Solid forms of pyrazolo[3,4-d]pyrimidine compounds

Abstract

The present invention provides solid forms of 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, as well as methods of making and using same.

Description

[Technical field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 290,136, filed December 16, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The phosphodiesterase (PDE) enzyme family hydrolyzes cGMP and cAMP. The PDE9 enzyme preferentially hydrolyzes cGMP over cAMP. PDE9 is present in smooth muscle cells in various human tissues, namely the testis, brain, small intestine, skeletal muscle, heart, lung, thymus, and spleen, as well as in the human vasculature in various tissues.

[0003] Various physiological processes in the cardiovascular system, nervous system, and immune system are controlled by NO / cGMP pathway, including ion channel conduction, glycogenolysis, cell apoptosis, and smooth muscle relaxation.In blood vessels, vascular smooth muscle relaxes, leading to vasodilation and increased blood flow.PDE9 inhibitors reduce or prevent the hydrolysis of cGMP by PDE9, thereby increasing the intracellular level of cGMP, thereby enhancing or prolonging its effect.

[0004] Thus, there is a need for PDE9 inhibitors that are effective in treating conditions that can be controlled or normalized by inhibition of PDE9. The present disclosure addresses such a need. Summary of the Invention

[0005] The present disclosure provides solid forms of 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, as well as methods of making and using same.

[0006] In one aspect, the disclosure provides a compound comprising 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound X) of the following structure: [ka] wherein solid form A is characterized by having X-ray powder diffraction peaks at about 18.9, 20.4, and 23.1 degrees 2θ using CuKα radiation.

[0007] In another aspect, the disclosure provides solid form B of compound X, wherein solid form B is characterized by having X-ray powder diffraction peaks at about 8.0, 15.0, and 19.3 degrees 2θ using CuKα radiation.

[0008] In yet another aspect, the disclosure provides solid form C of compound X, wherein solid form C is characterized by having X-ray powder diffraction peaks at about 8.6, 8.7, 15.0, and 18.9 degrees 2θ using CuKα radiation.

[0009] In yet another aspect, the disclosure provides solid form D of compound X, wherein solid form D is characterized by having X-ray powder diffraction peaks at about 9.1, 6.8, and 15.5 degrees 2θ using CuKα radiation.

[0010] The present invention also provides a pharmaceutical composition comprising solid Forms A, B, C, or D disclosed herein and a pharma- ceutically acceptable carrier or excipient.

[0011] The present invention further provides a method of treating or preventing a disease or disorder comprising administering to a subject in need thereof solid form A, B, C, or D, or a pharmaceutical composition comprising solid form A, B, C, or D disclosed herein. [Brief description of the drawings]

[0012] [Figure 1A] FIG. 1A is an X-ray powder diffraction diagram (XRPD) of solid form A showing the full range of angles from 0° 2θ to 60° 2θ.

[0013] [Figure 1B] FIG. 1B is an XRPD of solid form A showing the full range of angles from about 9° 2θ to about 30° 2θ.

[0014] [Figure 1C] FIG. 1C is an XRPD of solid form A showing the full range of angles from about 31° 2θ to about 55° 2θ.

[0015] [Diagram 2] FIG. 2 is a differential scanning calorimetry (DSC) thermogram of solid form A.

[0016] [Diagram 3] FIG. 3 is a thermogravimetric (TG) thermogram of solid form A.

[0017] [Figure 4] FIG. 4 is a Fourier transform infrared spectrum of solid form A.

[0018] [Diagram 5] FIG. 5 is an FT-Raman spectrum of solid form A.

[0019] [Figure 6] FIG. 6 is a 13C solid state nuclear magnetic resonance spectrum of solid Form A.

[0020] [Figure 7] FIG. 7 is a dynamic water vapor sorption isotherm plot of solid form A.

[0021] [Figure 8] FIG. 8 is a photomicrograph of solid form A (unmilled) at 40x magnification.

[0022] [Figure 9] FIG. 9 is a photomicrograph of solid form A (milled) at 40x magnification.

[0023] [Figure 10] FIG. 10 is a photomicrograph of solid form A (unmilled) at 7x magnification.

[0024] [Figure 11] FIG. 11 is a graph showing the solubility of solid Form A in various solvents as a function of temperature.

[0025] [Figure 12] FIG. 12 is an XRPD of solid form B showing the angle range from 0° 2θ to 35° 2θ.

[0026] [Figure 13] FIG. 13 is a series of VT-XRPDs of solid form B showing the range of angles from 0° 2θ to 35° 2θ.

[0027] [Figure 14] FIG. 14 is a series of VT-XRPDs of solid form B showing the range of angles from 0° 2θ to 35° 2θ.

[0028] [Figure 15] FIG. 15 is a dynamic vapor sorption (DVS) isotherm plot of solid form B.

[0029] [Figure 16] FIG. 16 is a set of polarized light microscope (PLM) images of solid form B at 20x magnification.

[0030] [Figure 17] FIG. 17 is a set of polarized light microscope (PLM) images of solid form B at 5x (left) and 50x (right).

[0031] [Figure 18] FIG. 18 is a differential scanning calorimetry and thermogravimetry thermogram (TG / DSC) of solid form B.

[0032] [Figure 19] FIG. 19 is a DSC thermogram of solid form B.

[0033] [Figure 20] FIG. 20 is a Fourier transform infrared spectrum of solid form B.

[0034] [Figure 21] FIG. 21 is a set of XRPDs of a 7-day stability study of solid form B.

[0035] [Figure 22] FIG. 22 is a set of VH-XRPDs of solid form B.

[0036] [Figure 23] FIG. 23 is a set of VH-XRPDs of solid form B.

[0037] [Figure 24] FIG. 24 is a set of VH-XRPDs of solid form B.

[0038] [Diagram 25] FIG. 25 is a set of XRPDs of the thermodynamic solubility assessment of solid form B.

[0039] [Figure 26] FIG. 26 is an XRPD of solid form C showing the angle range from 0° 2θ to 35° 2θ.

[0040] [Figure 27] FIG. 27 is an XRDP of solid form D.

[0041] [Figure 28] FIG. 28 is a differential scanning calorimetry and thermogravimetry thermogram (TG / DSC) of solid form D. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The present disclosure relates to 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound X), having the following structure: [ka] The polymorphs of

[0043] Solid form A (“Form A”) In one aspect, the disclosure provides solid form A of compound X, characterized by having X-ray powder diffraction ("XRPD") peaks at about 18.9, 20.4, and 23.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form A is characterized by having XRPD peaks at about 9.6, 17.2, 18.9, 20.4, and 23.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form A is characterized by having XRPD peaks at about 9.6, 17.2, 18.9, 20.4, 20.7, 21.9, 23.1, and 24.5 degrees 2θ using CuKα radiation. In certain embodiments, solid Form A is characterized by having XRPD peaks at about 9.6, 10.9, 17.2, 18.2, 18.9, 20.4, 20.7, 21.9, 23.1, 24.5, 25.1, 25.6, 28.9, and 32.9 °2θ using CuKα radiation.

[0044] In certain embodiments, "about" means that the indicated XRPD peaks may vary by ±0.2 degrees 2θ. In certain embodiments, solid form A of compound X is characterized by having X-ray powder diffraction ("XRPD") peaks at 18.9±0.2, 20.4±0.2, and 23.1±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form A is characterized by having XRPD peaks at 9.6±0.2, 17.2±0.2, 18.9±0.2, 20.4±0.2, and 23.1±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid Form A is characterized by having XRPD peaks at 9.6±0.2, 17.2±0.2, 18.9±0.2, 20.4±0.2, 20.7±0.2, 21.9±0.2, 23.1±0.2, and 24.5±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid Form A is characterized by having XRPD peaks at 9.6±0.2, 10.9±0.2, 17.2±0.2, 18.2±0.2, 18.9±0.2, 20.4±0.2, 20.7±0.2, 21.9±0.2, 23.1±0.2, 24.5±0.2, 25.1±0.2, 25.6±0.2, 28.9±0.2, and 32.9±0.2 degrees 2θ using CuKα radiation.

[0045] In certain embodiments, "about" means that the indicated XRPD peaks may vary by ±0.1 degrees 2θ. In certain embodiments, solid form A of compound X is characterized by having X-ray powder diffraction ("XRPD") peaks at 18.9±0.1, 20.4±0.1, and 23.1±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form A is characterized by having XRPD peaks at 9.6±0.1, 17.2±0.1, 18.9±0.1, 20.4±0.1, and 23.1±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid Form A is characterized by having XRPD peaks at 9.6±0.1, 17.2±0.1, 18.9±0.1, 20.4±0.1, 20.7±0.1, 21.9±0.1, 23.1±0.1, and 24.5±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid Form A is characterized by having XRPD peaks at 9.6±0.1, 10.9±0.1, 17.2±0.1, 18.2±0.1, 18.9±0.1, 20.4±0.1, 20.7±0.1, 21.9±0.1, 23.1±0.1, 24.5±0.1, 25.1±0.1, 25.6±0.1, 28.9±0.1, and 32.9±0.1 degrees 2θ using CuKα radiation.

[0046] In certain embodiments, solid form A is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 1-3 of the table below. Note: The relative intensities provided in column 4 ("Relative Intensity (%)") are for reference only and are not required as part of the XRPD peak characteristics. [Table 1]

[0047] In certain embodiments, solid form A is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0042] ,

[0043] , and

[0044] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from the first column for the embodiment in paragraph

[0042] , the second column for the embodiment in paragraph

[0043] , or the third column for the embodiment in paragraph

[0044] , respectively).

[0048] In certain embodiments, solid form A is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 1 through 3 of the table below. Note: The relative intensities provided in column 4 ("Relative Intensity (%)") are for reference only and are not required as part of the XRPD peak characteristics. [Table 2]

[0049] In certain embodiments, solid form A is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0042] ,

[0043] , and

[0044] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from the first column for the embodiment in paragraph

[0042] , the second column for the embodiment in paragraph

[0043] , or the third column for the embodiment in paragraph

[0044] , respectively).

[0050] In certain embodiments, solid form A is characterized by an XRPD pattern substantially the same as that shown in FIG. 1A.

