Salts, co-crystals, pharmaceutical compositions thereof, and methods of treatment involving same

Abstract

Provided are solid forms, such as pharmaceutically acceptable salts and co-crystals, of compounds useful for the treatment of cancer, pharmaceutical compositions thereof, and uses for the treatment of cancer comprising administering the solid forms described herein to a patient in need thereof.

Description

[0001] background

[0002] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutaric acid (i.e., α-ketoglutaric acid). These enzymes belong to two distinct subclasses: one utilizes NAD(+) as an electron acceptor, and the other utilizes NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases located in the mitochondrial matrix; and two NADP(+)-dependent isocitrate dehydrogenases, one located in the mitochondria and the other primarily in the cytoplasm. Each NADP(+)-dependent isoenzyme is a homodimer.

[0003] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytoplasm) is also known as IDH; IDP; IDCD; IDPC, or PICD. The protein encoded by this gene is an NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisome targeting signaling sequence. The presence of this enzyme in peroxisomes indicates its role in the regeneration of NADPH through reductive reactions within the peroxisome, such as the conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA, and the peroxisome reaction that consumes 2-oxoglutarate, namely the α-hydroxylation of phytanoic acid. Cytoplasmic enzymes play a crucial role in cytoplasmic NADPH production.

[0004] The human IDH1 gene encodes a protein with 414 amino acids. The nucleotide and amino acid sequences of human IDH1 can be found in GenBank entries NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences of IDH1 have also been described in, for example, Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684 (1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533 (1999); Wiemann et al., Genome Res. 11:422-435 (2001); The MGC Project Team, Genome Res. 14:2121-2127 (2004); Lubec et al., submitted (DEC-2008) to UniProtKB; Kullmann et al., submitted (JUN-1996) to the EMBL / GenBank / DDBJ database; and Sjoeblom et al., Science 314:268-274 (2006).

[0005] Non-mutant (e.g. wild-type) IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutaric acid.

[0006] Mutations in IDH1 found in certain cancer cells have led to a novel ability of this enzyme to catalyze the reduction of NADPH-dependent α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to cancer formation and progression (Dang, L et al., Nature 2009, 462:739-44).

[0007] IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondria) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is an NADP(+)-dependent isocitrate dehydrogenase found in mitochondria. It plays a role in intermediate metabolism and energy production. This protein may bind tightly to or interact with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a protein with 452 amino acids. The nucleotide and amino acid sequences of IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2, respectively. The nucleotide and amino acid sequences of human IDH2 are also described, for example, in Huh et al., submission (NOV-1992) to the EMBL / GenBank / DDBJ database; and The MGC Project Team, Genome Res. 14:2121-2127 (2004).

[0008] Non-mutant (e.g. wild-type) IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG).

[0009] Mutations in IDH2 found in certain cancer cells have resulted in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Wild-type IDH2 does not form 2HG. The production of 2HG is believed to contribute to cancer formation and progression (Dang, L et al., Nature 2009, 462:739-44).

[0010] US Patent Publication No. 2015 / 0018328 A1 discloses a chemical name of 6-(6-chloropyridin-2-yl)-N 2 N 4 -A compound of bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine, which has been shown to be used as an inhibitor of mutant IDH1 and IDH2 proteins in biochemical and cellular assays. Invention Overview

[0012] This disclosure relates to the solid form (e.g., salt, eutectic and other crystalline forms) of compounds of formula (I).

[0013] .

[0014] In one aspect, this disclosure relates to the solid form of compounds of formula (I).

[0015] In one aspect, this disclosure relates to pharmaceutically acceptable salts of compounds of formula (I).

[0016] In one aspect, this disclosure relates to the crystalline form of a pharmaceutically acceptable salt of a compound of formula (I).

[0017] In one aspect, this disclosure relates to eutectic compounds comprising formula (I).

[0018] In one aspect, this application relates to amorphous solid dispersions containing compounds of formula (I).

[0019] In one aspect, this application relates to amorphous solid dispersions prepared from pharmaceutically acceptable salts of compounds of formula (I).

[0020] In one aspect, this application relates to amorphous solid dispersions prepared from eutectic compounds comprising formula (I).

[0021] In another aspect, this application relates to pharmaceutical compositions comprising a compound of formula (I) in solid form and one or more pharmaceutical excipients.

[0022] In another aspect, this application relates to pharmaceutical compositions comprising a pharmaceutically acceptable salt of a compound of formula (I) and one or more pharmaceutical excipients.

[0023] In another aspect, this application relates to pharmaceutical compositions comprising a cocrystal of a compound of formula (I) and one or more pharmaceutical excipients.

[0024] In another aspect, this application relates to a pharmaceutical composition comprising an amorphous solid dispersion containing a compound of formula (I) in solid form, and one or more pharmaceutical excipients. In yet another aspect, this application relates to a pharmaceutical composition comprising an amorphous solid dispersion containing a pharmaceutically acceptable salt of a compound of formula (I), and one or more pharmaceutical excipients.

[0025] In another aspect, this application relates to pharmaceutical compositions comprising an amorphous solid dispersion prepared by eutectic formation of a compound of formula (I), and one or more pharmaceutical excipients.

[0026] In another aspect, this application relates to a method for preparing the solid form of the compound of formula (I).

[0027] In another aspect, this application relates to a method for preparing a pharmaceutically acceptable salt of a compound of formula (I).

[0028] In another aspect, this application relates to a method for preparing a eutectic of a compound of formula (I).

[0029] In another aspect, this application relates to a method for treating cancer characterized by the presence of IDH1 and / or IDH2 mutations in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a solid form of a compound of formula (I) or a pharmaceutical composition thereof.

[0030] In another aspect, this application relates to a method for treating cancer characterized by the presence of IDH1 and / or IDH2 mutations in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) or a pharmaceutical composition thereof.

[0031] In another aspect, this application relates to a method for treating cancer characterized by the presence of IDH1 and / or IDH2 mutations in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a cocrystal of a compound of formula (I) or a pharmaceutical composition thereof. Brief description of the attached diagram

[0033] Figure 1 The X-ray diffraction patterns of the benzenesulfonate of compound (I) are described.

[0034] Figure 2 The benzenesulfonate of compound (I) is described 1 H NMR spectrum.

[0035] Figure 3 The X-ray diffraction pattern of (+)-camphor-10-sulfonate of compound (I) is described.

[0036] Figure 4 The (+)-camphor-10-sulfonate of compound (I) is described. 1 H NMR spectrum.

[0037] Figure 5 The X-ray diffraction pattern of ethane-1,2-disulfonate of compound (I) is described.

[0038] Figure 6 The ethane-1,2-disulfonate of compound (I) is described. 1 H NMR spectrum.

[0039] Figure 7 The X-ray diffraction pattern of the ethanesulfonate of compound (I) is described.

[0040] Figure 8The ethanesulfonate of compound (I) is described 1 H NMR spectrum.

[0041] Figure 9 The X-ray diffraction pattern of the hydrobromide of compound (I) is described.

[0042] Figure 10 The hydrobromide of compound (I) is described 1 H NMR spectrum.

[0043] Figure 11 The X-ray diffraction pattern of the hydrochloride salt of compound (I) is described.

[0044] Figure 12 The hydrochloride salt of compound (I) is described 1 H NMR spectrum.

[0045] Figure 13 The X-ray diffraction pattern of the naphthalene-1,5-disulfonate of compound (I) is described.

[0046] Figure 14 The naphthalene-1,5-disulfonate of compound (I) is described. 1 H NMR spectrum.

[0047] Figure 15 The X-ray diffraction pattern of the naphthalene-2-sulfonate of compound (I) is described.

[0048] Figure 16 The naphthalene-2-sulfonate of compound (I) is described 1 H NMR spectrum.

[0049] Figure 17 The X-ray diffraction pattern of p-toluenesulfonate of compound (I) is described.

[0050] Figure 18 The p-toluenesulfonate of compound (I) is described. 1 H NMR spectrum.

[0051] Figure 19 The X-ray diffraction patterns of the sulfates of compound (I) are described.

[0052] Figure 20 The sulfate of compound (I) is described 1 H NMR spectrum.

[0053] Figure 21 The X-ray diffraction pattern of the 3-hydroxy-2-naphthoic acid cocrystal of compound (I) is described.

[0054] Figure 22The 3-hydroxy-2-naphthoic acid cocrystal of compound (I) is described. 1 H NMR spectrum.

[0055] Figure 23 The X-ray diffraction pattern of the L-serine cocrystal of compound (I) is described.

[0056] Figure 24 The L-serine cocrystal of compound (I) is described 1 H NMR spectrum.

[0057] Figure 25 The X-ray diffraction pattern of the glycine cocrystal of compound (I) is described.

[0058] Figure 26 The glycine eutectic of compound (I) is described 1 H NMR spectrum.

[0059] Figure 27 The X-ray diffraction pattern of the D-gluconic acid eutectic of compound (I) is described.

[0060] Figure 28 The D-gluconic acid eutectic of compound (I) is described 1 H NMR spectrum.

[0061] Figure 29 Differential scanning calorimetry (DSC) thermograms of ethane-1,2-disulfonate of compound (I) are described.

[0062] Figure 30 The DSC thermogram of the naphthalene-1,5-disulfonate of compound (I) is described.

[0063] Figure 31 The DSC thermogram of the 3-hydroxy-2-naphthoic acid cocrystal of compound (I) is described.

[0064] Figure 32 The glycolic acid eutectic of compound (I) is described 1 H NMR spectrum.

[0065] Figure 33 The X-ray diffraction pattern of the glycolic acid eutectic of compound (I) is described.

[0066] Figure 34 The L-malic acid eutectic of compound (I) is described. 1 H NMR spectrum.

[0067] Figure 35 The X-ray diffraction pattern of the L-malic acid eutectic of compound (I) is described.

[0068] Figure 36 The oxalic acid eutectic of compound (I) is described 1 H NMR spectrum.

[0069] Figure 37 The X-ray diffraction pattern of the oxalic acid eutectic of compound (I) is described.

[0070] Figure 38 The benzoic acid eutectic of compound (I) is described 1 H NMR spectrum.

[0071] Figure 39 The X-ray diffraction pattern of the benzoic acid eutectic of compound (I) is described.

[0072] Figure 40 The DSC thermogram of the benzoic acid eutectic of compound (I) is described.

[0073] Figure 41 The fumaric acid eutectic of compound (I) is described 1 H NMR spectrum.

[0074] Figure 42 The X-ray diffraction pattern of the fumaric acid eutectic of compound (I) is described.

[0075] Figure 43 The gentianic acid eutectic of compound (I) is described. 1 H NMR spectrum.

[0076] Figure 44 The X-ray diffraction pattern of the gentianic acid eutectic of compound (I) is described.

[0077] Figure 45 The glutaric acid eutectic of compound (I) is described 1 H NMR spectrum.

[0078] Figure 46 The X-ray diffraction pattern of the glutaric acid eutectic of compound (I) is described.

[0079] Figure 47 The orthophosphate of compound (I) is described 1 H NMR spectrum.

[0080] Figure 48 The X-ray diffraction pattern of the orthophosphate of compound (I) is described.

[0081] Figure 49 The 4-hydroxybenzoic acid eutectic of compound (I) is described. 1 H NMR spectrum.

[0082] Figure 50The X-ray diffraction pattern of the 4-hydroxybenzoic acid cocrystal of compound (I) is described.

[0083] Figure 51 The α-ketoglutaric acid eutectic of compound (I) is described. 1 H NMR spectrum.

[0084] Figure 52 The X-ray diffraction pattern of the α-ketoglutaric acid eutectic of compound (I) is described.

[0085] Figure 53 The malonic acid eutectic of compound (I) is described. 1 H NMR spectrum.

[0086] Figure 54 The X-ray diffraction pattern of the malonic acid eutectic of compound (I) is described.

[0087] Figure 55 The salicylic acid eutectic of compound (I) is described 1 H NMR spectrum.

[0088] Figure 56 The X-ray diffraction pattern of the salicylic acid eutectic of compound (I) is described.

[0089] Figure 57 The L-tartaric acid eutectic of compound (I) is described. 1 H NMR spectrum.

[0090] Figure 58 The X-ray diffraction pattern of the L-tartaric acid eutectic of compound (I) is described.

[0091] Figure 59 The urea eutectic of compound (I) is described 1 H NMR spectrum.

[0092] Figure 60 The X-ray diffraction pattern of the urea eutectic of compound (I) is described.

[0093] Figure 61 The pyroglutamic acid co-crystal of compound (I) is described 1 H NMR spectrum.

[0094] Figure 62 The X-ray diffraction pattern of the pyroglutamic acid cocrystal of compound (I) is described.

[0095] Figure 63 The hexanoic acid eutectic of compound (I) is described 1 H NMR spectrum.

[0096] Figure 64The X-ray diffraction pattern of the hexanoic acid eutectic of compound (I) is described.

[0097] Figure 65 The glycerol eutectic of compound (I) is described 1 H NMR spectrum.

[0098] Figure 66 The X-ray diffraction pattern of the glycerol eutectic of compound (I) is described.

[0099] Figure 67 The L-lysine cocrystal of compound (I) is described 1 H NMR spectrum.

[0100] Figure 68 The X-ray diffraction pattern of the L-lysine cocrystal of compound (I) is described.

[0101] Figure 69 The S-proline cocrystal of compound (I) is described 1 H NMR spectrum.

[0102] Figure 70 The X-ray diffraction pattern of the S-proline cocrystal of compound (I) is described.

[0103] Figure 71 The pyruvate eutectic of compound (I) is described 1 H NMR spectrum.

[0104] Figure 72 The X-ray diffraction pattern of the pyruvate eutectic of compound (I) is described. Invention Details

[0106] This disclosure relates to the solid form of compounds of formula (I) as defined herein, pharmaceutical compositions comprising them, methods of preparing them, and treatment methods relating to them.

[0107] U.S. Publication No. 2015 / 0018328 A1 describes compound of formula (I) in paragraphs

[1032] -

[1036] , namely 6-(6-chloropyridin-2-yl)-N 2 N 4 Synthesis of bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine.

[0108] U.S. Publication No. 2021 / 0198234 discloses an alternative method for synthesizing the compound of formula (I) in paragraphs

[0343] -

[0349] .

[0109] Under certain conditions, compounds of formula (I) exist at least partially in one or more tautomer forms, including but not limited to one or more of the following:

[0110]

[0111] As used herein, the term compound of formula (I) should be understood to refer to 6-(6-chloropyridin-2-yl)-N 2 N 4 -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine or any of its tautomers. The double bond geometry of the above tautomers is not determined, and therefore the chemical structures representing the above tautomers are not intended to suggest a specific double bond geometry.

[0112] The presence of one or more tautomers of the compound of formula (I) was investigated in paragraphs

[0321] -

[0325] of U.S. Publication No. 2021 / 0198234.

[0113] As used herein, compounds of formula (I) include compounds having the defined chemical structure, as well as any of their rotational isomers.

[0114] In the specification and claims, each atom of the compound of formula (I) is intended to represent any stable isotope of the specified element. In the embodiments, no attempt is made to enrich any specific isotope of any atom of the compound of formula (I), so each atom may be present with an isotopic composition of approximately the natural abundance of the specified element.

[0115] As used herein, the term "stable" when referring to an isotope means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, VS Shirley & CM. Isotopes for which no decay mode was identified in the Table of Nuclides (January 1980), Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory.

[0116] In some embodiments, the compound of formula (I) comprises each constituent atom of approximately the natural abundance isotopes of the specified element.

[0117] In one aspect, this disclosure relates to the solid form of compounds of formula (I).

[0118] .

[0119] In one aspect, this disclosure relates to pharmaceutically acceptable salts of compounds of formula (I).

[0120] In another aspect, this disclosure relates to the crystalline form of a pharmaceutically acceptable salt of a compound of formula (I).

[0121] In one aspect, a pharmaceutically acceptable salt of a compound of formula (I) is formed using a pharmaceutically acceptable acid selected from: benzenesulfonic acid, (+)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, hydrobromic acid, hydrochloric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, sulfuric acid, or phosphoric acid.

[0122] In one aspect, this disclosure relates to eutectic compounds comprising formula (I).

[0123] In one aspect, this disclosure relates to a cocrystal comprising a compound of formula (I) and a co-forming agent selected from 3-hydroxy-2-naphthoic acid, L-serine, glycine, D-gluconic acid, glycolic acid, L-malic acid, oxalic acid, benzoic acid, fumaric acid, gentic acid, glutaric acid, 4-hydroxybenzoic acid, α-ketoglutaric acid, malonic acid, salicylic acid, L-tartaric acid, urea, pyroglutamic acid, hexanoic acid, glycerol, L-lysine, S-proline, and pyruvic acid.

[0124] In this article, pyroglutamic acid is used to refer to 2-pyrrolidone-5-carboxylic acid.

[0125] As used herein, the term "eutectic" refers to a crystalline solid composed of two or more neutral chemical substances in a defined stoichiometric ratio, which possesses different crystallographic and spectroscopic properties compared to the individual substances. A "eutectic" differs from a "salt," which is composed of charged substances in a charge balance. The substances constituting a eutectic are typically linked by hydrogen bonds and other non-covalent and nonionic interactions. Therefore, a pharmaceutical eutectic typically comprises the drug and one or more co-forming agents. The combination of drug and co-forming agents that will form a eutectic is often unpredictable de novo, and eutectic formation often affects the physicochemical properties of the drug in unpredictable ways.

[0126] As used in this article, the term “crystallization” refers to a solid material in which the constituent particles (e.g., molecules) are arranged in a regular and repeating lattice in space.

[0127] In one aspect, the pharmaceutically acceptable salt of the compound of formula (I) is a benzenesulfonate.

[0128] In another respect, the benzenesulfonate of the compound of formula (I) is crystalline.

[0129] In some embodiments, the crystalline benzenesulfonate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflectance mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from those listed in Table 3 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from: 5.83, 8.17, 14.40, and 17.90. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from: 5.83, 8.17, 14.40, and 17.90. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions (in 2θ degrees, ±0.2 2θ degrees): 5.83, 8.17, 14.40, and 17.90. In other embodiments, the X-ray powder diffraction pattern includes four peak positions (in 2θ degrees, ±0.2 2θ degrees): 5.83, 8.17, 14.40, and 17.90. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.83 and 14.40, and at least one peak position selected from 8.17 and 17.90 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 3. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 1 The X-ray powder diffraction pattern shown is shown in the figure.

[0130] As used herein, when an X-ray powder diffraction pattern is described as having a specified number of peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from a specified group of peak positions, the error range (±0.2 2θ degrees) should be understood to apply to each peak position within that group.

[0131] As used herein, the term “similar” when referring to two or more X-ray powder diffraction patterns means that a person skilled in the art will understand that the patterns represent the same crystalline form and that the patterns are identical, except for the types of variation that a person skilled in the art would expect from experimental variations (e.g., the instrument used, time of day, humidity, season, pressure, temperature, etc.).

[0132] In one aspect, the pharmaceutically acceptable salt of the compound of formula (I) is (+)-camphor-10-sulfonate.

[0133] In another aspect, the (+)-camphor-10-sulfonate of compound (I) is crystalline.

[0134] In some embodiments, the crystalline (+)-camphor-10-sulfonate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflectance mode (sometimes referred to as reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 4 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.29, 10.19, 12.07, 18.12, and 19.97. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.29, 10.19, 12.07, 18.12, and 19.97. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.29, 10.19, 12.07, 18.12, and 19.97. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.29, 10.19, 12.07, 18.12, and 19.97. In other embodiments, the X-ray powder diffraction pattern includes peak positions at 10.19 and 12.07 and at least one peak position selected from the following: 8.29, 18.12, and 19.97 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 4 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 3 The X-ray powder diffraction pattern shown is shown in the figure.

[0135] In one respect, the pharmaceutically acceptable salt of the compound of formula (I) is ethane-1,2-disulfonate.

[0136] In another aspect, the ethane-1,2-disulfonate of compound (I) is crystalline.

[0137] In some embodiments, the crystalline ethane-1,2-disulfonate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflectance mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 5 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.59, 14.75, 18.08, and 18.87. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.59, 14.75, 18.08, and 18.87. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 14.75, 18.08, and 18.87. In other embodiments, the X-ray powder diffraction pattern includes four peak positions: 5.59, 14.75, 18.08, and 18.87. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.59 and 18.87 and at least one peak position selected from the following: 14.75 and 18.08 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 5 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 5 The X-ray powder diffraction pattern shown is shown in the figure.

[0138] In some embodiments, the ethane-1,2-disulfonate of formula (I) is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at an onset temperature of 304.30 °C (±5.0 °C). In other embodiments, the ethane-1,2-disulfonate of formula (I) is characterized by a DSC thermogram containing an endothermic peak at an onset temperature of 304.30 °C (±2.0 °C).

[0139] In one respect, the pharmaceutically acceptable salt of the compound of formula (I) is an ethanesulfonate.

[0140] In another respect, the ethanesulfonate of the compound of formula (I) is crystalline.

[0141] In some embodiments, the crystalline ethanesulfonate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflectance mode (sometimes referred to as reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 6 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.86, 13.97, 14.27, 17.00, and 17.72. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.22θ degrees) selected from the following: 6.86, 13.97, 14.27, 17.00, and 17.72. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.86, 13.97, 14.27, 17.00, and 17.72. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.86, 13.97, 14.27, 17.00, and 17.72. In other embodiments, the X-ray powder diffraction pattern includes peak positions at 13.97 and 14.27 and at least one peak position selected from the following: 6.86, 17.00, and 17.72 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 6 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 7 The X-ray powder diffraction pattern shown is shown in the figure.

[0142] In one respect, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrobromide.

[0143] In another respect, the hydrobromide of the compound of formula (I) is crystalline.

[0144] In some embodiments, the crystalline hydrobromide of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 7 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.74, 8.56, 13.63, 14.90, and 15.08. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.74, 8.56, 13.63, 14.90, and 15.08. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 8.56, 13.63, 14.90, and 15.08. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.22θ degrees): 5.74, 8.56, 13.63, 14.90, and 15.08. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.74 and 8.56 and at least one peak position selected from the following: 13.63, 14.90, and 15.08 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 7 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 9 The X-ray powder diffraction pattern shown is shown in the figure.

[0145] In one respect, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt.

[0146] In another respect, the hydrochloride salt of the compound of formula (I) is crystalline.

[0147] In some embodiments, the crystalline hydrochloride salt of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 8 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.73, 9.71, 13.78, 14.64, and 16.25. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.73, 9.71, 13.78, 14.64, and 16.25. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.73, 9.71, 13.78, 14.64, and 16.25. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.22θ degrees): 5.73, 9.71, 13.78, 14.64, and 16.25. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.73 and 14.64 and at least one peak position selected from the following: 9.71, 13.78, and 16.25 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 8 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 11 The X-ray powder diffraction pattern shown is shown in the figure.

[0148] In one aspect, the pharmaceutically acceptable salt of the compound of formula (I) is naphthalene-1,5-disulfonate.

[0149] In another aspect, the naphthalene-1,5-disulfonate of compound (I) is crystalline.

