately 10 mg of the amorphous HCl salt (from a 500 mg batch) was placed in each of 28 vials and 5 aliquots by volume of the respective solvent systems were added to the appropriate vial. Between each addition, the mixture was checked for dissolution and, if dissolution was not apparent, the mixture was heated to a temperature of approximately 40° C. and checked again. This procedure was continued until either dissolution was observed or 100 volumes of solvent were added. Then another 100 volumes were added to the samples that did not dissolve. If 200 volumes of solvent were added without material dissolving, solubility was calculated as observed below this point. The results are shown in table 2.

[00456] Amorphous Compound 2 was found to be completely soluble (≥5 mg/mL) in 15 of 28 solvent systems. A sample of acetone:water (50%) was observed to precipitate after approximately 2 hours, dissolution initially observed at 18 mg/mL. It was found that samples of dichloromethane, tetrahydrofuran and 2-ethoxyethanol precipitated overnight.

[00457] Dissolved samples were allowed to evaporate (except solvents DMA, DMF, DMSO and NMP). XRPD analysis was performed on all remaining samples in which solids were obtained. From these samples, the solid from 14 solvent systems (acetone, anisole, dichloromethane, diisopropyl ether, ethanol, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, t-butyl methyl ether, tetrahydrofuran, toluene, 2-ethoxyethanol, 2-methyltetrahydrofuran and t-amyl alcohol) was a previously unobserved form, Compound 2 Form 2, and the solid from 3 solvent systems (1,4-dioxane, ethyl acetate and 2-propanol) was Compound 2 Form 1. Five solvent systems (1:1::acetone:water, 1:1::methanol:water, 1:1::2-propanol:water, water and 1-butanol) did not give either solid material or free base (Compound 1). Two solvent systems (acetonitrile and methanol) gave a mixture of Forms 1 and 2 of Compound 2 (FIGS. 24A-24D).

Example 15 Primary Screening for Compound 2 Polymorphs

I. Investigation of polymorphism using reactive crystallization

[00458] Eight solvent systems (acetone, dichloromethane, ethanol, ethyl acetate, methanol, 2-propanol, t-butyl methyl ether, and tetrahydrofuran) were selected for reactive crystallization. Approximately 50 mg of free base was dissolved in 250-150 µl of solvent. Added one equivalent of HCl from the stock solution (200 μl) in the appropriate solvent. The addition of the acid was carried out at a temperature of 40°C with stirring, then the solution was allowed to cool. Upon addition of the acid, the tert-butyl methyl ether sample was the only sample where direct precipitation was observed. However, the precipitate was redissolved and then reprecipitated upon cooling to ambient temperature. After stirring at ambient temperature for approximately 20 hours, the 2-propanol sample showed very little precipitate. Heptane was then added to all samples except t-BME to give 50:50 solvent:antisolvent mixtures. The resulting methanol sample was not mixed with heptane. Precipitation was observed in samples of acetone, ethyl acetate, 2-propanol and THF. The precipitate was obtained from mixtures of DCM/heptane and ethanol/heptane after storage in the refrigerator for approximately 5 days.

[00459] Samples were analyzed by the XRPD method. Acetone, ethanol and tert-butyl methyl ether gave Form 2 of Compound 2. Solids from dichloromethane gave weak data for Form 2 of Compound 2. Ethyl acetate and tetrahydrofuran gave Form 1 of Compound 2. 2-Propanol gave a mixture of Forms 1 and 2, and methanol did not give solids (Fig. 25).

[00460] TG/DTA Form 2 from tert-butyl methyl ether showed that the material was different from Form 1 and was an anhydrous form. TGA showed a gradual loss of 0.3% from the start followed by the onset of degradation. DTA shows slight endothermicity with onset at approximately 78.8°C, endothermicity with onset at approximately 163.7°C, and endothermicity with a peak at approximately 199.5°C (FIG. 26).

[00461] DSC analysis of Form 2 from ethanol showed endothermicity with an initial temperature of 200.4°C (FIG. 27).

[00462] KF analysis calculated 1.6% water for Form 2 from acetone. This value is higher than expected from thermal analysis. Any water present must be unbound to the grate.

[00463] By analyzing the IC of Form 2 from tert-butyl methyl ether (sample preparation using water:methanol (50% solvent)) 6.0% w/w was calculated. HCl, which corresponds to 0.89 mol. HCl: free base.