[0051] In certain embodiments, solid form A is characterized by an endothermic event with an onset between about 155°C and about 168°C as measured by DSC. In certain embodiments, solid form A is characterized by an endothermic event with a peak temperature of about 162°C as measured by DSC. In certain embodiments, "about" means that the temperature varies within ±2°C. In certain embodiments, solid form A is characterized by an endothermic event with an onset between 155±2°C and 168±2°C as measured by DSC. In certain embodiments, solid form A is characterized by an endothermic event with a peak temperature of 162±2°C as measured by DSC. In certain embodiments, "about" means that the temperature varies within ±1°C. In certain embodiments, solid form A is characterized by an endothermic event with an onset between 155±1°C and 168±1°C as measured by DSC. In certain embodiments, solid form A is characterized by an endothermic event as measured by DSC with a peak temperature of 162±1° C. In certain embodiments, solid form A is characterized by a DSC thermogram substantially the same as that shown in FIG.

[0052] In certain embodiments, solid form A exhibits a weight loss of about 0.05% to about 0.3% between about 150° C. and about 225° C. as measured by TGA. In certain embodiments, solid form A exhibits a weight loss of about 0.11% between about 150° C. and about 225° C. as measured by TGA. In certain embodiments, "about" means within ±2° C. of temperature variation. In certain embodiments, solid form A exhibits a weight loss of about 0.05% to about 0.3% between 150±2° C. and about 225±2° C. as measured by TGA. In certain embodiments, solid form A exhibits a weight loss of about 0.11% between 150±2° C. and about 225±2° C. as measured by TGA. In certain embodiments, "about" means within ±1° C. of temperature variation. In certain embodiments, solid form A exhibits a weight loss of about 0.05% to about 0.3% as measured by TGA between 150±1° C. and 225±1° C. In certain embodiments, solid form A exhibits a weight loss of about 0.11% as measured by TGA between 150±1° C. and 225±1° C.

[0053] Solid Form A is non-hygroscopic. In certain embodiments, solid Form A is non-hygroscopic (e.g., less than 0.2% w / w water absorption) at about 25° C. at 0%-90% relative humidity (RH). In certain embodiments, solid Form A is non-hygroscopic (e.g., less than 0.2% w / w water absorption) at about 25° C. at 0%-70% relative humidity (RH).

[0054] Solid Form A is stable. In certain embodiments, solid form A is stable (e.g., no decrease in HPLC area purity % or change in polymorphic form) under various storage conditions. In certain embodiments, solid form A is stable (e.g., no decrease in HPLC area purity % or change in polymorphic form) at about 20° C. to about 90° C. (e.g., 22° C., 25° C., 40° C., 50° C., 60° C., 70° C., or 80° C.) for at least 1 week, preferably at least 2 weeks, preferably at least 3 weeks, preferably at least 1 month, preferably at least 2 months, preferably at least 3 months, preferably at least 4 months, preferably at least 6 months, preferably at least 1 year, preferably at least 2 years, preferably at least 3 years, preferably at least 4 years, or at least 5 years.

[0055] In certain embodiments, solid Form A is stable (e.g., no decrease in HPLC area purity % or change in polymorphic form) at about 20% to about 98% relative humidity (RH) (e.g., RH 40%, RH 60%, RH 75%, or RH 96%) for at least 1 week, preferably at least 2 weeks, preferably at least 3 weeks, preferably at least 1 month, preferably at least 2 months, preferably at least 3 months, preferably at least 4 months, preferably at least 6 months, preferably at least 1 year, preferably at least 2 years, preferably at least 3 years, preferably at least 4 years, preferably at least 5 years.

[0056] In certain embodiments, solid Form A is stable (e.g., no decrease in HPLC area % purity or change in polymorphic form) at 40° C. / 75% relative humidity (RH) for at least 1 week, preferably at least 2 weeks, preferably at least 3 weeks, preferably at least 1 month, preferably at least 2 months, preferably at least 3 months, preferably at least 4 months, preferably at least 6 months, preferably at least 1 year, preferably at least 2 years, preferably at least 3 years, preferably at least 4 years, preferably at least 5 years.

[0057] Solid Form A is not a hydrate. Solid Form A is not a solvate.

[0058] Solid Form A is an anhydrous solid form

[0059] Solid Form A is a non-hygroscopic solid form.

[0060] Solid Form A is an anhydrous and non-hygroscopic solid form.

[0061] Solid Form A is an anhydrous, non-solvate, and non-hygroscopic solid form.

[0062] In certain embodiments, solid form A is prepared by slurrying the amorphous form of compound X in a solvent. In certain embodiments, solid form A is prepared by slurrying the amorphous form of compound X in a solvent selected from tetrahydrofuran, ethyl acetate, isopropyl alcohol, toluene, heptane, water, 1-butanol, 1,2-xylene, acetone, and ethanol, and any combination thereof. In certain embodiments, solid form A is prepared by slurrying the amorphous form of compound X in a solvent selected from tetrahydrofuran, ethyl acetate, isopropyl alcohol, heptane, 1,2-xylene, acetone, and ethanol, and any combination thereof. In certain embodiments, the slurrying is performed at about 20° C. In certain embodiments, the slurrying is performed at about 25° C. In certain embodiments, the slurrying is performed at about 40° C. In certain embodiments, the slurrying is performed with continuous stirring.

[0063] In certain embodiments, solid form A is prepared by a process comprising combining an amorphous form of compound X with a solvent to form a mixture, heating the mixture to form a solution, cooling the solution, and optionally isolating solid form A. In certain embodiments, the solvent is tetrahydrofuran, ethyl acetate, isopropyl alcohol, toluene, heptane, water, 1-butanol, 1,2-xylene, acetone, and ethanol, and any combination thereof. In certain embodiments, the solvent is tetrahydrofuran, ethyl acetate, isopropyl alcohol, heptane, 1,2-xylene, acetone, and ethanol, and any combination thereof. In certain embodiments, the solvent is tetrahydrofuran. In certain embodiments, the solution is heated to a temperature of about 30° C. In certain embodiments, the solution is heated to a temperature of about 35° C. In certain embodiments, the solution is heated to a temperature of about 40° C. In certain embodiments, the solution is heated to a temperature of about 45° C. In certain embodiments, the solution is heated to a temperature of about 50° C. In certain embodiments, the solution is heated to a temperature greater than 30° C. In certain embodiments, the solution is heated to a temperature greater than 40° C. In certain embodiments, the solution is heated to a temperature greater than 50° C. In certain embodiments, the solution is cooled to a temperature of about 25° C. or less. In certain embodiments, the solution is cooled to a temperature of about 20° C. or less. In certain embodiments, the solution is cooled to a temperature of about 15° C. or less. In certain embodiments, the cooling comprises multiple cooling steps. In certain embodiments, the cooling comprises cooling to a first temperature followed by cooling to a second temperature.

[0064] Solid form B (“Form B”) In another aspect, the disclosure provides solid form B of compound X, characterized by having X-ray powder diffraction ("XRPD") peaks at about 8.0, 15.0, and 19.3 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0, 15.0, 19.3, 25.6, and 26.9 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0, 15.0, 16.2, 19.3, 19.6, 25.6, and 26.9 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0, 14.5, 15.0, 16.2, 19.3, 19.6, 25.3, 25.6, 26.9, 28.8, 28.9, and 29.2 degrees 2θ using CuKα radiation.

[0065] In certain embodiments, "about" means that the indicated XRPD peaks may vary by ±0.2 degrees 2θ. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.2, 15.0±0.2, and 19.3±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.2, 15.0±0.2, 19.3±0.2, 25.6±0.2, and 26.9±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.2, 15.0±0.2, 16.2±0.2, 19.3±0.2, 19.6±0.2, 25.6±0.2, and 26.9±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.2, 14.5±0.2, 15.0±0.2, 16.2±0.2, 19.3±0.2, 19.6±0.2, 25.3±0.2, 25.6±0.2, 26.9±0.2, 28.8±0.2, 28.9±0.2, and 29.2±0.2 degrees 2θ using CuKα radiation.

[0066] In certain embodiments, "about" means that the indicated XRPD peaks may vary by ±0.1 degrees 2θ. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.1, 15.0±0.1, and 19.3±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.1, 15.0±0.1, 19.3±0.1, 25.6±0.1, and 26.9±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.1, 15.0±0.1, 16.2±0.1, 19.3±0.1, 19.6±0.1, 25.6±0.1, and 26.9±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form B is characterized by having XRPD peaks at about 8.0±0.1, 14.5±0.1, 15.0±0.1, 16.2±0.1, 19.3±0.1, 19.6±0.1, 25.3±0.1, 25.6±0.1, 26.9±0.1, 28.8±0.1, 28.9±0.1, and 29.2±0.1 degrees 2θ using CuKα radiation.

[0067] In certain embodiments, solid form B is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2 through 4 of the table below. [Table 3]

[0068] In certain embodiments, solid form B is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0063] ,

[0064] , and

[0065] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from the second column for the embodiment in paragraph

[0063] , the third column for the embodiment in paragraph

[0064] , and the fourth column for the embodiment in paragraph

[0065] , respectively).

[0069] In certain embodiments, solid form B is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 4]

[0070] In certain embodiments, solid form B is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0063] ,

[0064] , and

[0065] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from the second column for the embodiment in paragraph

[0063] , the third column for the embodiment in paragraph

[0064] , and the fourth column for the embodiment in paragraph

[0065] , respectively).

[0071] In certain embodiments, solid form B is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 5]

[0072] In certain embodiments, solid form B is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0063] ,

[0064] , and

[0065] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from column 2 for the embodiment in paragraph

[0063] , column 3 for the embodiment in paragraph

[0064] , and column 4 for the embodiment in paragraph

[0065] , respectively).

[0073] In certain embodiments, solid form B is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0074] In certain embodiments, solid form B is characterized by three endothermic events with an onset at about 39° C. and a peak temperature of about 85° C.; an onset at about 127° C. and a peak temperature of about 131° C.; and / or an onset at about 162° C. and a peak temperature of about 163° C., as measured by DSC. In certain embodiments, solid form B is characterized by an endothermic event with an onset at about 39° C. and a peak temperature of about 85° C., as measured by DSC. In certain embodiments, solid form B is characterized by an endothermic event with an onset at about 127° C. and a peak temperature of about 131° C., as measured by DSC. In certain embodiments, solid form B is characterized by an endothermic event with an onset at about 162° C. and a peak temperature of about 163° C., as measured by DSC.