[0150] In some embodiments, the crystalline naphthalene-1,5-disulfonate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflectance mode (sometimes referred to as reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 9 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.52, 13.79, 14.17, 19.28, 19.63, and 19.97. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.52, 13.79, 14.17, 19.28, 19.63, and 19.97. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.52, 13.79, 14.17, 19.28, 19.63, and 19.97. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.52, 13.79, 14.17, 19.28, 19.63, and 19.97. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.52 and 19.97 and at least one peak position selected from the following: 13.79, 14.17, 19.28, and 19.63 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 9 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 13 The X-ray powder diffraction pattern shown is shown in the figure.

[0151] In some embodiments, the naphthalene-1,5-disulfonate of formula (I) is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at an onset temperature of 324.30 °C (±5.0 °C). In other embodiments, the naphthalene-1,5-disulfonate of formula (I) is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at an onset temperature of 324.30 °C (±2.0 °C).

[0152] In one respect, the pharmaceutically acceptable salt of the compound of formula (I) is naphthalene-2-sulfonate.

[0153] In another aspect, the naphthalene-2-sulfonate of compound (I) is crystalline.

[0154] In some embodiments, the crystalline naphthalene-2-sulfonate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflectance mode (sometimes referred to as reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 10 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.41, 13.65, 26.09, and 26.47. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.22θ degrees) selected from the following: 8.41, 13.65, 26.09, and 26.47. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.41, 13.65, 26.09, and 26.47. In other embodiments, the X-ray powder diffraction pattern includes four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.41, 13.65, 26.09, and 26.47. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 8.41 and 26.47 and at least one peak position selected from the following: 13.65 and 26.09 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 10 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 15 The X-ray powder diffraction pattern shown is shown in the figure.

[0155] In one aspect, the pharmaceutically acceptable salt of the compound of formula (I) is p-toluenesulfonate.

[0156] In another aspect, the p-toluenesulfonate of compound (I) is crystalline.

[0157] In some embodiments, the crystalline p-toluenesulfonate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflectance mode (sometimes referred to as reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 11 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.64. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.64. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.64. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.64. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.29 and 12.96 and at least one peak position selected from the following: 8.37, 8.66, 13.47, 20.42, and 20.64 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 11. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 17 The X-ray powder diffraction pattern shown is shown in the figure.

[0158] In one respect, the pharmaceutically acceptable salt of the compound of formula (I) is a sulfate.

[0159] In another respect, the sulfate of the compound of formula (I) is crystalline.

[0160] In some embodiments, the crystalline sulfate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflectance mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 12 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.80, 8.50, 13.62, 14.21, 14.87, and 18.04. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.80, 8.50, 13.62, 14.21, 14.87, and 18.04. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.80, 8.50, 13.62, 14.21, 14.87, and 18.04. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.80, 8.50, 13.62, 14.21, 14.87, and 18.04. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.80 and 14.87 and at least one peak position selected from the following: 8.50, 13.62, 14.21, and 18.04 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 12. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 19 The X-ray powder diffraction pattern shown is shown in the figure.

[0161] In one respect, the pharmaceutically acceptable salt of the compound of formula (I) is an orthophosphate.

[0162] In another respect, the orthophosphate of compound (I) is crystalline.

[0163] In some embodiments, the crystalline orthophosphate of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflectance mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 24 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.47, 14.27, 14.91, 18.35, 19.72, and 21.29. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.47, 14.27, 14.91, 18.35, 19.72, and 21.29. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.47, 14.27, 14.91, 18.35, 19.72, and 21.29. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.47, 14.27, 14.91, 18.35, 19.72, and 21.29. In other embodiments, the X-ray powder diffraction pattern includes peak positions at 18.35 and 21.29 and at least one peak position selected from the following: 5.47, 14.27, 14.91, and 19.72 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 24. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 48 The X-ray powder diffraction pattern shown is shown in the figure.

[0164] In one aspect, the eutectic of the compound comprising formula (I) is a eutectic of 3-hydroxy-2-naphthoic acid.

[0165] In some embodiments, the 3-hydroxy-2-naphthoic acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from those listed in Table 13 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from: 6.41, 13.34, 13.69, 15.84, and 20.21. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from: 6.41, 13.34, 13.69, 15.84, and 20.21. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.41, 13.34, 13.69, 15.84, and 20.21. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.41, 13.34, 13.69, 15.84, and 20.21. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 6.41 and 13.34 and at least one peak position selected from the following: 13.69, 15.84, and 20.21 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes peak positions (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 13. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 21 The X-ray powder diffraction pattern shown is shown in the figure.

[0166] In some embodiments, the 3-hydroxy-2-naphthoic acid eutectic of compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at an onset temperature of 202.79 °C (±5.0 °C). In other embodiments, the 3-hydroxy-2-naphthoic acid eutectic of compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at an onset temperature of 202.79 °C (±2.0 °C).

[0167] In one aspect, the cocrystal of the compound containing formula (I) is an L-serine cocrystal.

[0168] In some embodiments, the L-serine cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 14 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.90, 8.46, 13.28, 13.88, and 18.72. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.22θ degrees) selected from the following: 5.90, 8.46, 13.28, 13.88, and 18.72. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.90, 8.46, 13.28, 13.88, and 18.72. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.90, 8.46, 13.28, 13.88, and 18.72. In other embodiments, the X-ray powder diffraction pattern includes peak positions at 8.46 and 13.88 and at least one peak position selected from the following: 5.90, 13.28, and 18.72 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes peak positions (in 2θ degrees, ±0.22θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 14. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 23 The X-ray powder diffraction pattern shown is shown in the figure.

[0169] In one aspect, the eutectic of the compound containing formula (I) is a glycine eutectic.

[0170] In some embodiments, the glycine cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 15 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.62, 14.04, 14.79, and 26.04. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.62, 14.04, 14.79, and 26.04. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions (in 2θ degrees, ±0.2 2θ degrees): 8.62, 14.04, 14.79, and 26.04. In other embodiments, the X-ray powder diffraction pattern includes four or more peak positions (in 2θ degrees, ±0.2 2θ degrees): 8.62, 14.04, 14.79, and 26.04. In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 15. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 25 The X-ray powder diffraction pattern shown is shown in the figure.

[0171] In one aspect, the eutectic of the compound comprising formula (I) is a D-gluconic acid eutectic.

[0172] In some embodiments, the D-gluconic acid eutectic of the compound of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 16 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.17, 14.14, 15.32, 19.17, and 19.32. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.17, 14.14, 15.32, 19.17, and 19.32. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.17, 14.14, 15.32, 19.17, and 19.32. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.17, 14.14, 15.32, 19.17, and 19.32. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 15.32 and 19.32 and at least one peak position selected from the following: 6.17, 14.14, and 19.17 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 16 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 27 The X-ray powder diffraction pattern shown is shown in the figure.

[0173] In one aspect, the eutectic of the compound comprising formula (I) is a glycolic acid eutectic.

[0174] In some embodiments, the glycolic acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 17 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from: 7.90, 14.04, and 16.25. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees): 7.90, 14.04, and 16.25. In other embodiments, the X-ray powder diffraction pattern contains three or more peak positions (in 2θ degrees, ±0.2 2θ degrees): 7.90, 14.04, and 16.25. In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 17. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 33 The X-ray powder diffraction pattern shown is shown in the figure.

[0175] In one aspect, the eutectic of the compound comprising formula (I) is an L-malic acid eutectic.

[0176] In some embodiments, the L-malic acid eutectic of the compound of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 18 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.87, 8.49, 14.13, 15.40, and 19.55. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.22θ degrees) selected from the following: 5.87, 8.49, 14.13, 15.40, and 19.55. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.87, 8.49, 14.13, 15.40, and 19.55. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.87, 8.49, 14.13, 15.40, and 19.55. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.87 and 14.13 and at least one peak position selected from the following: 8.49, 15.40, and 19.55 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 18 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 35 The X-ray powder diffraction pattern shown is shown in the figure.

[0177] In one aspect, the eutectic of the compound containing formula (I) is an oxalic acid eutectic.

[0178] In some embodiments, the oxalic acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 19 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from: 5.81, 13.67, and 14.90. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees): 5.81, 13.67, and 14.90. In other embodiments, the X-ray powder diffraction pattern contains three or more peak positions (in 2θ degrees, ±0.2 2θ degrees): 5.81, 13.67, and 14.90. In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 19. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 37 The X-ray powder diffraction pattern shown is shown in the figure.

[0179] In one aspect, the eutectic of the compound comprising formula (I) is a benzoic acid eutectic.

[0180] In some embodiments, the benzoic acid eutectic of the compound of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 20 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.00, 8.50, 9.80, 18.05, and 19.99. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.00, 8.50, 9.80, 18.05, and 19.99. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.00, 8.50, 9.80, 18.05, and 19.99. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.00, 8.50, 9.80, 18.05, and 19.99. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 6.00 and 18.05 and at least one peak position selected from the following: 8.50, 9.80, and 19.99 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 20 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 39 The X-ray powder diffraction pattern shown is shown in the figure.

[0181] In some embodiments, the benzoic acid eutectic of the compound of formula (I) is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak with an onset temperature of 128.06 °C (±5.0 °C). In other embodiments, the benzoic acid eutectic of the compound of formula (I) is characterized by a differential scanning calorimetry (DSC) thermogram containing an endothermic peak with an onset temperature of 128.06 °C (±2.0 °C).

[0182] In one aspect, the eutectic of the compound containing formula (I) is a fumaric acid eutectic.

[0183] In some embodiments, the fumaric acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 21 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.59, 9.45, 13.63, 14.25, and 19.46. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.59, 9.45, 13.63, 14.25, and 19.46. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 9.45, 13.63, 14.25, and 19.46. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.22θ degrees): 5.59, 9.45, 13.63, 14.25, and 19.46. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.59 and 14.25 and at least one peak position selected from the following: 9.45, 13.36, and 19.46 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 21 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 42 The X-ray powder diffraction pattern shown is shown in the figure.

[0184] In one aspect, the eutectic of the compound comprising formula (I) is a gentianic acid eutectic.

[0185] In some embodiments, the gentianic acid eutectic of the compound of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 22 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.46, 12.63, 13.84, 17.34, and 26.08. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.22θ degrees) selected from the following: 6.46, 12.63, 13.84, 17.34, and 26.08. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.46, 12.63, 13.84, 17.34, and 26.08. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.46, 12.63, 13.84, 17.34, and 26.08. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 13.84 and 26.08 and at least one peak position selected from the following: 6.46, 12.63, and 17.34 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 22 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 44 The X-ray powder diffraction pattern shown is shown in the figure.

[0186] In one aspect, the eutectic of the compound containing formula (I) is a glutaric acid eutectic.

[0187] In some embodiments, the glutaric acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 23 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.72, 7.19, 12.00, 12.65, and 15.23. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.72, 7.19, 12.00, 12.65, and 15.23. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.72, 7.19, 12.00, 12.65, and 15.23. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.22θ degrees): 6.72, 7.19, 12.00, 12.65, and 15.23. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 6.72 and 7.19 and at least one peak position selected from the following: 12.00, 12.65, and 15.23 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 23 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 46 The X-ray powder diffraction pattern shown is shown in the figure.

[0188] In one aspect, the eutectic of the compound comprising formula (I) is a eutectic of 4-hydroxybenzoic acid.

[0189] In some embodiments, the 4-hydroxybenzoic acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 25 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.67, 14.64, 17.52, 20.59, 26.40, and 26.88. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.67, 14.64, 17.52, 20.59, 26.40, and 26.88. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.67, 14.64, 17.52, 20.59, 26.40, and 26.88. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.67, 14.64, 17.52, 20.59, 26.40, and 26.88. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 6.67 and 14.64 and at least one peak position selected from the following: 17.52, 20.59, 26.40, and 26.88 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 25. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 50 The X-ray powder diffraction pattern shown is shown in the figure.

[0190] In one aspect, the eutectic of the compound containing formula (I) is an α-ketoglutaric acid eutectic.

[0191] In some embodiments, the α-ketoglutaric acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 26 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.89, 7.39, 17.30, and 26.89. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.89, 7.39, 17.30, and 26.89. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.89, 7.39, 17.30, and 26.89. In other embodiments, the X-ray powder diffraction pattern includes four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.89, 7.39, 17.30, and 26.89. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.89 and 17.30 and at least one peak position selected from the following: 7.39 and 26.89 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 26 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 52 The X-ray powder diffraction pattern shown is shown in the figure.

[0192] In one aspect, the eutectic of the compound containing formula (I) is a malonic acid eutectic.

[0193] In some embodiments, the malonic acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 27 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 7.97, 13.74, 16.07, and 19.34. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 7.97, 13.74, 16.07, and 19.34. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 7.97, 13.74, 16.07, and 19.34. In other embodiments, the X-ray powder diffraction pattern includes four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 7.97, 13.74, 16.07, and 19.34. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 7.97 and 19.34 and at least one peak position selected from the following: 13.74 and 16.07 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 27 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 54 The X-ray powder diffraction pattern shown is shown in the figure.

[0194] In one aspect, the eutectic of the compound containing formula (I) is a salicylic acid eutectic.

[0195] In some embodiments, the salicylic acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectivity mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 28 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.77, 7.29, 16.36, 18.24, and 21.21. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.77, 7.29, 16.36, 18.24, and 21.21. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.77, 7.29, 16.36, 18.24, and 21.21. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.22θ degrees): 6.77, 7.29, 16.36, 18.24, and 21.21. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 6.77 and 16.36 and at least one peak position selected from the following: 7.29, 18.24, and 21.21 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 28 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 56 The X-ray powder diffraction pattern shown is shown in the figure.

[0196] In one aspect, the eutectic of the compound containing formula (I) is an L-tartaric acid eutectic.

[0197] In some embodiments, the L-tartaric acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 29 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.74, 11.84, 13.62, and 17.98. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.74, 11.84, 13.62, and 17.98. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 11.84, 13.62, and 17.98. In other embodiments, the X-ray powder diffraction pattern includes four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 11.84, 13.62, and 17.98. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 13.62 and 17.98 and at least one peak position selected from the following: 5.74 and 11.84 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 29 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 58 The X-ray powder diffraction pattern shown is shown in the figure.

[0198] In one aspect, the eutectic of the compound comprising formula (I) is a urea eutectic.

[0199] In some embodiments, the urea eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 30 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.79, 13.76, 16.34, and 26.43. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.79, 13.76, 16.34, and 26.43. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.79, 13.76, 16.34, and 26.43. In other embodiments, the X-ray powder diffraction pattern includes four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.79, 13.76, 16.34, and 26.43. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 8.79 and 13.76 and at least one peak position selected from the following: 16.34 and 26.43 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 30 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 60 The X-ray powder diffraction pattern shown is shown in the figure.

[0200] In one aspect, the cocrystal of the compound containing formula (I) is a pyroglutamic acid cocrystal.

[0201] In some embodiments, the pyroglutamic acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 31 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.20, 13.87, 25.30, 26.24, and 27.26. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.20, 13.87, 25.30, 26.24, and 27.26. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.20, 13.87, 25.30, 26.24, and 27.26. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.20, 13.87, 25.30, 26.24, and 27.26. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 6.20 and 13.87 and at least one peak position selected from the following: 25.30, 26.24, and 27.26 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 31 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 62 The X-ray powder diffraction pattern shown is shown in the figure.

[0202] In one aspect, the eutectic of the compound containing formula (I) is a hexanoic acid eutectic.

[0203] In some embodiments, the hexanoic acid eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 32 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.55, 9.80, 14.25, and 23.10. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 8.55, 9.80, 14.25, and 23.10. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.55, 9.80, 14.25, and 23.10. In other embodiments, the X-ray powder diffraction pattern includes four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.55, 9.80, 14.25, and 23.10. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 8.55 and 14.25 and at least one peak position selected from the following: 9.80 and 23.10 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 32. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 64 The X-ray powder diffraction pattern shown is shown in the figure.

[0204] In one aspect, the eutectic of the compound comprising formula (I) is a glycerol eutectic.

[0205] In some embodiments, the glycerol eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 33 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.91, 8.41, 11.85, 14.32, and 17.99. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.91, 8.41, 11.85, 14.32, and 17.99. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 8.41, 11.85, 14.32, and 17.99. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.22θ degrees): 5.91, 8.41, 11.85, 14.32, and 17.99. In other embodiments, the X-ray powder diffraction pattern includes peak positions at 11.85 and 17.99 and at least one peak position selected from the following: 5.91, 8.41, and 14.32 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 33 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 66 The X-ray powder diffraction pattern shown is shown in the figure.

[0206] In one aspect, the cocrystal containing the compound of formula (I) is an L-lysine cocrystal.

[0207] In some embodiments, the L-lysine cocrystal of compound (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 34 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.00, 6.68, 12.61, 18.50, and 23.45. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.22θ degrees) selected from the following: 5.00, 6.68, 12.61, 18.50, and 23.45. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.00, 6.68, 12.61, 18.50, and 23.45. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.00, 6.68, 12.61, 18.50, and 23.45. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.00 and 18.50 and at least one peak position selected from the following: 6.68, 12.61, and 23.45 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions listed in Table 34 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 68 The X-ray powder diffraction pattern shown is shown in the figure.

[0208] In one aspect, the cocrystal of the compound containing formula (I) is an S-proline cocrystal.

[0209] In some embodiments, the S-proline cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern obtained in a reflection mode (sometimes called a reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 35 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.91, 7.19, 14.02, and 26.36. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 5.91, 7.19, 14.02, and 26.36. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 7.19, 14.02, and 26.36. In other embodiments, the X-ray powder diffraction pattern includes four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 7.19, 14.02, and 26.36. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 5.91 and 7.19 and at least one peak position selected from the following: 14.02 and 26.36 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 35. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 70 The X-ray powder diffraction pattern shown is shown in the figure.

[0210] In one aspect, the eutectic of the compound comprising formula (I) is a pyruvate eutectic.

[0211] In some embodiments, the pyruvate eutectic of formula (I) is characterized by an X-ray powder diffraction pattern obtained in reflection mode (sometimes called reflectance mode) containing one or more peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the peak positions listed in Table 36 below. In other embodiments, the X-ray powder diffraction pattern contains at least one peak position (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.61, 7.81, 14.40, 18.99, 26.41, and 27.10. In other embodiments, the X-ray powder diffraction pattern contains at least two peak positions (in 2θ degrees, ±0.2 2θ degrees) selected from the following: 6.61, 7.81, 14.40, 18.99, 26.41, and 27.10. In other embodiments, the X-ray powder diffraction pattern includes at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.61, 7.81, 14.40, 18.99, 26.41, and 27.10. In other embodiments, the X-ray powder diffraction pattern includes at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.61, 7.81, 14.40, 18.99, 26.41, and 27.10. In other embodiments, the X-ray powder diffraction pattern includes peak positions of 6.61 and 7.81 and at least one peak position selected from the following: 14.40, 18.99, 26.41, and 27.10 (in 2θ degrees, ±0.2 2θ degrees). In other embodiments, the X-ray powder diffraction pattern includes the peak positions (in 2θ degrees, ±0.2 2θ degrees) listed in Table 36. In other embodiments, the X-ray powder diffraction pattern is similar to... Figure 72 The X-ray powder diffraction pattern shown is shown in the figure.

[0212] As used herein, the term "unit cell" refers to the smallest group of particles (e.g., molecules) that constitute a repeating pattern in a crystalline solid. In a eutectic, the term "unit cell" refers to the smallest group of two or more neutral chemical substances that constitute a repeating pattern in the eutectic.

[0213] In another aspect, this disclosure relates to amorphous solid dispersions comprising compounds of formula (I), or prepared from pharmaceutically acceptable salts or eutectics thereof.

[0214]

[0215] And polymers.

[0216] As used herein, the term "dispersion" refers to a dispersed system in which one substance (dispersed phase) is distributed in discrete units throughout a second substance (continuous phase or carrier). Typically, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids.

[0217] As used herein, the term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, typically a therapeutically active compound and a polymer (or polymers), but may also contain other components, such as surfactants or other pharmaceutical excipients, wherein the therapeutically active compound is in an amorphous phase. In some embodiments, the amorphous solid dispersion comprises a polymer (and optionally a surfactant) constituting a dispersed phase, and the therapeutically active compound constitutes a continuous phase. In some embodiments, the amorphous solid dispersion comprises a polymer (and optionally a surfactant) constituting a continuous phase, and the therapeutically active compound constitutes a dispersed phase.

[0218] In some embodiments, the polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate, and polyvinylpyrrolidone (PVP), or mixtures thereof. In other embodiments, the polymer is HPMCAS.

[0219] In some embodiments, the polymer is present in the amorphous solid dispersion in an amount of about 10% w / w to 90% w / w (e.g., about 20% w / w to about 80% w / w; about 30% w / w to about 70% w / w; about 40% w / w to about 60% w / w; or about 15% w / w to about 35% w / w). In some embodiments, the polymer (or one or more polymers) is present in the amorphous solid dispersion in an amount of about 10% w / w to about 80% w / w, for example about 30% w / w to about 75% w / w or about 40% w / w to about 65% w / w or about 45% w / w to about 55% w / w, for example about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w or about 54% w / w. In some embodiments, the amount of polymer (or one or more polymers) present in the amorphous solid dispersion is about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0220] In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or eutectic in the amorphous solid dispersion is from about 10% w / w to 90% w / w (e.g., from about 20% w / w to about 80% w / w; from about 30% w / w to about 70% w / w; from about 40% w / w to about 60% w / w; or from about 15% w / w to about 35% w / w). In some embodiments, the compound of formula (I) is present in the amorphous solid dispersion in an amount of about 10% w / w to about 80% w / w, for example about 30% w / w to about 75% w / w or about 40% w / w to about 65% w / w or about 45% w / w to about 55% w / w, for example about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w or about 54% w / w. In some embodiments, the compound of formula (I) is present in the amorphous solid dispersion in an amount of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0221] In some embodiments, the amorphous solid dispersion further comprises a surfactant. In some embodiments, the surfactant is selected from sodium lauryl sulfate (SLS), vitamin E or its derivatives (e.g., vitamin E TPGS), sodium docusate, sodium lauryl sulfate, polysorbates (e.g., Tween 20 and Tween 80), poloxamers (e.g., poloxamer 335 and poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, Prönkel copolymers (e.g., Prönkel F108, Prönkel P-123), and mixtures thereof. In some embodiments, the surfactant is SLS.

[0222] In some embodiments, the surfactant is present in the amorphous solid dispersion at an amount of about 0.1% w / w to about 10% w / w, for example, about 0.5% w / w to about 2% w / w, or about 1% w / w to about 3% w / w, about 1% w / w to about 4% w / w, or about 1% w / w to about 5% w / w. In some embodiments, the surfactant is present in the solid dispersion at an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, or about 1% w / w. In some embodiments, the surfactant is present in the solid dispersion at an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, or about 5% w / w.

[0223] In some embodiments, the amorphous solids dispersion comprises a compound of formula (I) and HPMCAS. In some embodiments, the amorphous solids dispersion is primarily composed of a compound of formula (I) and HPMCAS. In some embodiments, the amorphous solids dispersion is composed of a compound of formula (I) and HPMCAS. In some embodiments, the weight ratio of the compound of formula (I) to HPMCAS is about 1:1.5, from about 3:1 to about 1:3, from about 2:1 to about 1:2, or from about 1.5:1. In some embodiments, the weight ratio of the compound of formula (I) to HPMCAS is about 1:1.