II. Use of Amorphous HCl Salt to Screen for Polymorphs by Crystallization of HCl Salt

[00464] Approximately 1 g of the HCl salt (Compound 2) was ground in a ball mill at 50 Hz and analyzed by XRPD every hour for 5 hours. The HCl salt (1 g) was found to be predominantly amorphous after 5 hours of milling, and the crystallinity was shown to decrease only slightly during 4-5 hours of milling.

[00465] Twenty-four solvent systems were used for this polymorph screening. Water and aqueous mixtures were excluded due to dissociation observed in the solubility evaluation.

[00466] A. Thermal Cycling Resistance Experiments

[00467] The results obtained from the solubility approximation experiments were used to prepare suspensions for thermal cycling. The slurries were thermally cycled at 40° C. in cycles of 4 hours for 24 hours (the slurries were held at 40° C. for 4 hours followed by 4 hours at ambient temperature, cooling/heating rates after holding for periods 4 hours were approximately 1°C/min).

[00468] B. Rapid cooling resistance experiments

[00469] Rapid cooling stability experiments were performed by placing filtered saturated solutions of the material in each of 24 selected solvent systems in environments with a temperature of 2°C and -18°C. Any solid material was then removed and allowed to dry at ambient conditions prior to analysis.

[00470] C. Antisolvent Addition Experiments

[00471] Antisolvent addition experiments were carried out at ambient temperature (approximately 22°C) by adding the selected antisolvent to saturated filtered material solutions, in each of 24 selected solvent systems, to obtain 50:50 solvent:antisolvent mixtures. These samples were stored in a refrigerator to speed up the precipitation. t-BME was used as the anti-solvent for all samples except for the DMSO and t-BME samples where toluene was used. Another aliquot of anti-solvent was added to samples that did not precipitate.

[00472] E. Evaporation Experiments

[00473] Evaporation experiments were performed by allowing the solvents from the filtered saturated solutions in each of the 24 solvent systems to evaporate at ambient conditions in open vials. Any resulting solid material was then recovered and analyzed after the sample had evaporated to dryness. After about 17 days at room temperature, the anisole sample was evaporated at 50° C. to give a solid.

[00474] Samples from these experiments were analyzed using XPRD. Thermal cycling results were consistent with solubility patterns, except:

1,4-диоксан, этилацетат и 2-пропанол: Форму 1 получали из образцов растворимости, а Форму 2 получали из термоциклирования;

1,4-dioxane, ethyl acetate and 2-propanol: Form 1 was obtained from solubility samples and Form 2 was obtained from thermal cycling;

DIPE и t-BME: Форму 2 получали из скрининга растворимости, а смеси Форм 1 и 2 получали из термоциклирования;

DIPE and t-BME: Form 2 was obtained from dissolution screening and mixtures of Forms 1 and 2 were obtained from thermal cycling;

ацетонитрил и метанол: смеси Формы 1 и 2 получали из скрининга растворимости, а Форму 2 получали из термоциклирования;

acetonitrile and methanol: Forms 1 and 2 mixtures were obtained from dissolution screening and Form 2 was obtained from thermal cycling;

MIBK: Форму 2 получали из скрининга растворимости, а аморфный материал получали из термоциклирования, хотя небольшое количество твердого вещества можно было анализировать.

MIBK: Form 2 was obtained from a solubility screen and an amorphous material was obtained from thermal cycling, although a small amount of solid could be analyzed.

[00475] Form 2 was obtained from 50 different experiments and was found to consist of lamellar or needle-like morphologies.

[00476] "Form 3" from anisole evaporation (obtained by burner evaporation at 50°C) was shown to be likely a degradation product, the purity was measured to be 96.5%. Due to the small amount of sample, this sample was not analyzed by PLM.

[00477] Additional peaks were observed at approximately 6.2 and 18.1°2θ from MIBK form 2 evaporation, but this was not sufficient for assignment as another form.