[0075] In certain embodiments, "about" means that the temperature varies within ±2°C. In certain embodiments, solid form B is characterized by three endothermic events, as measured by DSC, with an onset at about 39±2°C and a peak temperature of about 85±2°C; an onset at about 127±2°C and a peak temperature of about 131±2°C; and / or an onset at about 162±2°C and a peak temperature of about 163±2°C. In certain embodiments, solid form B is characterized by an endothermic event, as measured by DSC, with an onset at about 39±2°C and a peak temperature of about 85±2°C. In certain embodiments, solid form B is characterized by an endothermic event, as measured by DSC, with an onset at about 127±2°C and a peak temperature of about 131±2°C. In certain embodiments, solid form B is characterized by an endothermic event with an onset at about 162±2° C. with a peak temperature of about 163±2° C. as measured by DSC.

[0076] In certain embodiments, "about" means that the temperature varies within ±1°C. In certain embodiments, solid form B is characterized by three endothermic events, as measured by DSC, with an onset at about 39±1°C and a peak temperature of about 85±1°C; an onset at about 127±1°C and a peak temperature of about 131±1°C; and / or an onset at about 162±1°C and a peak temperature of about 163±1°C. In certain embodiments, solid form B is characterized by an endothermic event, as measured by DSC, with an onset at about 39±1°C and a peak temperature of about 85±1°C. In certain embodiments, solid form B is characterized by an endothermic event, as measured by DSC, with an onset at about 127±1°C and a peak temperature of about 131±1°C. In certain embodiments, solid form B is characterized by an endothermic event with an onset at about 162±1° C. with a peak temperature of about 163±1° C. as measured by DSC.

[0077] In certain embodiments, solid form B is characterized by a DSC thermogram substantially similar to that shown in FIG.

[0078] In certain embodiments, solid form B exhibits a weight loss of about 3% to about 5% between about 25° C. and about 100° C. as measured by TGA. In certain embodiments, solid form B exhibits a weight loss of about 3.5% to about 4.5% between about 25° C. and about 100° C. as measured by TGA. In certain embodiments, solid form B exhibits a weight loss of about 4% between about 25° C. and about 100° C. as measured by TGA.

[0079] In certain embodiments, "about" means that the percent weight loss varies within ±0.3% and the temperature varies within ±3°C. In certain embodiments, solid form B exhibits a weight loss of about 3±0.3% and about 5±0.3% between about 25±3°C and about 100±3°C as measured by TGA. In certain embodiments, solid form B exhibits a weight loss of about 3.5±0.3% and about 4.5±0.3% between about 25±3°C and about 100±3°C as measured by TGA. In certain embodiments, solid form B exhibits a weight loss of about 4±0.3% between about 25±3°C and about 100±3°C as measured by TGA.

[0080] In certain embodiments, solid form B is a solvate. In certain embodiments, solid form B is a hydrate.

[0081] In certain embodiments, solid form B is prepared by slurrying an amorphous form of compound X in a solvent comprising water. In certain embodiments, solid form B is prepared by slurrying an amorphous form of compound X in water. In certain embodiments, the slurrying is performed at about 20° C. In certain embodiments, the slurrying is performed at about 25° C. In certain embodiments, the slurrying is performed at about 40° C. In certain embodiments, the slurrying is performed with continuous stirring.

[0082] In certain embodiments, solid form B is prepared by a process comprising combining an amorphous form of compound X with a solvent comprising water to form a mixture, heating the mixture to form a solution, cooling the solution, and optionally isolating solid form B. In certain embodiments, the solvent is water. In certain embodiments, the solution is heated to a temperature of about 30° C. In certain embodiments, the solution is heated to a temperature of about 35° C. In certain embodiments, the solution is heated to a temperature of about 40° C. In certain embodiments, the solution is heated to a temperature of about 45° C. In certain embodiments, the solution is heated to a temperature of about 50° C. In certain embodiments, the solution is heated to a temperature greater than 30° C. In certain embodiments, the solution is heated to a temperature greater than 40° C. In certain embodiments, the solution is heated to a temperature greater than 50° C. In certain embodiments, the solution is cooled to a temperature of about 25° C. or less. In certain embodiments, the solution is cooled to a temperature of about 20° C. or less. In certain embodiments, the solution is cooled to a temperature of about 15° C. or less. In certain embodiments, the cooling comprises multiple cooling steps. In certain embodiments, the cooling comprises cooling to a first temperature followed by cooling to a second temperature.

[0083] Solid form C (“Form C”) In yet another aspect, the disclosure provides solid form C of compound X, characterized by having X-ray powder diffraction ("XRPD") peaks at about 8.6, 8.7, 15.0, 18.9, and 24.7 degrees 2θ using CuKα radiation. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6, 8.7, 15.0, 18.9, 19.6, 19.7, 24.7, and 26.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6, 8.7, 15.0, 17.2, 18.9, 19.6, 19.7, 21.3, 23.6, 24.7, 26.2, 26.6, 28.1, 28.8, and 30.3 degrees 2θ using CuKα radiation.

[0084] In certain embodiments, "about" means that the indicated XRPD peaks may vary by ±0.2 degrees 2θ. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6±0.2, 8.7±0.2, 15.0±0.2, 18.9±0.2, and 24.7±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6±0.2, 8.7±0.2, 15.0±0.2, 18.9±0.2, 19.6±0.2, 19.7±0.2, 24.7±0.2, and 26.2±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6±0.2, 8.7±0.2, 15.0±0.2, 17.2±0.2, 18.9±0.2, 19.6±0.2, 19.7±0.2, 21.3±0.2, 23.6±0.2, 24.7±0.2, 26.2±0.2, 26.6±0.2, 28.1±0.2, 28.8±0.2, and 30.3±0.2 degrees 2θ using CuKα radiation.

[0085] In certain embodiments, "about" means that the indicated XRPD peaks may vary by ±0.1 degrees 2θ. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6±0.1, 8.7±0.1, 15.0±0.1, 18.9±0.1, and 24.7±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6±0.1, 8.7±0.1, 15.0±0.1, 18.9±0.1, 19.6±0.1, 19.7±0.1, 24.7±0.1, and 26.2±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form C is characterized by having XRPD peaks at about 8.6±0.1, 8.7±0.1, 15.0±0.1, 17.2±0.1, 18.9±0.1, 19.6±0.1, 19.7±0.1, 21.3±0.1, 23.6±0.1, 24.7±0.1, 26.2±0.1, 26.6±0.1, 28.1±0.1, 28.8±0.1, and 30.3±0.1 degrees 2θ using CuKα radiation.

[0086] In certain embodiments, solid form C is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 6]

[0087] In certain embodiments, solid form C is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0082] ,

[0083] , and

[0084] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from column 2 for the embodiment in paragraph

[0082] , column 3 for the embodiment in paragraph

[0083] , and column 4 for the embodiment in paragraph

[0084] , respectively).

[0088] In certain embodiments, solid form C is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 7]

[0089] In certain embodiments, solid form C is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0082] ,

[0083] , and

[0084] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from column 2 for the embodiment in paragraph

[0082] , column 3 for the embodiment in paragraph

[0083] , and column 4 for the embodiment in paragraph

[0084] , respectively).

[0090] In certain embodiments, solid form C is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 8]

[0091] In certain embodiments, solid form C is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0082] ,

[0083] , and

[0084] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from the second column for the embodiment in paragraph

[0082] , the third column for the embodiment in paragraph

[0083] , or the fourth column for the embodiment in paragraph

[0084] , respectively).

[0092] In certain embodiments, solid form C is characterized by an XRPD pattern substantially the same as that shown in FIG.

[0093] Solid form D (“Form D”) In another aspect, the disclosure provides solid form D of compound X, characterized by having X-ray powder diffraction ("XRPD") peaks at about 6.8, 9.1, and 15.5 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8, 9.1, 14.3, 15.5, and 25.8 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8, 9.1, 13.6, 14.3, 15.5, 18.6, and 25.8 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8, 9.1, 13.6, 14.3, 15.5, 18.6, 20.9, 25.8, and 27.5 °2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8, 9.1, 13.6, 14.3, 15.5, 18.6, 20.9, 21.2, 24.5, 25.8, 27.5, and 27.7 °2θ using CuKα radiation.

[0094] In one aspect, the disclosure provides solid form D of compound X, characterized by having X-ray powder diffraction ("XRPD") peaks at about 6.8±0.2, 9.1±0.2, and 15.5±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.2, 9.1±0.2, 14.3±0.2, 15.5±0.2, and 25.8±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.2, 9.1±0.2, 13.6±0.2, 14.3±0.2, 15.5±0.2, 18.6±0.2, and 25.8±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.2, 9.1±0.2, 13.6±0.2, 14.3±0.2, 15.5±0.2, 18.6±0.2, 20.9±0.2, 25.8±0.2, and 27.5±0.2 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.2, 9.1±0.2, 13.6±0.2, 14.3±0.2, 15.5±0.2, 18.6±0.2, 20.9±0.2, 21.2±0.2, 24.5±0.2, 25.8±0.2, 27.5±0.2, and 27.7±0.2 degrees 2θ using CuKα radiation.

[0095] In one aspect, the disclosure provides solid form D of compound X, characterized by having X-ray powder diffraction ("XRPD") peaks at about 6.8±0.1, 9.1±0.1, and 15.5±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.1, 9.1±0.1, 14.3±0.1, 15.5±0.1, and 25.8±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.1, 9.1±0.1, 13.6±0.1, 14.3±0.1, 15.5±0.1, 18.6±0.1, and 25.8±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.1, 9.1±0.1, 13.6±0.1, 14.3±0.1, 15.5±0.1, 18.6±0.1, 20.9±0.1, 25.8±0.1, and 27.5±0.1 degrees 2θ using CuKα radiation. In certain embodiments, solid form D is characterized by having XRPD peaks at about 6.8±0.1, 9.1±0.1, 13.6±0.1, 14.3±0.1, 15.5±0.1, 18.6±0.1, 20.9±0.1, 21.2±0.1, 24.5±0.1, 25.8±0.1, 27.5±0.1, and 27.7±0.1 degrees 2θ using CuKα radiation.

