Solid forms of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

Abstract

To provide thyroid hormone analogs which exhibit increased thyroid hormone receptor beta selectivity and / or tissue selective action.SOLUTION: The present invention is directed to morphic forms, co-crystals, salts, and amorphous solid dispersions of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.SELECTED DRAWING: Figure 76

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 692,914, filed July 2, 2018, the contents of which are incorporated herein by reference in their entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING The contents of the text file named "MDRI-024_SEQ_LISTING.txt", created on May 21, 2019 and having a size of 3.66KB, are incorporated herein by reference in their entirety.

[0002] The present invention relates to morphic forms, co-crystals, salts and amorphous solid dispersions of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Compound A). [Background technology]

[0003] Thyroid hormones are crucial for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen, Physiological reviews, vol. 81(3):1097-1126 (2001)). Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamic / pituitary / thyroid (HPT) axis. Thyroid dysfunction, resulting in hypo- or hyperthyroidism, clearly demonstrates the profound effects of thyroid hormones on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0004] The biological activity of thyroid hormones is mediated by the thyroid hormone receptor (TR or THR) (MA Lazar, Endocrine Reviews, vol. 14:348-399 (1993)). TRs belong to a superfamily known as nuclear receptors. TRs form heterodimers with retinoid receptors, which act as ligand-inducible transcription factors. TRs have ligand-binding, DNA-binding and amino-terminal domains and regulate gene expression through interactions with gene expression DNA response elements and diverse nuclear coactivators and corepressors. Thyroid hormone receptors are derived from two separate genes, α and β. These significantly different gene products result in multiple forms of their respective receptors through differential RNA processing. The major thyroid receptor isoforms are α1, α2, β1 and β2. Thyroid hormone receptors α1, β1 and β2 bind thyroid hormones. It has been shown that thyroid hormone receptor subtypes may differ in their contribution to specific biological responses. Recent studies suggest that TRβ1 plays an important role in regulating TRH (thyrotropin releasing hormone) and the action of thyroid hormones in the liver. TRβ2 plays an important role in regulating TSH (thyroid stimulating hormone) (Abel et al., J. Clin. Invest., 104:291-300 (1999)). TRβ1 plays an important role in regulating heart rate (B. Gloss et al., Endocrinology, 142:544-550 (2001); C. Johansson et al., Am. J. Physiol., 275:R640-R646 (1998)).

[0005] Attempts have been made to synthesize thyroid hormone analogs that exhibit increased selectivity and / or tissue-selective action on the thyroid hormone receptor beta. Such thyroid hormone mimetics can provide the desired reduction in body weight, lipids, cholesterol and lipoproteins, and can reduce the impact on cardiovascular function or the normal function of the hypothalamus / pituitary / thyroid axis (see, for example, Joharapurkar et al., J.Med.Chem., 2012, 55(12), pp. 5649-5675). The development of thyroid hormone analogs that maintain the beneficial effects of thyroid hormone while avoiding the undesirable effects of hyperthyroidism and hypothyroidism will pave the way for new treatments for patients with metabolic diseases such as hepatic steatosis and NASH, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, refractory thyroid hormone (RTH) disease and related disorders and diseases, including obesity, hyperlipidemia, hypercholesterolemia, diabetes and other disorders and diseases. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Paul M. Yen, Physiological reviews, 81(3):1097-1126 (2001) [Non-Patent Document 2] MA Lazar, Endocrine Reviews, 14:348-399 (1993) [Non-Patent Document 3] Abel et al., J. Clin. Invest., 104:291-300 (1999) [Non-Patent Document 4] B. Gloss et al., Endocrinology, 142:544-550 (2001) [Non-Patent Document 5] C. Johansson et al., Am. J. Physiol., 275:R640-R646 (1998) [Non-Patent Document 6] Joharapurkar et al., J.Med.Chem., 2012, 55(12), pp. 5649-5675 Summary of the Invention [Means for solving the problem]

[0007] Summary of the Invention The present disclosure presents morphic forms, co-crystals, salts and amorphous solid dispersions of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Compound A).

[0008] One aspect of the disclosure relates to a crystalline salt of Compound A. Another aspect of the disclosure relates to a pharmaceutical composition comprising the crystalline salt disclosed herein.

[0009] In some embodiments, the crystalline salt is characterized as having a counterion, where the counterion is L-lysine, L-arginine, 2-hydroxy-N,N,N-trimethylethane-1-aminium, diethylamine, ethanolamine, ethanol-2-diethylamine, Na + , Mg 2+ , K + , Ca 2+ , diethanolamine, triethanolamine, L-histidine and meglumine.

[0010] In some embodiments, the counterion is L-lysine.

[0011] In some embodiments, the counterion is L-arginine.

[0012] In some embodiments, the counterion is 2-hydroxy-N,N,N-trimethylethan-1-aminium.

[0013] In some embodiments, the crystalline salt (L-lysine salt) is characterized by an X-ray powder diffraction pattern containing peaks at about 8.70, 9.22, 11.3, 17.0, and 24.8 degrees 2θ, where the x-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å).

[0014] In some embodiments, the crystalline salt has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0015] In some embodiments, the crystalline salt has a melting point of about 250°C.

[0016] In some embodiments, the crystalline salt has an X-ray diffraction pattern substantially similar to the X-ray diffraction patterns depicted in any one of Figures 67-70.

[0017] In some embodiments, the crystalline salt has a melting point of about 200°C.

[0018] In some embodiments, the crystalline salt has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0019] In some embodiments, the crystalline salt has a melting point of about 229°C.

[0020] In some embodiments, the crystalline salt has a purity of Compound A of greater than 90% by weight.

[0021] In some embodiments, the crystalline salt has a purity of Compound A of greater than 95% by weight.

[0022] In some embodiments, the crystalline salt has a purity of Compound A of greater than 99% by weight.

[0023] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form B), characterized by an X-ray powder diffraction pattern comprising peaks at about 5.92, 11.8, and 17.5 degrees 2θ, the X-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form B has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0024] Another aspect of the present disclosure relates to a morphic form of Compound A (Form C), characterized by an X-ray powder diffraction pattern comprising peaks at about 5.74, 11.5, 17.7, 19.3, 19.7, 21.4, 24.3 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form C has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0025] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form D), characterized by an X-ray powder diffraction pattern comprising peaks at about 5.52, 8.52, 11.0, 16.5, 18.3, 21.0, 21.2, and 24.0 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form D has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0026] Another aspect of the present disclosure relates to a morphic form of Compound A (Form E), characterized by an X-ray powder diffraction pattern comprising peaks at about 7.13, 10.8, 12.3, 14.1, 14.7, 15.5, 16.1, 17.5, 18.1, 19.9, 20.2, 21.0, 21.2, 22.7, 22.9, 24.4, 25.3, and 26.3 degrees 2θ, wherein the x-ray powder diffraction pattern was obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form E has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0027] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form F), characterized by an X-ray powder diffraction pattern comprising peaks at about 10.1, 10.4, 11.4, 13.9, 16.2, 16.4, 17.1, 22.0, 23.8, and 29.5 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form F has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0028] Another aspect of the present disclosure relates to a morphic form of Compound A (Form G), characterized by an X-ray powder diffraction pattern comprising peaks at about 9.50, 12.9, 16.7, 17.3, 19.5, 20.2, 25.6, and 28.3 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form G has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0029] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form H), characterized by an X-ray powder diffraction pattern comprising peaks at about 9.22, 19.8, 23.6, 25.9, and 28.0 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form H has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0030] Another aspect of the present disclosure relates to a morphic form of Compound A (Form I), characterized by an X-ray powder diffraction pattern comprising peaks at about 5.77, 9.30, 10.2, 11.6, and 21.9 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form I has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0031] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form K), characterized by an X-ray powder diffraction pattern comprising peaks at about 8.42, 11.4, 14.5, 18.9, 21.1, and 21.6 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form K has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0032] Another aspect of the present disclosure relates to a morphic form of Compound A (Form L), characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, 11.5, 11.9, 15.2, 15.7, 16.0, 16.9, 17.1, 18.4, 18.7, 22.0, 22.8, 23.5, and 26.4 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form L has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0033] Another aspect of the present disclosure relates to a morphic form of Compound A (Form S+T) characterized by an X-ray powder diffraction pattern comprising peaks at about 7.42, 10.5, 11.3, 12.4, 14.3, 15.8, 16.8, 17.7, 18.1, 18.4, 20.1, 20.5, 21.1, 21.9, 23.2, 25.5, 26.9, and 28.3 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form S+T has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0034] Another aspect of the present disclosure relates to a morphic form of Compound A (Form S), characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, 12.3, 14.4, 15.8, 16.7, 17.7, 18.1, 18.4, 20.1, 20.6, 21.2, 21.9, 23.3, 24.4, 25.5, and 27.8 degrees 2θ, wherein the x-ray powder diffraction pattern was obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form S has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0035] Another aspect of the present disclosure relates to a morphic form of Compound A (Form U), characterized by an X-ray powder diffraction pattern comprising peaks at about 5.79, 8.43, 11.4, 11.6, 14.5, 18.9, 21.1, and 21.6 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form U has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0036] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form V), characterized by an X-ray powder diffraction pattern comprising peaks at about 6.35, 10.6, 15.6, 16.5, 16.8, and 18.3 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form V has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0037] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form W), characterized by an X-ray powder diffraction pattern comprising peaks at about 10.1, 10.4, 10.7, 11.7, 13.9, 24.4, and 29.5 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form W has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0038] Another aspect of the present disclosure relates to a morphic form of Compound A (Form X), characterized by an X-ray powder diffraction pattern comprising peaks at about 9.66, 10.2, 10.5, 11.2, 18.7, and 24.7 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form X has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0039] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form Y), characterized by an X-ray powder diffraction pattern comprising peaks at about 6.51, 13.0, 13.3, 19.5, and 24.2 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form Y has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0040] Another aspect of the present disclosure relates to a morphic form of Compound A (Form Z), characterized by an X-ray powder diffraction pattern comprising peaks at about 10.6, 11.2, 11.6, 12.0, 14.3, 15.6, 16.2, 17.6, 18.1, 18.7, 24.1, and 24.3 degrees 2θ, wherein the x-ray powder diffraction pattern was obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form Z has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0041] Another aspect of the present disclosure relates to a morphic form of Compound A (Form α), characterized by an X-ray powder diffraction pattern comprising peaks at about 7.26, 10.1, 10.4, 10.6, 11.9, 13.9, 16.5, 21.9, 22.4, and 24.1 degrees 2θ, wherein the x-ray powder diffraction pattern was obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form α has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0042] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form β), characterized by an X-ray powder diffraction pattern comprising peaks at about 7.36, 10.5, 14.3, 15.7, 18.3, 20.4, 21.0, 21.8, and 23.2 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form β has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0043] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form χ), characterized by an X-ray powder diffraction pattern comprising peaks at about 8.53, 11.2, 18.4, 20.1, and 21.4 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form χ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0044] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form δ), characterized by an X-ray powder diffraction pattern comprising peaks at about 10.9, 12.1, 14.4, 18.1, 19.6, 24.5, and 27.0 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form δ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0045] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form ε), characterized by an X-ray powder diffraction pattern comprising peaks at about 5.73, 11.4, 16.6, 17.6, 23.2, and 24.2 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form ε has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0046] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form φ), characterized by an X-ray powder diffraction pattern comprising peaks at about 6.95, 13.9, 20.9, 22.3, and 27.9 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form φ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0047] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form η), characterized by an X-ray powder diffraction pattern comprising peaks at about 6.87, 7.69, 20.5, 23.0, 23.9, and 28.2 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form η has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0048] Another aspect of the present disclosure pertains to a morphic form of Compound A (Form λ), characterized by an X-ray powder diffraction pattern comprising peaks at about 10.6, 12.0, 14.3, 16.2, 17.6, 18.0, and 24.3 degrees 2θ, the x-ray powder diffraction pattern being obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, Form λ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0049] Another aspect of the present disclosure relates to a co-crystal of Compound A and glutaric acid, characterized by an X-ray powder diffraction pattern comprising peaks at about 9.74, 10.8, 11.0, 12.2, 16.1, 17.0, 19.2, 21.9, and 23.1 degrees 2θ, wherein the x-ray powder diffraction pattern was obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0050] Another aspect of the present disclosure relates to an amorphous solid dispersion of compound A comprising a polymer. In some embodiments, the polymer is polyvinylpyrrolidone. In some embodiments, the weight ratio of compound A to the polymer is about 1:2 or 1:4.