Example 16 Secondary Screening for Compound 2 Polymorphs

[00478] Compound 2 Form 2 was scaled up proportionally in two solvents. The material was subjected to a 7-day stability test and/or water solubility evaluation. A 7-day stability test was performed as follows. The material was exposed to the environment at 40°C/75% relative humidity, ambient light and 80°C for 7 days, and the resulting solids were analyzed by XRPD to determine if any changes occurred and using HPLC to determine purity. The water solubility was evaluated as follows. The suspension was created in deionized water (5.1 mg form 2 and 300 μl of water) and shaken for approximately 24 hours at ambient temperature (approximately 22°C). The initial pH value and the final pH value were measured. The resulting mixture was then isolated by centrifugal filtration, and the resulting solution was analyzed by HPLC to calculate the concentration of dissolved material. The remaining solid was analyzed by XRPD to determine if any changes had occurred during suspension.

[00479] A. Proportional increase of Form 2 (Compound 2) from acetone

[00480] Approximately 300 mg of Compound 1 was dissolved in 1 ml of acetone. One equivalent of HCl was added from the stock solution in acetone (200 µl) at 40° C. with stirring. The resulting solution was then left to cool. When the acid was added, the sample remained a clear solution. Heptane was then added to obtain a 50:50 solvent:antisolvent mixture. After stirring for approximately 1 hour, a thin slurry formed (with insufficient solids for XRPD analysis) and the sample was stored in a refrigerator for approximately 64 hours to provide a white suspension. Solid material was isolated by filtration and analyzed by the XRPD method (Fig. 28). The material was then dried under vacuum for approximately 6 hours and reanalyzed by XRPD. The yield obtained was 127 mg.

[00481] X-ray diffraction analysis showed that Form 2 was successfully proportionally enlarged, but with reduced crystallinity after drying. PLM analysis showed that Form 2 consists of birefringent particles of lamellar morphology. TG/DTA showed that the material was Form 2 from reactive crystallization of t-BME with artifact no longer present at approximately 79°C. TGA showed a loss of 0.5% from the very beginning, followed by the onset of destruction. DTA shows endothermicity with an initial temperature of approximately 159.1°C. DSC analysis showed endothermicity with an initial temperature of 197.6°C; this analysis was performed with a small amount of material due to lack of material. DVS analysis indicates that Form 2 is non-hygroscopic with an overall absorbance of <0.12% at 90% relative humidity. The difference in initial and final weight at 40% relative humidity may indicate a small amount of residual solvent present in the starting material. XRPD analysis after DVS showed that the material remained in the same crystalline form. ¹ H-NMR analysis showed that the material conformed to the provided structure with no residual solvent. HPLC purity was 99.9%. By IC analysis (sample preparation using water:methanol (50% solvent)) a 6.3% w/w was calculated. HCl, which corresponds to 0.95 mol. HCl: free base. The material has been shown to remain the same shape under ambient temperature conditions of 40°C/75% relative humidity, ambient light and temperature of 80°C for 7 days. HPLC purity was found to be unchanged: >99.9% purity (40°C/75% RH); >99.9% purity (environment); purity 99.9% (80°C). Solubility in water was measured to 0.5 mg/ml. Form 2 was found to dissociate to the free base as previously observed in dissolution screening using amorphous material. The initial pH was measured to be 1.87 and the final pH was 1.68 (measured pH of deionized water is 5.91).

[00482] B. Expansion of Form 2 (Compound 2) from Acetone (Reduced Drying)

[00483] Approximately 300 mg of the free base was dissolved in 0.5 ml of acetone. One equivalent of HCl was added from the stock solution in acetone (200 µl) at 40° C. with stirring. The resulting solution was then left to cool. When the acid was added, the sample remained a clear solution. Heptane was then added to obtain a 50:50 solvent:antisolvent mixture. After stirring for about 1 hour, a white precipitate formed. The sample was stored in the refrigerator for approximately 3-4 days, providing a white suspension. The solid material was separated by filtration and dried in vacuum for approximately 2 h, then analyzed using XRPD. The yield obtained was 90 mg.

[00484] XRPD analysis showed that Form 2 was successfully proportionately increased with improved crystallinity achieved with re-drying. GVS analysis showed Form 2 to be (very) non-hygroscopic with an overall absorbance of <0.08% at 90% relative humidity. The difference in initial and final weight at 40% relative humidity may indicate a small amount of residual solvent present in the starting material. XRPD analysis after GVS showed that the material remained in the same crystalline form.

