Cocrystals, pharmaceutical compositions thereof, and methods of treatment involving same

Abstract

To provide solid forms of a compound, drug substances comprising the same, pharmaceutical compositions comprising the same, methods of preparing the same, and treatment methods therewith.SOLUTION: The invention provides a crystalline form of a compound of formula (I), where the crystalline form has an X-ray powder diffraction pattern including peak positions, in degrees 2-theta (±0.2 degrees 2-theta), of 11.7, 17.8 and 21.8, and at least three peak positions selected from the group consisting of 12.8, 14.2, 19.8, 20.7, 22.2, and 25.0.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) and the other NADP(+) as the electron acceptor. Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases localized in the mitochondrial matrix, and two NADP(+)-dependent dehydrogenases, one mitochondrial and the other primarily cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

[0002] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) 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. The protein contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests a role in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA, as well as in the alpha-hydroxylation of phytanic acid, a peroxisomal reaction that consumes 2-oxoglutarate. The cytosolic enzyme plays a significant role in cytosolic NADPH production.

[0003] The human IDH1 gene encodes a protein consisting of 414 amino acids. The nucleotide and amino acid sequences for human IDH1 can be found in GenBank accessions NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences for IDH1 can be found, for example, in 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 to UniProtKB (December 2008), Kullmann et al., submitted to the EMBL / GenBank / DDBJ database (June 1996), and Sjoeblom et al., Science 314:268-274 (2006).

[0004] Non-mutant, eg, wild-type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate.

[0005] Mutations in IDH1 present in certain cancer cells have been found to result in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is thought to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44).

[0006] IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) 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. The protein is involved in the intermediate It plays a role in metabolism and energy production. This protein may be closely related to or interact with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a protein consisting of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found in GenBank accessions 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., submitted to the EMBL / GenBank / DDBJ database (November 1992), and in The MGC Project Team, Genome Res. 14:2121-2127 (2004).

[0007] Non-mutant, eg, wild-type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). It has been discovered that mutations in IDH2 present in certain cancer cells result in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), which is not formed by wild-type IDH2. The production of 2HG is thought to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44). U.S. Publication No. 2015 / 0018328 A1 discloses a compound having the chemical name 6-(6-chloropyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, which have been shown to act as inhibitors of mutant IDH1 and IDH2 proteins in biochemical and cellular assays. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US Patent Application Publication No. 2015 / 0018328 [Non-patent literature]

[0009] [Non-Patent Document 1] Nekrutenko et al.,Mol.Biol.Evol.15:1674-1684(1998) [Non-patent document 2] Geisbrecht et al.,J.Biol.Chem.274:30527-30533(1999) [Non-patent document 3] Wiemann et al.,Genome Res.11:422-435(2001) [Non-patent document 4] The MGC Project Team,Genome Res.14:2121-2127(2004) [Non-patent document 5] Sjoeblom et al.,Science 314:268-274(2006) [Non-patent document 6] Dang,L et al.,Nature 2009,462:739-44 Summary of the Invention

[0010] The present disclosure relates to solid forms (e.g., co-crystals and other crystalline forms) of compounds of formula (I). [ka]

[0011] In one aspect, the present disclosure relates to a co-crystal comprising a compound of formula (I) and citric acid.

[0012] In another aspect, the present disclosure relates to a co-crystal comprising a compound of formula (I) and maleic acid.

[0013] In other aspects, the present disclosure relates to crystalline forms of the free compound of formula (I).

[0014] In another aspect, the present disclosure relates to a drug substance comprising a solid form of the compound of formula (I).

[0015] In another aspect, the present disclosure relates to methods of preparing crystalline forms of the compound of formula (I).

[0016] In another aspect, the present application relates to a pharmaceutical composition comprising a solid form of the compound of formula (I) and one or more pharmaceutical excipients.

[0017] In another aspect, the application relates to a method of treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a solid form of the compound of (I) or a pharmaceutical composition thereof. [Brief explanation of the drawings]

[0018] [Figure 1] Figure 1 shows the one-dimensional 1H NMR spectrum of compound 1 in CD3OD measured over the temperature range of 25 °C to 85 °C. [Figure 2] Figure 2 shows a portion of the one-dimensional 1H NMR spectrum of compound 1 in CD3OD measured over the temperature range 25 °C to 85 °C. [Figure 3] FIG. 3 shows the one-dimensional 1H NMR spectrum of compound 1 in DMSO-d6. [Figure 4] FIG. 4 shows the one-dimensional 13H NMR spectrum of compound 1 in DMSO-d6. [Figure 5] FIG. 5 shows the one-dimensional NOE-enhanced 13N NMR spectrum of compound 1 in DMSO-d6. [Figure 6] FIG. 6 shows the X-ray powder diffraction (XRPD) pattern of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 11. [Figure 7] FIG. 7 shows the H nuclear magnetic resonance (NMR) spectrum of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 11. [Figure 8]FIG. 8 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of citric acid co-crystal Type A of compound of formula (I), prepared as described in Example 11. [Figure 9] FIG. 9 shows a dynamic vapor sorption (DVS) isotherm plot of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 11. [Figure 10] FIG. 10 shows the Oak Ridge Thermal Ellipsoid Plot (ORTEP) of a single crystal of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 12. [Figure 11] FIG. 11 shows a unit cell diagram of a single crystal of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 12. [Figure 12] FIG. 12 shows the X-ray powder diffraction (XRPD) pattern of maleic acid co-crystal Type A of compound of formula (I), prepared as described in Example 13. [Figure 13] FIG. 13 shows the H nuclear magnetic resonance (NMR) spectrum of maleic acid co-crystal Type A of the compound of formula (I), prepared as described in Example 13. [Figure 14] FIG. 14 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of maleic acid co-crystal Type A of compound of formula (I), prepared as described in Example 13. [Figure 15] FIG. 15 shows a dynamic vapor sorption (DVS) isotherm plot of maleic acid co-crystal Type A of the compound of formula (I), prepared as described in Example 13. [Figure 16] FIG. 16 shows the H NMR spectrum of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 14. [Figure 17] FIG. 17 shows the C NMR spectrum of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 14. [Figure 18]FIG. 18 shows the Fourier transform infrared (FTIR) spectrum of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 14. [Figure 19] FIG. 19 shows the ultraviolet (UV) / visible spectrum of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 14. [Figure 20] FIG. 20 shows the XRPD pattern of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 14. [Figure 21] FIG. 21 shows a DSC thermogram of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 14. [Figure 22] FIG. 22 shows a TGA thermogram of citric acid co-crystal Type A of the compound of formula (I), prepared as described in Example 14. [Figure 23] FIG. 23 shows the XRPD pattern of the free form Type A of the compound of formula (I), prepared as described in Example 17. [Figure 24] FIG. 24 shows the DSC thermogram of the free form Type A of the compound of formula (I), prepared as described in Example 17. [Figure 25] FIG. 25 shows the TGA thermogram of the free form Type A of the compound of formula (I), prepared as described in Example 17. [Figure 26] FIG. 26 shows the Oak Ridge Thermal Ellipsoid Plot (ORTEP) of edge crystals of free form Type A of compound of formula (I), prepared as described in Example 18. [Figure 27] FIG. 27 shows a unit cell diagram of a single crystal of free form Type A of the compound of formula (I), prepared as described in Example 18. [Figure 28] FIG. 28 shows the XRPD pattern of the free form Type B of the compound of formula (I), prepared as described in Example 19. [Figure 29]FIG. 29 shows the DSC and TGA thermograms of the free form Type B of the compound of formula (I), prepared as described in Example 19. [Figure 30] FIG. 30 shows the Oak Ridge Thermal Ellipsoid Plot (ORTEP) of a single crystal of free form Type B of the compound of formula (I), prepared as described in Example 20. [Figure 31] FIG. 31 shows a unit cell diagram of a single crystal of free form Type B of the compound of formula (I), prepared as described in Example 20. [Figure 32] FIG. 32 shows the XRPD pattern of the free form Type C of the compound of formula (I), prepared as described in Example 21. [Figure 33] FIG. 33 shows the DSC and TGA thermograms of the free form Type C of the compound of formula (I), prepared as described in Example 21. [Figure 34] FIG. 34 shows the Oak Ridge Thermal Ellipsoid Plot (ORTEP) of a single crystal of the free form Type C of the compound of formula (I), prepared as described in Example 22. [Figure 35] FIG. 35 shows a unit cell diagram of a single crystal of free form Type C of the compound of formula (I), prepared as described in Example 22. [Figure 36] FIG. 36 shows the XRPD pattern of the free form Type D of the compound of formula (I), prepared as described in Example 23. [Figure 37] FIG. 37 shows the DSC and TGA thermograms of the free form Type D of the compound of formula (I), prepared as described in Example 23. [Figure 38] FIG. 38 shows the 1H NMR spectrum of the free form Type D of the compound of formula (I), prepared as described in Example 23. [Figure 39] FIG. 39 shows the mean plasma concentration time profiles of Compound 1 measured in the pharmacokinetic study described in Example 25. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present disclosure relates to solid forms of the compound of formula (I) as defined herein, drug substances comprising same, pharmaceutical compositions comprising same, methods of preparing same, and methods of treatment involving same.

[0020] As used herein, compounds of formula (I) include compounds having the specified chemical structure as well as any tautomers or rotamers thereof.

[0021] In this specification and claims, each atom of the compounds of formula (I) is meant to represent any stable isotope of the specified element. In the examples, no effort was made to enrich any atom of compound 1 in a particular isotope, and therefore each atom was likely present in the isotopic composition of about the natural abundance of the specified element.

[0022] 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, isotopes whose decay mode is not specified in the Table of Nuclides, V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, January 1980.

[0023] In some embodiments, the compounds of formula (I) contain each constituent atom in an isotopic composition at about the natural abundance of the specified element.

[0024] solid form In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a cocrystal containing citric acid (hereinafter referred to as "citric acid cocrystal").

[0025] As used herein, the term "cocrystal" refers to a crystalline solid consisting of two or more neutral chemical species in a defined stoichiometric ratio that have distinct crystallographic and spectroscopic properties when compared to the species individually. A "cocrystal" differs from a "salt," which consists of charge-balanced charged species. The species that make up a cocrystal are typically linked by hydrogen bonds and other non-covalent and non-ionic interactions. Thus, the pharmaceutical cocrystal of a drug The crystal typically comprises a drug and one or more coformers. The combination of drug and coformer(s) that forms a cocrystal generally cannot be predicted a priori, and cocrystal formation typically affects the physicochemical properties of the drug in unpredictable ways.

[0026] As used herein, the term "crystalline" refers to a solid material in which the constituent particles (eg, molecules) are spatially arranged in an orderly and repeating lattice.

[0027] In another embodiment, the citric acid co-crystal is citric acid co-crystal Type A.

[0028] In some embodiments, citric acid cocrystal Type A is characterized by an X-ray powder diffraction pattern, obtained in reflectance mode (sometimes referred to as reflectance mode), comprising one or more peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the peak positions set forth below in Tables 7 and 11. In other embodiments, the X-ray powder diffraction pattern comprises at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. In other embodiments, the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. In other embodiments, the X-ray powder diffraction pattern comprises at least three peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. In other embodiments, the X-ray powder diffraction pattern comprises at least four peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at 5.7 and 8.4 degrees 2-theta (±0.2 degrees 2-theta), and at least three peak positions selected from the group consisting of 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at degrees 2-theta (±0.2 degrees 2-theta) at 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at degrees 2-theta (±0.2 degrees 2-theta) set forth in Table 7. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at degrees 2-theta (±0.2 degrees 2-theta) set forth in Table 11. In other embodiments, the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in FIG.In other embodiments, the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in FIG.

[0029] As used herein, when an X-ray powder diffraction pattern is described as having a particular number of peak positions "in degrees 2-theta (±0.2 degrees 2-theta)" selected from a particular group of peak positions, it is to be understood that a margin of error (±0.2 degrees 2-theta) applies to each peak position within the group.

[0030] As used herein, the term "similar," when referring to two or more X-ray powder diffraction patterns, means that the patterns would be understood by one of ordinary skill in the art to represent the same crystalline form, and that the patterns are identical except for variations of the type that would be expected by one of ordinary skill in the art to result from experimental variations in the instruments used, time of day, humidity, season, pressure, temperature, etc.

[0031] In some embodiments, citric acid co-crystal Type A is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 170.6° C. (±5.0° C.). In other embodiments, citric acid co-crystal Type A is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 170.6° C. (±2.0° C.). It is characterized by a differential scanning calorimetry thermogram containing an endothermic peak having a temperature.

[0032] In some embodiments, citric acid co-crystal Type A further comprises water.

[0033] In some embodiments, citric acid co-crystal Type A includes the compound of Formula (I), citric acid, and water in a molar ratio of 2:1:1. One of ordinary skill in the art will understand that the measured molar ratio of the compound of Formula (I), citric acid, and water in a given co-crystal sample may vary slightly from 2:1:1 due to experimental error associated with available analytical methods, the presence of impurities (e.g., water or citric acid not incorporated into the crystal lattice), etc. It will be understood that a co-crystal having a molar ratio of the compound of Formula (I), citric acid, and water of 2:1:1 is within the scope of this embodiment, even if the measured ratio varies slightly from 2:1:1.

[0034] In some embodiments, citric acid co-crystal Type A contains four molecules of the compound of formula (I), two molecules of citric acid, and two molecules of water per cell.

[0035] As used herein, the term "unit cell" refers to the smallest grouping of particles (e.g., molecules) in a crystalline solid that make up the repeating pattern of the crystalline solid. In a eutectic crystal, the term "unit cell" refers to the smallest grouping of two or more neutral chemical species that make up the repeating pattern of the cocrystal.

[0036] As discussed in more detail in the Examples, citric acid co-crystal Type A was found to have a variety of favorable physicochemical properties, including high crystallinity, a sharp melting endotherm, and low hygroscopicity, and favorable bioavailability.

[0037] In another aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a cocrystal containing maleic acid (hereinafter referred to as "maleic acid cocrystal").

[0038] In another embodiment, the maleic acid co-crystal is maleic acid co-crystal Type A.

[0039] In some embodiments, maleic acid cocrystal Type A is characterized by an X-ray powder diffraction pattern, obtained in reflection mode (sometimes referred to as reflectance mode), comprising one or more peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the peak positions set forth in Table 9 below. In other embodiments, the X-ray powder diffraction pattern comprises at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. In other embodiments, the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. In other embodiments, the X-ray powder diffraction pattern has a raster of 1.0, 1.2, 1.6, 1.8, 1.9, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 ... In other embodiments, the X-ray powder diffraction pattern comprises at least three peak positions at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2 (±0.2 degrees two-theta). In other embodiments, the X-ray powder diffraction pattern comprises peak positions at 8.1, 17.8, and 18.5 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 5.9, 15.0, 15.2, 16.9, 21.1, 23.4, 26.9, and 28.2. In other embodiments, the X-ray powder diffraction pattern comprises peak positions in degrees 2-theta (±0.2 degrees 2-theta) at: 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. In other embodiments, the X-ray powder diffraction pattern comprises peak positions in degrees 2-theta (±0.2 degrees 2-theta) set forth in Table 9. In other embodiments, the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in FIG.

[0040] In some embodiments, maleic acid co-crystal Type A is characterized by a differential scanning calorimetry thermogram comprising endothermic peaks with onset temperatures of 91.2° C. and 128.4° C. (±5.0° C.). In other embodiments, maleic acid co-crystal Type A is characterized by a differential scanning calorimetry thermogram comprising endothermic peaks with onset temperatures of 91.2° C. and 128.4° C. (±2.0° C.).

[0041] In some embodiments, maleic acid co-crystal Type A includes the compound of Formula (I) and maleic acid in a 1:1 molar ratio. One of ordinary skill in the art will understand that the measured molar ratio of the compound of Formula (I) and maleic acid in a given co-crystal sample may vary slightly from 1:1 due to experimental error associated with available analytical methods, the presence of impurities (e.g., maleic acid not incorporated into the crystal lattice), etc. It will be understood that a co-crystal having a 1:1 molar ratio is within the scope of this embodiment even if the measured ratio of the compound of Formula (I):maleic acid varies slightly from 1:1.

[0042] In another aspect, the present disclosure relates to a crystalline form of the compound of formula (I), sometimes referred to as Free Form Type A, [ka] The crystalline form is characterized by an X-ray powder diffraction pattern, obtained in reflection mode (sometimes called reflectance mode), comprising one or more peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the peak positions set forth in Table 15 below. In other embodiments, the X-ray powder diffraction pattern comprises at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. In some embodiments, the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. In other embodiments, the X-ray powder diffraction pattern has a resolution of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0 degrees 2-theta (±0.05). In other embodiments, the X-ray powder diffraction pattern comprises at least two peak positions at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. In other embodiments, the X-ray powder diffraction pattern comprises at least three peak positions at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. In other embodiments, the X-ray powder diffraction pattern comprises at least four peak positions at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at 11.7, 17.8, and 21.8 degrees 2-theta (±0.2 degrees 2-theta), and at least three peak positions selected from the group consisting of 12.8, 14.2, 19.8, 20.7, 22.2, and 25.0. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0 degrees 2-theta (±0.2 degrees 2-theta). In other embodiments, the X-ray powder diffraction pattern comprises peak positions at degrees 2-theta (±0.2 degrees 2-theta) set forth in Table 15. In other embodiments, the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in FIG. 23.

[0043] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.9° C. (±5.0° C.). In some embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an onset temperature of 221.9° C. (±2.0° C.).

[0044] In another aspect, the present disclosure relates to a crystalline form of the compound of formula (I), sometimes referred to as Free Form Type B, [ka] The crystalline form is characterized by an X-ray powder diffraction pattern, obtained in reflection mode (sometimes called reflectance mode), comprising one or more peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the peak positions set forth in Table 19 below. In other embodiments, the X-ray powder diffraction pattern comprises at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. In some embodiments, the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. In other embodiments, the X-ray powder diffraction pattern comprises at least three peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. In other embodiments, the X-ray powder diffraction pattern comprises at least four peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. In other embodiments, the X-ray powder diffraction pattern comprises at least four peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 17.8, and 23.9 degrees 2-theta (±0.2 degrees 2-theta). , and 26.5. In other embodiments, the X-ray powder diffraction pattern comprises peak positions in degrees 2-theta (±0.2 degrees 2-theta) at: 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. In other embodiments, the X-ray powder diffraction pattern comprises peak positions in degrees 2-theta (±0.2 degrees 2-theta) set forth in Table 19. In other embodiments, the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in Figure 28.

[0045] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.5° C. (±5.0° C.). In some embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an onset temperature of 221.5° C. (±2.0° C.).

[0046] In some embodiments, the crystalline form is anhydrous.

[0047] In another aspect, the present disclosure relates to a crystalline form of the compound of formula (I), sometimes referred to as free form type C, [ka] The crystalline form is characterized by an X-ray powder diffraction pattern, obtained in reflection mode (sometimes called reflectance mode), comprising one or more peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the peak positions set forth in Table 21 below. In other embodiments, the X-ray powder diffraction pattern comprises at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. In some embodiments, the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. In other embodiments, the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. In other embodiments, the X-ray powder diffraction pattern comprises at least three peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. In other embodiments, the X-ray powder diffraction pattern comprises at least four peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at 8.6 and 21.1 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9 degrees two-theta (±0.2 degrees two-theta). In other embodiments, the X-ray powder diffraction pattern comprises peak positions at degrees two-theta (±0.2 degrees two-theta) set forth in Table 21. In other embodiments, the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in FIG. 32.