[0051] The crystalline salts, morphic forms, co-crystals or amorphous solid dispersions of the present disclosure may be used in (a) methods for treating thyroid hormone insensitivity (RTH) disease; (b) methods for treating non-alcoholic steatohepatitis; (c) methods for treating familial hypercholesterolemia; (d) methods for treating fatty liver disease and (e) methods for treating dyslipidemia. In some embodiments, the crystalline salts, morphic forms, co-crystals or amorphous solid dispersions are administered daily.

[0052] Another aspect of the present disclosure relates to a crystalline salt, morphic form, co-crystal or amorphous solid dispersion of the present disclosure for the manufacture of a medicament for treating (a) responsiveness to thyroid hormone (RTH); (b) non-alcoholic steatohepatitis; (c) familial hypercholesterolemia; (d) fatty liver disease and (e) dyslipidemia, wherein the crystalline salt, morphic form, co-crystal or amorphous solid dispersion of the present disclosure is for administration to a subject in at least one therapeutically effective amount. In some embodiments, the crystalline salt, morphic form, co-crystal or amorphous solid dispersion is administered daily.

[0053] Another aspect of the present disclosure relates to a crystalline salt, morphic form, co-crystal or amorphous solid dispersion of the present disclosure for use in treating (a) thyroid hormone refractory (RTH) disease; (b) non-alcoholic steatohepatitis; (c) familial hypercholesterolemia; (d) fatty liver disease and (e) dyslipidemia, wherein the crystalline salt, morphic form, co-crystal or amorphous solid dispersion of the present disclosure is for administration to a subject in at least one therapeutically effective amount. In some embodiments, the crystalline salt, morphic form, co-crystal or amorphous solid dispersion is administered daily. [Brief description of the drawings]