[00485] C. Proportional increase of Form 2 (Compound 2) from ethanol

[00486] Approximately 300 mg of the free base was dissolved in 4 ml of ethanol. One equivalent of HCl was added from the stock solution in ethanol (200 µl) at 40° C. with stirring. The resulting solution was then left to cool. When the acid was added, the sample remained a clear solution. Heptane was then added to obtain a 50:50 solvent:antisolvent mixture. After stirring for approximately 1 hour, another 2.3 ml of heptane was added. The sample was stored in the refrigerator for approximately 3-4 days, providing a white suspension. The solid material was separated by filtration and dried in vacuum for approximately 2 h, then analyzed using XRPD. The resulting yield was 154 mg.

[00487] XRPD analysis showed that Form 2 was successfully proportionately increased with improved crystallinity achieved with re-drying. KF analysis calculated 0.8% water. DSC analysis showed endothermicity with the onset of degradation at 200.7°C. IR analysis was performed to obtain a control spectrum.

[00488] This secondary screen indicated that Form 2 was the non-hydrated/solvated, non-hygroscopic mono-HCl salt with no change in solid form or chemical purity after 1 week stability testing, but with low aqueous solubility and dissociation to free base . Notably, Form 1 also readily dissociates to the free base in water.

Example 17 Stability Studies of Compound 2 Polymorphs (Competitive Suspension)

[00489] A. Solubility measurement in t-BME

[00490] The solubility of Compound 2 Form 1 was measured using the solvent addition method as described in Example 14 per 10 mg of sample. t-BME was added in 1 ml aliquots up to 10 ml, then in 5 ml and 10 ml aliquots for a total volume of 100 ml.

[00491] The solubility of Form 1 in t-BME was measured to be <0.1 mg/mL and therefore this solvent was not selected for competitive suspension.

[00492] B. Competitive Suspension Procedure

[00493] Four solvents (acetone, ethyl acetate, methyl ethyl ketone and 2-propanol) were selected for competitive suspension. Saturated solutions were prepared from Form 1 in selected solvents and added to 20 mg mixtures of Forms 1 and 2 in a 50:50 ratio to create suspensions. The suspensions were shaken at 60° C. and ambient temperature for approximately 48 hours. Solids were then isolated by centrifugal filtration and analyzed by XRPD.

[00494] XRPD analysis of solids obtained from suspensions at 60° C. and ambient temperature indicated the presence of Form 2 only. These results indicate that Form 2 is thermodynamically more stable than Form 1. MEK and acetone samples were observed to at 60° C. orange/brown suspensions were formed, but the isolated solid remained white. This may indicate chemical decomposition at higher temperatures.

Example 19: Compound 1 Focused Screening of Salt Forms

A. Primary Screening of Salt Forms: Addition of Counterion at 40°C

[00495] A total of 42 experiments were performed using 7 counterions (fumaric acid, citric acid, L-tartaric acid, hippuric acid, benzenesulfonic acid, methanesulfonic acid or HCl) in 6 different solvents (acetone, acetonitrile, ethyl acetate, 2-propanol, tert-butyl methyl ether or THF). HCl was used for the positive control experiments. Approximately 25 mg of Compound 1 (free base) was weighed into 2 ml glass vials followed by dissolution in an appropriate solvent (500 μl) at 40°C. 1 equivalent counterions were weighed separately and dissolved in the selected solvent at 40°C to obtain 0.5 M solutions. In tubes where the counterions did not dissolve, another 200 µl of deionized water was added to dissolve the counterion. In some cases where dissolution was not possible, an acid slurry was added. If the counterion was a liquid (eg, methanesulfonic acid), it was added as a pure solution. After adding the counterion, the vials were shaken at 40° C. for 1 hour. The resulting solids were analyzed by XRPD. Where sufficient solids were available, ¹ H NMR and TGA analysis were also performed.

[00496] Samples still in solution were allowed to evaporate at ambient temperature by piercing the vial caps. Any solids were analyzed by XRPD, and new crystalline forms were also analyzed by ¹ H NMR and TGA if sufficient material was obtained.

[00497] Samples that were still in solution were stored in a refrigerator at 5°C to promote solid formation. Any solids were analyzed by the XRPD method.

[00498] Samples that did not give solid materials after cooling were subjected to the addition of an anti-solvent. Any precipitate was isolated by centrifugation and analyzed by the XRPD method.