[0096] In certain embodiments, solid form D is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 9]

[0097] In certain embodiments, solid form D is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0092] ,

[0093] , and

[0094] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from column 2 for the embodiment in paragraph

[0092] , column 3 for the embodiment in paragraph

[0093] , and column 4 for the embodiment in paragraph

[0094] , respectively).

[0098] In certain embodiments, solid form D is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 10]

[0099] In certain embodiments, solid form D is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0092] ,

[0093] , and

[0094] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from column 2 for the embodiment in paragraph

[0092] , column 3 for the embodiment in paragraph

[0093] , and column 4 for the embodiment in paragraph

[0094] , respectively).

[0100] In certain embodiments, solid form D is characterized by having an XRPD peak at about the position (degrees 2 theta or °2 theta) shown in any one of columns 2-4 of the table below. [Table 11-1] [Table 11-2]

[0101] In certain embodiments, solid form D is characterized by one or more of the XPRD peaks set forth in any one of the embodiments described in paragraphs

[0092] ,

[0093] , and

[0094] above, as well as the remaining distinct XPRD peaks selected from those set forth in the table immediately above (wherein the remaining distinct peaks are selected from the second column for the embodiment in paragraph

[0092] , the third column for the embodiment in paragraph

[0093] , or the fourth column for the embodiment in paragraph

[0094] , respectively).

[0102] In certain embodiments, solid form D is characterized by an XRPD pattern substantially the same as that shown in FIG.

[0103] In certain embodiments, solid form D is characterized by an endothermic event with an onset between about 45°C and about 50°C as measured by DSC. In certain embodiments, solid form D is characterized by an endothermic event with a peak temperature of about 64°C as measured by DSC. In certain embodiments, "about" means that the temperature varies within ±3°C. In certain embodiments, solid form D is characterized by an endothermic event with an onset between about 45±3°C and 50±3°C as measured by DSC. In certain embodiments, solid form D is characterized by an endothermic event with a peak temperature of about 64±3°C as measured by DSC. In certain embodiments, "about" means that the temperature varies within ±2°C. In certain embodiments, solid form D is characterized by an endothermic event with an onset between 45±2°C and 50±2°C as measured by DSC. In certain embodiments, solid form D is characterized by an endothermic event with a peak temperature of 64±2°C as measured by DSC. In certain embodiments, "about" means within ±1° C. of temperature variation. In certain embodiments, solid form D is characterized by an endothermic event with an onset at 45±1° C. to 50±1° C. as measured by DSC. In certain embodiments, solid form D is characterized by an endothermic event with a peak temperature of 64±1° C. as measured by DSC. In certain embodiments, solid form D is characterized by a DSC thermogram substantially the same as that shown in FIG. 28.

[0104] The terms "crystalline polymorphs", "crystal polymorph", "crystal form", "polymorph" or "polymorphic form" refer to crystal structures in which a compound (e.g., its free base, salt, or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, crystal shape, optical and electrical properties, stability, and solubility. The crystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystal form to predominate. Crystal polymorphs of a compound can be prepared by crystallizing under different conditions. Additionally, crystal polymorphism may exist, but is not limited to, and any crystal form may be a single crystal form or a mixture of crystal forms or anhydrous or hydrated crystal forms.

[0105] The term "amorphous form" refers to a non-crystalline solid state form of a substance.

[0106] Additionally, the compounds (e.g., free bases and salts, as well as their amorphous, crystalline, and polymorphic forms) can exist in hydrated or non-hydrated (anhydrous) forms, or as solvates with other solvent molecules, or in unsolvated forms. Non-limiting examples of hydrates include hemihydrates, monohydrates, dihydrates, and the like. Non-limiting examples of solvates include DMSO solvates, DMSO hemisolvates, acetone solvates, acetone hemisolvates, acetonitrile solvates, acetonitrile hemisolvates, and the like.

[0107] All forms of the compounds of the present application are contemplated, either in admixture or in pure or substantially pure form, including crystalline forms of racemic mixtures and crystalline forms of individual isomers.

[0108] Polymorphs of a molecule can be obtained by many methods known in the art, including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

[0109] Techniques for characterizing solid forms of a compound, such as polymorphs, include, but are not limited to, DSC, X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy (such as IR or Raman spectroscopy), TGA, DTA, DVS, solid state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.

[0110] As used herein, the term "solvate" refers to a solvate form that contains either a stoichiometric amount of solvent or a non-stoichiometric amount of solvent. Some compounds tend to form solvates by trapping a fixed molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as H2O, and such combinations can form one or more hydrates. For example, the solvate may be a DMSO solvate, a dichloromethane (DCM) solvate, a methyl ethyl ketone (MEK solvate), an acetone solvate, an acetonitrile solvate, or a tetrahydrofuran (THF) solvate.

[0111] As used herein, the terms "unsolvated" or "desolvated" refer to the solid state (e.g., crystalline forms, amorphous forms, and polymorphs) of a compound that is free of solvent.

[0112] As used herein, the term "pure" means that the indicated compound is present at about 90-100%, preferably 95-100%, more preferably 98-100% or 99-100%, by weight or molar ratio, with, for example, less than about 10%, less than about 5%, less than about 2%, or less than about 1% of impurities, including, for example, decomposition products, oxidation products, solvents, and / or other undesirable impurities.

[0113] As used herein, a compound is "stable" if no significant amount of degradation products are observed under conditions of humidity (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% relative humidity [RH]), light exposure, and temperature (e.g., above 0°C, e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C) for a specified period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks). A compound is not considered stable under certain conditions if degradation impurities appear or the area fraction of impurities present (e.g., AUC as characterized by HPLC) begins to increase. The amount of increase in degradation as a function of time is important in determining the stability of a compound.

[0114] As used herein, the term "mix" means to combine, blend, stir, shake, swirl, or agitate. The term "mix" means to mix, shake, stir, or swirl. The term "mix" means to mix, shake, stir, or swirl.

[0115] Unless otherwise indicated, the terms "approximately" and "about" are synonymous. In certain embodiments, "approximately" and "about" refer to ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the indicated amount, value, or time period. In some embodiments, "approximately" and "about" refer to ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the listed amount, value, or time period. In some embodiments, "approximately" and "about" refer to ±5% of the listed amount, value, or time period. In some embodiments, "approximately" and "about" refer to ±2% or ±1% of the listed amount, value, or time period.

[0116] When the terms "approximately" and "about" are used in describing an XRPD peak, these terms refer to the listed XRPD peak ±0.3 °2θ, ±0.2 °2θ, or ±0.1 °2θ. In some embodiments, the terms "approximately" and "about" refer to the listed XRPD peak ±0.2 °2θ. In some embodiments, the terms "approximately" and "about" refer to the listed XRPD peak ±0.1 °2θ.

[0117] When the terms "approximately" and "about" are used in referring to a temperature or temperature range, these terms refer to the indicated temperature or temperature range ±5° C., ±2° C., or ±1° C. In some embodiments, the terms "approximately" and "about" refer to the indicated temperature or temperature range ±2° C.

[0118] Pharmaceutical Compositions In another aspect, the present disclosure also provides a pharmaceutical composition comprising a solid form of Compound X in combination with at least one pharma- ceutically acceptable excipient or carrier.

[0119] In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D.

[0120] A "pharmaceutical composition" is a formulation that contains a compound of the present application in a form suitable for administration to a subject. In certain embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., one or more formulations of a compound of the present disclosure) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that routine variations in the amount may need to be made depending on the age and condition of the patient. Dosages also vary depending on the route of administration. Various routes are contemplated, such as oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In certain embodiments, the active compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any needed preservatives, buffers, or propellants.

[0121] As used herein, the phrase "pharmacologically acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0122] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one excipient and more than one excipient.

[0123] The pharmaceutical compositions of the present application are formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral (intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous administration may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, phosphates, and the like; and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be placed into glass or plastic ampoules, disposable syringes, or multiple dose vials.

[0124] The compounds or pharmaceutical compositions of the present application can be administered to a subject in many well-known ways currently used for chemotherapy treatment. For example, in the case of cancer treatment, the compounds of the present application can be directly injected into a tumor, injected into the bloodstream or body cavity, or taken orally, or applied through the skin using a patch. The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. It is advisable to closely monitor the patient's condition (e.g., cancer, precancerous condition) and health status during and for a reasonable period after treatment.

[0125] The term "therapeutically effective amount" as used herein refers to an amount of an agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a particular situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In certain embodiments, the disease or disorder is selected from immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, and neurological disorders. In another embodiment, the disease or condition being treated is cancer. In certain embodiments, the disease or condition being treated is a cell proliferative disorder.

[0126] For any compound, the therapeutically effective amount can be estimated initially in cell culture assays, such as neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal models may be used to determine appropriate concentration ranges and routes of administration. Such information may then be used to determine useful doses and routes of administration for administration to humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form used, the sensitivity of the patient, and the route of administration.

[0127] Dosage and administration methods are adjusted to provide sufficient levels of active agent or to maintain the desired effect.Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, timing and frequency of administration, drug combinations, sensitivity of reactions, and tolerability / response to treatment.Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0128] Pharmaceutical compositions containing the active compounds of the present application may be manufactured in a generally known manner, such as by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers, including excipients and / or auxiliaries, that facilitate processing of the active compounds into preparations that can be used as pharmaceuticals. Of course, the appropriate formulation depends on the chosen route of administration.

[0129] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippan, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents in the composition, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0130] Injectable sterile solution can be prepared by incorporating the active compound in the required amount in a suitable solvent with one or combination of the above-listed components as required, followed by filtration sterilization.Generally, dispersion is prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and other components required from the above-listed ones.For the preparation of sterile powder for preparing injectable sterile solution, the preparation method is vacuum drying and freeze-drying, whereby the powder of active ingredient and any additional ingredient is obtained from its solution that has been previously sterilized and filtered.

[0131] Oral compositions generally include an inert diluent or an edible pharma- ceutically acceptable carrier. They can be placed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied orally, swished in the mouth, and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0132] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, such as a gas such as carbon dioxide, or a nebulizer.

[0133] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for permeating the barrier is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be carried out by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams generally known in the art.