[0054] [Figure 1] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of the anhydrous crystalline form (Form A) of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Compound A). [Diagram 2] FIG. 2 shows the XRPD pattern of the methanol solvate of Compound A (Form B). [Diagram 3] FIG. 2 shows the XRPD pattern of the ethanol solvate of Compound A (Form C). [Figure 4] FIG. 2 shows the XRPD pattern of the acetone solvate of Compound A (Form D). [Diagram 5] FIG. 2 shows the XRPD pattern of the tetrahydrofuran solvate of Compound A (Form E). [Figure 6] FIG. 2 shows the XRPD pattern of an ethyl acetate desolvate of Compound A (Form F). [Figure 7] FIG. 2 shows the XRPD pattern of a methyl isobutyl ketone (MIBK) solvate of Compound A (Form G). [Figure 8] FIG. 2 shows the XRPD pattern of an isopropyl acetate (IPAc) solvate of Compound A (Form H). [Figure 9] FIG. 2 shows the XRPD pattern of the acetic acid solvate of Compound A (Form I). [Figure 10] FIG. 2 shows the XRPD pattern of the dimethylacetamide solvate of Compound A (Form K). [Figure 11] FIG. 2 shows the XRPD pattern of the acetonitrile solvate of Compound A (Form L). [Figure 12] FIG. 2 shows the XRPD pattern of the MIBK desolvate of Compound A (forms S+T). [Figure 13] FIG. 2 shows the XRPD pattern of the IPAc desolvate of Compound A (Form S). [Figure 14]FIG. 2 shows the XRPD pattern of acetic acid desolvate of Compound A (Form U). [Figure 15] FIG. 2 shows the XRPD pattern of the acetonitrile desolvate of Compound A (Form V). [Figure 16] FIG. 2 shows the XRPD pattern of ethyl acetate desolvate of Compound A (Form W). [Figure 17] FIG. 2 shows the XRPD pattern of the acetonitrile solvate of Compound A (Form X). [Figure 18] FIG. 2 shows the XRPD pattern of the ethanol desolvate of Compound A (Form Y). [Figure 19] FIG. 2 shows the XRPD pattern of the acetic acid desolvate of Compound A (Form Z). [Figure 20] FIG. 2 shows the XRPD pattern of an acetone desolvate of Compound A (Form α). [Figure 21] FIG. 2 shows the XRPD pattern of N-methylpyrrolidone (NMP) solvate of Compound A (Form β). [Figure 22] FIG. 2 shows the XRPD pattern of the dimethylsulfoxide (DMSO) solvate of Compound A (Form χ). [Figure 23] FIG. 2 shows the XRPD pattern of a possible THF solvate of compound A (form δ). [Figure 24] FIG. 2 shows the XRPD pattern of a mixture of Form C and a possible acetone solvate (Form ε) of Compound A. [Diagram 25] FIG. 2 shows the XRPD pattern of the acetone solvate of Compound A (Form φ). [Figure 26] FIG. 2 shows the XRPD pattern of the IPA solvate of Compound A (Form η). [Figure 27] FIG. 2 shows the XRPD pattern of the IPAc desolvate of Compound A (Form λ). [Figure 28]1 shows the XRPD pattern of the co-crystal obtained from heating a mixture of Form A and glutaric acid, which shows no change before and after drying. The patterns of Form A and the coformer glutaric acid are presented for comparison. [Figure 29] FIG. 1 shows the XRPD pattern with peak positions of Compound A, calcium salt (Form 1-A) from experiment L100110-68-1. [Diagram 30] FIG. 1 shows the XRPD pattern of Compound A, calcium salt (Form 1-B) from experiment L100110-68-3-Wet with peak positions. [Diagram 31] FIG. 2 shows the XRPD pattern with peak positions of Compound A, calcium salt (Form 2-B) from experiment L100110-68-8. [Diagram 32] FIG. 2 shows the XRPD pattern with peak positions of Compound A, calcium salt (Form 2-D), from experiment L100110-68-10, after exposure to a saturated humidity environment. [Diagram 33] FIG. 1 shows an XRPD pattern of the magnesium salt of Compound A (3-A) from experiment L100110-68-11-Dry with peak positions. [Diagram 34] FIG. 1 shows the XRPD pattern with peak positions of the magnesium salt (3-C) of Compound A from experiment L100110-68-11 when exposed to a saturated humidity environment at room temperature. [Diagram 35] FIG. 2 shows the XRPD pattern of the magnesium salt (3-B) of compound A from experiment L100110-68-13 before drying. [Diagram 36] FIG. 1 shows the XRPD pattern of the magnesium salt (3-D) of compound A from experiment L100110-68-13, after deliquescence and subsequent drying. [Figure 37] FIG. 2 shows the XRPD pattern of Compound A, magnesium salt (Form 4-B), from experiment L100110-68-17, before drying. [Figure 38]FIG. 2 shows the XRPD pattern of Compound A, magnesium salt (Form 4-D), from experiment L100110-68-20, before drying. [Figure 39] FIG. 2 shows the XRPD pattern of Compound A, magnesium salt (Form 4-E), from experiment L100110-68-20, after drying. [Diagram 40] FIG. 2 shows the XRPD pattern with peak positions of Compound A, sodium salt (Form 5-A) from experiment L100110-68-21. [Diagram 41] FIG. 2 shows the XRPD pattern of Compound A, sodium salt (Form 5-B) from experiment L100110-68-24 with peak positions. [Diagram 42] FIG. 2 shows the XRPD pattern of Compound A, sodium salt (Form 5-C) from experiment L100110-68-25 with peak positions. [Diagram 43] FIG. 1 shows an XRPD pattern with peak positions of Compound A, sodium salt (Form 5-D) from experiment L100110-68-25, after exposure to humidity, which resulted in a substantial improvement in crystallinity. [Diagram 44] FIG. 2 shows the XRPD pattern with peak positions of Compound A, potassium salt (Form 6-A) from experiment L100110-68-26 after drying. [Diagram 45] FIG. 2 shows the XRPD pattern of Compound A, potassium salt (Form 6-B) from experiment L100110-68-29 with peak positions. [Figure 46] FIG. 2 shows the XRPD pattern with peak positions of Compound A, potassium salt (Form 6-C) from experiment L100110-68-30 after drying. [Figure 47] FIG. 1 shows the XRPD pattern of Compound A, potassium salt (Form 6-D) from experiment L100110-68-30-H with peak positions. [Figure 48]FIG. 1 shows the XRPD pattern with peak positions of Compound A, ethanolamine salt (Form 7-A) from experiment L100110-68-31. [Figure 49] FIG. 2 shows the XRPD pattern of Compound A, ethanolamine salt (Form 7-B) from experiment L100110-68-32, after drying, with peak positions. [Figure 50] FIG. 1 shows the XRPD pattern with peak positions of Compound A, diethanolamine salt (Form 8-A) from experiment L100110-68-36. [Figure 51] FIG. 1 shows the XRPD pattern with peak positions of Compound A, diethanolamine salt (Form 8-B) from experiment L100110-68-38. [Figure 52] FIG. 2 shows the XRPD pattern with peak positions of Compound A, diethanolamine salt (Form 8-C) from experiment L100110-68-36 after exposure to a saturated humidity environment at RT. [Figure 53] FIG. 2 shows the XRPD pattern with peak positions of Compound A, diethanolamine salt (Form 8-D) from experiment L100110-68-40, before drying. [Figure 54] FIG. 1 shows the XRPD pattern of Compound A, diethanolamine salt (Form 8-E) from experiment L100110-68-40, after drying followed by exposure to a saturated humidity environment, with peak positions (essentially Form 8-B, but with extra peaks). [Figure 55] FIG. 1 shows the XRPD pattern with peak positions of Compound A, triethanolamine salt (Form 9-A) from experiment L100110-68-42. [Figure 56] FIG. 1 shows the XRPD pattern with peak positions of Compound A, triethanolamine salt (Form 9-B) from experiment L100110-68-44. [Figure 57]FIG. 2 shows the XRPD pattern with peak positions of Compound A, triethanolamine salt (Form 9-C) from experiment L100110-68-41 after drying at room temperature (RT) and placing in a saturated humidity environment. [Figure 58] FIG. 2 shows the XRPD pattern with peak positions of Compound A, triethanolamine salt (Form 9-D) from experiment L100110-68-44, after drying and placing in a saturated humidity environment at RT. [Figure 59] FIG. 1 shows the XRPD pattern with peak positions of Compound A, triethanolamine salt (Form 9-E) from experiment L100110-68-45. [Figure 60] FIG. 1 shows the XRPD pattern of Compound A, diethylamine salt (Form 10-A) from scale-up experiment L100110-85-9 with peak positions. [Figure 61] FIG. 1 shows the XRPD pattern with peak positions of Compound A, diethylamine salt (Form 10-C) from experiment L100110-68-46, following drying. [Figure 62] FIG. 1 shows the XRPD pattern of Compound A, diethylamine salt (Form 10-B + extra minor peaks) from experiment L100110-68-49 with their peak positions. [Figure 63] FIG. 1 shows the XRPD pattern of Compound A, ethanol-2-diethylamine salt (Form 12-A) from experiment L100110-68-56, with their peak positions. [Figure 64] FIG. 1 shows the XRPD pattern of Compound A, ethanol-2-diethylamine salt (Form 12-B) from experiment L100110-68-60, with their peak positions. [Figure 65] FIG. 1 shows the XRPD pattern of Compound A, ethanol-2-diethylamine salt (Form 12-C) from experiment L100110-68-60, after exposure to a saturated humidity environment at RT with their peak positions. [Figure 66]FIG. 1 shows the XRPD pattern of Compound A, choline hydroxide salt (Form 13-A) from experiment L100110-68-64 with their peak positions. [Figure 67] FIG. 1 shows the XRPD pattern of Compound A, L-arginine salt (Form 14-A) from experiment L100110-68-66 with their peak positions. [Figure 68] FIG. 1 shows the XRPD pattern of Compound A, L-arginine salt (Form 14-B) from experiment L100110-68-68 with their peak positions. [Figure 69] FIG. 1 shows the XRPD pattern of Compound A, L-arginine salt (Form 14-C) from experiment L100110-68-69 with their peak positions. [Figure 70] FIG. 2 shows the XRPD pattern of Compound A, L-arginine salt (Form 14-E) from experiment L100110-68-70, after drying with their peak positions. [Figure 71] FIG. 1 shows the XRPD pattern of Compound A, L-histidine salt (Form 15-A), from experiment L100110-68-71, after drying, with their peak positions. [Figure 72] FIG. 1 shows the XRPD pattern with peak positions of Compound A, L-histidine salt (Form 15-B) from experiment L100110-68-71, after drying at RT followed by exposure to a saturated humidity environment. [Figure 73] FIG. 2 shows the XRPD pattern of Compound A, L-histidine salt (Form 15-C) from experiment L100110-68-72, after drying, with its peak positions. [Figure 74] FIG. 2 shows the XRPD pattern of Compound A, L-histidine salt (Form 15-D) from experiment L100110-68-75, with peak positions, before drying. [Figure 75]FIG. 1 shows the XRPD pattern of Compound A, L-histidine salt (Form 15-E) from experiment L100110-68-75 with their peak positions. [Figure 76] FIG. 1 shows the XRPD pattern of Compound A, L-lysine salt (Form 16-A) from experiment L100110-68-79 with their peak positions. [Figure 77] FIG. 1 shows the XRPD pattern of Compound A, meglumine salt (Form 17-A) from experiment L100110-68-82, with their peak positions. [Figure 78] FIG. 1 shows the XRPD pattern of Compound A, meglumine salt (Form 17-B) from experiment L100110-68-85, with their peak positions. [Figure 79] 1 is a series of XRPD patterns of amorphous solids produced when Compound A was tested with a 1:4 mixture with a polymer. [Figure 80] 1 is a graph showing a series of XRPD patterns of amorphous solids produced during testing of Compound A with a 1:4 mixture with polymer after 1 month of storage. [Figure 81] 1 is a graph showing a series of XRPD patterns of amorphous solids produced when testing Compound A with a 1:2 mixture with a polymer. [Figure 82] 1 is a graph showing a series of XRPD patterns of amorphous solids produced during testing of Compound A with a 1:2 mixture with polymer after one month of storage. [Figure 83] 1 is a dynamic vapor sorption / desorption (DVS) isotherm of glutaric acid co-crystal of Compound A showing a total mass gain of 1.12 wt % in relative humidity environments between 2% and 95%. [Figure 84] FIG. 13 shows the XRPD pattern of glutaric acid co-crystal after DVS analysis (L100129-24-Dry-Post_DVS), where no changes were observed compared to the starting material. [Figure 85] FIG. 2 shows the XRPD pattern of a mixture of Form B and Form M. [Figure 86] FIG. 2 shows the XRPD pattern of a mixture of Form F and Form N. [Figure 87] FIG. 2 shows the XRPD pattern of a mixture of Form A and Form O. [Figure 88] FIG. 2 shows the XRPD pattern of a mixture of Form B and Form P. [Figure 89] FIG. 2 shows the XRPD pattern of a mixture of Form C and Form Q. [Figure 90] FIG. 2 shows the XRPD pattern of a mixture of Form F and Form R. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] Presented herein are various morphic forms, co-crystals, salts and amorphous solid dispersions of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Compound A). Synthetic methods for Compound A can be found in U.S. Pat. No. 7,452,882 and U.S. Pat. No. 9,266,861, the contents of each of which are incorporated herein by reference. U.S. Pat. No. 9,266,861 also discloses Form A of Compound A (FIG. 1) and methods for making it.

[0056] All XRPD patterns reported herein are based on Cu Kα radiation wavelength (1.54 Å).

[0057] In one aspect, the disclosure provides a morphic form of Compound A. In some embodiments, the morphic form is a solvate, such as a methanol solvate, an ethanol solvate, an acetone solvate, a tetrahydrofuran solvate, an N-methylpyrrolidone solvate, a methyl isobutyl ketone solvate, an isopropyl acetate solvate, an acetic acid solvate, a dimethylacetamide solvate, a dimethylsulfoxide solvate, an isopropanol solvate, and an acetonitrile solvate.

[0058] In some embodiments, the morphic form is a desolvate, such as an acetic acid desolvate, an acetonitrile desolvate, an ethyl acetate desolvate, an ethanol desolvate, and an acetone desolvate.

[0059] In some embodiments, the morphic form of Compound A (Form B) is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.92, 11.8, and 17.5 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form B may further comprise a peak at about 15.0 degrees 2θ. In some embodiments, Form B has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 2.

[0060] In some embodiments, the morphic form of Compound A (Form C) is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.74, 11.5, 17.7, 19.3, 19.7, 21.4, 24.3 °2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form C may further comprise one or more peaks according to Table 5. In some embodiments, Form C has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0061] In some embodiments, the morphic form of Compound A (Form D) is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.52, 8.52, 11.0, 16.5, 18.3, 21.0, 21.2, and 24.0 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form D may further comprise one or more peaks according to Table 6. In some embodiments, Form D has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 4.

[0062] In some embodiments, the morphic form of Compound A (Form E) is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.13, 10.8, 12.3, 14.1, 14.7, 15.5, 16.1, 17.5, 18.1, 19.9, 20.2, 21.0, 21.2, 22.7, 22.9, 24.4, 25.3, and 26.3 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form E may further comprise one or more peaks according to Table 7. In some embodiments, Form E has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 5.