[0224] In some embodiments, the amorphous solid dispersion has a glass transition temperature (T0) of at least about 80°C. g In other embodiments, the T of the amorphous solid dispersion g The range is approximately 80°C to approximately 130°C, approximately 80°C to approximately 120°C, approximately 80°C to approximately 100°C, or approximately 80°C to approximately 90°C.

[0225] This disclosure also relates to tautomers of compounds identified as having the chemical structure of formula (I). The tautomers include:

[0226]

[0227] 4-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoroprop-2-yl)-6-(((R)-1,1,1-trifluoroprop-2-yl)imino)-1,6-dihydro-1,3,5-triazine-2-amine;

[0228]

[0229] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoroprop-2-yl)-4-(((R)-1,1,1-trifluoroprop-2-yl)imino)-1,4-dihydro-1,3,5-triazine-2-amine;

[0230]

[0231] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoroprop-2-yl)-4-(((R)-1,1,1-trifluoroprop-2-yl)imino)-4,5-dihydro-1,3,5-triazine-2-amine; and

[0232]

[0233] 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4(1H,3H)-diimide.

[0234] As used herein, tautomers include the specified compound and any of its double bond isomers.

[0235] In one embodiment, this disclosure relates to a compound, namely:

[0236]

[0237] 4-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoroprop-2-yl)-6-(((R)-1,1,1-trifluoroprop-2-yl)imino)-1,6-dihydro-1,3,5-triazine-2-amine;

[0238] Or its pharmaceutically acceptable salt.

[0239] In one embodiment, this disclosure relates to a compound, namely:

[0240]

[0241] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoroprop-2-yl)-4-(((R)-1,1,1-trifluoroprop-2-yl)imino)-1,4-dihydro-1,3,5-triazine-2-amine;

[0242] Or its pharmaceutically acceptable salt.

[0243] In one embodiment, this disclosure relates to a compound, namely:

[0244]

[0245] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoroprop-2-yl)-4-(((R)-1,1,1-trifluoroprop-2-yl)imino)-4,5-dihydro-1,3,5-triazine-2-amine;

[0246] Or its pharmaceutically acceptable salt.

[0247] In one embodiment, this disclosure relates to a compound, namely:

[0248]

[0249] 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4(1H,3H)-diimide;

[0250] Or its pharmaceutically acceptable salt.

[0251] As used herein, the term "pharmaceutically acceptable salt" means salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of a compound includes any non-toxic salt that, upon administration to a recipient, can directly or indirectly provide the compound. A detailed description of pharmaceutically acceptable salts is found in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

[0252] Methods for preparing compounds of formula (I) in solid form

[0253] This disclosure also relates to a method for preparing compounds of formula (I) in solid form.

[0254] In one aspect, this disclosure relates to a method for preparing a pharmaceutically acceptable salt of a compound of formula (I), said method comprising:

[0255] - Dissolve the compound of formula (I) and a pharmaceutically acceptable acid in a solvent to obtain a solution; and

[0256] - Precipitate the corresponding salt.

[0257] In one aspect, this disclosure relates to a method for preparing a pharmaceutically acceptable crystalline form of a salt of a compound of formula (I), said method comprising:

[0258] - Dissolve the compound of formula (I) and a pharmaceutically acceptable acid in a solvent to obtain a solution; and

[0259] - The corresponding salt in precipitated crystalline form.

[0260] In some implementations, seed crystals are added to the solution to obtain a pharmaceutically acceptable salt that can be crystallized.

[0261] In some embodiments, the pharmaceutically acceptable acid in the method for preparing a pharmaceutically acceptable salt of compound (I) is selected from benzenesulfonic acid, (+)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, hydrobromic acid, hydrochloric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, sulfuric acid, and phosphoric acid.

[0262] The pharmaceutically acceptable salt used in this method can be crystalline or amorphous and can be in any hydrated or solvated state.

[0263] The solvent used in this method can be any liquid or liquid mixture suitable for dissolving compound (I) and pharmaceutically acceptable salts. In some embodiments, the solvent includes polar organic solvents such as methanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran (THF), or n-butanol, which are miscible with water. In some embodiments, the solvent comprises acetone and water. In some embodiments, the solvent comprises acetone and water (3:1 v / v to 1:1 v / v).

[0264] The compound of formula (I) and the pharmaceutically acceptable acid can be dissolved in the solvent in any molar ratio and at any concentration, as long as subsequent precipitation of the eutectic from the solution is permitted. In some embodiments, the compound of formula (I) and the pharmaceutically acceptable acid are contacted with the solvent in a molar ratio of about 1:2 to 2:1, or about 2:1, 1:1, or 1:2. In some embodiments, the amount of compound of formula (I) in contact with the solvent is sufficient to form a solution of about 0.1 M to 0.4 M, based on the amount of compound of formula (I). However, those skilled in the art will understand that if a portion of the compound of formula (I) and / or the pharmaceutically acceptable acid is not dissolved in the solvent, the actual molar ratio of the pharmaceutically acceptable acid to the compound of formula (I) in the solution, and the actual concentration of the compound of formula (I) in the solution, may differ from the values ​​calculated based on the amount of compound of formula (I) and the pharmaceutically acceptable acid in contact with the solvent.

[0265] In one aspect, this disclosure relates to a method for preparing a eutectic of a compound of formula (I), the method comprising:

[0266] - Dissolve the compound of formula (I) and the co-forming agent in a solvent to obtain a solution; and

[0267] - Precipitate the corresponding eutectic.

[0268] In some implementations, seed crystals are added to the solution.

[0269] In some embodiments, the co-forming agent used in the method for preparing the cocrystallization of compound (I) is selected from 3-hydroxy-2-naphthoic acid, L-serine, glycine, D-gluconic acid, glycolic acid, L-malic acid, oxalic acid, benzoic acid, fumaric acid, gentian acid, glutaric acid, 4-hydroxybenzoic acid, α-ketoglutaric acid, malonic acid, salicylic acid, L-tartaric acid, urea, pyroglutamic acid, hexanoic acid, glycerol, L-lysine, S-proline, and pyruvic acid.

[0270] The co-forming agent used in this method can be crystalline or amorphous, and can be in any hydrated or solvated state.

[0271] The solvent used in this method can be any liquid or liquid mixture suitable for dissolving the (I) compound and the co-forming agent. In some embodiments, the solvent includes polar organic solvents such as methanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran (THF), or n-butanol. In some embodiments, the solvent comprises acetone and water. In some embodiments, the solvent comprises acetone and water (4:1 / 1 to 2:1 v / v). In some embodiments, the solvent comprises ethyl acetate or methanol.

[0272] The compound of formula (I) and the co-forming agent can be dissolved in the solvent at any molar ratio and at any concentration, as long as subsequent precipitation of the eutectic from the solution is permitted. In some embodiments, the compound of formula (I) and the co-forming agent are contacted with the solvent at a molar ratio of about 1:2 to 2:1, or about 2:1, 1:1, or 1:2. In some embodiments, the amount of compound of formula (I) in contact with the solvent is sufficient to form a solution of about 0.1 M to 1 M, based on the amount of compound of formula (I). However, those skilled in the art will understand that if a portion of the compound of formula (I) and / or the co-forming agent is not dissolved in the solvent, the actual molar ratio of pharmaceutically acceptable acid to compound of formula (I) in the solution, and the actual concentration of compound of formula (I) in the solution, may differ from the values ​​calculated based on the amount of compound of formula (I) and the co-forming agent in contact with the solvent.

[0273] In another aspect, this disclosure relates to a method for preparing amorphous solid dispersions of compounds of formula (I).

[0274] In some embodiments, the method includes spray drying a mixture of a compound of formula (I), a polymer, and a suitable solvent or solvent mixture.

[0275] In some embodiments, the solvent is a volatile solvent (e.g., dichloromethane, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or mixtures thereof). In some embodiments, the solvent is acetone.

[0276] In some embodiments, according to any of the embodiments described herein, the compound of formula (I) used in the spray drying process is in the form of a pharmaceutically acceptable salt or its crystalline form, or in the form of a eutectic or its crystalline form.

[0277] Spray drying involves atomizing a liquid mixture containing, for example, a solid and a solvent or solvent mixture, and removing the solvent or solvent mixture. Atomization can be accomplished by, for example, a two-fluid nozzle, a pressure nozzle, an electroacoustic nozzle, or a rotating disk. Removal of the solvent or solvent mixture may require subsequent drying steps, such as tray drying, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying, or double-cone vacuum drying (e.g., from about room temperature to about 200°C). Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th Edition, edited by RH Perry, DW Green & JO Maloney, McGraw-Hill Book Co. (1984); and Marshall “Atomization and Spray-Drying” 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0278] As used herein, the term "dissolve" when referring to dissolving one or more substances in a solvent to obtain a solution means contacting one or more substances with an amount of solvent sufficient to dissolve at least a portion of each of the substances. The mixture containing one or more substances and a solvent may be stirred and / or heated to promote the dissolution of the substances in the solvent. Those skilled in the art will understand that some undissolved material (including some substances and / or some other materials) may still remain suspended in the solution, and such suspensions can be separated from the solution (e.g., by filtration or decantation) before precipitation into a solid form. In some embodiments, water is added to the solution before precipitation into a solid form.

[0279] As used herein, the term “about” when referring to a molar ratio or concentration (e.g., molar concentration) means a molar ratio or concentration having a specified value within ±10%. For example, a molar ratio of “about 2:1” would include molar ratios between 1.8:1 and 2.2:1. Similarly, a concentration of “about 1.5 M” would include concentrations between 1.35 M and 1.65 M.

[0280] As used herein, the term “precipitation” when referring to the precipitation of a solid form from a solution means causing the solid form to precipitate out of the solution. Not intended to be bound by any theory, precipitation can be caused by saturating the solution with the solid form (e.g., by increasing the concentration of the solid form in the solution or by decreasing the solubility of the solid form in the solution).

[0281] In some implementations, "precipitation" includes cooling the solution. Without being bound by any theory, cooling the solution can cause precipitation of the solid form by reducing its solubility in the solution to its saturation concentration.

[0282] In some implementations, "precipitation" involves evaporating a portion of the solvent from the solution. Without being bound by any theory, evaporating solvent from the solution can induce precipitation in solid form by increasing the concentration of the solid form in the solution to its saturation point.

[0283] In some embodiments, "precipitation" includes adding an antisolvent to the solution. As used herein, the term "antisolvent" refers to a liquid in which the solubility of the solid form is lower than that of the solvent used to form the solution. Without being bound by any theory, adding an antisolvent to a solution can cause precipitation of the solid form by reducing its solubility in the solution to its saturation concentration. In some embodiments, the antisolvent comprises a nonpolar organic solvent. In some embodiments, the antisolvent comprises toluene. In some embodiments, the antisolvent comprises methyl tert-butyl ether. In some embodiments, the antisolvent comprises C5-C... 12 Alkanes or cycloalkanes.

[0284] In some implementations, "precipitation" includes adding a seed crystal, which is a solid form of crystal to be precipitated from the solution, to the solution. As used herein, the term "adding a seed crystal" refers to adding a particular crystalline material to the solution to induce recrystallization or crystallization of that particular crystalline material.

[0285] As used in this article, the term "C5-C" 12 "Alkanes or cycloalkanes" refer to saturated straight-chain, branched, or cyclic hydrocarbons with 5 to 12 carbon atoms. Examples include pentane, hexane, heptane, octane, and cyclohexane.

[0286] In some embodiments, the method further includes separating the solid form. As used herein, the term "separation" refers to separating the precipitated solid form from the solution. Such separation can be accomplished by any method known in the art, including but not limited to filtering the precipitated solid form and decanting the solution from the precipitated solid form.

[0287] Composition and route of administration

[0288] In another aspect, this disclosure relates to pharmaceutical compositions comprising a pharmaceutically acceptable salt or cocrystal of a compound of formula (I) as described in any embodiment herein, and one or more pharmaceutical excipients.

[0289] In another aspect, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of a pharmaceutically acceptable salt or cocrystal of a compound of formula (I) as described in any embodiment herein, and one or more pharmaceutical excipients.

[0290] As used herein, the term "therapeuticly effective amount," when referring to the amount of the solid form (i.e., pharmaceutically acceptable salt or cocrystal) described herein, means an amount that will elicit a biological or medical response in a patient, such as reducing or inhibiting enzyme or protein activity, alleviating or improving certain symptoms, curing the disease, reducing the severity of the disease, slowing or delaying the progression of the disease, or preventing the disease. In some embodiments, the term "therapeuticly effective amount" means an amount of the solid form (i.e., pharmaceutically acceptable salt or cocrystal) described herein that effectively inhibits mutated IDH1 and / or mutated IDH2 when administered to a patient. In other embodiments, the term "therapeuticly effective amount" means an amount of the solid form (i.e., pharmaceutically acceptable salt or cocrystal) described herein that effectively treats the patient's cancer when administered to a patient.

[0291] As used herein, the term "drug excipient" refers to a carrier, adjuvant, or medium that can be administered to a patient in the solid form (i.e., a pharmaceutically acceptable salt or eutectic) described herein without impairing the pharmacological activity of the compound of formula (I) and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound of formula (I).

[0292] Pharmaceutical excipients that may be used in the pharmaceutical compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins or other solubilizing derivatives, may also be advantageously used for the delivery of enhanced (I) compounds.

[0293] In some cases, the pH of a pharmaceutical composition can be adjusted using pharmaceutically acceptable acids, bases, or buffers.

[0294] The pharmaceutical compositions described herein can be administered orally, over the intestines, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir, preferably orally or by injection. The pharmaceutical compositions may contain any conventional, non-toxic, and pharmaceutically acceptable excipients.

[0295] As used in this article, “non-enteric” administration includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0296] The pharmaceutical composition may be in the form of a sterile injectable formulation, for example, as a sterile injectable aqueous or oily suspension. This suspension may be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, non-enteric-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable media and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glycerol derivatives, may be used to prepare injectable formulations, as may natural, pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (e.g., emulsions and / or suspensions). Other commonly used surfactants such as Tween or Span and / or other similar emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0297] Pharmaceutical compositions can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, aqueous suspensions, dispersions, and solutions. In the case of tablets for oral administration, common excipients include lactose, corn starch, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica, and sodium lauryl sulfate. Lubricants, such as magnesium stearate, are often also added. For oral administration in capsule form, available diluents include lactose and dry corn starch. When administered orally in aqueous suspensions and / or emulsions, the active ingredient may be suspended or dissolved in an oil phase combined with emulsifiers and / or suspending agents. If desired, certain sweeteners and / or flavoring agents and / or coloring agents may be added.

[0298] Pharmaceutical compositions can also be administered in the form of suppositories for rectal use. These compositions can be prepared by mixing the solid form described herein (i.e., a pharmaceutically acceptable salt or eutectic) with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0299] The pharmaceutical composition can be applied topically to the skin. The pharmaceutical composition should be formulated as a suitable ointment containing an active ingredient suspended or dissolved in a pharmaceutically acceptable excipient suitable for topical application, said excipient including, but not limited to, mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene / polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing an active compound suspended or dissolved in a carrier having a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, dehydrated sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. The pharmaceutical composition of one aspect of the invention can also be applied topically to the lower intestine via a rectal suppository formulation or a suitable enema formulation. Transdermal patches are also included in one aspect of the invention.

[0300] Pharmaceutical compositions can be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as saline solutions using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0301] The amount of active ingredient that can be combined with one or more pharmaceutical excipients to produce a single dosage form will vary depending on the patient being treated and the specific route of administration. Typical formulations will contain approximately 5% to approximately 95% (w / w) of the active compound. Alternatively, such formulations may contain approximately 20% to approximately 80% of the active compound. In some embodiments, the pharmaceutical composition contains 1-10% (w / w) of the compound of formula (I) (based on the weight of the free compound of formula (I), excluding the weight of any co-forming agents, salt-forming agents, hydrated water, solvated solvents, etc.). In some embodiments, the pharmaceutical composition contains 20-30% (w / w) of the compound of formula (I) (based on the weight of the free compound of formula (I), excluding the weight of any co-forming agents, salt-forming agents, hydrated water, solvated solvents, etc.). In some embodiments... The pharmaceutical composition comprises about 10 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of a compound of formula (I) (based on the weight of the free compound of formula (I), excluding the weight of any co-forming agents, salt-forming agents, hydrated water, solvated solvents, etc.). In some embodiments, the pharmaceutical composition comprises about 10 mg or about 40 mg of a compound of formula (I) (based on the weight of the free compound of formula (I), excluding the weight of any co-forming agents, salt-forming agents, hydrated water, solvated solvents, etc.).

[0302] The pharmaceutical composition may also contain a therapeutically effective amount of an additional therapeutic agent, including but not limited to any additional therapeutic agent identified below as being suitable for combination therapy.

[0303] As used herein, the term “therapeutic effective amount” when referring to the amount of another therapeutic agent means the amount of an active agent that will elicit a biological or medical response in a patient, such as reducing or inhibiting the activity of an enzyme or protein, alleviating or improving certain symptoms, curing a disease, reducing the severity of a disease, slowing or delaying the progression of a disease, or preventing a disease.

[0304] In another aspect, the present invention relates to pharmaceutical compositions prepared by a method comprising mixing a therapeutically effective amount of a solid form (i.e., a pharmaceutically acceptable salt or eutectic) as described in any of the embodiments herein with one or more pharmaceutical excipients to provide a pharmaceutical composition.

[0305] As used herein, the term "mixing" means any process in which the solid form described herein (i.e., a pharmaceutically acceptable salt or cocrystal) is contacted with one or more pharmaceutical excipients to provide a pharmaceutical composition, regardless of whether the resulting pharmaceutical composition contains the solid form described herein (i.e., a pharmaceutically acceptable salt or cocrystal). Therefore, the term "mixing" includes processes in which the solid form described herein (i.e., a pharmaceutically acceptable salt or cocrystal) remains the same as described herein, or is dissolved and / or converted into a different solid form. Examples of "mixing" processes include wet or dry blending, wet or dry granulation, and suspending the solid form described herein (i.e., a pharmaceutically acceptable salt or cocrystal) in a pharmaceutical excipient.

[0306] The solid form (i.e., pharmaceutically acceptable salt or cocrystal) and the uses of the pharmaceutical compositions described herein

[0307] In another aspect, the present invention relates to a method for treating cancer characterized by the presence of IDH1 and / or IDH2 mutations in patients in need, the method comprising administering to the patient a therapeutically effective amount of a solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof as described in any embodiment herein.

[0308] In another aspect, the present invention relates to the use of solid forms (i.e., pharmaceutically acceptable salts or eutectics) or pharmaceutical compositions thereof as described in any embodiment herein in the preparation of a medicament for treating cancers characterized by the presence of IDH1 and / or IDH2 mutations in patients of need.

[0309] In another aspect, the present invention relates to a solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof as described in any embodiment herein, for the treatment in patients in need of cancer characterized by the presence of IDH1 and / or IDH2 mutations.

[0310] As used herein, the term "treatment," when referring to cancer, means having a therapeutic effect on cancer, reducing or improving one or more symptoms of cancer, altering the progression of cancer, eradicating cancer, reducing the size of cancer, slowing or inhibiting the growth or progression of cancer, delaying or minimizing one or more symptoms associated with cancer, reducing the malignancy of cancer, or inducing cancer stasis. When referring to diseases other than cancer, the term "treatment" means having a therapeutic effect on the disease, reducing or improving one or more symptoms of the disease, altering the progression of the disease, eradicating the disease, or delaying or minimizing one or more symptoms associated with the disease.

[0311] As used herein, the term "patient" refers to a mammal, including mice, rats, dogs, and humans, who suffers from cancer characterized by the presence of IDH1 and / or IDH2 mutations. In some embodiments, the patient is a human. In some embodiments, the patient is an adult (i.e., a person at least 18 years of age). In some embodiments, the patient is a child (i.e., a person under 18 years of age).

[0312] In some embodiments, the cancer is characterized by the presence of an IDH1 mutation. In other embodiments, the IDH1 mutation is an R132X mutation. In other embodiments, the IDH1 mutation is an R132H or R132C mutation. In other embodiments, the IDH1 mutation is an R132H, R132C, R132L, R132V, R132S, or R132G mutation. In other embodiments, the IDH1 mutation is an R132H mutation. In other embodiments, the IDH1 mutation is an R132C mutation. In other embodiments, the IDH1 mutation is an R132S, R132L, or R132G mutation. In other embodiments, the IDH1 mutation results in the accumulation of R(-)-2-hydroxyglutaric acid in the patient's body. In other embodiments, the IDH1 mutation results in IDH1 having a novel ability to catalyze the NADPH-dependent reduction of α-ketoglutaric acid to R(-)-2-hydroxyglutaric acid. Therefore, in some implementations, treating cancers characterized by IDH1 mutations includes inhibiting the activity of mutated IDH1.

[0313] In some implementations, cancer is a tumor in which at the time of diagnosis or treatment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the tumor cells carry an IDH1 mutation, and in particular, an IDH1 R132H, R132C, R132S, R132L, or R132G mutation.

[0314] Unbound by theory, the applicant believes that mutant alleles of IDH1, where IDH1 mutations result in enzymes with novel abilities, namely catalyzing the reduction of NADPH-dependent α-ketoglutarate to R(-)-2-hydroxyglutarate, and particularly IDH1 R132H, R132C, R132S, R132L, or R132G mutations, are characteristic of all types of cancer subclasses, regardless of their cellular nature or location in vivo. Therefore, the compounds and methods of the present invention can be used to treat any type of cancer characterized by the presence of IDH1 mutant alleles conferring such activity, and particularly IDH1 R132H, R132C, R132S, R132L, or R132G mutations.

[0315] As shown in Table 1, the IDH1 R132X mutation is known to occur in a variety of cancers.

[0316] Table 1. Cancers associated with IDH1 R132X mutation

[0317]

[0318] Therefore, in some implementations, the cancer is selected from the cancer types listed in Table 1, and the IDH1 mutation is one or more of the IDH1 R132X mutations listed in Table 1 for that particular cancer type.

[0319] The IDH1 R132H mutation has been identified in glioma, acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angioimmunoblastic non-Hodgkin lymphoma (NHL). Therefore, in some embodiments, the cancer is selected from glioma, acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), colon cancer, or angioimmunoblastic non-Hodgkin lymphoma (NHL). In some embodiments, the cancer is a glioma, and said glioma is a low-grade glioma or a secondary high-grade glioma. In other embodiments, the cancer is a glioma, and the glioma is a low-grade glioma (grade II), an anaplastic glioma (grade III), or a glioblastoma (GBM, grade IV).