[0134] The active compound can be prepared with a pharma- ceutically acceptable carrier that prevents Compound X from being rapidly eliminated from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be clear to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells with monoclonal antibodies against viral antigens, can also be used as pharma-ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0135] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in dosage unit form.Dosage unit form as used herein refers to a physically separate unit suitable as a unitary dosage for a therapeutic subject, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect in association with a required pharmaceutical carrier.The specification of dosage unit form of this application is determined and directly depends on the inherent properties of active compound X and the specific therapeutic effect to be achieved.

[0136] In therapeutic applications, the dosage of the pharmaceutical compositions used in accordance with the present application will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or professional administering the treatment, among other factors influencing the dosage selected. In general, the dosage should be sufficient to slow and preferably cause regression of tumor growth, preferably even complete regression of the cancer. Dosages may range from about 0.01 mg / kg to about 5000 mg / kg per day. An effective amount of an agent is an amount that produces an improvement that is objectively identifiable by a clinician or other qualified observer. For example, tumor regression in a patient may be measured in terms of tumor diameter. A decrease in tumor diameter indicates regression. Failure of tumors to recur after cessation of treatment also indicates tumor regression. As used herein, the term "dosage effective manner" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0137] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0138] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present application, where the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, acid), hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and those derived from inorganic and organic acids selected from commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0139] Other examples of pharma- ceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, etc. The present application also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0140] It should be understood that all references to pharma- ceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) of the same salt as defined herein.

[0141] The compounds of the present application can also be prepared as esters, for example, pharma- ceutically acceptable esters. For example, a carboxylic acid function in a compound can be converted to a corresponding ester, for example, a methyl ester, an ethyl ester, or other ester. Also, an alcohol group in a compound can be converted to a corresponding ester, for example, an acetate ester, a propionate ester, or other ester.

[0142] The compound or its pharma- ceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative is administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In certain embodiments, the compound or its pharma- ceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0143] Dosage regimens using the compounds are selected depending on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the renal and hepatic function of the patient, and the particular compound or a pharma- ceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof being used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0144] For techniques regarding formulation and administration of the compounds disclosed in this application, see Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton PA (1995). In one embodiment, the compounds described herein are used in pharmaceutical preparations in combination with a pharma- ceutically acceptable carrier or diluent. Suitable pharma-ceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0145] Treatment method In a further aspect, the present disclosure provides a method for inhibiting PDE9 in a subject, comprising administering to the subject a solid form of compound X. In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D.

[0146] The present disclosure also provides a method of treating a disease or disorder, comprising administering to a subject in need thereof an amount of a solid form of Compound X. In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D. In certain embodiments, the amount is a therapeutically effective amount. In certain embodiments, the disease or disorder is mediated by PDE9 or is one in which PDE9 is involved or plays a role in the initiation and / or development.

[0147] In certain embodiments, the disease or disorder is a neurodegenerative disease or disorder, a cardiovascular disorder or disorder, a genitourinary system such as sexual dysfunction, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), diabetes, cognitive impairment, cognitive dysfunction, obesity, or cardiometabolic syndrome.

[0148] The present disclosure also provides a method of treating a neurodegenerative disease or disorder, comprising administering to a subject in need thereof an amount of a solid form of Compound X. The present disclosure further provides a method of preventing a neurodegenerative disease or disorder, comprising administering to a subject in need thereof an amount of a solid form of Compound X. In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D. In certain embodiments, the amount is a therapeutically effective amount.

[0149] The present disclosure further provides the use of a solid form of compound X in the manufacture of a medicament for treating or preventing a neurodegenerative disease or disorder. In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D.

[0150] Neurodegenerative diseases or disorders are diseases and disorders associated with neurodegeneration. Neurodegenerative diseases of the disclosure include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease or motor neuron disease), ataxia telangiectasia, Batten disease (also known as Speelmeyer-Voght-Sjogren-Batten disease), Binswanger dementia (subcortical arteriosclerotic encephalopathy), bipolar disorder, bovine spongiform encephalopathy (BSE), Canavan disease, chemotherapy-induced dementia, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, depression, Down's syndrome, frontotemporal lobar degeneration (including frontotemporal dementia, semantic dementia, and progressive non-fluent aphasia), Gerstmann-Straussler-Scheinker disease, glaucoma, Huntington's disease (chorea), HIV-associated dementia, hyperactivity disorder, Kennedy's disease, disease, Korsakoff's syndrome (amnesic-confabulatory syndrome) syndrome), Krabbe disease, dementia with Lewy bodies, wordless progressive aphasia, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy (olivopontocerebellar atrophy), myasthenia gravis, Parkinson's disease, Pelizaeus-Merzbach disease, Pick's disease, presenile dementia (mild cognitive impairment), primary lateral sclerosis, primary progressive aphasia, radiation-induced dementia, Refsum's disease (phytanic acid storage disease), Sandhoff disease, Schilder's disease, schizophrenia, semantic dementia, senile dementia, Shy-Drager syndrome, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), tabes dorsalis, tardive dyskinesia, vascular amyloidosis, and vascular dementia (multi-infarct dementia).

[0151] In certain preferred embodiments, the neurodegenerative disease or disorder is Alzheimer's disease.

[0152] The present disclosure also provides a method of treating a cardiovascular disease or disorder, comprising administering to a subject in need thereof an amount of a solid form of Compound X. The present disclosure further provides a method of preventing a cardiovascular disease or disorder, comprising administering to a subject in need thereof an amount of a solid form of Compound X. In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D. In certain embodiments, the amount is a therapeutically effective amount.

[0153] Cardiovascular disorders or diseases may include systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery disease, atherosclerosis, stroke, thrombosis, conditions of reduced blood vessel patency (e.g., after percutaneous coronary intervention), peripheral vascular disease, renal disease associated with cardiovascular problems, angina pectoris (including stable angina, UI1 stable angina, and variant (Prinzmetal) angina), aortic disease, Marfan syndrome, myocardial disease, congenital heart disease, deep vein thrombosis, heart failure, pericardial disease, valvular heart disease, rheumatic heart disease, and any condition in which improved blood flow leads to improved end-organ function.

[0154] Other PDE9-related diseases or disorders that can be treated or prevented by the methods of the present disclosure include diseases or disorders of the urogenital system, such as sexual dysfunction, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and diabetes.

[0155] The present disclosure also provides a method of treating cardiometabolic syndrome or obesity, comprising administering to a subject in need thereof an amount of a solid form of Compound X. The present disclosure further provides a method of preventing cardiometabolic syndrome or obesity, comprising administering to a subject in need thereof an amount of a solid form of Compound X. In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D. In certain embodiments, the amount is a therapeutically effective amount.

[0156] The present invention further provides the use of a solid form of compound X in the manufacture of a medicament for treating or preventing cardiometabolic syndrome or obesity. In certain embodiments, the solid form is solid form A. In certain embodiments, the solid form is solid form B. In certain embodiments, the solid form is solid form C. In certain embodiments, the solid form is solid form D.

[0157] In some embodiments, the obesity is central obesity (ie, abdominal obesity or central adiposity).

[0158] In some embodiments, the subject is male. In some embodiments, the subject is female.

[0159] The present invention also provides a method for promoting neural repair and functional recovery in subjects suffering from traumatic or non-traumatic brain injury, spinal cord injury, or peripheral nerve injury. Traumatic brain injury includes both closed head injury (skull not fractured) and open or penetrating head injury (object penetrates the skull and breaks the dura). In open or penetrating head injury, acute trauma (e.g., accident, fall, or assault) causes damage to brain tissue by tearing, stretching, bruising, or swelling. Causes of non-traumatic brain injury include aneurysm, stroke, meningitis, lack of oxygen due to anoxia, hypoxia, or ischemia, brain tumor, infection (e.g., encephalitis), poisoning, drug abuse, etc.

[0160] The present invention provides methods for treating cognitive impairment and cognitive dysfunction resulting from brain injury and from neurodegenerative diseases and disorders.

[0161] The present invention also provides methods for improving cognitive disorders, including deficits in perception, concentration, learning, memory, communication, reasoning, and problem-solving.

[0162] As used herein, "treatment" or "treating" means the management and care of a patient for the purpose of overcoming a disease, condition, or disorder, and includes the administration of a compound of the present application to alleviate the symptoms or complications of the disease, condition, or disorder or to eliminate the disease, condition, or disorder.

[0163] As used herein, "prophylaxis" or "preventing" refers to reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0164] As used herein, the term "alleviate" is meant to describe the process by which the severity of a sign or symptom of a disorder is reduced. Importantly, a sign or symptom may be alleviated without being eliminated. In a preferred embodiment, administration of a compound of the present application results in the elimination of a sign or symptom, but elimination is not necessary. An effective dosage is expected to reduce the severity of a sign or symptom. For example, a sign or symptom of a disorder such as cancer, which may occur in multiple locations, is alleviated if the severity of the cancer is reduced in at least one of the multiple locations.

[0165] As used herein, the term "symptom" is defined as an indication of a disease, illness, injury, or something unwell in the body. Symptoms are felt or noticed by the individual experiencing them, but may not be readily noticeable by others.

[0166] As used herein, the term "sign" is also defined as something that indicates that something is not right with the body, however a sign is defined as something that a doctor, nurse, or other medical professional would recognize.

[0167] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present application are apparent from the different examples. The examples provided illustrate components and methodologies useful for implementing the present application. These examples do not limit the uses described in the claims. Based on the present application, a person skilled in the art can identify and use other components and methodologies useful for implementing the present application. EXAMPLES

[0168] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present application to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to limit the scope of the present application. It should also be understood that other various embodiments, modifications, and equivalents thereof that may be suggested to those skilled in the art may be resorted to without departing from the spirit of the present application and / or the scope of the appended claims.