[0063] In some embodiments, the morphic form of Compound A (Form F) is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.1, 10.4, 11.4, 13.9, 16.2, 16.4, 17.1, 22.0, 23.8, and 29.5 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form F may further comprise one or more peaks according to Table 8. In some embodiments, Form F has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 6.

[0064] In some embodiments, the morphic form of Compound A (Form G) is characterized by an X-ray powder diffraction pattern comprising peaks at about 9.50, 12.9, 16.7, 17.3, 19.5, 20.2, 25.6, and 28.3 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form G may further comprise one or more peaks according to Table 9. In some embodiments, Form G has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0065] In some embodiments, the morphic form of Compound A (Form H) is characterized by an X-ray powder diffraction pattern comprising peaks at about 9.22, 19.8, 23.6, 25.9, and 28.0 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form H may further comprise one or more peaks according to Table 10. In some embodiments, Form H has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0066] In some embodiments, the morphic form of Compound A (Form I) is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.77, 9.30, 10.2, 11.6, and 21.9 °2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form I may further comprise one or more peaks according to Table 11. In some embodiments, Form I has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0067] In some embodiments, the morphic form of Compound A (Form K) is characterized by an X-ray powder diffraction pattern comprising peaks at about 8.42, 11.4, 14.5, 18.9, 21.1, and 21.6 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form K may further comprise one or more peaks according to Table 12. In some embodiments, Form K has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0068] In some embodiments, the morphic form of Compound A (Form L) is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, 11.5, 11.9, 15.2, 15.7, 16.0, 16.9, 17.1, 18.4, 18.7, 22.0, 22.8, 23.5, and 26.4 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form L may further comprise one or more peaks according to Table 13. In some embodiments, Form L has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 11.

[0069] In some embodiments, the morphic form of Compound A (Form S+T) is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.42, 10.5, 11.3, 12.4, 14.3, 15.8, 16.8, 17.7, 18.1, 18.4, 20.1, 20.5, 21.1, 21.9, 23.2, 25.5, 26.9, and 28.3 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form S+T may further comprise one or more peaks according to Table 14. In some embodiments, Form S+T has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 12.

[0070] In some embodiments, the morphic form of Compound A (Form S) is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.5, 12.3, 14.4, 15.8, 16.7, 17.7, 18.1, 18.4, 20.1, 20.6, 21.2, 21.9, 23.3, 24.4, 25.5, and 27.8 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form S may further comprise one or more peaks according to Table 15. In some embodiments, Form S has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0071] In some embodiments, the morphic form of Compound A (Form U) is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.79, 8.43, 11.4, 11.6, 14.5, 18.9, 21.1, and 21.6 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form U may further comprise one or more peaks according to Table 16. In some embodiments, Form U has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 14.

[0072] In some embodiments, the morphic form of Compound A (Form V) is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.35, 10.6, 15.6, 16.5, 16.8, and 18.3 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form V may further comprise one or more peaks according to Table 17. In some embodiments, Form V has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0073] In some embodiments, the morphic form of Compound A (Form W) is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.1, 10.4, 10.7, 11.7, 13.9, 24.4, and 29.5 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form W may further comprise one or more peaks according to Table 18. In some embodiments, Form W has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0074] In some embodiments, the morphic form of Compound A (Form X) is characterized by an X-ray powder diffraction pattern comprising peaks at about 9.66, 10.2, 10.5, 11.2, 18.7, and 24.7 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form X may further comprise one or more peaks according to Table 19. In some embodiments, Form X has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0075] In some embodiments, the morphic form of Compound A (Form Y) is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.51, 13.0, 13.3, 19.5, and 24.2 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form Y may further comprise one or more peaks according to Table 20. In some embodiments, Form Y has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0076] In some embodiments, the morphic form of Compound A (Form Z) is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.6, 11.2, 11.6, 12.0, 14.3, 15.6, 16.2, 17.6, 18.1, 18.7, 24.1, and 24.3 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form Z may further comprise one or more peaks according to Table 21. In some embodiments, Form Z has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 19.

[0077] In some embodiments, the morphic form of Compound A (Form α) is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.26, 10.1, 10.4, 10.6, 11.9, 13.9, 16.5, 21.9, 22.4, and 24.1 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form α may further comprise one or more peaks according to Table 22. In some embodiments, Form α has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 20.

[0078] In some embodiments, the morphic form of Compound A (Form β) is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.36, 10.5, 14.3, 15.7, 18.3, 20.4, 21.0, 21.8, and 23.2 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form β may further comprise one or more peaks according to Table 23. In some embodiments, Form β has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0079] In some embodiments, the morphic form of Compound A (Form χ) is characterized by an X-ray powder diffraction pattern comprising peaks at about 8.53, 11.2, 18.4, 20.1, and 21.4 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form χ may further comprise one or more peaks according to Table 24. In some embodiments, Form χ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0080] In some embodiments, the morphic form of Compound A (Form δ) is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.9, 12.1, 14.4, 18.1, 19.6, 24.5, and 27.0 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form δ may further comprise one or more peaks according to Table 25. In some embodiments, Form δ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0081] In some embodiments, the morphic form of Compound A (Form ε) is characterized by an X-ray powder diffraction pattern comprising peaks at about 5.73, 11.4, 16.6, 17.6, 23.2, and 24.2 °2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form ε may further comprise one or more peaks according to Table 26. In some embodiments, Form ε has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 24.

[0082] In some embodiments, the morphic form of Compound A (Form φ) is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.95, 13.9, 20.9, 22.3, and 27.9 °2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form φ may further comprise one or more peaks according to Table 27. In some embodiments, Form φ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0083] In some embodiments, the morphic form of Compound A (Form η) is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.87, 7.69, 20.5, 23.0, 23.9, and 28.2 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form η may further comprise one or more peaks according to Table 28. In some embodiments, Form η has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG.

[0084] In some embodiments, the morphic form of Compound A (Form λ) is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.6, 12.0, 14.3, 16.2, 17.6, 18.0, and 24.3 degrees 2θ, where the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of Form λ may further comprise one or more peaks according to Table 29. In some embodiments, Form λ has an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern set forth in FIG. 27.

[0085] In some embodiments, the morphic form has a purity of more than 85% by weight, e.g., more than 86% by weight, more than 90% by weight, more than 92.5% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 97.5% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, or more than 99.8% by weight. For example, the content of impurities (i.e., any components of the composition other than Compound A, such as by-products, starting materials, solvent residues, heavy metals, etc.) is less than 15% by weight, less than 14% by weight, less than 10% by weight, less than 8% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.8% by weight, less than 0.5% by weight, or less than 0.2% by weight.

[0086] In another aspect, the present disclosure provides an amorphous solid dispersion of Compound A. As used herein, the term "solid dispersion" refers to a system in the solid state that includes at least two components, where one component is dispersed throughout one or more other components. As used herein, the term "amorphous solid dispersion" refers to a stable solid dispersion that includes an amorphous drug substance and a stabilizing polymer. Non-limiting examples of stabilizing polymers are polyvinylpyrrolidone MW 10,000 (PVP-10), polyvinylpyrrolidone MW 40,000 (PVP-40) and poly(1-vinylpyrrolidone-Co-vinyl acetate) (PVP-Co-VA), hydroxy-propyl methylcellulose (hypromellose), methylcellulose, hydroxypropyl cellulose and polyethylene glycol (PEG) 6000. In some embodiments, the stabilizing polymer is polyvinylpyrrolidone.

[0087] The amorphous solid dispersion of the present disclosure comprises compound A and a stabilizing polymer. The amount of compound A in the amorphous solid dispersion of the present disclosure may range from about 0.1% to about 60% by weight relative to the stabilizing polymer. In some embodiments, the amount of compound A in the amorphous solid dispersion of the present disclosure may range from about 15% to about 50% by weight relative to the stabilizing polymer. In some embodiments, the amount of compound A in the amorphous solid dispersion of the present disclosure may be about 50% by weight relative to the stabilizing polymer. In some embodiments, the amount of compound A in the amorphous solid dispersion of the present disclosure may be about 25% by weight relative to the stabilizing polymer.

[0088] In another aspect, the present disclosure presents cocrystals of Compound A. Cocrystal screening was performed on Compound A with 20 different potential coformers. Coformers tested include adipic acid, L-arginine, ascorbic acid, benzoic acid, citric acid, D(+) glucose, glutaric acid, L-histidine, 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, L-lysine, malic acid, salicylic acid, succinic acid, tartaric acid, urea, vanillin, and vanillic acid. Thus far, only Compound A / glutaric acid cocrystals have been observed.

[0089] In some embodiments, the co-crystal may be characterized by an XRPD pattern including peaks at about 9.74, 10.8, 11.0, 12.2, 16.1, 17.0, 19.2, 21.9, and 23.1 °2θ. In some embodiments, the X-ray powder diffraction pattern of the co-crystal may further include one or more peaks according to Table 30. In some embodiments, the co-crystal has an XRPD pattern substantially similar to the XRPD pattern set forth in FIG. 28. In some embodiments, the co-crystal has a purity of greater than 85% by weight, e.g., greater than 86% by weight, greater than 90% by weight, greater than 92.5% by weight, greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 97.5% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, or greater than 99.8% by weight. For example, the content of impurities (i.e., any components of the composition other than Compound A, such as by-products, starting materials, solvent residues, heavy metals, etc.) is less than 15% by weight, less than 14% by weight, less than 10% by weight, less than 8% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.8% by weight, less than 0.5% by weight, or less than 0.2% by weight.

[0090] In yet another aspect, the present disclosure provides a crystalline salt of Compound A. The crystalline salt comprises Compound A and one or more counterions. The molar ratio of Compound A to the counterion can be 1:1 to 2:1. In some embodiments, the molar ratio of Compound A to the counterion is 1:1.1. In some embodiments, the molar ratio of Compound A to the counterion is 1:1. In some embodiments, the counterion is selected from L-lysine, L-arginine, 2-hydroxy-N,N,N-trimethylethan-1-aminium, diethylamine, ethanolamine, ethanol-2-diethylamine, Na + , Mg 2+ , K + , Ca 2+, diethanolamine, triethanolamine, L-histidine, meglumine, or combinations thereof. In some embodiments, the crystalline salt has an XRPD pattern substantially similar to the XRPD patterns depicted in any one of Figures 29-78.