[0320] In some embodiments, the cancer is characterized by the presence of an IDH2 mutation. In other embodiments, the IDH2 mutation is an R140X mutation. In other embodiments, the IDH2 mutation is an R140Q, R140W, or R140L mutation. In other embodiments, the IDH2 mutation is an R172X mutation. In other embodiments, the IDH2 mutation is an R172K or R172G mutation. In other embodiments, the IDH2 mutation is an R140X mutation. In other embodiments, the IDH2 mutation is an R140Q mutation. In other embodiments, the IDH2 mutation is an R140W mutation. In other embodiments, the IDH2 mutation is an R140L mutation. In other embodiments, the IDH2 mutation is an R172X mutation. In other embodiments, the IDH2 mutation is an R172K mutation. In other embodiments, the IDH2 mutation is an R172G mutation. In other embodiments, the IDH2 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient's body. In other embodiments, the IDH2 mutation results in a novel ability of IDH2 to catalyze the reduction of NADPH-dependent α-ketoglutarate to R(-)-2-hydroxyglutarate. Therefore, in some embodiments, treating cancers characterized by IDH2 mutations involves inhibiting the activity of the mutant IDH2.

[0321] Unbound by theory, the applicant believes that mutant alleles of IDH2, wherein the IDH2 mutation results in an enzyme with a novel ability to catalyze the reduction of NADPH-dependent α-ketoglutarate to R(-)-2-hydroxyglutarate, and particularly IDH2 R140Q and / or R172K mutations, are characteristic of all types of cancer subclasses, regardless of their cellular nature or location in vivo. Therefore, compounds and methods of one aspect of the invention can be used to treat any type of cancer characterized by the presence of IDH2 mutant alleles conferring such activity, particularly IDH2 R140Q and / or R172K mutations.

[0322] In some implementations, cancer is a tumor in which at the time of diagnosis or treatment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the tumor cells carry IDH2 mutations, and in particular IDH2R140Q, R140W, or R140L and / or R172K or R172G mutations.

[0323] In some implementations, the cancer is characterized by the presence of IDH1 and IDH2 mutations, which together lead to the accumulation of R(-)-2-hydroxyglutarate in the patient.

[0324] In some implementations, brain tumors (such as gliomas) are characterized by the presence of IDH1 and IDH2 mutations, which together lead to the accumulation of R(-)-2-hydroxyglutarate in the patient's body.

[0325] Cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of any mutations that characterize cancer.

[0326] In some embodiments, the cancer is glioma, acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma (IHCC)), chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemia (B-ALL), myeloid sarcoma, multiple myeloma, lymphoma, colon cancer, or angioimmunoblastic non-Hodgkin lymphoma (NHL). In some embodiments, the cancer is glioma, and the glioma is a low-grade glioma or a secondary high-grade glioma. In other embodiments, the cancer is glioma, which is a low-grade glioma (grade II), an anaplastic glioma (grade III), or glioblastoma (GBM, grade IV).

[0327] In some implementations, the cancer is a lymphoma (e.g., non-Hodgkin's lymphoma (NHL), such as B-cell lymphoma (e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, or mantle cell lymphoma) or a T-cell lymphoma (e.g., mycosis fungoides, anaplastic large cell lymphoma, or precursor T-lymphoblastic lymphoma)).

[0328] In some embodiments, the cancer is glioma, myelodysplastic syndrome (MDS), myelodysplastic neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic lymphoma. In other embodiments, the cancer is glioma, myelodysplastic syndrome (MDS), myelodysplastic neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin lymphoma (NHL). In some embodiments, the cancer is glioma, and the glioma is a low-grade glioma or a secondary high-grade glioma. In other embodiments, the cancer is glioma, and the glioma is a low-grade glioma (grade II), anaplastic glioma (grade III), or glioblastoma (GBM, grade IV).

[0329] In some implementations, the cancer is refractory or recurrent. In other implementations, the cancer is newly diagnosed or previously untreated.

[0330] In one aspect of this implementation scheme, the efficacy of cancer treatment is monitored by measuring the 2HG level described herein.

[0331] In some embodiments, the efficacy of cancer treatment is monitored by measuring the patient's 2HG levels. Typically, 2HG levels are measured before treatment, where an elevated level indicates the use of a compound of formula (I) as described in any of the embodiments herein, including in solid form, i.e., a pharmaceutically acceptable salt or a pharmaceutical composition thereof, to treat cancer. Once an elevated level is established, 2HG levels are measured during and / or after treatment to determine efficacy. In some embodiments, 2HG levels are measured only during and / or after treatment. A decrease in 2HG levels during and after treatment is an indicator of efficacy. Similarly, the absence of an elevation in 2HG levels during or after treatment is also an indicator of efficacy. Typically, 2HG measurements will be used in conjunction with other well-known assays of cancer treatment efficacy, such as reductions in the number and size of tumors and / or other cancer-related lesions, improvements in the patient's overall health, and changes in other biomarkers associated with cancer treatment efficacy.

[0332] 2HG can be detected in the sample by LC / MS. The sample was mixed with methanol at an 80:20 ratio and centrifuged at 3,000 rpm for 20 min at 4 °C. The resulting supernatant was collected and stored at -80 °C before LC-MS / MS evaluation of the 2-hydroxyglutaric acid level. Various liquid chromatography (LC) separation methods can be used. Each method can be coupled to a triple quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) mode via negative electrospray ionization (ESI, -3.0 kV), with mass spectrometry parameters optimized on injected metabolite standard solutions. Metabolites can be separated by reversed-phase chromatography using 10 mM tributylamine as an ion-pairing reagent in an aqueous mobile phase, according to a modified embodiment of the previously reported method (Luo et al. J Chromatogr A 1147, 153-64, 2007). One method allows the separation of TCA metabolites: t=0, 50% B; t=5, 95% B; t=7, 95% B; t=8, 0% B, where B refers to an organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutaric acid, employing a rapid linear gradient from 50% to 95% B (buffer as defined above) over 5 minutes. As described above, a Synergi Hydro-RP column, 100 mm × 2 mm, 2.1 µm particle size (Phenomonex), can be used. Metabolites can be quantified by comparing peak areas to pure metabolite standards of known concentrations. 13 Metabolite flux studies of C-glutamine can be conducted, for example, as described by Munger et al., Nat Biotechnol 26, 1179-86, 2008.

[0333] In some implementations, 2HG is evaluated directly.

[0334] In other embodiments, the 2HG derivatives formed during the execution of the analytical method are evaluated. For example, such derivatives may be those formed during MS analysis. Derivatives may include salt adducts such as Na adducts, hydrated variants, or hydrated variants that are also salt adducts, such as Na adducts, for example, those formed during MS analysis.

[0335] In another embodiment, metabolic derivatives of 2HG are evaluated. Examples include substances that accumulate or increase or decrease due to the presence of 2HG, such as glutaric acid or glutamate, which will be associated with 2HG (e.g., R-2HG).

[0336] Exemplary 2HG derivatives include dehydrated derivatives, such as the compounds provided below or their salt adducts:

[0337] .

[0338] In some embodiments, multiple evaluation steps are performed before and / or after treatment with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof as described herein. Therefore, in some embodiments, the method herein further includes evaluation steps before and / or after treatment with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof as described herein.

[0339] In some embodiments, the evaluation step includes assessing the growth, size, weight, invasiveness, stage, and / or other phenotypes of the cancer. Therefore, in some embodiments, the method described herein further includes the step of assessing the growth, size, weight, invasiveness, stage, and / or other phenotypes of the cancer before and / or after treatment with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition described herein.

[0340] In some embodiments, the method further includes a step of assessing the IDH1 genotype of the cancer before and / or after treatment with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition described herein. This can be achieved by conventional methods in the art, such as DNA sequencing, immunoassay, and / or assessment of the presence, distribution, or level of 2HG.

[0341] In some embodiments, the method further includes a step of determining the patient's 2HG level before and / or after treatment with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition described herein. This can be achieved through spectroscopic analysis, such as magnetic resonance-based analysis, such as MRI and / or MRS measurements, analysis of bodily fluid samples, such as serum or cerebrospinal fluid analysis, or analysis of surgical materials, such as by mass spectrometry.

[0342] 2HG is known to accumulate in the hereditary metabolic disorder 2-hydroxyglutarateuria. This disease is caused by a deficiency of the enzyme 2-hydroxyglutarate dehydrogenase, which converts 2HG to α-KG (Struys, EA et al., Am J Hum Genet 76, 358-60 (2005)). Patients with 2-hydroxyglutarate dehydrogenase deficiency accumulate 2HG in the brain (assessed by MRI and CSF analysis), develop leukoencephalopathy, and have an increased risk of brain tumors (Aghili, M., Zahedi, F. & Rafiee, J Neurooncol 91, 233-6 (2009); Kolker, S., Mayatepek, E. & Hoffmann, GF Neuropediatrics 33, 225-31 (2002); Wajner, M., Latini, A., Wyse, AT & Dutra-Filho, CS J Inherit Metab Dis 27, 427-48 (2004)). Furthermore, elevated brain 2HG levels lead to increased ROS levels (Kolker, S. et al., Eur J Neurosci 16, 21-8 (2002); Latini, A. et al., Eur J Neurosci 17, 2017-22 (2003)), which may increase cancer risk. The ability of 2HG as an NMDA receptor agonist may contribute to this effect (Kolker, S. et al., Eur J Neurosci 16, 21-8 (2002)). 2HG may also be cytotoxic by competitively inhibiting glutamate and / or αKG-utilizing enzymes. These include transaminases that allow the biosynthesis of amino acids and nucleic acids using glutamate nitrogen, and αKG-dependent prolyl hydroxylases that regulate HIF1-α levels.

[0343] Therefore, according to another embodiment, one aspect of the invention provides a method for treating a patient with 2-hydroxyglutaric aciduria, particularly D-2-hydroxyglutaric aciduria, by administering to the patient a therapeutically effective amount of a solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof as described in any of the embodiments herein.

[0344] A method for treating diseases selected from Maffucci syndrome and Ollier's disease is also provided, characterized by the presence of a mutated allele of IDH1, the method comprising the step of administering a therapeutically effective amount of a solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof as described in any of the embodiments herein to a patient in need.

[0345] The treatment methods described herein may also include a variety of evaluation steps before and / or after treatment with the solid form (i.e., pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition described herein.

[0346] In one embodiment, before and / or after treatment with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition described herein, the method further includes the step of assessing the growth, size, weight, invasiveness, stage, and / or other phenotypes of the cancer.

[0347] In one embodiment, before and / or after treatment with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition described herein, the method further includes the step of assessing the IDH2 genotype of the cancer. This can be achieved by conventional methods in the art, such as DNA sequencing, immunoassay, and / or assessing the presence, distribution, or level of 2HG.

[0348] All dosages disclosed herein are based on the amount of compound (I), that is, based on the amount of free base of compound (I) contained in the administered pharmaceutical composition.

[0349] The solid form (i.e., pharmaceutically acceptable salt or cocrystal) and pharmaceutical compositions thereof described in any of the embodiments herein may be administered, for example, by injection, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or subcutaneous administration; or orally, buccally, nasally, transmucosally, topically, in ophthalmic preparations, or by inhalation, at a dose ranging from about 0.5 to about 100 mg / kg body weight, optionally at a dose between about 1 mg and about 1000 mg / dose (every 4 to 120 hours), based on the amount of the compound of formula (I). In some embodiments, the solid form (i.e., pharmaceutically acceptable salt or cocrystal) or pharmaceutical compositions thereof described herein are administered once, twice, or three times daily. In other embodiments, the solid form (i.e., pharmaceutically acceptable salt or cocrystal) or pharmaceutical compositions thereof described herein are administered once daily. In other embodiments, the solid form (i.e., pharmaceutically acceptable salt or cocrystal) or pharmaceutical compositions thereof described herein are administered twice daily. In other embodiments, the solid form (i.e., pharmaceutically acceptable salt or cocrystal) or pharmaceutical compositions thereof described herein are administered three times daily. The methods described herein envision administering a therapeutically effective amount of the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof described herein to achieve the desired or stated effect. Typically, the pharmaceutical composition of one aspect of the invention will be administered about 1 to about 6 times daily, or alternatively, as a continuous infusion. In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof described herein is administered once daily. In other embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof described herein is administered twice daily. Such administration can be used for chronic or acute treatment.

[0350] In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or pharmaceutical composition thereof, as described in any of the embodiments herein, is administered in the following doses based on the amount of a compound of formula (I): (1) 1 to 100 mg / day, 2 to 50 mg / day, 3 to 30 mg / day, 4 to 20 mg / day, 5 to 15 mg / day, 8 to 12 mg / day, or about 10 mg / day; (2) 1 to 500 mg / day, 1 to 250 mg / day, 5 to 100 mg / day, 8 to 75 mg / day, 10 to 50 mg / day, 15 to 40 mg / day, 20 to 30 mg / day, about 20 mg / day, or about 25 mg / day; (3) 1 to 500 mg / day, 10 to 250 mg / day, 20 to 100 mg / day, 30 to 80 mg / day, 40 to 60 mg / day, 45 to 55 mg / day, or about 40 mg / day. (4) 1 to 500 mg / day, 20 to 400 mg / day, 40 to 200 mg / day, 50 to 150 mg / day, 75 to 125 mg / day, 85 to 115 mg / day, 90 to 110 mg / day or about 100 mg / day; (5) 1 to 500 mg / day, 50 to 400 mg / day, 100 to 300 mg / day, 150 to 250 mg / day, 175 to 225 mg / day, 185 to 215 mg / day, 190 to 210 mg / day or about 200 mg / day; or (6) 1 to 500 mg / day, 100 to 500 mg / day, 200 to 400 mg / day, 250 to 350 mg / day, 275 to 375 mg / day, 285 to 315 mg / day. mg / day, 290 to 310 mg / day or about 300 mg / day.

[0351] In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition as described in any of the embodiments herein is administered at the following doses based on the amount of the compound of formula (I): 0.01 to 10 mg / kg body weight / day, 0.2 to 8.0 mg / kg body weight / day, 0.4 to 6.0 mg / kg body weight / day, 0.6 to 4.0 mg / kg body weight / day, 0.8 to 2.0 mg / kg body weight / day, 0.1 to 1 mg / kg body weight / day, 0.2 to 1.0 mg / kg body weight / day, 0.15 to 1.5 mg / kg body weight / day, or 0.1 to 0.5 mg / kg body weight / day.

[0352] In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition as described in any of the embodiments herein is administered once daily or more than once daily (e.g., twice daily, three times daily, four times daily, etc.) to achieve the daily dose described herein. In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition as described in any of the embodiments herein is administered once daily to achieve the daily dose described herein. In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition as described in any of the embodiments herein is administered twice daily to achieve the daily dose described herein. In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or pharmaceutical composition thereof, as described in any of the embodiments herein, is administered once daily in a dose based on the amount of the compound of formula (I) as follows: (1) about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg per dose; (2) 30-70 mg, 35-65 mg, 40-60 mg, 45-55 mg, about 40 mg, or about 50 mg per dose; or (3) 5-35 mg, 5-20 mg, 5-15 mg, about 20 mg, or about 10 mg per dose. In some embodiments, the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or pharmaceutical composition thereof, as described in any of the embodiments herein, is administered twice daily at doses based on the amount of compound (I): (1) 30-70 mg, 35-65 mg, 40-60 mg, 45-55 mg, about 40 mg, or about 50 mg per dose; or (2) 5-35 mg, 5-20 mg, 5-15 mg, about 20 mg, or about 10 mg per dose. The amount of the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or pharmaceutical composition thereof described herein is based on the amount of compound (I). The specific dosage and treatment regimen for any particular individual will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, excretion rate, drug combination, severity and duration of disease, symptoms or condition, individual predisposition to disease, symptoms or condition, and the judgment of the treating physician.

[0353] As used herein, the term “about” when referring to a dose means that the dose is ±10% of the specified value. For example, a dose of “about 100 mg / kg” would include doses between 90 mg / kg and 110 mg / kg.

[0354] Lower or higher doses may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, combination of drugs, severity and course of the disease, symptoms or signs, the patient’s predisposition to the disease, symptoms or signs, and the judgment of the treating physician.

[0355] After the patient's condition improves, a maintenance dose of a compound of formula (I) may be administered, if necessary, in the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or a pharmaceutical composition thereof, or in combination with a combination of any aspect of the invention, as described in any of the embodiments herein. Subsequently, the dose or frequency of administration, or both, may be reduced to a level that maintains the improved condition, at which point the symptoms have been relieved to the desired level, depending on the symptoms. However, if the disease symptoms recur, the patient may require long-term intermittent treatment.

[0356] Patients who have been previously treated

[0357] In some implementations, patients requiring treatment for cancer characterized by the presence of IDH1 and / or IDH2 mutations have previously received cancer treatment. In some implementations, the patient has previously received cancer treatment specifically for that cancer. The previously administered cancer treatment may have been effective or ineffective in treating the cancer, or may have been effective for a period of time.

[0358] As used herein, the term "cancer treatment" refers to a cancer therapeutic agent or a method of treating cancer. As used herein, the term "cancer therapeutic agent" refers to a therapeutic agent (excluding compounds of formula (I), solid forms (i.e., pharmaceutically acceptable salts or cocrystals) as described herein, or pharmaceutical compositions thereof) suitable for treating cancer. Cancer therapeutic agents include, for example, chemotherapy, targeted therapies, antibody therapies, immunotherapies, hormone therapies, and checkpoint inhibitors. Examples of each class of cancer therapeutic agents are provided below. As used herein, the term "cancer treatment method" refers to a method of treating cancer. Cancer treatment methods include, for example, surgery and radiation therapy.

[0359] In some implementations, the cancer treatment agent is a chemotherapeutic agent. Examples of chemotherapeutic agents used for cancer treatment include, for example, antimetabolites (e.g., folic acid, purine and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustard, nitrosourea, platinum, alkyl sulfonates, hydrazine, triazine, aziridine, spindle toxins, cytotoxic agents, topoisomerase inhibitors, etc.), and demethylating agents (e.g., decitabine (5-aza-deoxycytidine), zablaline, isothiocyanates, azacitidine (5-azacitidine), 5-fluoro-2'-deoxycytidine, 5,6-dihydro-5-azacitidine, etc.). Exemplary active agents include arubicin, actinomycin, retinoic acid, hexamethylmelamine, aminopterin, 5-aminolevulinic acid, arubicin, amidrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecone, bexarotine, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquinone, carmoflurane, carmustine, celecoxib, chlorambucil, nitrogen mustard, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide. Amine, Cytarabine, Dacarbazine, Actinomycin D, Daunorubicin, Decitabine, Colchicine, Docetaxel, Doxorubicin, Efaxiro, Ilismo, Exalucin, Enoxabine, Epirubicin, Estrostine, Etomostatin, Etoglucoside, Etoposide, Fluorouracil, Fludarabine, Fluorouracil (5FU), Formosine, Gemcitabine, Carmustine Implants, Hydroxycarbamate, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irovvin, Ixaspirone, Larotaxel, Leucovorin, Liposome Doxorubicin, Liposome Daunorubicin Clonidamine, Lomustine, Thianthrone, Mannosulfan, Masrophenone, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methylaminolevulinate, Dibromomannitol, Mitoguanidine, Mitotan, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Olimerson, Omacitazine, Otapaclitaxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pianthraquinone, Procaycin, Porphyrom sodium, Prenimustine, Procarbazine, Raltitrexed, Ramustine, Rubotecan, Saparcitabine, Semustine The following are prohibited: cecimatrix, stroboplatin, zozocin, tarapofen, tegafur-uracil, temopofen, temozolomide, teniposide, testathine, testrolide, tetranitrate, thiotepa, thiazofuran, thioguanine, tepifenabine, topotecan, trabectedin, triamine, triethylene melamine, triplatin, retinoic acid, trosofafen, trophosphatide, uracil nitrogen mustard, penoxuridine, vertepofen, vincristine, vinblastine, vinorelbine, vinorelbine, vorinostat, zorobacterium, and other cell inhibitors or cytotoxic agents described herein.

[0360] Because some drugs are more effective when used together than when used alone, two or more drugs are often administered simultaneously. Typically, two or more chemotherapeutic agents are used as combination chemotherapy.

[0361] In some implementations, the cancer therapeutic agent is a differentiator. Differentiators include retinoids (e.g., all-trans retinoic acid (ATRA), 9-cis retinoic acid, 13-cis retinoic acid (13-cRA), and 4-hydroxy-fenivelamine (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDAC (e.g., azoxycytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate)); hybrid polar compounds (e.g., hexamethylenediacetamide ((HMBA)); vitamin D; and cytokines (e.g., colony-stimulating factors, including G-CSF and GM-CSF, and interferon).

[0362] In some implementations, cancer therapeutics are targeted therapies. Targeted therapies consist of the use of specific active agents targeting dysregulated proteins in cancer cells. Small molecule targeted therapies are typically inhibitors of enzyme domains on mutated, overexpressed, or other key proteins within cancer cells. Prominent examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cidinib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, letatinib, nilotinib, semasanib, sorafenib, sunitinib, and vandetanib, as well as cyclin-dependent kinase inhibitors such as avozidil ​​and celecoxib.

[0363] Other targeted therapies include biguanides, such as metformin or phenformin.

[0364] Targeted therapy can also involve small peptides that act as “homing mechanisms,” binding to cell surface receptors or the affected extracellular matrix surrounding the tumor. If the radionuclide decays near the cell, the radionuclide attached to these peptides (such as RGD) eventually kills the cancer cells. One example of such a treatment is BEXXAR®.

[0365] In some implementations, the cancer therapeutic agent is an antibody. Monoclonal antibody therapy is a strategy in which the therapeutic agent is an antibody that specifically binds to proteins on the surface of cancer cells. Examples include trastuzumab (HERCEPTIN®), an anti-HER2 / neu antibody commonly used for breast cancer, and rituximab and tosimob, anti-CD20 antibodies commonly used for various B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, ezetizumab, and gemtruzumab. Exemplary fusion proteins include aflibercept and diftitox.

[0366] In some implementations, the cancer therapeutic agent is an immunotherapeutic agent. Cancer immunotherapy refers to a diverse set of treatment strategies designed to induce a patient's own immune system to fight tumors. Contemporary methods for generating an immune response against tumors include intracystic BCG immunotherapy for superficial bladder cancer, and the use of interferon and other cytokines to induce immune responses in patients with renal cell carcinoma and melanoma.

[0367] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy because the donor's immune cells typically attack the tumor in the graft-versus-tumor effect.

[0368] In some implementations, cancer therapeutic agents are hormone therapeutic agents. The growth of certain cancers can be suppressed by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast cancer and prostate cancer. Removing or blocking estrogen or testosterone is often an important additional treatment. In some cancers, administering hormone agonists, such as progesterone, may have therapeutic benefits.

[0369] In some implementations, the cancer therapeutic agent is a checkpoint inhibitor. Checkpoint inhibitor therapy is a form of cancer treatment in which the manipulation of checkpoints in the immune system is used to restore the function of the immune system against cancer cells. Examples of checkpoint inhibitors include ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and others.

[0370] Other cancer treatments include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorine toxins, radiolabeled drugs and antibodies, chimeric antigen receptors or CAR-T (e.g., Kymriah®, Yescarta®), Gliadel®, and Avastin®).

[0371] In some implementations, cancer treatment is radiation therapy. Radiation therapy involves using high-energy radiation (e.g., X-rays, gamma rays, or charged particles) to damage and / or kill cancer cells and shrink tumors. In the method of the present invention, radiation can be delivered to a brain tumor (e.g., glioma) via an externally located machine (external beam radiation therapy), via radioactive material placed near the brain tumor inside the body (internal radiation therapy, also known as brachytherapy), or via whole-body administration of radioactive material (e.g., radioactive iodine) through the bloodstream. Alternatively, these delivery methods can be combined.