B. Benzenesulfonic acid salt (Compound 4): Forms 1 and 2

[00499] For counterion experiments in acetone, acetonitrile, 2-propanol, and tert-butyl methyl ether, precipitation occurred when the vials were stored at ambient conditions overnight. Precipitation was observed in EtOAc and THF after 5 days of cooling at 5°C. XRPD analysis revealed two forms of the benzenesulfonate salt. Form 1 (Fig. 30) was prepared from acetone, acetonitrile, ethyl acetate, 2-propanol and THF. Form 2 (FIG. 31) was prepared from tert-butyl methyl ether. Comparison of XRPD models provided clear evidence for different crystal forms (Fig. 32).

[00500] ¹ H NMR analysis was then performed to confirm salt formation and check salt stoichiometry. Due to the small amount of Form 1 benzenesulfonate formed in each vial, solids from the crystalline hits of acetone and acetonitrile were combined for ¹ H NMR spectroscopy. The ¹ H NMR spectrum showed the presence of both the API and the counter ion, but several additional peaks were present. In an attempt to obtain a cleaner spectrum, samples from 2-propanol and THF were combined and a second ¹ H NMR spectrum was recorded. The same additional peaks were found, possibly corresponding to degradation products. The NMR spectrum of Form 2 benzenesulfonate showed that the material corresponded to the benzenesulfonate salt with no impurities present. The spectra for both Forms 1 and 2 showed significant shifts and broadening in the peaks, which confirms the formation of salt.

[00501] While not enough sample was recovered from the experiments to allow any thermal analysis for Form 1 benzenesulfonate, a TG/DTA experiment was performed for Form 2 benzenesulfonate derived from tert-butyl methyl ether (Fig. 33). The material was anhydrous with no loss of mass prior to degradation. An acute endothermic event was observed with an onset at approximately 161.9°C and a peak at approximately 162.8°C. This was followed by a wide exothermic effect, which was probably caused by the degradation of the salt.

C. Methanesulfonic acid salt (Compound 5): Form 1

[00502] Pure solutions of methanesulfonic acid were added to the free base in all solvents. In tert-butyl methyl ether, precipitation occurred 15 minutes after the counterion was added to the free base. Other solids were obtained from ethyl acetate overnight and from THF after 5 days of cooling at 5°C. The addition of the anti-solvent to water to acetone, acetonitrile and 2-propanol led to the instantaneous formation of a solid. XRPD analysis identified one form of the methanesulfonic acid salt (FIGS. 34 and 35).

[00503] ¹ H NMR analysis was then performed to confirm salt formation and check salt stoichiometry. The spectrum shows the presence of both API and counterion with significant shifts and broadening in the peaks, giving clear evidence of salt formation.

[00504] A TG/DTA experiment was also performed on methanesulfonate derived from tert-butyl methyl ether to explore the nature of the solid. A 0.4% residual solvent loss was observed before the melting point of the compound. The trace is similar to that obtained for benzenesulfonate, but the melting point for methanesulfonate was significantly higher than for the former. An acute endothermic event was observed with an onset at approximately 180.2°C and a peak at approximately 181.5°C. This was followed by a wide exothermic effect, which was probably caused by the degradation of the salt.

D. Fumaric Acid Salt (Compound 6): Form 1

[00505] Fumaric acid had low solubility in all solvents tested, so 0.5 M solutions could not be prepared. An additional 200 µl of water was added to the vials to help dissolve the counterion. Samples in acetone, acetonitrile, ethyl acetate and 2-propanol still did not dissolve, so they were added as suspensions. Samples were added to the free base in all solvents. In tert-butyl methyl ether, precipitation occurred 15 minutes after the counterion was added to the free base. Other solids were obtained from EtOAc overnight and from THF after 5 days of cooling at 5°C. The addition of an anti-solvent in water to acetone, acetonitrile and 2-propanol led to the instantaneous formation of a solid.

[00506] Samples prepared from all solvents except acetonitrile gave radiographs consistent with those of the free base, with high degrees of preferred orientation. Overnight the sample in acetonitrile was evaporated to dryness and the XRPD of the resulting solid indicated a potential new form (FIGS. 36 and 37). To rule out that the new solid was not associated with degradation, a proportional increase experiment was performed in acetonitrile using 50 mg of the free base. The resulting solid was characterized by XRPD, which confirmed the new shape.