[0091] In some embodiments, the counterion is L-lysine. In some embodiments where the counterion is L-lysine, the crystalline salt may be characterized by an XRPD pattern including peaks at about 8.70, 9.22, 11.3, 17.0, and 24.8 °2θ. The XRPD pattern may further include peaks at about 7.12, 18.4, 19.1, 20.4, and 25.7 °2θ. In some embodiments, the L-lysine salt has an XRPD pattern substantially similar to the XRPD pattern set forth in Figure 76. The L-lysine salt may have a melting point of about 250°C.

[0092] In some embodiments, the counterion is L-arginine. The L-arginine salt may have an XRPD pattern substantially similar to the XRPD patterns depicted in any one of Figures 67-70. The L-arginine salt may have a melting point of about 200°C.

[0093] In some embodiments, the counterion is 2-hydroxy-N,N,N-trimethylethane-1-aminium. In some embodiments, the 2-hydroxy-N,N,N-trimethylethane-1-aminium salt can have an XRPD pattern substantially similar to the XRPD pattern set forth in Figure 66. The 2-hydroxy-N,N,N-trimethylethane-1-aminium salt can have a melting point of about 229°C.

[0094] In yet another aspect, the disclosure includes a salt of Compound A in the form of a solvate (referred to herein as a "salt solvate"). The salt solvate may contain one or more counterions. In some embodiments, the counterion may be potassium, sodium, or magnesium. In some embodiments, the salt solvate is a salt of Compound A in the form of an acetic acid solvate (e.g., a potassium salt, a sodium salt, or a magnesium salt). In some embodiments, the salt solvate is a salt of Compound A in the form of a tetrahydrofuran solvate. In some embodiments, the salt solvate is a salt of Compound A that includes a solvent and water. Such morphic forms may include the solvent and water in a single chemical entity with Compound A and the counterion, or may include a physical mixture of Compound A as a salt in a hydrate and a salt in a solvate.

[0095] The potassium salt solvate of Compound A is useful for removing impurities that may be removed during isolation of the salt solvate.

[0096] In another embodiment of the invention, one type of morphic form can be converted to another type of morphic form. Morphic forms, including solvates or hydrates, can be converted to forms with counterions.

[0097] In some embodiments, the crystalline salt has a purity of more than 85% by weight, e.g., more than 86% by weight, more than 90% by weight, more than 92.5% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 97.5% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, or more than 99.8% by weight. For example, the content of impurities (i.e., any components of the composition other than Compound A, such as by-products, starting materials, solvent residues, heavy metals, counterions, etc.) is less than 15% by weight, less than 14% by weight, less than 10% by weight, less than 8% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.8% by weight, less than 0.5% by weight, or less than 0.2% by weight.

[0098] The present disclosure also provides a mixture of two or more of the forms disclosed herein. The forms can be present in any weight ratio in the mixture. For example, two or more of the morphic forms disclosed herein can be present in the mixture.

[0099] The present disclosure also provides pharmaceutical compositions comprising any one of the morphic forms, co-crystals, salts and amorphous solid dispersions of Compound A disclosed herein. The pharmaceutical compositions may further comprise at least one pharma- ceutically acceptable excipient or carrier.

[0100] A "pharmaceutical composition" is a formulation containing a compound of the present invention in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be in any of a variety of forms, including, for example, a capsule, an intravenous bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of active ingredient (e.g., the disclosed morphic forms, cocrystals, salts, and amorphous solid dispersion formulations) in a unit dosage composition is an effective amount, which will vary according to the particular treatment involved. Those skilled in the art will appreciate that, in some cases, it may be necessary to make routine variations in the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are envisioned, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrathoracic, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, Compound A is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives, buffers or propellants required.

[0101] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical) and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application 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 acetate, citrate, or phosphate, and agents for adjusting isotonicity, such as sodium chloride or dextrose. The pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0102] In carrying out the method of the present invention, an effective amount of any one of the morphic forms, co-crystals, salts and amorphous solid dispersions of the present invention is administered alone or in combination via any of the conventional and acceptable methods known in the art. Thus, the composition may be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously or subcutaneously), rectally (e.g., suppository or lavage solution), transdermally (e.g., skin electroporation), by inhalation (e.g., aerosol) and in solid, liquid or gas dosage forms, including tablets and suspensions. Administration may be in a single unit dosage form, by continuous therapy, or, optionally, by single dose therapy. The therapeutic composition may also be in the form of an oil emulsion or dispersion with a lipophilic salt, such as pamoic acid, or in the form of a biodegradable sustained release composition for subcutaneous or intramuscular administration.

[0103] Pharmaceutical carriers useful for preparing the compositions herein can be solid, liquid, or gaseous, and thus the compositions can take the form of tablets, pills, capsules, suppositories, powders, enteric coatings or other protective formulations (e.g., bound to ion exchange resins or packaged in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. Carriers can be selected from a variety of oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration include sterile aqueous solutions of the active ingredient(s) prepared by dissolving the solid active ingredient(s) in water to make an aqueous solution and render the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. The composition may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, humectants or emulsifiers, salts for adjusting osmotic pressure, buffers, etc. Suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences", EW Martin. Such compositions will in any event contain an effective amount of the active compound together with a suitable carrier so as to prepare a suitable dosage form for proper administration to the recipient.

[0104] The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, moisturizers, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, coating agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances, including further active ingredients other than the active ingredient Compound A.

[0105] The compositions disclosed herein are useful as medicaments for treating thyroid hormone resistance (RTH) in subjects with at least one TRβ mutation. Thus, the present disclosure provides compositions disclosed herein for use in treating thyroid hormone resistance (RTH) in subjects with at least one TRβ mutation. The present disclosure also provides a method for treating RTH in a subject with at least one TRβ mutation, comprising administering to the subject a therapeutically effective amount of any one of the morphic forms, co-crystals, salts, and amorphous solid dispersions disclosed herein. The present disclosure also provides a crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein for the manufacture of a medicament for treating RTH in a subject with at least one TRβ mutation, the crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein being for administration to the subject in at least one therapeutically effective amount. The present disclosure also provides a crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein for use in treating RTH disease in a subject having at least one TRβ mutation, wherein the crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein is for administration to the subject in at least one therapeutically effective amount.

[0106] The subject may exhibit one or more symptoms of RTH syndrome, such as obesity, hyperlipidemia, hypercholesterolemia, heterozygous familial hypercholesterolemia, diabetes, nonalcoholic steatohepatitis, fatty liver, fatty liver disease, bone disease, dyslipidemia, thyroid axis abnormalities, atherosclerosis, cardiovascular disorders, tachycardia, hyperactive behavior, hypothyroidism, goiter, attention deficit hyperactivity disorder, learning disability, mental retardation, hearing loss, delayed bone age, neurological or psychiatric disorders, or thyroid cancer. More information on RTH syndrome can be found in Weiss and Refetoff, "Resistance to Thyroid Hormone (RTH) in the Absence of Abnormal Thyroid Hormone Receptor (TR) (nonTR-RTH)," Hot Thyroidology, 09 / 09, all 11 pages, the contents of which are incorporated herein by reference in their entirety.

[0107] Nucleic acids and polypeptides of thyroid hormone receptors from various species (e.g., human, rat, chicken, etc.) have been described. See, for example, R. L. Wagner et al. (2001), Molecular Endocrinology, 15(3):398-410; J. Sap et al. (1986), Nature, 324:635-640; C. Weinberger et al. (1986), Nature, 324:641-646, and CC Tompson et al. (1986), Science, 237:1610-1614, the contents of each of which are incorporated herein by reference in their entireties. The amino acid sequence of human TRβ is provided, for example, by Genbank Accession No. P10828.2, which is incorporated herein by reference.

[0108] [Table 1]

[0109] In SEQ ID NO: 1, the residues at positions 234, 243, 316 and 317 of human TRβ are underlined. A portion of the human TRβ nucleotide sequence encoding the above amino acid sequence is SEQ ID NO: 2. The nucleotide sequence of human TRβ is provided, for example, by Genbank Accession No: NM_000461.4, which is incorporated herein by reference.

[0110] [Table 2]

[0111] The TRβ mutation is selected from the group consisting of a substitution of the wild type residue alanine (A) at amino acid position 234 of SEQ ID NO:1 with threonine (T) (A234T); a substitution of the wild type residue arginine (R) at amino acid position 243 of SEQ ID NO:1 with glutamine (Q) (R243Q); a substitution of the wild type residue arginine (R) at amino acid position 316 of SEQ ID NO:1 with histidine (H) (R316H); and a substitution of the wild type residue alanine (A) at amino acid position 317 of SEQ ID NO:1 with threonine (T) (A317T).

[0112] The compositions disclosed herein are also useful as medicaments for treating non-alcoholic steatohepatitis (NASH). NASH is inflammation and damage of the liver caused by the accumulation of fat in the liver. Thus, the present disclosure provides the compositions disclosed herein for use in treating NASH in a subject in need thereof. The present disclosure also provides a method for treating NASH in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the morphic forms, co-crystals, salts and amorphous solid dispersions disclosed herein. The present disclosure also provides the crystalline salts, morphic forms, co-crystals or amorphous solid dispersions disclosed herein for the manufacture of a medicament for treating non-alcoholic steatohepatitis in a subject in need thereof, the crystalline salts, morphic forms, co-crystals or amorphous solid dispersions disclosed herein being for administration to the subject in at least one therapeutically effective amount. The present disclosure also provides a crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein for use in treating non-alcoholic steatohepatitis in a subject in need thereof, wherein the crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein is for administration to the subject, in at least one therapeutically effective amount.