[0372] In some implementations, radiation therapy includes external beam therapy (e.g., external beam therapy, including fractionated external beam therapy, stereotactic radiation such as Cyberknife® or Gamma Knife®, proton therapy, etc.), wherein radiation is delivered to the brain tumor (e.g., glioma) via an externally inserted instrument. External beam therapy can be administered as several courses over several days or weeks. In one aspect of these implementations, the radiation is applied in the form of X-rays.

[0373] In other embodiments, radiation therapy includes internal radiation therapy, where radiation originates from an implant or material (liquid, solid, semi-solid, or other substance) placed within the body. In one aspect of these embodiments, internal radiation therapy is brachytherapy, in which a solid-state radiation source is placed within the body close to the location of the brain tumor. In another aspect of these embodiments, internal radiation therapy involves the whole-body administration of a radiation source, typically a radionuclide (radioisotope or unsealed source). The radiation source can be administered orally or intravenously.

[0374] Combination therapy

[0375] In some implementations, the methods described herein include the additional step of co-administering additional treatments to patients in need.

[0376] In some implementations, drugs used to treat cancers characterized by the presence of IDH1 and / or IDH2 mutations in patients in need are used in combination with other treatments administered concurrently.

[0377] In another aspect, solid forms (i.e., pharmaceutically acceptable salts or cocrystals) or pharmaceutical compositions thereof, as described herein, for the treatment of cancers characterized by the presence of IDH1 and / or IDH2 mutations, are used in combination with other treatments administered co-administered.

[0378] As used herein, the term "alternative treatment" includes cancer treatments (including cancer therapeutic agents and cancer treatment methods) as described above, as well as non-cancer treatments (including non-cancer therapeutic agents and non-cancer treatment methods) administered to treat symptoms and / or secondary effects of cancer. In other words, the term "alternative treatment" includes additional therapeutic agents (i.e., cancer therapeutic agents and non-cancer therapeutic agents) and additional treatment methods (i.e., cancer treatment methods and non-cancer treatment methods).

[0379] In some implementations, the additional treatment is cancer treatment (i.e., cancer treatment agents or cancer treatment methods) as described above.

[0380] In some implementations, the additional treatment is non-cancer treatment (i.e., non-cancer therapeutic agents or non-cancer treatment methods).

[0381] In some implementations, additional treatments include one or more DNA responsive agents, PARP inhibitors, antiemetics, anticonvulsants or antiepileptics, checkpoint inhibitors, PVC chemotherapy, bevacizumab, and gemcitabine.

[0382] In some implementations, additional treatments include DNA reactants. As used herein, “DNA reactant” refers to active agents that covalently or nonvalently interact with cellular DNA, such as alkylating agents, cross-linking agents, and DNA intercalating agents. Examples of DNA reactants include adorexin, hexamethylmelamine, biferexin, busulfan, carboplatin, carboquinone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estradiol, formustine, hepsulfam, ifosfamide, inprofen, iroflavone, lomustine, nitrogen mustard, melphalan, mitozolamide, nedaplatin, oxaliplatin, piperazine, procarbazine, semustine, strepzoline, temozolomide, thiotepa, treoxazine, diethylnitrosamine, benzo(a)pyrene, doxorubicin, mitomycin-C, etc. Many of these DNA reactants can be used as DNA-reactive chemotherapeutic agents in cancer treatment.

[0383] In some implementations, additional treatment includes a PARP inhibitor. As used herein, a "PARP inhibitor" refers to an inhibitor of the enzyme poly(ADP-ribose) polymerase (PARP). Examples of PARP inhibitors include pamiparib, olaparib, rucaparib, veraparib, iniparib, tapazoparib, niraparib, and others.

[0384] In some implementations, an additional treatment is a checkpoint inhibitor. As used herein, a "checkpoint inhibitor" refers to a therapeutic agent that inhibits immune checkpoints (such as CTLA-4, PD-1 / PD-L1, etc.) (which would otherwise prevent the immune system from attacking cancer cells), thereby allowing the immune system to attack cancer cells. Examples of checkpoint inhibitors include ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, BGB-A317, spartazolizumab, etc.

[0385] In some implementations, the additional treatment is PCV chemotherapy. As used herein, “PCV chemotherapy” refers to a chemotherapy regimen that includes the combined administration of procarbazine, lomustine (sold under the brand name CCNU®), and vincristine (sold under the brand name Onocovin®). Typically, vincristine is administered intravenously, while procarbazine and lomustine are administered orally. PCV chemotherapy is usually administered in cycles, with each cycle consisting of a single dose of vincristine and lomustine followed by 10 days of procarbazine treatment.

[0386] In some implementations, the additional treatment is bevacizumab. Bevacizumab, marketed under the brand name Avastin®, is a recombinant humanized monoclonal antibody.

[0387] In some implementations, the additional treatment is gemcitabine. Gemcitabine, marketed under the brand name Gemzar®, is a pyrimidine nucleoside analog.

[0388] In some implementations, the additional treatment is a non-cancer therapeutic agent. As used herein, the term "non-cancer therapeutic agent" refers to a therapeutic agent used to treat symptoms suffered by a patient who has cancer and / or is undergoing cancer treatment, but not to treat the cancer itself. Examples of "non-cancer therapeutic agents" include anti-seizure and antiepileptic agents, antiemetics, antidiarrheals, etc.

[0389] In some implementations, the additional treatment is anti-seizure or antiepileptic agents. As used herein, "anti-seizure or antiepileptic agent" refers to a medication that effectively treats or prevents seizures (including epileptic seizures). Examples of anti-seizure and antiepileptic agents include acetazolamide, babixaron, becpromide, brivaceran, cannabidiol, carbamazepine, clonazepam, clonazepam, chlordiazepoxide, diazepam, sodium valproate, eslicarbazepine acetate, ixacinone, ethosuximide, etorizine, ethracetam, femoxanil, fosphenytoin, gabapentin, lacoamide, lamotrigine, levetiracetam, lorazepam, mephenytoin, mesoxamide, acetazolamide, phenobarbital, midazolam, nimesapam, and nitrazepam. Pan, oxcarbazepine, triacetaldehyde, paramethadoine, perampanel, piracetam, phenylacetylurea, phenytoin, phenosuccinylurea, phenytoin, potassium bromide, pregabalin, primidone, progazin, pyridoxine, rufenamide, seletracetam, sodium valproate, stethamide, thiazide sulfamethoxazole, temazepam, tiagabin, topiramate, trimethyldione, penoxamide, valproic acid, valproamide, aminohexenoic acid, zonisamide, etc.

[0390] In some implementations, an additional treatment is an antiemetic. As used herein, an "antiemetic" refers to a medication that effectively reduces vomiting and nausea. Examples of antiemetics include 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, tropisetron, palonosetron, mirtazapine, etc.), dopamine agonists (e.g., domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, aripiprazole, prochlorperazine, metoclopramide, etc.), NK1 receptor antagonists (e.g., aprepitant, cassospirant, rorapitant, etc.), and antihistamines (e.g., cinnarizine, cyproheptadine, diphenhydramine). Cannabinoids (e.g., cannabis, dronabinol, synthetic cannabinoids, etc.), benzodiazepines (e.g., midazolam, lorazepam, etc.), anticholinergics (e.g., scopolamine, etc.), steroids (e.g., dexamethasone, etc.), trimethoprim, ginger, propofol, glucose / fructose / phosphate (sold under the brand name Emetrol®), menthol, muscarinic acid, ajwain, bismuth subsalicylate, etc.

[0391] In some implementations, an additional treatment is an antidiarrheal agent. Examples of antidiarrheal agents include bismuth basic gallate, freeze-dried Saccharomyces boulardii, atropine, diphenoxylate, diphenoxylate, Lactobacillus acidophilus, bismuth basic salicylate, loperamide, Lactobacillus bulgaricus, Lactobacillus rhamnosus GG, palygorskite, crofimo, simethicone, etc.

[0392] In some implementations, additional treatments are non-cancer treatments. As used herein, the term "non-cancer treatment" refers to treatments intended to address symptoms experienced by patients with and / or undergoing cancer treatment, but not to treat the cancer itself. Examples of non-cancer treatments include acupuncture, biofeedback, distraction, emotional support and counseling, hypnosis, imagery, relaxation, and skin stimulation.

[0393] As used herein, the term "co-administration" means, as part of a treatment regimen, the administration of an additional treatment before, simultaneously, sequentially, or after the administration of the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) or its pharmaceutical composition described herein, to provide the beneficial effects of the combined action of the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) (or its pharmaceutical composition) described herein and the additional treatment. When the additional treatment is an additional therapeutic agent, the additional therapeutic agent may be administered as part of a single dosage form (e.g., a composition of one aspect of the invention comprising a cocrystal, a pharmaceutically acceptable salt, a crystalline form of a pharmaceutically acceptable salt, or an amorphous solid dispersion of a pharmaceutically acceptable salt, and a therapeutic agent) together with the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) described herein, or as separate, multiple dosage forms. Alternatively, the therapeutic agent may be administered before, sequentially, or after the administration of the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) described herein. In such combination therapy, both the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) described herein and the additional therapeutic agent are administered by conventional methods. Administering a composition of one aspect of the invention, comprising the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) described herein and an additional therapeutic agent to a patient, does not preclude the administration of the same therapeutic agent, any other additional therapeutic agent, or the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) described herein to the patient alone at another time during treatment. When the additional treatment is a separate treatment method, the additional treatment method may be performed before, continuously, simultaneously, or after the administration of the solid form (i.e., a pharmaceutically acceptable salt or cocrystal) described herein or its pharmaceutical composition.

[0394] In some implementations, when the additional treatment is cancer treatment, both the solid form described herein (i.e., a pharmaceutically acceptable salt or eutectic) and the cancer treatment are administered at approximately 1 to 100% of the dose typically administered in a monotherapy regimen, or approximately 5 to 95% of the dose level.

[0395] List of implementation plans

[0396] In some implementations, this disclosure relates to:

[0397] 1. Pharmaceutically acceptable salts of compounds of formula (I)

[0398]

[0399] The pharmaceutically acceptable salt is characterized by being formed using benzenesulfonic acid, (+)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, hydrobromic acid, hydrochloric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, sulfuric acid, or phosphoric acid.

[0400] 2. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is crystalline.

[0401] 3. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using benzenesulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.83, 8.17, 14.40 and 17.90.

[0402] 4. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using benzenesulfonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.83, 8.17, 14.40 and 17.90.

[0403] 5. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using benzenesulfonic acid, and the X-ray powder diffraction pattern contains four peak positions (in 2θ degrees, ±0.22θ degrees): 5.83, 8.17, 14.40, and 17.90.

[0404] 6. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using (+)-camphor-10-sulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.29, 10.19, 12.07, 18.12, and 19.97.

[0405] 7. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using (+)-camphor-10-sulfonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.29, 10.19, 12.07, 18.12, and 19.97.

[0406] 8. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using (+)-camphor-10-sulfonic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.29, 10.19, 12.07, 18.12, and 19.97.

[0407] 9. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using (+)-camphor-10-sulfonic acid, and the X-ray powder diffraction pattern contains peak positions at 10.19 and 12.07 and at least one peak position selected from the group consisting of 8.29, 18.12 and 19.97 (in 2θ degrees, ±0.2 2θ degrees).

[0408] 10. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethane-1,2-disulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 14.75, 18.08, and 18.87.

[0409] 11. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethane-1,2-disulfonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 14.75, 18.08, and 18.87.

[0410] 12. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethane-1,2-disulfonic acid, and the X-ray powder diffraction pattern contains the following four peak positions (in 2θ degrees, ±0.2 2θ degrees): 5.59, 14.75, 18.08, and 18.87.

[0411] 13. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethane-1,2-disulfonic acid, and the X-ray powder diffraction pattern contains peak positions of 5.59 and 18.87 and at least one peak position selected from 14.75 and 18.08 (in 2θ degrees, ±0.2 2θ degrees).

[0412] 14. The pharmaceutically acceptable salt according to embodiments 10-13, characterized in that the ethane-1,2-disulfonate is characterized by a differential scanning calorimetry thermogram containing an endothermic peak at an initial temperature of 304.30 °C (±2.0 °C).

[0413] 15. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethanesulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.86, 13.97, 14.27, 17.00 and 17.72.

[0414] 16. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethanesulfonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.86, 13.97, 14.27, 17.00 and 17.72.

[0415] 17. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethanesulfonic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.86, 13.97, 14.27, 17.00 and 17.72.

[0416] 18. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using ethanesulfonic acid, and the X-ray powder diffraction pattern contains peak positions at 13.97 and 14.27 and at least one peak position selected from the following: 6.86, 17.00 and 17.72 (in 2θ degrees, ±0.2 2θ degrees).

[0417] 19. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrobromic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 8.56, 13.63, 14.90 and 15.08.

[0418] 20. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrobromic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 8.56, 13.63, 14.90, and 15.08.

[0419] 21. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrobromic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 8.56, 13.63, 14.90, and 15.08.

[0420] 22. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrobromic acid, and the X-ray powder diffraction pattern contains peak positions at 5.74 and 8.56 and at least one peak position selected from the following: 13.63, 14.90 and 15.08 (in 2θ degrees, ±0.2 2θ degrees).

[0421] 23. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrochloric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.73, 9.71, 13.78, 14.64, and 16.25.

[0422] 24. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrochloric acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.73, 9.71, 13.78, 14.64, and 16.25.

[0423] 25. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrochloric acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.73, 9.71, 13.78, 14.64, and 16.25.

[0424] 26. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using hydrochloric acid, and the X-ray powder diffraction pattern contains peak positions of 5.73 and 14.64 and at least one peak position selected from the following: 9.71, 13.78 and 16.25 (in 2θ degrees, ±0.2 2θ degrees).

[0425] 27. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-1,5-disulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.52, 13.79, 14.17, 19.28, 19.63, and 19.97.

[0426] 28. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-1,5-disulfonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.52, 13.79, 14.17, 19.28, 19.63, and 19.97.

[0427] 29. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-1,5-disulfonic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.52, 13.79, 14.17, 19.28, 19.63, and 19.97.

[0428] 30. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-1,5-disulfonic acid, and the X-ray powder diffraction pattern contains peak positions of 5.52 and 19.97 and at least one peak position selected from the following: 13.79, 14.17, 19.28 and 19.63 (in 2θ degrees, ±0.2 2θ degrees).

[0429] 31. The pharmaceutically acceptable salt according to embodiments 27-30, characterized in that the naphthalene-1,5-disulfonate is characterized by a differential scanning calorimetry thermogram containing an endothermic peak at an initial temperature of 324.30 °C (±2.0 °C).

[0430] 32. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-2-sulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.41, 13.65, 26.09, and 26.47.

[0431] 33. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-2-sulfonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.41, 13.65, 26.09, and 26.47.

[0432] 34. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-2-sulfonic acid, and the X-ray powder diffraction pattern contains four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.41, 13.65, 26.09, and 26.47.

[0433] 35. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-2-sulfonic acid, and the X-ray powder diffraction pattern contains peak positions of 8.41 and 26.47 and at least one peak position selected from 13.65 and 26.09 (in 2θ degrees, ±0.2 2θ degrees).

[0434] 36. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using p-toluenesulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.64.

[0435] 37. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using p-toluenesulfonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.64.

[0436] 38. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using p-toluenesulfonic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.64.

[0437] 39. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using p-toluenesulfonic acid, and the X-ray powder diffraction pattern contains peak positions of 5.29 and 12.96 and at least one peak position selected from the following: 8.37, 8.66, 13.47, 20.42 and 20.64 (in 2θ degrees, ±0.2 2θ degrees).

[0438] 40. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using sulfuric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.80, 8.50, 13.62, 14.21, 14.87, and 18.04.

[0439] 41. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using sulfuric acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.80, 8.50, 13.62, 14.21, 14.87, and 18.04.

[0440] 42. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using sulfuric acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.80, 8.50, 13.62, 14.21, 14.87, and 18.04.

[0441] 43. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using sulfuric acid, and the X-ray powder diffraction pattern contains peak positions at 5.80 and 14.87 and at least one peak position selected from the following: 8.50, 13.62, 14.21 and 18.04 (in 2θ degrees, ±0.2 2θ degrees).

[0442] 44. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using orthophosphoric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.47, 14.27, 14.91, 18.35, 19.72 and 21.29.

[0443] 45. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using orthophosphoric acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.47, 14.27, 14.91, 18.35, 19.72 and 21.29.

[0444] 46. ​​The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using orthophosphoric acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.47, 14.27, 14.91, 18.35, 19.72 and 21.29.

[0445] 47. The pharmaceutically acceptable salt according to embodiment 2, characterized in that the pharmaceutically acceptable salt is formed using orthophosphoric acid, and the X-ray powder diffraction pattern contains peak positions at 18.35 and 21.29 and at least one peak position selected from the following: 5.47, 14.27, 14.91 and 19.72 (in 2θ degrees, ±0.2 2θ degrees).

[0446] 48. A pharmaceutical composition comprising a pharmaceutically acceptable salt and one or more pharmaceutical excipients according to any one of embodiments 1-47.

[0447] 49. The pharmaceutical composition according to embodiment 48, characterized in that the pharmaceutical composition comprises 1-10% w / w of a compound of formula (I).

[0448] 50. The pharmaceutical composition according to embodiment 48 or 49, characterized in that the pharmaceutical composition is in an orally acceptable dosage form and comprises about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg or about 300 mg of a compound of formula (I).

[0449] 51. The pharmaceutical composition according to embodiment 50, characterized in that the pharmaceutical composition comprises about 10 mg or about 40 mg of the compound of formula (I).

[0450] 52. The pharmaceutical composition according to embodiment 48, characterized in that the pharmaceutical composition comprises 20-30% w / w of a compound of formula (I).

[0451] 53. The pharmaceutical composition according to embodiment 52, characterized in that the pharmaceutical composition is in an orally acceptable dosage form and comprises about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg or about 300 mg of a compound of formula (I).

[0452] 54. An amorphous solid dispersion prepared from a pharmaceutically acceptable salt and a polymer according to any one of embodiments 1-47.

[0453] 55. An amorphous solid dispersion prepared from a pharmaceutically acceptable salt according to embodiment 54, characterized in that the polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate, and polyvinylpyrrolidone (PVP) or mixtures thereof.

[0454] 56. An amorphous solid dispersion prepared from a pharmaceutically acceptable salt according to embodiment 55, characterized in that the polymer is HPMCAS.

[0455] 57. A pharmaceutical composition comprising a solid dispersion according to any one of embodiments 54 to 56 and one or more acceptable excipients.

[0456] 58. Eutectic, comprising compound of formula (I)

[0457]

[0458] And a co-forming agent selected from 3-hydroxy-2-naphthoic acid, L-serine, glycine, D-gluconic acid, glycolic acid, L-malic acid, oxalic acid, benzoic acid, fumaric acid, gentic acid, glutaric acid, 4-hydroxybenzoic acid, α-ketoglutaric acid, malonic acid, salicylic acid, L-tartaric acid, urea, pyroglutamic acid, hexanoic acid, glycerol, L-lysine, S-proline and pyruvic acid.

[0459] 59. The eutectic according to embodiment 58, characterized in that the co-forming agent is 3-hydroxy-2-naphthoic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.41, 13.34, 13.69, 15.84 and 20.21.

[0460] 60. The eutectic according to embodiment 58, characterized in that the co-forming agent is 3-hydroxy-2-naphthoic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.41, 13.34, 13.69, 15.84 and 20.21.

[0461] 61. The eutectic according to embodiment 58, characterized in that the co-forming agent is 3-hydroxy-2-naphthoic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.41, 13.34, 13.69, 15.84 and 20.21.

[0462] 62. The eutectic according to embodiment 58, characterized in that the co-forming agent is 3-hydroxy-2-naphthoic acid, and the X-ray powder diffraction pattern includes peak positions of 6.41 and 13.34 and at least one peak position selected from the following: 13.69, 15.84 and 20.21 (in 2θ degrees, ±0.2 2θ degrees).

[0463] 63. The eutectic according to any one of embodiments 59 to 62, characterized in that the eutectic is characterized by a differential scanning calorimetry thermogram containing an endothermic peak with an initial temperature of 202.79℃ (±2.0℃).

[0464] 64. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-serine, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.90, 8.46, 13.28, 13.88 and 18.72.

[0465] 65. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-serine, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.90, 8.46, 13.28, 13.88 and 18.72.

[0466] 66. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-serine, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.90, 8.46, 13.28, 13.88 and 18.72.

[0467] 67. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-serine, and the X-ray powder diffraction pattern includes peak positions of 8.46 and 13.88 and at least one peak position selected from the following: 5.90, 13.28 and 18.72 (in 2θ degrees, ±0.2 2θ degrees).

[0468] 68. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycine, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.62, 14.04, 14.79 and 26.04.

[0469] 69. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycine, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.62, 14.04, 14.79 and 26.04.

[0470] 70. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycine, and the X-ray powder diffraction pattern contains the following four peak positions (in 2θ degrees, ±0.2 2θ degrees): 8.62, 14.04, 14.79 and 26.04.

[0471] 71. The eutectic according to embodiment 58, characterized in that the co-forming agent is D-gluconic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.17, 14.14, 15.32, 19.17 and 19.32.

[0472] 72. The eutectic according to embodiment 58, characterized in that the co-forming agent is D-gluconic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.17, 14.14, 15.32, 19.17 and 19.32.

[0473] 73. The eutectic according to embodiment 58, characterized in that the co-forming agent is D-gluconic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.17, 14.14, 15.32, 19.17 and 19.32.

[0474] 74. The eutectic according to embodiment 58, characterized in that the co-forming agent is D-gluconic acid, and the X-ray powder diffraction pattern includes peak positions at 15.32 and 19.32 and at least one peak position selected from the following: 6.17, 14.14 and 19.17 (in 2θ degrees, ±0.2 2θ degrees).

[0475] 75. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycolic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 7.90, 14.04, and 16.25.

[0476] 76. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycolic acid, and the X-ray powder diffraction pattern contains the following three peak positions (in 2θ degrees, ±0.2 2θ degrees): 7.90, 14.04, and 16.25.

[0477] 77. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-malic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.87, 8.49, 14.13, 15.40 and 19.55.

[0478] 78. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-malic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.87, 8.49, 14.13, 15.40 and 19.55.

[0479] 79. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-malic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.87, 8.49, 14.13, 15.40 and 19.55.

[0480] 80. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-malic acid, and the X-ray powder diffraction pattern includes peak positions of 5.87 and 14.13 and at least one peak position selected from the following: 8.49, 15.40 and 19.55 (in 2θ degrees, ±0.2 2θ degrees).

[0481] 81. The eutectic according to embodiment 58, characterized in that the co-forming agent is oxalic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.81, 13.67, and 14.90.

[0482] 82. The eutectic according to embodiment 58, characterized in that the co-forming agent is oxalic acid, and the X-ray powder diffraction pattern contains the following three peak positions (in 2θ degrees, ±0.2 2θ degrees): 5.81, 13.67 and 14.90.