[00507] ¹ H NMR analysis confirmed the formation of the salt and clarified the stoichiometry of the salt. The spectrum showed that both API and counterion were present. The API : fumaric acid ratio ranged from 1 to 0.91. The spectrum showed significant shifts in peaks, providing clear evidence of salt formation.

[00508] The TG/DTA experiment showed that there was no loss of solvent up to the melting point of the compound. There was very little endothermicity in the DTA trace starting at 80.1°C (peak at 82.9°C) corresponding to the free base. A second, abrupt endothermic event was observed starting at approximately 133.2°C and peaking at approximately 140.2°C.

E. Citric acid

[00509] Citric acid had low solubility in all solvents tested, so 0.5 M solutions could not be prepared. An additional 200 µl of water was added to the vials to completely dissolve the counterion. In tert-butyl methyl ether, precipitation occurred after 3 days of slow evaporation after the addition of the counterion to the free base. Additional solids were obtained from acetone and 2-propanol after 5 days of cooling at 5°C and from acetonitrile and ethyl acetate after an additional 2 days of slow evaporation. Adding anti-solvent to water to THF did not give solids. Most of the solids crystallized as single crystals. After XRPD analysis of the milled crystals, it was found that the resulting materials exhibited structures consistent with the pure free base.

F. L-tartaric acid

[00510] L-tartaric acid had low solubility in all solvents tested, so 0.5 M solutions could not be prepared. An additional 200 µl of water was added to the vials to completely dissolve the counterion. In tert-butyl methyl ether, precipitation occurred after 3 days of slow evaporation after the addition of the counterion to the free base. Other solids were obtained from 2-propanol after 5 days of cooling at 5° C. and from acetone and acetonitrile and after another 2 days of slow evaporation. Addition of anti-solvent in water to ethyl acetate and THF gave solids in both cases. Most of the solids crystallized as single crystals. After XRPD analysis, it was found that the resulting materials exhibited structures corresponding to either the free base or a mixture of free base and counterion.

G. Hippuric acid

[00511] Hippuric acid had low solubility in all solvents tested, so 0.5 M solutions could not be obtained. An additional 200 µl of water was added to the vials to completely dissolve the counterion. Samples in acetone, acetonitrile, ethyl acetate and 2-propanol still did not dissolve, so they were added as suspensions. In acetonitrile, 2-propanol and tert-butyl methyl ether, solids precipitated overnight after the counterion was added to the free base. Other solids were obtained from acetone, ethyl acetate and THF after 3 days of slow evaporation. After XRPD analysis, it was found that the resulting materials showed structures corresponding to either the free base, counterion, or a mixture of free base and counterion.

H. Secondary Screening of Salt Forms:

[00512] After primary screening, two salts were proportionally increased: the methanesulfonate (or mesylate) salt (Compound 5) and the fumarate salt (Compound 6).

Mesylate salt (Compound 5)

[00513] 300 mg of Compound 1 was weighed into a 20 ml glass scintillation vial. The solid was completely dissolved in tert-butyl methyl ether (6.0 ml) at 40°C. 1.0 equivalent of pure methanesulfonic acid (38.4 μl) was added to the free base solution. Precipitation was observed within a few minutes after the addition. The mixture was stirred at 40°C for 1 hour, then cooled to room temperature. The resulting solid was isolated by centrifugation (Substance 1) and the remaining suspension from the vial was left to slowly evaporate. This gave a more solid substance (Substance 2). Both cultures were dried in a desiccator for 3 hours and analyzed separately by XRPD and HPLC. According to XRPD analysis Substances 1 and 2 correspond to the same form and have similar levels of crystallinity. In addition, XRPD analysis confirmed that the mesylate obtained from the secondary screen matched the form obtained from the primary screen. The total substance was 85.3%. Substance 1 was used for the complete characterization of the salt.

[00514] The radiograph of the mesylate confirmed the new shape (FIG. 38).

[00515] ¹ H NMR analysis was performed to confirm salt formation and check salt stoichiometry. The spectrum shows the presence of both API and counterion with significant shifts and broadening in the peaks, giving clear evidence of salt formation (FIG. 39).

[00516] HPLC analysis showed Substance 1 to be 99.97% pure. Purity levels were 99.98% after 7 days exposure to 40° C./75% relative humidity; 99.97% after 7 days of exposure to 80°C and 99.95% after 7 days of exposure to ambient conditions were not considered significant changes. The purity of Substance 2 was 99.96%.