[0048] In some embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.3° C. (±5.0° C.). In some embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an onset temperature of 221.3° C. (±2.0° C.).

[0049] In some embodiments, the crystalline form is a trihydrate.

[0050] In another aspect, the present disclosure relates to a crystalline form of the compound of formula (I), sometimes referred to as Free Form Type D, [ka] The crystalline form is characterized by an X-ray powder diffraction pattern, obtained in reflection mode (sometimes called reflectance mode), comprising one or more peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the peak positions set forth below in Table 23. In other embodiments, the X-ray powder diffraction pattern comprises at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. In some embodiments, the X-ray powder diffraction pattern comprises at least two peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. In other embodiments, the X-ray powder diffraction pattern comprises at least two peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. In other embodiments, the X-ray powder diffraction pattern comprises at least three peak locations in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. In other embodiments, the X-ray powder diffraction pattern comprises at least four peak locations in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. In other embodiments, the X-ray powder diffraction pattern comprises peak positions at 15.9, 16.7, and 21.2 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 17.9, 20.3, 24.9, 26.6, and 27.0.In other embodiments, the X-ray powder diffraction pattern comprises peak positions in degrees 2-theta (±0.2 degrees 2-theta) at: 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. In other embodiments, the X-ray powder diffraction pattern comprises peak positions in degrees 2-theta (±0.2 degrees 2-theta) set forth in Table 23. In other embodiments, the X-ray powder diffraction pattern is similar to the X-ray powder diffraction pattern shown in Figure 36.

[0051] In some embodiments, the crystalline form has an onset temperature of 221.3°C (± 5.0°C). In some embodiments, the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 221.3° C. (±2.0° C.).

[0052] In some embodiments, the crystalline form is a dioxane solvate.

[0053] In another aspect, the present disclosure provides a compound of formula (I): [ka] and a polymer.

[0054] As used herein, the term "dispersion" refers to a disperse system in which one substance (the dispersed phase) is distributed in discrete units throughout a second substance (the continuous phase or vehicle). Generally, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed and continuous phases are solids.

[0055] As used herein, the term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, usually a therapeutically active compound and a polymer(s), but optionally containing other components such as surfactants or other pharmaceutical excipients, wherein the therapeutically active compound is in the amorphous phase. In some embodiments, the amorphous solid dispersion comprises a polymer(s) (and optionally a surfactant) that constitutes the dispersed phase, and the therapeutically active compound constitutes the continuous phase. In some embodiments, the amorphous solid dispersion comprises a polymer(s) (and optionally a surfactant) that constitutes the continuous phase, and the therapeutically active compound constitutes the dispersed phase.

[0056] In some embodiments, the polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethyl cellulose, cellulose acetate phthalate, and polyvinylpyrrolidone (PVP), or mixtures thereof. In other embodiments, the polymer is HPMCAS.

[0057] In some embodiments, the polymer is present in the amorphous solid dispersion in an amount of about 10% w / w to about 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 solid amorphous dispersion in an amount of from about 10% w / w to about 80% w / w, e.g., from about 30% w / w to about 75% w / w, or from about 40% w / w to about 65% w / w, or from about 45% w / w to about 55% w / w, e.g., 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 polymer (or one or more polymers) 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 or about 52.5% w / w in the amorphous solid dispersion.

[0058] 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 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 compound of Formula (I) is present in the amorphous solid dispersion in an amount of from about 10% w / w to about 80% w / w, e.g., from about 30% w / w to about 75% w / w, or from about 40% w / w to about 65% w / w, or from about 45% w / w to about 55% w / w, e.g., 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 solid amorphous 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.

[0059] In some embodiments, the amorphous solid dispersion further comprises a surfactant. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate (SLS), vitamin E or a derivative thereof (e.g., vitamin E TPGS), docusate sodium, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, Pluronic® copolymers (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof. In some embodiments, the surfactant is SLS.

[0060] In some embodiments, the surfactant is present in the amorphous solid dispersion in an amount of about 0.1% w / w to about 10% w / w, e.g., about 0.5% w / w to about 2% w / w, or about 1% w / w to about 3% w / w, or 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 in 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 in 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.

[0061] In some embodiments, the amorphous solid dispersion comprises a compound of Formula (I) and HPMCAS. In some embodiments, the amorphous solid dispersion consists essentially of a compound of Formula (I) and HPMCAS. In some embodiments, the amorphous solid dispersion consists of a compound of Formula (I) and HPMCAS. In some embodiments, the compound of Formula (I) and HPMCAS are present in a weight ratio of about 3:1 to about 1:3, or about 2:1 to about 1:2, or about 1.5:1 to about 1:1.5. In some embodiments, the compound of Formula (I) and HPMCAS are present in a weight ratio of about 1:1.

[0062] In some embodiments, the amorphous solid dispersion has a glass transition temperature (T g In other embodiments, the amorphous solid dispersion has a T of about 80°C to about 130°C, about 80°C to about 120°C, about 80°C to about 100°C, or about 80°C to about 90°C. g It has.

[0063] drug substance The present disclosure also relates to drug substances comprising solid forms of the compounds of formula (I) described herein.

[0064] As used herein, the term "drug substance" refers to an active pharmaceutical ingredient. This term includes, but is not limited to, an active pharmaceutical ingredient that is incorporated into a pharmaceutical composition along with one or more pharmaceutical excipients.

[0065] In some embodiments, the present disclosure provides a method for the preparation of a compound containing certain impurities, namely, (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (Compound 2), (R)-6-(6-chloropyridin-2-yl)-N 2-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (Compound 3), (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol (Compound 4), (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (Compound 5), (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (Compound 6), 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol (Compound 7), 6-(6-chloropyridin-2-yl)-N 2 -((R)-1,1,1-trifluoropropan-2-yl)-N 4 -((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 8), and 6-(6-chloropyridin-2-yl)-N 2 ,N 4 -bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (Compound 9).

[0066] For purposes of these embodiments, the concentration of each of compounds 2-7 refers to the % HPLC peak area attributable to such compound as a percentage of the total HPLC peak area attributable to the compound of formula (I) and any organic impurities (compounds 2-9) as measured by HPLC Method 1, as described in Examples 14 and 16. The concentration of each of compounds 8 and 9 refers to the % HPLC peak area attributable to such compound as a percentage of the total HPLC peak area attributable to the compound of formula (I) and compounds 8 and 9 as measured by HPLC Method 2, as described in Examples 14 and 16.

[0067] In one aspect, the present disclosure relates to a drug substance comprising a citric acid co-crystal of the compound of Formula (I), as described in any of the embodiments described herein. In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 -ethyl-N 4 In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 -Isopropyl-N 4 In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 ,N 4 In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N-bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 -((R)-1,1,1-trifluoropropan-2-yl)-N4-((S)-1,1,1-trifluoropropan-2-yl)- In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol. In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine. In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol.

[0068] In another aspect, the disclosure relates to a drug substance comprising the free form Type A of the compound of Formula (I), as described in any of the embodiments described herein. In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 -ethyl-N 4 In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 -Isopropyl-N 4 In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 ,N 4In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N-bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 2 -((R)-1,1,1-trifluoropropan-2-yl)-N4-((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol. In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine. In some embodiments, the drug substance contains 1.0% or less (area % by HPLC) of 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol.

[0069] impurities The present disclosure also relates to compounds that may be present as impurities in the solid forms described herein. Such compounds are useful as standards for determining the purity of the solid forms described herein (e.g., cocrystals, drug substances, crystalline forms, and amorphous solid dispersions).

[0070] In one aspect, the disclosure relates to a compound selected from the group consisting of: (R)-6-(6-chloropyridin-2-yl)-N 2 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine hmm, (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol, (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine, and 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol.

[0071] In one embodiment, the compound is (R)-6-(6-chloropyridin-2-yl)-N 2 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine.

[0072] In one embodiment, the compound is (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine.

[0073] In one embodiment, the compound is (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine.

[0074] In one embodiment, the compound is (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol.

[0075] In one embodiment, the compound is (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine.

[0076] In one embodiment, the compound is 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol.

[0077] tautomers The present disclosure also relates to tautomers of the chemical structures identified as compounds of formula (I). Such tautomers include: [ka] 4-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-6-(((R)-1,1,1-trifluoropropan-2-yl)imino)-1,6-dihydro-1,3,5-triazin-2-amine, [ka] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-4-(((R)-1,1,1-trifluoropropan-2-yl)imino)-1,4-dihydro-1,3,5-triazin-2-amine, [ka] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-4-(((R)-1,1,1-trifluoropropan-2-yl)imino)-4,5-dihydro-1,3,5-triazin-2-amine, and [ka] 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4(1H,3H)-diimine.

[0078] As used herein, tautomers include the specified compounds as well as any double bond isomers thereof.

[0079] In one embodiment, the present disclosure provides: [ka] 4-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-6-(((R)-1,1,1-trifluoropropan-2-yl)imino)-1,6-dihydro-1,3,5-triazin-2-amine, or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, the present disclosure provides: [ka] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-4-(((R)-1,1,1-trifluoropropan-2-yl)imino)-1,4-dihydro-1,3,5-triazin-2-amine, or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, the present disclosure provides: [ka] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-4-(((R)-1,1,1-trifluoropropan-2-yl)imino)-4,5-dihydro-1,3,5-triazin-2-amine, or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the present disclosure provides: [ka] 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4(1H,3H)-diimine, or a pharmaceutically acceptable salt thereof.

[0083] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" of a compound includes any salt that, upon administration to a recipient, is capable of providing the compound, either directly or indirectly. Pharmaceutically acceptable salts include non-toxic salts of the formula: Pharmaceutically acceptable salts are described in detail in SM Berge, et. al, J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Methods for preparing solid forms of compounds of formula (I)

[0084] The present disclosure also relates to methods of preparing solid forms of compounds of formula (I).

[0085] In one aspect, the present disclosure relates to a method of preparing citric acid co-crystals, comprising: dissolving a compound of formula (I) and citric acid in a solvent to obtain a solution; and precipitating the co-crystal.

[0086] In some embodiments, the co-crystal precipitated in the method is citric acid co-crystal Type A (as described in any of the embodiments herein).

[0087] In some embodiments, the present disclosure relates to co-crystals prepared by any of the methods for preparing citric acid co-crystals disclosed herein.

[0088] The citric acid used in the present method may be crystalline or amorphous, and may be in any state of hydration or solvation. In some embodiments, the citric acid is anhydrous citric acid or citric acid monohydrate. In other embodiments, the citric acid is anhydrous citric acid. In other embodiments, the citric acid is citric acid monohydrate.

[0089] The solvent used in the method can be any liquid or mixture of liquids suitable for dissolving the compound of Formula (I) and citric acid. In some embodiments, the solvent comprises a polar organic solvent such as methanol, ethyl acetate, acetonitrile, acetone, THF (e.g., THF / water (9:1 v / v)), or n-butanol (e.g., n-butanol / heptane (1 / 3 v / v)). In some embodiments, the solvent comprises acetonitrile or acetone.

[0090] The compound of Formula (I) and citric acid can be dissolved in the solvent in any molar ratio and at any concentration that allows for subsequent precipitation of the cocrystal from the solution. In some embodiments, the compound of Formula (I) and citric acid are contacted with the solvent in a molar ratio of about 1:2 to 4:1, or about 1:1 to 3:1, or about 1.5:1 to 2.5:1, or about 2:1. In some embodiments, the amount of the compound of Formula (I) contacted with the solvent is sufficient to form an about 0.01M to 3M solution, or about 1M to 2M solution, or about 1.5M solution, based on the amount of the compound of Formula (I). However, one of ordinary skill in the art will understand that if a portion of the compound of Formula (I) and / or citric acid does not dissolve in the solvent, the actual molar ratio of citric acid to the compound of Formula (I) in the solution, and the actual concentration of the compound of Formula (I), may differ from that calculated from the amount of the compound of Formula (I) and citric acid contacted with the solvent.

[0091] In another aspect, the present disclosure relates to a method of preparing maleic acid co-crystals, comprising: dissolving a compound of formula (I) and maleic acid in a solvent to obtain a solution; and precipitating the co-crystal.

[0092] In some embodiments, the co-crystal precipitated in the present method is maleic acid co-crystal Type A (as described in any of the embodiments herein).

[0093] In some embodiments, the present disclosure relates to a co-crystal prepared by any of the methods for preparing maleic acid co-crystals disclosed herein.

[0094] The solvent used in the present method may be any liquid or mixture of liquids suitable for dissolving the compound of formula (I) and maleic acid. In some embodiments, the solvent comprises acetonitrile or acetone.

[0095] In another aspect, the present disclosure relates to a method of preparing a crystalline form of a compound of formula (I): dissolving a compound of formula (I) in ethyl acetate to obtain a solution; and precipitating the crystalline form.

[0096] In some embodiments, the crystalline form precipitated in the method is free form Type A (as described in any of the embodiments herein).

[0097] In some embodiments, the present disclosure relates to a crystalline form prepared by any of the methods for preparing a crystalline form of the compound of Formula (I) disclosed herein.

[0098] In some embodiments, precipitating the crystalline form comprises adding heptane to the solution.

[0099] In another aspect, the present disclosure relates to a method of preparing a crystalline form of a compound of formula (I): dissolving a compound of formula (I) in methyl isobutyl ketone to obtain a solution; and precipitating the crystalline form.

[0100] In some embodiments, the crystalline form precipitated in the method is free form type B (as described in any of the embodiments herein).

[0101] In some embodiments, the present disclosure relates to a crystalline form prepared by any of the methods for preparing a crystalline form of the compound of Formula (I) disclosed herein.

[0102] In some embodiments, precipitating the crystalline form comprises adding heptane to the solution.

[0103] In another aspect, the present disclosure relates to a method of preparing a crystalline form of a compound of formula (I): dissolving a compound of formula (I) in dioxane to obtain a solution; and precipitating the crystalline form.

[0104] In some embodiments, the crystalline form precipitated in the method is free form type C (as described in any of the embodiments herein).

[0105] In some embodiments, the present disclosure relates to a crystalline form prepared by any of the methods for preparing a crystalline form of the compound of Formula (I) disclosed herein.

[0106] In some embodiments, precipitating the crystalline form comprises adding water to the solution.

[0107] In another aspect, the present disclosure relates to a method for preparing an amorphous solid dispersion of a compound of formula (I).

[0108] In some embodiments, the method comprises spray drying a mixture comprising a compound of formula (I), a polymer, and a suitable solvent or solvent mixture.

[0109] In some embodiments, the solvent is a volatile solvent (e.g., methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or a mixture thereof). In some embodiments, the solvent is acetone.

[0110] In some embodiments, the compound of Formula (I) used in the spray drying procedure is in a co-crystal form or a crystalline form according to any of the embodiments described herein.

[0111] Spray drying involves the atomization of a liquid mixture containing, for example, a solid and a solvent or solvent mixture, and the removal of the solvent or solvent mixture. Atomization can be carried out, for example, through a two-fluid, pressure, or electrosonic nozzle or a rotating disk. Removal of the solvent or solvent mixture can require a subsequent drying step, such as tray drying, fluidized bed drying (e.g., room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying, or double-cone vacuum drying (e.g., room temperature to about 200°C). Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th Ed., R.H. Perry, D.W. Green & J.O. Maloney, eds., McGraw-Hill Book Co. (1984), and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

[0112] As used herein, the term "dissolving," when referring to dissolving one or more substances in a solvent, means contacting the substance(s) with an amount of solvent sufficient to dissolve at least a portion of each of the substance(s). A mixture containing the substance(s) and the solvent may be stirred and / or heated to promote dissolution of the substance(s) in the solvent. Those skilled in the art will understand that some undissolved material (including some of the substance(s) and / or some other materials) may remain suspended in the solution, and such suspended material may be separated from the solution (e.g., by filtration or decantation) before precipitation of the solid form. In some embodiments, water is added to the solution before precipitation of the solid form.

[0113] As used herein, the term "about," when referring to a molar ratio or concentration (e.g., molar concentration), means that the molar ratio or concentration has a specified value ±10%. For example, a molar ratio of "about 2:1" includes molar ratios of 1.8:1 to 2.2:1. Similarly, a concentration of "about 1.5M" includes concentrations of 1.35M to 1.65M.

[0114] As used herein, the term "precipitating" refers to precipitating a solid form from a solution when the solid form is precipitated from the solution. Without intending 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 reducing the solubility of the solid form in the solution).

[0115] In some embodiments, "precipitating" includes cooling the solution. Without intending to be bound by any theory, cooling the solution may decrease the solubility of the solid form in the solution, thereby causing the solid form to reach its saturation concentration, thereby causing precipitation of the solid form.

[0116] In some embodiments, "precipitating" includes evaporating a portion of the solvent from the solution. Without intending to be bound by any theory, evaporation of the solvent from the solution may cause the precipitation of the solid form by increasing the concentration of the solid form in the solution to its saturation concentration.

[0117] In some embodiments, "precipitating" includes adding an anti-solvent to the solution. As used herein, the term "anti-solvent" refers to a liquid in which a solid form is less soluble than the solvent used to form the solution. Without intending to be bound by any theory, adding an anti-solvent to a solution may decrease the solubility of the solid form in the solution, thereby causing the solid form to reach its saturation concentration, thereby causing precipitation of the solid form. In some embodiments, the anti-solvent includes a non-polar organic solvent. In some embodiments, the anti-solvent includes toluene. In some embodiments, the anti-solvent includes methyl tert-butyl ether. In some embodiments, the anti-solvent includes a C5-C6 12 Contains an alkane or cycloalkane.

[0118] In some embodiments, "precipitating" includes seeding a solution with solid form crystals to precipitate from the solution. As used herein, the term "seeding" refers to adding a particular crystalline material to a solution to initiate recrystallization or crystallization of that particular crystalline material.

[0119] As used herein, "C5-C 12 The term "alkane or cycloalkane" means a saturated straight-chain, branched-chain, or cyclic hydrocarbon having 5 to 12 carbon atoms. Examples include pentane, hexane, heptane, octane, cyclohexane, etc.

[0120] In some embodiments, the method further comprises isolating the solid form. As used herein, the term "isolating" refers to separating the precipitated solid form from the solution. Such separation can be accomplished by any means known in the art, including, but not limited to, filtering the precipitated solid form and decanting the solution from the precipitated solid form.

[0121] Compositions and Routes of Administration In another aspect, the present disclosure relates to a pharmaceutical composition comprising a solid form, drug substance, or compound or pharmaceutically acceptable salt described in any of the embodiments herein and one or more pharmaceutical excipients.

[0122] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt described in any of the embodiments herein and one or more pharmaceutical excipients.

[0123] As used herein, the term "therapeutically effective amount," when referring to an amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt described herein, refers to an amount that elicits a biological or medical response in a patient, such as reducing enzyme or protein activity, alleviating or ameliorating a certain symptom, curing a disease, reducing the severity of a disease, slowing or delaying the progression of a disease, or preventing a disease. In some embodiments, the term "therapeutically effective amount" refers to an amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt that, when administered to a patient, is effective to inhibit mutant IDH1 and / or mutant IDH2. In other embodiments, the term "therapeutically effective amount" refers to an amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt that, when administered to a patient, is effective to treat cancer in the patient.

[0124] As used herein, the term "pharmaceutical excipient" refers to a carrier, adjuvant, or vehicle that can be administered to a subject together with a solid form, drug substance, or compound or pharmaceutically acceptable salt thereof, that does not destroy the pharmacological activity of the compound of (I), and that is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound of (I).