[0113] The compositions disclosed herein are also useful as medicaments for treating familial hypercholesterolemia (FH). FH is a genetic disorder that causes dangerously high cholesterol levels at a young age, which, if left untreated, can lead to heart disease, heart attack, or stroke. There are two types of FH: homozygous FH (HoFH) and heterozygous FH (HeFH). Thus, the present disclosure provides the compositions disclosed herein for use in treating HoFH or HeFH in a subject in need thereof. The present disclosure also provides a method for treating HoFH or HeFH in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the morphic forms, cocrystals, salts, and amorphous solid dispersions disclosed herein. The present disclosure also provides a crystalline salt, morphic form, co-crystal or amorphous solid dispersion disclosed herein for the manufacture of a medicament for treating familial hypercholesterolemia in a subject in need thereof, the crystalline salt, morphic form, co-crystal or amorphous solid dispersion disclosed herein is for administration to a subject in at least one therapeutically effective amount.The present disclosure also provides a crystalline salt, morphic form, co-crystal or amorphous solid dispersion disclosed herein for use in treating familial hypercholesterolemia in a subject in need thereof, the crystalline salt, morphic form, co-crystal or amorphous solid dispersion disclosed herein is for administration to a subject in at least one therapeutically effective amount.

[0114] The compositions disclosed herein are also useful as medicaments for treating fatty liver disease. Fatty liver disease is a condition in which large vacuoles of triglyceride fat accumulate in liver cells through the process of steatosis. Thus, the present disclosure provides the compositions disclosed herein for use in treating fatty liver disease in a subject in need thereof. The present disclosure also provides a method for treating fatty liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the morphic forms, co-crystals, salts and amorphous solid dispersions disclosed herein. The present disclosure also provides the crystalline salts, morphic forms, co-crystals or amorphous solid dispersions disclosed herein for the manufacture of a medicament for treating fatty liver disease in a subject in need thereof, the crystalline salts, morphic forms, co-crystals or amorphous solid dispersions disclosed herein being for administration to the subject in at least one therapeutically effective amount. The present disclosure also provides a crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein for use in treating fatty liver disease in a subject in need thereof, wherein the crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein is for administration to the subject in at least one therapeutically effective amount.

[0115] The compositions disclosed herein are also useful as medicaments for treating dyslipidemia. Dyslipidemia is a condition characterized by abnormal amounts of lipids (e.g., triglycerides, cholesterol, and / or fatty phospholipids) in the blood. Thus, the present disclosure provides the compositions disclosed herein for use in treating dyslipidemia in a subject in need thereof. The present disclosure also provides a method for treating dyslipidemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the morphic forms, co-crystals, salts, and amorphous solid dispersions disclosed herein. The present disclosure also provides a crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein for the manufacture of a medicament for treating dyslipidemia in a subject in need thereof, the crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein being for administration to the subject in at least one therapeutically effective amount. The present disclosure also provides a crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein for use in treating dyslipidemia in a subject in need thereof, wherein the crystalline salt, morphic form, co-crystal, or amorphous solid dispersion disclosed herein is for administration to the subject in at least one therapeutically effective amount.

[0116] The therapeutically effective amount or dosage according to the present invention may vary over a wide range and may be determined by methods known in the art. For example, the drug may be administered according to body weight. Such dosage is adjusted in light of the individual requirements in each particular case, including the specific compound administered, the route of administration, the condition being treated, as well as the patient being treated. In another embodiment, the drug may be administered by a fixed dose, e.g., a dose that is not adjusted according to body weight. In general, for oral or parenteral administration to adult humans, a daily dosage of about 0.5 mg to about 1000 mg is appropriate, although the upper limit may be exceeded in cases of indication. The dosage is preferably about 5 mg to about 400 mg per day. For example, the dosage is about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg per day. A preferred dosage may be about 20 mg to about 200 mg. The daily dosage may be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.

[0117] An effective amount of a pharmaceutical agent is that amount that produces an objectively identifiable improvement as noted by a clinician or other qualified observer. As used herein, the term "dosage effective form" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0118] Details of the present invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein may be used in practicing or testing the present invention, exemplary methods and materials are described herein. Other features, objects, and advantages of the present invention will be apparent from the description and claims. In this specification and the appended claims, the singular form also includes the plural form unless the context clearly dictates otherwise. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0119] definition In this disclosure, the articles "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one or more elements.

[0120] In this disclosure, unless otherwise indicated, the term "and / or" is used to mean "and" or "or."

[0121] The term "solvate" is used herein to describe morphic forms that contain organic solvents chemically incorporated in various, fractional or integer molar ratios with the parent molecule.

[0122] The term "hydrate" is used herein to describe morphic forms that contain water chemically incorporated in various, fractional or integer molar ratios with the parent molecule.

[0123] The term "desolvate" is used herein to describe a morphic form resulting from the solvent being substantially removed from the solvate, typically by heat, vacuum, or both. In some embodiments, at least 75% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 80% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 85% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 90% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 95% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 99% by weight of the solvent is removed from the solvate to form a desolvate.

[0124] As used herein, the phrase "pharmacologically acceptable" refers to those compounds, materials, compositions, carriers, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0125] "Pharmaceutically acceptable excipient or carrier" generally means an excipient or carrier that is safe, non-toxic, and not biologically or otherwise harmful, useful in preparing a pharmaceutical composition, and includes excipients that are acceptable for veterinary use as well as for pharmaceutical use in humans. As used herein and in the claims, "pharmaceutically acceptable excipient" includes one or more such excipients.

[0126] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents an identified disease or condition, or that exhibits 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, height, 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 given situation can be determined by routine experimentation, which is within the skill and judgment of the physician. In a preferred embodiment, the disease or condition being treated is a metabolic disorder.

[0127] As used herein, the term "subject" refers to a mammal, preferably a human.

[0128] As used herein, "treating" or "treatment," in reference to a condition, refers to preventing the condition, slowing the onset or rate of development of the condition, reducing the risk of developing the condition, preventing or delaying the onset of symptoms associated with the condition, alleviating or terminating symptoms associated with the condition, causing complete or partial regression of the condition, or some combination thereof.

[0129] As used herein, the term "about," when used in conjunction with a numerical value and / or range, generally refers to a numerical value and / or range that is near the recited numerical value and / or range. In some cases, the term "about" can mean within ±10% of the recited value. For example, in some cases, "about 100 [units]" can mean within ±10% of 100 (e.g., 90-110).

[0130] The term "substantially similar," as used in reference to XRPD patterns, means that XRPD patterns of polymorphs may exhibit "batch-to-batch" variations due to differences in the type of equipment used for the measurements, as well as perturbations in both experimental conditions (e.g., purity and particle size of the sample) and instrumental conditions (e.g., wavelength of the X-rays; precision and sensitivity of the diffractometer, and "instrument drift") typically associated with X-ray diffraction measurements. Due to these variations, the same polymorphs may not contain XRPD peaks at exactly the same positions or intensities as shown in the figures disclosed herein. Thus, the term "about," as used in reference to peaks in an XRPD pattern, takes into account these variations, with ranges readily appreciated by one of ordinary skill in the art. EXAMPLES

[0131] The present disclosure is further illustrated by the following examples and synthetic examples, which are not to be construed as limiting the present disclosure in scope or spirit to the specific procedures described herein. It is to be understood that the examples are illustrative of certain embodiments, and no limitations to the scope of the present disclosure are intended thereby. It is to be further understood that various other embodiments, modifications, and equivalents thereof that may be suggested to those skilled in the art may be utilized without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0132] [Example 1] Solvates and desolvates of compound A A suspension of Compound A and methanol was stirred for 2 days and then filtered. XRPD analysis indicated the formation of a methanol solvate (form B, Figure 2), as well as an ethanol solvate (form C, Figure 3), an acetone solvate (form D, Figure 4), a THF solvate (form E, Figure 5), a MIBK solvate (form G, Figure 7), an isopropyl acetate solvate (form H, Figure 8), an acetic acid solvate (form I, Figure 9), a dimethylacetamide solvate (form K, Figure 10) and an acetonitrile solvate (form L, Figure 11).

[0133] A suspension of Compound A and ethyl acetate was stirred for 2 days and then filtered. Heating to 100° C. for 1 hour produced a desolvate (Form F, FIG. 6). Similarly, a different desolvate, Form λ, is formed by heating the isopropyl acetate solvate (Form H, FIG. 27).

[0134] Forms S+T were generated from the MIBK solvate of Compound A (Form G) by drying overnight under vacuum at 30° C. (FIG. 12). Similarly, Form S was generated from Form H. Form U was generated from Form I. Form V was generated from Form L. Form W was generated from the ethyl acetate solvate formed by suspending Compound A in ethyl acetate at 50° C.

[0135] A desolvate, Form Y (Figure 18), was generated by evaporating a saturated solution of Compound A in ethanol at 50°C and atmospheric pressure to dryness. Similarly, the following forms were isolated from saturated solutions of Compound A: Form Z (Figure 19) from acetic acid solution and Form α (Figure 20) from acetone solution.

[0136] Approximately 50-70 mg of Compound A was accurately weighed into a 4 mL vial and heated to 60° C. Ethanol and a few drops of N-methylpyrrolidone (NMP) were then added. The contents were stirred with a magnetic stir bar until the solids were dissolved. The vial was placed in an ice / water mixture and kept cold until a precipitate formed. The solid was filtered to yield Compound A form β, an NMP solvate (FIG. 21). Similarly, form χ, a DMSO solvate (FIG. 22), was obtained by crystallization from IPA:DMSO (96.5:3.5).

[0137] A possible THF solvate, Form δ (Figure 23), was obtained when a solution of Compound A in THF at 60°C was added to heptane or cyclohexane at room temperature. Similarly, a possible acetone solvate, Form C+ε (Figure 24), was obtained by adding a solution of Compound A in ethanol:acetone (1:1) to heptane. Form φ (Figure 25) and the acetone solvate were obtained by adding the acetone solution to heptane or cyclohexane.