[0169] Materials and Methods: X-ray powder diffraction XRPD patterns were collected on a Bruker-AXS Ltd. D4 Endeavor powder X-ray diffractometer equipped with an automatic sample changer, a theta-2 theta goniometer, an automatic beam divergence slit, and a PSD Vantec-1 detector. The X-ray tube voltage and current were set at 35 kV and 40 mA, respectively. Data were collected at Cu wavelengths from 2.0 to 55.0 degrees two theta (°2θ) using a step size of 0.018°2θ and a time of 0.2 seconds per step. Sample powders were prepared by placing the powder in a silicon low background cavity holder and spun at 60 rpm during data collection. Data were analyzed with DIFFRAC.EVA V5.0 software (e.g., for solid form A). Alternatively, XRPD analysis was performed on a PANalytical X'pertpro equipped with a PIXcel detector (128 channels) and samples were scanned from 3 to 35°2θ (e.g., for solid forms B and C). The material was gently ground to release any aggregates and loaded into a multi-well plate with a Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed in the diffractometer and analyzed using CuK radiation (α1λ=1.54060 Å, α2=1.54443 Å; β=1.39225 Å, α1:α2 ratio=0.5) run in transmission mode (step size 0.0130°2θ, step time 18.87 s) using a generator setting of 40 kV / 40 mA. Data were visualized and images were generated using the High Score Plus 4.9 desktop application (PANalytical, 2020).

[0170] To obtain absolute peak positions, the powder patterns were aligned against a simulated powder pattern from a crystal structure of the same morphology dissolved at room temperature.

[0171] Differential Scanning Calorimetry 1.487 mg of solid Form A was weighed into an aluminum Tzero pan. This was sealed with a Tzero lid and crimped shut. Samples were run against an empty reference pan of the same type in a TA Instruments Discovery Differential Scanning Calorimeter using nitrogen purge gas and heating the sample from 25°C to 275°C at 10°C / min. Alternatively, approximately 1-5 mg of material was weighed into an aluminum DSC pan and non-hermetically sealed with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC2500 Differential Scanning Calorimeter equipped with an RC90 cooler. The samples and standards were all heated to 190°C at a scan rate of 10°C / min and the resulting heat flow response was monitored. The samples were re-cooled to 20°C and then all re-heated to 190°C at 10°C / min. Nitrogen was used as the purge gas at 50 cm. 3 A flow rate of 1 / min was used.

[0172] Thermogravimetric analysis 10.9587 mg of solid Form A was placed in a platinum crucible. This was analyzed on a TA Instruments Discovery Thermogravimetric Analyzer using nitrogen purge gas and heating the sample from 25 °C to 300 °C at 10 °C / min. Alternatively, approximately 5-10 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and held at room temperature. The sample was then heated at a rate of 10 °C / min from 20 °C to 400 °C while the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas at 300 cm. 3 A flow rate of 1 / min was used.

[0173] Polarized Light Microscopy (PLM) The presence of crystallinity (birefringence) was determined using an Olympus BX53 microscope equipped with cross-polarized lenses and a Motic camera. Images were taken using Motic Images Plus 3.0. All images were recorded using a 20x objective unless otherwise stated.

[0174] Karl Fischer Coulometric Titration (KF) Approximately 10-15 mg of solid material was accurately weighed into a vial. The solid was then manually introduced into the titration cell of a Mettler Toledo C30 Compact Titrator. After the solid was added, the vial was reweighed and the weight of the added solid was entered into the instrument. The titration began 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.

[0175] Infrared spectroscopy (FT-IR) Infrared spectroscopy was performed on a Bruker ALPHAP spectrometer. A sufficient amount of material was placed in the center of the spectrometer plate and spectra were acquired using the following parameters: o Resolution: 4cm -1 o Background scan time: 16 scans o Sample scan time: 16 scans Data collection: 4000~400cm -1 oResult Spectrum: Transmittance o Software: OPUS version 6

[0176] nuclear magnetic resonance (NMR) NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated dimethylsulfoxide and samples were prepared to a concentration of approximately 10 mM.

[0177] Variable Temperature X-ray Powder Diffraction (VT-XRPD) VT-XRPD analysis was performed on a Philips X'Pert Pro Multipurpose diffractometer equipped with a temperature chamber. It was performed in Bragg-Brentano geometry (step size 0.008°2θ) using a generator setting of 40 kV / 40 mA, and samples were scanned from 4 to 35.99°2θ using CuK radiation (α1λ = 1.54060 Å, α2 = 1.54443 Å, β = 1.39225 Å, α1:α2 ratio = 0.5).

[0178] Variable Humidity X-ray Powder Diffraction (VH-XRPD) VH-XRPD analysis was performed on a Philips X'Pert Pro Multipurpose diffractometer equipped with a humidity chamber. It was performed in Bragg-Brentano geometry (step size 0.008°2θ) using a generator setting of 40 kV / 40 mA, and samples were scanned from 4 to 35.99°2θ using CuK radiation (α1λ=1.54060 Å, α2=1.54443 Å, β=1.39225 Å, α1:α2 ratio=0.5). High performance liquid chromatography-ultraviolet detection (HPLC-UV) [Table 12] mass spectrometry o HPLC instrument: Agilent 1290 with Agilent 6410 triple quadrupole mass spectrometer o Column: X-Bridge C18, 50mm x 3mm, 3.5μm, or equivalent Column temperature: 40℃ Autosampler temperature: Ambient temperature oDetector parameters: UV210nm monitor only oUV scan 190~900nm oMS+ / -ESI Fragmenter 135V Injection volume: 1 μL oFlow rate: 1.0mL / min Mobile phase A: 0.1% formic acid in deionized water Mobile phase B: 0.1% formic acid in acetonitrile o Gradient Program: [Table 13]

[0179] Example 1. Solid Form A Preparation of Solid Form A Two crystallization steps were performed on compound X, one before and one after the chromatographic step.

[0180] Pre-chromatographic isolation Compound X was prepared by reacting 6-((3S,4S)-4-methylpyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one with 2-(chloromethyl)pyrimidine hydrochloride in the presence of cesium carbonate. This step was carried out in a biphasic mixture of 2-methylTHF / water. At the end of the reaction the aqueous phase was removed so that compound X remained mainly in the 2-methylTHF organic phase. This was filtered to remove carbon, concentrated at 68-88°C to approximately 5.3 volumes and cooled to 20-30°C. Five volumes of n-heptane were then added at 20-30°C. During part of the addition the mixture became biphasic. The mixture was held at 20-30°C for at least 5 hours during which time the product precipitated. The product was filtered and washed with a further 2 volumes of n-heptane. The crude product was then dried in a vacuum oven at 35-45° C. with a slight nitrogen sweep.

[0181] Final crystallization step The crude product was chromatographed, then concentrated and then swapped into isopropyl alcohol. n-heptane was added to the reaction vessel while maintaining the temperature between 35°C and 55°C to give a ratio of IPA:n-heptane of 3:1. The mixture was heated to 70-80°C and held at this temperature to dissolve any solids present. The mixture was then cooled to 15°C over at least 3 hours during which time crystallization occurred. More n-heptane was added to give a ratio of IPA:n-heptane of 1:1.4. The mixture was then held at 15°C for at least 12 hours. The product was filtered and the reactor was washed with n-heptane on the filter and all solids were transferred to the filter. The solids were dried by blowing with nitrogen for 1 hour and then dried under vacuum with a nitrogen sweep resulting in a solid containing less than 0.5% IPA and less than 0.5% n-heptane.

[0182] Slurries in two IPA:heptane ratios were performed at 40° C., room temperature, and 4° C. to give solid Form A. Crystallization from ethyl acetate and isopropyl acetate was also successful on a smaller scale. Additional solvent mixtures were tested. See FIG. 11.

[0183] The Atlas instrument was fitted with an overhead stirrer, temperature probe, heptane inlet port, and a condenser. 100 ml of tetrahydrofuran (200 mL, 2457 mmol) was weighed into the vessel. Compound X (39.9961 g, 101.1 mmol) was weighed by difference into the vessel and the remaining 100 ml of tetrahydrofuran (200 mL, 2457 mmol) was added.

[0184] Reaction temperature control was used throughout and agitation was set at 200 rpm. The vessel was set to heat from 20° C. to 30° C. at 1° C. / min. This was held for a few minutes (compound X was observed to dissolve). It was then cooled to 20° C. at 1° C. / min. When the temperature reached 20.4° C., solid Form A seeds (0.4093 g, 1.035 mmol) were added. A slurry formed after a few minutes and was held. The syringe pump was then set to charge heptane (500 mL, 3413.2 mmol) over 60 minutes. The vessel was set to keep the reaction temperature at 20° C. overnight.

[0185] Crystallization occurred in the vessel. The top few centimeters of the liquid contained far fewer crystals than the bottom, indicating that larger particles had formed. A sample was taken using a microscopy pipette. The vessel was stopped and the reaction mixture was drained from the bottom of the vessel. Due to the large crystal size, compound X precipitated almost immediately after stirring was stopped. The material in the drain beaker was filtered under vacuum and then the liquid was poured back into the crystallization vessel. The crystallization vessel was turned on again at 20°C with stirring and once the crystals were resuspended, the reaction mixture was drained with the stirrer still on. This material was then filtered under vacuum. The filtrate was used to rinse the beaker towards the filter and then recycled again in the same manner. The solids were filtered under vacuum for approximately 30 minutes.

[0186] The solid was transferred to a pre-tared crystallization dish, which was placed in a vacuum oven at 50° C. with slow de-airing for 4 hours.

[0187] All isolated crystals were analyzed by XRPD as described below.

[0188] The powder was placed on a silicon wafer lightly coated with silicone grease and pressed down with a microscope slide. Samples were run on a Bruker D4 Endeavour diffractometer using the 1VAN2-55 (10 min) method. 1VAN2-55 (10 min) method: Diffraction patterns were measured from 2 to 55°2theta, with a step size of 0.018° and a step time of 0.20 s.

[0189] Alternatively, solid form A was prepared in the following manner.

[0190] Approximately 80-100 mg of compound X was placed into 21 HPLC vials. 5 ml of water / 1-butanol and IPA / heptane mixtures were prepared in various ratios. 0.7 ml of water / 1-butanol or IPA / heptane mixtures were added to each vial. These were then mixed in a Worley mixer and allowed to sit. Additional compound X was added to a solvent system that dissolves all of compound X (such as a solvent system containing toluene).

[0191] All water / 1-butanol solvent systems completely dissolved Compound X. Additional Compound X was added to the vial and allowed to dissolve.

[0192] All vials were capped and set down on a roller mixer at various temperatures.

[0193] The slurry was removed from the stirrer block and analyzed wet using the XRPD method described herein, and the solid phase of the slurry was then isolated using a 0.2 μm centrifugal filter and spun at 13,200 rpm for at least 10 minutes.