[0125] Pharmaceutical excipients that may be used in the pharmaceutical compositions described herein include, but are not limited to, ion exchange agents, 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 polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to enhance delivery of the compounds of formula (I).

[0126] In some cases, the pH of a pharmaceutical composition may be adjusted with pharmaceutically acceptable acids, bases, or buffers.

[0127] The pharmaceutical compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, preferably orally or by injection. The pharmaceutical compositions can contain any conventional non-toxic pharmaceutically acceptable excipients.

[0128] The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0129] The pharmaceutical compositions may be in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated by techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, may be employed. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethylcellulose, or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants, such as Tween or Spans, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0130] The pharmaceutical compositions may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For oral use tablets, commonly used excipients include lactose, corn starch, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, and sodium lauryl sulfate. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are orally administered, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If desired, certain sweeteners and / or flavorings and / or colorings can be added.

[0131] Pharmaceutical compositions can also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing solid form, drug substance, or compound or pharmaceutically acceptable salt with suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in rectum to release active ingredient.Such materials include but are not limited to cocoa butter, beeswax, and polyethylene glycol.

[0132] The pharmaceutical composition may be administered topically to the skin. The pharmaceutical composition should be formulated using a suitable ointment containing the active ingredient suspended or dissolved in a pharmaceutically acceptable excipient suitable for topical administration, including, but not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated using a suitable lotion or cream containing the active compound suspended or dissolved in a carrier using a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of one embodiment of the present invention may also be applied topically to the lower gastrointestinal tract via a rectal suppository formulation or in a suitable enema formulation. Transdermal patches are also included in one embodiment of the present invention.

[0133] Pharmaceutical compositions can be administered by nasal aerosol or inhalation. Such compositions can be prepared by techniques well known in the art of pharmaceutical formulation and can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0134] The amount of active ingredient that may be combined with one or more pharmaceutical excipients to produce a single dosage form will vary depending on the patient treated and the particular mode of administration. Typical preparations will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations will contain from about 20% to about 80% active compound. In some embodiments, the pharmaceutical composition comprises 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 coformers, salt formers, water of hydration, solvents of solvation, etc.). In some embodiments, the pharmaceutical composition comprises 2-30% w / w of the compound of Formula (I) (based on the weight of the free compound of Formula (I) excluding the weight of any coformers, salt formers, water of hydration, solvents of solvation, etc.). In some embodiments, the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of Formula (I) (based on the weight of the free compound of Formula (I) excluding the weight of any coformers, salt formers, water of hydration, solvents of solvation, etc.). In some embodiments, the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of Formula (I) (based on the weight of the free compound of Formula (I) excluding the weight of any coformers, salt formers, water of hydration, solvents of solvation, etc.).

[0135] The pharmaceutical compositions may contain additional therapeutic agents identified below as useful in combination therapy. The composition may further comprise a therapeutically effective amount of an additional therapeutic agent, including but not limited to any one of the following:

[0136] As used herein, the term "therapeutically effective amount," when referring to the amount of additional therapeutic agent, refers to the amount of agent that elicits a biological or medical response in a patient, such as reducing enzyme or protein activity, alleviating or ameliorating a particular symptom, curing a disease, reducing the severity of a disease, slowing or delaying the progression of a disease, or preventing a disease.

[0137] In another aspect, the present invention relates to a pharmaceutical composition prepared by the process of mixing a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt described in any of the embodiments herein with one or more pharmaceutical excipients to obtain a pharmaceutical composition.

[0138] As used herein, the term "mixing" is meant to include any process in which a solid form, drug substance, or compound or pharmaceutically acceptable salt is contacted with one or more pharmaceutical excipients to obtain a pharmaceutical composition (regardless of whether the pharmaceutical composition so obtained contains a solid form, drug substance, or compound or pharmaceutically acceptable salt). Thus, the term "mixing" includes processes in which the solid form, drug substance, or compound or pharmaceutically acceptable salt remains in the same solid form, as well as processes in which the solid form, drug substance, or compound or pharmaceutically acceptable salt is dissolved and / or converted into a different solid form. Examples of "mixing" processes include wet or dry blending, wet or dry granulation, suspension of the solid form, drug substance, or compound or pharmaceutically acceptable salt in a pharmaceutical excipient, etc.

[0139] Solid forms, drug substances, and compounds and salts, and uses thereof in pharmaceutical compositions In another aspect, the invention relates to a method of treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt thereof described in any of the embodiments herein, or a pharmaceutical composition thereof.

[0140] In another aspect, the invention relates to the use of a solid form, drug substance, or compound or pharmaceutically acceptable salt thereof, as described in any of the embodiments herein, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof.

[0141] In another aspect, the invention relates to a solid form, drug substance, or compound or pharmaceutically acceptable salt thereof, as described in any of the embodiments herein, or a pharmaceutical composition thereof, for use in treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof.

[0142] As used herein, the terms "treat" and "treating," when referring to cancer, mean having a therapeutic effect on alleviating or ameliorating one or more symptoms of, altering the progression of, eradicating, reducing the size of, slowing or inhibiting the growth or progression of, delaying or minimizing one or more associated symptoms of, reducing malignancy, or inducing stasis of, the cancer. When referring to a disease other than cancer, "treat" and "treating" mean having a therapeutic effect on, alleviating or ameliorating one or more symptoms of, altering the progression of, eradicating, or delaying or minimizing one or more associated symptoms of the disease.

[0143] As used herein, the term "patient" refers to a mammal, including a mouse, rat, dog, and human, suffering from a cancer characterized by the presence of an IDH1 or IDH2 mutation. In some embodiments, the patient is a human. In some embodiments, In some embodiments, the patient is a human adult (i.e., a human who is at least 18 years of age). In some embodiments, the patient is a human child (i.e., a human who is under 18 years of age).

[0144] 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 results in R(-)-2-hydroxyglutarate in the patient. In other embodiments, the IDH1 mutation results in a new ability of IDH1 to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate. Thus, in some embodiments, treating a cancer characterized by an IDH1 mutation comprises inhibiting mutant IDH1 activity.

[0145] In some embodiments, the cancer is a tumor in which at least 30, 40, 50, 60, 70, 80, or 90% of the tumor cells carry an IDH1 mutation, particularly an IDH1 R132H or R132C mutation, at the time of diagnosis or treatment.

[0146] Without being bound by theory, the applicants believe that mutant alleles of IDH1, particularly the IDH1 R132H and R132C mutations, which confer the enzyme's new ability to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate, characterize a subset of all types of cancer, regardless of their cellular nature and location in the body. Thus, the compounds and methods of the present invention are useful for treating any type of cancer characterized by the presence of mutant alleles of IDH1 that confer such activity, particularly the IDH1 R132H and R132C mutations.

[0147] As shown in Table 1, the IDH1 R132X mutation is known to occur in a variety of cancers. [Table 1]

[0148] Thus, in some embodiments, the cancer is selected from the types of cancer 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.

[0149] 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's 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's lymphoma (NHL).In some embodiments, the cancer is glioma, and the glioma is low-grade glioma or secondary high-grade glioma. In other embodiments, the cancer is a glioma, and the glioma is a low-grade glioma (grade II), anaplastic (grade III), or glioblastoma (GBM, grade IV).

[0150] 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 results in R(-)-2-hydroxyglutarate in the patient. In other embodiments, the IDH2 mutation results in a novel ability of IDH2 to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate. Thus, in some embodiments, treating a cancer characterized by an IDH2 mutation comprises inhibiting mutant IDH2 activity.

[0151] Without being bound by theory, Applicants believe that mutant alleles of IDH2, particularly the IDH2 R140Q and / or R172K mutations, which confer the enzyme's new ability to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate, characterize a subset of all types of cancer, regardless of their cellular nature and location in the body. Accordingly, the compounds and methods of one embodiment of the present invention are useful for treating any type of cancer characterized by the presence of mutant alleles of IDH2 that confer such activity, particularly the IDH2 R140Q and / or R172K mutations.

[0152] In some embodiments, the 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 IDH2 mutation, particularly an IDH2 R140Q, R140W, or R140L, and / or an R172K or R172G mutation.

[0153] Cancers can be analyzed by sequencing cell samples to determine the presence and specific nature of any mutation(s) that characterize the cancer.

[0154] In some embodiments, the cancer is selected from the group consisting of glioma, acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma (IHCC)), chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemia (B-ALL ... and leukemia-associated leukemia (LEU). In some embodiments, the cancer is a glioma, and the 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), anaplastic (grade III), or glioblastoma (GBM, grade IV).

[0155] In some embodiments, the cancer is a lymphoma (e.g., non-Hodgkin's lymphoma (NHL), e.g., a B-cell lymphoma (e.g., Burkitt's 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)).

[0156] In some embodiments, the cancer is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic lymphoma. In some embodiments, the cancer is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's 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 (grade III), or glioblastoma (GBM, grade IV).

[0157] In some embodiments, the cancer is refractory or recurrent, hi other embodiments, the cancer is newly diagnosed or previously untreated.

[0158] In one aspect of this embodiment, the effectiveness of cancer treatment is monitored by measuring levels of 2HG as described herein.

[0159] In some embodiments, the effectiveness of cancer treatment is monitored by measuring the level of 2HG in the patient. Typically, the level of 2HG is measured before treatment, and an elevated level is indicated for the use of a compound of Formula (I), a drug substance, or a compound or pharmaceutically acceptable salt thereof, including a solid form, or a pharmaceutical composition thereof, as described in any of the embodiments herein, to treat cancer. Once an elevated level is established, the level of 2HG is determined during and / or after the course of treatment to establish efficacy. In certain embodiments, the level of 2HG is determined only during and / or after the course of treatment. A decrease in the level of 2HG during and after treatment indicates efficacy. Similarly, a determination that the level of 2HG is not elevated during or after treatment also indicates efficacy. Typically, the 2HG measurement is utilized in conjunction with other known determinations of the effectiveness of cancer treatment, such as a reduction in the number and size of tumors and / or other cancer-related lesions, an improvement in the patient's general health, and changes in other biomarkers associated with the effectiveness of cancer treatment.

[0160] 2HG can be detected in samples by LC / MS. Samples are mixed 80:20 with methanol and centrifuged at 3,000 rpm for 20 minutes at 4°C. The resulting supernatant can be collected and stored at -80°C prior to LC-MS / MS to assess 2-hydroxyglutarate levels. A variety of different liquid chromatography (LC) separation methods can be used. Each method can be coupled by negative electrospray ionization (ESN, -3.0 kV) to a triple quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on injected metabolite standards. Metabolites can be analyzed using a previously reported method (Luo et al. J Chromatogr A 1 147, 153-64, 2007), can be separated by reversed-phase chromatography using 10 mM tributylamine as an ion-pairing agent in the aqueous mobile phase. One method allows for the resolution 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 and runs a fast linear gradient from 50% to 95% B (buffer as defined above) over 5 min. A Synergi Hydro-RP, 100 mm x 2 mm, 2.1 μm particle size (Phenomonex) can be used as the column, as described above. Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentrations. 13 Metabolic flux studies from C-glutamine can be performed, for example, as described in Munger et al. Nat Biotechnol 26, 1179-86, 2008.

[0161] In some embodiments, 2HG is assessed directly.

[0162] In other embodiments, the derivatives of 2HG formed during the process of performing the analytical method are evaluated.For example, such derivatives can be derivatives formed during MS analysis.Derivatives can include salt adducts, such as Na adducts, hydrated variants, or hydrated variants that can also be salt adducts, such as Na adducts, as formed during MS analysis.

[0163] In another embodiment, metabolic derivatives of 2HG are assessed. Examples include species that increase, elevate, or decrease as a result of the presence of 2HG, such as glutarate or glutamate, which are related to 2HG, e.g., R-2HG.

[0164] Exemplary 2HG derivatives include dehydrated derivatives or salt adducts thereof, such as the compounds provided below. [ka]

[0165] In some embodiments, various evaluation steps are performed before and / or after treatment of cancer with the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof. Thus, in some embodiments, the methods described herein further comprise evaluation steps before and / or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0166] In some embodiments, the evaluating step comprises evaluating the growth, size, weight, invasiveness, stage, and / or other phenotype of the cancer. Thus, in some embodiments, the methods described herein further comprise evaluating the growth, size, weight, invasiveness, stage, and / or other phenotype of the cancer before and / or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0167] In some embodiments, the method further comprises assessing the IDH1 genotype of the cancer before and / or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. This can be accomplished by conventional methods in the art, such as DNA sequencing, immunoassay, and / or assessing the presence, distribution, or level of 2HG.

[0168] In some embodiments, the method further comprises determining 2HG levels in the patient before and / or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof. This can be accomplished by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and / or MRS measurement, analysis of a sample of body fluids, such as serum or spinal fluid analysis, or analysis of surgical material, e.g., gravimetric analysis.

[0169] 2HG is known to accumulate in the inherited metabolic disorder 2-hydroxyglutaric aciduria, which 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, develop leukoencephalopathy, and are at increased risk of developing brain tumors, as assessed by MRI and CSF analysis (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, CSJ Inherit Metab Dis 27, 427-48 (2004)). Furthermore, elevated brain levels of 2HG 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 contribute to an increased risk of cancer. 2HG's ability to act 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 toxic to cells by competitively inhibiting glutamate and / or αKG through enzymes. These include transaminases that enable the utilization of glutamate nitrogen for amino acid and nucleic acid biosynthesis, and αKG-dependent prolyl hydroxylases, such as those that regulate HIF1-alpha levels.

[0170] Thus, according to another embodiment, one aspect of the present invention provides a method of treating 2-hydroxyglutaric aciduria, particularly D-2-hydroxyglutaric aciduria, by administering to a patient a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt as described in any one of the embodiments herein, or a pharmaceutical composition thereof.

[0171] Also provided is a method of treating a disease selected from Maffucci syndrome and Ollier disease characterized by the presence of a mutant allele of IDH1, comprising administering a therapeutically effective amount of a solid form, drug substance, or compound or pharmaceutically acceptable salt thereof described in any one of the embodiments herein, or a pharmaceutical composition thereof, to a patient in need thereof.

[0172] The treatment methods described herein can additionally include various evaluation steps before and / or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0173] In one embodiment, the method further comprises assessing the growth, size, weight, invasiveness, stage, and / or other phenotype of the cancer before and / or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0174] In one embodiment, the method further comprises assessing the IDH2 genotype of the cancer before and / or after treatment with the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof. This can be done by DNA sequencing, immunoassay, and This can be achieved by methods routine in the art, such as assessing the presence, distribution, and / or levels of 2HG.

[0175] The solid form, drug substance, or compound or pharmaceutically acceptable salt, and pharmaceutical compositions thereof described in any of the embodiments herein can be administered, for example, by injection, intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous administration, or orally, buccal, intranasal, transmucosal, topical, ophthalmic preparation, or by inhalation, at a dosage ranging from about 0.5 to 100 mg / kg body weight, or at a dosage of 1 mg to 1000 mg / dose, based on the amount of compound of Formula (I), every 4 to 120 hours. In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof is administered once, twice, or three times daily. In other embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof is administered once daily. In other embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof is administered twice daily. In other embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, is administered three times daily. The methods herein contemplate administering a therapeutically effective amount of the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, to achieve a desired or predetermined effect. Typically, the pharmaceutical composition of one aspect of the present invention is administered about 1 to about 6 times per day, or as a continuous infusion. In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, is administered once daily. In other embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, is administered twice daily. Such administration can be used as a chronic or acute therapy.

[0176] In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt described in any of the embodiments herein, or pharmaceutical composition thereof, is administered at a dose of 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, based on the amount of the compound of Formula (I), (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, 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 or about 50 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 It is administered at a dose of 225 mg / day, 185 to 215 mg / day, 190 to 210 mg / day, or approximately 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, 290 to 310 mg / day, or approximately 300 mg / day.

[0177] In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, is administered at a dosage of 0.01-10 mg / kg body weight / day, 0.2-8.0 mg / kg body weight / day, 0.4-6.0 mg / kg body weight / day, 0.6-4.0 mg / kg body weight / day, 0.8-2.0 mg / kg body weight / day, 0.1-1 mg / kg body weight / day, 0.2-1.0 mg / kg body weight / day, 0.15-1.5 mg / kg body weight / day, or 0.1-0.5 mg / kg body weight / day, based on the amount of the compound of Formula (I).

[0178] In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt described in any of the embodiments herein, or pharmaceutical composition thereof, is administered once daily, or more than once daily (e.g., In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt thereof described in any of the embodiments herein, or pharmaceutical composition thereof, is administered once daily to achieve the daily dosages described herein. In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt thereof described in any of the embodiments herein, or pharmaceutical composition thereof, is administered twice daily to achieve the daily dosages described herein. In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt described in any of the embodiments herein, or pharmaceutical composition thereof, is administered in a dosage of (1) about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg per administration, (2) 30-70 mg, 35-65 mg, 40-60 mg, 45-55 mg, or about 50 mg per administration, or (3) 5-35 mg, 5-20 mg, 5-15 mg, or about 10 mg, based on the amount of the compound of Formula (I). In some embodiments, the solid form, drug substance, or compound or pharmaceutically acceptable salt described in any of the embodiments herein, or pharmaceutical composition thereof, is administered at a dosage of (1) 30-70 mg, 35-65 mg, 40-60 mg, 45-55 mg, or about 50 mg per dose, or (2) 5-35 mg, 5-20 mg, 5-15 mg, or about 10 mg per dose, based on the amount of the compound of Formula (I). The amount of the solid form, drug substance, or compound or pharmaceutically acceptable salt described herein, or pharmaceutical composition thereof, is based on the amount of the compound of Formula (I). The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition, or symptom, predisposition of the subject to the disease, condition, or symptom, and the judgment of the treating physician.

[0179] As used herein, the term "about," when referring to a dosage, means that the dosage has a specified value ±10%. For example, a dosage of "about 100 mg / kg" includes dosages from 90 mg / kg to 110 mg / kg.

[0180] Lower or higher doses than those recited above 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 employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition, or symptom, the patient's predisposition to the disease, condition, or symptom, and the judgment of the treating physician.

[0181] When the patient's condition improves, a maintenance dose of the compound of formula (I) can be administered as needed, in the form of a solid form, drug substance, or compound or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, or a combination of one aspect of the present invention, as described in any of the embodiments herein.Subsequently, the dosage or frequency of administration, or both, can be reduced as a function of symptoms, to a level at which the improved condition is maintained when symptoms are alleviated to a desired level.However, patients may require intermittent treatment in the long term to treat any recurrence of disease symptoms.

[0182] Previously treated patients In some embodiments, the patient in need of treatment for a cancer characterized by the presence of an IDH1 or IDH2 mutation has previously received cancer therapy. In some embodiments, the patient has previously received cancer therapy for the cancer. The previously administered cancer therapy may or may not have been effective in treating the cancer, or may have been effective for some time in treating the cancer.

[0183] As used herein, the term "cancer therapy" refers to a cancer drug or treatment. As used herein, the term "cancer therapeutic agent" refers to a therapeutic agent (other than a compound of Formula (I), a solid form, a drug substance, or a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof) that is adapted to treat cancer. Cancer therapeutic agents include, for example, chemotherapy, targeted therapy agents, antibody therapy, immunotherapy agents, hormonal therapy agents, and checkpoint inhibitors. Examples of each of these types of cancer therapeutic agents are provided below. As used herein, the term "cancer therapy" refers to a therapy that is adapted to treat cancer. Cancer therapy includes, for example, surgery and radiation therapy.