[0138] The isopropyl alcohol (IPA) solvate, Form η (FIG. 26), was generated by suspending the MIBK solvate, Form G, of Compound A in IPA at room temperature.

[0139] A mixture of Form B and Form M (Figure 85) can be made by suspending Form A in methanol at 50°C.

[0140] A mixture of Form F and Form N (Figure 86) can be made by suspending Form A in ethyl acetate at 50°C.

[0141] A mixture of Form A and Form O (Figure 87) can be made by suspending Form A in acetonitrile at 50°C.

[0142] A mixture of Form B and Form P (Figure 88) can be created by drying the methanol solvate under vacuum at 30°C overnight.

[0143] A mixture of Form C and Form Q (Figure 89) can be created by drying the ethanol solvate under vacuum at 30°C overnight.

[0144] A mixture of Forms F and R (Figure 90) can be created by drying the ethyl acetate solvate under vacuum at 30°C overnight.

[0145] [Example 2] Amorphous solid dispersion of compound A The procedure used to prepare the amorphous solid dispersion of Compound A is as follows: The procedure for the experiment with a compound A:polymer ratio of 1:4: (1) about 10 mg of compound A was weighed into a 4 mL vial and about 40 mg of polymer was added to each of the respective vials; (2) solvent was added to each of the respective vials for saturation; (3) the contents of the vials were stirred at room temperature and when dissolution was achieved at room temperature, the clear solution was transferred to a 2 mL centrifuge tube; (4) if complete dissolution was not achieved, the vial was heated to 60° C. to achieve dissolution. If dissolution was still not achieved at 60° C., the vial was centrifuged and the supernatant was collected; (5) the solution / supernatant was subjected to evaporation in a SpeedVac at about 50° C. and under vacuum; (6) the resulting solid / gel was further dried in a vacuum oven for at least 3 hours resulting in a solid, and (7) X-ray diffraction was performed on the resulting solid.

[0146] The polymers used were polyvinylpyrrolidone MW 10000 (PVP-10), polyvinylpyrrolidone MW 40000 (PVP-40), hypromellose or hydroxypropyl methylcellulose (HPR), poly(1-vinylpyrrolidone-Co-vinyl acetate) (PVP-Co-VA). The solvent systems used were 9:1 THF:water, 1:1 ethanol:acetone, acetone and acetic acid. In addition, amorphous solid dispersions were prepared using a 2:1 ratio of polymer to Compound A and 1:1 ethanol:acetone and acetic acid solvent systems.

[0147] [Example 3] Preparation of cocrystals of compound A The creation of co-crystals was attempted through different methods, including milling of solvent droplets, evaporation of Compound A / coformer solutions and co-melting above the melting point of the coformer. Compound A Form A was used as the starting material in all experiments.

[0148] The procedure for making Compound A / glutaric acid cocrystal is described below.

[0149] Compound A (154.7 mg) was weighed into a 4 mL vial and 56.7 mg of glutaric acid was added to the vial (approximately 1.2 molar equivalents). The contents of the vial were mixed with a spatula and heated to 118° C. (20° C. above the melting point of the coformer). The vial was held for approximately 5 minutes, cooled to 88° C., held for 15-20 minutes, and cooled to RT. Partial conversion of Compound A to the cocrystal was observed by XRPD.

[0150] An additional 0.8 equivalents of glutaric acid was added to the solid. The vial was heated to 118° C. The internal temperature of the system was also checked with a thermocouple and found to be 108° C. The system was kept at this temperature for 15-20 minutes with mixing with a spatula and cooled to 88° C. XRPD analysis confirmed the co-crystallization of Compound A and its conversion to glutaric acid.

[0151] The solid obtained after heat treatment following the addition of additional glutaric acid was washed with distilled water (four 500 μL portions, approximately 13.5 volumes relative to Compound A) and subjected to XRPD, which showed no trace of excess glutaric acid. The solid was further dried in a vacuum oven at 50° C. for 3-4 minutes.

[0152] The co-crystal was not hygroscopic, increasing in mass by only 1.12% in relative humidity (RH) environments between 2% and 95%, and was stable at 40° C. and 75% RH for one week. The isotherm is shown in Figure 83. No difference in the XRPD pattern was observed after DVS analysis, and the XRPD patterns before and after DVS analysis are shown in Figure 84.

[0153] The kinetic and thermodynamic solubility of the glutaric acid cocrystal was evaluated in simulated fasting gastric and intestinal fluids (FaSSGF and FaSSIF) and also in water. The pH of the system was also measured. Solubility evaluation was also performed on compound A for comparison. A small amount of compound A, as well as the cocrystal, was suspended in each biological fluid and samples were collected after 1 hour for kinetic solubility evaluation. Samples were collected after 24 hours for equilibrium solubility measurements. Solubility determination is performed by HPLC via a short, 20 minute run-through method used during the salt screening project, 100177FF. The solubility data is presented in Table 1.

[0154] [Table 3]

[0155] [Example 4] Salt screening of compound A Anhydrous Form A of Compound A was used as the starting material in all experiments.

[0156] Several different counterions (CI) were used in an attempt to make salts with Compound A. The counterions Ca and Mg were used as their hydroxides in two different ways and also to make hydroxides in situ (in the form of CaO+water or MgCl2+NaOH) to improve the possibility of salt formation, since the solubility of Ca and Mg hydroxides is low in most of the solvents / solvent systems. Some counterion systems used were calcium hydroxide, calcium oxide (reacted with water in situ), magnesium hydroxide, magnesium chloride (reacted with sodium hydroxide in situ), sodium hydroxide, potassium hydroxide, ethanolamine, diethanolamine, triethanolamine, diethylamine, ethylenediamine, ethanol, 2-(diethylamine), choline hydroxide, L-arginine, L-histidine, L-lysine, meglumine. The IUPAC name for choline is 2-hydroxy-N,N,N-trimethylethane-1-aminium.

[0157] Initial salt screening was performed starting with 30 mg of Compound A and 1.1 equivalents of counterion, all added as solutions in all cases (except for Ca and Mg counterions) to improve salt formation. Vials were evaporated to dryness and slurried in five different processing solvents to further improve the possibility of salt formation. The slurries were filtered and the solids were analyzed by XRPD. Solids with unique patterns were dried and analyzed again by XRPD to see the effect of drying on the solid morphology, and then all unique patterns were exposed to a saturated humidity environment at room temperature overnight and subjected to XRPD again. TGA / DSC was performed on all unique dried solids to identify their melting points and also weight loss on heating (to identify whether the solids were solvates). H-NMR and HPLC analysis were performed on at least one salt form to look for Compound A:counterion stoichiometry, residual solvent content, and also signs of Compound A decomposition during salt formation.

[0158] All counterions formed salts with Compound A, except ethylenediamine. The use of ethylenediamine resulted in the decomposition of Compound A, as observed via HPLC. Scale-up was performed for all salts, starting with approximately 200 mg of Compound A. Two experiments were also performed using 0.5 equivalents of Ca and Mg hydroxides to investigate the possibility of forming half salts. The experiment using 0.5 equivalents of calcium hydroxide resulted in a new pattern that was different from the pattern obtained with 1 equivalent of counter ion, indicating the formation of calcium half salts. However, magnesium hydroxide resulted in a solid with the same pattern as its counterpart with 1 equivalent of counter ion.

[0159] The solubility of each salt in one form was measured in fasting simulated gastric fluid (FaSSGF), fasting simulated intestinal fluid (FaSSIF) and water at 37°C. Usually, for each salt, the solid form that showed relatively good stability under dry or wet conditions was scaled up and used in these experiments. In general, the effect of the salt itself is more profound than the effect of the individual solid form of the salt compared to the free molecule. However, the salts resulted in disproportionation in FaSSGF. By XRPD, the resulting solid was the dihydrate form of the free molecule. However, the L-histidine salt remained as a salt. Some salts were highly soluble in water. In particular, the sodium and potassium salts showed a solubility of more than 20 mg / mL in water. For physical form stability evaluation, all salts of Compound A obtained from the scale-up experiments were exposed to a 75% relative humidity environment for one week, and changes were observed mainly in the case of the half Ca and meglumine salts of Compound A compared to their starting solids.

[0160] Preparation of potassium salt acetic acid solvate of compound A: A 20 L stainless steel pressure vessel was charged with Int.G (950 g, 1 eq, 1.97 mol), KOAc (213 g, 1.1 eq, 2.17 mol) and THF (14.25 L, 15 vol). The vessel was closed, pressurized with 10 psig nitrogen, stirred with an overhead stirrer at 1000 rpm and heated to 90° C. During this time, the pressure of the vessel rose to 41 psig and the reaction was continued at this pressure and at a temperature of 92° C. for about 12 hours. The batch was then cooled to ambient temperature. The fine solids were filtered under nitrogen through an 18 inch Nutsche filter setup with a tightly woven polypropylene cloth. The batch was filtered for 2 hours. After initial filtration, the cake was washed 4 times with 5 volumes of THF (4.75 L), then conditioned under nitrogen for 12 hours, transferred to a tray, and slurried in a vacuum oven (45° C.) for 2 days. The final isolated Compound A K-salt (18AK0164H) yielded 732 g (79% yield) and was 99.60% AUC by UPLC with N / DMG1-100171 (UPLC method) with <20 ppm dimer impurity. NMR for the batch showed a 1:1.1 ratio of Compound A K-salt to AcOH. The material showed 5.7% by weight THF and 117% potency with no correction required.