[0194] All isolated slurries were analyzed by dry XRPD.

[0195] Wet XRPD: A small amount of the slurry was pipetted onto a silicon wafer and covered with a Kapton film. The sample was run on a Bruker D4 Endeavour diffractometer using the 1VAN2-40 method (5 min). 1VAN2-40 method: Diffraction patterns were measured from 2 to 40°2theta with a step size of 0.018° and a step time of 0.15 s.

[0196] Dry XRPD method: Powder was placed on a silicon wafer lightly coated with silicone grease and pressed with a microscope slide. Samples were run on a Bruker D4 Endeavour diffractometer using the 1VAN2-55 method (10 min). 1VAN2-55 method: Diffraction patterns were measured from 2 to 55°2theta with a step size of 0.018° and a step time of 0.20 s.

[0197] Solid-state properties of solid form A Solid Form A is highly crystalline, non-hygroscopic, has a high melting point and high water and organic solubility. It has been shown to be chemically and physically stable. [Table 14] [Table 15] [Table 16]

[0198] Solid form A exhibits a tetrahedral and nearly equant morphology observed from crystallization (see Figures 8 and 10).

[0199] water absorption Solid Form A is non-hygroscopic, absorbing less than 0.05% moisture at 90% RH and 25° C. The absorption at various humidities at 25° C. is provided below in Table 4. See Figure 7 for the isotherm plot. [Table 17]

[0200] Solid Form A is non-hygroscopic. Solid Form A was analyzed before grinding and showed a very similar adsorption profile. The low hygroscopicity indicates that no special storage conditions are required for Solid Form A.

[0201] water soluble The solubility of solid form A is high over a wide range of solvent conditions. Solid form A is highly water soluble over a range of biologically relevant pH conditions as shown below. [Table 18] [Table 19] [Table 20]

[0202] Particle characteristics of solid form A The particle characteristics are summarized below.

[0203] particle shape Unmilled, the primary particles are irregular isotropic or tetrahedral particles as shown in Figure 8. The particles described were subsequently milled. They appear to remain irregularly shaped, as shown in Figure 9.

[0204] Particle size Primary particles with sizes of less than 100 μm to approximately 500 μm were observed, along with soft agglomerates up to a few millimeters in size. The D[4,3] of this material was 195 μm. Subsequent milling of this material resulted in very few large particles and an overall very small average primary particle size, D[4,3] of 49.5 μm. See Table 8 for a comparison of particle size characteristics of the various batches. [Table 21] [Table 22]

[0205] Chemical and physical stability of solid form A Chemical stability (including excipient compatibility) Real-time stability data for unmilled solid Form A showed that it was chemically and physically stable in bulk packaging (double polyethylene bags in fiberboard drums) at accelerated conditions of 40°C / 75% RH for 6 months and at room temperature conditions (15-30°C for 63 months and 25°C / 60% RH for 21 months). Photostability studies were completed under ICH conditions. No change in stability was noted when milled solid Form A was stored at 70°C / 75% RH for 1 week.

[0206] Clinical stability data for solid Form A tablets in foil / foil blister or HDPE bottle / induction seal (IS) with desiccant showed stability over 60 months at 25° C. / 60% RH and over 6 months at 5° C. / 60% RH and 40° C. / 75% RH. No significant changes / trends were observed for assay, decomposition products, or disintegration.

[0207] Physical stability (against compression, grinding, milling, micronization, etc.) A sample of solid form A was milled to reduce the particle size. No effect on the polymorphic form was observed.

[0208] A ground sample of solid form A was re-ground and exposed to 40° C. / 75% RH. XRPD showed no indication of change in morphology or loss of crystallinity.

[0209] Example 2. Solid Form B Preparation of Solid Form B The following method was used for the preparation of solid form B:

[0210] Method 1 1. 100 mg of amorphous Compound X was dissolved in 10 mL of water at room temperature. 2. The solution was frozen and lyophilized at -85°C. 3. Deionized water was added to the lyophilized material in 100 μL aliquots. 4. Dissolution was observed after the first addition. 5. After approximately 30 seconds, a pale yellow precipitate was observed. 6. An additional 800 μL of water was added to form a flowable slurry. 7. The slurry was temperature cycled from 25° C. to 5° C. at a ramp rate of 0.1° C. / min and held at 25° C. and 5° C. for 1 hour with stirring. 8. After approximately 24 hours, an aliquot of the slurry was collected using a plastic pipette and the solids were analyzed by XRPD. 9. The bulk material was isolated by centrifugation and the isolated solid was dried in vacuum at room temperature for approximately 24 hours. 10. The dried solid was reanalyzed by XRPD. 11.VT-XRPD, DVS and post-DVS XRPD analyses were performed.

[0211] Method 2 1.1 g of amorphous Compound X was weighed and transferred to a 100 mL Duran flask. 2.40 mL of deionized water was added and the vessel was agitated for 5 minutes until complete dissolution was observed. 3. The flask was placed in the freeze dryer chamber at approximately -90°C for 2 hours. After 4.2 hours, the samples were transferred to a desiccator and freeze-drying was initiated. After 5.72 hours, the samples were removed from the freeze dryer. 6.1 μL of deionized water was added to 500 mg of lyophilized material and was completely dissolved upon addition. 7. After a few minutes a precipitate appeared. 8. Additional 500 μL aliquots of deionized water were added until dissolution was observed, for a total of 4.5 mL of water. 9. The experiment was placed in a temperature controlled block and temperature cycled according to the following method: Keep at 25℃ for 1 hour. o Rise to 5°C at 0.1°C / min, Keep at 5℃ for 1 hour. o Rise to 25°C at 0.1°C / min After 10.24 hours the experiment had turned into a pale yellow slurry. 11. An aliquot was taken and the solids were isolated by centrifugation. 12. The solid was analyzed by XRPD. 13. The slurry was filtered through a Buchner filter and the wet solids were collected and dried under vacuum at room temperature. After 14.24 hours the samples were removed from the oven and the dried solids were weighed. 15. A small amount of material was transferred to a 40°C / 75% RH chamber for 5 days. After 16.5 days, XRPD analysis was performed. 17. The remaining material was exposed to 40°C / 75% RH for 72 hours and the conversion was monitored every 24 hours. 18. Solid form B was characterized by PLM, TG / DSC, DSC, DVS, and XRPD after DVS, FT-IR, KF, and HPLC.

[0212] Method 3 1.1 g of amorphous Compound X was weighed and transferred to a 100 mL Duran flask. 2.40 mL of deionized water was added and the vessel was agitated for 5 minutes until complete dissolution was observed. 3. The flask was placed in the freeze dryer chamber at approximately -90°C for 2 hours. After 4.2 hours, the samples were transferred to a desiccator and freeze-drying was initiated. After 5.72 hours, the samples were removed from the freeze dryer. 6. The material was split into two samples: 500 μL of deionized water was added to 500 mg of lyophilized material and dissolved completely upon addition. 7. After a few minutes a precipitate appeared. 8. Additional 500 μL aliquots of deionized water were added until dissolution was observed, for a total of 4.5 mL of water each. 9. The experiment was placed in a temperature controlled block and temperature cycled according to the following method: o Hold at 25°C for 1 hour, o Ramp up to 5°C at 0.1°C / min, o Hold at 5°C for 1 hour, o Ramp to 25°C at 0.1°C / min, After 10.24 hours the experiment had turned into a pale yellow slurry. 11. The slurry was filtered through a Buchner filter and the wet solids were collected and dried at 40° C. for 72 hours. 12. The solid was analyzed by XRPD.

[0213] VT-XRPD analysis of solid form B Solid Form B was analyzed by VT-XRPD to assess the change in morphology upon heating.

[0214] The sample was heated at 10° C. / min and diffraction patterns were collected at different temperatures (based on TG / DSC data).

[0215] Experimental details are summarized in Table 10 below. [Table 23]

[0216] VT-XRPD showed that upon heating to 85° C. (beyond dehydration), a new solid, Solid C, was observed. At 130° C. (beyond a potential solid-solid transition), the material appeared to be a mixture of solid forms A and C. After further heating to 135° C., the material was consistent with solid form A. The results are shown in FIG. 13 and FIG. 14. [Table 24] [Table 25]

[0217] Dynamic Vapor Sorption (DVS) Evaluation of Solid Form B DVS analysis of solid form B showed that the material had a large mass loss upon desorption / adsorption at 0-10% RH, approximately 2.6 wt% (0.6 equivalents of water). Equilibrium was not reached at 0% RH (maximum step time was 500 min), indicating incomplete dehydration. The DVS profile showed that solid form B was hydrated. See Figure 15.

[0218] DVS analysis of solid form B showed an absorption of 4.3 wt% at 80% RH, while the absorption from 40% RH to 80% RH in the first adsorption cycle was 0.2 wt%. Dehydration occurred below 10% RH. After completion of the DVS analysis, the XRPD diffractogram was consistent with solid form B, with trace amounts of solid form C.

[0219] Polarized light microscopy PLM analysis showed that the material consisted of small, agglomerated birefringent crystals, see Figures 16 and 17.

[0220] TG and DSC analysis TG analysis showed a weight loss of 4.2 wt.% from the start of heating to 100° C., which theoretically corresponds to 0.96 equivalents of water. Concurrent DSC analysis showed the following events: 1) a broad endothermic event with an onset at 39.1° C. and a peak at 84.8° C. (due to dehydration), 2) a small endothermic event with an onset at 127.2° C. and a peak at 131° C. (probably a solid-solid transition), and 3) a sharp endothermic event with an onset at 161.8° C. and a peak at 163.2° C. (final melting event).

[0221] Standalone DSC analysis showed the following events in the first thermal cycle: 1) a broad endothermic event: onset 86°C, peak 93.5°C, 2) a small endothermic event: onset 128°C, peak 132.5°C, followed by a very small exothermic event (onset at 133.3°C with a peak at 133.5°C), and 3) a sharp endothermic event: onset 162.2°C, peak 163.6°C.

[0222] Upon cooling and the second thermal cycle, glass transitions were observed with midpoints of 44.2° C. and 53.6° C., respectively.

[0223] See Figures 18 and 19.

[0224] Karl Fischer titration Karl Fischer analysis showed that the material had a moisture content of 4.8 wt. % (average of two determinations), which theoretically corresponds to 1.1 equivalents of water.