[0184] In some embodiments, the cancer therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, triazines, spindle inhibitors, cytotoxic agents, topoisomerase inhibitors, and others), and hypomethylating agents (e.g., decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5-azacytidine), 5-fluoro-2'-deoxycytidine, 5,6-dihydro-5-azacidine, and others). Exemplary agents include aclarubicin, actinomycin, alitretinoin, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine ... Pirubicin, estramustine, etoglucide, etoposide, floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucanthone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel,Pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene seradenovec, satraplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate These include acetaminophen, thiotepa, tiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triaziconazole, triethylenemelamine, triplatin, tretinoin, treosulfan, trophosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, zorubicin, and other cytostatic or cytotoxic drugs described herein.

[0185] Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more chemotherapy drugs are used as combination chemotherapy.

[0186] In some embodiments, the cancer therapeutic agent is a differentiation agent. Differentiation agents include retinoids (all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13-cis retinoic acid, etc.). These include arsenic trioxide; histone deacetylase inhibitors HDACs (such as azacyatidine (Vidaza) and butyrates (e.g., phenylbutyrate)); hybrid polar compounds (hexamethylene bisacetamide (HMBA)); vitamin D; and cytokines (such as colony-stimulating factors, including G-CSF and GM-CSF, and interferons).

[0187] In some embodiments, the cancer therapeutic agent is a targeted therapy drug. Targeted therapy is the use of drugs specific to the deregulated protein of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of the enzyme domain of mutated, overexpressed, or otherwise important proteins in cancer cells. Notable examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestautinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and also cyclin-dependent kinase inhibitors such as alvocidib and seliciclib.

[0188] Other targeted therapy drugs include biguanides such as metformin or phenformin.

[0189] Targeted therapy can also involve small peptides as "homing devices" that can bind to cell surface receptors or the affected extracellular matrix surrounding tumors. Radionuclides attached to these peptides (e.g., RGD) ultimately kill cancer cells when the nuclides decay near the cells. An example of such a therapy is BEXXAR®.

[0190] In some embodiments, 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 a protein on the surface of cancer cells. Examples include the anti-HER2 / neu antibody trastuzumab (HERCEPTIN®), which is typically used in breast cancer, and the anti-CD20 antibodies rituximab and tositumomab, which are typically used in various B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin diftitox.

[0191] In some embodiments, the cancer therapeutic agent is an immunotherapy drug.Cancer immunotherapy refers to a collection of diverse therapeutic strategies designed to induce the patient's own immune system to fight tumors.Modern methods for generating immune responses against tumors include intravesicular 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.

[0192] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, as the donor's immune cells will often attack the tumor in a graft-versus-tumor effect.

[0193] In some embodiments, the cancer treatment drug is a hormone therapy drug. The growth of some cancers can be inhibited 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 certain cancers, administering hormone agonists such as progestogens can be therapeutically beneficial.

[0194] In some embodiments, the cancer therapeutic agent is a checkpoint inhibitor. Checkpoint inhibitor therapy is a form of cancer treatment in which manipulation of immune system checkpoints is used to restore immune system function against cancer cells. Examples of checkpoint inhibitors include ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and the like.

[0195] Other cancer treatments include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxin, radiolabeled drugs and antibodies, chimeric antigen receptors, or CAR-T (e.g., Kymriah® (tisagenlecleucel), Yescarta® (axicabtagene ciloleucel), Gliadel® (carmustine implant), and Avastin® (bevacizumab).

[0196] In some embodiments, cancer treatment is radiation therapy.Radiation therapy involves the use of high-energy radiation (for example, 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 brain tumors (for example, gliomas) by a machine placed outside the body (external beam radiation therapy), by a radioactive material placed inside the body near the brain tumor (internal radiation therapy, also called brachytherapy), or by systemically administered radioactive material (for example, radioactive iodine) that travels to the brain tumor through bloodstream.Alternatively, these delivery methods can be used in combination.

[0197] In some embodiments, radiation therapy comprises external radiation therapy (e.g., external beam radiation therapy, including fractionated external beam radiation therapy, stereotactic radiation such as Cyberknife® or Gamma Knife®, proton therapy, etc.), in which radiation is delivered to the brain tumor (e.g., glioma) by a device outside the body. External radiation therapy can be given as a course of several treatments over the course of days or weeks. In one aspect of these embodiments, radiation is administered in the form of x-rays.

[0198] In other embodiments, radiation therapy includes internal radiation therapy, where radiation comes from an implant or material (liquid, solid, semi-solid, or other substance) placed inside the body. In one aspect of these embodiments, internal radiation therapy is brachytherapy, where a solid radioactive source is placed inside the body near the brain tumor. In another aspect of these embodiments, internal radiation therapy involves systemic administration of a radiation source, typically a radionuclide (radioisotope or unsealed source). The radiation source can be administered orally or injected intravenously.

[0199] Combination therapy In some embodiments, the methods described herein comprise the additional step of co-administering an additional therapy to a patient in need thereof.

[0200] In some embodiments, the agent for use in treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof is for use in combination with the concomitant administration of an additional therapy.

[0201] In another aspect, the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof for use in treating a cancer characterized by the presence of an IDH1 or IDH2 mutation, is for use in combination with the concomitant administration of an additional therapy.

[0202] As used herein, the term "additional therapy" includes cancer therapies (including cancer therapeutic agents and cancer treatments) as described above, as well as non-cancer therapies (including non-cancer therapeutic agents and non-cancer treatments) that are administered to treat the symptoms and / or secondary effects of cancer. The term "additive therapy" includes additional therapeutic agents (ie, cancer therapeutic agents and non-cancer therapeutic agents) and additional treatments (ie, cancer treatments and non-cancer treatments).

[0203] In some embodiments, the additional therapy is a cancer therapy (ie, a cancer therapeutic agent or cancer treatment) as described above.

[0204] In some embodiments, the additional therapy is a non-cancer therapy (ie, a non-cancer therapeutic agent or treatment).

[0205] In some embodiments, the additional therapy comprises one or more of a DNA reactive agent, a PARP inhibitor, an antiemetic, an anticonvulsant or antiepileptic drug, a checkpoint inhibitor, PVC chemotherapy, bevacizumab, and gemcitabine.

[0206] In some embodiments, one or more additional therapies are DNA-reactive agents. As used herein, a "DNA-reactive agent" refers to an agent that interacts with cellular DNA covalently or non-covalently, such as an alkylating agent, a cross-linking agent, or a DNA intercalating agent. For example, DNA-reactive agents include adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, mitozolomide, nedaplatin, oxaliplatin, piposulfan, procarbazine, semustine, streptozocin, temozolomide, thiotepa, treosulfan, diethylnitrosamine, benzo(a)pyrene, doxorubicin, mitomycin C, and the like. Many of these DNA reactive agents are useful as DNA reactive chemotherapeutic agents in cancer therapy.

[0207] In some embodiments, the additional therapy comprises a PARP inhibitor. As used herein, "PARP inhibitor" refers to an inhibitor of the enzyme poly ADP-ribose polymerase (PARP). Examples of PARP inhibitors include pamiparib, olaparib, rucaparib, velaparib, iniparib, talazoparib, niraparib, etc.

[0208] In some embodiments, the additional therapy is a checkpoint inhibitor. As used herein, "checkpoint inhibitor" refers to a therapeutic agent that inhibits immune checkpoints (e.g., CTLA-4, PD-1 / PD-L1, etc.) that 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, spartalizumab, etc.

[0209] In some embodiments, the additional therapy is PVC chemotherapy. As used herein, "PVC chemotherapy" refers to a chemotherapy regimen that includes the combined administration of procarbazine, lomustine (sold under the trade name CCNU®), and vincristine (sold under the trade name Onocovin®). Typically, vincristine is administered intravenously, while procarbazine and lomustine are administered orally. PCV chemotherapy is often administered in cycles, with each cycle including a single administration of vincristine and lomustine and a 10-day course of treatment with procarbazine.

[0210] In some embodiments, the additional therapy is bevacizumab. Bevacizumab, sold under the trade name Avastin®, is a recombinant humanized monoclonal antibody.

[0211] In some embodiments, the additional therapy is gemcitabine. Gemcitabine, sold under the trade name Gemzar®, is a pyrimidine nucleoside analog.

[0212] In some embodiments, the additional therapy is a non-cancer therapeutic agent. As used herein, the term "non-cancer therapeutic agent" refers to a therapeutic agent that is used to treat symptoms suffered by a patient suffering from cancer and / or being treated for cancer, but is not indicated for the treatment of cancer itself. Examples of "non-cancer therapeutic agents" include anticonvulsants and antiepileptics, antiemetics, antidiarrheals, etc.

[0213] In some embodiments, the additional therapy is an anticonvulsant or antiepileptic drug. As used herein, "anticonvulsant or antiepileptic drug" refers to an agent that is effective in treating or preventing convulsions, including epileptic seizures. Examples of anticonvulsants and antiepileptic drugs include acetazolamide, barbexaclone, beclamide, brivaracetam, cannabidiol, carbamazepine, clobazam, clonazepam, clorazepate, diazepam, divalproex sodium, eslicarbazepine acetate, ethadione, ethosuximide, ethotoin, etiracetam, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, mephenytoin, mesuximide, methazolamide, methylphenobarbital, midazolam, thiazolinone ... These include zolam, nimetazepam, nitrazepam, oxcarbazepine, paraldehyde, paramethadoine, perampanel, piracetam, phenacemide, feneturide, phenobarbital, phensuximide, phenytoin, potassium bromide, pregabalin, primidone, progabide, pyridoxine, rufinamide, seletracetam, sodium valproate, stiripentol, sulthiame, temazepam, tiagabine, topiramate, trimethadione, valnoctamide, valproic acid, valpromide, vigabatrin, and zonisamide.

[0214] In some embodiments, the additional therapy is an antiemetic. As used herein, "antiemetic" refers to an agent that is effective in reducing the symptoms of 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, alizapride, prochlorperazine, metoclopramide, etc.), NK1 receptor antagonists (e.g., aprepitant, casopitant, rolapitant, etc.), antihistamines (e.g., cinnarizine, cyclizine, diphenhydramine, diazepam, etc.), and the like. menhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, etc.), cannabinoid drugs (e.g., cannabis, dronabinol, synthetic cannabinoids, etc.), benzodiazepines (e.g., midazolam, lorazepam, etc.), anticholinergic drugs (e.g., scopolamine, etc.), steroids (e.g., dexamethasone, etc.), trimethobenzamide, ginger, propofol, glucose / fructose / phosphate (sold under the trade name Emetrol®), peppermint, muscimol, ajowan, bismuth subsalicylate, etc.

[0215] In some embodiments, the additional therapy is an antidiarrheal agent. Examples of antidiarrheal agents include bismuth subgallate, Saccharomyces boulardii lyo, atropine, diphenoxylate, difenoxin, Lactobacillus acidophilus, bismuth subsalicylate, loperamide, Lactobacillus bulgaricus, Lactobacillus rhamnosus gg, attapulgite, crofelemer, simethicone, and the like.

[0216] In some embodiments, the additional therapy is non-cancer therapy.As used herein, the term " non-cancer therapy " refers to the therapy that is used to treat the symptoms suffered by patients who suffer from cancer and / or are being treated for cancer, but is not applied to the treatment of cancer itself.Examples of non-cancer therapy include acupuncture, biofeedback, distraction, psychological support and counseling, hypnosis, imagery, relaxation, skin stimulation, etc.

[0217] As used herein, the term "co-administration" means that the additional therapy is administered prior to, simultaneously with, sequentially with, or subsequent to the administration of a solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof, as part of a treatment regimen, to provide a beneficial effect from the combined action of the solid form, drug substance, or compound or pharmaceutically acceptable salt (or pharmaceutical composition thereof) and the additional therapy. When the additional therapy is an additional therapeutic agent, the additional therapeutic agent may be administered together with the solid form, drug substance, or compound or pharmaceutically acceptable salt as part of a single dosage form (such as a composition of one aspect of the present invention comprising a cocrystal, drug substance, crystalline form, or amorphous solid dispersion and a therapeutic agent) or as separate multiple dosage forms. Alternatively, the therapeutic agent may be administered prior to, sequentially with, or subsequent to the administration of the solid form, drug substance, or compound or pharmaceutically acceptable salt. In such combination therapy treatments, both the solid form, drug substance, or compound or pharmaceutically acceptable salt and the additional therapeutic agent(s) are administered by conventional methods. The administration to a patient of a composition of one aspect of the invention that includes both a solid form, drug substance, or compound or pharmaceutically acceptable salt and an additional therapeutic agent does not preclude the separate administration to said patient of that same therapeutic agent, any other additional therapeutic agent, or solid form, drug substance, or compound or pharmaceutically acceptable salt at another time during the course of treatment. When the additional therapy is an additional treatment, the additional treatment may be administered prior to, consecutively with, or following the administration of the solid form, drug substance, or compound or pharmaceutically acceptable salt, or pharmaceutical composition thereof.

[0218] In some embodiments, when the additional therapy is a cancer therapy, the solid form, drug substance, or both the compound or pharmaceutically acceptable salt and the cancer therapy are administered at dosage levels that are about 1-100%, or about 5-95% of the dosage normally administered in a monotherapy regimen.