[00517] TG/DTA Substance 1 showed a 0.3% weight loss before melting. There was one acute endothermicity, beginning at 178.6°C and peaking at 181.3°C, followed by an exotherm that corresponded to sample degradation (FIG. 40).

[00518] DSC salt studies were consistent with TGA, confirming the presence of acute endothermicity with onset at 179.0°C (peak at 181.8°C). In addition, there was slight endothermicity beginning at 77.0°C (peak at 79.4°C) corresponding to the melting of the free base (Fig. 41)

[00519] GVS studies show that the material was moderately hygroscopic with a gradual increase in mass at relative humidity. Mass absorption ranged from 2.8% to 70% moisture and from 3.5% to 90% moisture with no hysteresis between the sorption and desorption cycle. X-ray diffraction analysis of the material after GVS showed that the sample retained its shape and crystallinity.

Fumarate Salt (Compound 6), Form 1

[00520] 300 mg of Compound 1 was weighed into a 20 ml glass scintillation vial. The solid was completely dissolved in MeCN (1.5 ml) at 40°C. 1.05 equivalents of fumaric acid (72.06 mg) were weighed into another vial and the solid was completely dissolved in EtOH (2.4 ml) at 40°C. The fumaric acid solution was added to the free base solution, and the mixture was stirred at 40° C. for 1 hour. The mixture was cooled to room temperature and the solution was subjected to slow evaporation for 2 days. Thereafter, the vial was stored at 5°C for another 3 days to promote precipitation. The resulting solid was isolated by centrifugation (Substance 1) and the resulting stock solution was left to slowly evaporate. This gave a more solid (Substance 2). Both substances were dried in a desiccator for 3 hours and analyzed by XRPD and HPLC.

[00521] Substance 1 was used to fully characterize the salt. The same form was obtained from both cultures with the same levels of crystallinity.

[00522] X-ray fumarate confirmed the new shape (FIG. 42).

[00523] HPLC analysis showed that fumarate substance 1 was >99.9% pure. Purity remained at 99.9% after 7 days exposure to 40°C/75% relative humidity, 80°C and ambient conditions. Changes are not considered significant.

[00524] The ¹ H NMR spectrum showed that the material corresponded to fumarate (Fig. 43).

[00525] TG/DTA Substance 1 fumarate showed no weight loss before melting. There is one acute endothermicity with onset at 128.1°C and peak at 133.4°C. Endothermicity corresponding to the free base was not visible in proportionally enlarged material (Fig. 44).

[00526] DSC studies of the salt were consistent with TGA, confirming the presence of acute endothermicity with onset at 126.4°C and peak at 132.1°C (FIG. 45).

[00527] GVS studies show that the material is non-hygroscopic with very little weight gain above 50% relative humidity. Mass absorption ranges from 0.11% to 90% moisture. X-ray diffraction analysis of the material after GVS showed that the sample retains its shape and crystallinity.

Screening for Fumarate Polymorphs (Compound 6), Forms 2 and 3

[00528] Compound 6 polymorph screening identified two additional crystalline forms of Compound 6. Compound 6, Form 2, was isolated from a 95/5 acetone/water suspension, and Compound 6, Form 3, was isolated from a 80/20 dioxane/water mixture. . Compound 6, Form 1 was the thermodynamically most stable form of the three polymorphs of Compound 6.

Claims (8)

1. Method for obtaining a crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate monohydrochloride , and the method includes the steps: i) preparing a saturated solution of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate monohydrochloride in a solvent selected from acetone, ethanol and tert-butyl methyl ether at a temperature of approximately 60°C; ii) adding a heptane antisolvent to the saturated solution at a temperature of approximately 60°C; iii) cooling to a temperature of from about -5°C to about 15°C; iv) collecting the solid in the presence of a precipitate and evaporating the solvent to collect the solid in the absence of a precipitate; And v) optionally drying; wherein the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate monohydrochloride is 2, characterized by an X-ray powder diffractometry (XRPD) pattern with characteristic peaks at 8.6° 2-theta, 14.3° 2-theta, 15.6° 2-theta, 19.0° 2-theta, 19.8° 2 -theta and 20.7° 2-theta. 2. The method of claim 1 wherein the ratio by volume of solvent to anti-solvent is approximately 1:9.

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