[0483] 83. The eutectic according to embodiment 57, characterized in that the co-forming agent is benzoic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.00, 8.50, 9.80, 18.05 and 19.99.

[0484] 84. The eutectic according to embodiment 58, characterized in that the co-forming agent is benzoic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.00, 8.50, 9.80, 18.05 and 19.99.

[0485] 85. The eutectic according to embodiment 58, characterized in that the co-forming agent is benzoic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.00, 8.50, 9.80, 18.05 and 19.99.

[0486] 86. The eutectic according to embodiment 58, characterized in that the co-forming agent is benzoic acid, and the X-ray powder diffraction pattern includes peak positions of 6.00 and 18.05 and at least one peak position selected from the following: 8.50, 9.80 and 19.99 (in 2θ degrees, ±0.2 2θ degrees).

[0487] 87. The eutectic according to any one of embodiments 83-86, characterized in that the eutectic is characterized by a differential scanning calorimetry thermogram containing an endothermic peak with an initial temperature of 128.06℃ (±2.0℃).

[0488] 88. The eutectic according to embodiment 58, characterized in that the co-forming agent is fumaric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 9.45, 13.63, 14.25 and 19.46.

[0489] 89. The eutectic according to embodiment 58, characterized in that the co-forming agent is fumaric acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 9.45, 13.63, 14.25 and 19.46.

[0490] 90. The eutectic according to embodiment 58, characterized in that the co-forming agent is fumaric acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 9.45, 13.63, 14.25 and 19.46.

[0491] 91. The eutectic according to embodiment 58, characterized in that the co-forming agent is fumaric acid, and the X-ray powder diffraction pattern includes peak positions of 5.59 and 14.25 and at least one peak position selected from the following: 9.45, 13.36 and 19.46 (in 2θ degrees, ±0.2 2θ degrees).

[0492] 92. The eutectic according to embodiment 58, characterized in that the co-forming agent is gentianic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.46, 12.63, 13.84, 17.34 and 26.08.

[0493] 93. The eutectic according to embodiment 58, characterized in that the co-forming agent is gentianic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.46, 12.63, 13.84, 17.34 and 26.08.

[0494] 94. The eutectic according to embodiment 58, characterized in that the co-forming agent is gentianic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.46, 12.63, 13.84, 17.34 and 26.08.

[0495] 95. The eutectic according to embodiment 58, characterized in that the co-forming agent is gentianic acid, and the X-ray powder diffraction pattern includes peak positions at 13.84 and 26.08 and at least one peak position selected from the following: 6.46, 12.63 and 17.34 (in 2θ degrees, ±0.2 2θ degrees).

[0496] 96. The eutectic according to embodiment 58, characterized in that the co-forming agent is glutaric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.72, 7.19, 12.00, 12.65 and 15.23.

[0497] 97. The eutectic according to embodiment 58, characterized in that the co-forming agent is glutaric acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.72, 7.19, 12.00, 12.65 and 15.23.

[0498] 98. The eutectic according to embodiment 58, characterized in that the co-forming agent is glutaric acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.72, 7.19, 12.00, 12.65 and 15.23.

[0499] 99. The eutectic according to embodiment 58, characterized in that the co-forming agent is glutaric acid, and the X-ray powder diffraction pattern includes peak positions of 6.72 and 7.19 and at least one peak position selected from the following: 12.00, 12.65 and 15.23 (in 2θ degrees, ±0.2 2θ degrees).

[0500] 100. The eutectic according to embodiment 58, characterized in that the co-forming agent is 4-hydroxybenzoic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.67, 14.64, 17.52, 20.59, 26.40 and 26.88.

[0501] 101. The eutectic according to embodiment 58, characterized in that the co-forming agent is 4-hydroxybenzoic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.67, 14.64, 17.52, 20.59, 26.40 and 26.88.

[0502] 102. The eutectic according to embodiment 58, characterized in that the co-forming agent is 4-hydroxybenzoic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.67, 14.64, 17.52, 20.59, 26.40 and 26.88.

[0503] 103. The eutectic according to embodiment 58, characterized in that the co-forming agent is 4-hydroxybenzoic acid, and the X-ray powder diffraction pattern includes peak positions of 6.67 and 14.64 and at least one peak position selected from the following: 17.52, 20.59, 26.40 and 26.88 (in 2θ degrees, ±0.2 2θ degrees).

[0504] 104. The eutectic according to embodiment 58, characterized in that the co-forming agent is α-ketoglutaric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.89, 7.39, 17.30 and 26.89.

[0505] 105. The eutectic according to embodiment 58, characterized in that the co-forming agent is α-ketoglutaric acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.89, 7.39, 17.30 and 26.89.

[0506] 106. The eutectic according to embodiment 58, characterized in that the co-forming agent is α-ketoglutaric acid, and the X-ray powder diffraction pattern contains four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.89, 7.39, 17.30 and 26.89.

[0507] 107. The eutectic according to embodiment 58, characterized in that the co-forming agent is α-ketoglutaric acid, and the X-ray powder diffraction pattern includes peak positions of 5.89 and 17.30 and at least one peak position selected from the following: 7.39 and 26.89 (in 2θ degrees, ±0.2 2θ degrees).

[0508] 108. The eutectic according to embodiment 58, characterized in that the co-forming agent is malonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 7.97, 13.74, 16.07 and 19.34.

[0509] 109. The eutectic according to embodiment 58, characterized in that the co-forming agent is malonic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 7.97, 13.74, 16.07 and 19.34.

[0510] 110. The eutectic according to embodiment 58, characterized in that the co-forming agent is malonic acid, and the X-ray powder diffraction pattern contains four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 7.97, 13.74, 16.07 and 19.34.

[0511] 111. The eutectic according to embodiment 58, characterized in that the co-forming agent is malonic acid, and the X-ray powder diffraction pattern includes peak positions of 7.97 and 19.34 and at least one peak position selected from the following: 13.74 and 16.07 (in 2θ degrees, ±0.2 2θ degrees).

[0512] 112. The eutectic according to embodiment 58, characterized in that the co-forming agent is salicylic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.77, 7.29, 16.36, 18.24 and 21.21.

[0513] 113. The eutectic according to embodiment 58, characterized in that the co-forming agent is salicylic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.77, 7.29, 16.36, 18.24 and 21.21.

[0514] 114. The eutectic according to embodiment 58, characterized in that the co-forming agent is salicylic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.77, 7.29, 16.36, 18.24 and 21.21.

[0515] 115. The eutectic according to embodiment 58, characterized in that the co-forming agent is salicylic acid, and the X-ray powder diffraction pattern includes peak positions of 6.77 and 16.36 and at least one peak position selected from the following: 7.29, 18.24 and 21.21 (in 2θ degrees, ±0.2 2θ degrees).

[0516] 116. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-tartaric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 11.84, 13.62 and 17.98.

[0517] 117. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-tartaric acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 11.84, 13.62 and 17.98.

[0518] 118. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-tartaric acid, and the X-ray powder diffraction pattern contains four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 11.84, 13.62 and 17.98.

[0519] 119. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-tartaric acid, and the X-ray powder diffraction pattern contains peak positions at 13.62 and 17.98 and at least one peak position selected from the following: 5.74 and 11.84 (in 2θ degrees, ±0.2 2θ degrees).

[0520] 120. The eutectic according to embodiment 58, characterized in that the co-forming agent is urea, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.79, 13.76, 16.34 and 26.43.

[0521] 121. The eutectic according to embodiment 58, characterized in that the co-forming agent is urea, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.79, 13.76, 16.34 and 26.43.

[0522] 122. The eutectic according to embodiment 58, characterized in that the co-forming agent is urea, and the X-ray powder diffraction pattern contains four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.79, 13.76, 16.34 and 26.43.

[0523] 123. The eutectic according to embodiment 58, characterized in that the co-forming agent is urea, and the X-ray powder diffraction pattern includes peak positions of 8.79 and 13.76 and at least one peak position selected from the following: 16.34 and 26.43 (in 2θ degrees, ±0.2 2θ degrees).

[0524] 124. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyroglutamic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.20, 13.87, 25.30, 26.24 and 27.26.

[0525] 125. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyroglutamic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.20, 13.87, 25.30, 26.24 and 27.26.

[0526] 126. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyroglutamic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.20, 13.87, 25.30, 26.24 and 27.26.

[0527] 127. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyroglutamic acid, and the X-ray powder diffraction pattern includes peak positions at 6.20 and 13.87 and at least one peak position selected from the following: 25.30, 26.24 and 27.26 (in 2θ degrees, ±0.2 2θ degrees).

[0528] 128. The eutectic according to embodiment 58, characterized in that the co-forming agent is hexanoic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.55, 9.80, 14.25 and 23.10.

[0529] 129. The eutectic according to embodiment 58, characterized in that the co-forming agent is hexanoic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.55, 9.80, 14.25 and 23.10.

[0530] 130. The eutectic according to embodiment 58, characterized in that the co-forming agent is hexanoic acid, and the X-ray powder diffraction pattern contains four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.55, 9.80, 14.25 and 23.10.

[0531] 131. The eutectic according to embodiment 58, characterized in that the co-forming agent is hexanoic acid, and the X-ray powder diffraction pattern includes peak positions of 8.55 and 14.25 and at least one peak position selected from the following: 9.80 and 23.10 (in 2θ degrees, ±0.2 2θ degrees).

[0532] 132. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycerol, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 8.41, 11.85, 14.32 and 17.99.

[0533] 133. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycerol, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 8.41, 11.85, 14.32 and 17.99.

[0534] 134. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycerol, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 8.41, 11.85, 14.32 and 17.99.

[0535] 135. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycerol, and the X-ray powder diffraction pattern includes peak positions of 11.85 and 17.99 and at least one peak position selected from the following: 5.91, 8.41 and 14.32 (in 2θ degrees, ±0.2 2θ degrees).

[0536] 136. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-lysine, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.00, 6.68, 12.61, 18.50 and 23.45.

[0537] 137. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-lysine, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.00, 6.68, 12.61, 18.50 and 23.45.

[0538] 138. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-lysine, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.00, 6.68, 12.61, 18.50 and 23.45.

[0539] 139. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-lysine, and the X-ray powder diffraction pattern includes peak positions of 5.00 and 18.50 and at least one peak position selected from the following: 6.68, 12.61 and 23.45 (in 2θ degrees, ±0.2 2θ degrees).

[0540] 140. The eutectic according to embodiment 58, characterized in that the co-forming agent is S-proline, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 7.19, 14.02 and 26.36.

[0541] 141. The eutectic according to embodiment 58, characterized in that the co-forming agent is S-proline, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 7.19, 14.02 and 26.36.

[0542] 142. The eutectic according to embodiment 58, characterized in that the co-forming agent is S-proline, and the X-ray powder diffraction pattern contains four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.91, 7.19, 14.02 and 26.36.

[0543] 143. The eutectic according to embodiment 58, characterized in that the co-forming agent is S-proline, and the X-ray powder diffraction pattern contains peak positions of 5.91 and 7.19 and at least one peak position selected from the following: 14.02 and 26.36 (in 2θ degrees, ±0.2 2θ degrees).

[0544] 144. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyruvic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.61, 7.81, 14.40, 18.99, 26.41 and 27.10.

[0545] 145. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyruvic acid, and the X-ray powder diffraction pattern contains at least three peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.61, 7.81, 14.40, 18.99, 26.41 and 27.10.

[0546] 146. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyruvic acid, and the X-ray powder diffraction pattern contains at least four peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.61, 7.81, 14.40, 18.99, 26.41 and 27.10.

[0547] 147. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyruvic acid, and the X-ray powder diffraction pattern includes peak positions at 6.61 and 7.81 and at least one peak position selected from the following: 14.40, 18.99, 26.41 and 27.10 (in 2θ degrees, ±0.2 2θ degrees).

[0548] 148. A pharmaceutical composition comprising a cocrystal according to any one of embodiments 58-147 and one or more pharmaceutical excipients.

[0549] 149. The pharmaceutical composition according to embodiment 148, characterized in that the pharmaceutical composition comprises 1-10% w / w of a compound of formula (I).

[0550] 150. The pharmaceutical composition according to embodiment 148 or 149, characterized in that the pharmaceutical composition is in an orally acceptable dosage form and comprises about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg or about 300 mg of a compound of formula (I).

[0551] 151. The pharmaceutical composition according to embodiment 150, characterized in that the pharmaceutical composition comprises about 10 mg or about 40 mg of the compound of formula (I).

[0552] 152. The pharmaceutical composition according to embodiment 148, characterized in that the pharmaceutical composition comprises 20-30% w / w of a compound of formula (I).

[0553] 153. The pharmaceutical composition according to embodiment 152, characterized in that the pharmaceutical composition is in an orally acceptable dosage form and comprises about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg or about 300 mg of a compound of formula (I).

[0554] 154. An amorphous solid dispersion prepared from a eutectic and a polymer according to any one of embodiments 58 to 147.

[0555] 155. An amorphous solid dispersion prepared by eutectic according to embodiment 154, characterized in that the polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate, and polyvinylpyrrolidone (PVP) or mixtures thereof.

[0556] 156. An amorphous solid dispersion prepared by eutectic according to embodiment 155, characterized in that the polymer is HPMCAS.

[0557] 157. A pharmaceutical composition comprising a solid dispersion according to any one of embodiments 154 to 156 and one or more acceptable excipients.

[0558] 158. A method for preparing a pharmaceutically acceptable salt according to embodiment 1, the method comprising:

[0559] - Dissolve the compound of formula (I) and a pharmaceutically acceptable acid in a solvent to obtain a solution; and

[0560] - Precipitate the corresponding salt.

[0561] 159. A method for preparing a pharmaceutically acceptable crystalline salt according to Embodiment 2, the method comprising:

[0562] - Dissolve the compound of formula (I) and a pharmaceutically acceptable acid in a solvent to obtain a solution; and

[0563] - The corresponding salt in precipitated crystalline form.

[0564] 160. The method according to embodiment 159, characterized in that seed crystals are added to the solution.

[0565] 161. The method according to any one of embodiments 158 to 160, characterized in that the pharmaceutically acceptable acid is selected from benzenesulfonic acid, (+)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, hydrobromic acid, hydrochloric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, sulfuric acid, and phosphoric acid.

[0566] 162. The method according to any one of embodiments 158 to 161, characterized in that the solvent is a polar organic solvent selected from methanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran (THF) or n-butanol.

[0567] 163. The method according to any one of embodiments 158 to 161, characterized in that the solvent is a mixture of acetone and water.

[0568] 164. A method for preparing a eutectic of the compound of formula (I) according to embodiment 58, the method comprising:

[0569] - Dissolve the compound of formula (I) and the co-forming agent in a solvent to obtain a solution; and

[0570] - Precipitate the corresponding eutectic.

[0571] 165. The method according to embodiment 164, characterized in that seed crystals are added to the solution.

[0572] 166. The method according to any one of embodiments 163 to 165, characterized in that the co-forming agent is selected from 3-hydroxy-2-naphthoic acid, L-serine, glycine, D-gluconic acid, glycolic acid, L-malic acid, oxalic acid, benzoic acid, fumaric acid, gentic acid, glutaric acid, 4-hydroxybenzoic acid, α-ketoglutaric acid, malonic acid, salicylic acid, L-tartaric acid, urea, pyroglutamic acid, hexanoic acid, glycerol, L-lysine, S-proline, and pyruvic acid.

[0573] 167. The method according to any one of embodiments 163 to 166, characterized in that the solvent comprises a polar organic solvent selected from methanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran (THF) or n-butanol.

[0574] 168. The method according to any one of embodiments 163 to 166, characterized in that the solvent is a mixture of acetone and water.

[0575] 169. The method according to any one of embodiments 163 to 166, characterized in that the solvent comprises ethyl acetate or methanol.

[0576] 170. A method for preparing an amorphous solid dispersion according to any one of embodiments 54 to 56 or 154 to 156.

[0577] 171. A pharmaceutically acceptable salt according to any one of embodiments 1-47, or a pharmaceutical composition according to any one of embodiments 48 to 53 or 57, or an amorphous solid dispersion according to any one of embodiments 54 to 56, for the treatment of cancers characterized by the presence of IDH1 and / or IDH2 mutations.

[0578] 172. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to embodiment 171, characterized in that the cancer is characterized by the presence of an IDH1 mutation.

[0579] 173. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to embodiment 172, characterized in that the IDH1 mutation is an R132X mutation.

[0580] 174. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to embodiment 173, characterized in that the IDH1 mutation is an R132H, R132C, R132S, R132L, or R132G mutation.

[0581] 175. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the purpose according to any one of embodiments 172 to 125, characterized in that the IDH1 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

[0582] 176. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to embodiment 171, characterized in that the cancer is characterized by the presence of an IDH2 mutation.

[0583] 177. A pharmaceutically acceptable salt for the stated purpose according to embodiment 176, characterized in that the IDH2 mutation is an R140X mutation.

[0584] 178. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to embodiment 177, characterized in that the IDH2 mutation is an R140Q, R140W, or R140L mutation.

[0585] 179. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to embodiment 176, characterized in that the IDH2 mutation is an R172X mutation.

[0586] 180. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to embodiment 179, characterized in that the IDH2 mutation is an R172K or R172G mutation.

[0587] 181. A pharmaceutically acceptable salt, pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 176 to 180, characterized in that the IDH2 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

[0588] 182. A pharmaceutically acceptable salt, pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 171 to 181, characterized in that the cancer is characterized by the presence of IDH1 mutation and IDH2 mutation.

[0589] 183. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to embodiment 182, characterized in that the IDH1 and IDH2 mutations together lead to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

[0590] 184. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the purpose according to any one of embodiments 171 to 183, characterized in that the cancer is a brain tumor.

[0591] 185. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to embodiment 184, characterized in that the brain tumor is a glioma.

[0592] 186. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to embodiment 185, characterized in that the glioma is a low-grade glioma or a secondary high-grade glioma.

[0593] 187. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to embodiment 185 or 186, characterized in that the glioma is a secondary high-grade glioma and the secondary high-grade glioma is glioblastoma.

[0594] 188. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the purpose according to any one of embodiments 171 to 187, characterized in that the cancer is refractory or recurrent.

[0595] 189. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of embodiments 171 to 188, characterized in that the cancer is newly diagnosed or previously untreated.

[0596] 190. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of embodiments 171 to 189, characterized in that the pharmaceutically acceptable salt is administered together with an additional treatment.

[0597] 191. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of embodiments 171 to 190, characterized in that, based on the amount of the compound of formula (I), the amount of the pharmaceutically acceptable salt administered is about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg per day.

[0598] 192. A pharmaceutically acceptable salt, pharmaceutical composition or amorphous solid dispersion for the said use according to any one of embodiments 171 to 190, characterized in that, based on the amount of the compound of formula (I), the amount of the pharmaceutically acceptable salt administered is about 10 mg, about 20 mg or about 40 mg per day.

[0599] 193. A pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the stated purpose according to any one of embodiments 171 to 190, characterized in that, based on the amount of the compound of formula (I), the amount of the pharmaceutically acceptable salt administered is about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg, twice daily.

[0600] 194. A pharmaceutically acceptable salt, pharmaceutical composition or amorphous solid dispersion for the said use according to any one of embodiments 171 to 190, characterized in that, based on the amount of the compound of formula (I), the amount of the pharmaceutically acceptable salt administered is about 10 mg, about 20 mg or about 40 mg, twice daily.

[0601] 195. A eutectic according to any one of embodiments 58 to 147, or a pharmaceutical composition according to any one of embodiments 148 to 153 or 157, or an amorphous solid dispersion according to any one of embodiments 154 to 156, for the treatment of cancers characterized by the presence of IDH1 and / or IDH2 mutations.

[0602] 196. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 195, characterized in that the cancer is characterized by the presence of an IDH1 mutation.

[0603] 197. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 196, characterized in that the IDH1 mutation is an R132X mutation.

[0604] 198. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 197, characterized in that the IDH1 mutation is an R132H, R132C, R132S, R132L or R132G mutation.

[0605] 199. A eutectic or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 196 to 198, characterized in that the IDH1 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

[0606] 200. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said use according to embodiment 195, characterized in that the cancer is characterized by the presence of an IDH2 mutation.

[0607] 201. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 200, characterized in that the IDH2 mutation is an R140X mutation.

[0608] 202. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 201, characterized in that the IDH2 mutation is an R140Q, R140W or R140L mutation.

[0609] 203. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 200, characterized in that the IDH2 mutation is an R172X mutation.

[0610] 204. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 203, characterized in that the IDH2 mutation is an R172K or R172G mutation.

[0611] 205. A eutectic or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 200 to 204, characterized in that the IDH2 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

[0612] 206. The cocrystal for the said use according to any one of embodiments 195 to 205, characterized in that the cancer is characterized by the presence of IDH1 mutation and IDH2 mutation.

[0613] 207. The eutectic or pharmaceutical composition or amorphous solid dispersion for the stated purpose according to embodiment 206, characterized in that the IDH1 and IDH2 mutations together lead to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

[0614] 208. A eutectic or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 207, characterized in that the cancer is a brain tumor.

[0615] 209. The eutectic or pharmaceutical composition or amorphous solid dispersion for the stated purpose according to embodiment 208, characterized in that the brain tumor is a glioma.

[0616] 210. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 209, characterized in that the glioma is a low-grade glioma or a secondary high-grade glioma.

[0617] 211. The eutectic or pharmaceutical composition or amorphous solid dispersion for the said purpose according to embodiment 209 or 210, characterized in that the glioma is a secondary high-grade glioma and the secondary high-grade glioma is glioblastoma.

[0618] 212. A eutectic or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 211, characterized in that the cancer is refractory or recurrent.

[0619] 213. A eutectic or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 212, characterized in that the cancer is newly diagnosed or previously untreated.

[0620] 214. A eutectic or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 213, characterized in that the eutectic is administered together with an additional treatment.

[0621] 215. A cocrystal or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 214, characterized in that, based on the amount of the compound of formula (I), the amount of the cocrystal applied is about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg or about 300 mg per day.

[0622] 216. A cocrystal or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 214, characterized in that, based on the amount of the compound of formula (I), the amount of cocrystal applied is about 10 mg, about 20 mg or about 40 mg per day.

[0623] 217. A cocrystal or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 214, characterized in that, based on the amount of the compound of formula (I), the amount of the cocrystal applied is about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg or about 300 mg, twice daily.

[0624] 218. A cocrystal or pharmaceutical composition or amorphous solid dispersion for the purpose according to any one of embodiments 195 to 214, characterized in that, based on the amount of the compound of formula (I), the cocrystal is applied in an amount of about 10 mg, about 20 mg or about 40 mg, twice daily.

[0625] 219. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using benzenesulfonic acid.

[0626] 220. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using (+)-camphor-10-sulfonic acid.

[0627] 221. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using ethane-1,2-disulfonic acid.

[0628] 222. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using ethanesulfonic acid.

[0629] 223. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using hydrobromic acid.

[0630] 224. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using hydrochloric acid.

[0631] 225. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-1,5-disulfonic acid.

[0632] 226. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using naphthalene-2-sulfonic acid.

[0633] 227. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using p-toluenesulfonic acid.

[0634] 228. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using sulfuric acid.