[0219] Enumerated Embodiments In some embodiments, the present disclosure relates to: 1. A compound of formula (I) [ka] A co-crystal comprising citric acid and 2. The co-crystal of embodiment 1, wherein the co-crystal is characterized by an X-ray powder diffraction pattern obtained in reflection mode comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. 3. The X-ray powder diffraction pattern has a resolution of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0 degrees 2-theta (±0.05°C) selected from the group consisting of: 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. 3. The cocrystal of embodiment 1 or 2, comprising at least two peak positions at 0.2 degrees 2-theta. 4. The co-crystal of any one of embodiments 1-3, wherein the X-ray powder diffraction pattern comprises at least three peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. 5. The co-crystal of any one of embodiments 1-4, wherein the X-ray powder diffraction pattern comprises at least four peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. 6. The cocrystal of any one of embodiments 1-5, wherein the X-ray powder diffraction pattern comprises peak positions at 5.7 and 8.4 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. 7. The co-crystal of any one of embodiments 1-6, wherein the co-crystal is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 170.6°C (± 2.0°C). 8. The co-crystal of any one of embodiments 1-7, further comprising water. 9. The co-crystal of any one of embodiments 1-8, wherein the compound of formula (I), citric acid, and water are present in a molar ratio of 2:1:1. 10. The co-crystal of any one of embodiments 1-9, wherein the co-crystal comprises four molecules of the compound of formula (I), two molecules of citric acid, and two molecules of water per unit cell. 11. A drug substance comprising a co-crystal according to any one of embodiments 1 to 10. 12. The drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 The drug substance of embodiment 11, which contains -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 13. The drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 13. The drug substance of embodiment 11 or 12, which contains -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 14. The drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 14. The drug substance of any one of embodiments 11-13, comprising -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 15. The drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N 2 ,N 4 15. The drug substance of any one of embodiments 11-14, comprising -bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 16. The drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N 2 16. The drug substance of any one of embodiments 11-15, comprising -((R)-1,1,1-trifluoropropan-2-yl)-N4-((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 17. The drug substance of any one of embodiments 11-16, wherein the drug substance contains 1.0% or less (area % by HPLC) of (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol. 18. The drug substance of any one of embodiments 11-17, wherein the drug substance has 1.0% or less (area % by HPLC) of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine. 19. The drug substance of any one of embodiments 11-18, wherein the drug substance contains 1.0% or less (area % by HPLC) of 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol. 20. A pharmaceutical composition comprising a therapeutically effective amount of a cocrystal of any one of embodiments 1-10, or a drug substance of any one of embodiments 11-19, and one or more pharmaceutical excipients. 21. The pharmaceutical composition according to embodiment 20, wherein the pharmaceutical composition comprises 1-10% w / w of the compound of formula (I). 22. The pharmaceutical composition according to embodiment 20 or 21, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 23. The pharmaceutical composition according to embodiment 22, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 24. The pharmaceutical composition according to embodiment 20, wherein the pharmaceutical composition comprises 20-30% w / w of the compound of formula (I). 25. The pharmaceutical composition of embodiment 24, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 26. The pharmaceutical composition according to embodiment 25, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 27. A pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of a cocrystal according to any one of embodiments 1-10, or a drug substance according to any one of embodiments 11-19, with one or more pharmaceutical excipients to obtain a pharmaceutical composition. 28. A compound of formula (I), [ka] and citric acid, dissolving a compound of formula (I) and citric acid in a solvent to obtain a solution; and precipitating the co-crystal. 29. The method of embodiment 28, wherein the solvent comprises acetonitrile or acetone. 30. The method of embodiment 28 or 29, wherein said precipitating comprises cooling the solution. 31. The method of any one of embodiments 28-30, wherein said precipitating comprises evaporating a portion of the solvent from the solution. 32. The method of any one of embodiments 28-31, wherein said precipitation comprises adding an anti-solvent to the solution. 33. Antisolvents are C5 to C 1233. The method of embodiment 32, comprising an alkane or cycloalkane. 34. The method of embodiment 32, wherein the anti-solvent comprises toluene or MTBE. 35. The method of any one of embodiments 28-34, wherein said precipitation comprises seeding the solution with crystals of the co-crystal. 36. The method of any one of embodiments 28 to 35, further comprising isolating the co-crystal. method. 37. A compound of formula (I), [ka] A co-crystal comprising maleic acid. 38. The co-crystal of embodiment 37, wherein the co-crystal is characterized by an X-ray powder diffraction pattern obtained in reflection mode, comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. 39. The co-crystal of embodiment 37 or 38, wherein the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. 40. The cocrystal of any one of embodiments 37-39, wherein the X-ray powder diffraction pattern comprises at least three peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. 41. The cocrystal of any one of embodiments 37-39, wherein the X-ray powder diffraction pattern comprises at least three peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. 42. The cocrystal of any one of embodiments 37-41, wherein the X-ray powder diffraction pattern comprises peak positions at 8.1, 17.8, and 18.5 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 5.9, 15.0, 15.2, 16.9, 21.1, 23.4, 26.9, and 28.2. 43. The co-crystal of any one of embodiments 37-42, wherein the co-crystal is characterized by a differential scanning calorimetry thermogram comprising endothermic peaks with onset temperatures of 91.2°C and 128.4°C (±2.0°C). 44. The co-crystal of any one of embodiments 37-43, wherein the compound of formula (I) and aqueous citric acid are present in a 1:1 molar ratio. 45. A pharmaceutical composition comprising a therapeutically effective amount of a cocrystal according to any one of embodiments 37-44, and one or more pharmaceutical excipients. 46. ​​The pharmaceutical composition according to embodiment 45, wherein the pharmaceutical composition comprises 1-10% w / w of the compound of formula (I). 47. The pharmaceutical composition according to embodiment 45 or 46, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 48. The pharmaceutical composition according to embodiment 47, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 49. The pharmaceutical composition according to embodiment 45, wherein the pharmaceutical composition comprises 20-30% w / w of the compound of formula (I). 50. A pharmaceutical composition is in the form of an orally acceptable dosage form and contains about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of a compound of formula (I). 50. The pharmaceutical composition of embodiment 49. 51. The pharmaceutical composition according to embodiment 50, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 52. A pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of a cocrystal according to any one of embodiments 37-44 with one or more pharmaceutical excipients to obtain a pharmaceutical composition. 53. A compound of formula (I), [ka] and maleic acid, dissolving a compound of formula (I) and maleic acid in a solvent to obtain a solution; and precipitating the co-crystal. 54. The method of embodiment 53, wherein the solvent comprises acetonitrile or acetone. 55. The method of embodiment 53 or 54, wherein said precipitation comprises seeding the solution with crystals of the co-crystal. 56. The method of any one of embodiments 53-55, further comprising isolating the co-crystal. 57. A crystalline form of the compound of formula (I), [ka] 1. A crystalline form characterized by an X-ray powder diffraction pattern obtained in reflection mode that includes at least one peak position at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. 58. The crystalline form of embodiment 57, wherein the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. 59. The crystalline form of embodiment 57 or 58, wherein the X-ray powder diffraction pattern comprises at least three peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. 60. The crystalline form of any one of embodiments 57-59, wherein the X-ray powder diffraction pattern comprises at least four peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. 61. The crystalline form of any one of embodiments 57-60, wherein the X-ray powder diffraction pattern comprises peak positions at 11.7, 17.8, and 21.8 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 12.8, 14.2, 19.8, 20.7, 22.2, and 25.0. 62. The crystalline form of any one of embodiments 57-61, wherein the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.9°C (±2.0°C). 63. A drug substance comprising the crystalline form according to any one of embodiments 57-62. 64. The drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 The drug substance of embodiment 63, which contains -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 65. The drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 65. The drug substance of embodiment 63 or 64, which contains -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 66. The drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 66. The drug substance of any one of embodiments 63-65, comprising -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 67. The drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N 2 ,N4 67. The drug substance of any one of embodiments 63-66, comprising -bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 68. The drug substance contains 1.0% or less (area % by HPLC) of 6-(6-chloropyridin-2-yl)-N 2 68. The drug substance of any one of embodiments 63-67, comprising -((R)-1,1,1-trifluoropropan-2-yl)-N4-((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine. 69. The drug substance of any one of embodiments 63-68, wherein the drug substance contains 1.0% or less (area % by HPLC) of (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol. 70. The drug substance of any one of embodiments 63-69, wherein the drug substance has 1.0% or less (area % by HPLC) of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine. 71. The drug substance of any one of embodiments 63-70, wherein the drug substance contains 1.0% or less (area % by HPLC) of 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol. 72. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form according to any one of embodiments 57-62, or the drug substance according to any one of embodiments 63-71, and one or more pharmaceutical excipients. 73. The pharmaceutical composition according to embodiment 72, wherein the pharmaceutical composition comprises 1-10% w / w of the compound of formula (I). 74. The pharmaceutical composition according to embodiment 72 or 73, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 75. The pharmaceutical composition according to embodiment 74, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 76. The pharmaceutical composition according to embodiment 72, wherein the pharmaceutical composition comprises 20-30% w / w of a compound of formula (I). The pharmaceutical composition described above. 77. The pharmaceutical composition according to embodiment 76, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 78. The pharmaceutical composition according to embodiment 77, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 79. 72. A pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of the crystalline form of any one of embodiments 57-62, or the drug substance of any one of embodiments 63-71, with one or more pharmaceutical excipients to obtain a pharmaceutical composition. 80. A method for preparing a crystalline form of a compound of formula (I), comprising: [ka] dissolving a compound of formula (I) in ethyl acetate to obtain a solution; and precipitating the crystalline form. 81. The method of embodiment 80, wherein precipitating the crystalline form comprises adding heptane to the solution. 82. The method of embodiment 80 or 81, wherein said precipitation comprises seeding the solution with crystals of the crystalline form. 83. The method of any one of embodiments 80-82, further comprising isolating the crystalline form. 84. A crystalline form of the compound of formula (I), [ka] 1. A crystalline form characterized by an X-ray powder diffraction pattern obtained in reflection mode that includes at least one peak position at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. 85. The crystalline form of embodiment 84, wherein the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. 86. The crystalline form of embodiment 84 or 85, wherein the X-ray powder diffraction pattern comprises at least three peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. 87. The crystalline form of any one of embodiments 84-86, wherein the X-ray powder diffraction pattern comprises at least four peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. 88. The crystalline form of any one of embodiments 84-87, wherein the X-ray powder diffraction pattern comprises peak positions at 11.9, 17.8, and 23.9 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 13.2, 15.5, 18.6, 20.8, 23.2, and 26.5. 89. The crystalline form of any one of embodiments 84-88, wherein the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.5°C (±2.0°C). 90. The crystalline form according to any one of embodiments 84 to 89, wherein the crystalline form is anhydrous. 91. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form according to any one of embodiments 84 to 90 and one or more pharmaceutical excipients. 92. The pharmaceutical composition according to embodiment 91, wherein the pharmaceutical composition comprises 1-10% w / w of the compound of formula (I). 93. The pharmaceutical composition according to embodiment 91 or 92, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 94. The pharmaceutical composition according to embodiment 93, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 95. The pharmaceutical composition according to embodiment 91, wherein the pharmaceutical composition comprises 20-30% w / w of the compound of formula (I). 96. The pharmaceutical composition according to embodiment 95, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 97. The pharmaceutical composition according to embodiment 96, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 98. A pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of the crystalline form according to any one of embodiments 84-90 with one or more pharmaceutical excipients to obtain a pharmaceutical composition. 99. A method for preparing a crystalline form of a compound of formula (I), comprising: [ka] dissolving a compound of formula (I) in methyl isobutyl ketone to obtain a solution; and precipitating the crystalline form. 100. The method of embodiment 99, wherein precipitating the crystalline form comprises adding heptane to the solution. 101. The method of embodiment 99 or 100, wherein said precipitation comprises seeding the solution with crystals of the crystalline form. 102. The method of any one of embodiments 99-101, further comprising isolating the crystalline form. 103. A crystalline form of the compound of formula (I), [ka] The crystalline form is characterized by an X-ray powder diffraction pattern obtained in reflection mode that includes at least one peak position at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. 104. The crystalline form of embodiment 103, wherein the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. 105. The crystalline form of embodiment 103 or 104, wherein the X-ray powder diffraction pattern comprises at least three peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. 106. The crystalline form of any one of embodiments 103-105, wherein the X-ray powder diffraction pattern comprises at least four peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. 107. The crystalline form of any one of embodiments 103-106, wherein the X-ray powder diffraction pattern comprises peak positions at 8.6 and 21.1 degrees 2-theta (±0.2 degrees 2-theta), and at least three peak positions selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. 108. The crystalline form of any one of embodiments 103-107, wherein the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.3°C (±2.0°C). 109. The crystalline form of any one of embodiments 103-108, wherein the crystalline form is a trihydrate. 110. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form according to any one of embodiments 103-109 and one or more pharmaceutical excipients. 111. The pharmaceutical composition according to embodiment 110, wherein the pharmaceutical composition comprises 1-10% w / w of the compound of formula (I). 112. The pharmaceutical composition according to embodiment 110 or 111, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 113. The pharmaceutical composition according to embodiment 112, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 114. The pharmaceutical composition according to embodiment 110, wherein the pharmaceutical composition comprises 20-30% w / w of the compound of formula (I). 115. The pharmaceutical composition according to embodiment 114, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 116. The pharmaceutical composition according to embodiment 115, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 117. A pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of the crystalline form according to any one of embodiments 103 to 109 with one or more pharmaceutical excipients to obtain a pharmaceutical composition. A pharmaceutical composition. 118. A method for preparing a crystalline form of a compound of formula (I), comprising: [ka] dissolving a compound of formula (I) in dioxane to obtain a solution; and precipitating the crystalline form. 119. The method of embodiment 118, wherein precipitating the crystalline form comprises adding water to the solution. 120. The method of embodiment 118 or 119, wherein said precipitation comprises seeding the solution with crystals of the crystalline form. 121. The method of any one of embodiments 118-120, further comprising isolating the crystalline form. 122. A crystalline form of the compound of formula (I), [ka] 1. The crystalline form is characterized by an X-ray powder diffraction pattern obtained in reflection mode that includes at least one peak position at degrees two-theta (±0.2 degrees two-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. 123. The crystalline form of embodiment 122, wherein the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. 124. The crystalline form of embodiment 122 or 123, wherein the X-ray powder diffraction pattern comprises at least three peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. 125. The crystalline form of any one of embodiments 122-124, wherein the X-ray powder diffraction pattern comprises at least four peak positions in degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of: 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. 126. The crystalline form of any one of embodiments 122-125, wherein the X-ray powder diffraction pattern comprises peak positions at 15.9, 16.7, and 21.2 degrees two-theta (±0.2 degrees two-theta), and at least three peak positions selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 17.9, 20.3, 24.9, 26.6, and 27.0. 127. The crystalline form of any one of embodiments 122-126, wherein the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.3°C (±2.0°C). 128. The crystalline form of any one of embodiments 122-127, wherein the crystalline form is a dioxane solvate. 129. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form according to any one of embodiments 122-128 and one or more pharmaceutical excipients. 130. The pharmaceutical composition according to embodiment 129, wherein the pharmaceutical composition comprises 1-10% w / w of the compound of formula (I). 131. The pharmaceutical composition according to embodiment 129 or 130, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 132. The pharmaceutical composition according to embodiment 131, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 133. The pharmaceutical composition according to embodiment 29, wherein the pharmaceutical composition comprises 20-30% w / w of the compound of formula (I). 134. The pharmaceutical composition according to embodiment 133, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 135. The pharmaceutical composition according to embodiment 134, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 136. A pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of the crystalline form according to any one of embodiments 122-128 with one or more pharmaceutical excipients to obtain a pharmaceutical composition. 137. A compound of formula (I), [ka] and a polymer. 138. The amorphous solid dispersion of embodiment 137, wherein the polymer is HPMCAS. 139. The amorphous solid dispersion of embodiment 138, wherein the compound of formula (I) and HPMCAS are present in a weight ratio of about 1:1. 140. A method for preparing an amorphous solid dispersion of a compound of formula (I), comprising: [ka] mixing a compound of formula (I), a polymer, and a solvent to obtain a mixture; spray drying the mixture to obtain an amorphous solid dispersion. 141. The method according to embodiment 140, wherein the compound of formula (I) used in said mixture is in the form of a co-crystal characterized by an X-ray powder diffraction pattern obtained in reflection mode comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. 142. The method according to embodiment 140, wherein the compound of formula (I) used in said mixture is in the form of a co-crystal characterized by an X-ray powder diffraction pattern obtained in reflection mode comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.9, 8.1, 15.0, 15.2, 16.9, 17.8, 18.5, 21.1, 23.4, 26.9, and 28.2. 143. The method according to embodiment 140, wherein the compound of formula (I) used in said mixture is in a crystalline form characterized by an X-ray powder diffraction pattern obtained in reflection mode comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0. 144. The method according to embodiment 140, wherein the compound of formula (I) used in said mixture is in a crystalline form characterized by an X-ray powder diffraction pattern obtained in reflection mode comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 11.9, 13.2, 15.5, 17.8, 18.6, 20.8, 23.2, 23.9, and 26.5. 145. The method according to embodiment 140, wherein the compound of formula (I) used in said mixing is in a crystalline form characterized by an X-ray powder diffraction pattern obtained in reflection mode comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 10.5, 18.2, 20.2, 21.1, and 25.9. 146. The method according to embodiment 140, wherein the compound of formula (I) used in said mixing is in a crystalline form characterized by an X-ray powder diffraction pattern obtained in reflection mode comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 8.6, 9.7, 10.5, 15.6, 15.9, 16.7, 17.9, 20.3, 21.2, 24.9, 26.6, and 27.0. 147. A pharmaceutical composition comprising a therapeutically effective amount of the amorphous solid dispersion according to any one of embodiments 137-139, and one or more pharmaceutical excipients. 148. The pharmaceutical composition according to embodiment 147, wherein the pharmaceutical composition comprises 1-10% w / w of the compound of formula (I). 149. The pharmaceutical composition according to embodiment 147 or 148, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 150. The pharmaceutical composition according to embodiment 149, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 151. The pharmaceutical composition according to embodiment 147, wherein the pharmaceutical composition comprises 20-30% w / w of the compound of formula (I). 152. The pharmaceutical composition according to embodiment 151, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and comprises about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). 153. The pharmaceutical composition according to embodiment 152, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). 154. A pharmaceutical composition prepared by a process comprising mixing a therapeutically effective amount of the spray-dried dispersion of any one of embodiments 137-139 with one or more pharmaceutical excipients to obtain a pharmaceutical composition. 155. [ka] 4-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-6-(((R)-1,1,1-trifluoropropan-2-yl)imino)-1,6-dihydro-1,3,5-triazin-2-amine, or a pharmaceutically acceptable salt thereof. 156. [ka] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-4-(((R)-1,1,1-trifluoropropan-2-yl)imino)-1,4-dihydro-1,3,5-triazin-2-amine, or a pharmaceutically acceptable salt thereof. 157. [ka] 6-(6-chloropyridin-2-yl)-N-((R)-1,1,1-trifluoropropan-2-yl)-4-(((R)-1,1,1-trifluoropropan-2-yl)imino)-4,5-dihydro-1,3,5-triazin-2-amine, or a pharmaceutically acceptable salt thereof. 158. [ka] 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4(1H,3H)-diimine, or a pharmaceutically acceptable salt thereof. 159. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 114-117 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients. 160. A method of treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a cocrystal described in any one of embodiments 1 to 10 and 37 to 44, a crystalline form described in any one of embodiments 57 to 62, 84 to 90, 103 to 109, and 122 to 128, an amorphous solid dispersion described in any one of embodiments 137 to 139, a drug substance described in any one of embodiments 11 to 19 and 63 to 71, a compound or pharmaceutically acceptable salt thereof described in any one of embodiments 155 to 158, or a pharmaceutical composition described in any one of embodiments 20 to 27, 45 to 52, 72 to 79, 91 to 98, 110 to 117, 129 to 136, 147 to 154, and 159. 161. The method of embodiment 160, wherein the cancer is characterized by the presence of an IDH1 mutation. 162. The method of embodiment 161, wherein the IDH1 mutation is an R132X mutation. 163. The method of embodiment 161, wherein the IDH1 mutation is a R132H or R132C mutation. 164. The method of any one of embodiments 161-163, wherein the IDH1 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient. 165. The method of embodiment 160, wherein the cancer is characterized by the presence of an IDH2 mutation. 166. The method of embodiment 165, wherein the IDH2 mutation is an R140X mutation. 167. The method of embodiment 165, wherein the IDH2 mutation is a R140Q, R140W, or R140L mutation. 168. The method of embodiment 165, wherein the IDH2 mutation is an R172X mutation. 169. The method of embodiment 165, wherein the IDH2 mutation is a R172K or R172G mutation. 170. The method of any one of embodiments 165-169, wherein the IDH2 mutation leads to the accumulation of R(-)-2-hydroxyglutaric acid in the patient. 171. A method of treating cancer characterized by the presence of an IDH mutation and an IDH2 mutation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a cocrystal described in any one of embodiments 1 to 10 and 37 to 44, a crystalline form described in any one of embodiments 57 to 62, 84 to 90, 103 to 109, and 122 to 128, an amorphous solid dispersion described in any one of embodiments 137 to 139, a drug substance described in any one of embodiments 11 to 19 and 63 to 71, a compound or pharmaceutically acceptable salt thereof described in any one of embodiments 155 to 158, or a pharmaceutical composition described in any one of embodiments 20 to 27, 45 to 52, 72 to 79, 91 to 98, 110 to 117, 129 to 136, 147 to 154, and 159. 172. The method of any one of embodiments 160-171, wherein the cancer is selected from glioma, acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), colon cancer, and angioimmunoblastic non-Hodgkin's lymphoma (NHL). 173. The method of any one of embodiments 160-172, wherein the cancer is a glioma. 174. The method of embodiment 173, wherein the glioma is a low-grade glioma or a secondary high-grade glioma. 175. The method of embodiment 173 or 174, wherein the glioma is a secondary high-grade glioma, and the secondary high-grade glioma is a glioblastoma. 176. The method of any one of embodiments 160-175, wherein the cancer is refractory or recurrent. 177. Embodiments 160 to 165, in which the cancer is newly diagnosed or has not been previously treated. 175. The method according to any one of claims 175 to 175. 178. The method of any one of embodiments 160-177, further comprising co-administering an additional therapy to the patient. 179. The method of any one of embodiments 160-178, wherein the patient has previously been administered cancer treatment for the cancer. 180. The method of any one of embodiments 160-179, wherein the co-crystal, crystalline form, amorphous solid dispersion, drug substance, compound or pharmaceutically acceptable salt, or pharmaceutical composition is administered in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg per day, based on the amount of the compound of formula (I). 181. The method of any one of embodiments 160-179, wherein the co-crystal, crystalline form, amorphous solid dispersion, drug substance, compound or pharmaceutically acceptable salt, or pharmaceutical composition is administered in an amount of about 10 mg or about 50 mg per day, based on the amount of the compound of formula (I). 182. The method of any one of embodiments 160-179, wherein the co-crystal, crystalline form, amorphous solid dispersion, drug substance, compound or pharmaceutically acceptable salt, or pharmaceutical composition is administered twice daily in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg, based on the amount of the compound of formula (I). 183. The method of any one of embodiments 160-179, wherein the co-crystal, crystalline form, amorphous solid dispersion, drug substance, compound or pharmaceutically acceptable salt, or pharmaceutical composition is administered twice daily in an amount of about 10 mg or about 50 mg, based on the amount of the compound of formula (I). 2 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol, (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine, and 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol. [Example]

[0220] General Experimental Notes In the following examples, unless otherwise noted, reagents (chemicals) were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification.

[0221] Instruments and Methods X-ray powder diffraction (XRPD) analysis. XRPD analysis was performed on either a PANalytical Empyrean X-ray diffractometer or a Bruker D8 Advance X-ray diffractometer equipped with a 12" automated sample stage.

[0222] The parameters used for XRPD analysis on a PAnalytical Empyrean diffractometer are provided in Table 2. [Table 2]

[0223] The parameters used for XRPD analysis on a Bruker D8 Advance diffractometer are provided in Table 3. [Table 3]

[0224] 1 H and 13 C NMR analysis unless otherwise specified. 1 H and 13 C liquid NMR spectra were collected on a Bruker 400 MHz NMR spectrometer.

[0225] Dynamic Vapor Sorption (DVS) Analysis. DVS was measured via SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25 °C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters used for DVS analysis are listed in Table 4. [Table 4]

[0226] High Performance Liquid Chromatography (HPLC) Analysis - Method 1. Herein referred to as HPLC Method 1 The gradient reverse-phase HPLC procedures specified were performed under the conditions described in Table 5. [Table 5]

[0227] High Performance Liquid Chromatography (HPLC) Analysis—Method 2. An isocratic normal phase HPLC procedure identified herein as HPLC Method 2 was carried out under the conditions described in Table 5. [Table 6]

[0228] Example 1 6-(6-chloropyridin-2-yl)-N 2 ,N 4 Preparation of -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (Compound 1) [ka] 6-(6-chloropyridin-2-yl)-N, referred to as Compound 1 in the Examples2 ,N 4 The synthesis of -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine is described in paragraphs

[1032] to

[1036] of U.S. Patent Application Publication No. 2015 / 0018328 A1, which paragraphs are incorporated herein by reference.

[0229] Under some conditions, Compound 1 includes, but is not limited to, one or more of the following: It exists at least partially in one or more tautomeric forms. [ka]

[0230] As used in the examples, the term "Compound 1" refers to 6-(6-chloropyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, or any tautomer(s) 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 imply a particular double bond geometry.