[0161] Conversion of the potassium salt acetic acid solvate of compound A to the THF solvate-hydrate: A 9L carboy was charged with the K salt of compound A (620 g, 1 eq., Lot#: 18AK0164H), K2CO3 (72 g, 0.4 eq.), THF (1.24 L, 2 vol., bulk quality) and water (3.72 L, 6 vol.). The batch was stirred with an air motor agitator to dissolve all solids. After stirring for 15 minutes, the orange solution was transferred to a 10L jacketed reactor through a 10 micron polypropylene filter using a transfer pump over 5 minutes. The lines were rinsed with a deionized water (465 mL) / THF (175 mL) mixture followed by a deionized water rinse. The batch temperature was adjusted to 20° C. and acetic acid (0.165 L, 2.20 eq.) was charged to the batch over 1 hour. After approximately one-quarter of the acid had been charged to the batch, a slurry began to form. After a 2-hour hold time, deionized water (1.86 L, 3.00 vol) was charged to the batch over 2 hours at 20° C., and the slurry was aged overnight at 20° C. The batch was filtered, the filter cake was washed with 1:5 THF / water (2×2 vol) and dried in a vacuum oven at 45° C. for 12 hours to yield 570 g (86% yield) of the THF solvate of Compound A (Lot#: 18AK0193C) with a purity of 99.81% by UPLC and a molar ratio of THF:H2O of 0.56:0.67.

[0162] Preparation of the tetrahydrofuran solvate of the potassium salt of compound A from the DMAc solvate of compound A (ASV-BO-194): A 500 mL jacketed reactor equipped with a mechanical stirrer, temperature probe, condenser and N2 inlet was charged with the DMAc solvate of compound A (24.5 g, 46.90 mmol, 1.00 equiv), potassium carbonate (7.13 g, 51.59 mmol, 1.10 equiv), MEK (245 mL, 10.0 vol) and deionized water (1.27 mL, 70.36 mmol, 1.50 equiv). The slurry was heated to 45° C. over 1 hour and held at this temperature for 6 hours. The batch was cooled to 20° C. over 3 hours and then held at 20° C. overnight. The batch was then cooled to 5-10°C and then aged at this temperature for 1 hour 45 minutes before being manually smoothed on the filter and filtered to recover the solid product that was conditioned to deliquor the cake. The wet cake was suspended in THF (49 mL, 2.0 vol) and aged for 30 minutes. The slurry was then filtered under vacuum. This THF slurry procedure was repeated four more times for a total of 5 x 2 vol THF washes. After the fifth wash, the batch was conditioned until no more THF appeared on the cake and then dried under vacuum at 40°C (on the filter) to yield the K salt of Compound A (22.47 g, 85% uncorrected, Lot#: ASV-BO-194-12). 1 H NMR showed the molar ratio of K salt of compound A / THF / water: 1.00:0.22:0.51.

[0163] Conversion of the potassium salt of compound A to the tetrahydrofuran solvate of compound A: Potassium salt of compound A (16.50 g, 34.86 mmol, Lot#: ASV-BP-6-8): Analysis: The potassium salt of compound A / DMAc / THF / water molar ratio: 1.00:0.02:0.16:0.65) on a filter frit was suspended in 60 mL of a THF / water solution prepared by mixing 99 mL (6 volumes) of deionized water and 33 mL (2 volumes) of THF, and the resulting slurry was stirred at room temperature, resulting in partial dissolution. The mixture was filtered, and then the solid residue was suspended in about 30 mL of a THF / water solution. Further dissolution occurred after stirring. The mixture was then filtered. Again, the solid residue was suspended in about 30 mL of a THF / water solution. Most of the remaining solid was dissolved, and then it was filtered. A 500 mL jacketed reactor as a receiver was placed under vacuum and the filtrate was transferred to the reactor through an in-line filter (Whatman, 0.3 micron glass microfiber filter). During the transfer process, residual solids were observed in the filter line. This was rinsed into the reactor with the help of an additional 3:1 water / THF solution (1 vol) followed by a deionized water rinse (16 mL, 1.0 vol). The batch temperature was adjusted to 20° C. and acetic acid (4.4 mL, 2.20 molar equivalents) was charged to the batch over 30 minutes. After holding for 1.25 hours, deionized water (50 mL, 3.00 vol) was charged to the slurry batch over 2 hours at 20° C. and the slurry was aged overnight at 20° C. The batch was filtered and the filter cake was washed with 1:5 THF / water (2×49 mL, 2×2 vol) and dried in a vacuum oven at 41° C. to yield the THF solvate of Compound A (13.08 g, Lot#: ASV-BP-18-3). 1 1 H NMR showed a molar ratio of Compound A:THF of 1.00:0.95.

[0164] [Table 4]

[0165] [Example 5] Methods for obtaining XRPD patterns X-ray powder diffraction was performed using a Rigaku MiniFlex 600. Samples were prepared on Si zero-return wafers. Typical scans were from 4 to 30 degrees 2θ with a step size of 0.05 degrees at 40 kV and 15 mA over 5 minutes. High resolution scans were from 4 to 40 degrees 2θ with a step size of 0.05 degrees at 40 kV and 15 mA over 30 minutes. Typical parameters for XRPD are listed below.

[0166] X-ray wavelength: Cu Kα1, 1.540598 Å; X-ray tube settings: 40 kV, 15 mA; slit state: variable + fixed slit system; scanning method: continuous; scanning range (2θ°): 4-30; step size (2θ°): 0.05; scanning speed (° / min): 5.

[0167] Tables 3-80 provide the major 2θ peaks and d-spacings for each of the crystalline forms disclosed herein.

[0168] [Table 5]

[0169] [Table 6]

[0170] [Table 7]

[0171] [Table 8]

[0172] [Table 9]

[0173]

Table 10

[0174]

Table 11

[0175]

Table 12

[0176]

Table 13

[0177]

Table 14

[0178]

Table 15

[0179]

Table 16

[0180]

Table 17

[0181]

Table 18

[0182]

Table 19

[0183]

Table 20

[0184]

Table 21

[0185]

Table 22

[0186]

Table 23

[0187]

Table 24

[0188]

Table 25

[0189]

Table 26

[0190]

Table 27

[0191]

Table 28

[0192]

Table 29

[0193]

Table 30

[0194]

Table 31

[0195]

Table 32

[0196]

Table 33

[0197]

Table 34

[0198]

Table 35

[0199]

Table 36

[0200]

Table 37

[0201]

Table 38

[0202]

Table 39

[0203]

Table 40

[0204]

Table 41

[0205]

Table 42

[0206]

Table 43

[0207]

Table 44

[0208]

Table 45

[0209]

Table 46

[0210]

Table 47

[0211]

Table 48

[0212]

Table 49

[0213]

Table 50

[0214]

Table 51

[0215]

Table 52

[0216]

Table 53

[0217]

Table 54

[0218]

Table 55

[0219]

Table 56

[0220]

Table 57

[0221]

Table 58

[0222]

Table 59

[0223]

Table 60

[0224]

Table 61

[0225]

Table 62

[0226]

Table 63

[0227]

Table 64

[0228]

Table 65

[0229]

Table 66

[0230]

Table 67

[0231]

Table 68

[0232]

Table 69

[0233]

Table 70

[0234]

Table 71

[0235]

Table 72

[0236]

Table 73

[0237]

Table 74

[0238]

Table 75

[0239]

Table 76

[0240]

Table 77

[0241]

Table 78

[0242]

Table 79

[0243]

Table 80

[0244]

Table 81

[0245]

Table 82

[0246] equivalent While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those skilled in the art, and all such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A crystal of the morphic form λ of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

2. The crystal described in claim 1, characterized by an X-ray powder diffraction pattern including peaks at about 10.6, about 12.0, about 14.3, about 16.2, about 17.6, about 18.0 and about 24.3°2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å).

3. The crystal described in claim 2, further characterized by an X-ray powder diffraction pattern including one or more additional peaks at about 11.2, about 15.6, about 17.3 and about 22.3°2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å).

4. A crystal described in claim 1 having an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern shown in Figure 27.

5. The crystal of claim 1, wherein the crystal has a purity of greater than 90% by weight.

6. The crystal described in claim 1, wherein the crystal has a purity of greater than 95% by weight.

7. The crystal of claim 1, wherein the crystal has a purity of greater than 99% by weight.

8. A pharmaceutical composition comprising the crystal described in claim 1.

9. The pharmaceutical composition of claim 8, further comprising at least one pharma- ceutically acceptable excipient or carrier.

10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is a tablet.

11. A crystal of morphic form F of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

12. The crystal described in claim 11, characterized by an X-ray powder diffraction pattern including peaks at about 10.1, about 10.4, about 11.4, about 13.9, about 16.2, about 16.4, about 17.1, about 22.0, about 23.8 and about 29.5°2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å).

13. The crystal described in claim 12, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks at about 18.4, about 19.3, about 22.5 and about 28.0°2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å).

14. The crystal of claim 11 having an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern shown in FIG.

15. The crystal of claim 11, wherein the crystal has a purity of greater than 90% by weight.

16. The crystal of claim 11, wherein the crystal has a purity of greater than 95% by weight.

17. The crystal of claim 11, wherein the crystal has a purity of greater than 99% by weight.

18. A pharmaceutical composition comprising the crystal described in claim 11.

19. The pharmaceutical composition of claim 18, further comprising at least one pharma- ceutically acceptable excipient or carrier.

20. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is a tablet.

21. A crystal of morphic form L of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

22. The crystal described in claim 21, characterized by an X-ray powder diffraction pattern including peaks at about 10.5, about 11.5, about 11.9, about 15.2, about 15.7, about 16.0, about 16.9, about 17.1, about 18.4, about 18.7, about 22.0, about 22.8, about 23.5 and about 26.4°2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å).

23. The crystal described in claim 22, further characterized by an X-ray powder diffraction pattern containing one or more additional peaks at about 8.1, about 12.3, about 24.1 and about 24.7°2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Kα radiation source (1.54 Å).

24. The crystal of claim 21 having an X-ray diffraction pattern substantially similar to the X-ray diffraction pattern shown in FIG.

25. The crystal of claim 21, wherein the crystal has a purity of greater than 90% by weight.

26. The crystal of claim 21, wherein the crystal has a purity of greater than 95% by weight.

27. The crystal of claim 21, wherein the crystal has a purity of greater than 99% by weight.

28. A pharmaceutical composition comprising the crystal described in claim 21.

29. The pharmaceutical composition of claim 28, further comprising at least one pharma- ceutically acceptable excipient or carrier.

30. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is a tablet.

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