[0225] 7-day stability evaluation of solid form B The stability evaluation was carried out as follows.

[0226] 15 mg of solid Form B was weighed into 3 x 1.5 mL vials. o One vial was left uncapped and placed in a scintillation vial and stored at ambient conditions (approximately 20°C). o One vial was placed, with the cap still attached, inside a scintillation vial, which was then placed in a stability oven at 40°C / 75% RH. o One vial was capped and placed in a scintillation vial, which was then placed in an oven at 80°C.

[0227] After 7 days, samples were removed from each condition and analyzed by XRPD and submitted for HPLC analysis. The XRPD results are summarized in Figure 21.

[0228] A 7-day stability analysis (Table 13) showed that there was no loss of purity over the conditions examined: solid form B was kept at ambient temperature and at 40° C. / 75% RH, whereas solid form B converted to a mixture of solid forms A and C at 80° C. [Table 26]

[0229] VH-XRPD analysis of solid form B Variable humidity XRPD was performed using the following method:

[0230] Diffractograms were collected when each target % RH was reached and after the reporting times had elapsed (Table 14 below).

[0231] After 20 h at 2% RH, some P2O5 was introduced into the stage chamber to further dry the environment.

[0232] The sample was kept under these conditions for a further 16 hours, during which time diffractograms were collected every hour. [Table 27]

[0233] VH-XRPD analysis of solid form B showed no change in shape during the experiment, see Table 15 and Figures 22, 23, and 24. [Table 28]

[0234] Thermodynamic solubility evaluation of solid form B Thermodynamic solubility evaluation was performed as follows: · 25 mg of solid Form B was weighed into 3 x 1.5 mL vials. To each vial, 250 μL of the appropriate buffer was added to obtain a slurry. The samples were placed on an incubator shaker at 25°C for 1 hour. After 1 hour, the pH value was measured and adjusted accordingly. · Samples were placed back into the incubator shaker for 24 hours. After 16 hours, the pH 1.2 and 4.5 samples were clear solutions so more material was added and the samples were returned to the shaker. After 24 hours, the pH was measured again and adjusted accordingly. The samples were syringe filtered and the mother liquors were subjected to HPLC to determine the concentration of dissolved free base and the solids were analyzed by XRPD.

[0235] The results are summarized in Table 16 below and plotted in Figure 25.

[0236] Thermodynamic solubility evaluation (Table 16) showed that solid form B has high solubility (>150 mg / mL) at pH 4.5. Solid form B was retained across the pH range. [Table 29]

[0237] Example 3. Solid Form C Solid Form C was observed during VT-XRPD analysis of solid Form B at 85°C.

[0238] Solid Form C was also observed multiple times during polymorph screening, but only as a mixture with Solid Form A or Solid Form B. Multiple attempts were made to re-prepare Solid Form C, but again, it was only observed as a mixture of Solid Form A and Solid Form B.

[0239] [Table 30] [Table 31]

[0240] Example 4. Solid Form D Preparation of solid form D The following method was used for the preparation of solid form D: 500 mg of crystalline form A was weighed into a scintillation vial. A stir bar was added and 12.5 mL of water was added to obtain a slurry. The vial was placed in a temperature control block set at 25° C. and magnetically stirred for 48 hours.

[0241] After 48 hours, an aliquot was taken from the slurry and the solid was isolated by centrifugation. The solid was analyzed by XRPD and was found to be Form D. The XRPD 2θ diffractogram of the single crystal growth experiment of Form D is shown in FIG. XRPD Analysis of Solid Form D [Table 32-1] [Table 32-2] [Table 33]

[0242] Differential Scanning Calorimetry / Thermogravimetry The TG trace showed a weight loss of 15.87 wt % (theoretically equivalent to 4.14 equivalents of water) from the start of heating to 90° C. The DSC trace showed a major endothermic event with an onset at 47.1° C. and a peak at 64.2° C., a minor exothermic event with an onset at 90.6° C. and a peak at 97.6° C., and a second endothermic event with an onset at 161.2° C. and a peak at 163.6° C., along with the weight loss observed in the TG trace. The TG / DSC profile of Form D is shown in FIG.

[0243] Karl Fischer Analysis Moisture content analysis was performed by adding the material directly to the titrator. Analyses were performed in duplicate and the results were averaged. Moisture content (average): 15.82% (equivalent to 4.13 equivalents of water).

[0244] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed within the scope of the following claims.

Claims

1. A solid form of Compound X, 【Chemistry 1】 Form A, characterized by having X-ray powder diffraction peaks at about 18.9, 20.4, and 23.1 degrees 2θ using CuKα radiation; Form B, characterized by having X-ray powder diffraction peaks at about 8.0, 15.0, and 19.3 degrees 2θ using CuKα radiation; Form C, characterized by having X-ray powder diffraction peaks at about 15.0, 18.9, and 24.7 degrees 2θ using CuKα radiation; and Form D, characterized by X-ray powder diffraction peaks at about 6.8, 9.1, and 15.5 degrees 2θ using CuKα radiation. A solid form selected from:

2. 2. The solid form of claim 1, wherein the solid form is Form A.

3. 3. The solid form of claim 2, wherein Form A is characterized by having X-ray powder diffraction peaks at about 9.6±0.2, 17.2±0.2, 18.9±0.2, 20.4±0.2, and 23.1±0.2 degrees 2θ using CuKα radiation.

4. 3. The solid form of claim 2, wherein Form A is characterized by having X-ray powder diffraction peaks at about 9.6±0.2, 17.2±0.2, 18.9±0.2, 20.4±0.2, 20.7±0.2, 21.9±0.2, 23.1±0.2, and 24.5±0.2 degrees 2θ using CuKα radiation.

5. 3. The solid form of claim 2, wherein the X-ray powder diffraction pattern is substantially the same as that shown in Figure 1A.

6. 6. The solid form of any one of claims 2 to 5, wherein said Form A is characterized by an endothermic event with an onset temperature of about 155°C to about 168°C as measured by DSC.

7. 6. The solid form of any one of claims 2 to 5, wherein Form A is characterized by an endothermic event with a peak temperature of about 162°C as measured by DSC.

8. 6. The solid form of any one of claims 2 to 5, wherein said Form A is characterized by a DSC thermogram substantially the same as that shown in Figure 2.

9. 3. The solid form of claim 2, wherein Form A is characterized by a weight loss of about 0.11% between about 150°C and about 225°C as measured by TGA.

10. 2. The solid form of claim 1, wherein the solid form is Form B.

11. 11. The solid form of claim 10, wherein Form B is characterized by having X-ray powder diffraction peaks at about 8.0±0.2, 15.0±0.2, 19.3±0.2, 25.6±0.2, and 26.9±0.2 degrees 2θ using CuKα radiation.

12. 11. The solid form of claim 10, wherein Form B is characterized by having X-ray powder diffraction peaks at about 8.0±0.2, 15.0±0.2, 16.2±0.2, 19.3±0.2, 19.6±0.2, 25.6±0.2, and 26.9±0.2 degrees 2θ using CuKα radiation.

13. 11. The solid form of claim 10, wherein the X-ray powder diffraction pattern is substantially the same as that shown in Figure 12.

14. 14. The solid form of any one of claims 10-13, wherein Form B is characterized by an endothermic event with an onset temperature of about 39°C, 127°C, and / or 162°C as measured by DSC.

15. 11. The solid form of claim 10, wherein Form B is characterized by an endothermic event with peak temperatures of about 85°C, 131°C, and / or 163°C as measured by DSC.

16. 11. The solid form of claim 10, wherein said Form B is characterized by a DSC thermogram substantially the same as that shown in Figure 19.

17. 11. The solid form of claim 10, wherein said Form B is characterized by a weight loss of about 4% between about 25°C and about 100°C as measured by TGA.

18. 2. The solid form of claim 1, wherein the solid form is Form C.

19. 20. The solid form of claim 18, wherein Form C is characterized by having X-ray powder diffraction peaks at about 8.6±0.2, 8.7±0.2, 15.0±0.2, 18.9±0.2, and 24.7±0.2 degrees 2θ using CuKα radiation.

20. 20. The solid form of claim 18, wherein Form C is characterized by having X-ray powder diffraction peaks at about 8.6±0.2, 8.7±0.2, 15.0±0.2, 18.9±0.2, 19.6±0.2, 19.7±0.2, 24.7±0.2, and 26.2±0.2 degrees 2θ using CuKα radiation.

21. 20. The solid form of claim 18, wherein the X-ray powder diffraction pattern is substantially the same as that shown in Figure 26.

22. 2. The solid form of claim 1, wherein the solid form is Form D.

23. 23. The solid form of claim 22, wherein Form D is characterized by having X-ray powder diffraction peaks at about 6.8±0.2, 9.1±0.2, 14.3±0.2, 15.5±0.2, and 25.8±0.2 degrees 2θ using CuKα radiation.

24. 23. The solid form of claim 22, wherein Form D is characterized by having X-ray powder diffraction peaks at about 6.8±0.2, 9.1±0.2, 13.6±0.2, 14.3±0.2, 15.5±0.2, 18.6±0.2, and 25.8±0.2 degrees 2θ using CuKα radiation.

25. 23. The solid form of claim 22, wherein the X-ray powder diffraction pattern is substantially the same as that shown in Figure 27.

26. 26. The solid form of any one of claims 22-25, wherein said Form D is characterized by an endothermic event with an onset temperature of about 45°C to about 50°C as measured by DSC.

27. A pharmaceutical composition comprising the solid of claim 1 and a pharmaceutically acceptable carrier or excipient.

28. 28. A method for treating or preventing a cardiovascular disease or disorder, comprising administering to a subject in need thereof the solid form of claim 1 or the pharmaceutical composition of claim 27.

29. 29. The method of claim 28, wherein the cardiovascular disease or disorder is systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery disease, atherosclerosis, stroke, thrombosis, post-percutaneous transluminal coronary angioplasty, peripheral vascular disease, renal disease associated with cardiovascular problems, angina pectoris (including stable angina, stable UI1 angina, and variant (Prinzmetal) angina), aortic disease, Marfan syndrome, myocardial disease, congenital heart disease, deep vein thrombosis, heart failure, pericardial disease, valvular heart disease, or rheumatic heart disease.

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