[0231] The presence of more than one tautomer can be confirmed by the solution phase 1 H, 13 C, and 15 The NMR spectra were collected on a Varian Unity Inova 500 MHz NMR spectrometer equipped with a pentaprobe and a broadband probe. Compound 1 samples were dissolved in CD3OD or DMSO-d6. 1 H and 13 C NMR chemical shifts were referenced to the corresponding solvent peak. 15 N NMR chemical shifts were set using the vendor's "setref" macro.

[0232] One-dimensional analysis of compound 1 in CD3OD measured over the temperature range 25°C to 85°C 1 H The NMR spectra are shown in FIGS. 1 The 1 H NMR spectrum contained multiple resonances in the methine region (4.90-5.40 ppm), which merged at elevated temperatures (e.g., 85 °C), consistent with the presence of tautomerism.

[0233] 1D of compound 1 in DMSO-d6 1 The H NMR spectrum (Figure 3) also contains multiple -NH (8.21, 8.49, and 8.60 ppm), aromatic (8.25 and 8.35 ppm), and methine (4.94 and 5.11 ppm) resonances that would be expected to appear as single resonances in the absence of tautomerism.

[0234] 1D of compound 1 in DMSO-d6 13 The C NMR spectrum (Figure 4) also contains multiple resonances that would be expected to appear as single resonances in the absence of tautomerism. For example, the spectrum contains two resonances (46.8 and 47.1 ppm) corresponding to methine carbons.

[0235] One-dimensional NOE enhancement of compound 1 in DMSO-d6 15 The N NMR spectrum (Figure 5) also contains multiple resonances that would be expected to appear as single resonances in the absence of tautomerism. For example, the spectrum contains three resonances (-285.0, -284.9, and -284.4 ppm) corresponding to -NH groups.

[0236] Example 2 Preparation of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (Compound 2) [ka] A 3 L three-necked round-bottom flask was charged with 2,4-dichloro-6-(6-chloropyridin-2-yl)-1,3,5-triazine (120 g, 458.9 mmol) (the synthesis of which is described in U.S. Patent Application Publication No. 2015 / 0018328 A1, paragraph

[1034] ), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (72 g, 481.5 mmol), and 1,4-dioxane (960 mL). To the mixture was added N,N-diisopropylethylamine (DIPEA) (303 mL, 1.735 mol) for 30 minutes. o The resulting mixture was added dropwise at 45°C. o The mixture was stirred at RT for 2 hours at RT. The reaction mixture was concentrated in vacuo. To the residue was added water (1 L) and ethyl acetate (1 L). The layers were separated, and the organic layer was washed with water (1 L x 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography to give (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (compound 2, 135 g) in 87% yield. LC-MS (Chromolith SpeedROD, RP-18e, 50*4.6 mm column elution water / CH3CN over 5 min) found (M+1). 1 H NMR(CDCl3)δ 8.38-8.28(m,1H),7.80-7.75(m,1H),7.48-7.46(m,1H),6.05-5.73(m,1H),5.09-4.87(m,1H),1.43-1.38(m,3H)ppm.

[0237] Example 3 (R)-6-(6-chloropyridin-2-yl)-N 2 Preparation of -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 3) [ka] To a mixture of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (compound 2, 20 g, 59.2 mmol) in tetrahydrofuran (THF) (100 mL) was added ammonium hydroxide (NHOH) (40 mL). o The mixture was stirred at RT for 16 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the mixture. The layers were separated, and the organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was recrystallized from ethanol (36 mL) and n-heptane (36 mL) to give (R)-6-(6-chloropyridin-2-yl)-N 2 1,1,1-Trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 3, 10.2 g) was obtained as a white solid in 54% yield. LC-MS (Chromolith SpeedROD, RP-18e, 50*4.6 mm column for 5 min) was performed. Rum elution water / CH3CN) Found value (M+1) = 319. 1 H NMR(DMSO-d6)δ 8.33-8.00(m,3H),7.65(d,1H),7.40-7.21(m,2H),5.13-4.86(m,1H),1.33(d,3H)ppm.

[0238] Example 4 Preparation of (R)-4-(6-chloropyridin-2-yl)-6-(1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol (compound 4) [ka] In a 1 L three-necked round-bottom flask, (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (compound 2, 20 g, 59.2 mmol), N-methyl-2-pyrrolidone (NMP) (200 mL), sodium acetate (24 g, 292.6 mmol), and acetic acid (7.2 g, 119.9 mmol) were added for 25 minutes. oC. The reaction mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, and water (1 L) and dichloromethane (DCM) (400 mL) were added. The layers were separated, and the organic layer was washed with water (200 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography and then triturated with ethyl acetate (30 mL) to give (R)-4-(6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol (compound 4, 10.4 g) as a white solid in 55% yield. LC-MS (Chromolith SpeedROD, RP-18e, 50*4.6 mm column elution water / CH3CN over 5 min) found (M+1) = 320. 1 H NMR(DMSO-d6)δ 11.85(br.s,1H),8.78-8.13(m,3H),7.84(d,1H),5.16-4.86(m,1H),1.34(d,3H)ppm.

[0239] Example 5 (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 Preparation of -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 5) [ka] To a mixture of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (compound 2, 30 g, 88.7 mmol) in tetrahydrofuran (THF) (100 mL) was added isopropylamine (15.3 mL, 186.4 mmol). 15~20 o The mixture was stirred at RT overnight and then concentrated in vacuo. The residue was recrystallized from ethyl acetate (70 mL) and n-heptane (140 mL) to give (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4-(1,1,1-Trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 5, 20.4 g) was obtained as a white solid in 64% yield. LC-MS (Chromolith SpeedROD, RP-18e, 50*4.6 mm column elution water / CH3CN over 5 min) found (M+1) = 361. 1 H NMR(CDCl3)δ 8.25-8.19(m,1H),7.72-7.68(m,1H),7.38(d,1H),5.39-5.33(m,2H),5.03 -4.86(m,1H),4.15-4.08(m,1H),1.35-1.29(m,3H),1.19-1.17(m,6H)ppm.

[0240] Example 6 (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 Preparation of -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 6) [ka] To a mixture of (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (compound 2, 30 g, 88.7 mmol) in tetrahydrofuran (THF) (100 mL), ethylamine (12 g, 65-70% in water) was added. The reaction mixture was stirred for 15-20 minutes. o The mixture was stirred at RT overnight and then concentrated in vacuo. The residue was recrystallized from ethyl acetate (70 mL) and n-heptane (140 mL) to give (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 -(1,1,1-Trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 6, 20.2 g) was obtained as a white solid in 65% yield. LC-MS (Chromolith SpeedROD, RP-18e, 50*4.6 mm column elution water / CH3CN over 5 min) found (M+1) = 347. 1H NMR(CDCl3)δ 8.25-8.19(m,1H),7.72-7.68(m,1H),7.38(d,1H),5.52-5.16(m,2H),4.94 -4.88(m,1H),3.54-3.35(m,2H),1.35-1.29(m,3H),1.20-1.14(m,3H)ppm.

[0241] Example 7 Preparation of 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol (Compound 7) [ka] Sodium methoxide solution (CHONa) (150 mL, 30 wt % in methanol) was added to 6-(6-chloropyridin-2-yl)-N 2 ,N 4 To the reaction mixture was added 1,3,5-triazine-2,4-diamine (compound 1, 30 g, 72.3 mmol) in portions at 15-20°C. The reaction mixture was heated to reflux and stirred for 4 hours. The reaction mixture was then cooled to room temperature and poured into ice water (300 mL) at less than 10°C. To the reaction mixture was added dichloromethane (DCM) (500 mL). The layers were separated, and the organic layer was washed with water (200 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give 6-(6-methoxypyridin-2-yl)-N 2 ,N 4 -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (27 g) was obtained as a white solid in 90% yield. 1 H NMR(DMSO-d6)δ 8.31-8.12(m,2H),7.92-7.83(m,2H),6.99-6.97(m,1H),5.10-4.93(m,2H),3.94(s,3H),1.35(m,6H)ppm.

[0242] 6-(6-methoxypyridin-2-yl)-N in hydrogen bromide (HBr) (200 mL, 40 wt% aqueous solution) 2,N 4 A solution of 4,6-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (20 g, 48.7 mmol) was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, water (1 L) was added, and the pH was adjusted to 7 by adding sodium hydroxide (1 N aqueous solution). The resulting slurry was filtered, and the solid was dissolved in ethyl acetate (200 mL). The organic layer was washed with water (200 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to give 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol (compound 7, 18 g) as a white solid in 93% yield. LC-MS (Chromolith SpeedROD, RP-18e, 50*4.6 mm column elution water / CH3CN over 5 min) found (M+1)=397. 1 H NMR(DMSO-d6)δ 11.32(br.s,1H),8.48-8.00(m,2H),7.63-7.56(m,1H),7.33-7.18(m,1H) ,6.62-6.58(m,1H),5.66-5.45(m,1H),5.00-4.87(m,1H),1.30(m,6H)ppm.

[0243] Example 8 6-(6-chloropyridin-2-yl)-N 2 -((R)-1,1,1-trifluoropropan-2-yl)-N 4 Preparation of -((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 8) [ka] 6-(6-chloropyridin-2-yl)-N, referred to in the Examples as Compound 8 2 -((R)-1,1,1-trifluoropropan-2-yl)-N 4The synthesis of -((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine is described in paragraphs

[1032] to

[1034] ,

[1037] , and

[1040] to

[1041] of U.S. Patent Application Publication No. 2015 / 0018328 A1, which paragraphs are incorporated herein by reference.

[0244] Example 9 6-(6-chloropyridin-2-yl)-N 2 ,N 4 Preparation of -bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 9) [ka] 6-(6-chloropyridin-2-yl)-N, referred to in the Examples as Compound 9 2 ,N 4 The synthesis of -bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine is described in paragraphs

[1032] to

[1034] and

[1037] to

[1039] of U.S. Patent Application Publication No. 2015 / 0018328 A1, which paragraphs are incorporated herein by reference.

[0245] Example 10 6-(6-chloropyridin-2-yl)-N 2 ,N 4 Alternative preparation of -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (compound 1) [ka] An alternative preparation of compound 1 is described in Scheme 1.

[0246] [ka] Step 1: Preparation of 6-(6-chloropyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (Compound A) A 2000 L reactor was charged with ethanol (344 kg), methyl 6-chloropicolinate (20.1 kg, 117.1 mol), and biuret (2-imidodicarbondiamide) (14.85 kg, 140.5 mol). The resulting mixture was warmed to 30-35 °C and stirred at this temperature for 30-60 minutes, at which point trimethyl orthoformate (15.4 kg, 140.5 mol) and trifluoroacetic acid (1.4 kg, 12.3 mol) were added. The resulting mixture was warmed to 50-55 °C, stirred at this temperature for 2 hours, and then cooled to 25-30 °C. Water (200 kg) was added, and the pH was adjusted to below 1 by the addition of HCl (35% aqueous). The mixture was stirred at 30-35 °C for 2-4 hours and then filtered. The wet cake was washed with 60% aqueous ethanol (185 kg) and returned to the reactor. Dichloromethane (213 kg) was added, and the resulting mixture was stirred at 25-30°C for 2-3 hours and then filtered. The wet cake was washed with dichloromethane (40 kg) and dried under vacuum at 45-50°C for 40-80 hours to give crude Compound A (11.7 kg).

[0247] Crude Compound A (11.5 kg) and DMSO (250 kg) were added to a 2000 L reactor, and the resulting mixture was stirred at 25-30°C for 2-4 hours and then filtered. The wet cake was washed with water (38 kg), and the cake was then returned to the reactor. Water (227 kg) was added to the reactor, and the resulting mixture was stirred at 25-30°C for 30-60 minutes and then filtered. The wet cake was washed with water (50 kg) and dried under vacuum at 45-50°C for 30-60 hours to give Compound A (9.05 kg).

[0248] Step 2: Preparation of 2,4-dichloro-6-(6-chloropyridin-2-yl)-1,3,5-triazine (Compound B) A 250 L reactor was charged with Compound A (8.9 kg, 39.7 mol), benzyltriethylammonium chloride (19.0 kg, 79.4 mol), and POCl3 (37.0 kg, 238.2 mol). The resulting mixture was stirred at 95-105 °C for 18-24 hours, cooled to 30-40 °C, and concentrated under reduced pressure to 18-36 L. Ethyl acetate (3 × 53.0 kg) was added, and the resulting solution was concentrated under reduced pressure to 18-36 L. Additional ethyl acetate was added. Chill (112.0 kg) was added and the resulting mixture was cooled to 10-20°C.

[0249] A 1000 L reactor was charged with NaHPO (6.6 kg), NaHPO 2H0 (20.0 kg), and process water (98.0 kg), and the mixture was cooled to 0-15°C. The solution in the 250 L reactor was transferred to the 1000 L reactor. Ethyl acetate (26 kg) was charged to the 250 L reactor and transferred to the 1000 L reactor. The resulting solution was stirred at 15-25°C for 2-4 hours and then allowed to stand for 30-60 minutes. The layers were separated, and the organic layer was washed three times with aqueous sodium chloride. Ethyl acetate (133.0 kg) was added to the organic layer, and the resulting solution was transferred to a separate reactor through a cartridge filter. The solution was concentrated under reduced pressure to 1-2 volumes, additional ethyl acetate (54.0 kg) was added, and the solution was again concentrated under reduced pressure to 1-2 volumes. N-heptane (2 x 50.0 kg) was added over 2-3 hours, and the resulting mixture was stirred for 1-2 hours and then concentrated to 3-5 volumes under reduced pressure after each addition of n-heptane. The mixture was then filtered, and the wet cake was returned to the reactor, slurried with n-heptane (40.0 kg), and filtered. The wet cake was dried in the filter at 20-30°C for 10-15 hours to give compound B (9.4 kg).

[0250] Step 3: 6-(6-chloropyridin-2-yl)-N 2 ,N 4 Preparation of -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (Compound 1) A 300 L reactor was charged with Compound B (7.3 kg, 27.9 mol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (9.7 kg, 64.2 mol), and N-methyl-2-pyrrolidone (44.4 kg). The reaction mixture was cooled to 10-25°C, and diisopropylethylamine (17.0 kg, 128.4 mol) was added over approximately 1 hour. The mixture was stirred at 10-20°C for approximately 10 minutes, at 45-55°C for approximately 1-2 hours, and at 95-105°C for approximately 20 hours, then cooled to 45-55°C. Process water (4 kg) was added dropwise over approximately 1 hour, and the resulting solution was transferred to a 500 L reactor and washed with N-methyl-2-pyrrolidone (2 kg). Additional process water (34.0 kg) was added dropwise over approximately 3 hours at 45-55°C, and the resulting mixture was stirred at 20-30°C for approximately 3.5 hours. Additional process water (7.4 kg) was added, the resulting mixture was centrifuged, and washed with process water (9 kg). The wet cake was slurried with process water (89 kg), the resulting slurry was centrifuged, and washed with process water (21 kg). The wet cake was returned to the 500 L reactor, and acetonitrile (2 x 133 kg) was added. The resulting solution was concentrated under reduced pressure to 3-5 volumes, and carbon (1.1 kg) and diatomaceous earth (6.0 kg) were added. The mixture was filtered, washed with acetonitrile (37 kg), and the filtrate was transferred to a 100 L reactor through a cartridge filter. The solution was concentrated under reduced pressure to 5-5.5 volumes, and purified water (55 kg) was added dropwise through the cartridge filter over 2-3 hours. The mixture was stirred at 20-30°C for 2-5 hours, and additional purified water (4 kg) was added dropwise over 1 hour through a cartridge filter. The mixture was filtered, washed with acetonitrile / water (15 kg, 1:1), and the wet cake was dried at 50-60°C for 20-80 hours to give compound 1 (8.38 kg).

[0251] Example 11 Preparation and characterization of citric acid cocrystal type A of compound 1 A 20 mL vial was charged with 1.02 g of Compound 1 and 508.0 mg of citric acid monohydrate, and acetonitrile (20 mL) was added. The resulting solution was stirred at room temperature (20-25 °C) for 24 hours, during which time a precipitate formed. The precipitate was collected by filtration through a Buchner funnel, and the solid was dried at room temperature for 15.5 hours to obtain the citric acid cocrystal Type A of Compound 1. The cocrystal was identified by XRPD. 1 It was analyzed by 1 H NMR, DSC, TGA, and DVS analysis.

[0252] The XRPD pattern of the co-crystal, obtained on a PANalytical Empyrean diffractometer in reflector mode, is shown in Figure 6. The peak positions, peak heights, and relative intensities of the peaks in the XRPD pattern are listed in Table 7. [Table 7]

[0253] of cocrystals measured in CD3OD 1 The 1 H NMR spectrum is shown in FIG. 1 Peak integration of the H NMR spectrum revealed a 1:0.5 molar ratio between compound 1 and citric acid. 1 H NMR(CD3OD)δ 8.46-8.42(m,1H),8.00-7.95(m,1H),7.63-7.61(m,1H),2.93(d,J=16 Hz,1H),2.81(d,J=16 Hz,1 H)ppm.

[0254] DSC and TGA thermograms of the co-crystal are shown in Figure 8. DSC analysis was performed using a TA Instruments Q2000 DSC in a crimped aluminum pan. Temperature and heat flow were calibrated to an indium fusion. DSC analysis was performed over the temperature range from room temperature to the desired temperature at a ramp rate of 10 °C / min using N2 as the purge gas. TGA was performed in an open aluminum pan using a TA Instruments Q5000 TGA using N2 as the purge gas. The DSC thermogram contains an endothermic peak with an onset temperature of 171.5° C. The TGA thermogram shows a weight loss of 3.5% up to 120° C.

[0255] The hygroscopicity of the co-crystal was determined by DVS analysis at 25 °C over the range of 0-95% relative humidity. The DVS isotherm plot is shown in Figure 9 and shows a water uptake of 0.5% at 80% relative humidity, revealing that the citric acid co-crystal is slightly hygroscopic. XRPD analysis of the material remaining after DVS analysis confirmed that no morphological changes occurred.

[0256] Example 12 Single-crystal X-ray diffraction analysis of citric acid cocrystal type A of compound 1 Single crystals of citric acid cocrystal Type A suitable for structure determination were obtained by slowly cooling a solution of Compound 1 and anhydrous citric acid in n-butanol / heptane (1 / 3, v / v). The experimental details were as follows: 12.5 mg of Compound 1 and 6.1 mg of anhydrous citric acid were weighed into a 3 mL vial. 1.2 mL of solvent (n-butanol / heptane, 1 / 3 v / v) was added to the vial, and the mixture was equilibrated at 45 °C to form a suspension, which was filtered (0.45 μm PTFE membrane) into two 3 mL vials. Seed crystals of citric acid cocrystal Type A were added to the saturated solution, which was then cooled from 45 °C to 5 °C at a rate of 0.01 °C / min (4000 min). After 5 days, needle-like crystals of citric acid cocrystal Type A were obtained.

[0257] X-ray intensity data were collected at 290(2) K using a Bruker D8 ADVANCE diffractometer (Mo Kα radiation, λ = 0.71073 Å). Direct structure solution, difference Fourier calculations, and full-matrix least-squares refinement for F2 were performed with SHELXTL (Sheldrick G MA short history of SHELX. Acta Crystallogr A, 2008, 64:112-122) and OLEX2 (OV Dolomanov, LJ Bourhis, RJ Gildea, JAK Howard and H. Puschmann. "OLEX2: a complete structure solution, refinement and analysis program". J. Appl. Cryst. 2009, 42, 339-341). Molecular graphics were generated by Diamond (Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany) and Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. J. Appl. Cryst. 2006, 39, 453-457).