[0635] 229. The pharmaceutically acceptable salt according to embodiment 1, characterized in that the pharmaceutically acceptable salt is formed using orthophosphoric acid.

[0636] 230. The eutectic according to embodiment 58, characterized in that the co-forming agent is 3-hydroxy-2-naphthoic acid.

[0637] 231. The co-crystal according to embodiment 58, characterized in that the co-forming agent is L-serine.

[0638] 232. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycine.

[0639] 233. The eutectic according to embodiment 58, characterized in that the co-forming agent is D-gluconic acid.

[0640] 234. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycolic acid.

[0641] 235. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-malic acid.

[0642] 236. The eutectic according to embodiment 58, characterized in that the co-forming agent is oxalic acid.

[0643] 237. The eutectic according to embodiment 58, characterized in that the co-forming agent is benzoic acid.

[0644] 238. The eutectic according to embodiment 58, characterized in that the co-forming agent is fumaric acid.

[0645] 239. The eutectic according to embodiment 58, characterized in that the co-forming agent is gentian acid.

[0646] 240. The eutectic according to embodiment 58, characterized in that the co-forming agent is glutaric acid.

[0647] 241. The eutectic according to embodiment 58, characterized in that the co-forming agent is 4-hydroxybenzoic acid.

[0648] 242. The eutectic according to embodiment 58, characterized in that the co-forming agent is α-ketoglutaric acid.

[0649] 243. The eutectic according to embodiment 58, characterized in that the co-forming agent is malonic acid.

[0650] 244. The eutectic according to embodiment 57, characterized in that the co-forming agent is salicylic acid.

[0651] 245. The eutectic according to embodiment 58, characterized in that the co-forming agent is L-tartaric acid.

[0652] 246. The eutectic according to embodiment 58, characterized in that the co-forming agent is urea.

[0653] 247. The co-crystal according to embodiment 58, characterized in that the co-forming agent is pyroglutamic acid.

[0654] 248. The eutectic according to embodiment 58, characterized in that the co-forming agent is hexanoic acid.

[0655] 249. The eutectic according to embodiment 58, characterized in that the co-forming agent is glycerol.

[0656] 250. The co-crystal according to embodiment 58, characterized in that the co-forming agent is L-lysine.

[0657] 251. The co-crystal according to embodiment 58, characterized in that the co-forming agent is S-proline.

[0658] 252. The eutectic according to embodiment 58, characterized in that the co-forming agent is pyruvic acid.

[0659] Example

[0660] vocabulary

[0661] Table 2

[0662]

[0663] General test instructions

[0664] In the following examples, unless otherwise stated, the reagents (chemicals) were purchased from commercial sources (e.g., Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Co., Ltd.) and were ready for use without further purification.

[0665] Instruments and methods

[0666] X-ray powder diffraction (XRPD) analysis

[0667] XRPD patterns were recorded using a Panalytical Empyrean diffractometer, from 3.5°2q to 35°2q, in transmission mode, with CuKα radiation (l = 1.5418 Å), 45 kV and 40 mA, in steps of 0.013°2q, for 15 minutes (Examples 1 to 6, 8, 10 and 13).

[0668] XRPD patterns were recorded using a Panalytical Empyrean diffractometer, from 3.5°2θ to 55°2θ, in transmission mode, with CuKα radiation (l = 1.5418 Å), 45 kV and 40 mA, in steps of 0.013°2q, for 30 minutes (Examples 7, 9, 11, 12 and 14 to 34).

[0669] Table 3-36 only describes peaks with a relative intensity higher than 10%.

[0670] 1 H NMR analysis

[0671] 1 The H liquid NMR spectra were collected using a Bruker 400MHz NMR spectrometer.

[0672] Chemical shifts are given in ppm relative to tetramethylsilane (TMS), with partial deuterated dimethyl sulfoxide or partial deuterated methanol as internal standards.

[0673] In partially deuterated dimethyl sulfoxide solutions, 1D 1 The resonance at 2.5 ppm in the H NMR spectrum is attributed to partially deuterated dimethyl sulfoxide, and the resonance at 3.30 ppm is attributed to the presence of water.

[0674] In some deuterated methanol solutions, 1D 1 The resonance at 3.3 ppm in the H NMR spectrum is attributed to partially deuterated methanol, and the resonance at 4.83 ppm is attributed to the presence of water.

[0675] DSC / TGA Analysis

[0676] DSC (Differential Scanning Calorimetry) analysis was recorded from 0°C to 200°C, 250°C, or 350°C (depending on the nature of the crystal phase) at a rate of 10°C / min. Crystal phase characterization was performed using a TA instrument with a DSC Q2000. For anhydrous Tg measurements, a first cycle was performed from 25°C to 110°C at 10°C / min to remove water, followed by a second cycle from 110°C to 20°C to obtain a fresh glassy state, and finally a third cycle from 20°C to 200°C at 1°C / min, modulated by + / - 0.32°C every 60 seconds to determine the Tg value.

[0677] TG (thermogravimetric) analysis was recorded at a range of 25°C to 200°C, 250°C, or 350°C (depending on the nature of the crystal phase), at a rate of 10°C / minute, using a TGA Q5000 TA instrument.

[0678] In the examples, the compound of formula (I), namely 6-(6-chloropyridin-2-yl)-N 2 N4 -Bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine, is referred to as compound 1.

[0679] As used in the examples, the term "compound 1" should be understood to refer to 6-(6-chloropyridin-2-yl)-N 2 N 4 -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine or any tautomer or rotatable isomer thereof. The double bond geometry of the above tautomers is not determined, and therefore the chemical structures representing the above tautomers are not intended to suggest a specific double bond geometry.

[0680] As used in the examples, the term "free form" refers to crystalline form A of compound 1, which can be prepared according to the methods detailed in Examples 10 and 16 of PCT application WO2019 / 090059.

[0681] Example 1: Preparation and characterization of crystalline benzenesulfonate of compound 1

[0682] Compound 1 (200 mg) and benzenesulfonic acid (1 equivalent) were placed in acetone (1.7 mL), followed by the addition of water (0.8 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by filtration.

[0683] The benzenesulfonate of compound 1 1 The H NMR spectrum is shown in Figure 2 middle.

[0684] 1 H NMR (DMSO-d 6 ) δ 8.60 ppm / 8.55 ppm / 8.36 ppm / 8.25 ppm (3H,bd s ), 8.05 ppm (1H, m) 7.69 ppm (1H, m), 7.59 ppm (1H, m), 7.35-7.26 ppm (1H,m), 5.20-4.83 ppm (2H, bm), 1.34 ppm (6H, bd).

[0685] The XRPD pattern of the salt is shown in Figure 1 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 3.

[0686] Table 3. XRPD peaks of benzenesulfonate of compound 1

[0687]

[0688] Example 2: Preparation and characterization of crystalline (+)-camphor-10-sulfonate of compound 1

[0689] Compound 1 (200 mg) and (+)-camphor-10-sulfonic acid (1 equivalent) were placed in acetone (1 mL), followed by the addition of water (0.5 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and vacuum dried overnight at 40 °C.

[0690] (+)-camphor-10-sulfonate of compound 1 1 The H NMR spectrum is shown in Figure 4 middle.

[0691] 1 H NMR (DMSO-d 6 ) δ 8.60 ppm / 8.54 ppm / 8.36 ppm / 8.25 ppm and 8,24 ppm (3H, bd s ), 8.04 ppm (1H, m) 7.69 ppm (1H, bd), 5.20-4.82 ppm (2H, bm), 2.87 and 2.38 ppm (1H, dd), 2.69 ppm (1H, bqi), 2.23 ppm (1H, bm), 2.08 ppm (1H, s), 1.93 ppm (1H, bt), 1.85 ppm (1H, m), 1.79 ppm (1H, d), 1.34 ppm (6H, bd), 1.27ppm (1H, m), 1.05 ppm (1H, s), 0.74 ppm (1H, s).

[0692] The XRPD pattern of (+)-camphor-10-sulfonate of compound 1 is shown in... Figure 3 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 4.

[0693] Table 4. XRPD peaks of (+)-camphor-10-sulfonate of compound 1

[0694]

[0695] Example 3: Preparation and characterization of crystalline ethane-1,2-disulfonate of compound 1

[0696] Compound 1 (200 mg) and ethane-1,2-disulfonic acid (0.5 equivalents) were placed in acetone (2.4 mL), followed by the addition of water (1.2 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and dried under vacuum at 40 °C overnight.

[0697] The ethane-1,2-disulfonate of compound 1 1 The H NMR spectrum is shown in Figure 6 middle.

[0698] 1 H NMR (DMSO-d 6 ) δ 8.63 ppm / 8.61 ppm / 8.37 ppm / 8.29 ppm and 8.26 ppm (3H, bd s ), 8.0 ppm (1H, bm) 7.71 ppm (1H, bm), 5.20-4.82 ppm (2H, bm), 2.65ppm (4H, s), 1.34 ppm (6H, bd).

[0699] The XRPD pattern of the salt is shown in Figure 5 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 5.

[0700] Table 5. XRPD peaks of ethane-1,2-disulfonate of compound 1

[0701]

[0702] like Figure 29 As shown, the DSC thermogram of ethane-1,2-disulfonate of compound 1 contains an endothermic peak with an onset temperature of 304.30 °C and a peak temperature of 305.53 °C.

[0703] Example 4: Preparation and characterization of crystalline ethanesulfonate of compound 1

[0704] Compound 1 (50 mg) and ethanesulfonic acid (0.5 equivalents) were placed in acetone (0.8 mL), followed by the addition of water (0.4 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and finally cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by filtration.

[0705] The ethanesulfonate of compound 1 1 The H NMR spectrum is shown in Figure 8 middle.

[0706] 1 H NMR (DMSO-d 6 ) δ 8.60 ppm / 8.54 ppm / 8.36 ppm and 8.25 ppm 8.24 ppm (3H, bd s ), 8.04 ppm (1H, m) 7.69 ppm (1H, d), 5.20-4.83 ppm (2H, bm), 2.39ppm (2H, qa), 1.34 ppm (6H, bd), 1.06 ppm (3H, t)

[0707] The XRPD pattern of the salt is shown in Figure 7 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 6.

[0708] Table 6. XRPD peaks of ethanesulfonate of compound 1

[0709]

[0710] Example 5: Preparation and characterization of crystalline hydrobromide of compound 1

[0711] Compound 1 (200 mg) and hydrobromic acid (1 equivalent in 0.2 mL of water) were placed in acetone (1 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day and then filtered.

[0712] The hydrobromide of compound 1 1 The H NMR spectrum is shown in Figure 10 middle.

[0713] 1 H NMR (DMSO-d 6 ) δ 8.61 ppm / 8.57 ppm / 8.36 ppm and 8.26 ppm (3H, bd s ),8.05 ppm (1H, bm) 7.70 ppm (1H, bm), 5.20-4.83 ppm (2H, bm), 1.34 ppm (6H,d).

[0714] The XRPD pattern of the salt is shown in Figure 9 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 7.

[0715] Table 7. XRPD peaks of hydrobromide of compound 1

[0716]

[0717] Example 6: Preparation and characterization of crystalline hydrochloride of compound 1

[0718] Compound 1 (1 g) and hydrochloric acid (1 equivalent in 7.5 mL of water) were placed in acetone (10 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 3 days, filtered, and dried under vacuum at 40 °C overnight.

[0719] The hydrochloride salt of compound 1 1 The H NMR spectrum is shown in Figure 12 middle.

[0720] 1 H NMR (DMSO-d 6 ) δ 8.63 ppm / 8.56 ppm / 8.36 ppm / 8.26 ppm and 8,25 ppm (3H, bd s ), 8.05 ppm (1H, bm) 7.70 ppm (1H, bd), 5.20-4.83 ppm (2H, bm), 1.34ppm (6H, bd).

[0721] The XRPD pattern of the salt is shown in Figure 11 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 8.

[0722] Table 8. XRPD peaks of the hydrochloride salt of compound 1

[0723]

[0724] Example 7: Preparation and characterization of crystalline naphthalene-1,5-disulfonate of compound 1

[0725] Compound 1 (200 mg) and naphthalene-1,5-disulfonic acid (0.5 equivalents) were placed in acetone (2.4 mL), followed by the addition of water (1.2 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and finally cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 3 days, filtered, and vacuum dried overnight at 40 °C.

[0726] The naphthalene-1,5-disulfonate of compound 1 1The H NMR spectrum is shown in Figure 14 middle.

[0727] 1 H NMR (DMSO-d 6 ) δ 8.85 ppm (1H, d), 8.64 ppm / 8.63 ppm / 8.37 ppm / 8.31 ppm and 8.26 ppm (3H, bd s ), 8.06 ppm (1H, bm), 7.92 ppm (1H, dd), 7.71 ppm (1H, bt), 7.41 ppm (1H, dd), 5.20-4.82 ppm (2H, bm), 1.34 ppm (6H, bd).

[0728] The XRPD pattern of the salt is shown in Figure 13 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 9.

[0729] Table 9. XRPD peaks of naphthalene-1,5-disulfonate of compound 1

[0730]

[0731] like Figure 30 As shown, the DSC thermogram of naphthalene-1,5-disulfonate contains an endothermic peak with an onset temperature of 324.30℃ and a peak temperature of 330.49℃.

[0732] Example 8: Preparation and characterization of crystalline naphthalene-2-sulfonate of compound 1

[0733] Compound 1 (50 mg) and naphthalene-2-sulfonic acid (2 equivalents) were placed in acetone (0.8 mL), followed by the addition of water (0.4 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and finally cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by filtration.

[0734] The naphthalene-2-sulfonate of compound 1 1 The H NMR spectrum is shown in Figure 16 middle.

[0735] 1 H NMR (DMSO-d 6 ) δ 8.61 ppm / 8.55 ppm / 8.37 ppm / 8.26 ppm and 8.25 ppm (3H, bd s), 8.14 (1H, bs), 8.05 ppm (1H, bm), 7.97 ppm and 7.90 ppm (2H, m), 7.86ppm (1H, bd), 7.73-7.50 ppm (4H, m), 5.20-4.83 ppm (2H, bm), 1.35 ppm (6H,bd).

[0736] The XRPD pattern of the salt is shown in Figure 15 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 10.

[0737] Table 10. XRPD peaks of naphthalene-2-sulfonate of compound 1

[0738]

[0739] Example 9: Preparation and characterization of p-toluenesulfonate crystals of compound 1

[0740] Compound 1 (1 g) and p-toluenesulfonic acid (2 equivalents) were placed in acetone (5 mL), followed by the addition of water (2.5 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and vacuum dried overnight at 40 °C.

[0741] p-Toluenesulfonate of Compound 1 1 The H NMR spectrum is shown in Figure 18 middle.

[0742] 1 H NMR (DMSO-d 6 ) δ 8.63 ppm / 8.37 ppm / 8.30 ppm (2H, d) and 8.26 ppm (3H, bd s ), 8.05 ppm (1H, bm), 7.71 ppm (1H, bt), 7.47 ppm (2H, d), 7.11 ppm(2H, d), 5.20-4.83 ppm (2H, bm), 2.29 ppm (3H, s), 1.34 ppm (6H, bd).

[0743] The XRPD pattern of the salt is shown in Figure 17 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 11.

[0744] Table 11. XRPD peaks of p-toluenesulfonate of compound 1

[0745]

[0746] Example 10: Preparation and characterization of crystalline sulfate of compound 1

[0747] Compound 1 (1 g) and sulfuric acid (1 equivalent, in 1.5 mL of water) were placed in acetone (5 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day and then filtered.

[0748] The sulfate of compound 1 1 The H NMR spectra are shown in Figure 20 middle.

[0749] 1 H NMR (DMSO-d 6 ) δ8.60 ppm / 8.55 ppm / 8.36 ppm and 8.25 ppm (3H, bd s ), 8.04 ppm (1H, bm) 7.69 ppm (1H, bm), 5.20-4.82 ppm (2H, bm), 1.34 ppm (6H, bd).

[0750] The XRPD pattern of the salt is shown in Figure 19 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 12.

[0751] Table 12. XRPD peaks of sulfate of compound 1

[0752]

[0753] Example 11: Preparation and characterization of crystalline 3-hydroxy-2-naphthoic acid cocrystal of compound 1

[0754] Compound 1 (1 g) and 3-hydroxy-2-naphthoic acid (1 equivalent) were placed in acetone (10 mL), and then water (2.5 mL) was added. The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and vacuum dried overnight at 40 °C.

[0755] 3-hydroxy-2-naphthoic acid cocrystal of compound 1 1 The H NMR spectrum is shown in Figure 22 middle.

[0756] 1 H NMR (DMSO-d 6 ) δ 14.07 ppm (1H, bs), 11.06 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 ppm and 8,21 ppm (3H, bd s 7.32 ppm (1H, s), 5.20-4.82 ppm (2H, bm), 1.34 ppm (6H, bd).

[0757] The XRPD pattern of the 3-hydroxy-2-naphthoic acid cocrystal of compound 1 is shown in the figure. Figure 21 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 13.

[0758] Table 13. XRPD peaks of the 3-hydroxy-2-naphthoic acid cocrystal of compound 1

[0759]

[0760] like Figure 31 As shown, the DSC thermogram of the 3-hydroxy-2-naphthoic acid cocrystal of compound 1 contains an endothermic peak with an onset temperature of 202.79 °C and a peak temperature of 203.65 °C.

[0761] Example 12: Preparation and characterization of crystalline L-serine cocrystal of compound 1

[0762] Compound 1 (200 mg) and L-serine (0.5 equivalents) were placed in acetone (2.7 mL), followed by the addition of water (1.3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and vacuum dried overnight at 40 °C.

[0763] L-serine cocrystal of compound 1 1 The H NMR spectrum is shown in Figure 24 middle.

[0764] 1H NMR (DMSO-d 6 ) δ 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bd s ), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82 ppm (2H, bm), 3.70ppm (1H, dd), 3.52 ppm (1H, dd), 3.16 ppm (1H, dd), 1.34 ppm (6H, bd).

[0765] The XRPD pattern of the L-serine cocrystal of compound 1 is shown in the figure. Figure 23 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 14.

[0766] Table 14. XRPD peaks of L-serine cocrystal of compound 1

[0767]

[0768] Example 13: Preparation and characterization of crystalline glycine cocrystal of compound 1

[0769] Compound 1 (50 mg) and glycine (2 equivalents) were placed in acetone (0.8 mL), followed by the addition of water (0.4 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and finally cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day and then filtered.

[0770] glycine co-crystal of compound 1 1 The H NMR spectrum is shown in Figure 26 middle.

[0771] 1 H NMR (CD3OD) δ 8.41 ppm (1H, bd), 7,95 ppm (1H, bm) 7.60 ppm (1H,bm), 5.39-4.92 ppm (2H, bm), 3.37 ppm (2H, s), 1.41 ppm (6H, bm).

[0772] The XRPD pattern of the glycine cocrystal of compound 1 is shown in the figure. Figure 25 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 15.

[0773] Table 15. XRPD peaks of glycine cocrystal of compound 1

[0774]

[0775] Example 14: Preparation and characterization of crystalline D-gluconic acid eutectic of compound 1

[0776] Compound 1 (200 mg) and D-gluconic acid (1 equivalent) were placed in acetone (2.7 mL), followed by the addition of water (1.3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, then stirred at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and dried under vacuum at 40 °C overnight.

[0777] D-gluconic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 28 middle.

[0778] 1 H NMR (DMSO-d 6 ) δ 8.33 and 8.25 ppm (1H, bd) s ), 8.01 ppm (1H, t) 7.66 ppm (1H, bd), 5.20-4.83 ppm (2H, bm), 4.11 ppm (1H, d), 3.89 ppm (1H, dd), 3.55-3.32 ppm (4H, m), 1.33 ppm (6H, bd).

[0779] The XRPD pattern of the D-gluconic acid eutectic of compound 1 is shown in the figure. Figure 27 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 16.

[0780] Table 16. XRPD peaks of the D-gluconic acid cocrystal of compound 1

[0781]

[0782] Example 15: Preparation and characterization of crystalline glycolic acid eutectic of compound 1

[0783] Compound 1 (400 mg) and glycolic acid (1 equivalent) were placed in ethyl acetate (1.25 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 3 days, filtered, and dried at 40 °C.

[0784] The glycolic acid eutectic of compound 1 1The H NMR spectrum is shown in Figure 32 middle.

[0785] 1 H NMR (DMSO-d 6 ) δ 12.31 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.36 ppm / 8.25 ppm and 8.21 ppm (3H, bd s ), 8.04 ppm (1H, bt) 7.68 ppm (1H, bd), 5.20-4.80ppm (2H, bm), 5.20-4.80 ppm (1H, bs), 3.91 ppm (2H, s), 1.34 ppm (6H, bd).

[0786] The XRPD pattern of the glycolic acid cocrystal of compound 1 is shown in the figure. Figure 33 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 17.

[0787] Table 17. XRPD peaks of the glycolic acid cocrystal of compound 1

[0788]

[0789] Example 16: Preparation and characterization of crystalline L-malic acid eutectic of compound 1

[0790] Compound 1 (400 mg) and L-malic acid (1 equivalent) were placed in ethyl acetate (1 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 3 days, filtered, and dried at 40 °C.

[0791] L-malic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 34 middle.

[0792] 1 H NMR (DMSO-d 6 ) δ 12.35 ppm (2H, bs), 8.60 ppm / 8.49 ppm / 8.36 ppm and 8.25 ppm 8.21 ppm (3H, bd s), 8.04 ppm (1H, bt) 7.69 ppm (1H, bd), 5.45 ppm (1H, bs), 5.20-4.83 ppm (2H, bm), 4.25 ppm (1H, dd), 2.61 ppm (1H, dd), 2.44ppm (1H, dd), 1.34 ppm (6H, bd).

[0793] The XRPD pattern of the glycolic acid cocrystal of compound 1 is shown in the figure. Figure 35 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 18.

[0794] Table 18. XRPD peaks of L-malic acid eutectic of compound 1

[0795]

[0796] Example 17: Preparation and characterization of crystalline oxalic acid eutectic of compound 1

[0797] Compound 1 (1 g) and oxalic acid (1 equivalent) were placed in acetone (10 mL), and then water (5 mL) was added. The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and dried at 40 °C.

[0798] oxalic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 36 middle.

[0799] 1 H NMR (DMSO-d 6 ) δ 14.10 ppm (1H, vbs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 ppm and 8,21 ppm (3H, bd s ), 8.04 ppm (1H, bt) 7.68 ppm (1H, bd), 5.20-4.80 ppm (2H, bm), 1.34 ppm (6H, bd).

[0800] The XRPD pattern of the oxalic acid eutectic of compound 1 is shown in the figure. Figure 37 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 19.

[0801] Table 19. XRPD peaks of oxalic acid eutectic of compound 1

[0802]

[0803] Example 18: Preparation and characterization of crystalline benzoic acid eutectic of compound 1

[0804] Compound 1 (2 g) and benzoic acid (1 equivalent) were placed in ethyl acetate (5 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and dried at 40 °C. The eutectic was subjected to XRPD... 1 H NMR analysis.

[0805] Benzoic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 38 middle.