[0258] The single crystal structure of citric acid co-crystal Type A was successfully solved. The crystal data and structure refinement are listed in Table 8. An ORTEP diagram of the crystal structure is shown in Figure 10, and the unit cell is shown in Figure 11. In the crystal structure, the molar ratio of compound 1:citric acid:HO is 2:1:1. There are four molecules of compound 1, two citric acid molecules, and two water molecules per unit cell. [Table 8]

[0259] Example 13 Preparation and characterization of maleic acid cocrystal type A of compound 1 Compound 1 (100.4 mg) and maleic acid (28.3 mg) were dissolved in acetone (2.0 mL), and the resulting solution was stirred at room temperature for 1 day, during which time a precipitate formed. The precipitate was isolated and air-dried at room temperature to obtain the maleic acid cocrystal Type A of Compound 1. The cocrystal was analyzed by XRPD. 1 It was analyzed by 1 H NMR, DSC, TGA, and DVS analysis.

[0260] The XRPD pattern of the co-crystal, obtained on a PANalytical Empyrean diffractometer in reflector mode, is shown in Figure 12. The peak positions, peak heights, and relative intensities of the peaks in the XRPD pattern are listed in Table 9. [Table 9]

[0261] of cocrystals measured in CD3OD 1 The 1 H NMR spectrum is shown in FIG. 1 H The peak integration of the NMR spectrum revealed a molar ratio of approximately 1:1.1 between compound 1 and maleic acid, suggesting that the ratio of compound 1 to maleic acid in the cocrystal was 1:1. 1 H NMR(CD3OD)δ 8.45-8.41(m,1H),8.01-7.96(m,1H),7.67-7.62(m,1H),6.31(s,2H).

[0262] DSC and TGA thermograms of the co-crystal are shown in Figure 14. DSC analysis was performed using a TA Instruments Q2000 DSC in a crimped aluminum pan. Temperature and heat flow were calibrated to an indium fusion. DSC analysis was performed over a temperature range from room temperature to the desired temperature and at a ramp rate of 10°C / min using N2 as the purge gas. TGA was performed in an open aluminum pan using a TA Instruments Q5000 TGA with ramping from room temperature to the desired temperature at 10°C / min using N2 as the purge gas. The DSC thermogram contains two endothermic peaks with onset temperatures of 91.2°C and 128.4°C. The TGA thermogram shows a 2.5% weight loss up to 115°C.

[0263] The hygroscopicity of the co-crystal was determined by DVS analysis at 25 °C over the range of 0 to 95% relative humidity. The DVS isotherm plot is shown in Figure 15 and shows a water uptake of 2.0% at 80% relative humidity, revealing that the maleic acid co-crystal is slightly hygroscopic. XRPD analysis of the material remaining after DVS analysis confirmed that no morphological changes occurred.

[0264] Example 14 Preparation and characterization of citric acid cocrystal type A of compound 1 A 100 L reactor was charged with 1.5 kg (7.9 mol) of anhydrous citric acid and 31.0 kg of acetone. The mixture was stirred at 20-30 °C until the citric acid was completely dissolved, and the resulting solution was transferred to a 500 L reactor. The 100 L reactor was washed with an additional 5.0 kg of acetone, which was then added to the 500 L reactor. Compound 1 (6.73 kg, 16.2 mol), prepared as described in Example 10, was added to the reactor, and the mixture was stirred at 20-30 °C until Compound 1 was completely dissolved (approximately 1 h). After stirring at 20-30 °C for an additional 1-2 h, 75.0 g of purified water was added to the reactor. N-heptane (13.0 kg) was added to the reactor over 1 h, followed by the addition of citric acid cocrystal Type A seed crystals (46 g). The mixture was stirred at 20-30° C. for 1-2 hours, and then additional n-heptane (104.0 kg) was added over 2-4 hours.

[0265] The resulting mixture was stirred at 20-30°C for an additional 2-3 hours, and then the reactor was cooled to 10-20°C. The mixture was wet-milled (7900 rpm) at 10-20°C. The mixture was filtered, and the filter cake was washed with 7 kg of an acetone / n-heptane solution (7 vol / 25 vol), then dried at 30°C or below for 10-20 hours to obtain 7.15 kg of citric acid cocrystal Type A. The isolated cocrystal was analyzed by elemental analysis. 1 H NMR analysis, 13 It was characterized by C NMR, FTIR, UV / visible spectroscopy, XRPD, DSC, TGA, and HPLC analyses.

[0266] The results of the elemental analysis of the co-crystal are reported in Table 10. The measured elemental composition is based on a 2:1:1 molar ratio of compound 1:citric acid:HO and corresponds to the chemical formula C 34 H 36 Cl2F 12 N 12 The composition is consistent with the theoretical composition as determined from O8. [Table 10]

[0267] of cocrystals measured in CD3OD 1 H and 13 The C NMR spectra are shown in Figures 16 and 17, respectively. 1 Peak integration of the H NMR spectrum revealed a 1:0.5 molar ratio between compound 1 and citric acid. 1 H NMR(CD3OD)δ 8.43-8.40(m,1H),7.98-7.93(m,1H),7.61-7.59(m,1H),2.91(d,J=16 Hz,1H),2.79(d,J=16 Hz,1 H)ppm.

[0268] The FTIR spectrum of the co-crystal obtained on a Nicolet IS10 FTIR spectrometer is shown in Figure 18. The FTIR spectrum was obtained on the solid material using an attenuated total reflectance accessory. The spectrum showed peaks at 1653, 1590, 1549, 1271, and 1143 cm. -1 The bands in

[0269] The UV / visible spectrum of the co-crystal obtained on an Agilent 8453 spectrophotometer at a concentration of 5.2 μg / mL in acetonitrile is shown in Figure 19. The spectrum has maximal absorption bands at 204 nm, 216 nm, and 281 nm.

[0270] The XRPD pattern of the co-crystal, obtained on a Bruker D8 Advance diffractometer in reflection mode at room temperature, is shown in Figure 20. The peak positions, peak heights, and relative intensities of the peaks in the XRPD pattern are listed in Table 11. [Table 11-1] [Table 11-2]

[0271] The DSC thermogram of the co-crystal is shown in Figure 21. DSC analysis was performed on a TA Q20 DSC instrument using a ramp rate of 10.0°C / min and N2 as the purge gas. The thermogram contains an endothermic peak with an onset temperature of 170.6°C and a peak temperature of 173.0°C.

[0272] The TGA curve of the co-crystal is shown in Figure 22. TGA was performed on a TA Q5000 IR TGA system at a ramp rate of 10.0 °C / min using N as the purge gas. The co-crystal exhibited a 1.692% weight loss with a maximum of 136.06 °C. A rapid weight loss was observed above about 165 °C, which is believed to result from decomposition.

[0273] The purity profile of the cocrystal was determined by HPLC analysis (Method 1). The concentrations (w / w%) of compounds 2–7 and total impurities are reported in Table 12. Based on the assumption that compounds 1–7 have a relative sensitivity factor of 1, the concentrations (w / w%) were determined by HPLC peak area. The concentration (w / w%) of each compound reported in Table 12 reflects the HPLC peak area attributable to the compound as a percentage of the total peak area attributable to compound 1 and any organic impurities. The concentrations (w / w%) of total impurities reported in Table 12 reflect the total HPLC peak area attributable to organic impurities (compounds 2–7) as a percentage of the total peak area attributable to compound 1 and any organic impurities. Stereoisomers of compound 1 (compounds 8 and 9) co-elute with compound 1 under the conditions of HPLC Method 1 and are therefore not included in the concentration of total impurities. [Table 12]

[0274] The stereochemical purity of the cocrystals was determined by HPLC analysis (Method 2). The concentrations (w / w%) of compounds 8 and 9 are reported in Table 13. Based on the assumption that compounds 1, 8, and 9 have a relative sensitivity factor of 1, the concentrations (w / w%) were determined by HPLC peak area. The concentrations (w / w%) of compounds 8 and 9 reported in Table 13 reflect the HPLC peak area attributable to the compound as a percentage of the total peak area attributable to compounds 1, 8, and 9. [Table 13]

[0275] Example 15 Preparation of citric acid cocrystal type A of compound 1 A 30 L reactor (Reactor 1) was charged with 1.2 kg of Compound 1 (2.9 mol) and 1.87 kg of acetone, and the resulting mixture was stirred at 25-28 °C for 0.5 h. A second reactor (Reactor 2) was charged with 297.9 g of citric acid monohydrate (1.42 mol) and 674 g of acetone, and the resulting mixture was stirred at 25-28 °C for 0.5 h. Half of the contents of Reactor 2 were transferred to Reactor 1 at 37-43 °C, and then citric acid cocrystal Type A seed crystals (6 g) were added to Reactor 1. The resulting mixture in Reactor 1 was stirred at 37-43 °C for 1.5 h. The remaining contents of Reactor 2 were transferred to Reactor 1 at 37-43 °C over 0.5-1.5 h, and then n-heptane (6690 g) was added to Reactor 1 over 2.5 h at 37-43 °C. Reactor 1 was cooled to 8 to 12°C over 2.5 hours, and stirring was continued at 8 to 12°C for 1 to 3 hours.

[0276] The reaction mixture in Reactor 1 was then filtered under nitrogen gas, and the filter cake was washed with 2800 mL of an acetone / n-heptane solution (1 / 3 v / v). The filter cake was dried under vacuum at 25-30 °C for 16-48 hours to obtain 1430 g of citric acid cocrystal Type A. Obtained as a coloured solid.

[0277] Example 16 Preparation and characterization of the free form Type A of compound 1 Compound 1 (450.0 g), prepared as described in Example 10, was dissolved in 1.0 L of ethyl acetate at 70-80°C. 4.0 L of n-heptane was added dropwise to the solution at 70-80°C over 2 hours. The mixture was cooled to 0-10°C over 3 hours and then stirred at 0-10°C for 16 hours. The resulting suspension was filtered, and the wet cake was dried at 40-45°C for 16 hours to yield 400 g of a dry cake of crystalline free form Type A. The isolated crystalline material was characterized by elemental analysis, XRPD analysis, DSC analysis, TGA analysis, and HPLC analysis.

[0278] The results of the elemental analysis are reported in Table 14. The measured elemental composition was determined to be 14 H 13 The theoretical composition, as determined from ClF6N6, is consistent with the theoretical composition. [Table 14]

[0279] The XRPD pattern of free form Type A obtained on a Bruker D8 Advance diffractometer in reflector mode at room temperature is shown in Figure 23. The peak positions, peak heights, and relative intensities of the peaks in the XRPD pattern are listed in Table 15. [Table 15-1] [Table 15-2]

[0280] The DSC thermogram of free form Type A is shown in Figure 24. DSC analysis was performed on a TA Q20 DSC instrument using a ramp rate of 10.0°C / min and N2 as the purge gas. The thermogram contains an endothermic peak with an onset temperature of 221.9°C and a peak temperature of 223.1°C.

[0281] The TGA curve of free form Type A is shown in Figure 25. The TGA was performed on a TA Q5000 IR TGA system at a ramp rate of 10.0 °C / min using N as the purge gas. The curve reflects a weight loss of 0.011%.

[0282] The purity profile of free form Type A was determined by HPLC analysis (Method 1). The concentrations (w / w%) of compounds 2–7 and total impurities are reported in Table 16. Based on the assumption that compounds 1–7 have a relative response factor of 1, the concentrations (w / w%) were determined by HPLC peak area. The concentration (w / w%) of each compound reported in Table 16 reflects the HPLC peak area attributable to the compound as a percentage of the total peak area attributable to compound 1 and any organic impurities. The concentrations (w / w%) of total impurities reported in Table 16 reflect the total HPLC peak area attributable to organic impurities (compounds 2–7) as a percentage of the total peak area attributable to compound 1 and any organic impurities. Stereoisomers of compound 1 (compounds 8 and 9) co-elute with compound 1 under the conditions of HPLC Method 1 and are therefore not included in the concentration of total impurities. [Table 16]

[0283] The stereochemical purity of free form Type A was determined by HPLC analysis (Method 2). The concentrations (w / w%) of compounds 8 and 9 are reported in Table 17. Based on the assumption that compounds 1, 8, and 9 have a relative sensitivity factor of 1, the concentrations (w / w%) were determined by HPLC peak area. The concentrations of compounds 8 and 9 reported in Table 17 reflect the HPLC peak area attributable to the compound as a percentage of the total peak area attributable to compounds 1, 8, and 9. [Table 17]

[0284] Example 17 Single-crystal X-ray diffraction analysis of the free form Type A of compound 1 Single colorless needles of compound 1 were recrystallized from a mixture of dichloromethane and toluene by slow evaporation.

[0285] A suitable crystal (0.55 × 0.17 × 0.11 mm) was selected and mounted on a nylon loop with paratone oil. Data were collected using a Bruker APEX-II CCD diffractometer equipped with an Oxford Cryosystems cryostat operating at T = 173(2) K.

[0286] Data were measured using CuKα radiation (sealed tube, 40 kV, 30 mA) with ω and φ scans of 1.00° per frame for 30.00 s. The total number of runs and images was based on strategy calculations from the program COSMO (BRUKER, V1.61, 2009). The actual resolution achieved was Θ = 72.008.

[0287] Cell parameters were obtained using SAINT (Bruker, V8.34A, 2013) software and refined using SAINT (Bruker, V8.34A, 2013) for 9424 reflections, 34 of the observed reflections.

[0288] Data reduction was performed using SAINT (Bruker, V8.34A, 2013) software, which corrects for Lorentzian polarization. The final completeness is Θ from 100.00 to 72.008. The absorption coefficient (MU) of this material is 2.490, and the minimum and maximum transmissions are 0.5542 and 0.7536.

[0289] ShelXS(Sheldrick G MA short history of The structure was solved by direct methods using the SHELX.Acta Crystallogr A,2008,64:112-122) structure solution program and refined by least squares using XL version 2014 / 6 (Sheldrick G MA short history of SHELX.Acta Crystallogr A,2008,64:112-122).

[0290] The structure was solved in space group C2221 (#20). All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions, except those on heteroatoms, were calculated geometrically and refined using a riding model. These were found by difference Fourier methods and refined isotropically. Olex2(OVDolomanov,LJBourhis,RJGildea,JAKHoward and H.Puschmann.“OLEX2:a The structure was refined by the least-squares method on F2, ShelXL-97, implemented in the "Complete Structure Solution, Refinement, and Analysis Program" (J. Appl. Cryst. 2009, 42, 339-341). All H atoms were placed in their calculated positions, and the structure was refined using a riding model.

[0291] The Flack parameter was refined to 0.025 (5), confirming the absolute stereochemistry. The absolute structure was also determined using Bayesian statistics for Bijvoet differences using a program within PLATON (ALSpek, Single-crystal structure validation with the program PLATON, J. Appl. Cryst., (2003), 36, 7-13). We report that we have the correct enantiomer based on this comparison.

[0292] The crystallographic data are listed in Table 18. An ORTEP diagram of the crystal structure is shown in Figure 26, and the unit cell is shown in Figure 27. A simulated powder diffraction pattern based on the single crystal intensity data matched the XRPD pattern of free form Type A, as described in Example 17. [Table 18]

[0293] Example 18 Preparation and characterization of the free form Type B of compound 1 A 20 mL vial was charged with 100 mg of Compound 1 (free form Type A) and 1 mL of methyl isobutyl ketone to form a solution. Heptane (15 mL) was added dropwise, and the mixture was stirred at room temperature for 90 minutes, during which time a precipitate formed. The precipitate was isolated and dried to obtain Compound 1 free form Type B. Free form Type B was analyzed by XRPD, DSC, and TGA analysis.

[0294] The XRPD pattern of free form Type B obtained on a PANalytical Empyrean diffractometer in reflector mode is shown in Figure 28. The peak positions, peak heights, and relative intensities of the peaks in the XRPD pattern are listed in Table 19. [Table 19-1] [Table 19-2]

[0295] DSC and TGA thermograms of free form Type B are shown in Figure 29. DSC analysis was performed using a TA Instruments Q2000 DSC in a crimped aluminum pan. DSC analysis was performed over the temperature range from room temperature to 300°C at a ramp rate of 10°C / min using N2 as the purge gas. TGA was performed in an open platinum pan using a TA Instruments Q5000 TGA with ramping from room temperature to 350°C at 10°C / min using N2 as the purge gas. The DSC thermogram contains an endothermic peak with an onset temperature of 221.5°C. The TGA thermogram , showing a weight loss of 2.3% up to 150°C.

[0296] Example 19 Single-crystal X-ray diffraction analysis of the free form type B of compound 1 Single crystals suitable for structure determination were obtained by vapor diffusion in a THF / heptane (1 / 3, v / v) cosolvent system. 21.0 mg of the free form Type A of Compound 1 was weighed into a 3 mL vial with the addition of 0.5 mL of the THF / heptane (1 / 3, v / v) cosolvent. The solution was filtered through a nylon filter (0.45 μm) and collected in three 4 mL vials. Seed crystals of the free form Type B were added to the vial. The vial was placed in a 20 mL vial (with 4 mL of heptane as an antisolvent) and the 20 mL vial was capped. The vial was kept at room temperature, allowing the heptane to diffuse into the THF / heptane solution. After 3 days, plate-like crystals of the free form Type B were obtained.

[0297] X-ray intensity data from prism-like crystals were collected at 290(2) K using a Bruker D8 ADVANCE diffractometer (Mo Kα radiation, λ=0.71073 Å). XRPD patterns of authentic samples of free form Type B were collected on an XPERT-3 Empyrean system at room temperature.

[0298] Direct structure solution, difference Fourier calculations, and full-matrix least-squares refinement for F2 were performed in SHELXTL (Sheldrick G MA short history of SHELX. Acta Crystallogr A, 2008, 64:112-122) and OLEX2 (OV Dolomanov, LJ Bourhis, RJ Gildea, JAK Howard and H. Puschmann. "OLEX2: a complete structure solution, refinement and analysis program". J. Appl. Cryst. 2009, 42, 339-341). Molecular graphics were generated by Diamond (Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany) and Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. J. Appl. Cryst. 2006, 39, 453-457). Simulated XRPD diagrams were performed by Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. J. Appl. Cryst. 2006, 39, 453-457).

[0299] The single crystal structure of free form Type B was successfully determined. Free form Type B was confirmed to be anhydrous and have eight molecules of Compound 1 per unit cell. Details of the crystal data and structure refinement are listed in Table 20. An ORTEP diagram of the crystal structure is shown in Figure 30, and the unit cell is shown in Figure 31. The simulated XRPD pattern based on the single crystal data and the experimental XRPD pattern obtained from an authentic sample of free form Type B were in good agreement. [Table 20]

[0300] Example 20 Preparation and characterization of the free form Type C of compound 1 A 20 mL vial was charged with 150 mg of Compound 1 (free form Type A) and 1.5 mL of 1,4-dioxane to form a solution. Water (2.25 mL) was added dropwise, and the resulting suspension was stirred at room temperature for 3 days. The solid material was isolated and dried to obtain Compound 1 free form Type C. Free form Type C was analyzed by XRPD, DSC, and TGA analysis.

[0301] The XRPD pattern of free form Type C obtained on a PANalytical Empyrean diffractometer in reflector mode is shown in Figure 32. The peak positions, peak heights, and relative intensities of the peaks in the XRPD pattern are listed in Table 21. [Table 21]

[0302] DSC and TGA thermograms of free form Type C are shown in Figure 33. DSC analysis was performed using a TA Instruments Q2000 DSC in a crimped aluminum pan. DSC analysis was performed over the temperature range from room temperature to 300°C at a ramp rate of 10°C / min using N2 as the purge gas. TGA was performed in an open platinum pan using a TA Instruments Q5000 TGA with ramping from room temperature to 350°C at 10°C / min using N2 as the purge gas. The DSC thermogram contains endothermic peaks at 81.9°C (peak temperature) and 221.3°C (onset temperature). The TGA thermogram shows a weight loss of 14.1% up to 150°C.

[0303] Example 21 Single-crystal X-ray diffraction analysis of the free form Type C of compound 1 Single crystals suitable for structure determination were obtained by slow evaporation in ACN / HO (4 / 1, v / v). 4.2 mg of the free form Type A of compound 1 and 2.1 mg of citric acid were weighed into a 3 mL vial, and 0.5 mL of ACN / HO (4 / 1, v / v) was added. The solution was filtered into a single crystal vial, and the solvent was allowed to evaporate. After 7 days, single crystals of the free form Type C were obtained.

[0304] X-ray intensity data from the prism-like crystals were collected at 290(2) K using a Bruker D8 ADVANCE diffractometer (Mo Kα radiation, λ=0.71073 Å). The XRPD pattern of an authentic sample of free form Type C was collected on an XPERT-3 Empyrean system at room temperature.

[0305] Direct structure solution, difference Fourier calculations, and full-matrix least-squares refinement for F2 were performed in SHELXTL (Sheldrick G MA short history of SHELX. Acta Crystallogr A, 2008, 64:112-122) and OLEX2 (OV Dolomanov, LJ Bourhis, RJ Gildea, JAK Howard and H. Puschmann. "OLEX2: a complete structure solution, refinement and analysis program". J. Appl. Cryst. 2009, 42, 339-341). Molecular graphics were generated by Diamond (Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany) and Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. J. Appl. Cryst. 2006, 39, 453-457). Simulated XRPD diagrams were performed by Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. J. Appl. Cryst. 2006, 39, 453-457).

[0306] The single crystal structure of free form Type C was successfully determined. Free form Type C was confirmed to be a trihydrate with two molecules of Compound 1 and six water molecules per unit cell. Details of the crystal data and structure refinement are listed in Table 22. An ORTEP diagram of the crystal structure is shown in Figure 34, and the unit cell is shown in Figure 35. The simulated XRPD pattern based on the single crystal data and the experimental XRPD pattern obtained from an authentic sample of free form Type C were in good agreement. [Table 22]

[0307] Example 22 Preparation and characterization of the free form Type D of compound 1 The free form Type A of Compound 1 (135.0 mg) was suspended in 2.0 mL of 1,4-dioxane / heptane (4:1, v / v). The suspension was stirred at room temperature for 17 days, and the solid material was isolated and air-dried to obtain the free form Type D of Compound 1. The free form Type D was identified by XRPD, 1 It was analyzed by 1 H NMR, DSC, and TGA analysis.

[0308] The XRPD pattern of free form Type D obtained on a PANalytical Empyrean diffractometer in reflector mode is shown in Figure 36. The peak positions, peak heights, and relative intensities of the peaks in the XRPD pattern are listed in Table 23. [Table 23]

[0309] DSC and TGA thermograms of free form Type B are shown in Figure 37. DSC analysis was performed using a TA Instruments Q2000 DSC in a crimped aluminum pan. DSC analysis was performed over the temperature range from room temperature to 300°C at a ramp rate of 10°C / min using N2 as the purge gas. TGA was performed in an open platinum pan using a TA Instruments Q5000 TGA with ramping from room temperature to 350°C at 10°C / min using N2 as the purge gas. The DSC thermogram contains endothermic peaks at 79.7°C (peak temperature) and 221.3°C (onset temperature). The TGA thermogram shows a weight loss of 12.48% up to 150°C.

[0310] Free form type D measured in CD3OD 1 The 1 H NMR spectrum is shown in Figure 38. 1Peak integration of the H NMR spectrum revealed that the free form Type D is a dioxane solvate, with compound 1 and dioxane present in a molar ratio of approximately 1.0:0.4. 1 H NMR(CD3OD)δ 8.43-8.39(m,1H),7.98-7.92(m,1H),7.61-7.58(m,1H),3.66(s,0.4H).

[0311] Example 23 Amorphous solid dispersion of Compound 1 A 50:50 spray-dried dispersion of Compound 1 and HPMCAS (hydroxypropyl methylcellulose acetate succinate) was prepared. A solution of Compound 1 and HPMCAS in acetone was spray-dried on a Buchi B-290. After spray-drying, the solid dispersion was dried overnight at 40°C to remove residual solvent. XRPD analysis of the resulting material revealed a diffraction pattern consistent with an amorphous form. The material exhibited a single glass transition temperature (T g DSC analysis determined that the material was a single-phase solid dispersion with a mean particle size (P < 0.05) of 0.05 (0.05) / 0.05 (0.05). Dissolution studies in simulated intestinal fluid demonstrated that the material was capable of maintaining sufficient supersaturation to achieve in vivo exposure.

[0312] Example 24 Pharmacokinetics of Compound 1 solid forms in plasma after a single PO administration in male Sprague Dawley rats Study Design. Twelve male Sprague Dawley rats (purchased from SLAC Laboratory Animal Co., Ltd.) were randomized into four groups (three animals per group). The animals were fasted overnight and then administered by oral gavage the form of Compound 1 shown in Table 24, with the animals being allowed to eat for four hours after administration. Each form of Compound 1 was administered as a suspension in water containing 0.5% microcrystalline cellulose and 0.1% Tween 80. The dose levels and dose concentrations shown in Table 24 are based on the corresponding amount of free Compound 1. [Table 24]

[0313] Blood collection. Blood was serially collected from each animal at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, and 72 hours post-dose. For each collection, the animal was manually restrained, and approximately 150 μL of blood sample was collected via the tail vein into a K2EDTA tube. The blood sample was placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma. Plasma samples were stored at approximately -70°C until analysis.

[0314] To allow for calculation of oral bioavailability, compounds were dissolved in a vehicle containing 10% N-methyl-2-pyrrolidone (NMP), 10% Solutol HS 15, and 80% saline and administered at 1 mg / kg as an intravenous (IV) bolus to separate groups of male Sprague-Dawley rats, with blood samples collected at the same time points as indicated above. Additionally, plasma samples were obtained from the collected blood samples and stored at approximately -70°C until analysis.

[0315] Furthermore, the amorphous solid dispersion of Compound 1 described in Example 23 was suspended at a concentration of 0.2 mg / mL in an aqueous vehicle containing 0.5% methylcellulose (MC) and 0.2% Tween 80, and administered as a single oral dose of 1 mg / kg to a separate group of male Sprague-Dawley rats after overnight fasting. Blood samples were collected at the same time points as indicated above. Furthermore, plasma was collected and stored at approximately -70°C until analysis.

[0316] Sample Preparation and Analysis. The concentration of Compound 1 in plasma samples was determined by LC-MS / MS analysis.

[0317] A 20 μL aliquot of each sample was diluted with dexamethasone as an internal standard (40 ng / mL). The resulting mixture was vortexed for 2 minutes and centrifuged at 5800 rpm for 10 minutes. 2 μL of the sample was injected into the LC-MS / MS.

[0318] LC-MS / MS analysis was performed on a UPLC / MS-MS-018 (API-5500) system under the conditions described in Table 25. [Table 25]

[0319] Results. The mean plasma concentration-time profiles of Compound 1 in each of the four study groups are shown in Figure 39. AUC of each form of Compound 1 inf and absolute bioavailability (%F) are reported in Table 26. Historical data for IV administration of Compound 1 and administration of Compound 1 as a spray-dried dispersion are also provided in Table 26. AUC inf AUC obtained by IV administration of Compound 1 inf The absolute bioavailability of each form of Compound 1 was determined by dividing by 1 and correcting for differences in dose. The measured absolute bioavailability of the citrate and maleate cocrystals reported in Table 26 was higher than the measured bioavailability of the other forms of Compound 1. [Table 26]

[0320] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) a compound of formula (I) [ka] A co-crystal comprising citric acid and (Section 2) Item 1. The cocrystal according to item 1, characterized by an X-ray powder diffraction pattern obtained in reflection mode, comprising at least one peak position at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. (Section 3) Item 3. The cocrystal according to item 1 or 2, wherein the X-ray powder diffraction pattern comprises at least two peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. (Section 4) 4. The cocrystal according to any one of items 1 to 3, wherein the X-ray powder diffraction pattern comprises at least three peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. (Section 5) 5. The cocrystal according to any one of items 1 to 4, wherein the X-ray powder diffraction pattern comprises at least four peak positions at degrees 2-theta (±0.2 degrees 2-theta) selected from the group consisting of 5.7, 8.4, 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. (Section 6) 6. The cocrystal according to any one of items 1 to 5, wherein the X-ray powder diffraction pattern comprises peak positions at 5.7 and 8.4 degrees 2-theta (±0.2 degrees 2-theta), and at least three peak positions selected from the group consisting of 11.4, 15.8, 18.1, 19.2, 21.1, 22.5, and 23.0. (Section 7) 7. The cocrystal according to any one of items 1 to 6, wherein the cocrystal is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of 170.6°C (±2.0°C). (Section 8) 8. The cocrystal according to any one of items 1 to 7, further comprising water. (Section 9) 9. The co-crystal according to any one of items 1 to 8, wherein the compound of formula (I), citric acid, and water are present in a molar ratio of 2:1:1. (Section 10) 10. The co-crystal according to any one of items 1 to 9, wherein the co-crystal contains four molecules of the compound of formula (I), two citric acid molecules, and two water molecules per unit cell. (Section 11) A drug substance comprising the cocrystal according to any one of items 1 to 10. (Section 12) The drug substance contains 1.0% or less (area % by HPLC) of (R)-6-(6-chloropyridin-2-yl)-N 2 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-6-(6-chloropyridin-2-yl)-N 2 -ethyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-6-(6-chloropyridin-2-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, 6-(6-chloropyridin-2-yl)-N 2 ,N 4 -bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, 6-(6-chloropyridin-2-yl)-N 2 -((R)-1,1,1-trifluoropropan-2-yl)-N4-((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine, (R)-4- Item 12. The drug substance according to item 11, which contains any one of (6-chloropyridin-2-yl)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-ol, (R)-4-chloro-6-(6-chloropyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine, and 6-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)pyridin-2-ol. (Section 13) A pharmaceutical composition comprising a therapeutically effective amount of the cocrystal according to any one of items 1 to 10, or the drug substance according to item 11 or 12, and one or more pharmaceutical excipients. (Section 14) Item 14. The pharmaceutical composition according to item 13, wherein the pharmaceutical composition comprises 1 to 10% w / w of the compound of formula (I). (Section 15) Item 14. The pharmaceutical composition according to item 13, wherein the pharmaceutical composition comprises 20 to 30% w / w of the compound of formula (I). (Section 16) 16. The pharmaceutical composition according to any one of items 13 to 15, wherein the pharmaceutical composition is in the form of an orally acceptable dosage form and contains about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I). (Section 17) Item 17. The pharmaceutical composition according to item 16, wherein the pharmaceutical composition comprises about 10 mg or about 50 mg of the compound of formula (I). (Section 18) a compound of formula (I) [ka] and citric acid, dissolving said compound of formula (I) and citric acid in a solvent to obtain a solution; and precipitating said co-crystal. (Section 19) Item 19. The method according to item 18, wherein the solvent comprises acetonitrile or acetone. (Section 20) 20. The method according to claim 18 or 19, wherein the precipitation comprises cooling the solution. (Section 21) 21. The method according to any one of items 18 to 20, wherein the precipitation comprises evaporating a portion of the solvent from the solution. (Section 22) 22. The method according to any one of items 18 to 21, wherein the precipitation comprises adding an anti-solvent to the solution. (Section 23) The anti-solvent is C 5~ C 12 23. The method according to claim 22, comprising an alkane or cycloalkane. (Section 24) 23. The method of claim 22, wherein the anti-solvent comprises toluene or MTBE. (Section 25) 25. The method according to any one of items 18 to 24, wherein the precipitation comprises seeding the solution with crystals of the co-crystal. (Section 26) 26. The method according to any one of items 18 to 25, further comprising isolating the co-crystal. (Section 27) 16. A method of treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the cocrystal described in any one of items 1 to 10, the drug substance described in any one of items 11 or 12, or the pharmaceutical composition described in any one of items 13 to 17. (Section 28) 28. The method according to paragraph 27, wherein the cancer is characterized by the presence of an IDH1 mutation. (Section 29) 29. The method according to item 28, wherein the IDH1 mutation is an R132X mutation. (Section 30) 29. The method according to item 28, wherein the IDH1 mutation is an R132H or R132C mutation. (Section 31) 31. The method according to any one of items 28 to 30 above, wherein the IDH1 mutation results in accumulation of R(-)-2-hydroxyglutaric acid in the patient. (Section 32) 28. The method according to paragraph 27, wherein the cancer is characterized by the presence of an IDH2 mutation. (Section 33) 33. The method according to item 32, wherein the IDH2 mutation is an R140X mutation. (Section 34) 33. The method according to item 32, wherein the IDH2 mutation is an R140Q, R140W, or R140L mutation. (Section 35) 33. The method according to item 32, wherein the IDH2 mutation is an R172X mutation. (Section 36) 33. The method according to item 32, wherein the IDH2 mutation is an R172K or R172G mutation. (Section 37) 37. The method according to any one of items 32 to 36, wherein the IDH2 mutation results in accumulation of R(-)-2-hydroxyglutaric acid in the patient. (Section 38) A method for treating a cancer characterized by the presence of an IDH1 mutation and an IDH2 mutation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the cocrystal described in any one of items 1 to 10, the drug substance described in any one of items 11 or 12, or the pharmaceutical composition described in any one of items 13 to 17. (Section 39) 39. The method according to any one of items 27 to 38, wherein 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, and angioimmunoblastic non-Hodgkin's lymphoma (NHL). (Section 40) 40. The method according to any one of items 27 to 39, wherein the cancer is glioma. (Section 41) 41. The method according to item 40 above, wherein the glioma is a low-grade glioma or a secondary high-grade glioma. (Section 42) 42. The method according to item 40 or 41, wherein the glioma is a secondary high-grade glioma, and the secondary high-grade glioma is a glioblastoma. (Section 43) 43. The method according to any one of items 27 to 42, wherein the cancer is refractory or recurrent. (Section 44) 43. The method according to any one of the above paragraphs 27 to 42, wherein the cancer is newly diagnosed or has not been previously treated. (Section 45) 45. The method according to any one of items 27 to 44, further comprising co-administering an additional therapy to the patient. (Section 46) 46. ​​The method according to any one of items 27 to 45, wherein the patient has previously been administered cancer treatment for the cancer. (Section 47) 47. The method according to any one of items 27 to 46, wherein the cocrystal, drug substance, or pharmaceutical composition is administered in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg per day, based on the amount of the compound of formula (I). (Section 48) 47. The method according to any one of items 27 to 46, wherein the cocrystal, drug substance, or pharmaceutical composition is administered in an amount of about 10 mg or about 25 mg per day, based on the amount of the compound of formula (I). (Section 49) 47. The method according to any one of items 27 to 46, wherein the cocrystal, drug substance, or pharmaceutical composition is administered twice daily in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg, based on the amount of the compound of formula (I). (Section 50) 47. The method according to any one of items 27 to 46, wherein the cocrystal, drug substance, or pharmaceutical composition is administered twice a day in an amount of about 10 mg or about 25 mg, based on the amount of the compound of formula (I).

Claims

1. A crystal of the compound of formula (I), 【Chemistry 47】 wherein the crystal is characterized by an X-ray powder diffraction pattern comprising peak positions at 11.7, 17.8, and 21.8 degrees 2-theta (±0.2 degrees 2-theta) and at least three peak positions selected from the group consisting of 12.8, 14.2, 19.8, 20.7, 22.2, and 25.

0.

2. 2. The crystal of claim 1, wherein the X-ray powder diffraction pattern comprises peak positions at 11.7, 12.8, 14.2, 17.8, 19.8, 20.7, 21.8, 22.2, and 25.0 degrees 2-theta (±0.2 degrees 2-theta).

3. 3. The crystal of claim 1 or 2, wherein the crystal is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of 221.9°C (±5.0°C).

4. A pharmaceutical composition comprising a therapeutically effective amount of the crystal according to any one of claims 1 to 3, and one or more pharmaceutical excipients.

5. A composition comprising the crystal of any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for treating a cancer characterized by the presence of an IDH1 or IDH2 mutation in a patient in need thereof, said composition or pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I).

6. 6. The composition or pharmaceutical composition of claim 5, wherein the cancer is characterized by the presence of an IDH1 mutation.

7. 7. The composition or pharmaceutical composition of claim 6, wherein the IDH1 mutation is an R132X mutation.

8. 7. The composition or pharmaceutical composition of claim 6, wherein the IDH1 mutation is an R132H or R132C mutation.

9. 8. The composition or pharmaceutical composition of claim 7, wherein the cancer is characterized by the presence of an IDH2 mutation.

10. 10. The composition or pharmaceutical composition of claim 9, wherein the IDH2 mutation is an R140X mutation.

11. 10. The composition or pharmaceutical composition of claim 9, wherein the IDH2 mutation is an R140Q, R140W, or R140L mutation.

12. 10. The composition or pharmaceutical composition of claim 9, wherein the IDH2 mutation is an R172X mutation.

13. 10. The composition or pharmaceutical composition of claim 9, wherein the IDH2 mutation is an R172K or R172G mutation.

14. 14. The composition or pharmaceutical composition of any one of claims 5 to 13, wherein the cancer is selected from glioma, acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), colon cancer, and angioimmunoblastic non-Hodgkin's lymphoma (NHL).

15. The composition or pharmaceutical composition of claim 14, wherein the cancer is glioma.

16. 16. The composition or pharmaceutical composition of claim 15, wherein the glioma is a low-grade glioma or a secondary high-grade glioma.

17. 16. The composition or pharmaceutical composition of claim 15, wherein the glioma is a low-grade glioma.

18. 16. The composition or pharmaceutical composition of claim 15, wherein the glioma is a secondary high-grade glioma, and the secondary high-grade glioma is a glioblastoma.

19. The composition or pharmaceutical composition according to any one of claims 5 to 18, wherein the cancer is refractory or recurrent.

20. The composition or pharmaceutical composition of any one of claims 5 to 18, wherein the cancer is newly diagnosed or has not been previously treated.

21. The composition or pharmaceutical composition of any one of claims 5 to 20, wherein the composition or pharmaceutical composition is administered to the patient in combination with an additional therapy.

22. The composition or pharmaceutical composition of any one of claims 5 to 21, wherein said patient has previously been administered a cancer treatment for said cancer.

23. 23. The composition or pharmaceutical composition of any one of claims 5 to 22, wherein the composition or pharmaceutical composition is administered to the patient at a daily dose of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 300 mg of the compound of formula (I) as part of the composition or pharmaceutical composition, where "about" means that the dose has ±10% of the specified value.

24. 23. The composition or pharmaceutical composition of any one of claims 5 to 22, wherein the composition or pharmaceutical composition is administered to the patient twice daily at a dose of about 10 mg or about 50 mg of the compound of formula (I) as part of the composition or pharmaceutical composition, where "about" means that the dose has ±10% of the specified value.

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