[0806] 1 H NMR (DMSO-d 6 ) δ 12.91 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 ppm and 8.21 ppm (3H, bd s ), 8.04 ppm (1H, bt), 7.95 ppm (2H, m), 7.68 ppm (1H, bd), 7.62 ppm (1H, m), 7.50 ppm (2H, m), 5.20-4.80 ppm (2H, bm), 1.34ppm (6H, bd).

[0807] The XRPD pattern of the benzoic acid eutectic of compound 1 is shown in the figure. Figure 39 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 20.

[0808] Table 20. XRPD peaks of benzoic acid eutectic of compound 1

[0809]

[0810] like Figure 40 As shown, the DSC thermogram of the benzoic acid eutectic of compound 1 contains an endothermic peak with an onset temperature of 128.06℃ and a peak temperature of 130.27℃.

[0811] Example 19: Preparation and characterization of crystalline fumaric acid eutectic of compound 1

[0812] Compound 1 (400 mg) and fumaric acid (1 equivalent) were placed in methanol (1.5 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 3 days, filtered, and dried at 40 °C.

[0813] Fumaric acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 41 middle.

[0814] 1 H NMR (DMSO-d 6 ) δ 13.10 ppm (2H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 ppm and 8.21 ppm (3H, bd s ), 8.04 ppm (1H, bt) 7.68 ppm (1H, bd), 6.63 ppm (2H, s), 5.20-4.80 ppm (2H, bm), 1.34 ppm (6H, d).

[0815] The XRPD pattern of the fumaric acid eutectic of compound 1 is shown in the figure. Figure 42 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 21.

[0816] Table 21. XRPD peaks of the fumaric acid eutectic of compound 1

[0817]

[0818] Example 20: Preparation and characterization of crystalline gentianic acid eutectic of compound 1

[0819] Compound 1 (400 mg) and gentian acid (1 equivalent) were placed in ethyl acetate (1.5 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and dried at 40 °C.

[0820] gentianic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 43 middle.

[0821] 1 H NMR (DMSO-d 6) δ13.75 ppm (1H, bs), 10.65 ppm (1H, bs), 9.12 ppm (1H, s), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 ppm and 8,21 ppm (3H, bds), 8.04ppm (1H, t), 7.68 ppm (1H, bd), 7.15 ppm (1H, bm), 6.95 ppm (1H, bm), 6.78ppm (1H, bm), 5.20-4.82 ppm (2H, bm), 1.34 ppm (6H, bd).

[0822] The XRPD pattern of the gentianic acid cocrystal of compound 1 is shown in the figure. Figure 44 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 22.

[0823] Table 22. XRPD peaks of gentianic acid eutectic of compound 1

[0824]

[0825] Example 21: Preparation and characterization of crystalline glutaric acid eutectic of compound 1

[0826] Compound 1 (400 mg) and glutaric acid (1 equivalent) were placed in ethyl acetate (0.5 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, filtered, and dried at 40 °C.

[0827] Glutaric acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 45 middle.

[0828] 1 H NMR (DMSO-d 6 ) δ 12.05 ppm (1H, s), 8.60 ppm / 8.48 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.03 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82 ppm (2H, bm), 2.24 ppm (4H, bt), 1.70 ppm (2H, qi), 1.34 ppm (6H, bd).

[0829] The XRPD pattern of the glutaric acid eutectic of compound 1 is shown in the figure. Figure 46 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 23.

[0830] Table 23. XRPD peaks of the glutaric acid eutectic of compound 1

[0831]

[0832] Example 22: Preparation and characterization of crystalline orthophosphate of compound 1

[0833] Compound 1 (300 mg) and orthophosphoric acid (1 equivalent) were placed in ethyl acetate (9 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day and then filtered.

[0834] The orthophosphate of compound 1 1 The H NMR spectrum is shown in Figure 47 middle.

[0835] 1 H NMR (DMSO-d 6 ) δ: 9.90 ppm (3H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.89 ppm (1H, bs), 7.68 ppm(1H, bd), 5.20-4.82 ppm (2H, bm s ), 1.34 ppm (6H, bd)

[0836] The XRPD pattern of the orthophosphate of compound 1 is shown in the figure. Figure 48 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 24.

[0837] Table 24. XRPD peaks of orthophosphate of compound 1

[0838]

[0839] Example 23: Preparation and characterization of crystalline 4-hydroxybenzoic acid cocrystal of compound 1

[0840] Compound 1 (300 mg) and 4-hydroxybenzoic acid (1 equivalent) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then kept stirred at 20 °C for 1 day, and then evaporated under nitrogen.

[0841] 4-hydroxybenzoic acid co-crystal of compound 1 1 The H NMR spectrum is shown in Figure 49 middle.

[0842] 1 H NMR (DMSO-d 6 ) δ: 12.39 ppm (1H, bs), 10.20 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.78 ppm (2H, m), 7.68 ppm (1H, bd), 6.81 ppm (2H, m), 5.20-4.82 ppm (2H, bm s ), 1.34ppm (6H, bd).

[0843] The XRPD pattern of the 4-hydroxybenzoic acid cocrystal of compound 1 is shown in the figure. Figure 50 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 25.

[0844] Table 25. XRPD peaks of the 4-hydroxybenzoic acid cocrystal of compound 1

[0845]

[0846] Example 24: Preparation and characterization of crystalline α-ketoglutaric acid eutectic of compound 1

[0847] Compound 1 (300 mg) and α-ketoglutaric acid (1 equivalent) were placed in ethyl acetate (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by evaporation under nitrogen.

[0848] α-ketoglutaric acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 51 middle.

[0849] 1 H NMR (DMSO-d 6) δ: 13.88 ppm (1H, bs), 12.22 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82 ppm (2H, bm s ), 2.99 ppm (4H, bs), 1.34 ppm (6H, bd)

[0850] The XRPD pattern of the α-ketoglutaric acid eutectic of compound 1 is shown in the figure. Figure 52 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 26.

[0851] Table 26. XRPD peaks of the α-ketoglutaric acid cocrystal of compound 1

[0852]

[0853] Example 25: Preparation and characterization of crystalline malonic acid eutectic of compound 1

[0854] Compound 1 (300 mg) and malonic acid (1 equivalent) were placed in ethyl acetate (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by evaporation under nitrogen.

[0855] malonic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 53 middle.

[0856] 1 H NMR (DMSO-d 6 ) δ: 12.62 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82ppm (2H, bm s ), 3.24 ppm (2H, bs), 1.34 ppm (6H, bd)

[0857] The XRPD pattern of the malonic acid eutectic of compound 1 is shown in the figure. Figure 54 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 27.

[0858] Table 27. XRPD peaks of the malonic acid eutectic of compound 1

[0859]

[0860] Example 26: Preparation and characterization of crystalline salicylic acid eutectic of compound 1

[0861] Compound 1 (300 mg) and salicylic acid (1 equivalent) were placed in ethyl acetate (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by evaporation under nitrogen.

[0862] The salicylic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 55 middle.

[0863] 1 H NMR (DMSO-d 6 ) δ: 13.90 ppm (1H, bs), 11.32 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.79 ppm (1H, dd ), 7.68 ppm (1H, bd), 7.51 ppm (1H, ddd ), 6.97-6.89 ppm (2H, m), 5.20-4.82 ppm (2H, bm s ), 1.34 ppm (6H, bd)

[0864] The XRPD pattern of the salicylic acid eutectic of compound 1 is shown in the figure. Figure 56 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 28.

[0865] Table 28. XRPD peaks of the salicylic acid eutectic of compound 1

[0866]

[0867] Example 27: Preparation and characterization of L-tartaric acid eutectic of compound 1

[0868] Compound 1 (150 mg) and L-tartaric acid (1 equivalent) were placed in ethyl acetate (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by evaporation under nitrogen.

[0869] L-tartaric acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 57 middle.

[0870] 1 H NMR (DMSO-d 6 ) δ: 12.66 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82ppm (2H, bm s ), 4.31 ppm (2H, s), 1.34 ppm (6H, bd)

[0871] The XRPD pattern of the L-tartaric acid eutectic of compound 1 is shown in the figure. Figure 58 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 29.

[0872] Table 29. XRPD peaks of L-tartaric acid eutectic of compound 1

[0873]

[0874] Example 28: Preparation and characterization of crystalline urea eutectic of compound 1

[0875] Compound 1 (300 mg) and urea (1 equivalent) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then kept stirred at 20 °C for 1 day, and then evaporated under nitrogen.

[0876] Urea eutectic of compound 1 1 The H NMR spectrum is shown in Figure 59 middle.

[0877] 1 H NMR (DMSO-d 6 ) δ: 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.39 ppm (4H, bs), 5.20-4.82ppm (2H, bm s ), 1.34 ppm (6H, bd)

[0878] The XRPD pattern of the urea cocrystal of compound 1 is shown in the figure. Figure 60 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 30.

[0879] Table 30. XRPD peaks of urea cocrystal of compound 1

[0880]

[0881] Example 29: Preparation and characterization of crystalline pyroglutamic acid cocrystal of compound 1

[0882] Compound 1 (300 mg) and pyroglutamic acid (1 equivalent) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day and then filtered.

[0883] The pyroglutamic acid cocrystal of compound 1 1 The H NMR spectrum is shown in Figure 61 middle.

[0884] 1 H NMR (DMSO-d 6 ) δ: 12.75 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.89 ppm (1H, bs), 7.68 ppm(1H, bd), 5.20-4.82 ppm (2H, bm s ), 4.05 ppm (1H, ddd), 2.40-1.90 ppm (4H, m s ), 1.34 ppm (6H, bd)

[0885] The XRPD pattern of the pyroglutamic acid cocrystal of compound 1 is shown in the figure. Figure 62 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 31.

[0886] Table 31. XRPD peaks of the pyroglutamic acid cocrystal of compound 1

[0887]

[0888] Example 30: Preparation and characterization of crystalline hexanoic acid eutectic of compound 1

[0889] Compound 1 (300 mg) and hexanoic acid (2 equivalents) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then kept stirred at 20 °C for 1 day, and then evaporated under nitrogen.

[0890] hexanoic acid eutectic of compound 1 1 The H NMR spectrum is shown in Figure 63 middle.

[0891] 1 H NMR (DMSO-d 6 ) δ: 11.95 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82ppm (2H, bm s ), 2.18 ppm (1H, t), 1.49 ppm (2H, qi), 1.40-1.20 ppm (4H, m s ),1.34 ppm (6H, bd), 0.86 ppm (3H, t)

[0892] The XRPD pattern of the hexanoic acid eutectic of compound 1 is shown in the figure. Figure 64 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 32.

[0893] Table 32. XRPD peaks of the hexanoic acid eutectic of compound 1

[0894]

[0895] Example 31: Preparation and characterization of crystalline glycerol eutectic of compound 1

[0896] Compound 1 (300 mg) and glycerol (1 equivalent) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then stirred at 20 °C for 1 day, followed by evaporation under nitrogen.

[0897] glycerol eutectic of compound 1 1 The H NMR spectrum is shown in Figure 65 middle.

[0898] 1 H NMR (DMSO-d 6) δ: 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82 ppm (2H, bm s ), 4.44ppm (1H, d), 4.36 ppm (2H, t), 3.42 ppm (1H, qi), 3.36 ppm (2H, td), 3.28 ppm (2H, td), 1.34 ppm (6H, bd)

[0899] The XRPD pattern of the glycerol cocrystal of compound 1 is shown in the figure. Figure 66 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 33.

[0900] Table 33. XRPD peaks of the glycerol cocrystal of compound 1

[0901]

[0902] Example 32: Preparation and characterization of crystalline L-lysine cocrystal of compound 1

[0903] Compound 1 (300 mg) and L-lysine (2 equivalents) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then kept stirred at 20 °C for 1 day, followed by evaporation under nitrogen.

[0904] L-lysine cocrystal of compound 1 1 The H NMR spectrum is shown in Figure 67 middle.

[0905] 1 H NMR (DMSO-d 6 ) δ: 8.41 ppm / 7.95 ppm / 7.61 ppm (3H, m s ), 5.41-4.92ppm (2H, bm s ), 3.36 ppm (1H, t), 2.80 ppm (2H, t), 1.83-1.65 ppm (2H, m), 1.60 ppm (2H, qi), 1.50-1.36 ppm (2H, m), 1.41 ppm (6H, bm)

[0906] The XRPD pattern of the L-lysine cocrystal of compound 1 is shown in the figure. Figure 68 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 34.

[0907] Table 34. XRPD peaks of L-lysine cocrystal of compound 1

[0908]

[0909] Example 33: Preparation and characterization of S-proline cocrystal of compound 1

[0910] Compound 1 (300 mg) and S-proline (1 equivalent) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then kept stirred at 20 °C for 1 day, and then evaporated under nitrogen.

[0911] S-proline cocrystal of compound 1 1 The H NMR spectrum is shown in Figure 69 middle.

[0912] 1 H NMR (DMSO-d 6 ) δ: 8.60 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82ppm (2H, bm s ), 3.64 ppm (1H, dd), 3.20 ppm (1H, m), 3.00 ppm (1H, td), 1.97ppm (2H, m), 1.73 ppm (2H, m), 1.34 ppm (6H, bd)

[0913] The XRPD pattern of the S-proline cocrystal of compound 1 is shown in the figure. Figure 70 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 35.

[0914] Table 35. XRPD peaks of S-proline cocrystal of compound 1

[0915]

[0916] Example 34: Preparation and characterization of crystalline pyruvate eutectic of compound 1

[0917] Compound 1 (300 mg) and pyruvate (2 equivalents) were placed in methanol (3 mL). The mixture was stirred and heated to 50 °C at 1 °C / min, followed by stirring at 50 °C for 2 hours, and then cooled to 20 °C at 0.1 °C / min. The mixture was then kept stirred at 20 °C for 1 day, and then evaporated under nitrogen.

[0918] pyruvate eutectic of compound 1 1 The H NMR spectrum is shown in Figure 71 middle.

[0919] 1 H NMR (DMSO-d 6 ) δ: 13.78 ppm (1H, bs), 8.60 ppm / 8.49 ppm / 8.35 ppm / 8.25 and 8.21 ppm (3H, bds), 8.04 ppm (1H, t), 7.68 ppm (1H, bd), 5.20-4.82ppm (2H, bm s ), 2.34 ppm (3H, s), 1.34 ppm (6H, bd)

[0920] The XRPD pattern of the pyruvate cocrystal of compound 1 is shown in the figure. Figure 72 The peak positions, peak heights, and relative intensities in the XRPD spectra are listed in Table 36.

[0921] Table 36. XRPD peaks of the pyruvate cocrystal of compound 1

[0922]

[0923] Example 35: Amorphous solid dispersion (ASD) of compound 1 in solid form

[0924] Compound 1 in solid form (salt, eutectic, or free form) (10 mg) was placed in tert-butanol (10 mL), and then water (1 mL) was added to completely dissolve it at room temperature. HPMCAS (40 mg) was dissolved in tert-butanol (20 mL) at room temperature. The two solutions were mixed, and the final solution was freeze-dried under a vacuum of 0.05 mbar to obtain an amorphous powder.

[0925] The amorphous powder was subjected to modulated DSC analysis to determine the anhydrous glass transition temperature (Table 37).

[0926] Table 37

[0927]

[0928] Developing amorphous solid dispersions (ASDs) is a formulation strategy commonly used for poorly soluble drug substances, such as compound 1.

[0929] ASDs can allow for reduced dosages or increased drug loadings in pharmaceutical products. They can also offer further possibilities if the pharmaceutical composition is required to meet specific requirements, such as if it is intended for pediatric populations or patients experiencing difficulty swallowing tablets (because ASDs allow for smaller tablet sizes).

[0930] ASD also allows for the use of innovative technologies such as 3D printing, which could help provide patients with personalized formulations. Compared to conventional tablet presses, printed pills can be coated to have a more porous surface, which helps them dissolve faster and eliminates the need for additional liquid intake.

[0931] For amorphous solid dispersions (ASDs), a high glass transition temperature (Tg) generally indicates better stability. Increasing the Tg value of ASDs may be valuable in ensuring better stability of the resulting ASDs and maximizing their potential applications.

[0932] Polymer selection is an important aspect of ASD formulations. In some cases, polymer selection can be made for other specific characteristics (such as controlled release properties), resulting in ASDs with low Tg values ​​and therefore potentially poor stability.

[0933] The method used in this study was to adjust the solid phase of the drug through salt formation or co-crystallization in order to improve the Tg value of the resulting ASD. The results highlight that salt formation of compound 1 is an interesting solution for improving the Tg value of the resulting ASD.

Claims

1. Pharmaceutically acceptable salts of compounds of formula (I) Its features The pharmaceutically acceptable salt is formed using benzenesulfonic acid, (+)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, hydrobromic acid, hydrochloric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, sulfuric acid, or phosphoric acid.

2. The pharmaceutically acceptable salt according to claim 1, characterized in that... The pharmaceutically acceptable salt is crystalline.

3. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using benzenesulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.83, 8.17, 14.40, and 17.

90.

4. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using (+)-camphor-10-sulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.29, 10.19, 12.07, 18.12 and 19.

97.

5. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using ethane-1,2-disulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.59, 14.75, 18.08 and 18.

87.

6. The pharmaceutically acceptable salt according to claim 5, characterized in that... The ethane-1,2-disulfonate is characterized in that the differential scanning calorimetry (DSC) thermogram includes an endothermic peak with an onset temperature of 304.30 °C (±2.0 °C).

7. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using ethanesulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 6.86, 13.97, 14.27, 17.00 and 17.

72.

8. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using hydrobromic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.74, 8.56, 13.63, 14.90, and 15.

08.

9. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using hydrochloric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.73, 9.71, 13.78, 14.64 and 16.

25.

10. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using naphthalene-1,5-disulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.52, 13.79, 14.17, 19.28, 19.63 and 19.

97.

11. The pharmaceutically acceptable salt according to claim 10, characterized in that... The naphthalene-1,5-disulfonate is characterized in that the differential scanning calorimetry (DSC) thermogram contains an endothermic peak with an onset temperature of 324.30 °C (±2.0 °C).

12. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using naphthalene-2-sulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 8.41, 13.65, 26.09 and 26.

47.

13. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using p-toluenesulfonic acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.29, 8.37, 8.66, 12.96, 13.47, 20.42, and 20.

64.

14. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using sulfuric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 5.80, 8.50, 13.62, 14.21, 14.87, and 18.

04.

15. The pharmaceutically acceptable salt according to claim 2, characterized in that... The pharmaceutically acceptable salt is formed using orthophosphoric acid, and the X-ray powder diffraction pattern contains at least two peak positions selected from the following (in 2θ degrees, ±0.2 2θ degrees): 3.65, 5.47, 7.04, 11.01, 14.27, 14.69, 14.91, and 18.

35.

16. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 1-15 and one or more pharmaceutical excipients.

17. The pharmaceutical composition according to claim 16, characterized in that... The pharmaceutical composition contains 1-10% w / w of a compound of formula (I).

18. The pharmaceutical composition according to claim 16 or 17, characterized in that... The pharmaceutical composition is in an orally acceptable dosage form and comprises about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg or about 300 mg of a compound of formula (I).

19. The pharmaceutical composition according to claim 18, characterized in that... The pharmaceutical composition contains about 10 mg or about 40 mg of a compound of formula (I).

20. An amorphous solid dispersion prepared from a pharmaceutically acceptable salt and a polymer according to any one of claims 1-15.

21. The amorphous solid dispersion prepared from a pharmaceutically acceptable salt according to claim 20, characterized in that... The polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate, and polyvinylpyrrolidone (PVP) or mixtures thereof.

22. The amorphous solid dispersion prepared from a pharmaceutically acceptable salt according to claim 21, characterized in that... The polymer is HPMCAS.

23. A pharmaceutical composition comprising a solid dispersion according to any one of claims 20 to 22 and one or more acceptable excipients.

24. A method for preparing a pharmaceutically acceptable salt according to claim 1, the method comprising: - Dissolve the compound of formula (I) and a pharmaceutically acceptable acid in a solvent to obtain a solution; and - Precipitate the corresponding salt.

25. A method for preparing a pharmaceutically acceptable crystalline salt according to claim 2, the method comprising: - Dissolve the compound of formula (I) and a pharmaceutically acceptable acid in a solvent to obtain a solution; and - The corresponding salt in precipitated crystalline form.

26. The method according to claim 25, characterized in that... Add seed crystals to the solution.

27. The method according to any one of claims 24 to 26, characterized in that... The solvent is a polar organic solvent selected from methanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran (THF), or n-butanol.

28. The method according to any one of claims 24 to 26, characterized in that The solvent is a mixture of acetone and water.

29. A pharmaceutically acceptable salt according to any one of claims 1-15, or a pharmaceutical composition according to any one of claims 16 to 19 or 23, or an amorphous solid dispersion according to any one of claims 20 to 22, for the treatment of cancers characterized by the presence of IDH1 and / or IDH2 mutations.

30. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 29, characterized in that... The cancer is characterized by the presence of an IDH1 mutation.

31. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 30, characterized in that... The IDH1 mutation is the R132X mutation.

32. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 31, characterized in that... The IDH1 mutation is an R132H, R132C, R132S, R132L, or R132G mutation.

33. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 30 to 32, characterized in that... The IDH1 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

34. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 29, characterized in that... The cancer is characterized by the presence of an IDH2 mutation.

35. The pharmaceutically acceptable salt for the said use according to claim 34, characterized in that... The IDH2 mutation is the R140X mutation.

36. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 35, characterized in that... The IDH2 mutation is R140Q, R140W, or R140L.

37. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 34, characterized in that... The IDH2 mutation is the R172X mutation.

38. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 37, characterized in that... The IDH2 mutation is either an R172K or R172G mutation.

39. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 34 to 38, characterized in that... The IDH2 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

40. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 29 to 39, characterized in that... The cancer is characterized by the presence of IDH1 and IDH2 mutations.

41. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 40, characterized in that... The IDH1 and IDH2 mutations together lead to the accumulation of R(-)-2-hydroxyglutaric acid in the patient.

42. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 29 to 39, characterized in that... The cancer in question is a brain tumor.

43. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 42, characterized in that... The brain tumor is a glioma.

44. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 43, characterized in that... The glioma is either a low-grade glioma or a secondary high-grade glioma.

45. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to claim 43 or 44, characterized in that... The glioma is a secondary high-grade glioma, and the secondary high-grade glioma is a glioblastoma.

46. ​​The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 29 to 45, characterized in that... The pharmaceutically acceptable salt is administered in combination with other treatments.

47. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 29 to 46, characterized in that, Based on the amount of the compound of formula (I), the amount of the pharmaceutically acceptable salt to be administered is about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg per day.

48. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 29 to 46, characterized in that, Based on the amount of the compound of formula (I), the amount of the pharmaceutically acceptable salt to be administered is about 10 mg, about 20 mg, or about 40 mg per day.

49. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for said use according to any one of claims 29 to 46, characterized in that, Based on the amount of the compound of formula (I), the pharmaceutically acceptable amount of the salt to be administered is about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg, twice daily.

50. The pharmaceutically acceptable salt, pharmaceutical composition, or amorphous solid dispersion for the said use according to any one of claims 29 to 46, characterized in that, Based on the amount of the compound of formula (I), the pharmaceutically acceptable amount of the salt to be administered is about 10 mg, about 20 mg, or about 40 mg twice daily.

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